SCD Expert-Public Review

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Comments
135
0 This entire section needs to be reconsidered. There is no discussion of non-pharmacological
interventions in patients with chronic pain. Cognitive and behavioral interventions, vocational
rehabilitation, occupational therapy, psychological interventions and many other therapies are
as important as chronic opioids in the management of chronic pain. Neuropathic pain has very
specific interventions that are not included. Formal psychological/psychiatric screening for
depression and other comorbid conditions that will exacerbate chronic pain and complicated
management. Goals of chronic pain treatment are not just pain control but increasing function
and quality of life.
Suggestions
Type
This section, at least the recommendations should Public
be completely rewritten. Although evidence is not
robust in sickle cell disease, recommendations from
chronic back pain, orthopedic problems, rheumatoid
disorders, diabetes, neuropathies can be utilized to
formulate some basic principles of approaching
chronic pain management.
Discussion
All of the items are covered in the document by the
American Pain Society. Rec. 9.1. A few sentences
should be added to the background.
Action/Recommendation
Revision subitted to this section. Done.
Revision subitted to this section. Done.
135
11 Could the panel comment on the difference between VOC and breakthrough pain episodes
among those with chronic pain syndromes?
Invited
The team discussed the issue of breakthrough pain.

APS talks about this, but cancer pain and SCD pain
can be very different. Consider acknowdging
breakthrough pain in SCD and indicate that it is
difficult to distinguish in the clinical setting between
the two. Language will be added to the
background/intro section. Will be crafted for team
review.
136
11 concept of two types of pan is introduced but then nociceptive pain never defined, elaborated
Invited
Nociceptive pain is a hallmark of acute pain (see

Revision subitted to this section.
Acute chapter, page #). Will submit a statement about
this.
Public
Will craft some wording about this. In the background. Revision subitted a revision to this section. Done.
140
141
143
7 The focus on pain relief is not consistent with most current chronic pain management
strategies which focus on improving function rather than pain relief
13 Only the Ficat classification is mentioned
Broaden definition of therapeutic outcomes to be

consistent with management of chronic pain in
other pain disorders
Included references to other classification systems Public

that have been used in the literature
5 (expand cell for full contents) AVN: First, the recommendations of Ficat staging is outdated and We strongly recommend that decompression coring Public
has been replaced by MRI imaging using the ARCO or Ficat-Arlet classifications (ref: Am J
be an early consideration in the treatment of AVN
Orthopedics, Sept 2011 p. E188). These recommendations utilize MRI. Furthermore, the
since these patients progress irregardless of the
primary symptom in patients with AVN is often in the groin and knee, and not necessarily the
physical therapy and are often bilateral, which
hip. In addition, 40-80% of patients develop bilateral hip disease. This complicates therapy
minimizes non-operative approaches. (ref: Physical
and should be mentioned. Coring decompression is a safe and clinically beneficial procedure. therapy alone compared with core decompression
A meta analysis of 21 studies demonstrated that non-operative management results in less
and physical therapy for femoral head
than a 20% satisfactory outcome leading to THA and other salvage procedures (ref:
osteonecrosis in sickle cell disease. Results of a
Amanatullah et al. Current Management Options for Osteonecrosis of the Femoral Head: Part multicenter study at a mean of three years after
1, Diagnosis and Nonoperative Management. American Journal of Orthopedics. 2011). The
treatment. Neumayr LD, Aguilar C, Earles AN, et al.
orthopedic literature does not recommend passive physical therapy and activity modification as J Bone Joint Surg Am. 2006 Dec;88(12):2573-82.;
the primary treatments for AVN. Even in SCD, progression is inevitable. We were the principal also: Clinical evaluation of avascular necrosis in
investigators in the one randomized trial for AVN vs. aggressive physical therapy.
patients with sickle cell disease: Children's Hospital
This protocol actually incorporates aggressive daily physical therapy as a primary intervention. Oakland Hip Evaluation Scale--a modification of the
This protocol actually incorporates aggressive daily physical therapy as a primary intervention. Harris Hip Score. Aguilar CM, Neumayr LD, et al.
This type of aggressive physical therapy without research funding is rarely practical and is
Arch Phys Med Rehabil. 2005 Jul;86(7):1369-75.).
replaced inadequate activity limitation. Our study demonstrated that decompression coring
was totally safe.
This is correct, we use only the Ficat classification.

Will submit wording to reference other methods. A
system of measurement should be used. Here we
use the FICAT. AVN should be classified either by the
FICAT system or by the Steinberg classification
(references).
Revision submitted to this section. References were added for (1) Ballas et al. 2010, "Definitions of
the phenotypic manifestations of sickle cell disease." American journal of hematology 85(1): 6-13; (2)
Steinberg, M. E., G. D. Hayken, et al. (1995). "A quantitative system for staging avascular necrosis."
J Bone Joint Surg Br 77(1): 34-41. (3) Steinberg, M. E. and D. R. Steinberg (2004). "Classification
systems for osteonecrosis: an overview." Orthop Clin North Am 35(3): 273-283, vii-viii. Done.
The study was evaluated by the panel. WILL

REVIEW AND SEE IF A CHANGE IS NEEDED.
Comment: We got the two references mentioned in the comments. Reference part I does mention
40-80 % of cases with AVN of the hip (all cases not only SCD) could be bilateral. However, the
commentator said 40-80 % of patients with SCD develop bilateral AVN. There is a big difference
between what the comment says and what the reference says. It also seems that a similar confusion
probably by the same person thought that SCD and SCA are the same. Perhaps we should check
the accuracy of every reference mentioned in the public comments.
Reference part II, however, clearly mentions that core decompression should be done for Ficat stage
I or II. This is contrary to what the comment says that the Ficat classification is obsolete although it is
used for decision making by the references the commentator recommends. The references are listed
below.
Based on the above, recommend the following changes in the background: Page 141 line 6 add:
About 40% to 80% of cases of AVN of the hips are bilateral and, hence, evaluation of patients with
AVN should focus on both hips (Amanatullah, Strauss et al. 2011). Revised exhibit added on the
stages of AVN. Then, Page 141 after line 21 (which would be at the end of the revised exhibit with
the definitions of the stages of AVN) add: Most orthopedists consider core decompression most
beneficial for Ficat stage I and II of AVN of the hip (Amanatullah, Strauss et al. 2011). Editor: Done
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143
6 As worded this is of little use
145
149
Comments
Suggestions
Give a clearer guideline of who should be imaged.
21 In leg ulcers please consider a recommendation to consult with local wound care specialists for
expert assistance. Again this document will be the model for payment by payors and this is a
consultation that is often difficult to get covered but is vitally necessary in leg ulcers expecially
recurrent ones.
3 CKD is defined as either GFR<60 or evidence of kidney damage 3 months. Only proteinuria Use KDIGO classifications or provide rationale for
is listed as a marker of kidney damage. The KDIGO (Kidney Disease: Improving Global
not using.
Outcomes) classification of CKD includes albuminuria, proteinuria, and hematuria as markers
of kidney damage. (Ref: Levey et al. Kid Intern 2005)
Type
Public
Discussion
Will review the background to see what needs to be I think this refers to page 143, line 6; the page number was missing in the original table received. No
added. Table, vocational therapy will be added to the change was made to Recommendation 1 in the AVN section.
background. Panel will weigh in on MRI/no MRI at a
later date. Consider a consensus rec.
Public
In the background, wound care specialist can be

Revised: Multidisciplinary teams including would care specialists have been developed to provide
added. "This requires a multi-disciplinary approach" support and consultation in the management of recurrent and recalcitrant leg ulcers. DONE.Also, a
new Recommendation #6 was added: 6. Consult or refer to a wound care specialist or
multidisciplinary wound team for persistent or recalcitrant leg ulcers. (ConsensusPanel Expertise)
Public
Include the severity index in a statement to address

1/7/13: p. 149, line 3: reviewed reference mentioned in the comment. Once again the comment
the second part of the comment. 5 stages. Do it after misquotes the reference. The reference lists microalbuminuria and proteinuria as markers of kidney
the definition.
damage but does not include hematuria as the commentator claims. The reference is listed below.
(Levey, Eckardt et al. 2005). On p. 149, line 7, add: Kidney disease severity is classified into five
stages according to the level of GFR as follows: Stage 1: kidney damage with normal or increased
GFR ((90 mL/min/1.73 m2); Stage 2: Kidney damage with mildly decreased GFR ((60-89
mL/min/1.73 m2), Stage 3: moderately decreased GFR (30-59 mL/min/1.73 m2), Stage 4: severely
decreased GFR (15-29 mL/min/1.73 m2), Stage 5: kidney failure (ESRD); GFR <15 mL/min/1.73
m2 or on dialysis). Levey AS, KU Eckardt, et al. (2005). Definition and classification of chronic kidney
disease: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney
Int 67(6):2089-2100. Editor: Done
149
17 Hypersecretion may occur many experts do state the need for microalbumin screening not just
dipstick see comments below on page 152.
Public
define microalbumin and macroalbumin precisely
On page 149 line 17 add:

Microlbuminuria is defined as urinary albumin excretion < 30 mg albumin per gram urine creatinine in
two of three spot urine specimens or 30-299 mg albumin in 24-hour urine collection.
Macroalbuminuria (Proteinuria) is defined as urinary albumin excretion of 300 - 3,500 mg albumin in
24- hour urine collection (Levey, Eckardt et al. 2005). Editor: Done, 1/7/13.
149
19 Cites prevalence of microalbuminuria to be 16% in children (Becton et al.) and 32.9% in adults incorporate additional information.
(Ataga et al.). Other studies show higher prevalence:
- Pediatrics: McPhersonYee 2011: 20.7% in HbSS/Sb0; 16.8% in HbSC/Sb+ (410 subjects)
- Adults: Guasch 2006: 68% in HbSS; 42% in other sickling hemoglobinopathies (300 subjects)
Public
Get references and see exactly what has been

reported. Then decide whether to add these
references. Will be reviewed and will be added to
background if appropriate.
p. 149, line 14: Added: "Finally, in a study of 300 adults with SCD, the prevalence of any
albuminuria in people with SCD was 68 percent, and the prevalence in other genotypes was 32
percent (Guasch 2006)." DONE
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Comments
150
1 In this section, renal disease in SCD is discussed. There are some notable omissions.
Suggestions
Please consider adding:
a) Type IV renal tubular acidosis
b) Papillary necrosis-in SCD or trait
c)The association of membranoproliferative
glomerularnephritis and membranous
glomerulopathy in SCD (therefore, the need for
biopsy in patients with significant, persistent
proteinuria.
Type
Public
Discussion
Will consider adding a sentence in the background
On p. 150, line 14, add: There have not been any studies looking at the utility of renal biopsy in
about biopsy Other comments will also be considered individuals with SCD. One study that examined 18 renal biopsy specimens found four histopatholigc
and reviewed.
variants: focal segmental glomerulosclerosis (FSGS( (39%), membranoproliferative
glomerulonephritis (28%), thrombotic microangiopathy glomerulopathy (17%), and specific sickle cell
disease glomerulopathy (17%). (Medicine (Baltimore). 2010 Jan;89(1):18-27). The authors of this
study note that the long-term outcomes were not different according to the histologic lesions that
were identified, with 50% of cases having chronic renal failure after a mean followup of 28 months.
The decision to perform renal biopsy should be individualized for each patients. Editor: DONE
1/7/13 Note: I made this a new paragraph, as a line of text here at the end of line 14 about the
management of gout in individuals with SCD was also added. Editor: Done 1/7/13.
151
7 This is a misleading citation of the results. 191 children were screened but only 9 were treated consider rewriting the section and
with hydroxyurea and 9 with ACE inhibitors. Some patients appeared to get both. There was
also a high complication rate. 4 of 9 on ACE developed hyperkalemia therapy stopped in 3 of
the 4. Some received chronic transfusions. 3 progressed to endstage kideny disease.
Public
Modest expansion of the description of the study

incorporating these comments should be done.
The following needs to be deleted pg. 151, line 7: "One observational study of 191 children (3-20
years of age) with HbSS demonstrated that microalbumin excretion normalized in 44 percent of
those treated with hydroxyurea and 56 percent of those treated with an angiotensin-converting
enzyme (ACE) inhibitor; in the analysis of this study, however, the investigators did not control for
other potential confounders that might have affected proteinuria (McKie et al. 2007)." Editor: Done
1/7/13
152
4 rather than renal complications here can you just say with microabuminuria, proteinura or Cr>1
- or are there other indications you would also use
Invited
Error; this comment doesn't apply to this line, but

page 153, line 4.
Comment: Leave as is; we described above for what indications we would prescribe ACE.
152
11 I am surprised by the moderate recommendation to start an ACE-I in both children and adutls
with isolated microalbuminuria given the very low quality evidence, especially for children
153
0 Renal Complications: Recommendations - Good chapter.

I have 2 questions: Unless I missed it, the panel did not mention management of Gout in sickle
cell disease and management of Gout in SCD patients with renal disease. The panel did not
give any guideline for the follow-up of high uric acid in a patient with SCD without gout
manifestation. The second question: If kidney biopsy indicated in patients with sickle disease
and if indicated when it has to be performed.
136
4 The principles of treating chronic pain differ from those of acute pain Nothing is said about
how these principles differ. There is a discussion of differences in pathophysiology, but not in
treatment principles.
139
10 Not clear if this includes individualized treatment plans
InvitedRecommendation based on low quality

Non
evidence.Specify the age ranges of the children.
Disclosed Evidence will be reviewed for ages and numbers of
children in study. Perhaps recommendations in
children should be held to a higher standard.
Public
Add a brief discussion of realities and principles of Public

chronic pain management chronicity, modest
effects of any one modality, generally agreed
superiority of multimodal treatment, thinking with
the long term and function preservation in mind;
etc. The fact that chronic pain tends to have modest
treatment effects and typically requires a
multimodal treatment plan should be mentioned 45.
It should also be noted that the course of chronic
pain in SCD is likely to be lifelong and probably
progressive.
Invited
Recommendations have been revised. This comment is resolved.
Information on gout is in the background. No review Comment: Gout is already mentioned on p. 150, line 13. On p. 150, line 14 add: Diagnosis and
of evidence on gout. New treatments for gout may
management of gout in individuals with sickle cell disease is the same as in other populations.
not be applicable to gout in SCD. Do we have enough Editor: Done 1/7/13
information in the background to address these
comments. Do not put treatment into the background.
The principles of acute pain are discussed in the

Revised section submitted. Done.
acute chapter. Statement will be added here: "The
pathophysiology and management of chronic pain
differs from treating acute pain and these differences
are discussed in the recommendations for these
chapters."
Change to "partnership agreement leading to a

written individualized treatment plan"
Done 1/4/13. Change necessitated changes in the second sentence of this recommendation, which
was revised to: "The partnership agreement should list the patient's rights" instead of "the agreement
form should list"
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Comments
139
15 Consider splitting this into more than 1 rec
140
4 not sure about use of stimulant laxatives chronically
140
7 "HbS-a-thalassemia", missing another "S"
141
5 This line with a 50% SS with AVN is in direct contradiction to line 3 with the prevalence of 10%.
Make it congruent.
141
7 HbS-alpha thalassemia
145
0 Refer to wound care clinic, some improvements have helped if engaged early or state may
need to adjust and live with the ulcers
145
18 Leg ulcers: there are no recommendations on local therapy
Suggestions
Note from Editor: This should be page 141, line 7.
HbSS-alpha thalassemia
Type
Invited
Discussion
CHANGE: remove second statement and make it a Done 1/4/13.
new recommendation. Leave the rest as the next
recommendation. New Rec: "Use long and short
acting opiods to manage chronic pain that is not
relieved by nonopiods." Same grade. Make it the new
#4 - needs to go after #3. Please add comment/query
- NEEDS PANEL REVIEW
Invited
CHANGE: After increase fluid intake to right after

Changed to: "Encourage people receiving opioids to increase their fluid intake, maintain dietary fiber
encourage people. Encourage people to increase
intake per the current dietary fiber recommendations, and to use stool softeners and bowel stimulant
their fluid intake, maintain fiber intake per the dietary laxatives such as senna and/or docusate as needed." 1/4/13.
fiber recommendations, and to use ....as needed.
Invited
HbSS
Public
We cannot make it congruent because we said it is

Done 1/6/13
10% in SCD and the other is SCA. Consider
juxtaposing in the document. The overall prevlaence
of AVN in SCD is about 10% whereas in hemoglobin
SS it is about 50% by age 33 years (Add references).
(keep next sentence..People with). DELETE
sentance "Fifty percent..." Place references after the
new sentence.
Public
Yes, make this change - add the S but use the "a" to Done.
represent alpha
Invited
Add New Recommendation #5: For persistent leg

Done 1/6/13
ulcers, consult or refer to a wound care specialist.
Consensus-Panel Expertise. Insert comment that this
requires panel review.
147
148
153
2 Syncope is the medical term for "passing out suddenly"

1 typo 200people
1 The panel recommends that people with modest elevations in Cr should be considered to have clarify wording.
renal impairment and treated as all others with renal impairment. This guideline is unclear.
What treatment is being recommended?
155
1 Important to have a hematogist and urologist consulted for priapism.
Given that recurrent prolonged priapism results in

ED, patients with priapism lasting >4 hours should
be referred to the emergency department and a
hematologist and urologist be consulted.
Done. This is actually page 141, line 7.
Initially treat leg ulcers in patients with SCD with

standard therapy (i.e. debridement, wet to dry
dressings, and topic agents). Moderate
recommendation, Low-quality evidence.
Done
Public
IND
Public
The team agrees to use this term
Done 1/6/13
Done 1/6/13
Done 1/6/13
Public
Recommendation on page 155, lines 1-3, should

Done 1/6/13
read: In men and boys with SCD and recurrent or
stuttering priapism, offer evaluation and treatment in
consultation with a sickle cell disease specialist and a
urologist, especially when etc.
Local ulcer/wound therapy, cultures should be done Public
Table of staging will be included. Already answered

in previous comment. Also beyond the scope of
document. However, one change will be made: the
word people on page 153, line 1, recommendation 7
will be changed to patients with sickle cell disease.
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Comments
158
18 Should this be AVN or are bisphosphonates proposed as a treatment for cutaneous ulceration?
Suggestions
Type
IND
Discussion
CHANGE: Replace "chronic leg ulcers" with AVN
Done 1/6/13
159
1 These are TWO separate issues to investigate. Separate and rephrase.
Public
Yes, separate out the topics with separate bullets.
Done 1/6/13
159
15 These are TWO separate issues to investigate. Separate and rephrase.
Public
Yes, separate out the topics with separate bullets.
Done 1/6/13
140
15 No recommendation is made for evaluation and/or treatment of co-morbid mood disorders in

individuals with chronic pain. The co-existence of mood disorders and pain is well described in
SCD and in other chronic pain disorders; successful treatment of mood disorders is often
associated with improvement in pain symptoms
This is a serious and potentially misleading

Public
omission from these guidelines; depression and
anxiety treatment stategies need to be included;
there is also a wealth of information on the efficacy
of these interventions in other chronic pain
disorders
We acknowledge this is a big issues. Rec #11: coPer email received on 2/7/13: We discussed this comment in one of the conference calls. We agreed
morbid conditions...including pain due to co-morbid that no change in the recommendations should be made and that the goal of the guidelines is to
conditions...including mood disorders that may impact address complications of SCD and not to address co-morbid conditions. Nevertheless, there was a
pain. Use the word "addressed".
request to mention the co-morbid conditions reported in patients with SCD. To that end a sentence
was added in the introduction to the chronic chapter (p133 lines 6-7). In addition, another 2
sentences were added in the background section on chronic pain about anxiety, depression, despair
etc. that are associated with chronic pain ( p 136 lines 7-10).
Accordingly, no change is needed and sentences have already been added in the chapter
introduction and in the background section on chronic pain. DONE
146
12 Once again, this is the definition for pulmonary hypertension of which PAH is a subgroup.
147
However, need to add that the study was stopped Public

21 There is no mention of the 3rd and probably best publicized randomized controlled trial of a
PAH therapy in this patient group, the NIH sponsored Walk-PHaSST trial (Machado RF Blood prematurely preventing determiniation of whether
2011). This is a significant omission.
sildenafil in SCD optimized on back groud SCD
therapy with RHC documented PAH would be
efficacious as well as would it be efficacious in RHC
documented "mixed" PH as defined above
148
148
6 It is not clear what the authors mean by various levels of benefit. Clearly, there is a bias on the
part of the authors to present these studies as being not useful but for the uneducated reader,
it would be helpful to give more information of the actual data and what construes a positive
treatment response.
11 The L-arginine study was not outlined in Machado 2005. The correct reference for that study
is Morris CR AJRCCM 2003.
Public
We should remove all screening from this chapter.

2/19/13: All references to screening removed. DONE.
Begin with initial diagnosis. Consider calling this PH
instead of PAH. Background is going to be redrafted.
This is outside our evidence report timeframe. Will

revise the background to include this study.
2/19/13: Walk-PHaSST added to the background. DONE
Public
Will look at the whole seciton and see if there is a

way to tweak the wording to remove any bias.
2/19/13: Beyond the scope of the discussion to delineate specifics (e.g. reduced pressures, exercise
capatiy, too varied to easily summarize given varied definitons of PAH, groups that were studied, etc
- statement as written is neutral.
Public
This reference will be fixed as we review the evidence From Editor: Machado ref deleted and Morris reference added. 2/19/13.
section
Page # Line #
Comments
148
15 Is there a role for doing ECHO before referring for right heart cath? Should clinicians do an
ECHO when a pt has sx/sx possibly indicating the need for a work-up of Pulm HTN?
Suggestions
Discussion
This needs to be fixed. Should read, have
2/19/13: Recommendations changed to reflect echo first, then referral for further evaluation. DONE
symptoms or signs suggestive of PH, refer them for
echocardiography for assessment of pulmonary
hypertension, such as elevated TRV. #2-Confirm all
diagnoses of PH with right heart catheritization.
Strong recommendation, moderate-quality evidence.
Public
Insufficient information to develop consensus

recommendation. Review gaps related therapy for
priapism to see if change should be made.
155
1 Chronic Complications - Stuttering Priapism: This section makes no recommendations other

than to refer the patient to a urologist. This is inadequate. Urologist interventions are very
variable and many urologists are not up-to-date with sickle cell priapism.
155
2 Priapism is not an acute and separate chronic problem, it is a continum. This section is a
waste of space. Combine the sections and make one rational discussion. Chronic prolonged
priapism is a major source of impotence risk and you do not really address it.
Public
Expand section to make clear we are talking about a No Change - the language is clear that we are talking about stuttering priapsim, which the public
chronic condition and that it has adverse
comment acknowledges; the evidence and scope of the document do not support further discussion
consequences.
or elaboration. No change made. Done
135
12 it might be helpful to have a sense of types of pain meds and average doses used by people
with SCD at different ages (ie % adult pts on chronic opiods and average dosing with range). I
know this is highly variable but the breakdown could provide some context for docs not seeing
many of these pts.
Invited
The panel has considered this during the

development process. Langauge will be crafted to
clarify.
Revision submitted. Done.
138
17 Managing Chronic Pain
Re-looking at rec #10 to consider an adjustment.
Revision submitted (to rec. #11). Done.
152
9 Is this what is supposed to happen to the peple who screen positive for proteinuria - see page
29. if these suggestions are linked, please indicate so in the report
There should be a consensus recommendation

concerning their treatment utilizing accepted
therapies, in order of priority.
Type
IND
The comments concerning referring patients for

Public
behavior issues and violation of agreement should
be preceded by statements indicating that
psychological and social support for all patients with
chronic pain syndrome is warranted. Providers
knowledgeable about hyper-analgesia syndrome,
tolerance, pseudo-addiction, and withdrawal are
necessary to optimally manage patients with
chronic pain.
Invited
Editor: The Recommendation was revised as follows: In men and boys with SCD and recurrent or
stuttering priapism, offer evaluation and treatment in consultation with a sickle cell disease specialist
and a urologist, especially when episodes increase in severity or frequency. DONE
Will be made consistent in the health mantenance

Health maintenance section was revised. Done.
section. Change will be made in health maintenance.
Page # Line #
Comments
136
7 These are symptoms of PTSD (posttraumatic stress disorder), and should be acknowledged
as such by medical professionals. Life-long severe, unpredictable, acute episodes of pain,
along with repeated bouts of poor pain treatment, and stigmatization by medical professionals
are the primary causes of these symptoms in SCD patients. [Also noted as an SS patient and
Clinical Lab Scientist.]
Suggestions
Type
Public
Discussion
Group discussed adding language about the multiple
barriers for some patients in the
introduction/background section. Social services
should also be addressed very early on and should
be part of the care process. Assess the unmet needs
- identify barriers to patients participating in
care...Assess potential barriers, participation in care,
follow-up visits, ability to follow healthcare
recommendation or appointments, which may be
indicative of unmet needs beyond those addressed
by the health care system alone..."Change needed.
Add to research gaps - research on how
understanding of PTSD affects the lives of people
with SCD. Also recommendation #10 will be adjusted.
Editor added gap to end of chapter. Revised rec. #11 as follows: Refer people with behavioral issues
for evaluation by a mental health professional such as a psychiatrist, social worker, or addiction
specialist if neededed to identify unmet needs. Perform neurocognitive testing to rule out underlying
neuropsychological deficits. (ConsensusAdapted). Done.
Public
This is defined in the document. "After being unable

to identify any other etiologies, chronic SCD pain of
unknown origins " Will look at the intro and see if
this issue is covered or needs clarification.
Revision submitted to this section. A new research gap was also submitted: Clinical and natural
history research to clarify the onset, risk factors, and description of neuropathic pain occurring after
recurrent episodes of nociceptive pain related to SCD. Done
Change in research gaps.
Revision submitted to this section. Done
135
14 In a sense, chronic sickle cell pain is an extension of recurrent acute painful episodes.
This may need some rephrasing. As noted elsewhere, there are chronically painful
complications of sickle cell disease that probably aren't extensions of crisis, such as
avascular necrosis or other osteopathies. We may be more accurate if we think of chronic SCD
pain as a diagnosis of exclusion (though a common one). This encourages us to look for
sources of pain with more specific interventions first. Describing it as an extension of acute
pain also tends to direct us away from the dramatic strategic differences in the management of
chronic pain and acute pain; I think this is to be avoided we should probably be emphasizing
these differences rather than minimizing them.
136
20 The second seems to be due to chronic pain . . .
139
15 Very difficult to manage this in many large hospital settings, especially clinics where many
Medicaid patients are seen, where they may not see the same physician each time. Nurse
practitioners are used more in clinics now, and they also may rotate. This is one of the
reasons SCD Day Hospital programs and SCD Clinics are needed, for continuity of care.
Additionally, it must be remembered that there are patients that are not in large urban centers
who will not get this level of care.
Public
Yes, we agree. A research gap will be added. We

Revision submitted a new research gap: Health services research to identify the value of the
need more research identifying the elements of the
elements of continuity care on management and outcomes of chronic pain associated with SCD.
bestuniformityinclude rural. Include coordination Done.
of care.
138
18 Chronic Pain Recommendations - Why is the first recommendation in the list the "Weak
recommendation, Low Quality Evidence"? The least effective treatment should not be listed
first. It encourages medical professionals to make this the first priority in treatment of the pain.
The therapies listed in #1 are complementary therapies, and should probably be #3 or #4 in
the list. [Also noted as an SS patient and Clinical Lab Scientist.]
Public
The current order is to prioritize recommendations

that have evidence, then those that are consensus.
Change
152
6 For this set of recommendations, provide in each recommendation statement the age limits or
clear definitions for children vs. adults
Fed
Defer decision to panel because affects entire

document
Change
I think some clarification of terms might be helpful Public

there seemed to be some cross-talk between the
concept of pain (a subjective, perceptual
experience) and its neurological substrates. It might
be more useful to state something like persistent
inflammation and activity in peripheral nociceptors
can sensitize both the peripheral afferent
nociceptors and more central pain processing
systems, leading to hyperalgesia and chronicity.
Page # Line #
Comments
152
13 1. is this potentially unclear or misleading, given the suggestion to screen for proteinuria only?
2. doesn't microalbuminuria often spontaneously resolve in patients with SCD?
3. microalbiminuria found during an episode of illness, or while on nephrotoxic drugs be a false
positive?
4. therefore, for this recommendation to hold, wouldn't screening for microalbuminuria at well
visits also be required?
135
17 wasn't there some concern about validity of some of the diary studies - like pts filling out a
weeks worth of days at once? Sorry I do not know more about this but if true may deserve a
qualifying sentence
137
11 I'm not sure we should still be using the word adjuvant for nonopioid analgesics. In general,
they have independent and additive analgesic effects and don't require an opioid to work.
138
0 See Recommendation - Chronic Pain
Suggestions
Type
Public
Discussion
Do testing in steady state; never make diagnosis with Change
one screening. Do the screening multiple times.
Health maintenance section will be changed to be
consistent with this section. Should this be a policy in
the document overall? i.e. should all similar
recommendations that are similar be modified to say
that positive results should be confirmed before
initiating treatment? Panel should decide if changes
should be made across-the board with attention to
the health maintenance chapter.
Invited
We agree that recall bias is always a concern, and

No change
assume that readers will understand this because it is
a diary study.
Perhaps simply analgesics.
Public
This is a key question and cannot be adjusted after

the evidence review. Adjuvants are not analgesics.
We are not using the word adjuvants.
Have you considered water therapy? It has been

helpful to soothe pain in addition to massage
therapy.
Public
We are not certain if this refers to physical therapy or No change

hydration. In either case, this was not included in the
evidence review.
No change
138
17 The recommendations do not comment on risk stratification as a consideration for chronic

opioid therapy. Should this issue be addressed as in the APS chronic pain guidelines?
Invited
This was not part of our evidence review therefore we No change

did not comment on it.
138
17 Consider revising this set of recommendations. There is insufficient detail in an area that is
much needed in practice
Invited
This was not part of our evidence review therefore we No change

did not comment on it.
139
5 Revisit first sentence. It is inconceivable that a single annual visit would be sufficient to
manage chronic pain. The remainder of this recommendation should be moved to #1 for this
section
Invited
The text says "annuallly or more often as needed".

Panel will re-evaluate the sequencing of recs.
No change
140
0 Chronic Pain: I agree with the recommendations of the panel

particularly with one member Dr. Ballas. However I would like to see mention in the etiology of
chronic pain the use of habit forming opiates ( dilaudid, oxycontin, high dose of oxycodone,
fentanyl patches), in young patients 18 and above admitted for VOCs and sent home on these
medications or given at the primary care providers at their office. We should remember chronic
pain is a disease on its own and when established is difficult to break its circle.
Public
This is outside of the scope of this chapter.
No change
140
7 Recom 9 ER need to not undertreat adolecsents with SCD
140
7 Chronic Pain - Recommendation #9 should be first (#1) on the list. This should be the treating
medical professionals primary goal in chronic pain treatment of SCD patients. [Also noted as
an SS patient and Clinical Lab Scientist.]
Fear of addicion in adolescents with SCD needs to IND

be made with care in ER without contacting
hematologist.
Public
The statement as written covers this suggestion. This No change

is not about treatment in the ED.
This is already being addressed in a previous
comment. Panel will reconsider the ordering of recs.
No change
Page # Line #
Comments
140
9 First, PTSD is a factor that should be acknowledged and treated. Second, transportation to
medical appointments has become a major problem for the elderly, disabled and chronically ill
in the US. Many SCD patients live in poverty, and are forced to use taxicabs to get to medical
appointments. Even if taxi vouchers are provided for the patient, this form of transportation is
not very reliable many times. Paratransit and ambulance systems are more reliable, but may
be cost prohibitive for many patients. This is a social services issue that is not given enough
attention for SCD patients, especially adults. This is partially due to lack of adequate medical
social workers assigned to service SCD patients, where as cancer patients are assigned plenty
of these services. [Also noted as an SS patient and Clinical Lab Scientist.]
Suggestions
Type
Public
Discussion
This was covered in a previous comment. Thank you No change
for this submission, language is being crafted to
address this in the Intro.
140
9 Revise/clarify this recommendation. Nonadherence is not necessarily a behavioral issue.

"Violation" of agreement too legalistic. Alternate language: "Engage other providers such as a
social worker, mental health professional or chronic pain specialist to address the needs of
patients with unmet needs." Neurocognitive testing should be a separate recommendation
Invited
This is already covered in a previous comment.
No change
140
9 Limiting the recommendation for mental health referral to mis-behavior issues is exceptionally This is a serious and potentially misleading
Public
short sighted
omission from these guidelines; psychologic
treatment stategies need to be included; there is
also a wealth of information on the efficacy of these
interventions in other chronic pain disorders
This is being addressed in a previous comment.
No change
Public
No change
140
10 CHANGE: Page 140, lines 10-12: change to "for evaluation by a psychiatrist, social worker,
psychologist, or addiction specialist if needed to identify unmet needs.Perform neurocognitive
testing or refer to a neuropsychologist, if needed, to rule out underlying neuropsychological
deficits."
SONAR: Psychologists are one of the specialty provider types most able and available to
evaluate and diagnose behavioral issues (Anie & Green, 2002). Neuropsychologists are
uniquely capable of evaluating, diagnosing, and recommending management strategies for
underlying neuropsychological deficits (Berkelhammer, 2007).
140
10 In many areas, providers consist of MD, Nurse and maybe specialist, can other options be
provided if do not have SW, psychiatrist, etc. Needed, what would be the impact of the
practice? May need to restate in regard to this
Invited
No change
140
11 in this section it would be useful to include specific recs on ancillary treatments often used in
scd pain, ie antidepressants, NSAIDS, etc.. Which agents are most effective (gabapentin vs.
nortryptilline, etcc and at what doses). This would make this more practical and useful for daily
care. Possible place a table with ancillary drugs
Invited
This is beyond the scope of this chapter. This is

addressed in the background section.
No change
140
11 I would separate the neurocognitive screening rec from the violating narcotic policy section and
also consider include depression, anxiety, sleep screening recs somewhere in this area as
these correlate strongly with chronic pain
Invited
This will be covered in another comment/change in

the document.
No change
141
1 The "Risk factors" sentence reads as if these are independent factors one of which is SCD. Hb
leve and a-gene deletion by themselves and independent of SCD, are not risk factors for AVN.
Suggest rewording the sentence such as: "Risk factors for AVN of the femoral head in people
with SCD include...."
Invited
Team did not agree with this comment.
No change
141
7 Assume "HbS--thalassemia" is to imply SS disease with alpha deletion. Need clarification for List both beta globin genes,ie SS, with alpha thal so Public
non-hematologists to minimize confusion.
not to confuse reader of description of different
globin genes.
This is covered in a previous change.
No change
Page # Line #
Comments
141
7 you have not prev mentioned HbS-alpha thal - want to include in initial table on genotypes?
142
143
11 helpful to know
0 Avascular Necrosis: Very good chapter. In the
comprehensive care of patients with SCD routine xray of Hips and shoulders should be done
when patient first seen and thereafter when the patient complains of Acute pain in one hip. A
patient admitted or seen in the clinic for acute Hip pain should have an xray, and a hip MRI to
determine early AVN. Beside analgesic and PT, a consult with an orthopedic surgeon expert in
AVN for advice in management. More studies are needed for conservative management
versus Hip coring. But for patients with symptomatic stage III and with stage IV, Hip
Replacement is the procedure of choice but it has to be done in an Institution where PT is
available. Chronic pain from AVN can and should be avoided.
143
5 Individuals with AVN also need occupational therapy and vocational rehabilitation in many
cases because their occupations are not compatible with AVN such as construction workers,
plumbers, cooks, hair stylists, etc. where the prolonged standing and repetitive lifting
accelerate degeneration and intensify pain.
143
6 Include shoulder pain
143
143
6 possible to be more specific on when MRI is recommended?

10 Leg Ulcers There is no mention of Apligraf or other skin substitute grafts. There has been
some success with these treatments. [NIH Public Access manuscript Leg ulcers in Sickle Cell
Disease 2010 pg 3, paragraphs 1-3.] There is no mention of treatment of SCD leg ulcers
without sharp dissection, use of chronic blood transfusion, hydroxyurea, or hyperbaric oxygen
therapy as treatments that need further study. There appears to be No wound care specialist
(dermatologist, plastic/reconstructive or vascular surgeon) involved in the formulation of this
Draft document. Primary care, internal medicine and hematology physicians are Not qualified
to properly treat chronic leg ulcers by themselves. [Also noted as an SS patient with 20 years
of leg ulcer hx, and as Clinical Lab Scientist.]
143
11 implication of guidelines is that surgical intervention is limited to advanced stage disease and
arthroplasty, and does not discuss potential interventions for earlier stage disease
Suggestions
Type
Invited
Discussion
Invited
Public
No change
No specific change proposed. We believe this will be No change
adressed with the classification revision that is
forthcoming.
Add a recommendation on evaluation for vocational Public

rehabilitation.
This is a serious and potentially misleading

omission from these guidelines; there are many
other surgical options being developed for earlier
stage disease; there is also extensive experience
with treatment of AVN related to other etiologies
(steroids, etc) that should be discussed
No change
We have a rec for PT, rec #2. This is out side of the
scope of the evidence review for this section.
No change
Invited
If it was supported by the evidence, it would be

included. This was not supported by our evidence
review.
No change
Invited
Public
Covered in previous comment

Thank you for your comments. Specific treatments
tried in a few people are outside the scope of this
guideline
No change
No change
Public
We believe Rec 3 covers the referral to the surgeon

and the follow up care thereafter. Something is also
being added to the background.
No change
Page # Line #
Comments
143
13 No studies of wound care products, tissue grafts, or tissue substitute grafts include SCD
patients. This is a major problem. Those physicians and researchers that perform these
studies typically do not want to include SCD leg ulcer patients in the studies because SCD leg
ulcers are the most difficult type of ulcer to heal [told to me as a patient by multiple
physicians, hematologist, dermatologist, surgeons], therefore, they would mess up our
numbers [told to me as a patient by vascular surgeon]. SCD patients should be included in
these studies, and SCD patient data can be kept separate from the primary data of studies that
usually include diabetic, arterial and vascular leg ulcer patients. Thus, we SCD patients would
not skew their data. There should be a push from NHLBI to Big Pharma for the inclusion of
SCD leg ulcer patients in their studies and clinical trials. [Also noted as an SS patient with 20
years of leg ulcer hx, and as Clinical Lab Scientist.]
Suggestions
Type
Public
Discussion
This would belong in the gaps section.We believe we No change
have addressed this concern about not including
SCD patients in many research studies in the gaps
section.
144
After "2006)" add: "However, long-standing

hemolysis may be involved in the pathogenesis of
leg ulcers since they also occur in other chronic
hemolytic states such as hereditary spherocytosis
and thalassemia intermedia."
Public
The panel does not agree with this change.
145
0 See Recommendation - Leg Ulcers
Have you considered oxygen therapy for wound

care? I've heard of people getting good benefits
with hard to heal wounds.
Public
We do not have evidence to make a recommendation No change

about this.
No change
145
18 No recommendations on actual treatment of ulcers?
Invited
We have included as much information as we have

evidence to support
No change
145
146
18 Recommendations are clear

0 Legs Ulcers: This chapter does not give any guidance to a
primary care provider for the management of leg ulcerations.
1 if MRI is test you recd I would add that here
3 include possible diabetic ulcers in differential diagnosis
Invited
Public
Thank you
Acklowledged. It is beyond our scope to do more.
No change
No change
Invited
Invited
It is not our intent.

This is beyond the scope of this chapter.
No change
No change
IND
Answer is yes. This is already in the document.
No change
146
146
146
3 Is arterial insufficiency a cause of cutaneous ulceration in people with SCD?
146
6 Recom 4 either need to make suggestion of appropriate antibiotic or recommend ID consult
146
7 No recommendations for therapy
If there is concern over chice of antibiotic than

IND
obtain an ID consult
Include recommendations for treatment. There is a Public
modest literature and some standard approaches
that work.
This is beyond the scope of this group to comment on No change

this.
This is beyond the scope of this evidence-based
No change
document.
146
16 Would include these references in the screening section as the literature for both sections
should match. Typically, prior to referral for a right heart catheterization, an echocardiogram
should be obtained. This should be included in this recommendation.
Public
This will be looked at in the revision
No change
146
16 While this recommendation is in concordance with our recommendations in the ATS document,
it is impossible for the reader to understand how this conclusion was drawn from the
presentation of the literature in this section of the document.
Public
This is not a recommendation, it is part of the

background.
No change
146
16 Would include these references in the screening section as the literature for both sections
should match.
20 This is the prevalence of PH, not PAH. Please reference Parent F NEJM 2011, Mehari A
JAMA 2012, Fonseca 2011.
21 this is probably an over-estimate of PAH prevalence, based on the best study to date in this
area, by Parent et al
Public
No change
Public
No change
Public
This will be looked at in the revision. Parent reference No change

will be featured. We will use the 6% reference.
Invited
this is actually page 148 and handled there.
146
146
147
1 missing a space bw 200 and people
6% prevalence of true PAH
No change
Page # Line #
Comments
147
3 This statement is an argument to support echocardiographic screening.
Suggestions
Type
Public
The team disagrees
Discussion
No change
147
6 Would refer to Parent F NEJM 2011 and Mehari A JAMA 2012 for some clarity on these issues.
Public
This will be addressed in the revision
No change
147
148
7 "remain" unclear; plural subject

0 Pulmonary Hypertension: I want to stress again that a patient with SCD symptomatic or not
and with a TR jet of 3 m/s needs a cardiac cath. I want to stress the importance of yearly
echocs to detect early change in the TR jet. I do not have many cases to report but ona limited
clinical experience. Hydroxyurea does not change the out-come of a patient with symptomatic
PH which will continue to progress to right sided heart failure with hypoxemia. This is a good
chapter for the primary care providers as they are made aware of the severity of sickle cell
disease.
Invited
Public
Remains is correct
Thank you for the comment, no change
No change
No change
Invited
Public
Change handled in prev comment

This is beyond the scope of this section.
No change
No change
148
148
1 "more than 200people" Leave a space between 200 and people.

16 How to use ECHO? Who should be cathed? What therapy?
148
16 It seemed from earlier discusison on screening that maybe echo was sens but not specific in
detecting people with pulm HTN; can you describe why rec would not be echo in sx pts, then
RHC if abnormal? I doubt many people would get RHC without an echo.
Invited
This is addressed in previous revisions
No change
148
16 Recommendation would be more useful if it was more specific. Consider additional

recommendations to include thrombophilia evaluation, anticoagulation, other treatment
options, and PAH diagnosis and Rx in children
Invited
This is beyond the scope of this section.
No change
148
18 Refer patient to pulmonology
Invited
It is implicit in a new recommendation drafted.
No change
148
18 See second comment above
Public
This is not the right chapter for this. This would be in No change
HM.
149
11 As above how much urine protein is too much. Probably 1+ but the panel needs to be explicit
if this is all they are willing to recommend. The microalbumin to creatinine ratio line 17 is what
most SCD renal experts recommend even with the creatinine hypersecretion issue.
Public
We are citing what the literature says.
No change
Respond to these comments
Add two recommendations (2): " Screen all adult

SCD patients with ECHO to determine their
tricuspic regurgitation velocity (TRV) and if
increased, refer for evaluation by specialists in
SCD-PH." (3): "For SCD adults with normal TRV,
repeat screening at intervals to 1 to 3 years."
150
5 This is an error in fact that hyposthenuria causes volume depletion n sickle cell disease . They consider changing to free water dehydration.
are more at risk for free water dehydration and hypernatemia more than volume depletion.
Most data in chronic anemia and sickle cell disease supports a normal blodd volume and
increased plasma volume. Sodium handling by the kidney is not impared.
Public
Not correct and could be confusing
No change
150
152
8 See comment on p12-line12 above

6 Recommendations 3 and 4, and recommendations 5 and 6 can be combined for "children and
adults" as has been done repeatedly in the document.
Invited
Invited
Not clear what this comment refers to.

Evidence is different for children and adults, so
should not be combined.
No change
No change
Page # Line #
Comments
152
6 There is insufficient data for the recommendations made by the Panel on initiating ACE
inhibitor therapy. No recommendations on hematuria are made. No recommendation on
assessing the renal function is made, so that proper monitoring can be initiated.
Suggestions
Type
Patients with Hematuria, proteinuria or albuminuria Public
should have a comprehensive renal function testing
assessed or referred to a nephrologist so that
baseline is obtained before initiating ACEI therapy.
E.g., BP, GFR/Crt clearance, 24 hr urine alb,
lytes,uric acid esp K+ should be evaluated before
initiating ACEI therapy. Patients with SCD are
unable to excrete potassium adequately and are at
high risk of hyperkalemia. Patients with GFR<30
(and this norm may be higher in sickle patients
where GFR is higher than normal) cannot be given
ACEI. They are also at risk of hyperuricemia.
Discussion
Outside the scope of this document. Data is
considered sufficient for the recommendation but of
low quality
Not appropriate for another group to rewrite this

section. The background section covers these
issues.
Public
No change
152
7 The text on pages 29 and 36 suggests to screen for renal disease by checking urinalysis for
protein, including patients with hypertension. Yet, the only recommendations for treatment
pertain to patients with microalbuminuria. Proteinuria is not synonymous with microalbuminuria
since the former is a more crude analysis.
The AAP Section on Nephrology believes that

clarification is required regarding screening and
treatment for proteinuria versus microabuminuria
since these are not synonymous. This will require
extensive review and editing. We respectfully ask
for permission to submit an extensive edit of the
section on proteinuria/microalbuminuria.
No change
152
7 The text recommends to assess 24 hour urine in patients with dipstick positive for protein.
Consider modifying this section to: "In patients with Public

persistent (at least two measurements) proteinuria
but without edema or hypertension, assess a first
morning urine for protein. If there is protein on that
specimen, measure a random urine for protein and
creatinine (to assess the protein-to-creatinine ratio).
If the ratio is >0.2, referral to a pediatric
nephrologist is suggested."
152
7 If the panel will not consider microalbumin screening as a feasible recommendation, obtaining
a 24 hours urine before referral to nephrology is not realistic.
Public
This is an opinion only.
152
7 need to reconcile this recommendation with earlier section. If the prior rec is to screen for
proteinuria, how would microalbuminuria be identified?
Invited
Responded to this comment already on previous line No change
152
Screening should include urine albumin/creatinine

7 The recommendations provide guidance on further testing, referrals, and therapies when
microalbuminuria is identified. However, the screening guidelines do not recommend any tests ratios.
to identify microalbuminuria. Urine dipstick will identify proteinuria but does not detect
microalbuminuria, an earlier indicator of glomerular damage. Summary of evidence suggests
that urine albumin/creatinine levels "have not been validated" in SCD and may be affected by
increased tubular secretion of creatinine. While this may alter A/C ratios quantitatively, it
seems substantially better that screening with a method that will not detect the endpoint that
will trigger intervention (albumin).
Public
Already done in accordance with previous comments. No change

Definition of microalbuminuria has already been
changed.
152
9 Should refer to a nephrologist who is knowledgable about SCD
Invited
Not necessary to make this change
Primary care physicians know how to assess this

No change
correctly. Do not need to spell out. Also beyond the
scope of document to list all the caveats.
No change
No change
Page # Line #
Comments
152
11 recommendations 4 through 4 are premature and not evidence based because there are no
controlled long-termed studies that support the use of ACE inhibitors for proteinuria in sickle
cell disease. The McKie article is misquoted (See above)
152
11 ACE-inhibitors are recommended treatment for albuminuria or proteinuria. I suggest

angiotensin blockade therapy which can include ACE-inhibitors or Angiotensin Receptor
Blockers (ARBs)
Suggestions
Reconsider the recommendations
Type
Public
acknowledge role of ARB in treating albuminuria in Public

other settings.
Discussion
Evidence is low-quality but based on two references. No change
We will be elaborating more on the recommendations
in the background. If change it would be in
background. Recommendations are evidence-based,
but low quality evidence.
Not enough evidence for change
No change
153
0 Page 153: RENAL COMPLICATIONS under recommendation #9, renal transplantation is listed
as an option that should be used in people with SCD if they need it, yet there is no mention of
when to intervene with HCT before they get ESRF.
Public
Beyond the scope of document to suggest when

patients should get transplants.
No change
154
0 no mention is made of the use of Sudafed for prevention of stuttering priapism
Invited
No evidence for change
No change
Public
Already addressed
No change
Public
Discussing devices is beyond the scope of the

document. Role of transfusion already addressed.
No change
Public
No evidence for change
No change
154
155
13 If you are going to mention finisteride for recurrent priapism you also have to include
lupron/leuprolide
0 Stuttering/Recurrent Priapism: The panel did not mention if any the role of transfusion. The
panel did not discuss either when prosthesis is indicated or other form of devices in the
management of patients with complications of priapism/complication of aspiration/shunt.
Have a discussion and recommendation. I know,

little data, but it is widely used and discussed so
should be addressed.
155
1 There is no comment on the use of pseudoephedrine in priapism
155
3 Should refer to a urologist 'who is knowledgable about SCD'?
Invited
Already been addressed in previous comments
No change
157
0 Ophthalmologic Complications: From a practical experience, a patient with sickle cell disease
should be followed by a competent ophthalmologist on a yearly basis so proper referral to a
specialist in Retinal Disease can be done on a timely fashion. I saw 2 cases of retinal
hemorrhage in 2 adolescents with SC age 15 and 17, the former was diagnosed because of
sudden blurry vision, the second because of routine eye examination as a component of health
maintenance. THis chapter again emphasizes the severity of sickle cell disease which includes
particularly SC and SB+thalassemia.
Public
This is about health care maintenance, and this is

covered in the HM chapter.
No change
157
17 Ophthalmic Recommendations There should be a recommendation of annual

ophthalmologist exam with dilation, regardless if the SCD patient has symptoms, especially in
Sickle C disease patients. Some visual changes are subtle, slow, and may not appear as a
problem to the patient until the problem is in a more advanced stage. In other words, be
proactive to save the patients sight. [Also noted as a 53yo SS patient with opthalmic
complications.]
Public
This is about health care maintenance, and this is

covered in the HM chapter.
No change
157
20 by medical management do you mean laser therapy?
Invited
We do not mean any one particular therapy.
No change
157
22 it would be useful to add sections on iron overload and how to follow and manage in chronic
section with empahsis on ferrtin, T-2 MRI and tx with new agents. It would also be sueful to
include a section on Vit D deficiency and tx in SCD
Invited
This is in the wrong chapter - this is a Transfusion

issue and outside the scope of this chapter. Not
157/22. HM will take this up in the background
No change
Public
Our guidelines were not for curative therapy. This is

beyond the scope of this chapter.
No change
Invited
This is addressed in the gaps, but discussing the

controversy is outside the scope of this panel.
No change
158
158
0 Page 158: KNOWLEDGE GAPS AND OPPORTUNITIES FOR RESEARCH - again no mention
of HCT and listed as an opportunity on page 160 is "Studies to improve outcomes in people
with SCD undergoing renal transplant. Again this is a non-curative therapy.
12 Calls for a registry are controversial. Does the document address this controversy?
Page # Line #
Comments
160
14 Duplicate recommendation from acute chapter.
Suggestions
Type
Public
Discussion
We are OK with that.
No change
Page #
202
Line #
Comments
0 The section on blood transfusion in the management of patients with SCD is well written for the most part and I would only
suggest a few additions. It seems on the summary of evidence regarding preoperative transfusion that the 10
observational studies were not given any weight. As stated (on page 202), these studies showed significantly lower
postoperative morbidity when compared to the one randomized trial where complication risks were not compared to those
not receiving any transfusions, which would have been the appropriate comparator. Therefore, I think recommendation
number 2 (page 203) should at least be moderate quality evidence and transfusion not be limited to high risk surgery.
Suggestions
Type
Discussion
Sounds like this person wants a more strong rec for Change made
use of transfusions. This change is for rec #2. We
are unable to increase the quality of evidence for
consulting b/c there is no evidence. Change protocol
to "method" on page 203, line 16
203
9 The recommendations for pre-op transfusions do not address those patients who are on hydroxyurea (which should be
the majority of SCA patients, especially pediatric SCA patients, as is true in my practice). I am not aware of studies on
patients on hydroxyure with Hgb close to 10 and HgbF>20% undergoing anesthesia (this is the majority of my patients).
What is the expert panel's position on this? It does not make sense to exchange transfuse these patients for low or
moderate risk surgery.
For patients on hydroxyurea whose hgb approaches 10 or greater

(and who have high Hgb F percentages) undergoing low or
moderate risk surgery, consult a sickle cell expert.
Public
Yes, add "on chronic HU therapy" to this rec.

without transfusion, on chronic HU therapy, or who
require high-risk surgery.
203
17 I am not sure the literature supports transfusion for SC and SB+ for all surgeries, as the low risk ones, even if a GA, were
not complicated, only the moderate risk.
0 exhibit9 - reduction of Hb by 1gm/dl does not match the previous advice I the guideliens on anemia, and comments on
page 95 also apply
change guidance on transfusion for non-SCA for low risk (SC) or

low and moderate risk (SB+)
revise Hb level for transfusion of ACS. Perhaps with Hb <8 as this
permits simple transfusion of 2 units without hyperviscosity. Rather
than saying a drop of 1gm/dl.
Public
Change this recommendation to Moderate from

Change made
Strong
Exhibit 9 use acute chest syndrome instead of ACS. Change made
Change to define ACS. This should be an editorial
exception or defined in each table reference.
Discuss with editor.
see comments for page 95
Public
204
Public
Change made
205
0 exhibit10 - symptomatic anemia not defined
205
3 The recommendation for recurrent acute splenic sequestration is not clear to me. Is this the recommendation is there is
not severe anemia/evidence of hypovolemia? I would still acutely transfuse a patietn with recurrent acute splenic
sequestration acutely until the spleen could be removed
InvitedThis section refers to a specific issue over time with Change made
Non
the spleen. It is not about pre-operative treatment.
Disclosed Consider to change wording to recurrent spenic
sequestration instead of acute. Take out the word
acute.
205
4 Line 4 of table recurrent acute splenic sequestration - somehow you have to indicate that you mean no CHRONIC
transfusion, simple transfusion IS indicated for recurrent acute sequestration during an episode with a hemoglobin below
baseline. Rephrasing needed
Public
Chronic complications-graded recs for when

transfusion is not indicated.This should be a new
title. Remove the last row from Exhibit 11 and put
that intot his new table. That will be the only row.
Create new exhibit 14 with one row about acute
splenic sequestration.
NEW EXHIBIT 14, CHRONIC COMPLICATIONS

GRADED RECOMMENDATIONS FOR WHEN
TRANSFUSION IS NOT INDICATED. This will be
one-row table, about acute splenic sequestration.
Remove last row from exhibit 11 DONE
205
Public
Clinically overt infarctive strokes is what is meant.

Silent strokes would be different. This should be
hyperlinked or expanded. "Adults and children with
previous clinically overt stroke".
Change made
205
9 Would clarify that TCD reading is the time averaged mean maximal cerebral blood flow velocity
Need to define WHAT TYPE of strokes should be transfused. As

written all with silent infarcts or hemmoraghic stoke should be
transfused.
This is already defined in the document in the acute Need to add hyperlink or page referral or both to to
chapter. can hyperlink or page referral be done?
information about symptomatic anemia. DONE.
Added page referral.
InvitedRefer back to HM chapter for this discussion.

Non
Disclosed
For more information about TCD, refer to page xx

of the HM chapter. Add definition as footnote to
chapter and then refer to HM chapter for more
information. DONE: Added definition of TCD
reading under exhibit 13 along with referral to HM
chapter.
Page #
206
Line #
Comments
Suggestions
Type
0 General Transfusion:
There should be a sentence on page 219 (under
Public
Alloimmunization is an important complication of SCD. Alloantibodies responsible for significan transfusion reactions may "recommendations" to prevent transfusion complications) saying
evanesce and difficult to detect prior to subsequent transfusion(CA Tormey, Transfusion 2009 and Blood 2009), making an that it is critically important to obtain a transfusion history (including
adequate history essential for transfusion safety.
RBC alloimmunization/RBC autoimmunization history) on all
patients.
Discussion
Consensus protocol is already included in chapter. Change made
Add to p. 209. First bullet point: Obtain patient tx
history to include locations of prior transfusions and
adverse effects . To blood bank bullet, add: ask the
blood bank to contact hospitals where patient
reported previous transfusion to obtain transfusion
information.
208
11 A missing recommendation: May seem obvious but clinicians should request blood that is Hb S negative when planning
transfusion for a patient with SCD. This is an extra and non-routine step for blood banks.
Invited
Background. Page 199, line 15.A specific request of Change made

the blood bank may be required to obtain sickle
negative erythrocytes. Should be final sentence of
the paragraph.
208
18 The transfusions may be at an interval other than monthly and this may not be clear to all providers. Suggest saying the
goal is to maintain a Hb S <30% immedaitely before the next transfusion.
IND
This should be clarified in the text. Change to 30

percent immediately prior to the next transfusion."
Delete "or less" until end of statement.
Change made
IND
Agreed.
Change made
210
5 Would change to Suggested Evaluation Before Each Transfusion
210
13 An indirect coombs is not the test most blood centers use, instead it is an "ANTIBODY SCREEN" suggest changing
wording since that is what is charged for by most transfusion programs.
Public
change "Type and Screen - this is done to assess" Change made

(delete monthly, month's) prior transfusion"
210
19 Annual monitoring of ferritin for someone on chronic transfusions is not enough, especially if they are on a chelation
regimen (compliance assessment, increase in dose, stopping chelation)
Invited
Change to quarterly - instead of annually or

semiannually.
Invited
Change bullet to insert such as "liver biopsy", MRI- Done. Changed to: Evaluation for iron overload
R2Please change this to look like p. 220 line 7.
every 12 years by validated liver iron
quantification methods such as liver biopsy, or
MRI- R2 or MRI T2*/ and R2 techniques." This
matches what is on page 220 line 7.
Public
Delete this line/bullet entirely.
Change made
Public
OK, but use this wording: "and increases the risk

for delayed hemolytic transfusion reactions."
Does the sentence end after the new wording? Or

should we retain the original end of this sentence:
Alloimmunization usually limits the ability to find
compatible blood for future transfusions, and
increases the risk for delayed hemolytic transfusion
reactions, so efforts to avoid alloantibodies seem
warranted. LEAVE END OF SENTENCE AS IS
FOR NOW. DO NOT DELETE IT.
211
2 Iron quantification methods by MRI is not available everywhere and should not be required,
211
4 what is the utility of tracking units if going to do MRI?
212
22
consider removing for those montiroed by MRI and in a

comprehensive care program
After "transfusions," add: "and place SCD patients at risk for
delayed hemolytic transfusion reactions."
Done.
Page #
213
Line #
Comments
17 Iron Overload and Chelation Therapy: Iron overload and chelation therapy for SCD are not necessarily equivalent to
thalassemia.
Suggestions
Type
The indication for initiating chelation in intermittently transfused
Public
patients should be indicated with recommendations about their
management or alternatively a specific document should be referred
to that is required reading for embarking on iron overload and
chelation management.
Sickle cell disease and thalassemia are not the same disease and
some statements about follow-up recommendations beyond iron
measurements should be made. Presently, Exjade is approved for
SCD. Deferiprone, which has been used in Europe, has not been
approved in the United States for SCD. Given the toxicities of the
medication, the document should briefly cover the baseline
monitoring tests required for their use such as audiology, renal, liver,
ophthalmology, and growth. Particular toxicities of chelators should
be mentioned such as neutropenia with Deferiprone and renal injury
with Exjade. Monitoring of patients for endocrine dysfunction, low
bone mass, and cardiac disease is necessary.
215
20 should the liver iron content be mg per g dry weight of liver?
Discussion
This is true- we do not have recommendations about Change made
chelation, and the different drugs. This is beyond the
scope of this project. We agree with the comments
of this contributor. We will add..."but a thorough
review of chelation dosing and management is
beyond the scope of these guidelines." Goes on 214,
line 8. "for chelation, but a thorough...
IND
Yes, this is an error in the guidelines. Change to

Done. Used language on pg 216 line 13: 2 mg
2mg/Fe per gram dry weight of liver" Change in
iron/g dry weight of liver tissue, and 5 mg iron/g dry
both places - line 20 and line 21. See p. 216, line 13 weight of liver tissue.
for wording. This is the preferred application of this.
217
1 Some DHTR (including some involving bystander hemolysis) don't have any new RBC alloantibodies associated with
them (de Montalembert et al, Haematologica 2011; Win et al, Transfusion 2008).
incorporate additional references and interpretation.
Public
Occassionally this can occur without identification of

new red cell antibodies. At the end of 217, line 16
end of para.Yes, include these citations/references.
Will send the one ref that is not already in the
document.
Added references de Montalembert et al,

Haematologica 2011; Win et al, Transfusion 2008)
as indicated. Has the following been addressed:
Will send the one ref that is not already in the
document. Also, need to confirm that de
Montalembert ref is correct as I located it in
Pubmed; it wasn't in the Transfusion evidence
table: de Montalembert M, Dumont MD,
Heilbronner C, Brousse V, Charrara O, Pellegrino
B, Piguet C, Soussan V, Noizat-Pirenne F. Delayed
hemolytic transfusion reaction in children with
sickle cell disease. Haematologica. 2011
Jun;96(6):801-7.
217
9 I am not sure that the statement that jaundice is more common in extravascular hemolysis is correct (assuming the
comparison is to intravascular hemolysis).
Would check this fact before inclusion
Public
Delete sentence on line 9 "Jaundice"
Change made
Replace "On rare occassions" with "Rather frequently"
Public
Change sentence to, "DHTRs can be associated"
Change made
Invited
We do not see an extra period. Editor please check. Done.
Public
Omit the parenthesis portion of the sentence. ,

remove the word "completely"
Change made
IND
Remove the word "packed"
Change made
217
11
217
20 Remove an extra period at the end of page 217, line 20.
218
11 K antigen should be included here
218
16 Again - the use of "packed" erythrocytes as noted above.
incorporate additional information.
Page #
219
Line #
Comments
Suggestions
16 redundant to p208
Type
Invited
219
220
220
221
Discussion
Editor review these 2 recs they should be identically Done. Revised 219 line 16 to read: RBC units that
worded.
are to be transfused to individuals with SCD should
include matching for C, E, and K antigens. This rec
is identical to the one on p. 208 of PDF of
guidelines.
MAKE THESE CONSENSUS
These are new recs #1 AND #2. Renumber
RECOMMENDATIONS ON PAGE 219. FIRST 2
remaining recs. Add Consensus? and a query to
RECS. First Rec: Obtain patient tx history to include the file. DONE
locations of prior transfusions and adverse effects .
Also add rec: Ask the blood bank to contact hospitals
where patient reported previous transfusion to obtain
transfusion information. Consensus - both.
3 Patients with low HbS levels can be transfused to > 10 g/dL, even if not on chronic transfusions - use of disjunction makes Would change "and" have low Hb S levels" to "or" have low Hb S
more sense than conjunction
levels
10 More specific recs would be useful to include agent, dose, how to titrate, toxicities and how to screen. Could also be
included under chronic complication section
Public
Yes, the team accepts this change.
Invited
Administer iron chelation therapy, in consultation with Change made

a hemotologist, to patients with SCD"
11
Change made
Assess the effect and prevention of hyperviscosity Change made

().
221
3rd bullet. Add this bullet: Clarify the need for

perioperative transfusions in patients who are
treated with HU
DONE
221
4th bullet. Add this bullet: Clarify the need for

perioperative transfusions for patients undergoing
monitored anesthesia care or minor surgical
procedures under general anesthesia.
Done.
221
From previous comment, new gap is needed. Add

gap about genotyping. "Analyze of the cost
effectiveness of red cell genotyping all patients with
SCD. "
Done. Bullet added at end of list.
Editor please advise
I am fine with changing it to person throughout but

we went through the document in June and opted
to leave some instances of "patient" in the
document. Please advise. Change "patient" to
person? Do I change "individuals" to person as
well? Also, please note we received an NHLBI
Guidelines and Reports Style Guide (Updated
6/21/12) which states: Avoid using "people." Use
individuals, patients, participants, adults,
practitioners, and so forth are preferable. Please
advise.
206
14
Should decide whether to use patient or person consistently in

whole document
Public
Page #
216
199
Line #
Comments
11 should mention cutoff used to allow assessment of sensitivity and specificity of serum ferritin
Suggestions
Add cutoff used to text or otherwise explain
Type
Public
Discussion
Is a period missing here. Methodologist please
address this question. Panel will be submitting a
sentence. Methodologists need to provide the
references.
10
After "Josephson 2012)." add: "To prevent alloimmunization to

minor RBC antigens most SCD experts recommend the use of
RBCs that have been matched also for Rh and Kell antigens (see
recommendaton 1 in page 208)."
Public
Yes, a change is warranted here. Will submit. Please

send paragraph.
DONE: Revised: To minimize adverse effects of

transfusion, selection and infusion of erythrocyte
units should follow standard blood banking and
transfusion practices. Many institutions provide all
people with SCD erythrocyte units that are sickle
negative and leukocyte reduced; to prevent
alloimmunization, many institutions also routinely
provide units matched for minor Rh and Kell
antigens. (Karafin, Shirey, Ness & King 2012;
Sloan 2012; Winkler & Josephson 2012). The
clinical benefits of transfusing sickle-negative
RBCs in SCD (as compared to sickle trait RBCs)
has not been specifically studied. Transfusing
sickle-negative erythrocytes assists with accurate
tracking of percent sickled hemoglobin when
specific HbS targets are used and avoids the
possibility of the transfused erythrocytes becoming
sickled, which has been described in extreme
circumstances (Murphy et al. 1980; Novak and
Brown 1982).
199
209
1 these defn are helpful along with the three listed advantages of exchange but does not seem to explain why simple recd
for certain conditions and exchange for others. A little bit more detail here might be good unless it gets too involved.
20 why is this recommendation only included under chronic transfusion therapy? Why would you not do this for any
transfusion? Many complications occur with episodic transfusions in SCD
Invited
Will add some content to this
Invited
We could put something in the Intro about notifying

the blood bank that a patient has SCD
p. 209, line 20, added before the first bullet:

Obtain patient treatment history to include locations
of prior transfusions and adverse effects.
Then revised next bullet to: Notify the blood bank
that the patient being initiated on chronic
transfusion therapy has SCD. Ask the blood bank
to contact hospitals where the patient reported
receiving previous transfusion to obtain transfusion
information. Does this address this?
Page #
220
208
Line #
Comments
9
18 Doesnt acknowledge about mention of keeping HbS <50%
Suggestions
Type
Add paragraph 5: "For SCD patients who are only sporadically
Public
transfused, check serum for formation of new alloantibodies
(primary alloimmunization) 2 -3 months after each transfusion. At
this time the transfused RBCs are no longer in circulation so there is
no hemolysis even if a new antibody has been formed. Detecting
primary alloantibody formation at this time is crucial, since up to
40% of formed alloantibodies become serologically undetectable
about one year after the alloimmunizing transfusion. Undetected
primary alloimmunization results in delayed hemolytic transfusion
reactions when subsequent transfusions elicit a secondary,
anamnestic alloantibody response."
Discussion
This is a good point. This can be discussed in the
background. Will re-word this and submit it.
Have clearer recommendation on HbS <30 versus <50%
Public
Will review the article.
204
8 Table (Exhibit 9)
Add rapidly progressive clinical or radiographic findings to

indications for exchange transfusion
Public
TABLE THIS COMMENT. NEEDS DISCUSSION

WITH THE ACUTE CHAPTER
EDITOR TO DO: Embed these final 3 comments in

the chapter file so that they can be resolved.
DONE
204
8 How can you recommend exchange Tx for ACS!!!!!!!!!
At least "Simple or Exchange" I'd prefer "Simple then Exchange"
Public


DONE
Public


DONE
204
Re: ACS with hypoxia recommendation: why is there no category for simple transfusion here in the case of ACS with
hypoxia?
197
0 Blood Transfusion in The Management of Sickle Cell Disease: This chapter is a good document from an extensive review
as well expert opinion of some Panel members. However, I want to stress 2 issues based on my review. The Transfusion
Guidelines needs to be simplified even for an expert in hematology. Recommendations should be simple, an Algorith
would be helpful. Exhibit 9 page 204/205 is clear and easy to follow. Except for simple transfusion for symptomatic
anemia, transfusion should be managed by the hematologist expert in SCD in consultation with the Blood Bank.
Public
Panel will consider these comments during revisions No change
197
1 Consider moving this section upfront, or provide references to the appropriate info in this section throughout the
guidelines where transfusions are recommended
Invited
Final document will refer readers to appropriate

sections/pages of the guidelines for similar/further
info.
No change
Consider adding appropriate reference.
Public
This is a brand new article, after our review
No change
include results of TAPS study
Public
This is newer evidence, not yet published.
No change
After "developed ACS." add: "Preliminary results from a recently

completed Phase III trial (TAPS) show that preoperative
transfusions of SS patients reduce sickle-related postoperative
complications (ASH 2011 abstract.
http://ash.confex.com/ash/2011/webprogram/Paper40722.html)."
Public
This is newer evidence, not yet published.
No change
200
202
202
203
10 Regarding sentence to the effect that exchange transfusions may increase RBC alloimmunization risk. Although this is
logical, Wahl SK et al (Transfusion 2012) just published a manuscript showing lower rates.
8 the TAPS study is not included, why?

17
9 Transfusion Recommendations
1. Red cell units:

Public
a. The panel should recommend that genotyping of antigens should
be obtained in all patients who are who are likely to be exposed to
transfusion therapy.
b. Extended (beyond C, E, Kell) phenotypic matched units should
be used for patients who have alloantibodies.
c. All units should be leukocyte reduced.
2. Guidelines to avoid hyperviscosity should be included.
The team discussed this comment and does not

No change
agree with recommendation a. No data for b. Some
of these are already addressed in the next section.
We do not recommend extended phenotype
matching. Leukocyte reduction was not addressed
by this chapter. We have a rec on avoiding
hyperviscosity.
Page #
203
203
203
203
203
203
204
204
Line #
Comments
10 Given the degree of evidence this recommendation is NOT WARRANTED. AS written it is phrased incorrectly "raise
hemoglobin to 10 g/dl" would be better. However the data are that 9 g/dl either by exchange or simple transfusion is
adequate so where does the 10 come from. Lower risk procedures especially MRIs should not require transfusion.
Suggest
the panel consider
stating Transfusion
to a hemoglobin
on 9-10g/dl
considered"
for all evidence
general that
10 The
recommendations
on transfusion
are very clear.
There is some
published"should
cases be
series
and emerging
anesthetics
and with
a decision
indivualized
procedure
and patient'sPE
history.
minor surgeries
GA in children
and based
adults on
(typcially
line placemnets,
tube placements, and similar
10 surgeries/procedures
Should specify more clearly
thatrequire
sickle transfusion.
negative ABO/D, C, E and Kell matched blood is preferred
may not
Suggestions
Type
Public
Discussion
The basis of this is the only randomized trial in
transfusion.
No change
InvitedThis lends itself to the gaps section. Change will be No change

Non
applied to gaps section
Invited
Already covered in recommendations section. Page No change
Disclosed
208, line 12.
Public
See above change
No change
17 It is unclear why there is a strong recommendation for pre-operative exchange transfusion for Hb SC and Hb S+
thalassemia.
17 WHERE is the evidence for this? SS is not the same as SC and you have managed to suggest that for most of the
document yet here you subject SC and S beta plus thal to a partial exchange transfusion? Consider softening this
recommendation as well. The data does not support it.
17 No data exists to support this in SC and S Beta plus thal
1 I have had dozens of transfusions. Im at the point now where I need one every month. Im all for tranfusions when done
the right way. Many times drs will gie you one when you dont need it thinking that its the solution but it could actually do
as a resulthere
of getting
ive hadingallstones,
overload,
and i have so
antibodies
takes
1 Imore
thinkharm.
the information
re useso
ofmany
transfusion
SCD is veryiron
helpful.
I do co-manage
all many
my SCD
pts withthat
Hemit and
longer
theinaverage
time
to find
a match.
i had here
to beisonnew
steroids
because
defer tothan
them
this area.
A good
bitme
of what
was once
presented
information
for finding
me andaImatch
would was
needliterally
to learn
impossible,
that
lasted
for
months.
Transfusions
should
be
a
last
resort,,
not
primary.
Its
not
a
cure
even
if
you
get
more before being comfortable with making these decisions without hem guidance. That being siad, this information will
transfused
could
still partner
be in crisis
many
think
opposite.
make me ayou
more
helpful
and but
better
allow
methe
to ensure
that necessary monitoring is being done and that patients
Public
See above change
No change
Public
There is observational data from one study.
No change
Public
No change
Invited
Excellent comment. We address throughout the

chapter the methods to use to avoid unnecessary
transfusion
Thank you for this comment.
Invited
Public
This is covered with new exhibit.
No change
are educated re transfusion therapy.
204
205
8 helpful to have summarized indications for transfusion in one place

4 Table (Exhibit 12) - Recommending that transfusion be withheld for certain "Acute Complications" in the header and then
mentioning recurrent acute splenic sequestration in the table is confusing and could lead to transffusion appearing to be
contraindicated for recurrences of acute sequestration
205
9 I would recommend modifying the recommendations for stroke by subtype of stroke. The evidence is moderate that
chronic transfusion is the best therapy for the secondary prevention of ishcemic stroke in children with SCD (bone marrow
transplant may be better, but the data are very limited). The data include prospective cohort studies with a pre and post
design and studies looking at stopping transfusions in those transfused for secondary ischemic stroke. In addition, there
was an RCT (SWiTCH) comparing transfusion to hydroxyurea, the study was stopped early because of a higher
proportion of strokes in the HU arm. The evidence for adults is very limited and the risk of recurrence of subarrachnoid
hemorrage or intracererbal hemorrhage may be lower than that of ischemic stroke, but the published data are insufficient
to say at this time what the best rx is for hemorrhagic stroke.
InvitedWe do not feel there is strong data for either

Non
subtypes of stroke, therefore, a more general
Disclosed recommendation for clinicially overt stroke is
warranted.
No change
205
Invited
Already addressed
No change
206
I disagree that transfusion is not indicated in recurrent splenic sequestration, especially in the management of young
children.
0 As far as I can see, there is no mention at all of genotyping in this draft. Given the number of Rh variants in the sickle
cell community, genotyping has become quite important as a diagnostic option for patients with unexpected antibodies.
And in the future it will have an even bigger role, both on the donor and the recipient side of the equation.
Public
We don't think genotyping for everyone is warrented No change

at this time based on the evidence and cost
effectiveness. Will add a knowledge gap. Analyze of
the cost effectiveness of red cell genotyping all
patients with SCD.
206
1 makes more sense to start the transfusion chapter with this section, or at least pages 206-209
Invited
Team does not agree
207
0 Next on page 207, 212, the rates of alloimmunization are discussed and as I pointed out earlier, range from 3 to 29%. It
is also emphasized of those who had stricter cross-matching criteria had more favorable results. I believe this area
should be bolstered with the information showing that more attention to detail in cross matching the donor blood would
give you a much lower rate of alloimmunization. This could be transported to the earlier area that I mentioned rather than
putting just the high 18.6% rate.
From
Email?
Our recommendations are based on available data. No change

This has been discussed thoroughally among the
panel.
This recommendation is weak enough and confusing enough to

omit completely
A sentence discussing use of selected genotyping should be

included (could ref Yazdanbakhsh K et al, Blood 2012).
No change
No change
No change
Page #
207
Line #
Comments
0 Finally, there is no information I can find on the use transfusion in pregnant women. The literature is replete with cohort
control studies, but there is only one randomized clinical trial (Koshy). This trial did not really reach the numbers needed
in their power calculations, but was nevertheless termed a negative study. When one reads the study carefully however,
over 85% of the non-transfusion group, received transfusions sometime during the pregnancy due to VOC. In the
transfusion group there was less morbidity, although because of small numbers, it did not reach statistical significance.
While this is not the number one treatment modality, it should be at least mentioned in compared and contrasted to the
cohort within the frame work of the report.
Suggestions
Type
From
Email?
Discussion
We do not discuss pregnancy because pregnancy
management is not discussed in these guidelines.
We appreciate this comment. This topic is beyond
the scope of this project.
No change
208
12 Should RBCs be leuko-filtrated?
Invited
This mentioned in the introduction of this chapter,

No change
but since this subject was not included in the review
there are no recommendations
208
12 Matching should be for RH and Kell, which is usually stated as CcDEe and Kell since C and c as well as E and e antigens
are codominant not dominant and recessive.
Public
This should be left as is, per team discussion. This is No change

being left as-is for practical application.
208
12 It is interesting that the quality of evidence for C/E/K matching is "low quality"----there are a few papers not referenced
that potentially should be, including LaSalle-Williams M et al, Transfusion 2011.
Public
This is an observational study, there are no RCTs on No change

this topic.
208
14 Why would this recommendation not apply to all genotypes of SCD? A patient with SCD-SC and acute anemia faces the
same risk of hyperviscocity if transfused to too high a level of Hb. (Also applies to p220-line1)
Invited
Change being made in gaps section.
No change
208
18 How about goals in adults. When or if is it safe to drop Hb S targets to below 50% in adults with chronic exchange
Invited
No data is available, so this is not addressed
No change
208
18 Chronic transfusion as discussed above indicates that you can decrease to < 50% S after a period of time (reference
Cohen 1992) yet here you just state 30%. Need to account for the change in parameters that many experts use.
Public
Comment covered in previous response.
No change
208
18 This recommendation for children implies that the practice of allowing Hb S level to rise to < 50% after 3 years of
neurologic stability in prior stroke patients is not recommended. Also, patients on chronic RCT for indications other than
stroke should be maintained at Hb S < 30%. Are these really intended?
3 refer people to p212 for more detail on alloimmunization
Invited
Comment covered in previous response.
No change
Invited
No changed, not needed
No change
Invited
No change needed
No change
6 ? Need for monthly retic counts. How does this change management
10 ? Need for monthly hb electrophoresis. This is costly and levels will likely not change that much month to month. Would
suggest Q 3-4 motnhs.
13 consider removing references to monthly
19 THIS is NOT a frequent enough monitoring of ferritin. Yes ferritin is a poor measure of iron burden as a single value, but
as a trend does indicate what is happending to a patient and does correlate in a specific patient with MRI or biopsy based
measurements of iron. SO suggest monthly or quarterly measurement of ferritin. Otherwise patients will be denied by
insurers one of the best re-enforcements of how iron burden is trending and of course something required for safe
monitoring of chelation per the FDA with deferisirox or deferiprone. This is not correct and should be rediscussed by the
panel.
Invited
Invited
No change
No change
IND
Public
Team decided to leave as-is.

This is an excellent suggestion for the dissemination
planning group.
This has been changed.
Change covered in previous comment.
19 Blood Transfusion-Suggested Periodic Evaluations Ferritin should be done more than semi-annually in a chronically
transfused patient, especially if on iron chelation. This assists in monitoring compliance with chelation therapy, and
effectiveness of the chelator and dosage.
Public
No change
209
209
210
210
210
210
210
7 thank you!
incorporate additional references.
No change
No change
Page #
210
Line #
Comments
19 serum ferritin once or twice a year seems inadequate to me to evaluate adherence to chelation
211
2 MRI evaluation liekly not required if on exchange transfusions
211
2 I'm not convinced monitoring hepatic iron in patients prescribed a maximum chelator dose is worth the risk/expense if
ferritin is over 2-3000
214
9 I would recommend commenting that proper deferoxamine SC administration is 18-24 hours as some physicians
misunderstand and believe a 2 hour bolus dose is effective. The longer administration times are required due to short
half-life of deferoxamine
214
10 I take exjade and I absolutely hate it. I dont know anyone who disagrees with me. Its so bad everyone I know who was on
the other medicaton first, chooses to stay with that verses having to drink some horrible gritty mess that they say has no
taste. Its the worst. I was just wondering if there was any other option. Is there a pill you can simply swallow, anything
would be better than drinking that horrid medicine.
215
18 I would recommend commenting that proper deferoxamine SC administration is 18-24 hours as some physicians
misunderstand and believe a 2 hour bolus dose is effective. The longer administration times are required due to short
half-life of deferoxamine
218
5 avoidance of transfusion is the best risk mitigator
Suggestions
Type
IND
Discussion
No change
Public
No change is needed here.
No change
Public
No change is needed here.
No change
Public
This is beyond the scope of this project
No change
Public
We appreciate the comment and this perspective.
No change
See comments for suggested addition
Public
This has been addressed in a previous comment.
No change
add avoid transfusion (unnecessary) to this section
Public
This is addressed elsewhere in the chapter under

"indications."
This was not included in the key questions for this
chapter, so the literature was not reviewed.
No change
clarify for those not on automated exchange transfusion program
See comments for suggested addition
219
15 Why no specific recommendations for blood-borne pathogen surveillance?
Invited
No change
220
Invited
Our strong recommendation is to perform these

tests.
No change
220
5 Is there really outcomes study to study that suggest pateints do better using MRI results as compared to ferritin. In my
expereince both are usally abnormal and you titrate your therapy as needed. This was given strong rec with mod quality
of evidence, but I am unaware that studies really show improvment in iron overload using MRI ( but I am y not be up-to10 date)
Need to define iron overload and guidelines for when to start

chelating.
Public

This is outside of the scope of the project.
No change
220
10 The mention of Iron chelation treatment is vague.
This should be specified in terms of currently available treatments,

and what the evidence base is for them.
Public

No change
220
10 Why no specific recommendations for chelation?
Invited

No change
Page #
221
Line #
Comments
3 STRONGLY suggest that this research opportuinity be pursued especially with reference to the need for transfusion for
low risk procedures (lines, ear tubes, hernias and imaging).
Suggestions
Type
Public
Discussion
This section is being revised
No change
Page # Line #
Comments
81
14 I'm not sure "prompt" imperic therapy requires gm neg coverage;
Suggestions
Type
I would emphasize providing urgent treatment to kill Public
pneumococcus
Discussion
Simplify these recommendations with a statement about
Editor: Changed to: 2. Promptly administer ongoing empiric parenteral antibiotics
how they address the initial stages of fever. Wording for the that provide coverage against Streptococcus pneumoniae and gram-negative
background to be submitted.
enteric organisms. Subsequent outpatient management using an oral antibiotic
is feasible in people who do not appear ill. (ConsensusPanel Expertise) 12-1212 Done
92
0 Worsening Anemia - Background: On the first black book published by NIH, we had
a table showing hematologic features of the different types of SCD. I modified it and I
will be happy to send it to the expert panel for their review. I feel that it would be a
good addition to the guidelines .
Public
Helpful to have ranges of values by SCD genotype to give Editor: Background Revised per panel. Added: Baseline values are typically 7
sense of baseline. Keep simple hemoglobin concentration 10 gm/dL for people with SCA, 912 gm/dL for people with HbSC, and 1013
for 4 main genotypes. Add that these are the most common gm/dL for people with HbS+-thalassemia. Done.
genotypes. Sentences will be drafted and they will be
passed by panel.
92
2 What is a "sickle cell expert"? What certification or credentials does this expert have?
Invited-Non
Disclosed
SCD experts can vary in expertise and training. Term is

No change needed here.
used throughout the document but not defined Cochairs will
review introduction of entire document and consider adding
clarification. Will not change here.
92
9 Choice of the term "Worsening Anemia" suggests a time dependent process requiring
multiple measurements. This is a new term and does not adequately describe the
often precipitousand life-threatening drop in Hb level detected in a single Hb
measurement. The term "Acute Anemia" was coined by the CSSCD and the term
"Acute exacerbation of anemia" was used in the definitions of SCD phenotypes
(Ballas et al, 2009) by the Comprehensive SC Centers - both programs funded by
NHLBI. "Acute" is the keyword as suggested by the recommendations.
Invited
Change the term to acute anemia. Look through

background and get rid of other terms used. When the
word worsening is used to describe anemia change it to
acute. Eliminating last two sentences.
93
3 The panel comments on having a high reticulocyte count during a delayed hemolytic
trahsfusion reaction. Usually a delayed hemolytic transfusion reaction is associated
with low reticulocyte count.
Invited
Good - thank you. Line 3 will change. Count will not always Delete the parenthetical statement per panel -AH. Editor: Done.
be elevated.
94
1 some redundancy with para above
Invited
Agreed. Editing of intro section needed
Editor: Paragraph about acute aplastic crisis was moved up and revised to read:
An aplastic episode or crisis is a common feature of SCD, especially in children
with HbSS (Smith-Whitley et al. 2004; Serjeant et al. 1981). The usual clinical
picture is gradual onset of fatigue, shortness of breath, and sometimes syncope.
Fever is quite common as well. Physical examination may reveal lethargy, rapid
heart rate, and occasionally frank heart failure. The hemoglobin value (typically
36 g/dL) is usually far below the persons baseline level, and the reticulocyte
count is reduced or even zero. Done
94
1 Consider moving this pargraph to the beginning of the section
Invited
Agreed. See above. Move to beginning and edit.
Done. See comment immediately above.
94
2 patients usually well-compensated
gradual onset of fatigue
Public
Agreed. panel will edit
Editor: per panel, changed to: The usual clinical picture is gradual onset of
fatigue, shortness of breath, and sometimes syncope. Done
94
often with normal or slightly increased heart rate
Public
Editor: Per panel: changed to: Physical examination may reveal lethargy, rapid
heart rate, and occasionally frank heart failure. Done
94
and rarely high-output congestive heart failure
Public
Done. See above.
Done. Section title changed to "Acute Anemia." "Worsening" deleted and

replaced with "acute" in rest of this section and the entire guidelines document.
Page # Line #
Comments
94
14 I think Steinberg showed G6PD has no impact on hemolysis
Suggestions
Type
A modest drop in Hb is frequently seen in acute pain Public
and chest episodes
Discussion
Agreed. Delete sentence starting with word concomitant
and ending in circumstances. Line 14-15, page 94. other
causes are (List them). Incorporated into other sentences.
Editor: Sentence deleted. DONE
Consider recommending a daily CBC and

reticulocyte count in individuals with severe pain
episodes, fever, or other complications.
Agreed. "Repeat daily in all hospitalized patients,"
Done. Repeat daily in all hospitalized patients added.
suggest parameters that may suggest symptomatic, Public

such as based on vital signs, such as resp rate,
tachycardia, or evidence of ischemia - lactate, ecg
changes chest pain
Panel will edit. Need to define symptoms of anemia and

those related to it.
Editor: P. 92, line 17: Added definition of acute anemia to Background section as
follows: Acute anemia, ordefined as a decline by 2.0 g/dL or more in hemoglobin
concentration below the patients baseline value, is often sudden and can have
diverse causes. Done.
95
6 Inadequate recommendation there needs to be some statement about the need to

follow these repeatedly
Public
95
13 symptomatic is not well defined and 2gm/dl below baseline seems very arbitary. If
their Hb is normally 9, then 7 is not necessary a suitable threshold for transfusion.
Conversely if normally 6, then 4 may be too low. Inappropriate transfusion is a huge
problem in community hospitals and these guidelines do not adequate mitigate this
risk, and could potentially worsen it through lack of firm guidance on this issue.
95
13 Rec#3 overlaps with Rec#5. Consider combining transfusion guidance in one

recommendation
Invited
Panel will edit. Need to define symptoms of anemia and

related to it.
Editor: Recs. 3-5 revised as follows: 3. Use simple transfusion in people with
SCD and acute anemia whose symptoms are due to anemia. (Consensus
Panel Expertise)
4. Perform a CBC and reticulocyte count promptly and again 7 to 10 days later in
siblings and others with SCD who are exposed to a person with an aplastic
episode. (ConsensusPanel Expertise)
5. Manage aplastic events with immediate red blood cell transfusion aimed at
restoring the hemoglobin to a safe (not necessarily baseline) value. Isolation of
hospitalized patients (droplet precautions) is required to prevent spread of the
parvovirus B19 to pregnant women and others with SCD or compromised
immunity. (ConsensusPanel Expertise). Done
95
14 I believe this may be a typo and <2 g/dL should read >2 g/dL
Public
panel will edit
Editor: This part of recommendation was deleted. Resolved.
95
14 THIS IS WRONG. You mean > or GREATER THAN 2 grams below baseline
Public
Panel will edit
See comment directly above. Resolved.
95
14 MAJOR CONCERN that stating a hemoglobin more than 2 grams below baseline
requires transfusion. IN SC this could mean that a child with a hemoglobin of 9.5 is
transfused not because of oxygen carrying capacity or problem but because they are
below their baseline of 11.5. Consider suggesting that the fall from baseline is ONLY
one part; concomitant oxygen requirements, falling reticulocyte count etc should also
be evaluated.
Public
Panel will edit
This is resolved. See comments above.
95
18 Regarding isolation for parvovirus infection, it should be mentioned that pregnant

women should not be exposed.
Invited
Recommendation # 5 will be revised
Editor: Rec. 5 revised to: Isolation of hospitalized patients (droplet precautions)

is required to prevent spread of the parvovirus B19 to pregnant women and
others with SCD or compromised immunity. (ConsensusPanel Expertise) Done
95
18 It is not clear why (slow) is listed without mention reason for slow transfusion and
what qualifies for slow. In a patient with Hb of 1.5 or 2 this recommendation maybe
misleading.
Invited
Eliminated the word slow. Panel will revise entire page
Editor: Rec. 5 revised to: 5. Manage aplastic events with immediate red blood
cell transfusion aimed at restoring the hemoglobin to a safe (not necessarily
baseline) value. Done
95
19 Retain only recommendation about isolation as #5
Invited
Same as above comment - this recommendation will be

modified.
Done. See comment above.
Page # Line #
Comments
96
5 Modify the sentence to read----because both the red cells and the platelets are
trapped in the spleen.
96
6 Toddlers not a precise term
97
2 modify the sentence to read as the sequestered erythrocytes.
97
97
Suggestions
Type
Invited
Discussion
" Both red cells and" at the end of line 6.
Done
Public
Invited
Define: between ages 1 and 4

Agreed. Change sickled to sequestered in line 2
Done
Done
Public
Public
Agreed. Change older people to patients

Already edited, including line 10. Reference would follow.
Disagree that risk of death is increased. May be different
with children. Panel will edit entire section and send
Done.
Editor: Revised to: Most people with chronic splenic sequestration accompanied
by local pain and hypersplenism are also managed with splenectomy.
Splenectomy for splenic sequestration does not further increase the risk of death
or bacteremia (Wright et al. 1999) since most patients are already functionally
asplenic. Done.
Public
Panel will edit.
Done. See comment immediately above.
Invited
Panel will edit
Done.
replace with "have not been proven to be beneficial
Public
Panel will edit. Not proven to be beneficial
Editor: Changed to: Regularly scheduled transfusions aimed at

avoiding the need for subsequent splenectomy have not been proven
to be beneficial. Done
..in children transfused for stroke prevention.
Public
add "in children with prior stroke"
Done.
Public
change the word equal to equivalent. But no other changes. Done.
Invited
change the word people to adults in line 19. Reference will Sentence deleted. Mallouh & Hamdan 1989 reference deleted. Done
be checked
Public
previously changed. Change the word people to the word

adults
Agreed. Will be included in revision
State intended age range
5 older people?
9 Throughout the document the authors need to be careful about declaritive statements
based on studies with large potential for B error. Thus, and for example, on page 97
"Splenectomy for splenic sequestration does not increase the risk of death or
bacteremia (Wright 1999)" seems highly improbable. The study was likley
underpowered to identify even large increases in clinically relevant outcomes. Why
would splenectomy for this indication be not associated with sepsis and yet is for othe
indications for splenectomy. There are numerous similar examples throughout the
text.
97
10 This statement is misleading and not supported by the other literature regarding risk
of overwhelming infection in patients with splenectomy.
97
10 consider adding "bc pts with SCD are already functionally asplenic"
97
12 "have not usually proven to be successful" is awkward
Delete the sentence or include a more complete

review of the relevant literature on overwhelming
infection post removal of the spleen.
98
5 mention reason for Tx
98
9 The reference cited documented occurrence of splenic sequestration in pts on chronic Clarify wording and conclusions.
transfusions. The goal of temporary transfusions is to prevent severe or fatal
sequestration until splenectomy can be performed. A transfused pt with Hb 10 drops
to 7.5 with enlarging spleen is better off than a pt with Hb 5.5 who has recurrence and
drops to 3. So this conclusion misses the point.
98
18 The endorsement of HU to restore function was disproven in BABY HUG. Consider

expanding HU references or eliminate altogether
98
18 HU effects on spleen function are overstated with minimal supportive data.
Delete sentence.
99
0 The ACS background is poor. There is National ACS study was not mentioned.
Invited
99
0 This section on ACS does not differentiate between ACS and simple pneumonia in
this population. If this is your intention, I suggest adding one or two sentences to this
effect for clarification.
Public
99
1 On p96-line21, the acuity of splenic sequestration in infants and the potential for
hypovolemic shock are mentioned however, fluid management is not included in the
recommendations. It may take hours in most settings to initiate blood transfusion; fluid
recuscitation may be the first life-saving intervention.
Invited
99
2 Why transfuse to increase Hgb by 2-3 versus to a stable level. I get not bringing to
baseline but if they present with Hgb of 3, do you bring up only to 6?
Resolved. See comment above.
Done. ACS background section was extensively revised.
Have goal of transfusion be to bring to a stable level. Public
New recommendation will be drafted. Will send to panel and

AIR before next call.
New wording will be submitted for this.
Panel will provide rewording for this.
Beyond scope. Differentiation of ACS and "simple pneumonia" not

possible.
Editor: Done. Per Dr. Buchanan's edits, added new recommendation
#1: 1. In people with hypovolemia due to severe acute splenic
sequestration, immediately provide IV fluid resuscitation. (Strong
Recommendation, Low-Quality Evidence)
Done. Revised to: 2. Transfuse people who have acute splenic

sequestration and severe anemia to raise the hemoglobin to a stable
level, while avoiding over-transfusion. (Weak Recommendation, Low
Quality Evidence)
Page # Line #
Comments
99
2 The issue is the hemoglobin that defines severe anemia, not necessarily the amount
of transfusion to be given although the discussion of do not overtransfuse is a good
one.
99
Suggestions
3 The recommendation to transfuse people with "severe anemia" is not very clear. The
recommendations on page 95 were to transfuse if symptoms and drop greater than 2
in Hgb. Can you make this recommendation fit with that one?
Type
Public
Discussion
Rewording will be provided for this.
Revised. See comment immediately above. Done
Invited
Rewording will be provided for this.
Revised. See comments above. Done
99
14 Clarify definition of ACS. Onset is not always sudden. Do you really want to require Have a less specific definition for ACS.
signs and symptons and infiltrate? Need acknowledgement of the various definitions
used in the literature.
Public
Text wiil be revised for this comment.
Insidious onset has been acknowledged and other changes in verbiage

have added clarity to the definition. Done.
99
14 concern here that it is not mentioned that the onset of ACS can be insidious, and the the subtley of presentation and expectant
S/S can be very subtle in a patient. The medical professional needs to be aware that investigation/management needs to be mentioned
a patient with ACS can look fairly good, and have only a mildly increased RR or mild
cough, and be very ill the next day with ACS; the CXR changes may also lag, so that
the initial CXR is normal.
Public
Text will be revised for this comment.
Same as above. Done
99
15 Chest retractions are only seen in children. Need to emphasize the importance of
hypoxemia as a physical sign.
16 In Vichinsky EP NEJM 2000, the largest study of ACS to date, the etiology of ACS
was unknown in 45.7%. This needs to be clarified in the text as ACS is often not
infectious, particularly in adults.
Public
Agreed. Changes will be made to this section.
Same as above. Subtle presentation is mentioned. Done.
Public
Wordsmithing was done. Refer to Vichinsky table. Entire

section will be revised to include Vichinsky.
Changes made as indicated above. Done
16 The Cooperative Study identified Chlamydia as the most common infectious agent
actually.
4 Would refer to table 3 of Vichinsky EP NEJM 2000 where predictors of a more severe
course included multi-lobar disease, the presence of a pleural effusion and
thrombocytosis.
Public
Acknowleged - this is being wordsmithed.
change made. Done
Public
Wordsmithing was done. Refer to Vichinsky table. Entire

section will be revised to include Vichinsky.
Change made. Done
Public
We agree with the comment. Will be included in a revision.
Invited
Panel will send a reference for sPLA2
99
99
100
100
5 the correct term for this is persistent hypoxemia
100
11 Add reference for sPLA2. Some mention of C-reactive protein as a surrogate marker
may be useful since it is more readily available than sPLA2
101
14 We note that there is no discussion of the risk of anesthesia in children with SCD,
who may have a greater than usual incidence of post operative hypoxemia and
atelectasis, and who are at increased risk of VOC and ACS following surgery.
We recommend a brief discussion of the appropriate Public

pre-operative safeguards for elective surgical
procedures in SCD patients, including pre-operative
transfusion guidelines. In addition, a brief mention of
the potential complications noted above would serve
as a useful guideline for post operative monitoring in
children with SCD.
Out of scope. Section deleted.

Disagree with comment. SPLA2 no longer widely regarded as a unique
marker.
Panel will draft some language to address this. For the ACS Out of scope. This is dealt with in Transfusion chapter.
background.
Page # Line #
Comments
105
6 Paragraph discussing secondary stroke prevention does not cite results of SWiTCH
trial, now reported.
Suggestions
incorparate additional reference.
Type
Public
Discussion
Submitting a revision to this.
Revision received 2/4/13: On p. 105, paragraph 1, add the following at the end
of the paragraph: These preliminary single-institution findings were then tested in
the prospective Stroke With Transfusions Changing to Hydroxyurea (SWiTCH)
multicenter phase 3 clinical trial. Children with previous stroke and iron overload
were randomized to receive either continued transfusions with iron chelation
(standard arm) or hydroxyurea with phlebotomy (alternative arm). The SWiTCH
trial had a noninferiority design, with a composite primary end point consisting of
recurrent stroke and liver iron concentration (Ware et al. 2011). At interim data
analysis, there were seven strokes on the standard arm (10 percent) and none
on the alternative arm; this was still within the noninferiority stroke margin, but
equivalent liver iron content between treatment arms, indicating futility for the
composite study end point. Accordingly, the study was closed, and the authors
concluded that transfusions and chelation remain a better way to manage
children with SCA, stroke, and iron overload (Ware and Helms 2012). Also add
2 new references: Ware RE, Schultz WH, Yovetich N, Mortier NA, Alvarez O,
Hilliard L, Iyer RV, Miller ST, Rogers ZR, Scott JP, Waclawiw M, Helms RW.
Stroke With Transfusions Changing to Hydroxyurea (SWiTCH): a phase III
randomized clinical trial for treatment of children with sickle cell anemia, stroke,
and iron overload. Pediatr Blood Cancer. 2011 Dec 1;57(6):1011-7. AND Ware
RE, Helms RW; SWiTCH Investigators. Stroke With Transfusions Changing to
Hydroxyurea (SWiTCH). Blood. 2012 Apr 26;119(17):3925-32.
105
19 Do all patients with rule out stroke really require CT if MRI is emergently available?
NO. ALSO what is the role of MRA. You do not mention. Since this document will be
used by payors to determine what is reasonable to pay for, this is one place that you
must indicate the need for MRI/MRA to evaluate thrombotic stroke especially in
children.
Public
The panel discussed these comments extensively and will

work on a revision on the second half of the rec that deals
with these comments
Minor change made in recommendation (should be discussed by entire

panel). Done.
107
10 An explanation of how to evaluate for multi-organ system failure is in order,

particularly how one would assess for respiratory failure. The proper way to do this in
clinical practice is via a history/physical exam, CXR and an ABG. This is not
mentioned anywhere in this section.
Public
Updating text. Same as page 99, line 14. This is for 106,
line 20, not page 107.
Beyond scope. No need to define "how one would assess organ

failure."
71
10 A VOC by definition requires parenteral medical therapy? Since 80% of pain episodes
are managed at home in the US, in effect, your definition considers only 20% of pain
episodes qualify as VOC. In much of the world people with SCD in severe pain never
receive "parenteral medical therapy."
Invited
On line 10, page 71 change wording to "and bone marrow Done 12-11-12
and usually requiring parenteral medical therapy." Consider
adding to chronic chapter.
71
10 Delete "and requiring parenteral therapy". Many patients with VOC may not even get
oral analgesic therapy.
Invited
On line 10, page 71 change wording to "and bone marrow

and usually requiring parenteral medical therapy."
Done 12-11-12. Same as comment above
72
2 "worsening anemia" is an indefinite terminology; are you not referring to acute

anemia, a term used in the CSSCD to describe a significant drop on Hb (> 20% drop
in previous steady state level). "Worsening" implies a dynamic process over time,
rather the acute state and applies to any progressive drop in Hb level whether from
12 to 11.5 or 7 to 3.5 g. dL
Invited
Change the wording to acutely worsened anemia or

something very similar. Better clarification of intent.
Done 12-11-12. 1/28/13: Revised to "acute anemia" per instruction below to

delete the word "worsening" before "anemia" and replace it with "acute"
throughout.
Page # Line #
Comments
72
4 add to relieve pain before mention of mortality.
72
5 Remove "are not life threatening".
73
6 "usually"? VOC is defined above as acute severe pain
Suggestions
call them APE's
Type
Invited
Discussion
To address comment, add the word morbidity to read
"treatment to reduce morbidity and mortality"
Done 12-11-12
Invited
Make this change as recommended
Done 12-11-12
Public
delete the word usually (that modifies the word manifests)

and keep the rest of the sentence the same
Done 12-11-12
73
17 The sentence THERE ARE NO TEST TO RULE IN A VOC needs to be emphasized

more strongly.
Public
Instead of "there are no tests to rule ina VOC" as it is

currently written, change to "there are no tests to rule in or
to rule out a VOC."
Done 12 -11-12
73
Invited
same change as made in line 17 previously: see directly

above
See next box for changes to line 19, page 73
Same as above
73
17 Change the sentence to read--there are no tests to confirm or rule in the diagnosis of
VOC.
19 however, there is great variation and some individuals with other genotypic forms
such as HbSC can have frequent crises as well. (comment: Hb SO Arab has the most
severe biological and clinical form of disease).
73
19 Often, primary care physicians think SC and SB+ thalassemia are benign
Public
Change line 18-19 to read "Persons with the genotypes

HbSS or ... are likely to experience more frequent VOCs.
Done 12-13-12
73
20 It should be stressed that some patients with SC and SB+Thal

have a disease as severe as SS.
Public
same as box directly above
same as box above
73
21 The expert panel needs to clarify their statement about AS.
Public
Change the beginning of line 21 to read "not experience

typical VOCs." (Instead of typically experience. )
Done 12-11-12
76
18 Reassessing pain at presentation needs to be every more often than q 30 minutes.

Would say "at least every 30 min"
1 I think people reading this guideline will want it to contain this "SCD-specific protocol"
referenced here
Invited
Change to "at least every 30 minutes"
Done 12-11-12
Invited
We do not believe there is a single protocol that would apply Done 12-11-12
to all patients in all settings. There are a lot of comments
about this issue. This is an implementation tool that could be
deferred to the NBDP. Add the following: Substitute
"use" with "develop and use" in the recommendation
Public
CHANGE TO: Discontinue use of oral short-acting opiods.

Add word, "oral".
Done 12-11-12
Invited
Spell it out - subcutaneous and intravenous - both
Done 12-11-12
Public
Line 10 rec #6, add a second sentence: In children with

Edits made 12-11-12; Update: Revised 1/17/13 per panel's revised
SCD and a VOC associated with severe pain and replace
Recommendations list for the VOC section. Done
subcutaneous routes use intranasal or subcutaneous opiods
when intravenous access is difficult. Delete parenteral.
"Administer intranasal opiods when intravenous" In
children with SCD and VOC.
77
77
6 This suggests not taking both long and short acting. Reads as never give long and
short. Or is this stopping short acting orals and adding parenteral? Regardless it
must be clarified.
77
7 Avoid "SC" for subcutaneous, since this is considered a "forbidden" abbreviation
78
11 I like the qualification "when IV access difficult"
Invited
Add a discussion on how to transition between long

and short acting or orals and IVs
see next box
Page # Line #
Comments
79
0 In Exhibit 5 (Acute Pain Algorithm) should "Triage as high priority" include a specific
recommendation for ESI level?
79
2 Last box8/13/2012 Avoid "SC" for subcutaneous, since this is considered a
"forbidden" abbreviation
79
2 Figure central diamond states APLASTIC ANEMIA when I believe aplastic crisis is
meant.
80
2 Splenic impairment may occur by age 3 months in infants with HbSS, but usually is
later
80
Suggestions
7 Change the sentence to read---Even though the incidence of sepsis and meningitis
has declined .. (the sentence at this time implies the incidence of febrile illnesses
has declined).
Type
Invited
Discussion
After "high priority" add in parens (ESI 2) in the box.
Done 2/13/13
Invited
Spell it out please
Done 2/13/13
Public
This is correct and should be changed as indicated.
Done 2/13/13
IND
This is line 5: add"with SCA begin to develop splenic

impairement"
Done 12-11-12
Invited
Although the incidence of invasive pneumo infection has

declined as a result ofpeople with SCD are still
considered
Done 12-13-12
80
10 Change the sentence to read --Serious infections can also affect persons with
Invited
Line 10: add "Serious infections can also affect persons

with other forms"
Done 12-12-12
80
80
81
14 How about patients with HbSbeta thal0?

19 Capitalize M in Mycoplasma
10 In the US most institutions still use F thermometers. Hence, sticking with 101.5 F is
more appropriate since it is consistent with all other recommendations.
Invited
Invited
Invited
Change HbSS to SCA

Not sure - check with editor
Panel will use 101.3F and 38.5 C
Done 12-12-12
Yes. Done. 12-12-12
Switched order so that 101.3 F occurs first and 38.5 C is in parens. Done. 12-1212
81
11 Urine culture is not included.
after blood culture, add"and urine culture, when clinically

indicated."
Done 12-12-12
81
11 Would recommend adding differential to the CBC and a reticulocyte count to the
evaluation-also urinalysis/urine cx in younger children and CXR in children, especailly
if they will not be admitted based on studies finding ACS in children with respiratory
findings initially
Invited-Non
Disclosed
Yes, change to, "CBC with differential, reticulocyte count,

blood culture, and urine culture when clinically indicated"
Done 12-12-12
81
81
13 Suggest adding EMPIRIC before intravenous antibiotics.

13 Would replace "intravenous antibiotic" with parenteral antibiotic (as IM administration
is sometimes necessary if vascular access is diffuclt to obtain,especailly in PMD office
Public
Invited-Non
Disclosed
Agreed. Not in all caps - add empiric

Yes, change to "empiric parenteral antibiotic" to go along
with previous change to add "empiric"
Done 12-12-12
Done 12-12-12
81
17 Suggest adding ONGOING before intravenous antibiotic therapy.
Public
Team agrees. Make this change
Done 12-12-12
Add urine culture because it is a common source of Public

infection/fever that may be asymptomatic.
82
0 The section Acute Kidney Injury (pgs 82-84) does not distinguish papillary necrosis Distinquish betweeen papillary necrosis and acute
from acute renal insufficiency (defined by decrease in GFR). The distinction between renal insufficiency and include guidelies for both
these 2 acute complications is important, and guidelines as to how to manage
complications.
papillary necrosis are needed.
Public
Re-name this section to Acute Renal Failure. Definitions are DONE 12-13-12 added comment to Word file requesting missing
needed up front. AKI needs to be replaced with Acute Renal definition
Failure (or ARF) in all cases.
82
9 change to read (e.g. renal papillary necrosis)--delete glomerular from within the
parenthesis since papillary necrosis does not involve glomeruli and sickle cell
nephropathy is generally not acute.
Invited
End after (e.g. glomerular injury).
Done 12-12-12
Invited
"in the vasa recta" instead of "to the vasa recta"
Done 12-12-12
Done 12-12-12
82
12 "obstruction of the blood supply to the vasa recta" suggestes that the occlusion
occurs pre-vasa recta and not in the vasa racta themselves. Not sure whether that is
accurate statement
82
18 In a discussion of acute kidney injury (AKI), the text does not mention the vulnerability Consider adding: "Children with SCD often display a Public
of patients with SCD to develop pre-renal AKI due to sub-optimal ability to develop a relative inability to maximally concentrate the urine,
maximally concentrated urine.
resulting in increased vulnerability to pre-renal
azotemia".
Change to statement provided, but change Children to

People. Insert after dehydrated
82
21 Change the sentence to read since the serum creatinine levels are generally low in
individuals with SCD, the values in AKI in SCD may still be within normal limits even if
they have doubled from baseline.
Line 21: Change to read, "Since the serum creatinine levels Done 12-12-12
are generally low or low-normal in individuals with SCD, the
values in ARF may still be within normal limits even if they
have doubled from baseline.
Invited
Page # Line #
Comments
83
14 Delete acute before renal---the complications listed in the parenthesis include both
acute and chronic renal problems.
84
0 Acute Kidney Injury: Recommendations - I feel this chapter needs to be more
organized. Different kidney injuries In SCD are mentioned and this will be confusing
for a primary care and even a hematologist. An immediate renal consult is necessary.
Chapter on chronic renal failure should follow.
84
11 Modify the sentence to read ---unless there are complications involving other organs
that necessitate transfusion therapy (such as ACS or multiple organ failure). This
sections should also have a recommendation for seeking consultation with a SCD
expert and Nephrologist.
87
89
4 If using "do not perform", define "routine".

13 always see urobilinogen
89
13 modify sentence to read-----thrombocytopenia and coagulation abnormalities may

also be present.
17 it is very concerning that surgical consultation is suggested here, without pointing out
that the risk of taking a person with sickle cell disease to the OR when they have
inection is very high, and that the acute gallbladder episode should be medically
resolved and the gallbladder removed at a later date when the patients is very stable.
91
93
95
Suggestions
delete?
6 Change section title: Aplastic Episode (Erythroblastopenia)
Type
Invited
Discussion
Agreed
Done 12-12-12
Public
Page 84 , line 10 add ", in consultation with a nephrologist

as needed." at end of statement.
Done 12-12-12
Invited
Change to: "Do not give blood transfusions to treat ARF

unless there are other indications for transfusion." Delete
examples.
Done 12-12-12
Public
Public
Change "routine" to "immediate"

"usually" before "without" on line 14. Change "may be"
Done 12-12-12
Done 12-13-12
Invited
Yes, make this change
Done 12-12-12
Public
Agree with that - but usually the surgeon makes that

Done. Copied same rec from page 87, line 6-7 into this section.
decision. ADD NEW RECOMMENDATION. Consult a
hemotologist for surgicalrecommendation from. Page 87,
line 6 and 7 rec #3. Make this the new #3, same level of
evidence.
Invited
Agreed. Change title but do not add the word

erythroblastopenia in parens
change the word crisis to episode as previously discussed.
Done. Changed "crisis" to "episode." . 12-12-12
11 Include statement that lack of reticulocytosis with worsening anemia favors aplastic
episode as the cause
6 this statement may be misleading because it seems to suggest that the spleen should remind the reader of the basic principles re:
immediately be removed after one transfusion given to reach Hb or 8. The child
preparation for surgery in patients with sickle cell
should be allowed to get over the acute illness and stabilze, which may require
disease, especially infants and small children.
several transfusions (short-term), appropriately speced.
Invited
Public
Panel agrees with this. This recommendation needs to be

deleted.
Done. Rec deleted 12-12-12.
100
11 The link between ACS and chronic pulmonary disease has become less clear since
1995. Would suggest familiarizing yourselves with some of the literature on this
subject published in the 21st century.
Public
change "may lead to" to "may contribute to"
Done 12-12-12
103
10
Public
Deleted both commas. Done 12-12-12
104
106
22 TYPO author is SCOTHORN no scothron.

1 This is different than prior and many recommendations that transfusion should not be Stick with emergent CT to r/o a bleed, but then
dleayed to obtain MRI/MRA confirmation of a clinical diagnosed stroke. Also, some MRI/MRA when availible but not if it delays
strokes in SCD are not seen initially on MRI.
exchange!
Public
Public
Editor please check. Looks like this needs to be there, but

wanted you to see.
Thank you. Please correct.
Add to line #1 "Perform simple or exchange transfusion"
INSERT COMMENT THAT THIS REQUIRES PANEL
REVIEW.
Invited
Strike "rapidly reversable" replace with "a recent history of"
Done 12-12-12
Public
STRIKE RECOMMENDATION #4 ENTIRELY FROM THE

LIST. On page 113, line 14, insert "thrombolytic therapy"
before aspirin. INSERT COMMENT THAT PANEL NEEDS
TO REVIEW/DISCUSS.
Done 12-12-12
99
106
3 "Rapidly reversible" implies clinical course under prospective observation; suggest

inserting "recent history" into the sentence. People with "recent history" of signs and
symptoms of stroke should be evaluated also as symptoms have disappeared by the
time some patients have reached the health care facility.
106
6 Are there anectodal data for avoiding lytics/anticoagulants in ischemic stroke-especially in adults?
remove comma
Please state rationale for reader.
Done 12-12-12
Done 12-12-12
made change and added comment about needing panel review. DONE
12-12-12
Page # Line #
Comments
106
8 I dont see a discussion of the panel's rationale for not using tpa in adults with scd
and acute stroke. I agree there is no reason to use anticoagulation
Suggestions
Type
Include some discussion of pro and con for tpa,
Public
given the lack of evidence I dont support this strong
a recommendation to avoid tpa. Also this section
should mention PRES which is often confused with
ischemic stroke.
Discussion
Rec #5 - "...stroke, initiate a program of monthly simple or
exchange transfusions."
Done 12-12-12
106
106
10 This is really a push from the data and should be omitted.

10 Could this statement be confusing since HU has not been shown to prevent strokes,
should it be removed from the discussion?, with emphasis on transfusions so cost
could be evaluated if office is in a very rural area.
Public
Invited
Delete recommendation #6.

Change Rec #6: In children and adults who have had a
stroke, if it is not possible to implement a transfusion
program, initiate HU therapy." (Keep rec level/grade)
Done 12-12-12
Done. Note: Added comment to file to confirm that change was made
correctly.
106
19 Acute respiratory failure is the correct term here.
Public
Yes, make this change to replace pulmonary failure
Done 12-12-12
107
107
10 Suggest add SEVERE before VOC.

12 Respiratory failure is the correct term. When a patient has respiratory failure it
implies ventilatory failure which implies that the patient will not survive regardless of
how much supplemental oxygen they receive. The patient needs to either be on
mechanical ventilation or non-invasive ventilation to improve gas exchange. This
needs to be re-written as it is clinically dangerous in its current form.
Public
Public
Replace sudden with severe in this line.

Done
Agreed. Please change "lung failure" to "respiratory failure" Done 12-12-12
107
14 Is it really necessary to recommend dialysis for renal failure?
Public
Change to: "Use renal replacement therapy, (e.g.

Done 12-12-12
hemodialysis) when needed for acute renal failure". AND on
Page 84, line 14 also make same change. Consensus-Panel
Expertise
108
14
OK, this is an acceptable change.
108
After "SCD," add "and even in healthy individuals

Public
with sickle cell trait"
14 Acute and chronic eye conditions do not address if transfusion should ever be
Helpful for providers to know of instances when/if
Public
considered. This is also not discussed in the transfusion (even periop) section. Given transfusion should be considered in eye events to
risk of increase sickling in the eye are there any consensus recommendations on this minimize amount of sickled cells that result in further
issue?
complications in these settings.
111
12 This is a very unclear recommendation.
Public
Change on line 12, Rec 3: Manage acute ocular

complications in consultation with an ophthalmologist,
hemotologist, and other specialists with expertise in SCD.
(Consensus-Panel Expertise) REMOVE lines 13, 14, 15.
Done
111
16 Administer narcotic and NSAID during severe VOC. Inflammation is a continuing

cause of much of the pain experienced during crisis, and long-term. This issue
should be of the highest priority for more RTCs. [Also noted as a 53yo SS patient
and Clinical Lab Scientist.]
Public
On page 112, line 6: after "nonopiods" add "including antiinflamatories"
Done 12-12-12
111
16 I agree with the expert Panel regarding studies for the
Public
Change on page 113, line 3 to "RCTs or comparative

effectiveness studies assessing management of acute
hepatobiliary complications in adults and children with SCD."
DELETE LINES 1-5, THIS SHOULD REPLACE.
113
11 RCT - studies related to CVA in adults should include at what age (if ever) to d/c
chronic transfusions if they began transfusion tx as a child.
IND
Change to "recurrent strokes" from just "strokes"
Done 12-12-12
Done 12-12-12
Public
add the word severe in front of the word AIC
Done 12-12-12
92
7 non severe IHC did well in the St Jude review and in Dallas (children)
These complications should be comanaged by a

hematologist and ophthomologist with expertice in
sickle cell disease and other subspecialists as
needed.
change "'confirmed" to severe
Done 12-12-12
Add a line: Summary of the Evidence section, on page 110, done 12-12-12
line 17 - remove "exchange transfusion" from parens. Add
on line 18 after OCS: There was not enough evidence to
make a recommendation about using transfusion to manage
these acute complications.
Page # Line #
Comments
95
18 Should the phrase "packed red blood cell" be changed to just "red blood cell" since
they are no longer "packed"?
Suggestions
Type
Invited-Non
Disclosed
Discussion
Eliminate the word packed. Panel will also make changes in Done 12-12-12
this section
101
10 There needs to be a greater description of these studies since it is completely unclear

how these recommendations are being developed.
Public
Can methodolgists provide more detailed information about done; see revisions to line 102-6 below
transfusion and the use of antibiotics and other supportive
care from the evidence in the summary?
102
1 This sentence mentions the term---"symptomatic ACS"---I thought all ACS was
symptomatic. This recommendation should be modified to say all patients with ACS
requiring oxygen supplementation (Fio2 >40% or whateve) or those with hypoxia
despite oxygen supplementation without mechanical ventilation. I would personally be
more liberal and recommend transfusino with anybody with decreasing Hb or hypoxia
that does not correct rapidly.
Invited
Ask methodologists for a better synthesis of this topic. Then for panel to decide
take to panel for further review. Look at evidence tables,
look at literature, possibly.
102
3 10cc per kg is simple, but not ideal for patient care, plus it is not clear where this
Have a target, such as baseline and rounding to
comes from. So if this is 1.25 units would you really just give a small fraction of a unit nearest unit without raising hgb too high. Have a
a expose the patient to another donor? If it were 1.75 units, wouldn't you give 2 full
comment about what to do if intial Hgb is high
units as long as the final HCT wasnt too high? I worry that this simple
recommendation will result in exposing patients to additonal donor units, and may
waste some potential benfits with little addioanl risk. Also, what if the intial Hgb is 9.5,
you wouldnt give 10cc/kg, you would exchange.
Public
Ask methodologists for a better synthesis of this topic. Then Transfusion team please review and OK recommendations. Then editor change
comments assigned to methodologists to 'no change.
102
3 the instructions starting here may cause a transfusion to be given that would result in put in the caution re: not to transfuse to Hb higher
a Hb greater than10.5 (if the pt's baseline Hb is 10, and is now 9 and 10 ml/kg is
than 10.5/11
given, the end Hb could be 12, with concern re: increased viscosity
Public
comments assigned to methodologists to 'no change'."
102
3 Simple blood transfusion if hemoglobin is >1 g below baseline may be dangerous.

With the oscillation in hemoglobin that are common with hydration, many patients will
be overtransfused. Further stating that the SC with a baseline hemoglobin of 11
needs transfusion at 10 is not correct. Consider suggesting if hemoglobin is >1-2 g/dl
below baseline or below 6 etc.
Public
comments assigned to methodologists to 'no change'.
102
3 Should the phrase "packed red blood cell" be changed to just "red blood cell" since
they are no longer "packed"?
Invited-Non
Disclosed
Ask methodologists for a better synthesis of this topic. Then Editor: Per panel, deleted "packed."
102
3 Partial exchange transfusion is a viable option here that may prevent increases in
viscosity that are detrimental
Change "Give simple blood transfusion" to "Give

simple blood transfusion or partial exchange"
Public
102
3 no more packed cells (Adsol)-can give more. Worsening resp status is more
important indication than a 1 gm drop in Hb.
4. Give simple blood transfusion (10-15 ml/kg red

Public
blood cells) to people with clinically severe/worsening
ACS and a hemoglobin concentration less than 9;
those less anemic will require a partial exchange
transfusion to reduce risk of over-transfusion and
hyperviscosity.
Page # Line #
Comments
Suggestions
102
3 "Give simple blood transfusion .. with symptomatic ACS and a Hgb concentration
Base recommendation for simple blood transfusion
>1gm/dl below baseline."
on maximum and minimum Hb targets rather than
Simple blood transfusion may be dangerous (hyperviscosity) in SC or S B thal with Hb specific Hgb drop.
over 10-11. The threshold for transfusion may vary among patients, and might be
Consider separate recommendations for adults and
inappropriate for some (e.g., SC patient with baseline Hgb of 11). The decison to
children.
transfuse and whether to use simple or exchange depends BBOTH od severity and
rate of progression of ACS as well as the hemoglobin at time transfusion ordered.
Further, some management decisions may be different for children and adults.
Type
Public
Discussion
102
add "or with rapid progression of symptoms" to end

of sentence
Public
102
6 Where is data for urgent exchange? With what O2 support? Does this imply
intubation or nasel prongs. Where is data for exchange versus direct?
Be more specific about degree of support and

discuss direct vs exchange.
Public
Ask methodologists for a better synthesis of this topic. Then add to page 101, line 13: Studies that evaluated antibiotics did not demonstrate
a significant effect on patient important outcomes. Multiple observational studies
evaluated opiates in ACS. In one, nalbuphine hydrochloride reduced the
incidence of ACS compared to morphine (12% vs 29%) and also reduced
hospital stay (buchanan). In the remaining studies opiates clearly reduced pain
but without other effects on the clinical course of ACS. Transfusion studies in
ACS showed conflicting results. In one study, length of hospital was similar
between simple transfusion and exchange transfusion. ICU stay was longer in
the exchange group, (5.6 days vs 2.6 days). (King) Another study found
significant correlation between exchange transfusion and fewer days of
hospitalization and oxygen requirement. (Liem). In these and other transfusion
studies, sicker patients were more likely to receive exchange transfusion; which
indicates a clear selection bias. Editor: Done 3/7/13. Also added refs: King et al.
1996, Liem et al. 2004, and Buchanan et al. 2005. Done.
102
6 lines 8 and 9 could be used as the indication for simple transfusion above. A drop in
Hb certainly is not an indication for exchange
5. Perform exchange transfusion in people with ACS Public

if the clinical condition is deteriorating in spite of
initial therapy, including transfusion.
102
6 Page 102 - exchange transfusion "(with)... decline in hemoglobin concentration" should be quantified or at least a range provided - what if the fall is 0.1 g per
decilitre ? Should a HbS be measured before exchange since it seems to me that
many patients have sufficient transfusions during the "resuciation phase" to cause
their HbS levels to be very low.
Public
102
6 recent systematic review failed to identify any studies comparing methods for
transfusion in ACS. This should not be a recommendation but should instead be
moved to the section on knowledge gaps/needs for research
Invited
Ask methodologists for a better synthesis of this topic. Then up to the panel: they can consider removing this recommendation or
downgrading it. It certainly should be downgraded as reviewer suggested.
Page # Line #
Comments
Suggestions
Type
84
5 In a discussion of acute kidney injury (AKI), the text mentions that a serum creatinine Please consider that in SCD, many patients exhibit Public
level of 0.7 is elevated.
increased secretion of creatinine (and high GFR).
Also, applying a cutoff level for AKI of 0.7 does not
take into account the influence of body habitus on
serum creatinine (lower levels in smaller children).
Suggest changing the definition of AKI to: "An acute
fall in glomerular filtration rate, defined by an
absolute increase in sedrum creatinine of greater
than or equal to 0.3 mg/dl or percentage increase in
serum creatinine of greater than or equal to 50%.
86
20 From the description of the evidence, there did not seem like there was high quality
evidence for any of the recommendations.
IND
Discussion
This needs to be cross-walked with the Chronic section and Changed lines 6 and 7 to read: "1. In the setting of an acute rise in serum
adjustments may be needed.
creatinine by greater than or equal to 0.3 mg/dl:" DONE 2/13/13
Consider lowering the level of the evidence, or further

changing based on AFUD decision.
Change Page 86, line 21 to read:

" - vigorous oral or intravenous hydration and oral or intravenous analgesia,
(Strong Recommendation, HIgh Quality Evidence)"
Change Page 87, line 1 to read:
" - consultation with a urologist who can perform further evaluation
and intervention for symptoms which do not remit with initial
conservative medical management (Consensus - Panel Expertise)
86
20 YOU MUST consult the AFUD (American Foundation for Urologic Disease) that is the
policy making group of the Americal Urologic Association AUA's recommendations for
PRIAPISM IN ANYONE. They clearly have recommended to their members the
experts in the management of priapism that any erection lasting longer than 4 hours
be relieved with intracavernosal injections of dilute phenyephrine. To be less explicit
here is simply WRONG. That this recommendation can also be applied to children is
also published by the Dallas group. AT LEAST mention ASPIRATION AND
IRRIGATION for prolonged priapism!
Public
We need to ask NHLBI about invoking these guidelines at

this phase of the guideline development. Team discussed
crafting consensus recommendations. Possible change.
Panel willing to work on incorporating this into consensus
adapted recommendations.
98
19 Comment on transfusioin seems inconsistent with earlier statements on transfusion in

same section
Invited
revision can't be in this section since it is a summary of the

evidence. Will contact methodologists for clarification
71
7 The term crisis to describe manifestations of SCD for instance is problematic and
has been for some time. It lacks specificity and this colloquialism instead connotes
circumstances that are unpredictable, catastrophic, difficult to control and scientifically
poorly understood. These guidelines should embrace a more progressive approach
to the discussion of SCD that uses more clear and less stigmatizing descriptors,
much in the same way that manifestations of other significant illnesses are described,
starting with a change in nomenclature. Terms such as vaso-occlusive 'event' or
'episode' carry far less "baggage" than crisis.
Invited
Deferred to panel because scope of change would affect

entire document.
71
8 Avoid the term crisis. It is emotional , doesn't represent how many patients are able
to deal with it, and can be demeaning and hard on pateints sense of self (especially
teens)
Public

entire document.
Editor: Comment added to master file.
Editor: Comment added to master file.
Use Vaso-occlusive episode
Page # Line #
Comments
71
8 Prior to this definition, various terms had been used to describe pain episodes in
SCD; you might go back to bring uniformity your pain terminology
Suggestions
I'd call it an acute pain episode rather than VOC
Type
Invited
Discussion
entire document.
Public

entire document.
Suggestion is broad in scope and should be referred to the
panel
Broad change that should be discussed by panel.
71
8 VO may be involved in complications other than pain; never liked "crisis"
73
4 Change title to VASO-OCCLUSIVE PAIN EPISODES
Invited
76
3 1. Should the exclusion of "cold packs" and ice therapy be specifically mentioned?
2. Should specific alternative agents, such as methadone, or adjunct medications
such as muscle relaxants be mentioned?
Public
77
4 Organization of recommendations are very confusing. Overlap between #3, 6 and 7.

Several recommendations under #3 applicable to subsequent recs
Invited
The team agrees that the recs should be re-organized, but

consistency in the document is a consideration. This will be
raised for full panel discussion.
77
9 This is an extremely dangerous recommendation without concurrent discussion about Ask the panel to carefully reconsider this
close monitoring for side-effects and complications and recommendation as to when recommendation.
to get input from an expert in pain management. This recommendation is going out to
the general medical community and one needs to know the patient well and have
significant experience in managing acute pain to avoid getting patients into trouble
with such recommendations without well defined limits.
Public
Defer to panel? Panel will propose a recommendation that

will take out some of the specificity.
78
10 There are other routes available - did the authors consider intranasal opioids?
Invited
This will be brought back to the panel
81
11 Consider a consensus recommendation about Chest Xrays in febrile patients without

respiratory symptoms (hopefully not) and adding urinalysis
Invited
Urinalysis added. There is a rec about chest x-rays already

(#4). The team is not sure about recommending x-rays
without respiratory symptoms.
81
13 It is more typical for children than adults to receive empiric antibiotics while fever is
being evaluated. Is your intention to extend the same practice to adults?
Public
Panel discussion is needed on this topic
81
15 I know there was a study using oral antibiotics after discharge, but why not return in
24 hours for a recheck and another IM dose of antibiotics. Some practitoners have a
24 hour return and if cultures are negative and patient is afebrile, stop antibiotics. I
think the written Panel expertise recommendation needs to be softened to allow for
other treatment regimens that are not necessarily less effective.
Invited
Panel will review this comment
81
18 This article by Morris et al. suggests that obtaining a CXR should be empiric for
Would modify recommendation to include all febrile
febrile patients with SCD and not based on respiratory symptoms. Ann Emerg Med. patients
1999 Jul;34(1):64-9. Clinician assessment for acute chest syndrome in febrile patients
with sickle cell disease: is it accurate enough? Morris C, Vichinsky E, Styles L.
Public
This will be discussed by the panel
81
18 Very young children with ACS may not demonstrate signs of respiratory illness initially.
Evaluation with chest xray for children < 3yr has become routine in fever management
Invited
This will be discussed by the panel
17 You really must include the results of the SWiTCH trial on this issue, published by
WARE et al in early 2012.
Public
This is outside of our systematic review. Refer back to

methodologists. Is there a legitimate way to include just this
update? Add it to the background?
105
please clarify if adults and pediatric patients should

be treated automatically with antibiotics?
Page # Line #
Comments
71
1 Change the statement regarding pathophysiology to read---"Unlike HbA that remains
dissolved and liquid whether or not oxygen is present, HbS has a tendency to become
gel-like under low oxygen concentration. The gelling, also called polymerization, can
change the flow of red cells in the blood, change their shape to crescent or sickle
form, and cause occlusion of blood vessels leading to tissue ischemia, pain crises
and organ damage. Red cells with HbS break down faster and the release of free Hb
may lead to changes in the blood vessel that cause vasculopathy, large vessel
disease and complications such as stroke and pulmonary hypertension. Leukocytes,
coagulation and inflammatory processes contribute to complications of SCD." This
statement can be improved upon but would be more inclusive of other elements of
pathophysiology of SCD than the current statement. The modified statement should
replace all other repetitions of this statement in the guidelines.
81
71
73
Suggestions
Type
Invited
Discussion
Defer to panel because making a change would require
changes to entire document. Therefore scope of change
requires panel.
13 ? If all adult SCD patients with fevers really need a dose of iv abx (if very stable,
outpatient, etc
0 The section on vaso-occlusive crisis (VOC), page 71-78 is very well written.
Although, there are no specific tests to diagnose VOC, I would suggest a list of
symptoms which accompany crisis and the percentage or frequency could be gleaned
from the literature (noted on page 72) and put in a table. Also, while the
recommendations and studies support using opiates for the control of pain, recent
work and national and state level suggest that oral/parenteral opiates be withheld
from all patients other than those having cancer. VOC and other acute/chronic
conditions such as, osteoporosis, and other degenerative diseases have strong
evidence that opiates are helpful versus placebo or non-steroidal but these studies
are being over looked. Perhaps a stronger statement in one sentence would be
helpful, so opiate would be available to the SCD patients.
Invited
Panel discussion is needed on this topic
18 Add a sentence--finding another cause such as pneumonia on chest x ray does not
rule out the presence of a concomitant VOC of ribs, sternum or vertebral column.
Invited
From Email? Do not agree with suggestion to list symptoms in a table.

Editor: Revised p. 74,line 18 per panel: A recent report from the
No evidence guidelines to justify. Agree with the suggestion American Pain Society suggests opioids are not effective in treating
for a stronger statement on opiate use. Considering, "These chronic non-cancer pain (Chou et al. 2009). It is important to
patients should be treated acutely for pain management" or understand treatment of acute VOC is considered acute, not chronic
something similar. Data does exist on accidental overdose. pain, and opioids are indicated and should be used to treat pain.
Patients are perceived as addicts sometimes and so are at
risk. Panel members to review.
Patients still have vasoinclusive crises when they have

pneumonia and abdominal pain. Change considered.
Changed to: There are no tests to rule in or to rule out a VOC; there
are only tests that potentially rule out other causes of pain. DONE
Page # Line #
Comments
Suggestions
74
3 This belittles the role of reversing triggers of pain episodes (e.g. hydration or warmth), Need to state role in non-analgesia management of
distraction, comfort measures, biofeedback or meditation, etc
pain
Type
Public
Discussion
Add another sentence to say the role of hydration and
Prior to start of line 3, add: "Pain management must be guided by
nonpharm interventions are important. They can be used in patient report of pain severity. No biomarkers or imaging studies can
the context of appropriate management. Hydration is not validate pain or assess its severity." Then, after "analgesic treatment,"
always needed, however. General statement can be added add "typically with opioids. No empiric data exist to indicate that rapid
analgesic administration results in better outcomes. However, as
patients with VOC present with severe pain and are at risk for other
complications, best practice suggests that rapid triage, placement,
and administration of analgesics should be encouraged. The
Emergency Severity Index Version 4 triage system, which is used by
more than 50 percent of emergency departments in the United States,
suggests persons with SCD be triaged as ESI level 2, a very high
priority, and rapid placement be facilitated (Gilboy et al. 2011). Many
specific recommendations for acute VOC management are included in
this section. A recommendation is included to guide providers in
managing persons who take both long- and short-acting opioids to
manage pain at home. There are no empirical data to guide whether
or not to continue long-acting opioids when ordering continuous
opioids via patient-controlled analgesia (PCA). The decision to
continue long-acting oral opioids should be made on an individual
basis. For example, in most circumstances, it is advisable to continue
methadone therapy even when ordering continuous opioids via PCA.
Finally, hydration and nonpharmacologic therapy are also very
important as is concurrent treatment of itching caused by histamine
release.
74
3 2nd revision received from Dr. Tanabe via e-mail 2/11/13
Change to: Many specific recommendations for acute VOC

management are included in this section that address treatment
beyond what is listed in the Key Question (below). The expert panel
felt it was important to include current practices that have not yet
been validated by evidence, but are currently being used. When
made, these recommendations are clearly identified as Consensus
Panel Expertise. A recommendation is included to guide providers in
managing persons who take both long- and short-acting opioids to
manage pain at home. There are no empirical data to guide whether
or not to continue long-acting opioids when ordering continuous
opioids via patient-controlled analgesia (PCA). The decision to
continue long-acting oral opioids should be made on an individual
basis. For example, in most circumstances, it is advisable to continue
methadone therapy even when ordering continuous opioids via PCA.
Finally, hydration and nonpharmacologic therapy are also very
important as is concurrent treatment of itching caused by histamine
release.
74
3 New section added by Dr. Tanabe 2/11/13
Add to gaps section: More research is needed to compare different

therapies (e.g., low-dose naloxone infusions and antihistamines) to
treat itching caused by histamine release. DONE 2/11/13
Page # Line #
Comments
74
5 Key Question - there were no comments on the use of oxygen when a pt is admitted
with VOC. Should there at least be a comment to check the pt's O2saturation given
the possibility of ACS or other pulmonary complication during the admission. This
would give clinicians the pt's baseline on admission.
74
5 Key question includes interventions not discussed in summary of evidence or

recommendations
Suggestions
Type
Invited-Non
Disclosed
Discussion
Not enough evidence on the use of oxygen to make
Added new Rec #17: In adults and children with SCD and a VOC with
evidence-based recommendation. Agree to incorporate a
an oxygen saturation <95 percent on room air, administer oxygen.
new line in concensus statements regarding oxygen.
(ConsensusPanel Expertise) 1/17/13 DONE
Concensus-based recommendations will be added by panel.
Panel will draft a sentence to be reviewed by panel.
Invited
New language will be drafted to be reviewed by panel
Panel submitted revision. See box 2 spaces above. Done
Public
This section should reflect a statement of the evidence, and

not be recommendations section. Panel will go back to the
study and consider changes will be made to lines 15 and 16
on page 74
Revision submitted: before p. 74, line 16, revised as: "One study
evaluated the effectiveness of meperidine versus placebo or other
opioids and found meperidine more effective than placebo in reducing
pain. Also, Rec. #8 added: In adults and children with SCD and a VOC,
do not use meperidine unless it is the only effective opioid for an
individual patient. (ConsensusAdapted) DONE
74
16 You clearly do not want to recommend the use of meperidine. The sentence however
leaves doubt about the panel's position. Suggest restructuring to state BECAUSE OF
NEUROTOXICITY CONCERNS MEPERIDINE SHOULD NOT BE USED TO TREAT
PAINFUL CRISIS.
74
19 Change received from Dr. Tanabe
76
16 Need to provide more specific information on how to do this
Invited
Will revise recommendation and submit. Need to add a 30- Editor: Revised Rec #2 to read as follows: 2. In adults and children
minute goal timeframe.
with SCD and a VOC,
Determine characteristics, associated symptoms, location, and
intensity of pain based on patient self-report and observation. If the
VOC pain is atypical, investigate other possible etiologies of pain.
(ConsensusAdapted)
Rapidly assess the patients recent analgesic use (opioid and
nonopioid). (ConsensusAdapted)
Rapidly initiate analgesic therapy within 30 minutes of triage or
within 60 minutes of registration. based upon pain assessment,
associated symptoms, and prior analgesic use. (Consensus
AdaptedPanel Expertise)
Base analgesic selection on pain assessment, associated symptoms,
outpatient analgesic use, patient knowledge of effective agents and
doses, and past experience with side effects. (ConsensusAdapted)
DONE
76
17 clarify if these recs are specific for inpatient vs. outpatient vs. day staty, etcc..here
and throughout this section
Invited
Team discussed clarifying the text to address this comment. Editor: on p. 76, line 6, added: These recommendations are intended
Pg. 76, line 4: "These recommendations are intended to be to be for all settings where patients present with VOC.
for all settings where patients present with VOC." Algorithm
may be adjusted as well.
Public
Line 15 on page 77, regarding use of antihistimes and non- Editor: changed Rec. #9 to: In adults and children with a VOC,
steroidals. panel will revise.
administer oral NSAIDS as an adjuvant analgesic in the absense of
contraindications (Consensus--Adapted). DONE 2/13/13
77
5 The role of NSAIDS as adjunctive therapy in addition to opioids in severe VOC needs
to be clarified. This should be included in Exhibit 5 as well.
Add: A recent report from the American Pain Society

Editor: Done 1/17/13
suggests opioids are not effective in treating chronic noncancer pain (ref.Chou et al. 2009). It is important to
understand treatment of acute VOC is considered acute, not
chronic pain, and opioids are indicated and should be used
to treat pain.
Page # Line #
Comments
77
15 Should you explicitly state that ANTIHISTAMINES are not needed for each dose of
opioid? That would be a big help in clinical management.
Suggestions
Type
Public
This rec will be revised.
Discussion
Editor: changed Red. #10 to: 10. In adults and children with a VOC
who require antihistamines for itching secondary to opioid
administration, prescribe agents orally, and do not re-administer with
each dose of opioid in the acute VOC management phase. Readminister every 4 to 6 hours if needed. (ConsensusPanel Expertise)
DONE
77
15 I am not clear why consultation with hem needed for antihist, antiemetics
Invited
77
15 Consult with a sickle cell expert regarding use of antihistamines or starting other
Please provide dosing recommendations for
adjuvant agent categories: Not useful in majority of settings where sickle cell experts frequently used medications, including Benadryl,
are not available.
Atarax, and low dose Narcan for pruritis; and antiemetics such as Zofran.
Public
Editor: changed rec. #13 to: In euvolemic adults and children with
SCD and a VOC who are unable to drink fluids, provide intravenous
hydration at no more than maintenance rate to avoid over-hydration.
(ConsensusAdapted) DONE
78
3 Provide IV hydration at maintenance rate (unless dehydration is present) when

patients are unable to drink fluids adequately
1) Please include that special consideration of IV

Public
fluids should be made for those with a history of ACS
(e.g., IVF at maintenance) to avoid fluid overload;
2) Please provide details as to how to manage the
dehydration if it is present, or provide reference to
where in the document this information can be found.
Panel will clarify what to do when dehydration is present
78
3 Additional comment for VOC
Include strategies to prevent ACS: 1) All patients

Public
admitted with pain should use incentive spirometry
while awake; 2) All patients should get out of bed
(e.g., sit in a chair) and ambulate as soon as
possible; 3) Use bronchodilators, as prescribed at
home, in those who have a diagnosis of asthma; and
4) Consider a trial of bronchodilators in those with
concerning pulmonary findings but without a known
diagnosis of asthma.
ACS is not VOC but will be addressed in the ACS portion of Editor: revised Rec. #11 to: To reduce the risk of acute chest syndrome
the guidelines. A sentence will be drafted and it will go to the in adults and children hospitalized for a VOC,
panel for review.
Encourage use of incentive spirometery while awake. (Strong
Recommendation, Moderate-Quality Evidence)
Encourage ambulation and activity as soon as possible.
(ConsensusPanel Expertise). DONE
78
10 Why isn't IM being considered
78
13
78
21 No mention of use of oxygen for simple painful event; this should be addressed - I
believe that no data exists validating its usefulness in this setting.
Invited-Non
Disclosed
Panel will look at the background and see about making an Editor: a logical place to address this comment was not found. Editor:
adjustment
comment added to master file.
Change received 2/11/13: Revised rec. 7 to: If ordering around the

clock, continuous infusion of opioids via the PCA, carefully consider
whether there is a need to withhold long-acting oral opioids to prevent
over sedation (Consensus--Panel Expertise). Sub-bullets are: --If
demand dosing is ordered via the PCA, continue use of long-acting oral
opioids. (Consensus---Panel Expertise). --At discharge, evaluate
inpatient analgesic requirements, wean parenteral opioids prior to
conversion to oral opioids, and adjust home dose of long- and shortacting opioid prescriptions to prevent opioid withdrawal after
discharge (Consensus--Panel Expertise). DONE 2/13/13
Public
The team thinks a rec on oxygen is needed. Was there

evidence? A statement is needed about oxygen and
hypoxemia. Statement will be drafted for group review.
Added new rec 17. In adults and children with SCD and a VOC with an
oxygen saturation <95 percent on room air, administer oxygen.
(ConsensusPanel Expertise). Does this address this?
Page # Line #
Comments
79
Figure: there is no evidence cited for the 30 minute time to begin analgesic
administration. Given the lack of evidence, it might be more accurate to say "as soon
as possible" Same comment about alternate routes of pain administration for figure why not intranasal pain meds?
Suggestions
Type
Invited
Discussion
There is no evidence, but a comment is needed to make
done 2/13/13
sure the figure matches the change we made in the
recommendations about timing of initial analgesic. Panel will
submit changes to the figure.
100
8 While there is no reason not to suggest incentive spirometry, the data to support its
use is quite limited and to say that it prevents ACS is a bit of an over-statement.
Public
New sentence will be added to the background. Ballas 1995 pg 100, line 8 and 9, replace the sentences and reference Belllet,
reference.
1995. Use of incentive spirometry in hospitalized patients with acute
chest pain has been found to prevent atelectasis and pulmonary
infiltrates. Have panel ok. DONE
100
14 A caution on hydration would be helpful; there is a tendency to overhydrate

hospitalized people with SCD, especially in pain management. Bed-ridden patients in
pain, receiving parenteral opioid therapy and increased IV hydration are a set up for
ACS.
Invited
panel will look into this.
101
14 The guidance on management of ACS seems appropriate, but fails to make mention 1. We recommend the addition of a statement
Public
of additional modalities of treatment which, in the opinion of experienced clinicians in indicating that there is some support in the literature
our group, appear to be effective adjuncts to the more traditional treatments indicated for the efficacy of incentive spirometry in preventing
here. We recognize that the the evidence for these treatment modalities is small, but the evolution of ACS in children who present with
we submit that they are in widespread use, and should be addressed here in order to VOC. As this modality is inexpensive, safe, and can
raise awareness of the need for further objective evaluation of outcomes. In particular, be performed easily by patients outside the hospital
we would like to see mention of incentive spirometry and non-invasive ventilation in
setting, its benefit would seem to far outweigh any
the setting of ACS.
risk or expense associates with its use.
I would simply add that the children with recurrent ACS predispose towards increasing 2. We recommend a brief discussion of the potential
airway obstruction (J Pediatr 2006;149:17-22), a fact that often goes unnoticed until use of non-invasive ventilation, particularly of BiPAP,
multiple episodes of ACS eventually produce the chronic restrictive pattern that many in treatment of children with severe or rapidly
of us see in advanced SCD. Also would emphasize the co-pathologies often seen in progressive ACS.
SCD, ie sleep disordered breathing and asthma, both contributing to hypoxemia and
sickling promotion. Thus the need for a good
database to generate long term data.
Editor: p.78, add new Rec. #13. 13. In euvolemic adults and children
with SCD and a VOC who are unable to drink fluids, provide
intravenous hydration at no more than maintenance rate to avoid
over-hydration. (ConsensusAdapted)
A recommendation to be written about incentive spirometry. Editor: revised p. 78 to include new Rec. #11: To reduce the risk of
acute chest syndrome in adults and children hospitalized for a VOC,
Encourage use of incentive spirometery while awake. (Strong
Recommendation, High-Quality Evidence)
Encourage ambulation and activity as soon as possible.
(ConsensusPanel Expertise) DONE.
73
8 consider adding a reference for this statement about pain during the lifetime
Invited
Agree to add a reference
71
0 All the recommendations in the Managing Acute Complications of Sickle Cell Disease
needs to reformated for the emergency department. Many of the recommendations
are not appropriate nor appropriate in the emergency department.
Invited-Non
Disclosed
Purpose of this document is not specifically for emergency No change

room. Dissemination group will reformat information for
emergency rooms. Experts will develop tools and test them.
Invited
This is from page 72, line 3. Disagree with suggestion

because literature refers to "acute stroke." It is a standard
term.
No change
Public
outside of scope
No change
72
73
delete acute before stroke. Stroke by definition is acute.
0 Sickle cell trait AS in normal condition may cause hematuria

from renal papillary necrosis, following exercises rhabdomyolysis and compartment
syndrome.Patients with AS also are prone to pyelonephritis. My suggestion whould
be also to speak about sudden death and explain when splenic infarction occurs. In
fact the expert panel should make a chapter about sickle cell trait at the end.
Editor: added Platt 1991 ref., p. 73, line 9. DONE
Page # Line #
73
4 Vaso-Occlusive Crisis
73
73
Comments
5 Change the sentence to read--"VOC occur with variable frequency in individuals with
SCD and the first crises can occur during early infancy".
14 at the Florida meeting in 2012, there was dentist who presented data on increased
rate of hosp when VOC was accompanied by dental pain/infection. Wondered if you
considered including dental abscess in this list
Suggestions
Type
This section should consider adding requirements for Public
incentive spirometry, stool softeners, specific tools to
assess pain, and at least discuss the complicating
issues of tolerance, withdrawal, and pseudoaddiction.
Discussion
Suggestions are beyond the scope of this document. Issues No change
will be dealt with at the dissemination stage.
Recommendations should not be changed at this point.
Invited
No change because concept occurs later in chapter
No change
Invited
Do not agree with suggestion because issue is not

significant enough and would make document needlessly
longer.
No change
74
4 The sentence NO BIOMARKERS OR IMAGING should be emphasized more strongly.
Public
The sentence is believed to be clear now
no change
74
5 I have sickle cell anemia and I know from experience that treatment for this disease is
in desperate need. Plenty could be avoided if doctors and nurses would listen to the
patient. Usually te patient knows whats best for them. Im my experience the pca
works much better than on demand. Theres a high risk of delay and thats part of the
reason it doesnt work, mostly nurses dont have time to run back and forth pushing
meds and it helpd more when the patient is in charge of teir own dosing. It saves time
and it actually works. I only wish that hospitals would start pca treatment in the er.only
one hospital i know of does it. when you strt with giving push doses ifyou dont stay on
top of if and do it about every 20 or 30 minutes it doesnt work. with the pca the patient
is in control and can push every few minutes to get a small dose but the consistency
is what makes the treatment a success. when the pca is given in the er theres a
strong chance the pain will b under control and there will be no need for admission,
but if there is it most likely will be a short one because the pain is being controlled in a
successful manor.
Public
No evidence to recommend. No evidence to make a

recommendation to start pca treatment in the ER.
no change
74
5 Key Question - no guidance on dosage was given other than using the pt's protocol or
their home regimen. If this document is to be useful to a broad base of clinicians,
some additional information eluding to higher doses than what other pts with pain may
require is necessary.
Invited-Non
Disclosed
Do not agree with change because not in the scope of the no change
document. Also not possible to change key question at this
stage of document development.
Also comments on biases against pts who know what they need as being "drug
seekers" should be made. Similar to pts with CF who kow what antibiotic works or pts
with DM who know their insulin response - pts with SCD usually are knowledgeable
about pain control. Many of us who treat pts with SCD are aware of this but
sometimes get pressure from other clinicians and nursing staff about the doses we
prescribe.
74
8 other interventions apparently have been limited to medical interventions; no mention Include non-pharmacologic management strategies; Public
is made of or psychological, physical, or supportive management strategies for acute there is a large body of clinical and research
pain
experience describing the psychologic component of
pain experience that is being conformed by brain
imaging studies
No change because suggestion has already been

addressed in recommendations
No change
Page # Line #
Comments
Suggestions
Type
74
9 It is not clear that any non-pharmacologic studies were included in this review, or that This is a serious and potentially misleading omission Public
psychological expertise was included on this panel
from these guidelines; psychologic and nonpharmacologic treatment stategies need to be
included; there is also a wealth of information on the
efficacy of these interventions in other acute pain
disorders
75
3 Consider adding a table of commonly used analgesics including dosing guidelines
Discussion
Recommendations are included for nonpharmacologic
interventions. Agree that psychological expertise was
missing, but can't change now.
no change
Invited
This should be referred to blood disorder group or

dissemination group. Dosing guidelines may need further
discussion.
No change
75
10 Consider an algorithm or flow diagram to summarize these steps
Invited
Disagree because not justified
No change
75
11 Day hospital programs definitely advantageous to patient in VOC, as opposed to ER

treatment. This needs immediate research, full evaluation of literature and hospitals
that already use this type of program. [Also noted as an SS patient and Clinical Lab
Scientist.]
Public
Suggestion is beyond the scope of this document. Also,

insufficient evidence to make change.
No change
76
3 In general, this section seems vague. Specific recommendations are not given as to
initial diagnostic workup, recommendations for opioid dosing. SCD-specific protocols
are referenced but not given.
Invited
Panel discussed considering a weight-based protocol.

Vague comment.
No change
76
3 Consider adding a first recommendation that providers discuss an age and

developmentally appropriate pain plan as part of a well-person or comprehensive
visit, including provision of prescription meds for a home pain management plan.
Alternative would be to include this recommendation under preventative measures
Invited
This comment addressed chronic pain management. No

change
No change
76
8 Need more specific information that are clinically relevant with these
recommendations. Need to start with rapid assessment of pain - how/with what
tools?
Invited
This is beyond the scope of these guidelines
No change
76
12 Atypical pain is misleading, do you wish to clarify as "atypical" for this patient?
Public
The team is OK with leaving this as it is.
No change
76
12 by "if VOC pain is atypical" do you for that pt or in general for VOC?
Invited
No change is needed
No change
76
14 Words such as "rapidly" are vague and difficult to implement, particularly if building
computer-based clinical decision support systems that depend on explictly-defined
triggers. If the vagueness is intentional, would state that explicitly and/or provide
parameters to help guide implementers.
Fed
This stays as-is for assessing.
No change
76
16 Meaning of "prior analgesic" use is unclear. Both "analgesics used as outpatient for
current VOC and past history of analgesic efficacy and side effects" are important.
Clarify wording.
Public
Same as above comment - this rec will be modified.
No change
76
18 agree in principle, but
Reassess for pain intensity and opioid toxicity and

readminister opioids if necessary and safe
Public
No change. Group discussed and decided not to add

anything further
No change
Invited
No change - outside the scope of this project.
No change
No change - this is covered elsewhere.
No change
76
77
It would be quite useful in this section to give more specific recs on pain management
ie PCA dosing recs, agents of such orally and IV and dose equivalence tables. This
would be very practical and make the document more applicable to daily care
0 discussion is opiate -centric
Need to acknowledge non-opiate interventions,

Public
especially NSAIDs for synergism, let alone reducing
inflammation.
Page # Line #
Comments
Suggestions
77
5 We recommend continuation of long acting home opiates at HALF the home dose. If continue long acting opiates at half the home dose
long acting opiates are continued at full dose, patients baseline home doses tend to while inpatient.
escalate with each admission. By cutting long acting dose in half, as short acting
opiates are titrated down during the hospital admission, the patient will eventually go
below their home long-acting dose.
Type
Public
No change
77
5 For acute pain, page 77, lines 5-6, is discontinuing short acting and using long acting
opioids the appropriate recommendation?
77
5 Continue use of long-acting opioids: This statement is inaccurate.
77
6 I found the recommendation to continue long-acting opiods and discontinue short

Clarify whether long acting and short acting opiod
acting opiods confusing, as short acting parenteral opiods will subsequently be used. comments relate to route of adminstration (oral vs
This could be very confusing to the uninitiated.
parenteral
Public
77
7 Please use other drugs beside morphine as an example. Such as Fentyl, didlauded
etc. When given examples of the dose that is recommended please consider patients
that are already on high levels of opioid For an example when I am admitted I am
given 100 mcg of Fentyl to start then depending on the pain the dosage is escalated
up.
Public
No change
77
7 I thinkour adult providers are beeing punitive by withholding IV opioids. I gather the
panel thinks SC (IM?) is OK?
7 consider adding equianagesic dosing table here; you hope people know that but
Public
No change
Invited
No change
77
11 by what % over what period of time with what period of assessment? I know you have
said there is insufficient evidence to know but as long as you're giving expert
consensus, be more specific
Invited
This is beyond the scope of this document
No change
77
11 Gradually titrate down parenteral opioids as VOC resolves: Too vague for nonsickle cell experts to use as guideline.
1) Do not wean medications in the first 24 hours of Public

admission to allow adequate pain capture; 2) Do not
wean at night-time, when patients are asleep and
may not recognize early signs of escalating pain.
No change
77
14 If not familiar at all, do not need to ask the question of time medication was taken and
the amount to prevent over sedation?
Invited
No change
77
18 ADD COMMENT that ICE IS NEVER RECOMMENDED as nonpharmacologic

treatment of pain since the vasoconstriction it causes may precipitate further vasoocclusion or VOC pain?
Public
Already addressed in previous comment.
No change
77
19 Many other cognitive-behavioral stategies have been demonstrated to be helpful
Public
No change - already addresssed in recommendations
No change
77
20 This is a good recommendation, many ER doctors or other specialists disregard the

SCD provider or fail to consult even when they both work for the same hospital or
institution.
Public
No change is needed here. Thank you for your comments
No change
77
20 not clear what diffference is bw first and third option in this list - protocol written by pt
SCD provider and individual protocol
Invited
This was already addressed in a previous comment
No change
77
Public
Discussion
It is appropriate to continue to administer methadone Public

in patients who are already taking it. Patients should
not receive long-acting opiates such as Oxycontin or
MS Contin in the acute care setting until short-acting
enteral or parenteral medications have captured their
pain.
Expand suggestions for non-pharmacologic

management stategies
Yes, it is.
No change
No change
No change
Already addressed in a previous comment
No change
Page # Line #
78
Comments
Suggestions
Type
Please include dosing recommendations for
Public
commonly used opiates in the acute care setting, as
many patients receive inadequate doses of pain
medications
Discussion
This was addressed in a previous comment.
No change
78
Include a statement to avoid the use meperidine in Public

the management of acute pain in sickle cell disease
patients
Addressed above in background discussion.
No change
78
If not capturing pain with optimal dosing of a given

Public
agent, consider switching to equi-analgesic dosing of
other agent (morphine and hydromorphone).
This is beyond the scope of these guidelines.
No change
78
Recommend proactive treatment of opiate-induced

constipation: 1) Recommend using stimulants and
stool softeners while treating with opiates; 2) Avoid
the use of osmotic agents to treat opiate-induced
ileus.
Public
This is beyond the scope of the guidelines
No change
78
3 Additional comment for Chronic Pain
Include the role of hydroxyurea or chronic

transfusions to manage chronic pain. Include brief
recommendations and hyperlinks to these sections
for additional detail.
Public
This is in the chronic pain chapter.
No change
78
There is no mention of co-management of chronic

Public
pain related to sickle cell disease between
multidisciplinary teams which include sickle cell
experts, primary care physicians, psychologists,
social workers OT/PT. This is critical to the possible
success of chronic pain management.
No change
78
There is no mention of approaching chronic sickle

Public
cell pain in the context of neuropathic pain, which is
currently treated with gabapentin, SSRIs and antiepileptics rather than opiates. These drugs may well
provide adjuvant analgesia in the chronic pain setting
for patients with sickle cell disease.
No change
78
If the intent is that management details for some of

the issues mentioned in this section are provided
elsewhere in the document, please reference the
areas where the details are to be found.
Public
No change
78
4 Revisit additional consensus recommendations of supportive care measures such as

incentive spirometry and, local warmth
Invited
We have non-pharm already defined.
No change
78
5 With line 8, again VOC apparently mis-defined above
Public
This has been deferred to the group in another comment
No change
Page # Line #
Comments
78
8 another place where more specifics, sample protocols would be helpful; obviously
these need vary by pt, but in absence of knowing the pt or having indiv protocol,
people need recd on where to start with agent choice and dosing
Suggestions
Type
Invited
Discussion
This has been discussed in a previous comment
No change
78
78
8 see line 54 above for similar comment

8 Incentive spirometry is the the supportive care recommendation for which we have
incorporate recommendation for use of incentive
the most evidence and a specific rec for use for moderate and severe VOC should be spirometry in treatment of VOC.
added.
Fed
Public
Unsure what this is about.
No change
No change
78
9 Here parenteral means IV? parenteral /prntrl/ Show Spelled[pa-ren-ter- say intravenous if that is what is meant
uhl] Show IPA
adjective Anatomy, Medicine/Medical, Physiology .
1. taken into the body in a manner other than through the digestive canal.
2. not within the intestine; not intestinal.
Public
No change
No change
Invited
This is an incorrect comment
No change
This is an incorrect comment

This is already addressed in a new rec.
No change
No change
78
13 The recommendation suggests that around-the-clock opioid administration should

only be performed through PCA. Please re-word to include other routes of
administration
78
78
13 same as above
21 maybe IS is somwhere else?
Invited
9. All patients hospitalized for pain, especially those Public
receiving opioids and/or experiencing pain in the
chest, back or abdomen, should be provided
incentive spirometry 10 puffs every two hours while
awake.
79
0 Since sickle patients can be medicated at triage, making sickle cell patients a high
priority may not be practical in busy emergency department.
Invited-Non
Disclosed
No change, this has been discussed and is out of the scope No change
of the document
79
0 It is impractical to manage pain in an emergency department for 6-8 hours.
Invited-Non
Disclosed
No change
79
0 Many Eds are not equiped nor experienced in giving PCA in the ED.
Invited-Non
Disclosed
No change
79
0 Algorithm - lacks NSAIDS
79
0 Exhibit 5 - Given many hospitals are trying to improve "thru-put" (i.e. decrease time in
ED, implement rapid assessment of need for in-pt care), this protocol should include
"consider arranging a direct admission for pt". We attempt to do this when possible if
it is clear that the pt is experiencing a VOC w/o complications. Our pts (adults) HATE
going through the ED. Since we have an IM Residency program, we often arrange for
a direct admission & have the residents see the pt aa soon as they arrive on the floor.
When we follow this process pts express increased satisfaction with pain control and
overall hospital experience.
OVERALL need to address utility of NSAIDs
Public
This was already discussed
No change
Invited-Non
Disclosed
This goes against CMS recommendations to avoid

rehospitalizations
No change
Page # Line #
Comments
79
0 Exhibit 5 - Although meperidine should be avoided per recommendations, can a
comment on its occaisional use be included. Annecdotally, we have a few pts that we
use it with.
Suggestions
Type
Invited-Non
Disclosed
Discussion
No change
As a person living with SCD (HbSS) & as a physician caring for pts with SCD, I chose
to "convert" myself from meperidine to hydromorphone due to recommendations
(trying to be an adherent pt). My pain control with hydromorphone (or morphine) has
never matched that of meperidine & the side effects I experience from the preferred
agents are significant. I had no untoward side effects from meperidine including no
euphoria. The primary reason my pain is inadequately controlled on the preferred
agents is that I choose to tolerate the pain over enduring their adverse side effects.
Perhaps this can be the subject of another study. I would be curious to know the
impression of persons with SCD who "grew up on" meperidine versus their current
management.
79
0 Exibit 5. Acute pain can be managed in a day hospital or

the ED. Not every Institution has a day hospital and patient acute pain has to be
managed in the ED.
Public
No change
79
1 Acute VOC recommendations are clear as is the Exhibit 5
Invited-Non
Disclosed
No change
79
2 having an algorithm such as this is much more likely to be used clinically than prose
above however it is not specific enough as to dx, disp criteria for setting (clinic vs day
hosp vs ER) and tx; also think there may be a word missing in the top line of the box
on the bottom - maybe add "or" between possible and within?
Invited
No change
79
3 Please indicate to triage SCD patients at Emergency Severity Index level 2
Public
80
9 The panel states that fever is an emergencybecause of penicillin resistance and

incomplete vaccines, rather the risk of overwhelming bacteremia is the risk with fever
in SCD a risk that may be made worse by penicillin resistance and incomplete
vaccines. Suggest rewording.
Public
Already addressed with a previous change
No change
No change
80
18 add relative freq of different org if possible
Invited
This is beyond the scope of these guidelines
No change
80
22 This statement is misleading.
Invited
Chapter team does not agree that this is misleading.
No change
IND
No evidence to support this change.
No change
81
9 Recom 1-5 should include antibiotic chocies
Would insert antibiotic as done for acute chest

syndrom
Page # Line #
Comments
81
10 emergency room care is terrible. The waits are long and the staff act like they dont
care about you. They dont bother to listen to you, most of the time they think youre
just there for the drugs. Half the time they gie you a shot and send you have without
even examining you or asking any questions, they dont even do a blood test
sometimes. If they do and it looks good to them, u cant be in pain, but blood results
do not always justify if you should be in pain or not. Many times I have been judged to
the point where if they hear my name they just send me home. It needs to come to a
hault its rediculous. I had a fever of 103+ and i had to wait in the er for 3 hours before
I was seen, then when I was finally seen I was so ba off i was uncontious for the next
few days. I woke up in icu in the worst shape of my life, I had pneumonia on top of a
crisis . i stayed for a month. theres no way my care shold have been delayed that
long. they wouldnt even give me oxygen.
Suggestions
Type
Public
Discussion
This is commentary
No change
81
81
10 see comment from line 47 above

12 I would mention checking urine in febrile patients/children based on the presence of
other risk factors - young age, previous UTIs. I don't think you want practitioners to
forget to check for other occult infections. I know it is not sickle cell specific, but if
someone is using this document as a guideline, I would want them to be considering
other tests based on patient charateristics.
Fed
Invited
No change indicated
Urinalysis has been addressed with a change. No further
change is being made.
No change
No change
81
81
13 be specific about preferred agents and dosing

14 The data for the recommendation of subsequent oral antibiotic empiric therapy as an
outpatient is not presented. To my knowledge there is no data and this
recommendation may need to be re-examined.
Invited
Public
Disagree - this is beyond our scope.

This is a consensus recommendation and is not reliant on
data.
No change
No change
81
14 I question the use of oral antibiotics. I'm concerned that antibiotic overuse will lead to
increased resistance and that antibiotic use gives a false sense of security to
caregivers and healthcare providers. Also, there are no recent studies that I'm aware
of to support antibiotic use in this setting.
Public
This has already been covered in a previous change. Panel No change

will be discussing this issue.
81
15 possible to be more specific than not appearing ill? Like maybe not meeting SIRS
criteria
16 Any consideration to recommend admission for very young patients with HbSS (ie,
patients < 1 year age who are not fully immunized with PCV13 and HIB vaccines)?
Invited
No change
Public
No change is needed.
No change
81
81
16 per Willimas
I would use 40 deg C
16 Feel that no strong data exists in regards to how high fever is and risk of sepsis;
Believe statement should be "consider hospitalization for fever greater than or eqial to
39.5"
Public
Public
No change
No change
81
16 "ill-appearing" is a difficult concept to operationalize whem implementing

recommendations using computer-based clinical decision support systems. To the
degree possible, would make the components of this concept clearer.
Fed
No change
No change
82
0 Somewhere in infection section need prophlactic antibiotics in spenectomized

patients.
1 Localized erythemia, swelling and tenderness has many other considerations that
need to be considered other than osteomyelitis.
Public
This is dealt with in the health maintenance chapter.
No change
No change - this is accurate as written
No change
No change
81
82
82
3 I would state what initial dx, tx is recd or reference appropriate guideline/resource
Have statement in the recommendations
Include a thorough evaluation for many causes of

Public
localized infection including abscess, septic arthritis,
cellulitis, etc.
Invited
Page # Line #
Comments
82
4 As written AKI is not sufficiently distinct from MSOF or renal problems described
under chronic complications, consider consolidating
82
82
83
84
84
84
9 RE: "(e.g. glomerular injury such as renal papillary necrosis or sickle cell
nephropathy.)" renal papillary necrosis is not a glomerular injury. Furthermore, renal
papillary necrosis often does not meet the panels definition of AKI (rapid rise in Cr
and reduction in GFR)
Suggestions
Clarify wording.
19 helpful to know
8 key question should relate to diagnosis or management of AKI not to ESRD
0 How about papillary necrosis?

4 No recommendations for IV hydration are given for either renal papillary necrosis or consider providing recommendations.
AKI
5 at what birthday should implementers begin to consider a child to be an adult for this
recommendation statement?
Type
Invited
Discussion
The panel disagrees that this should be consolidated.
No change
Public
Change already made in previous comment
No change
Invited
Invited
No change
We cannot change key questions in the document since the No change
evidence reviews were based on the key questions
Invited
Public
This is beyond the scope of this chapter

This beyond the scope of this chapter.
Fed
There is no specific distinction that the panel is ready to

No change
adopt. In the absence of that the panel is not going to assign
a definition. This is a guidelines-wide issues vs. this chapter.
No change
No change
84
11 Rec. 2 - "Do not give RBC transfusions to treat AKI unless there is evidence of acute Add to recommendation: "...or a significant
multisystem organ failure." This recommendation ignores an imporant potential
exacerbation of anemia."
indication: acute exacerbation of anemia.
Public
This is handled in a previous comment.
No change
84
12 Suggest omitting SEVERE PAIN here as one of the components of MSOF; above the
panel concludes correctly I believe that there is no data for transfusion in painful crisis
yet here it appears that they are endorsing transfusion for "severe pain" when in
reality it is for the MSOF.
Public
This is handled in a previous comment.
No change
86
0 Consider consolidating all the priapism information here since prolonged priapism is
the organ function risk, but recurrent stuttering priapism also needs management.
Recurrent prolonged priapism needs chronic management as well and you omit it
from the chronic chapter.
Public
Priapism is already included in the chronic chapter (p. 153). No change

This chapter focuses on acute conditions.
86
1 We are strong proponents of early aspiration/irrigation. I'm not sure I would rely on
urologists to do it without urging
8 Given the real possibilityconcern that a SCD patient could die while the provider is
wading through all the information in this sub-chapter, I would suggest the various
complications be listed in outline form with respective S&S and for possible AHS or
AIC an indication in BOLD that this is an Emergency situation.
Public
There is no data on this issue for the panel to consider a

No change
change.
This is an excellent suggestion for the implementation phase No change
of these guidelines.
86
86
19 Priapism Recommendations: The overall recommendation to "consult a urologist' for

management of priapism is reasonable, but is inadequate. Urologists, unless they
have a specific interest in sickle cell disease and priapism, often know less than the
clinically-involved hematologist.
86
20 In priapism section it would be much more helpful if doses and recs were given for
medical management of priapism ( ie terbutaline, pseudo-ephedrine
intervention (early penile aspiration/irrigation)
Invited
Practical guidelines for primary intervention after

Public
failure of hydration and analgesia should be
included. Recommendations should include the role
of corporeal irrigation using alpha adrenergic agents.
These patients should be seen at a program in
which there is expertise in their management and
some guidelines for the consulting urologist in terms
of treatment.
No change
Invited
No change
Page # Line #
Comments
86
20 There is no rationale for waiting 4 hours to treat an episode of priapism.
Suggestions
Type
Recommend treatment be initiated as soon as the
Public
patient presents for medical evaluation and therapy.
Patient who have repeated episodes should have a
treatment plan so they can also initiate treatment
immediately when they recognize an episode is
beginning.
Discussion
There is no evidence for waiting less than 4 hours either.
No change
87
0 Priapism: This chapter needs to be more organized. An Algorithm is necessary.

Transfusion is indicated for patient with recurrent episodes of severe priapism. A good
reference book for priapism is a book by Dr. A. Hasmat called the Penis.
Public
This is beyond the scope of this section. This is an

No change
implementation suggestion. Recurrent episodes are covered
in the chronic chapter.
87
1 Surprised that oral pseudoephedrine was not presented as option here prior to/in
conjuction with caling urology
Invited
We were not specific - no evidence to support suggesting

this. Consult a urologist.
No change
87
1 consultation should be with a urologist who is familiar with SCD. Consider adding
consensus recommendations on specific medical interventions, including irrigation
Invited
No change
87
2 Here is where the treatment should be limited to 4 hours.
87
6 There are several places where consultation with "experts" is recommended, but I see
no recommendations for those experts. As an example, for priapism recommendation 3 - consult with a hematologist - as a hematologist I would find this
unhelpful.
87
8 Hepatobiliary Complications: Cirrhosis and liver failure are growing causes of death in This should be mentioned somewhere in the
Public
SCD.
document. Screening for cirrhosis and appropriate
liver transplantation is often delayed in SCD.
Patients can be cured from liver failure and should
be referred appropriately (Ref: Hurtova, et al.
Transplantation for liver failure in patients with sickle
cell disease: Challenging but feasible. 2011).
Recommend that urologic consultation be obtained if Public

four hours of medical therapy has not resolved the
priapism.
Public
No data to support this timeline. This will be addressed as No change

part of the process of considering the inclusion of the AFUD
guidelines
No change
No change
No change
Page # Line #
Comments
87
15 When I was a patient at the childrens hospital I never had to wait because of my
illness I was always pushed to the front. It we were treated that way as children what
was the point if when we got older we would be tossed to the side like theres nothing
wrong with us at all.People should start listening to the patients. I complained of
stomach pain for months, because i was on tranfusions my dr would turn me away
every time i showed up. i got a second opinion and turned out that i had gallstones, a
result of what was supposed to be helping me, transfusions. no one even told me
about the risk. But there really was something wrong and it was totally ignored and
had a chance to keep getting worse. i needed surgery. Ive had a blood clot because
no one bothered to find out what was wrong. Its got to stop. I hae been deemed a
drug seeker even, like most of us, but if thats all you can offer what else am i
supposed to expect. when youre in pain the only treatment is to be relieved, does that
make you a drug addict, dont think so. the last thing i want to do is pump my body full
of drugs on a regular basis but if thats the only thing that helps you just dont have a
choice.
87
87
88
88
89
Suggestions
Type
Public
Discussion
There is no action required here
Public
There is no evidence to support a recommendation on this. No change
Invited
There is no suggested change in this comment. No line

number provided.
No change
Invited
Invited
This is beyond the scope of this section

This term is not as specific as the terms being used in this
chapter. The panel prefers the more specific wording.
No change
No change
see ref (OCallaghan A, OBrien SG et al, Gut 1995, Public

PMID 7672666; Altintas E, TiftikEN, et al, Turk J
Gastroenterol, 2003, PMID 14655071; maybe Cross
TJ, Berry PA et al, Am J Hematol 2007, PMID
17565724)
The panel cannot add references at this phase. This is not

the correct chapter for this topic
No change
Invited
No change
No change
Public
Public
Team wants to keep this.

This is a good suggestion for the implementation phase.
No change
No change
Invited
Public
Good - thank you.

This was addressed in a previous comment
No change
No change
20 Do not find the data convincing that surgical intervention has better long-term
outcomes than medical management.
alogorithm good, but need to have more dirtion aobut what can be done in PCP office,
may divert staff away from regular office duties; thus, making it too expensive for the
bottom line.
3 compare with baseline population
19 Modify the sentence to read (AIC)---also called sickle cell hepatopathy, can occure in
individuals with SCD.
0 There are a few patients that we have taken care of that have chronic intrahepatic
cholestasis, as well as a couple of case reports to support this rare complication
89
10 The syndrome of "benign" extreme hyperbilirubinemia in SCD (Buchanan, 1977;

Seeler, 1978) is not mentioned at all in this section
89
91
12 never saw light-colored stools

0 Hepatobiliary Complications - Summary of evidence needs organization. Confusing
for people not familiar with SCD even hematologist. An algorithm approach will be
very helpful.
91
91

18 Recommendations: Although surgical consult must be requested, a patient with acute
cholecystitis needs to be managed conservatively and prepared for elective surgery
within 4 weeks. ERCP and stent may be needed.
delete?
No change
92
1 Should we consider consulting GI if there is no SCD specialist available?
Invited-Non
Disclosed
Yes, but no need to spell out in the document since obvious No change
92
1 these 3 points appear to be a bit redundant and probably could be condensed.
Public
Disagree. Points should be separate
No change
92
1 Evaluation and management of AHS and intrahepatic cholestasis must include

exclusion of other causes of acute live disease such as infectious or autoimmune
hepatitis. There should be a recommendation for exclusion of these entities before
assuming it is related to SCD.
Invited
Wording does not make an assumption about SCD

diagnosis
No change
Page # Line #
Comments
92
4 order LFT, coags, cbc, retic, RUQ US
92
5 This recommendation is redundant and should be deleted or changed.
Suggestions
change to getting a consultation from a
gastroenterologist with expertise in hepatic sickle cell
complications.
Type
Invited
Public
Beyond the scope

Covered previously
Discussion
No change
No change
92
9 This is a mismash of many causes of anemia and actually confuses the many issues
in transfusion of patients. Restructure and make it make some sense. Your discuss
ASSC and ACS here before you present and discuss them in full.
Public
Disagree. This is background
No change
93
1 Add acute blood loss as with renal papillary necrosis or from another site as a cause
for worsening anemia.
Invited
Uncommon cause. Think about ulcers in adults with

comorbidities. Will revise on page 94 instead.
No change
Invited
Beyond scope; will address later in the document
No change
Public
Beyond the scope
No change
93
21 Add sentence about risks of parvovirus B19 to pregnant personnel, other patients
95
Add review of peripheral smear for acute anemia
96
0 Regarding splenic sequestration, there is no mention about management of young

children <2 years of age and about the risk of pulmonary hypertension postsplenectomy.
Invited
Beyond the scope
No change
96
1 Background should include data on sequestration related mortality
Invited
No change
96
98
11 could use a reference for this statement.

20 The sentence Transfusion was reported to be effective in treating ASSC is silly and
should be omitted. If you are anemic, the major problem with ASSC, transfusion is of
course effective.
Public
Public
Beyond scope. Mortality is now low but do not need to

mention
Disagree
Just reporting evidence; can't change
99
Public
No new key questions can be added at this stage.
No change
99
99
0 Page 99: ACUTE CHEST SYNDROME - A key question might be "when to consider
HCT."
4 Does this recommendation extend to children <age 2 years
6 Disagree with this recommendation, particularly with very young children
Invited
Invited
Yes.
This recommendation has been deleted.
No change
No change
99
6 Provide a definition for "short term" in the recommendation statement
Fed
No change
99
6 Strongly disagree with this oversimplified rec. Short-term transfusion may be very
appropriate to reduce risk of death until splenectomy can be performed.
Public
No change
99
6 "Avoid" is too strong based on clinical experience and antedotal reports that 6 month Clarify wording.
period of transfusions have a 50+ % chance of sparing splenectomy (ie successful
second chance)
Public
No change
8 The Section on ACS suggests that incentive spirometry during VOC hospitalizations is
preventive. This should be noted elsewhere (e.g., in the prevention section)
Public
No change
100
Clarify recommendation to accommodate the value

of shorterm transfusion.
No change
No change
Page # Line #
100
14 Acute Chest Syndrome
100
Comments
Suggestions
Type
Specific antibiotics should be recommended with
Public
dosing. Treatment for broncho-reactive lung disease
is indicated. Bronchospasm is difficult to detect
clinically. There is significant published data
documenting broncho-reactive lung disease during
acute chest syndrome. Relying on clinical detection
alone is not reliable. Techniques including peak
expiratory flow are warranted if available. Otherwise,
bronchodilators should be included. Patients should
be evaluated for acute pulmonary embolism if
appropriate symptoms exist. Patients are often
under or over treated for pulmonary embolism.
Recommendations concerning this and its therapy
should be included.
Discussion
This will be addressed in the Acute Pain section
No change
Invited
No change
Public
This is outside the scope of the document.
No change
101
15 What direction is needed to assess if office if need to go ED if saturation is below

what? 89% should this be stated.
15 Anyone being admitted to the hospital for a pain crisis should have a CXR as these
symptoms are non-specific and ACS frequently develops post-hospitalization for
VOC. Pulse oximetry should be monitored regularly (at least once a 8 hr shift) in all of
these patients regardless of symptoms.
101
15
Per comment on page 81, whould consider CXR for Public

all febrile patients to evaluate for ACS
This is covered in the fever section of the document
No change
101
15 There is no discussion of the need to establish a precise definition of acute chest

syndrome.
The first recommendation should be to define acute Public

chest syndrome accurately using established criteria.
No change
101
15 No mention of chest pain as a potential symptom of ACS
Invited-Non
Disclosed
No change
101
101
101
15 Add chest pain to the symptoms of ACS.

15 Evaluation labs should include CBC retic and blood culture
18 For clarity, does it need to be stated when transport is needed to take to ER if ACS is
suspected
19 Would construct guidelines for ICU admision - multi-lobar disease, multi-system organ
failure, severe hypoxemia, etc.
20 Need to specify what organisms you are covering. Not all IV cephalosporins have the
same spectrum. For example, Cefazolin is not the same as Cefepime. Additionally,
there are other regimens such as levofloxacin and the other quinolones that would be
equally effective here.
Invited
Invited
Invited
This is being handled in a re-write

This is being handled in a re-write
Beyond the scope of this document
No change
No change
No change
Public
Beyond the scope of this document
No change
Public
Panel working on revsions to this section. This will be

covered in the revision.
No change
101
20 For treatment of ACS would include IV extende spectrum fluroquinolone as adequate

therapy for adutls with SCD and ACS-like levofloxacin
Invited-Non
Disclosed

No change
101
20 macrolides can be given IV. Why cephalosporin? If additional antibiotics are needed, ACS with a macrolide and additional antibiotics as Public
ampicillin, unasyn, zosyn, vanco might be reasonable. Or a quinolone instead of a
indicated
macrolide?

No change
101
101
Page # Line #
Comments
101
20 "recommendation to start IV cephalosporin and oral macrolide":
Choice of antibiotics should be determined by local microbiological patterns and
individual needs.
101
101
101
Suggestions
We recommend editing to add "start IV
cephalosporin or other broad spectrum antibiotic
along with an oral macrolide."
Type
Public
Discussion
21 The rationale for a goal O2 sat of >95% is not supported by the literature or common
pulmonary physiology management.
21 Why does it have to be an oral macrolide? Can it be IV if necessary due to patient
condition? I might change this to a macrolide, oral if possible.
Public

No change
21 Oxygen to increase o2 sat to 95% may suppress reticulocytosis, and this risk should
be considered. Many authors feel 90-92% is sufficient.
Public

No change
Invited
No change
No change
102
0 Page 102: ACUTE STROKE - A key question might be when to consider HCT.
Public
This is covered in a previous comment.
No change
102
0 Recommendations: Based on clinical practice experience,

ACS due to hypoventilation can be avoided or minimized by the use of an Incentive
spirometer. Causes of hypoventilation are, among others: Pregnancy, bony chest
pain, upper back pain, right upper quadrant pain, following general anesthesia, upper
abdominal pain and narcotics.
Public
This is covered in a previous comment.
No change
102
After "oxygen," add: "the alveolar to arterial (A-a)

oxygen gradient suggests impending or overt
ARDS,"
Public
No change
102
add "in whom a more severe" before decline
Public
This is going to change after this section is revised. Panel is No change

working on revisions and will also take into account
Hassan's response.
Invited
This is already handled in a revision. Headache, sensory

No change
and motor changes, aphasia, and sometimes seziures or
coma.
Clarify wording.
Public
Panel is providing a revision of this that will help clarify.
No change
Patients either have strokes or do not, any single

patient does not have them infrequently. Why not
state the numbers.
Public
Dr. Buchanan will be sending a revision
No change
102
15 Add headache and other neurological signs in the symnptomatology of stroke.
102
17 "...but neuroimaging is negative and not predictive of stroke is confusing. confusing

phrase. Perhaps: " ..but neuroimaging is negative. In setting of TIA, strke risk is high
even with normal neuroimaging."
103
6 Poorly worded
103
6 Would suggest modify the statement -people of all ages with HbSC and HbSB+thal
rarely have overt CNS events as HbSC and HbSBthal is associated with increased
stroke risk in middle age adults-rare to see in children and young adults (age <35 to
40)
Invited-Non
Disclosed
Team will be sending a revision
No change
103
9 there are data now from the NIS that show hospitalizations for stroke among kids with example is Ovbiagele and Adams 2011
scd have falled in the Post STOP era
Public
No change
No change
104
Public
No change
No change
Public
This is mis-placed, we think it is p. 103, line 16. This has

been revised
This has been revised.
No change
Team will work on adding wording about this into the

Background of the chapter based on a previous comment.
No change
104
Would not start paragraph with "However"
105
16 The fact that data are limited does not suggest that TCD is not suggestive of stroke in Revise sentence
adults, as this sentence implies
2 There is a typo here are well. I think you mean goal of < 50% after a period of years
with a goal of <30%. At least that is what was published by Cohen. As it is now you
suggest that <30%=<50% and it is not.
105
17
Public
SWiTCH study results should be mentioned here for Public

completeness and comparison
No change
Page # Line #
105
18 Acute Stroke
Comments
Suggestions
Type
Transplantation is effective therapy for patients who Public
have had stroke. The data is very convincing. All
patients who have had a CNS event should have
HLA studies done, and families should be offered
sibling-matched transplantation.
There is increasing data available using
encephaloduroarteriosynangiosis (EDAS). EDAS
has been studied in several diseases, and appears
beneficial. It should be discussed in the
management section for stroke patients with
moyamoya.
Discussion
No change
105
18 It is worth mentioning that the most effective strategy at least in children is prevention
by annual screening with TCD and primary prophylactic transfusions
Invited
This comment is addressed in the HM chapter, and

mentioned briefly in this chapter.
No change
105
19 Not all emergency departments have neurologic consultation available for emergency
consultations.
Invited-Non
Disclosed
No change
No change
105
19 in this section it would be useful to have a comment on recs of antiplatelet agents,

lipid lowering agents, etc.. In SCD patients with stroke (ie do recs in non scd pateints
apply
Invited
Beyond the scope
No change
105
21 CT is not needed, if MRI is immediately available
Public

with these comments
No change
105
21 Would clarify that no head CT is necessary if urgent MRI can be obtained
Invited-Non
Disclosed

with these comments
No change
105
22 It seems that an emergent CT is indicated if the patient is unstable; however, if

someone has acute onset of paralysis and is otherwise stable, an emergent MRI is all
that is needed. Saying that a CT must preceed the MRI in all circumstances is not
true. Please allow for flexibility in this recommendation.
Invited

with these comments
No change
105
22 Recommendations: Followed by Magnetic Resonance Imaging (MRI) and a MRA.
Public

with these comments
No change
106
106
106
0 Beyond these comments its a good review of basically a data free zone.
Change sentence to reflect
Emphasize the need for more data, any kind of data Public
really in adults
0 there are several case reports when I search multiorgan failure and sickle cell.
Search pubmed using 'multiorgan failure' and 'sickle Public
cell'
1 Modify the recommendation. Some individuals with stroke who have very low Hb can
Invited
be managed by simple transfusion alone. In other patients, a simple transfusion
should be performed first while exchange is being arranged. These recommendations
have medicolegal impact, hence caution is necessary.
This is not the appropriate section for this and is dealt with in No change
research gaps.
So noted.
No change
Add to line #1 "Perform simple or exchange transfusion"
INSERT COMMENT THAT THIS REQUIRES PANEL
REVIEW.
No change
Page # Line #
106
6
Comments
Suggestions
Type
Perhaps include a clarification of thrombolytics and Public
anticoagulant agents regarding aspirin, since aspirin
is recommended in patients with MoyaMoya disease.
Discussion
Change covered in previous comment
No change
Consider input from neurologists and separate

Public
recommendations for children and adults. Certainly
they should be avoided in hemorrhagic stroke.
No change
106
6 The recommendation to avoid thrombolytic and anticoagulant therapy (aspirin) in

adults with thrombotic stroke is at odds with standard recommendations used in
ACLS, BCLS, Stroke Center guidelines and many others.
106
6 Would not recommend avoiding anticoagulant therapy in patient with SCD and
ischemic stroke if they have clear indication-such as atrial fibrillation or another cause
of embolic stroke or cerebral sinus thrombosis
Invited-Non
Disclosed
No change
106
6 Recommendation #4. This consensus opinion is potentially inaccurate, since it is

Clarify wording to accommodate discrepancy of
contrary to evidence-based practice for ischemic stroke in non-SCD patients. Also
recommendation with evidence-based practice in
need to clarify sentence since following acute ischemic event long-term anticoagulant non-SCD patients.
agents may reduce risk of recurrent stroke
Public
No change
Invited
Invited
Public

This comment is covered in a previous change.
No change
No change
No change
Invited
No change
Public
If patients cannot get transfusions, they cannot get a BMT.
No change
106
106
106
7 does this include aspirin?

8 consider adding information on goals
10 The authors recommend initiation of hydroxyurea therapy if transfusion therapy
cannot be provided. This is unclear to me. What does this mean, "cannot be
provided"? This statement seems out of context for the mission and goals of the
expert panel. Transfusion therapy is the standard recommendation therapy.
106
10 In children and adults who have had a stroke, initiate hydroxyurea therapy if
transfusion therapy cannot be provided. (Moderate Strength, Low-Quality Evidence)
I do not think this recommendation should be given. Maybe this is the panel expert
recommendation, but I do not think there is evidence for this.
106
10 There is no recommendation to consider a BMT
106
10 There is no mention of the strokes that occurred in the Hydrea arm in patients on the Please mention the evidence of recurrent strokes in Public
SWITCH study. Even though the primary endpoint of the study was not stroke, only
the SWITCH study and make recommendations
patients switched to hydroxyurea had recurrent strokes and no patients on the chronic keeping that trial in mind.
transfusion arm had a stroke recurrence. The panel has ignored this important RCT,
upon which a strong recommendation should have been based.
No change
106
10 very limited data to support this recommendation, including SWiTCH study results.
Why not consider stem cell transplant?
Invited
No change
106
11 What is the panel's recommendation for perfomance of an MRI/MRA with elevated

TCD values to rule out unsuspected clinical stroke. THIS should be discussed and
What is the Panel's comment on the role of a hypercoagulable evaluation in patients
with SCD and stroke? This should be stated.
Public
No change
More details should be provided concerning the

recommendation of hydroxyurea as a replacement
for transfusion therapy in stroke management in
order to prevent misuse of this option. You may want
to indicate that all patients should be treated with
transfusion therapy, but that in specific countries that
do not have access to safe blood, hydroxyurea
therapy may be considered.
Patients siblings should be HLA typed to find a

potential donor for BMT, if not previously done.
Page # Line #
106
11 Wording is confusing/ambiguous.
107
Comments
Suggestions
Type
In children and adult who have had a stroke, initiate Public
hydroxyurea therapy if transfusion therapy is not an
option due to other medical complications
Discussion
This is already revised based on earlier comments
No change
This is actually p. 106 and has been addressed
No change
Monitor mental, respiratory status, renal function,

Public
direct bilirubin, AST, ALT, hemoglobin and platelet
count to detect early multiorgan failure in individuals
with unusually severe pain episodes to detect early
multiorgan failure and prevent progression Hassell et
al. Amer J Med 1994. in references.
No change
8 Would consider separating the recommendations for children and adults for regualr
transfusions and hydroxyurea as almost all of the evidence is in children/pediatric age
group for first stroke and also ischemic and hemorrhagic stroke may differ
Invited-Non
Disclosed
107
10 Recommendation 1 lacks specificity.
107
10 specify recommended workup (even though described in section on evidence)
Invited
No change
107
Public
No change
Public
This is not necessary
No change
107
16 Any patient with multi-organ system failure needs to be seen by a critical care
specialist and be in an ICU setting.
17 The transfusion and exchange should be moved up to the 2nd or 3rd
recommendation.
17 MSOF should be managed in a hospital setting equipped with an intensive care unit.
Suggest that the Panel recommend that patients with Public

MSOF should referred to a well equipped hospital
where ICU and exchange transfusion capabilities
exist.
No change
108
110
14 helpful to know
3
Invited
After "nerves III and V." add: "Medical management Public
should include prompt transfusions or exchange
transfusions to prevent further orbital ischemia,
which in SCD can occur along with an infective
etiology of the orbital syndrome."
No change
Recommendations are not apporpriate in this section. There No change
was not enough evidence to make a recommendation about
using transfusion to manage these acute complications.
After "(Sokol 2008)." add: "Transfusions or

exchange transfusions should be carried out before
or at the start of sytemic steroid therapy to prevent
potential steroid-related vaso-occlusive events"
Public
Recommendations are not apporpriate in this section. There No change

was not enough evidence to make a recommendation about
using transfusion to manage these acute complications.
Public
The team has covered this issue as much as possible in the No change
chapter. Additional content is out of the scope of the chapter.
Invited
Public
Public
Thank you
107
110
111
0 Accute Occular Conditions: Recommendations - ( from Clinical practice experience)

Orbital compression syndrome(OCS) is a serious and very painful condition which
requires immediate hospitalization. Management include immediate ophthalmology
and hematology consults, pain management, IV antibiotic and Transfusion. As stated
in this chapter, OCS occurs often with a VOC.
111
111
112

5
1 Excellent suggestion. Pain management is one of the most challenging aspects of
the disease. People are still being treated as drug abusers by poorly trained
unqualified physicians.
Change order.
After "SCD" add: "or sickle cell trait"

Encourage hospital staffs to go through mandatory
training in treatment of SCD in order to be
accredited.
No change
No change
No change
Page # Line #
Comments
113
3 Is it ethical to do a study of open vs. laparoscopic cholecystectomy today?
Suggestions
Type
Public
Discussion
This has been addressed in a previous comment
No change
113
3 OMIT this research recommendation. The panel concludes, correctly, that

laparoscopic cholecystectomy is the way to go. To study the question is unrealistic
and denies persons with SCD the state of the art surgical management of their
common complication.
Public
This has been addressed in a previous comment
No change
132
1 from a primary care standpoint, I wonder if there was any SCD specific evidence on:
1)nutritional concerns or recommendations, 2) exercise limitations/adaptations given
AVN, issues of temperature disturbance triggering VOC 3) dental management given
risk of infection, ?exacerbation of VOC 4) sleep assessment, recommendations given
increased risk/impact sleep apnea 5) mental health assessment/management given
high prevalence chronic pain. I know these may not all fit into the chronic
management section - some better for health maintenance
INV
No change
133
1 Does each chapter need to repeat of the general introduction and methodology-It
makes the entire guidelines longer and more challenging to read
IND
133
3 I would suggest incorporating discussion on management of adult SCD patients and

how it differs from pediatrics. While I recognize this is a clinical guide, the practical
management issues of an adult patient (outside centers, requiring a transition
program, intermittently transfused) make management difficult and education
opportunities to health care professionals high.
71
77
0 Page 71: MANAGING ACUTE COMPLICATIONS OF SCD

9 What are the end-points of escalation? Is there an upper limit on dosing?
Would recommend adding a sub section
Public
No change
This is a chronic complications issue.
Public
Invited
81
10 Would add reticulocyte count to the CBC for diagnosis of transient red cell aplasia
Invited
Team agrees.
97
11 Statements about transfusions in this section confusing. Line 11 seems to contradict

line 21 on same page.
2 Consider adding more details on stroke management including admission to ICU,
goals for transfusion, mechanical ventilation, anticonvulsants, IV access
Invited
Will edit line 21, should we call it chronic transfusion? Clarify

with methodologists.
This is outside the scope of this document
106
Invited
No change
Page #
176
176
183
185
186
Line #
Comments
3 What "clinical outcomes" are you referring to---pain? ACS? I'm assuming these two because that's what you started
the chapter with.
9 Why limit the use of hydroxyurea for other disorders to the 1980s? Typo?
6 Please reference the "exhibit 8" table in the text about evidence of harm--make it clear that you review potential
adverse side effects.
17 I could not follow this statement, as BABY HUG was a clinical trial and did not require 3 crises per year as an entry
criterium
4 The strong recommendation with high quality evidence for treatment of infants and children with hydroxyurea is
overstated and not consistent with the opinion of most pediatric hematologists. The BABY HUG study was designed
to demonstrate a reduction of organ system damage, and failed in its primary objective, which was chosen to provide
strong evidence for the use of hydroxurea, and which was felt to be a demonstration necessary for a definitive
outcome. The duration of treatment (2 years) was not sufficient to guarantee the safety or efficacy of long term
treatment and is based on less than 100 patients treated with hydroxyurea for two years. This makes a broad and
strong recommendation very tenous. The BABY HUG Lancet paper recommended that treatment be offered to all
patients, a more reasonable conclusion. We recently obtained expert opinion from 17 pediatric hematologists at 17
centers, which indicated that 15 of 17 (88%) did not agree with treatment of all children with hydroxyurea at an early
age. This opinion was obtained in April 2012 at the SIT Trial investigator's meeting, well after publication of the BABY
HUG results and with the purpose of assessing the effect of the results on this opinion. This indicates that the
majority of the pediatric hematologists in the SIT Trial do not agree with universal treatment of all infants and children
with hydroxyurea.
Suggestions
Clarify statement
Type
Invited
Public
Discussion
"...outcomes, especially pain and ACS, Done
..."
Change 1980's to "for several decades Done
prior to its use in SCD"
Invited
Include reference, "See Exhibit

8."Change Evidence of Harm to
Evidence of Side Effects for both
subheading title and exhibit title
Public
Add phrase to line 17, which in most Done

cases would limit the use of HU".
Line 13 acknowledges that BABY
HUG did not require it.
Change recommendation to
Public
"hydroxyurea should be offered to all
infants and children with SCA."
Recommendation would be considered
Moderate, evidence as well.
Done
This is about recommendation #5 on Done, but grading is not the same for both age groups. One is
page 187. We will recommend to offer strong rec, high, the other is mod rec, mod. Added query to
treatment, but keep as
file requestijng clarification.
moderate/moderate. Combine the age
groups since the grading is the same.
Change recommendtation first
statement to "In infants 9 months of
age and older, children and
adolescents with SCA"
The recommendation for treatment of infants appears to be stronger than for adults, which seems odd. There is also
a disconnect in childhood, with a weaker recommendation for children over the age of 42 months. Should the reader
consider discontinuation at 42 months?
The following is a more elaborate discourse on this issue that I shared with the BABY HUG investigators in responding
to Letters to the Editor in Lancet, and may be of help:
"I do think that there are two issues that we should separate:
1) What does BABY HUG tell us, critically evaluated; and
2) What is the most reasonable course of action for our patients, given the present level of evidence
186
... During the deliberations on the design of BABY HUG, I remember several feelings that were expressed by many
people:
1) Simply demonstrating that events could be reduced by HU would not be a convincing endpoint, as this was almost
assumed from previous studies in adults and children. It was the low-hanging fruit, but not a convincing endpoint.
2) The endpoints were chosen to show that organ systems could be protected, which was felt to be necessary to
provide further evidence that the drug should be used early in life.
3) Demonstrating safety was of tantamount importance.
19 Definition for severe ACS. IS one recurrence enough to recommend HU?
Invited
Refer to the ACS section of the acute Done

chapter here.
189
9 "Give maximum of 35 mg/kg/day or until mild myelosuppression is achieved. This dose can be considered maximum
tolerated dose." It is unclear whether doses higher than 35 mg/kg/day are recommended until there is mild
myelosuppression. Also MTD deserves a clearer definition separated from the proposed maximum dose . Are you
implying that the MTD is the dose above 35 mg/kg/day at which there is mild myelosuppression or any dose at which
there is mild myelosuppression? First, MTD was originally thought of as a dose above which there is REPEATED
myelosuppression, not just once. Second, MTD is NOT a fixed characteristic for all patients; some children who had
repeatedly been intolerant of doses lower than the maximum dose have been able to tolerate increases above their
presumed MTD when challenged months later. (this may reflect the concomitatnt effect of other causes of
myelosuppression, e.g., viral suppression that may take several weeks to resolve. Third, why is the MTD defined in
terms of mild but not moderate or severe myelosuppression?
Invited
Give until mild mylelosuppression

(absolute4,000/uL) is achieved, up
to a maximum of 35 mg/kg/day.
Done
189
12 Need for hydroxyurea monitoring every 8 weeks seems excessive- in "real life", it will not happen! Toxicity is usually
evident early, but once patient arrives at therapeutic dosing, cytopenias are uncommon and rarely require dose
adjustments.
Public
change to 8-13 weeks and add

"reticulocyte count" to list of tests
Done
189
12 "Stable effective dose": What is the meaning of effective? A weakness in HU therapy in SCD is the lack of definition of
a therapeutic goal. If an intermediate goal such as Hb level were used to guide the treatment, clinicians could easily
use that to adjust doses until the goal is reached. For example, if Hb 10 were selected as a "surrogate" therapeutic
goal, clinicians would increase the dose until Hb 10 or the maximum dose was achieved, then assess the clinical
benefit over time as that Hb level is maintained with dose adjustments. That Hb goal will be achieved at different
doses of HU for different patients; the lowest dose at which that Hb level is achieved would be defined as the lowest
effective dose (LED), a potentially useful safety feature in HU therapy. Waiting for decreases in frequency of pain or
ACS in an individual patient is a very imprecise definition of "effectiveness" since these events may not occur that
frequently. This is especially important since HU therapy is being recommended for ALL infants and children. In an
infant without a long history of complications, how would the clinician assess the value or effectiveness of the therapy?
Treatment or no treatment, frequency of dactylitis decreases over time. I suggest a revision of the dosing protocol to
base it on an easily demonstrated effect such as Hb level.
Invited
Remove word "effective"
Done
Public
ADD at end of statement "...unless

hemotological toxisity is present."
190
190 5-6
191
0 more important than monitoring CBC for neutropenia is pt education around febrile illness.
Use of Hydroxyurea - Recommendation states "For the patient who has a clinical response, Hydroxyurea therapy
should be continued indefinitely."
15 panel sttes "data are needed concerning the effects of hydroxyurea therapy during pregnancy". Is that ethical to do subject an unborn child to potential harm of a known chemotherapeutic agent?
include pt education of fever whilst on

hydrea in the guidance.
This recommendation is stated as a

Public
treatment "fact", however, there is little
data to justify long-term use in adults.
According to "Knowledge Gap" pg. 190
"More research is also needed on the
long-term effects of Hydroxyurea
therapy on people." And, "Li
Hydroxyurea should not be given to
pregnant females due to the potential
risk to the unborn child.
Public
Done. Added query to file to confirm that this should

be: Monitor RBC MCV and HbF levels for evidence of
consistent or progressive laboratory response unless
hematological toxicity is present.
change, to: For the patient...long-term Done
HU therapy is indicated. (Delete HU
therapy should be continued
indefinately)
to first sentence add "in humans".

Second sentence delete human.
Change "Studying" to "Assessing"
Done.
191
18 It seems an important factor to study would be impact of the way HU is presented to the pt esp in terms of
risks/benefits; what is most effective communication in terms of discussion and written materials
174
3 The two introductory paragraphs seem out of place here--you discuss pain and then respiratory complications/ACS.
But the chapter is about hydroxyurea. How do these topics relate? I'm assuming that the reason these two
paragraphs are in here is because there is evidence to support the use of hydroxyurea in these two
instances/outcomes. But need to make this clear. If this is true, then at very minimum consider including
subheadings that clearly indicate why these two first paragraphs are in here....
175
7 Hsieh
reference
182
1 The table "exhibit 7" is very helpful, but need to reference it in the appropriate section in the text
178
7 Change received by Editor 10/4/12
186
12 General question: Is there any reason that universal education on hydroxyurea should not be recommended to all
patients with sickle cell anemia?
186
12 In this HU section it would be nice to comment and give recs on 1.)need to monitor electrolytes and LFTs If any 2.)any
worrisome drug/drug interactions to know about 3.) use or non use in patients on transfusion protocols 4.)efficacy or
nonefficacy to decrease stroke recurrence, priapism, pulm HTN etc...
190
8 The format of this future research section is different from that in the other chapters. It should be reformatted with
bullet points.
Missing in
list
Invited
Change to: Finally, data are needed

concerning patient-identified barriers
and facilitators to the use of
hydroxyurea, including methods (or
ways) to improve communication
between clinicians and patients
regarding the benefits and risks of
treatment.
Done
Invited
This needs to be mentioned. Perhaps

some re-wording/shortening of the
paragraphs is needed. Introductory
sentence.
Add on Line 4, after "This chapter addresses the use of

hydroxyurea in adults and children who have SCD":
"Hydroxyurea is efficacious in preventing sickle-cell
related pain and acute chest syndrome. A brief
overview of these complications will be presented.
DONE
Public
Yes, this is missing
Hsieh MM, Kang EM, Fitzhugh CD, Link MB, Bolan CD,
Kurlander R, Childs RW, Rodgers GP, Powell JD, Tisdale
JF. Allogeneic hematopoietic stem-cell transplantation
for sickle cell disease.
N Engl J Med. 2009 Dec 10;361(24):2309-17.
Invited
Will send reference
Done. See comment below. Call out for exhibit 7 added

to text.
P. 186, line 1: Add a statement to the end of the
opening paragraph for SUMMARY OF EVIDENCE, p. 178,
line 7: "Please see Exhibit 6 for participant
characteristics for the randomized trials and Exhibit 7
for the evidence profile of efficacy/effectiveness for
hydroxyurea in patients with SCA." DONE
Consider education of all patients with

sickle cell anemia on hydroxyurea as
part of recommendations.
Public
Interesting suggestion for a consensus 10/4: The following will be the first recommendation
statement. Agreement on this.
with renumbering of the others: "Educate all patients
with SCA and family members about hydroxyurea
therapy. (Consensus Panel Statement)." DONE
Invited
1. Data is not available to clarify the

intervals. Will submit wording and
placement. 2. Data not available to
allow us to make statements about
this. 3. Data not available to make
statements about this topic. 4. Data
not available. Will submit for #1. Will
also submit content for gaps section
related to this comment.
10/2: In reference to #1: Knowledge Gaps and

Research contains a bulleted point identifying type of
laboratory tests and optimal frequencies for monitoring
need to be identified through clinical studies.
Public
Will re-work that.
See attached Word document with reformmated

Knowledge Gaps and Research section.
188
18 neuts >2.0 is a generous cut-off and may limit dose escalation unecessarily. Many hem amd hem-onc physicians are
comfortable with neuts 1.5.
lower recommended low level of neuts

to 1.5
Public
Will submit changes to cover the ANC

comments about page 188 line 18. On
line 17 add ", reticulocyte count" after
"differential". 9/2312: Current:
Maintain absolute neutrophil count >
2,000/uL
Proposed: Aim for a target absolute
neutrophil count of >2000/uL;
however, younger patients with lower
baseline counts may safely tolerate
absolute neutrophil counts down to
1250-1500/uL.
Feel free to edit further
Added "reticulocyte count." Also, revised text per

suggested comment: Current: Maintain absolute
neutrophil count > 2,000/uL. Proposed: Aim for a
target absolute neutrophil count of >2000/uL;
however, younger patients with lower baseline counts
may safely tolerate absolute neutrophil counts down to
1250-1500/uL.
183
6 Is the animal data relavent to human reproductive toxicity?
Invited Not
Disclosed
Need to go back and check on this.

Check with methodologists on this.
Were animal studies included?
No change. Animal data are not included in our systematic

review and this is explicity mentioned in the search strategy in
the evidence report.
179
6 Need end parenthesis after.."group)".
Invited
Good catch.
Change needed possibly. Editor review please.
Invited Not
Disclosed
The panel has discussed this

Would not add anything to the Introduction section. On
extensively. We are not able to define page 185, lines 3-9 address spectrum of pain. I would
this exactly for all patients.
not make any additions.
186
13 Could mild to severe pain events be defined for clinicians using these guidelines?
183
6 Should rash be mentioned? Increased skin pigmentation is a fairly frequent, though mild, AE
Invited Not
Disclosed
We could add it as another side effect. No change needed. Mild skin pigmentation is not a patient
WE need to back and look at what the important outcome in this content and we typically do not
evidence is.
include it in evidence profiles (only serious side effects are the
ones considered as tradeoffs for stronke/mortality/pain crises.
181
174
9 Pediatric Hydroxyurea "Phase" the P is capitalized in phase studies.

0 Use of Hydroxyurea Therapy in People with Sickle Cell Disease: This chapter is a good document regarding what we
know
about hydroxyurea. Data collection is still needed regarding scheduling, dosage, long term toxicities. Because of
Bone Marrow suppression with the use of hydroxyurea, the dose may need to be lowered early.I feel that
patientsshould have a blood count every 2 weeks until adequate dosage is reached. With consult form a
hematologist a primary provider will determine when a stable dosage is reached and whether the patient should have
a blood count every month or every 2 months.
Public
Public
Good catch.
Will address this statement in the
appropriate section of the comment
file.
STET per GPO style.

No change
175
7 Editor Note: No line and page number provided. Used line and page number of commenter's previous comment.
Public
Skip, no page/line
No change
Invited
The team does not see the need for

subheadings. This is explained in the
text.
No change
175
19 Need to include a subheading to this paragraph about HbF---why do you talk about HbF? IF this is tied to the
mechanism of action of HbF, then include a subheading here
Should we not
include HbSC?
176
9 Would consider mentioning that Hydroxyurea approved by FDA in 1967
177
179
0 Would addressing cost of hosital vs. ER visit cost reduction of HU be helpful
Invited
We do not have ED studies available

for MSH. Agreed, this would be
helpful. This was a summary of MSH
findings.
No change
179
7 Overall costs were not statistically different between the two groups, so why is it relevant to just inlcude costs for pain
hospitalizations
Invited Not
Disclosed
Keep as is.
No change
183
6 Is there really moderate evidene that hydroxyurea does not cause cutaneous ulceration in adults or children? The
RCTs were not powered to show a differnce in cutaneous ulceration rates and there is a rate of 1% or so in other
populations treated with HU
Invited Not
Disclosed
The team believes moderate is

appropriate. It was not a primary
outcome.
No change
183
8 The reproductive effects of hydroxyurea are not adequately addressed. There are reports on azoospermia with long
term use, and it should not be given to pregnant women, unless there is evidence that hydroxyurea has no
teratogenicity. I am a big proponent of hydrozyurea since its benefits outweigh the risks. However, we should not
become incognizant of the harmful effects or ignore mentioning them.
Panel should include studies reporting

the potential harmful reproductive
effects of hydroxyurea.
Public
There are not enough studies for us to No change

discuss, and we do have a rec not to
use it in pregnancy. This is vaild
comment but there is not enough data
to support - this is an area for further
research. In gaps section already.
186
12 Hydroxyurea Recommendations: This is a detailed, well-developed review of hydroxyurea and its recommendations.
We are in agreement with these recommendations.
Similar detail by experts should be

applied to each of the other
complications.
Public
No change
186
13 In Voskaridou et al 2010 paper, hydroxyurea was shown to increase survival of the more symptomatic SCA patients
In all patients with SCA, treat with
over those patients not put on hydroxyurea because their symptoms were considered mild. This argues that adult SCA hydroxyurea.
patients should be on hydroxyurea regardless of symptom severity. From the BabyHUG study, we know that
symptoms of SCA begin early in life, even if the symptoms are not clinically obvious. I believe it can be stated that
there are no SCA patients who are asymptomatic. Therefore, why restrict the use of hydroxyurea to adult patients who
have severe symptoms? The guidelines do not place restrictions on the use of hydroxyurea in children, why restrict
adult usage of hydroxyurea when survival benefit was demonstrated not once, but twice, in adult patients? Limiting
hydroxyurea therapy in adults also contradicts guideline on p. 190 line 5 "For the patient who has a clinical response,
hydroxyurea therapy should be continues indefinitely."
Public
We have no clinical studies to support No change

doing otherwise. No clinical studies in
adults who are not symptomatic.
186
19 How are you defining "severe" and "recurrent"?
Invited
Change covered in previous comment No change
Need more documantation in

Public
background if you are arguing ALL kids
should be on hydroxyurea.
187
Invited Not
Disclosed
There should be a discussion on WBC Public

and response to hydroxyurea therapy!
Not needed. This is addressed

indirectly.
No change
This is addressed on page 177, line 3. No change
187
4 1. If this recommendation is intended to suggest that all children should receive HU regardless of disease severity"
then this should be emphasized.
2. Would recommend specifically stating patients with SS disease if that is what is intended.
Public
187
4 I would recommend modifying the force and strength of this recommendation as the BABYHUG study that serves as
the evidence did not demonstrate statistically significant findings either of its primary endpoints. The acute
complications were all secondary endpoints (threshold for significaince set at p<0.01 in the analytic plan for the study).
Only dactylitis, all pain events, and pain only events were below this threshold. Approximately 2 children would be
need to be treated for a year to prevent one pain event. Also is this recommendation for fixed HU dosing (20
mg/kg/day as used in BABYHUG) or dose escalated HU based on hematologic parameters?
Invited Not
Disclosed
187
4 Do you include adolescents here? If so need to specify (confusing because you mention the strength of evidence for
specific ages and adolescents right below)
4 This recommendation is premature and misleading for asymptomatic infants and young children and should not be
included at this time
4 I do not agree with the strong recommendations for infants, treat with hydroxyurea regardless of complications
5. In children with SCA, treat with
nor that the evidence is high quality for 9 - 42 month olds. The infant data is primarily comprised of the HU-SOFT (21 hydroxyurea regardless of clinical
patients, 11 who had up to 6 years of therapy) and BABY HUG trials (67 on HU, 2 years of therapy). I dont think that severity
this amount of experience is equivalent to the decades of work and long-term monitoring of the MSH and do not
believe that NIH should be making such a strongly worded guideline based on this small body of research. I also dont
think that the FDA would find this level of evidence convincing for the approval of HU for infant use.
Invited
Invited
Public
187
4 As a comparison, even though the STOP study showed that RBC transfusions reduce stroke incidence in children with Clincal registries of children with SCA Public
high TCD velocities by an impressive 90%, there were many critics who were concerned about over-treatment of the treated with hydroxyurea should be
roughly 50% of individuals with high TCD velocity who might not ever get a stroke and it took another 5+ years before developed and maintained to be able to
TCD screening and transfusion therapy became more mainstream in clinical practice. In the case of universal HU
adequately monitor efficacy and longtherapy for all infants, how many of the potential patients have high risk for severe outcomes, what outcomes can we term safety.
be confident in knowing HU will help, and what are the potential risks of lifetime HU therapy beginning in infancy?
187
4 The lack of published reports about potential toxicities in the infant group is not equivalent to the demonstration of
long-term safety. I am concerned that infants, with their rapid rate of growth, will be at increased risk of malignant
transformation beyond what has been observed in children > 5 years and adults. Of course, none of this has been
documented yet, due to lack of sufficient long-term follow-up studies. At the current time, I believe that treatment of
asymptomatic infants with SCA is still in the experimental phase, and fully agree with having a BABY-HUG follow-up
study, and the newly funded R34 study of the effects of HU on the development of CNS complications in infants with
SCA. I strongly agree with the Opportunities for Research that a national registry would be invaluable to fully
understanding the effectiveness and safety of HU, and I believe that this should be a funding priority. In addition,
more basic-translational research is needed to better understand the mechanisms of HUs beneficial actions are
there direct effects on inflammation, vascular remodeling, ischemia-reperfusion, the hallmarks of SCA
pathophysiology?
187
187
Recommendations for infants should

await longer follow-up of children
treated in recent infant HU treatment
trials and more basic-translational
research is needed to clearly define
HUs mechanisms of actions.
Public
187
4 While a 50% reduction in painful episodes in BABY-HUG is impressive, it is unlikely that SCA infants in the general
population will experience the same high rate of treatment adherence that was observed in a well-organized clinical
trial environment. Something as simple and indisputably life-saving as penicillin therapy has been reported to have
adherence rates as low as 40%. I am concerned that universally treating asymptomatic infants with SCA with HU will
lead to a (1) significant drain on the healthcare system, in terms of monitoring and tracking of adherence, toxicity and
efficacy, and social service interventions for non-adherent children, (2) early treatment adherence burn-out of
children and caretakers if there is not an obvious benefit for all children, and (3) exposure of many more children and
families to a potentially toxic medication (pregnant family members, sibs, healthcare workers, etc.). I also think that it
is very important to have a better understanding of HU knowledge, attitudes and acceptance of the patients and
families as we embark on the new era of possibly giving HU to all.
Public
187
7 The change in recommendation at age 42 months may be confusing-will this encourage some providers to stop HU at
42 months?
Invited Not
Disclosed
Invited
protocol is available in the document. No change
Invited
This is beyond the scope of these

guidelines.
187
188
13 You mention use of an established "protocol"--where are we to find these? Need to make reference to them or
resources available to find. This otherwise would be a big barrier for any PCP in a busy clinic.
1 this section and the section above on recommendation are both very clear and would be manageable to follow for
primary care physicians. Specific rec on starting dose, protocol for escalation and recd lab testing is all very helpful.
Interesting to think about techniques to ensure adherence with lab monitoring at the population level. I assume easiest
method would be to tie monthly refills to lab testing, but do not know if this has been studied.
188
188
1 Useful practical information about HU monitoring and dose escalation

12
188
12 The difficult question of what to do when they WANT to have a child with their partner is being dodged. How long
should they stop HU therapy? Or should they stop contraception, continue to use HU and stop at the earliest suspicion
of pregnancy?
Invited
This is already listed as a gap in the

No change
knowledge. Panel has no comment on
this issue due to lack of data.
188
16 What age cutoff for children?
Invited
188
18 SCD in U.S. primarily affects African Americans who may already run low wbc. Can goal ANC be any more lenient
than 2000?
Consider slightly more generous ANC

unless data shows this is unsafe.
Public
Change is covered in previous

No change
comment.
188
18 ANC of 1250/mm3 was used in BABY HUG, not 2000/mm3 - higher cutoff of 2000/mm3 will limit therapy
Adjust cutoffs or infants and toddlers

and those with sequestration
Public
188
18 What is the rationale for using ANC >2000 as a cutoff? In other heme-onc situations, ANC>1000 is considered safe.
Even in early data on fever and neutropenia cancer patients, increase in infections was noted for ANC<1000.
Maintain absolute neutrophil count >

1000.
Public
Replace "need for contraception" with

"need to avoid pregnancy"
Invited
Public
No change
The team disagrees with this

suggestion.
No change
No change
189
8 rationale for 8 week interval in dosing change not understood. What was the reasoning for this?
Public
189
9 Would conisder lower ANC threshold for young children on HU
Invited Not
Disclosed
Public
Change already covered in previous

comment
comment
189
189
12 Page 189 - is there evidence for testing counts every 8 weeks on hydrea ? This seems unneccessarily frequent in
patients who are stable on chronic therapy
13 Are there data to support the monitoring with CBC and differential every 8 weeks (vs. a shorter interval)-also would
consider adding a reticulocyte count to this monitoring
Invited
No change
No change
189
13 For patients with a stable effective dose, I have spaced monitoring visits to every 3 months, simply because 3 month
intervals coincide with administration of Depo-provera.
Once a stable effective dose is

Public
established, laboratoy safety monitoring
should include CBC with WBC
differential and platelet count every 8-12
weeks.

comment
No change
No change
190
0 no recommendation given on monitoring any biochemistry whilst on drug. Does this never need checking?
Public
This is addressed in the HM chapter
190
0 What is the impact if receive transfusion while on HU should this be addressed to prevent confusion
Invited
190
0 Question (1) Are results from non-clinical trial long-term "use" of Hydroxyurea going to be the data used to determine no recommendation
whether there are adverse effects?
Public
Change already covered in previous No change

comment.
There is follow up from BABY HUG
No change
and potential opportunity for additional
observational studies.
190
0 Question (2) Should "Monitoring Therapy" include organ function after the initial 6 months use and then annually?
Public
We have addressed that by doing lab No change

testing renal and liver profiles are on
an annual basis.
190
5 Seems to contradict benefit in MSH follow up study of reduced mortality even in patients who stopped HU
Invited
That is in interesting interpretation.

No change
MSH follow up showed some
exposure to HU, even if not
continuous was better than none at all.
The statement is correct as
written.This is included in the
knowledge gap section
190
7 hydroxyurea should probably be stopped during an admission for infection
Public
No change
190
7 Are there any times that HU should be stopped in the hospital-severe infections?
187
1 Is there any reason severe chronic anemia alone cannot be declared an indication by itself? This definition includes
symptoms which many patients underscore or over time accommodate quite well.

comment
comment
Table this for the all-panel call.
187
1 Is ANY level of anemia, as long as symptomatic, appropriate to consider treatment with HU?
Invited
No change at this time
Public
Invited
Public
No change at this time.
188
188
186
9 Folate should be given while on hydroxyurea, as MCV will not longer be indicator of folate deficiency and could mask
treatment effect
14 What age cutoff do you consider adult--18 or 21?
13 Discrepancy between adult and pediatric recommendations should be further explained, possibly eliminated- why start
ALL children on HU at 2 years, while waiting for adults to have 3 hospital admissions/year? I understand the data
sources, but this discrepancy makes no sense clinically.
no recommendation
clarify this line to include this

information
Invited
Consider severe anemia as indication Public
alone due to known disadvantages of
chronic anemic state. Many patients do
not report symptoms but have made
lifestyle changes (some they are not
even aware) that are due to the effects
of anemia were they challenged to
those tasks/activities.
Add administration of folate to

recommendations
No change
188
17 Would consider adding reticulocyte count to monitoring labs
184
186
6 thank you!
13 Are the events in this recommendation linked with admissions as in the MSH study?
Invited Not
Disclosed
Invited
Clarify if pain events mean hospitalized Public
events as many patients deal with
significant pain at home.
Panel members will discuss
No change at this time.
Answer is no.
No change needed
No change.
Page #
Line #
Comments
Suggestions
0 the boxed area does not add anything to the document. I do not know why remove boxed text from each section
it has been duplicated at the start of each section,
Type
Public
21
0 Boxed introduction should not start each chapter of the report. It should
only be in once at most, and again should not be necessary in this type of
document.
Public
21
21
0 Box: see comment above for p2-line22

0 On page 49 of the (2002) version of Management of Sickle Cell Disease
guideline - Health Maintenance (pg 21) there was mention of "identification
cards" to be used by adult patients with SCD for better ER treatment. This
is not mentioned in the (2012) Draft
21
0 Applicable to comment above.
21
21
No change
This will be addressed in implementation
No change
No change
i. NHLBI should direct doctors (who care Public

for people with SCD) to issue approved ID
cards for SCD patients under their care.
NOTE: I have attached identification cards
currently being used in India for patients
with SCD (see attached translated card)
No change
0 Applicable to comment above.
ii. Each patient with SCD would carry

Public
this HHS/NHLBI approved, "doctor issued"
card with them to all emergency room
visits. (see attached translated card)
No change
21
0 Figure
Attached word doc. entitled "SCD

Identification Card"
Public
No change
21
1 Consider using the box at the beginning of each section to summarize the
key findings of the chapter instead of stating the same intro over and over
Invited
Team will look at this across the guidelines
This can be done in later supporting documents.
21
1 SCD should also inculde other clinically significant sickle

hemoglobinopathies such as Hb S/ D
21
1 The first line suggests that sickle trait meets the definition of SCD as sickle SCD encompasses a group of disorders
Public
hemoglobin is present.
characterized by the presence of the sickle
hemoglobin mutation on one allele, and a
second abnormal beta-globin allele
allowing the sickle hemoglobin to
polymerize.
21
4 this sentence is unclear-If therapies help prevent complications, why are

they usually unsuccessful?
InvitedTeam considered suggestion below.

Non
Disclosed
No change
21
5 Change the sentence to read--such therapy is often unsuccessful in

completely preventing these complications
Invited
Team favorable about this suggestion.
Done 1/10/13
21
7 change the word disease to complications
Invited
Fine to change to this.
Done 1/10/13
NHLBI should add this management tool

back into the guideline to help inform ER
doctors how to better treat patients with
SCD.
Invited
Public
Discussion
Definition is needed as a reference in each chapter in case they No change
are used in isolation.
Add that SCD also includes additional less Public

common sickle hemoglobinopathies (e.g.
Hb S/D)
Need to add something to the definition. Add a sentence. There Definition has been updated.
are other less common genotypes such as Hemoglobin S/D or
hemoglobin arab.
No clarification is needed here.
No change
Page #
22
Line #
Comments
1 The explanation of rationale for screening (p22 1-5) is probably
unnecessary and can refer to standard texts. The specific items are
redundant and not clear
22
8 What is "Mayo-KER"?????
22
22
Suggestions
12 delete treatment after the word maintenance.

14 delete the word "complement" and change the sentence to read
"preventive services are also included in addition to SCD specific
recommendations."
Type
Public
No change
No change
Invited
Try to find a better way to abbreviate this. Editing to discuss
Changed to Mayo Clinic's Knowledge and Evaluation Research

(KER) Unit, and KER Unit thereafter.
Invited
Invited
Suggested to reverse the order.

Agreed. Make this change
Done 1/10/13
Done 1/10/13
Team agrees to move to exhibit and add clarifying language.

Language to br added will be supplied.
23
1 I'm not sure that adding the narrative or diagram with Healthy People 2020
objectives really adds much here, on the heels of talking about evidence
based guidelines. IF you keep this in, need to clarify whether or not
Healthy People 2020 objectives are evidence based or not, and/or
describe WHY you include them, where they come from?
Invited
23
4 This is a very nice Exhibit. Well written, comprehensive and commendable. No suggestions.
Public
23
24
Penicillin prophylaxis is recommended beginning at 2 months of age.

0 page 24 Prevention of Invasive Pneumococcus
Invited
Discussion
No change
We cannot change the HP 2020 objective wording.
No change
InvitedThis is a suggested change to the title. Change "disease" to

Non
"infection" for this section.
Disclosed
Done 1/10/13. Change title of section to "Prevention of Invasive

Pneumococcal Infection." Also changed "disease" to "infection"
throughout section.
No change
24
11 The description of the evidence and type of recommendations is very clear
InvitedNon
Disclosed
24
12 "lit search not conducted" add due to low anticipated yield
Invited
24
16 delete "extremely high" for the sentence to read "have a very high risk of
septicemia in absence of appropriate prophylaxis"
Invited
Team would like to take some time to consider this. THIS IS

TBD
septicemia and meningitis. Change as indicated but keep
meningitis.
"Due to low anticipated yield" added per revision.

Done 1/10/13
Page #
Line #
24
Comments
17 Inapprpriate Ref." Gaston et al".: this important intervention study was
based on previous studies reporting high incidence of these infections Barrett-Connor (1971), Seeler (1977), Pearson (1977), Overturf (1977),
and Zarkowsky (1986).
Suggestions
Type
Invited
Discussion
This needs to be verified with the evidence report for this
chapter. Change is TBD
DONE. Retained the Gaston et al. 1986 reference and added
Zarkowsky HS, Gallagher D, Gill FM, Wang WC, Falletta JM,
Lande WM, Levy PS, Verter JI, Wethers D. Bacteremia in sickle
hemoglobinopathies. J Pediatr. 1986 Oct;109(4):579-85.
Additional changes: Pg. 24, line 12, after "In some cases, a
literature search was not conducted" add "due to low anticipated
yield." p. 24, line 15: Change title of section to "Prevention of
Invasive Pneumococcal Infection." p. 24, line 16: after "Young
children with SCA have" delete "an extremely" and add "a very." P.
24, line 17, after Gaston et al. 1986 ref, add Zarkowsky HS et al. J.
Pediatr 1986; 109:579-85 ref. p. 24, line 19: after "with HbSS" add
"early in the first year of life" and delete "before 3 months of age."
Note: Panel also wanted to add "in the absence of appropriate
preventive strategies" prior to Gaston et al. and Zarkowsky
references, but I did not make this change since the comment
above proposed making the final sentence: "Young children with
SCA have a very high risk of septicemia and meningitis in the
absence of appropriate prophylaxis (Gaston etc.)."
24
18 "result from defective or absent splenic function that typically has its onset
in people with HbSS before 3 months of age"-the age of onset is usually
later in most-Median age of decreased splenic function was 13 months in
CSSCD
InvitedUse change below

Non
Disclosed
No change
24
24
19 change "before 3 months" to "early in 1st year of life. "

21 Two conflicting sources of data on risk of bacteremia in SCD-SC in first 2
years: Zarkowsky 1986 vs Rogers, 1995.
Invited
Invited
Yes, change as indicated

No change
Done 1/10/13
No change
25
0 Based on my own clinical experience, and this is a personal

statement: newborns with SC and SB+ Thalassemia may develop
asplenia and fulminant infection. My recommendation is that babies with
SC and SB+ Thalassemia during the first year of age should be evaluated
for prophylactic penicillin by a pediatric hematologist expert in detecting
asplenia early in these groups of patients .
Public
This is not what the literature says, but we respect that it is the No change
person's experience.
25
3 regarding the statement: "so currently the risk of invasive infection is

low", this sentence doesn't make sense to me. How does the use of
prevention (I'm assuming you mean a vaccine) alter the risk of infection,
and in what population---in the general public? In the immunized
population? Need to better define the population here.
Invited
Need to delete the whole sentence, "Prevention is effective.is Done 1/10/13 However, pls note that a handwritten edit was
low"
submitted to change this sentence to read, "Preventive strategies
are effective, so currently" Since the sentence was deleted, I did
not make this change.
Public
No action required on this comment.
25
12 Benefits are enormous, harm is minimal.
No change
Page #
Line #
25
Comments
13 Pen V K 125 mg BID between 2/3 months BID until 3 years
of Age and 250mg BID from 3 years of age to 5 years of age
unless specific indications.
Suggestions
Type
Public
Discussion
No change suggested here.
No change
25
20 "Do not administer regular penicillin prophylaxis to people with HbSC and
HBSB+ unless they have had a splenectomy". I do not think that lack of
evidence in the PROPS study is enough to give this recommendation.
Invited
This is a controversial topic and is debatable. This is a weak rec No change made after all. The background clearly states low risk
with mod quality evidence for this reason. This is a good point. of invasive infection in HbSC and HbSB+. No data support use of
Would like to use the word "consider discontinuing" Team would prophylactic penicillin in these genotypes, as indicated in the
like to work on wordsmithing this. Wording will be drafted for
Summary of the Evidence. DONE
background.
25
20 I do not understand when it is said that PROPS has low evidence because
of "imprecisions". Please define what these imprecisions are.
Invited
Methodologists would need to explain this. Consult with them

on this question.
Invited
Change needed. Panel members will work on this and submit

wording.
No change. No need to address HbSb0 since throughout the

document such individuals are considered as having SCA. DONE
Public
Change needed. Panel members will work on this and submit

wording.
Done. Revised to: The initiation of penicillin prophylaxis was

associated with a significant reduction in the risk offor developing
serious pneumococcal infections (2/105 versus. 13/110) and a
nonsignificant reduction in mortality (0/105 deaths versus. 3/110
deaths; very low-quality evidence due to severe imprecision).
26
26
4 Why not add the numbers for the statistically significant decrease in
pneumococcal morbidity instead of just the non-statistically significant
difference in mortality? This would provide demonstrable support for the
recommendation to give prophylaxis...
Add statistically significant decrease in

pneumoccocal morbidity.
26
11 Need at add "pneumococcal" before the first word "vaccination"
Invited
This is correct, change as indicated
Done 1/10/13. Also, p. 26, line 13, after "Evidence is lacking in

children with genotypes other than SS, panel added "even though
many clinicians prescribe prophylactic penicillin for them both
before and after age 5." Added.
26
15 Consider continuing penicillin prophylaxis beyond 5 years of age due to

recent reports of increased pneumococcal bacteremia in older patients
since Prevnar 7 licensure (Ellison et al, Pediatr Infect Dis J 2012; 31: 534536; McCavit et al, Pediatr Blood Cancer 2012; 58: 945-949; McCavit et al,
J Pediatr 2011; 158: 505-507)
Public
This will be added to background. Change needed - Will be

revised per previous discussion. This is Rec 1.
No change in view of comment in the Summary of the Evidence.

DONE
26
15 clarify if mg dosage is per dose or per day
Invited
Change to: Administer oral penicillin profilaxaxis twice daily

until age five in all children with hemoglobin ss.
Done 1/10/13
26
15 rec 1 is clearly stated, including dose. Might be useful to emphasize

initiating prophylaxis at first encounter even if screening results have been
confirmed yet. Might also want to provide recommendations on alternative
antibiotics for prophylaxis
Invited
No change recommended here.
No change
26
15 Clarify that the dosages for penicillin are per dose, not total daily dose.
Fed
See above. This change has already been made.
No change
26
16 Clarify whether 5 year olds should receive penicllin or not (i.e., should
penicillin prophylaxis end at the 5th birthday or the 6th birthday?)
Fed
This will be covered with changes to lines 2 and 4 on p. 26
No change
Page #
Line #
Comments
Suggestions
16 Use of PenVK prophylaxis for all sickling genotypes is a common practice Clarify wording.
in many centers. Until prevalence of IPD morbidity and mortality becomes
equal to general population, a sentence to acknowledge use of PenVK
use in other non HbSS patients may be used.
Type
Public
Discussion
We are not saying that they cannnot do it.
No change
26
18 Since evidence for stopping penicillin prophylaxis at age 5 is very weak,

parental preference should be considered- many parents choose to
continue.
Public
This will be covered with a previous change.
No change
26
18 comment on when to discontinue PCN prophy in adulthood if prior

Invited
splenectomy
18 Prevention of invasive pneumococcal infections; The recommendations
Incorporate noted language from the AAP Public
were consistent with the 2012 Red Book. However, the second
2012 Red Book.
recommendation related to discontinuing penicillin prophylaxis at age 5
years was qualified in the Red Book (fully immunized against
pneumococcus; prolonged penicillin prophylaxis; no prior invasive
pneumococcal infections; and receiving regular medical attention) but isnt
in this document. I believe that our qualifications are very appropriate and
should be strongly considered.
No change
No change
26
18 Rather than a weak recommendation for discontinuation of penicillin, a

statement that there is not clarity on this point would seem more
appropriate, as no benefit to discontinuation has been shown and there
may be benefit to continuation. Many immunologists feel strongly that
penicillin should be continued indefinitely in any patients with absent
splenic function.
Change to "Some evidence that penicillin Public

can be discontinued at age 5 exists, but
this should only be done after a complete
vaccination series against pneumococcus,
including 23-valent polysaccharide
vaccination at age 5." It is also reasonable
to continue this therapy in patients who are
tolerating penicillin.
No change
26
18 Basis for discontinuation of penicillin is weak and may still leave older
children with SCD at risk of peumococcal infection higher than that of
healthy children. PROPS II compared children with SS with each other.
The rates for pneumococcal bacteremia or meningitis, 0.33 per 100 pr-yrs
for penicillin group and 0.67 per 100 pr-yrs for the placebo group far
exceeded the rates in the healthy childhood population. The increased risk
faced by children with SCD was not completely eliminated even in the
Penicillin group in PROPS I. Err on the side of caution without causing
unintended harm.
Invited
No change
26
18 Disagree with the recommendation. I would agree with a recommendation

that states "penicilllin may be discontinued at age 5 in some children."
Invited
No change
26
18 weak recommendation is worded too decisively. Would be better to state

'Consider discontinuation of prophylactic' Many experts continue to treat
beyond age 5 years
Invited
No change
26
26
Page #
Line #
26
26
Comments
18 see line 45 above - need similar clarification
Throughout the document there is lack of clarity about SS vs SS and S
B0thal. These 2 recs are example, "SS" should read "SS and S B0thal"
There are numerous other instances of this inconsistency throughout.
Suggestions
Clarify wording.
Type
Fed
Public
Discussion
No change
We will have to look at this throughout the document. Take this Change
back to panel to ensure consistency.
26

Clarify wording.
Public
26

Clarify wording.
Public
27
0 The section is not clear in distinguishing renal tubular/medullary injury from See below for specifics
glomerular injury. Although it has been postulated that ischemic damage
in the medulla leads to glomerular hyperfiltration (the first stage of
glomerular injury) via prostaglandin and NO release, there is no direct
evidence to support that tubular/medullary injury is associated with or
results in glomerular damage. The statement Renal abnormalities can
start with defects in urine concentration and process with age to
microalbuminuria (pg 27, lines 16-18) is misleading, since there is no
direct evidence that urine concentration defects result in glomerular
defects. References and statements regarding prevalence of ESRD and
death due to ESRD are not accurate. (see below for specifics)
Public
Will re-look at this one.
Revision to this section submitted.
27
1 Would omit this recommendation, as there is not enough evidence to

support this approach
1 Is their adequate evidence to make even a weak recommendation to not
administer penicillin to children with HbSC or HbSB+ thal?
Public
Team stands by this rec
No change
InvitedTeam stands by this rec

Non
Disclosed
No change
27
27
1 as noted above: p24-line21

1 for point number 3, what does one do if you don't know the genotype????
Invited
Invited
No change
No change
27
1 consider revising language as this is also a weak recommendation with

low quality evidence
2 Consider giving penicillin prophylaxis also for history of invasive
pneumococcal infection.
4 Not all infants and young childrens should receive these
Invited
No change
Public
No change
27
27
27
27
27
4 Is there moderate quality evidence to support the meningococcus

vaccination recommendation?
4 the statement "vaccinate people of all ages" is vague---as an adult primary
care provider, how often do I need to do this? Do I vaccinate even if they
have already been vaccinated? This is unclear to me.
Have a table of age specific

immunizations. Need clarification on
boosters.
Team stands by this rec

This is addressed previously in the chapter.
Public
Re-word #4 - Assure that people of all ages with SCD have

been vaccinnatedchange as indicated
Done 1/10/13. Also, it was suggested adding to #4: Other

vaccinations should follow ACIP and CDC recommendations for all
persons.
Invited
Covered in previous edit.
No change
Invited
No change
Page #
Line #
27
Comments
4 All children are immunized with Prevnar and H inf vaccine within first two
years of life. What evidence is there to support giving meningococcal
vaccine early and what is the risk of meningococcal infection before 13
years of age? What evidence is there to support the recommendation for
Pneumovax over and above penicillin prophylaxis at 2 years of age and
again at 5 years. These recommendations are made without any
evaluation of proof.
Suggestions
Type
Invited
Discussion
No change
27
4 Be more specific about preferred vaccine schedule and agents or state

according to ACIP guidelines or direct reader to pg 53
Invited
No change
27
4 The separation of recommendations for prevention of pneumococcal

disease from the immunization recommendations was confusing. P 27, line
4. At least refer to the immunization section
Public
Needs discussion with panel. Might require some additional

content about the lack of clarity on this issue. Title of this
section might mean that we should not make recs about these
other pathogens. Link to the CDC is an appropriate thing to
have/keep. #4 Vaccinate people of all ages with SCD against
strep pneumonaii. Delete the rest.
Change
27
8 Clarify temperature. Should temperature be 38.3 C (101 F), 38.5 C (101.3

F), or 38.6 C (101.5 F)? I think whatever temperature is chosen should
correspond to temperature used for fever work-up in later acute
complication section. Temperature used on page 81, line 10, is 38.5 C
(101.3 F).
Public
Temperature instructions need to be clarified and made

consistent across all chapters. 38.5/101.3 should be the
standard. Change as indicated throughout.
Done 1/10/13
27
27
8 fever of 38.3 C is not 101.5 F

please make it consistent
8 Clarify the route by which temperatures should be taken and at which ages
the route for obtaining temperatures are applicable
Public
Fed

No change
No change
Needs to be clarified
27
10 The sections Screening for Renal Disease and Acute Kidney Injury are The panel should not suggest a causal link Public
not clear in distinguishing renal tubular & medullary injury from glomerular between tubular and glomerular injury, as
injury.
this has not been established.
Page #
Line #
Comments
Suggestions
10 The recommendations and definitions are not consistent with the KDIGO Annual screening for albuminuria by spot
(Kidney Disease: Improving Global Outcomes) position statement in 2005 urine albumin/creatinine ratio should be
(Levey et al. Kidney International, 2005; 67:2089-2100).
included in the recommendation.
This position paper recommends albuminuria, as assessed by spot urine
albumin/creatinine ratios, as a marker for kidney disease. The rationale
for testing for albuminuria includes the fact that higher levels are the
earliest marker of kidney damage due to diabetes, glomerular diseases,
and hypertension, higher levels are associated with adverse outcomes,
including progression of kidney disease, and therapies that reduce
albuminuria are associated with slowing the progression or diabetic and
nondiabetic kidney disease.
This paper also defines the classification of chronic kidney disease (CKD),
stages 1 -5. Stage 1 CKD has normal or high GFR with a marker of
kidney damage (markers include albuminuria, proteinuria, and hematuria).
Screening for albuminuria is therefore required in order to diagnose Stage
1 CKD.
Type
Public
Discussion
Need to review what the Acute section states so that we are
consistent. Will see if we need to clarify/add anything here.
27
10 The section Screening for Renal Disease (pgs 27-29) recommends urine Annual screening for albuminuria by spot
dipstick only, which may detect gross proteinuria, but is insensitive and
urine albumin/creatinine ratio should be
also is unable to detect albuminuria. The later section Renal
included in the recommendation.
Complications (pgs 149-153) gives recommendations on further testing
and treatments when microalbuminuria is identified; however it cannot be
identified if not recommended as a routine screening test.
Public
Will look at this and send something out for review
27
14 The Statement that renal blood flow and glomerular filtration are elevated
in childhood normalize in adolescents and declines in adults is incorrect.
They are elevated in early life and decline throughout life.
Will review and clarify this.
A revision to this section submitted on March 8th. However, this

statement (on pg. 27, line 14) was not revised.
27
14 The statement GFR and renal plasma flow are increased in childhood, Clarify wording.
normalize during adolescence, and decline with age
is incorrect. GFR and RPF are declining in adolescence due to ongoing
loss of renal function, not normalization of renal function.
Revision to this section submitted but this statement was not

revised.
27
This sentence be rewritten to state they

Public
are elevated in early life and decline with
age. I would also include a strong
statement here about the lack of sensitivity
of serum creatinine and creatinine
clearance in detecting reduction because
of the early elevation and tubular secretion
of creatinine in this population.
Public
Page #
Line #
27
27
Comments
Suggestions
Type
19 RE: "When significant proteinuria or azotemia is present, approx of
Correct reference and clarify interpretation. Public
individuals with SCD will progress to ESRD in less than 2 years (Herrera
2002). This is the wrong reference. Herrera et al. is a study of tubular
function in SCD pts with normal/supra-normal GFR. Herrera references
Bakir (Am J Nephro 1987) when stating when significant proteinuria or
azotaemia are present, approx half of the pts with SCA will go onto ESRD
in less than 2 years [Bakir 1987] however this quote is inaccurate. The
paper by Bakir examined 22 patients with biopsy-proven glomerulopathy
and showed that 11/22 died in 2 yrs (10/11 who died had renal failure vs.
5/11 who lived had renal failure). This is a small study of selected patients
with nephrotic-range proteinuria and shouldnt be used to claim that half of
patients with proteinuria (of any degree) progress to either ESRD or death
in 2 yrs.
Discussion
A revision to this section was submitted. This sentence was
modified and the Herrera et al. 2002 reference was deleted and
replaced by Alvarez et al. 2006.
21 RE: Renal failure may occur in as many as 18% of individuals with SCD Correct references and interpretation.
[ref: Falk NEJM 1992]. This is the wrong reference. Falk et al.
screened 381 with SCD and showed 7% had elevated serum Cr. Falk
references Causes of death in SCD in Jamaica by Thomas et al. (Br Med
J 1982) when stating renal failure may occur in as many as 18%... Other
more recent studies have shown a lower prevalence of renal failure:
Powars et al, Ann Int Med 1991: Renal failure 4.2% in HbSS (median
age 23.1 yr) and 2.4% in HbSC (median age 49.9 yr)
Powars et al, Medicine 2005: Renal failure 11.6% in HbSS (median age
37 yr).
Public
A revision to this section was submitted. The Falk reference was

deleted and this statistic (18%) was revised. The Alvarez et al.
2006 reference was added.
28
0 The section on screening for renal disease (p 28-9) would benefit from at
least a brief sentence or reference summarizing non-SCD literature on the
ability of preventive interventions to slow the progress of progression of
ESRD. This wasn't clear to me.
Public
Will review
A revision to this section was submitted, but no language was

added related to this comment.
28
5 The screening question should not be limited to Cr and urine protein. The Include urine albumin/creatinine ratio in
utility of albuminuria must also be included, as this is a recognized marker key question.
of early kidney disease.
Public
Will review
A revision to this section was submitted, which included screening

for albumin.
28
6 URINE PROTEIN here is very difficult to interpret. This entire section

needs to be carefully reread to be sure that the intent of the panel is clear.
A sentence or two to discuss the ways urine protein may be measured IS
VITAL. Specifically while the recommendation is understandable the
exclusive use of dipstick rather than urine microalbumin to creatinine ratios
should be discussed here as well as in the chronic disease chapter at the
end.
Public
Will review
Page #
Line #
28
28
28
29
Comments
Suggestions
7 Additional information to include:
Include additional data in summary.
- Guasch et al. (Kid Intern 1997) compared albumin excretion rates in
HbSS adults with normal GFR and with renal insufficiency; he showed
albuminuria was significantly higher in the renal insufficiency group,
supporting the role of albuminuria as a screening test for renal disease.
- Albuminuria is prevalent in pediatric and adult SCD populations (shown in
numerous observational studies), and the prevalence increases with age
(McPherson Yee et al. CJASN 2011; Guasch JASN 2006). Albuminuria
detected in 1st 2nd decades of life; for HbSS: albuminuria in 7% aged 26yo; 20% aged 7-12yo; 35% aged 13-19yo. (McPherson Yee)
Type
Public
7 38.3 C is 101 F, 38.5 C is101.4, so should ber >101.5 or >38.5
InvitedThis is dealt with in another change.

Non
Disclosed
No change
Invited
Invited
Done 1/10/13
no change
18 delete people
3 not clear if this statement includes Baby HUGS data on renal disease
Discussion
Will review this to make sure we used this reference.
ok
data not validated
A revision to this section was submitted. The Guasch et al. 1996
refrence was included: Guasch A, Cua M, Mitch WE. Early
detection and the course of glomerular injury in patients with sickle
cell anemia. Kidney Int. 1996 Mar;49(3):78691. This is not the
same as the 2 references noted in the comment.
29
9 Is there a reason urine microalbumin/creatinine ratio is not recommended

given its utility in diseases such as diabetes? Later in this document
routine screening for proteinuria us reommended. Why wait for gross
proteinuria when early proteinuria (microalbuminuria) may guide close
surveillence and earlier intervention?
Invitedrewrite needed for entire section. Entire panel should weigh in. Submitted
Non
Evidence insufficient but still need to come to concensus. Will
Disclosed gather data and present to panel
29
9 "Screen all people beginning at age 10 for proteinuria using standard urine Add urine albumin/creatinine ratio to
dipsticks. When negative, repeat annually."
recommended annual screening and
- Proteinuria is not defined (what concentration is considered abnormal?) define threshold per KDIGO guidelines.
- The KDIGO (Kidney Disease: Improving Global Outcomes) position
statement for defining CKD states: Retain albuminuria as a marker for
kidney damage. They recommend spot urine albumin/creatinine ratio,
with a threshold for abnormal at >30mg/g. (Ref: Levey et al. Kid Intern
2005).
- In the later section on managing chronic renal complications (page 152),
recommendations are given for treating patients with microalbuminuria and
macroalbuminuria, therefore the screening recommendation should assist
in detecting albuminuria.
Public
urine-protein creatinine ratio should not be used. Rewrite

needed. See item 85
Submitted
Public
background and summary for this topic good and addresses

many of the issues. Also, info is available in chronic chapter.
However,entire section on page 29 needs to be reviewed by
entire panel.
Submitted
29
10 1. Line 10-11 Does not state what to do if positive.

2. Why is there no recommendation for screening for microalbuminuria
and just do dipstick urine for protein if later they show studies that starting
ace inhibitors can decrease protein excretion and thus delay possibly renal
deterioration and progression to nephritic syndrome?
Page #
Line #
29
Comments
10 SAME COMMENT as above. URINE PROTEIN here is very difficult to
interpret. This entire section needs to be carefully reread to be sure that
the intent of the panel is clear. A sentence or two to discuss the ways
urine protein may be measured IS VITAL. Specifically while the
recommendation is understandable the exclusive use of dipstick rather
than urine microalbumin to creatinine ratios should be discussed here as
well as in the chronic disease chapter at the end.
Suggestions
Type
Public
Discussion
same as above items on this topic. Panel to assess after
research is done.
Public
further consulttion with specialist needed. Panel should weigh

in on changes to entire section
Submitted
don't use diabetic ratios for screening. Panel to assess after

research is done
Submitted
Invited
Perhaps screen all people beginning at age 10 who have

evidence of renal disease rather than everyone. Panel should
assess with more data
Submitted
Public
Panel to assess after research is done
Submitted
Submitted
29
10 NEED to also state the level of postive dipstick that should be considered
postitive. THAT is should trace protein be considered positive (no
probably not) but the panel needs to state. ALSO the further evaluation of
patients with 1+ protein should be listed here as well as in the chronic
disease chapter at the end.
29
10 Dip stick screening is insensitive and fails to detect microalbuminuria

making this recommendation suspect. Why screen with an insensitive
method?
29
10 Screen all people with SCD with urine dipsticks. Urine dipsticks is not a
very accurate method. Urine protein or urine albumin measureaments
over creatinine are more accurate.
29
10 This recommendation seems insufficient.
29
10 I am not clear why the rec is for urine dip when later under renal disease
management you rec initiating therapy if microalbuminuria is present
Invited
Panel to assess after researchis done
Submitted
29
10 should be consistent with recommendations on p153 under managing

complications. Screening for proteinuria starting at age 10 is fine, but
microalbuminuria can be detected at younger age and may enable earlier
intervention. If PCP is screening for protein when would they check for
microalbuminuria?
Invited
Submitted
29
10 How did you come up with age 10? This seems arbitrary to me
Invited
No data for age or most of these items in this section
Submitted
Follow published guidelines using

Public
Albumin/creatinine ratio for screening or do
not recommend screening outside of
research studies.
Suggest albuminuria be measured yearly

and referral to a nephrologist be made
even for microalbuminuria, and if not, a
comprehensive renal function evaluation
be performed before starting ACEI. A
nephrologist should be involved for the
care of SCD patients with
macroalbuminuria
Page #
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29
Comments
10 The recommendation for screening for proteinuria seems very weak.
There is nothing to address false positives, but more importantly, there is
nothing that tells the provider what to do if there is protein in the urine. I
would add a recommendation about what to do if a urine test is positive - is
it refer to a renal specialist? If no recommendation, then why screen. This
is very vague and therefore not very helpful.
Suggestions
Type
Invited
29
10 Would start screening for renal disease at 2-5 years of age
29
11 vague recommendation for when protein is present, should not a

recommendation be given here as well.
11 What should be done for patients with trace or greater proteinuria?
Invited
29
Discussion
same as item 85. Left vague so provider will seek consultation Submitted
with specialist
Urine protien inexpensive and relative easy Invitedsame as item 85

to do
Non
Disclosed
New renal revisions submitted. This issue not resolved. Editor please insert comment re: starting screening at age 2-5 yrs.
Submitted
InvitedPanel to assess after research is done

Non
Disclosed
Submitted
11 You have described here what to do if the screen is negative, but what do
you do if positive? Send them to a nephrologist?
Invited
Submitted
29
13 The section on pulmonary hypertension completely ignores the important

work by Gladwin, Kato, Minnitti and Gordeuk. The distinguished panel may
disagree with their findings but it is arrogant and unfair to completely
ignore it. Please include a few of their references and findings. There
should also be some mention of 6 minute walk as one of the standard
functional measure being used to study exercise tolerance.
Invited
This comment was discussed by the subgroup. There is no

evidence in any disease state for screening asymptomatic
individuals with a 6-min walk distance.
No change
29
14 Point of clarification - Pulmonary hypertension is defined as stated above

by a mean PAP > 25 mmHg. At the 4th World symposium of Pulmonary
Hypertension at Dana Point in 2008, Pulmonary Hypertension was subclassified into 5 different groups based upon similarities in histopathology
and pathogenesis. Pulmonary arterial hypertension (PAH) is Group 1
Pulmonary Hypertension and accounts for approximately 50% of cases of
SCD related PH. The remaining patients have hemodynamics consistent
with pulmonary venous hypertension (PVH), also called Group 2
Pulmonary Hypertension. Both PVH and PAH are risk factors for mortality
in this population. The use of the terms PAH and PH interchangeably in
this document is incorrect, particularly since half of the patients with SCD
related PH do not have PAH at all.
Would reference the numerous guidelines Public

documents published in 2009 devoted to
the subject of diagnosis and treatment of
pulmonary hypertension so that the NHLBI
guidelines are reflective of them.
29
This will be included in the background of this chapter.

This section revised.
Background needs to be revised. Changing wording to PH from
PAH.
Page #
Line #
29
Comments
14 Point of clarification - Pulmonary hypertension is defined as stated above
by a mean PAP > 25 mmHg. At the 4th World symposium of Pulmonary
Hypertension at Dana Point in 2008, Pulmonary Hypertension was subclassified into 5 different groups based upon similarities in histopathology
and pathogenesis. Pulmonary arterial hypertension (PAH) is Group 1
Pulmonary Hypertension and accounts for approximately 50% of cases of
SCD related PH. The remaining patients have hemodynamics consistent
with pulmonary venous hypertension (PVH), also called Group 2
Pulmonary Hypertension. Both PVH and PAH are risk factors for mortality
in this population. The use of the terms PAH and PH interchangeably in
this document is incorrect, particularly since half of the patients with SCD
related PH do not have PAH at all.
Suggestions
Type
wouldchange the sentence "The remaining Public
patients have PVH or "mixed" PH
defined as mPAP 25 mm Hg, inceased
PCWP wtih an increased PVR."Would
reference the numerous guidelines
documents published in 2009 devoted to
the subject of diagnosis and treatment of
pulmonary hypertension so that the NHLBI
guidelines are reflective of them.
Discussion
This will be covered in the previous comment. Changes being
made.
No change
29
15 The definition of PH was changed in 2009. The new definition is a mean Change this so that it is reflective of
PAP > or equal to 25 mm Hg at rest, the exercise part of the definition was current definitions
removed.
Public
This will be revised as part of the background.
29
18 consider defining elevated TRV; proxy used by some but not = PAH. Often
very confusing to providers outside of the field
Invited
Background will be revised accordingly.
A revision to the PH section was submitted.
30
0 In general, the inclusion of some evidence in the background sections and

then in the formal summary of evidence was confusing. I would suggest a
shorter background and including all the relevant evidence in the summary
of evidence. This was prominent in the PAH section 30-31.
Public
In this case, there is no change. Howerver, there needs to be a Is this done satisfactorily?
section in each chapter and in the Methods section and in
Introduction clarifying the evidence review periods.
30
6 state difference from this and background rate of general population
Invited
Will look this up again.
Revision submitted to this section.
30
8 Would use the term dyspnea instead of the colloquial shortness of breath
Public
OK, team agrees to this change.
Done 1/10/13
30
10 The medical term for "passing out suddenly" is syncope. In PH, typically it
is exertional syncope. Most importantly, many SCD patients are
asymptomatic despite having abnormal echos (see Klings ES AJH 2008)
and many SCD patients have symptoms such as dyspnea but do not have
an elevated TRV. Many of the symptoms of PH are non-specific in SCD
patients and this underlies why screening all patients regardless of
symptoms is warranted.
Public
OK, team agrees to this change.
Done 1/10/13
30
10 The medical term for "passing out suddenly" is syncope. In PH, typically it Would also include in the PAH definition,
is exertional syncope. The key thing to point out in your description of
PCWP 15 mmg and increased PVR
symptoms is that many SCD patients are asymptomatic despite having
abnormal echos (see Klings ES AJH 2008) and many SCD patients have
symptoms such as dyspnea but do not have an elevated TRV. Many of
the symptoms of PH are non-specific in SCD patients and this underlies
why screening all patients regardless of symptoms is warranted.
Public
Syncope change made in previous comment. This suggested

change about the PAH defi is beyond the scope. The last
sentence about screening is not supported by the panel.
No change
Page #
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30
Comments
14 This section needs to be updated with current references including Parent
F NEJM 2011 and Mehari A JAMA 2012. Additionally Gladwin MT NEJM
2004, Ataga et al., Br J Haematol 2006; De Castro et al., Am J Haematol
2010; Lorch et al., Acta Haematol, 2010. need to be added to support the
concept that an elevated TRV predicts mortality.
Suggestions
Discussion
The background will need to be revised to address some of
these issues and clarify the panel's recommendations about
screening.
Rrevision to the PH section was submitted. This included
additional references, including Parent et al. 2011; Gladwin et al.
2004 among others.
Public
The background will need to be revised to address some of

these issues and clarify the panel's recommendations about
screening.
A revision to this section was submitted that included additional

references, including Parent et al. 2011 and Gladwin et al. 2004
among others.
30
14 This section needs to be updated with current references including Parent

F NEJM 2011 and Mehari A JAMA 2012. Additionally Gladwin MT NEJM
2004 needs to be added to support the concept that an elevated TRV
predicts mortality.
30
17 There are epidemiologic studies of elevated TRV in HbSC disease and

these need to be commented on here.
Public
Will roll that in to the revision of the Chronic chapter

Revision to this section submitted, which included new references.
background and incorporate where appropriate. To be adapted
for this chapter.
30
31
20 The correct term is thromboembolic disease

2 You are actually screening for PH not PAH
Public
Public
Agreed
We agree that the correct term is PH not PAH.
Done 1/10/13
No change
Public
No change here.
No change
31
5 83 studies are mentioned in this report, yet the quality of the data is felt to
be very low. While studies that directly compare the effects of screening
with no screening on clinical outcomes are lacking, we hold that screening
identifies a high-risk group of patients for whom SCD-specific therapies
(e.g., hydroxyurea, chronic transfusion, supplemental oxygen, anticoagulation therapy) may be indicated because they improve clinical
outcomes in patients with SCD-related co-morbidities, including mortality,
quality of life, and the frequency of vasoocclusive crises (VOC) or acute
chest syndrome (ACS). As part of the American Thoracic Society funded
Clinical Guidelines for the Diagnosis and Treatment of PH of SCD, our
group of 24 hematologists, pulmonologists and cardiologists felt that
screening was the only method of identifying this high risk patient group
who may be asymptomatic at presentation but still at risk for morbidity and
mortality.
Other articles that support link of TRV to

mortality in SCD: Ataga et al., Br J
Haematol 2006; De Castro et al., Am J
Haematol 2010; Lorch et al., Acta
Haematol, 2010.
Type
Public
31
11 The correct reference for Bachir is Parent F NEJM 2011.
Public
Lines 11-12 be copied and pasted into the Chronic chapter

summary of the evidence. "Bachir and colleaguesusing
RHC." REMOVE RUBIN.
Editor: Deleted "Rubin 1997" reference 1/17/13.
31
31
12 6% of the 30%?
14 Would use the reference McLaughlin VV from Circulation which was the
official guidelines document. Additionally, an inclusion of their
recommendation to pursue further workup for a PASP > 40 mmHg as well
as the use of echocardiogram to evaluate RV size/function and assess for
a pericardial effusion would be a more balanced presentation of the
literature and reflective of the use of echocardiography in PH assessment
clinically.
Invited
Public
This will be clarified in the re-write.


No change
Page #
Line #
31
Comments
14 Would use the reference McLaughlin VV from Circulation which was the
official guidelines document. Additionally, an inclusion of their
recommendation to pursue further workup for a PASP > 40 mmHg as well
as the use of echocardiogram to evaluate RV size/function and assess for
a pericardial effusion would be a more balanced presentation of the
literature and would be more reflective of the true use of echocardiography
in PH assessment clinically.
Suggestions
Type
Public
Discussion
No change
31
31
15 over what time period?

15 Need to include data from Mehari A JAMA 2012 and Parent F NEJM 2011
in this statement. All of these studies have shown the high mortality risk of
PH in SCD despite the modest increases in pulmonary pressures.
Invited
Public
This will be included in the background.

This has been addressed in a previous change. These will be
added and discussed in the background section, not the
evidence reviews.

No change
31
16 The median survival in the Castro study was 25.6 months not 2.6.
Public
This was a typo and will be corrected.
Done 1/10/13
31
20 The following references need to be included here as a minimum: Gladwin

MT NEJM 2004, Ataga KI Brit J of Hematology 2006, Parent F NEJM
2011, Sachdev V J Am Coll Cardiology 2007. Of note, the Liem study that
is referenced is a pediatric study. An elevated TRV is not a mortality
predictor in the pediatric population.
Public
The panel will consider these in the revision to this section
Revision to this section submitted and added references, including

Parent et al. 2011 and Gladwin et al. 2004.
31
20 The statement about mortality here seems to contradict the statement on

page 30 line 13 regarding lack of mortality in chilfdren with elevated TRV
Public
This will be clarified in the revision.
Revision to this section submitted, but this language was not

revised.
31
21 Would include Ataga KI BJH 2006 which showed that 13% of those with a
normal echo develop an elevated TRV over 3 yrs.
Public
Available data suggests that TRV changes over time

Something will be added to the background.
Revision to this section was submitted.
32
0 Screening for Pulmonary Hypertension: Based on personal clinical

practice experience, echocardiography should be done yearly In every
adult with SCD starting at 20 years of age to detect and follow early
changes in echo. Cardiac catheterization should be performed when TRJ
velocity is 3 m/second.
Public
Team discussed possibly adding a consensus

PH sections are being revised.
recommendations around this issue. Consensus that we would
not universally screen children. Target screening at SCA as
adults. Those with normal jet velocities are not routinely
screenedlead to formal evaluation...Universal (targeted?) 1time screening with Echo. Then people with elevated go on for
further evaluation, including right-heart cath. People who have
normal results on that single screening will not have rescreening unless...Don't screen anyone under the age of
X...But make it a positive recommendation, not a "don't do."
Screen individuals with SCA who are at or above age 18 (or 20)
with an Echo. If normal, do not repeat screening for PAH unless
the following develops. If abnormal, refer for...
Page #
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32
Comments
5 There have been a multitude of studies published since 2000 describing
echocardiographic abnormalities observed in SCD. Yes, a reduced
ejection fraction is observed in a small percentage of SCD patients (Klings
ES AJH 2008), but the majority of patients with pulmonary venous
hypertension actually have diastolic dysfunction. Sachdev V JACC 2007
and Circulation 2011 should be referenced here.
Suggestions
Type
Public
Discussion
This could be addressed in the background. Will be considered This section revised.
in revision.
32
5 The USPSTF recommendation against routine screening seems out of

place here
InvitedWe could not find this on this page/line.

Non
Disclosed
No change
32
7 This statement is reflective of the state of the art management of PAH in

1997, not 2012. Yes, the management of PAH is complex and we agree
that these patients need to be referred to clinicians experienced in their
management. But no one who treats idiopathic pulmonary arterial
hypertension (the current term preferred over primary PAH) thinks of this
treatment as being controversial. Treatment of idiopathic PAH has
improved symptoms, quality of life, hemodynamics and survival for these
patients. This statement must be removed from this document because it
potentially places patients at risk.
Public
The team discussed changing the word "dangerous." Should be This section revised.
more specific - "at risk for x". Will consider a revision.
32
7 The reference quoted is out of date.
Include a discussion of more recent

Public
guidelines for screening for pulmonary
hypertension in a number of disease states
where incidence of pulmonary
hypertension is increased and where it
also contributes poor outcome. These
should be suggested by pulmonologists
and cardiologists who are experts in
pulmonary hypertension.
The team discussed changing the word "dangerous." Should be This section revised.
more specific - "at risk for x". Will consider a revision.
32
8 The use of the terms primary and secondary pulmonary hypertension is

outdated. Would refer to the 2009 PH guidelines from McLaughlin VV
Circulation to clarify.
Public
Agree - we will correct the term.
32
8 The sentence should start with "Management of secondary

hypertension..". This sentence does not make much sense for SCD. If
you are recommending against routine screening how will one be able to
accomplish early recognition. If one is to use only clinical symptomatology
then there should be clear recommendation based on panel expertise to
for example----perform echo if shortness of breath, edema etc. develop.
The current recommendation totally leaves everything up in the air.
Invited
Will work on a revision of this section. Discussion of symptom

based recognition is not appropriate in this chapter, however.
Page #
Line #
32
Comments
11 Echocardiogram Screening and PHT
Suggestions
Type
Recommendations for screening for
Public
pulmonary hypertension: The ATS clinical
practice guidelines which includes a
diverse, multi-disciplinary committee of
adult and pediatric experts, concluded that
screening echocardiograms are indicated.
We support the ATS recommendations and
believe their document, which you have
received, justifies this. The
recommendations section asks, "Do not
perform echocardiography to screen
asymptomatic sickle cell patients." We are
not really sure how you define
asymptomatic for PHT in sickle cell
disease. The NIH website states
"Symptoms of PAH include shortness of
breath with exercise, tiredness, episodes
of chest pain, a racing heart, decreased
appetite, and light-headedness with
exercise. These are common symptoms in
sickle cell disease that many adults have
intermittently, and can be due to PAH as
indicated on the NIH web site. If patients
have some of these symptoms, would
these be classified as asymptomatic or
symptomatic?
Discussion
In the background, will reference the NIH list. Also will take this This section revised.
comment into consideration in the revision of the background.
32
11 For patients who are symptomatic & PAH is in the differential dx, should
screening begin with ECHO? Why go directly to right heart cath given how
invasive the procedure is?
Invited
These recs are being revised for clarification. This issue will be No change
addressed in the revision.
32
11 concur with recommendations, but will likely be controversial
Invited
No change
Page #
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32
32
Comments
12 I am trying to bring attention to the effect of PAH on SCD patients. I had a
patient bouncing for years between EDs for repeated VOC because of her
sickle and when we ran echo we go a TRV of 3.2 m/s. When we asked her
about her SOB she mentioned shed been complaining about it for ever.
For years she is unable to climb stairs or even walk a block without
running out of breath and having to rest. She gets SOB at rest so
technically she is class IV FC on the WHO classification. My argument is
that there is no recommendation for PAH screening in SCD patients
despite the high mortality and morbidity that has been reported already in
different papers. Thalassemia patients on the other hand are routinely
screened for PAH.
12 Do not agree with not performing echos routinely (data are missing to
decide one way or another, but by recommending not to do it, insurance
companies will not pay for it!). If we wait for symptoms to occur, patient
may already have chronic heart damage. Would rephrase and mention
that routine echos should be done (every other year after age 10? And
should include assessment of TRV
Suggestions
Type
Since you mention in your argument that Public
increased TRV>2.5 increases two years
mortality, why don't you accept the fact that
screening for TRV instead of PAH is
advised? We are talking about 40%
mortality which is huge. Our patient is SOB
at rest and we didn't even need a right cath
to confirm the dx although I admit we need
it for staging and NO challenge testing and
to get a baseline for PAP. Nevertheless, A
simple ECHO test is able to tell if the
patient is going to have increased
mortality/morbidity so that we take it
seriously and be more aggressive in our
management. Moreover, many physicians
are swayed by the preaching that "if the
SOB/hypoxia is unexplained then search
and or screen for PAH." While this might
hold true to other diseases, SCD gives a
good excuse for the already prevalent
hypoxia and SOB. In our institute for
example, the patient has seen different
physicians and none was able to identify
the cause of repeated VOC and took it for
granted that it is the SCD that is bad and
not the concomitant PAH that is making
the SCD worse and the SCD that is
making the PAH worse. It is this synergistic
relation between those two pathologies
that we must break by primary preventive
medicine and not wait and hold off our
cheapest tools to put a full stop, an early
stop to the progression of this heinous
Invited
Discussion
Thank you for this input. We are also trying to raise awareness No change
of this issue.
The panel does not agree with this recommendation.
No change
Page #
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32
32
Comments
Suggestions
Type
12 I respectfully disagree with the recommendation not to screen for PAH in Recommend to screen for PAH by TTE all Public
HbSS disease. Almost all patients with HbSS disease have some level of adult patients with HbSS.
exertional dyspnea by virtue of their severe anemia, PAH or other
cardiopulmonary disease with the exception possibly being those with
HPFH of alpha thal, and most of them develop hypoxemia at some stage
of their illness or in crisis. Thus, it is hard to imagine a scenario of an
asymptomatic SCD patient for PAH, and the recommendation not to
screen asymptomatic patients becomes a moot point. Early signs of PAH
are easily missed and an echo is done almost invariably at some stage of
their care anyhow, so it would make sense to obtain it as a screening test
in steady state. Although there is no proven effective therapy for PAH in
SCD, it is intuitive that maximization of medical therapy with an attempt to
achieve disease control may be beneficial. Considering the mortality and
burden of PAH in SCD, I believe that to wait for a RCT before making a
recommendation of maximizing medical therapy in patients with suspected
or confirmed PAH is a risky approach. Moreover, finding of PAH should
prompt a workup for chronic thromboembolic lung disease, PFTs, OSA and
other pulmonary comorbidities and presence of PAH is a risk factor for
sudden death. This is an important piece of information during VOC
therapy in the hospital, when PA pressures may increase acutely and place
the patient at increased risk of pulmonary failure, particularly when IV
opiates are administered. Knowledge of the patients PAH may increase
the level of alertness in the staff and prompt more aggressive
cardiopulmonary monitoring.
Discussion
The team does not believe a change is warranted.Thank you
for the comment.
No change
12 data concerning echo is very controversial and may meet with criticism
Thank you.
No change
Invited
Page #
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32
32
Comments
12 After our guidelines group did a comprehensive assessment of the entire
body of literature concerning PH of SCD, a survey of was performed to
determine what each member thought was the most important
recommendation to emerge from the entire document. The overwhelming
first choice was universal screening of SCD adults. Our rationale for this is
as follows: 1) An elevated TRV predicts mortality and a significant number
of patients will not have symptoms early in their disease (Klings ES AJH
2008); 2) Although treatment of PAH has not been shown to improve
mortality, we would argue that no randomized controlled trial of PAH
therapy has been successfully completed in this population. This rationale
for not screening limits the ability to accurately assess and define the true
natural history of this disease. 3) While there is no clear established
specific therapy for PAH of SCD, identification of this patient group with an
increased mortality risk is an indication for a) intensification of treatment
for SCD with hydroxyurea and possibly chronic transfusions and b)
increased assessment of other conditions with known treatments which
increase cardiopulmonary risk such as venous thromboembolism,
obstructive sleep apnea, etc.
12 Though RCT-type evidence is lacking, it seems quite probable that in the

US the median survival of adult sickle cell disease (SCD) patients with
cardiac cath-proven pulmonary hypertension (PH) has improved and is
associated to ECHO screening and better care of patients with this
complication. Currently (JAMA 2012;307:1254) the median SCD-PH
patient survival estimate (>6 y) is 3 times longer than that reported for the
corresponding group of pts. less than a decade ago: 2.1 y (Blood
2003;102:1257). That the longer survival is not due to more severe
patients being studied in 2003 is supported by the similarity in their
pulmonary hemodynamics (PAm ~ 36 mm Hg in both series). Nor is it
likely that the longer SCD-PH patient survival was due merely to advances
in general SCD medical care: for pts. whose cath. results did not show PH,
the survival was similar in both studies, 70% at 9 y in 2012 vs. 87% at 6 y
in 2003. In my opinion, routine ECHO screening of SCD adults over the
last decade has identified a group of pts. who have a higher death risk and
whose referral to SCD-PH specialized centers has allowed interventions
such as intensification of SCD-specific treatment and/or, in selected cases,
PH-specific treatment that may have lowered their mortality. Unless NHLBI
guidelines recommend routine PH screening of SCD adults by ECHO, with
referral to specialized centers for follow-up cath. and evaluation for
treatment, we risk lowering their survival and losing a decade of progress
in the management of adult patients.
Suggestions
Type
Public
Change Recommendation 1 to "Perform

Public
routine ECHO screening for PH in all adult
sickle cell patients and refer those with
abnormally high tricuspid regurgitation
velocity for evaluation at centers
specializing in managing sickle-related
pulmonary hypertension."
Discussion
We adapted a recommnendation that acknowleges screen in
adults with SS. Appreciate the comment.
We have adapted recommendations to screening for adult

patients with SS.
No change
No change
Page #
Line #
32
Comments
12 Our guidelines group did a comprehensive assessment of the entire body
of literature concerning PH of SCD in the process of assembling our
guidelines. When a survey of our group was performed to determine what
each member thought was the most important recommendation to emerge
from the entire document, the overwhelming first choice was universal
screening of SCD adults. Our rationale for this is as follows: 1) An
elevated TRV predicts mortality and a significant number of patients will
not have symptoms early in their disease (Klings ES AJH 2008); 2)
Although treatment of PAH has not been shown to improve mortality, we
would argue that no randomized controlled trial of PAH therapy has been
successfully completed in this population. This rationale for not screening
limits the ability to accurately assess and define the true natural history of
this disease. 3) While there is no clear established specific therapy for
PAH of SCD, identification of this patient group with an increased mortality
risk is an indication for a) intensification of treatment for SCD with
hydroxyurea and possibly chronic transfusions and b) increased
assessment of other conditions with known treatments which increase
cardiopulmonary risk such as venous thromboembolism, obstructive sleep
apnea, etc.
Suggestions
Further, identification of these patients is
reaonable to consider for future clincal
drug trials, in SCD patients whose SCD
conventional treatment has already been
optimized, e.g. HU and/or transfusion
regimen.
Type
Public
Discussion
This suggested change is beyond the scope of this chapter.
Also, the comment appears to be a duplicate.
No change
No change
32
12 Although the evidence for use of echocardiography to determine the

Based on the recommendations of Drs.
Public
presence or absence of pulmonary hypertension in SCD is poor, the
Strunk and DeBaun in Kendig's textbook of
potential impact of undiagnosed pulmonary hypertension on patients is
pediatric pulmonology, we recommend
severe. Early signs of pulmonary hypertension can be difficult to diagnose screening all children with
in non-SCD pulmonaryhypertensives, and recognition in SCD patients is echocardiography at least once between
further complicated by the primary manifestations of the disease itself.
16 and 18 years of age. Syptoms of
While a mildly elevated TRJ may not be indicative of true pulmonary
pulmonary hypertension including
hypertension in a majority of patients, a trend of rising TRV over time, or a sustained hypoxemia without other
finding of associated changes in RV size and function or reduced septal
apparent cause, unexplained syncope or
motion may also point to patients who deserve closer monitoring and
physical exam findings consistent with the
further evaluation. Waiting for obvious symptoms can lead to an
diagnosis should prompt screening at an
unnecessary delay in treatment that might slow the progression of disease. earlier age.
The panel does not agree with this recommended change.
32
12 Can you clarify "universal" versus "routine"?
Invited
This recommendation has been re-written and will better define. No change
32
12 What is the evidence echocardiogram screening is not beneficial? I

disagree with not performing echocardiograms in the patients, unless there
is clear evidence that it is not beneficial.
Invited
This team does not agree.
No change
Page #
Line #
Comments
Suggestions
Type
12 I disagree that routine echos not be performed on adults with SCD: The Suggestion: Yearly echocardiogram should Public
controversy with TRV and its low predictive value in PH should not jade the not performed in children, since there is no
Panel in making the pendulum swing the complete opposite way. The
evidence of what this means in the
published evidence shows that (a) TRV elevation (>2.5m/s) is present in pediatric population as yet. However,
30% of adults with SCD. (b) Amongst those with elevated TRV, 25-33% of echocardiography should be performed at
the patients have cath-proven PH. (c) Elevated TRV, whether there is PH 1-2 year interval in adults. If TRV>2.5m/s,
or no PH, portends a poor prognosis (~8-15 fold higher mortality). (d) tthe and this finding is reproducible on a
cause of the elevation in TRV in 2/3rds of the patients is not known but the second echo, a cardiopulmonary
poor prognosis is universally seen in all studies. Therefore, even if cardiac evaluation should be done and the patient
cath proven PH is present only in a third to a fourth of the patients with
monitored more closely with a 6 minute
elevated TRV>2.5m/s, echocardiography still helps us identify patients at walk test and more frequent clinic visits. If
high risk of death, where more intense monitoring can be instigated, and elevated TRV is associated with a
measures like hydroxyurea, transfusions or a BMT can be offered. For the worsening 6 minute walk distance and/or
Panel to make a strong recommendation to stop a non invasive screening symptoms of PH, a cardiac catheterization
test in a third of adults that are at high risk of death does not seem ethical. should be performed to rule out PH.
Discussion
The team does not think further changes are needed - the
background and recommendation are being revised.
32
12 Recommendation not to perform routine/universal screening echos:

Consensus of group was that we cannot support screening echos in
children however would like to see the panel obtain input from experts in
the field to get input on PAH. However we all agreed that echo should be
part of a comprehensive cardiopulmonary evaluation in symptomatic
children and adults (although we dont agree that the symptoms identified
by the panel would appropriately fit all at risk patients)
Obtain additional input from cardiologists, Public

pulmonologists who are experts in PAH.
Clarify and expand symptomatology that
should trigger cardiopulmonary evaluation.
Acknowledge that symptoms described by
panel as indicative of PAH would also
warrant pulmonary function evaluation.
We will be referencing the NIH list of symptoms. We cannot do No change

an exhaustive list in the chapter. Revisions are being made to
the recs and the background to try to answer the questions
posed by commenters.
32
14 Incomplete recommendation
The right heart catheterization is essential Public

to both confirm the presence of an
elevated pulmonary artery pressure and to
define the path physiological etiology of the
elevation.
Agreed.
No change
32
14 "rt heart catheterization should be performed in patients with increased

TRV":
we agreed that right heart catheterization should be performed in patients
with TRV > 3m/s. Consensus is that patients need to be screened for both
cardiac and pulmonary disease. It is important to distinguish arterial
hypertension from venous hypertension resulting from cardiac dysfunction.
We recommend that the panel get input

from cardiologists and pulmonologists to
define the status of appropriate
treatments, based on other diseases, for
cardiopulmonary problems when found in
SCD patients and define what new
information is needed in SCD.
This will be addressed in a revision of the background.
No change
32
Public
No change
Page #
Line #
Type
Public
Discussion
A change is being made to address this comment.
Public
T be o reviewed and change introduction to health maintenance

section
34
10 ECG Screening: ECG screening is not recommended in this document.

There are general recommendations that Public
The section indicates there was no significant difference in mortality in
QTC should be screened for in high-risk
sickle cell disease with prolonged QT vs. without. It quotes Goldberg 2010. population receiving methadone, those
This is an abstract from ASPHO, a retrospective analysis of children with with PHT, and those with cardiac disease.
prolonged QT. In this young age group, mortality rate was higher, but not (ref: Fitzhugh 2010 Am J Hem; Rich 2012
statistically significant (4.4 vs. 2.9); it includes mostly borderline QTCs.
Intl J of Cardiology; Martin 2011 J Addictive
This pediatric abstract does not address the morbidity of QTC prolongation Diseases; Ogunabi 2012 ISRN Hematol;
seen in adults. There are several papers that indicate cardiopulmonary
Zhang 2011 Epidemiology, Lippincott).
complications from arrhythmias in both sickle cell disease and non-sickle These confounding variables should be
cell disease patients. Furthermore, sickle cell patients are repeatedly
addressed in the recommendations section
exposed to medications that increase the likelihood of QTC complications. rather than just eliminate ECG screening.
change needed in narrative. In the background for this chapter,

add a sentence. There may be certain situations where
screening is indicated. Page 33 line 2
34
10 ECG screening pag e34 line 10seems as though this should be a strong
or at least moderate negative recommendation to parallel the D rating from
USPSTF.
Public
need to be more specific about type of research needed. To be

reviewed
2/2/1900
1/10/1900 Do not agree with not performing routine ECG screening. Prolonged QT is
not uncommon and, if unrecognized, might lead to potentially lethal
arrhythmias. Patients and their physicians need to know about the
potential risk if they have prolonged QT and take certain common drugs,
such as macrolide antibiotics, methadone, certain anti-histamines or antiemetics
Invited
weak evidence to recommend ECG screening. Can we add a

sentence about reviewing narrative?
32
33
Comments
15 We agree with this recommendation, but think it needs to read that right
heart catheterization is required to confirm PH and to distinguish PAH from
PVH. This reflects the correct use of right heart catheterization.
0 The thought process behind NOT RECOMMENDING screening tests

(echo, EKG, PFTs) the results of which are not clearly linked to outcome
should be made more prominently. In line 20-21 you indicate for EKGs the
plethora of unknown clinical significance findings made the panel choose
not to recommend this screening test. If you made this clinical rationale
part of the introduction in the first chapter perhaps people will not scream
as loudly about your recommendations.
Suggestions
No change
34
11 This statement is to strong based on low-quality evidence
Public
recommendation does not need to be changeed
no change
34
11 Same goes for not performing ECG. Cardiovascular disease is killer

number 1. Screening should be proposed in order to learn more.
Invited
disagree, not the way to learn more
no change
Page #
Line #
Comments
12 do not recommend routine ECG screening":
We agree that screening ECGs are not necessary in the asymptomatic
patient, however it is important to note that many patients with SCD have
prolonged or borderline-prolonged QTc intervals (Liem et at, Pediatr Blood
Cancer. 2009; 52:842). ECGs they should be obtained prior to
medications at risk for to be harmful in pts with prolonged QTc intervals:
methadone, macrolides, tricyclic antidepressants and continuous albuterol
Suggestions
Acknowledge the frequency of
prolongation of QTc in SCD and include
recommendations for ECG screening as
indicated.
Type
Public
Discussion
will be addressed in the background section
15 Screening for hypertension: We agree that mean BP is lower in SCD than

non-SCD. The panel states that no studies were found that prognostically
defined normal or elevated BP for people with SCD at any age (Pg 35,
line 15-17). However Pegelow et al. (study of 3317 SCD subjects) defined
the median and 90th percentiles of SBP and DBP by age and gender,
showed that stroke risk is associated with increased SBP, and showed that
mortality is associated with increased BP in males (Pegelow Am J Med
102;171,1997).
Consider Using Specific Norms for BP in

SCD patients to define hypertension.
Include literature and recommendations
from previous studies of hypertension
risks/screening in the African American
population.
Public
do not have evidence to define norms for BP, evidence is not

available to define for specific populations
adolescent/children screening for BP at

each medical visit
Invitedstarting at age 3, screen SCD patientst annually as is done for

Non
general population.
Disclosed
A revision to this section was submitted, including revised

recommendations regarding screening children/adolescents for BP
according to JNC 7 and the NHLBI Fourth Report on the
Diagnosis, Evaluation, and Treatment of High Blood Pressure in
Children and Adolescents
13 comment on whether there are preferred anti-htn agents to be used in

SCD patients
13 Why not all ages? Vitals, that include BP measurements are performed at Screen for HTN on an annual basis on all
routine clinic visits. Why presume hypertension can only occur in adults? patients with SCD
Invited
not the subject we are addressing here
no change
Public
see recommendation 4, already addressed
No change
36
15 Do both the systolic and the diastolic blood pressures need to exceed the
levels indicated, or is it sufficient that either elevated systolic or diastolic
blood pressure should lead to treatment (issue also applies to the next
recommendation)? Also, the method by which renal disease should be
screened is absent in this recommendation statement but indicated in the
next recommendation statement.
Fed
they should have more than marginal high blood pressure
Revision submitted.
36
15 RE: For people with BP >140/90, screen for renal disease.

Clarify nomenclature and make consistent. Public
Screening for renal disease is already a universal recommendation. How
does this screening differ from standard renal screening? (Screen for renal
insufficiency with serum Cr?)
they should have more than marginal high blood pressure
Revision submitted.
34
35
36
36
36
1 Recomndation #4 should be expanded to give frequency
no change
no change
Page #
Line #
36
Comments
15 Recommendations 2 and 3 appear slightly inconsistent: parameters for
screening for renal disease are stated for BP > 120/80 but not for the for
BP > 140/90; also, for those with BP > 120/80, there is no
recommendation to initiate lifestyle modification but it is recommended that
"treatment" be considered. "Treatment" may be miscontrued as
pharmacologic therapy only.
36
15 In Internal Medicine, we rarely diagnose hypertension based on a single

elevated blood pressure. Therefore in this sentence I would clarify---when
you describe people with SCD with a BP > 140/90, do you mean after a
SINGLE reading above 140/90, or at least three readings > 140/90?
36
15 Recommendation 2 and 3 seem to be somewhat inconsistent
36
15 in this sentence/guideline to you recommend "screen for renal disease"-but need to be more specific--using what test? Serum creatinine? Urine
microalbumin?
36
15 The text (Recommendation #2) states "In people with SCD with BP>
140/90."
36
15 take (proteinuria and serum creatinine) and put it in line 15 instead of 18
36
18 Recommendation #3 suggests to screen for renal disease (by assessing

urinalysis for protein and measuring serum creatinine".
36
19 you recommend to lower BP to <120/80--but what parameters--keep

lowering until symptoms develop, for example? Or include a statement to
lower BP <120/80 AS TOLERATED--some people just don't feel well with
BPs that low and then you have a compliance issue
37
1 No action listed
Suggestions
Recommend treatment to a pressure of <

120/80 in both groups.
Type
Invited
Discussion
agree confusing. Possible to make one recommendation?
Submitted
Consider treating at the next bp level. Use consider when the
evidence is weak. Use the word consider very carefully. Needs
to stay as recommendation, but some disagreement on this.
May have to go to panel
Invited
clarify for inpatient versus office visits, change narrative instead Submitted
of recommendation. Follow JNC recommendations. Clarify. 2
or more separate office viisits with hypertenstion per JNC.
Public
See discussion below on item 173
Submitted
Invited
Don't give specifics here. They are In chronic chapter.

Incorporated in recommendations 2 and 3
No change
Consider modifying to: "address

Public
intervention for a blood pressure greater
than the 95th percentile for age, gender
and height and screening for renal disease
if the blood pressure is greater than the
90th percentile (or >120/80)."
Invited
Consider modifying text to: "In patients
Public
with SCD and BP> 95th percentile for age,
gender and height, or >120/80 mmHg,
assess urinalysis for protein and measure
serum creatinine.
Invited
If this is just the same as any child it isnt

Public
useful. In the adult there are specific
guidelines. Is there anythign sickle specific
here
do not have appropriate data and rec 3 does address this issue No change
see previous line
no change
delete "by assessing uranalysis for protein and measuring

serum creatinine"
Rec #3 is misquoted here. It currently reads: 3. In people with

SCD with BP >120/80 mmHg, screen for renal disease
(proteinuria and serum creatinine) and consider treatment to
lower BP to 120/80 mmHg. (Weak Recommendation, Very
Low-Quality Evidence) Confirm that "(proteinuria and serum
creatinine)" is what should be deleted.
will give consideration to adding as tolerated. Will be reviewed

any necessary changes proposed
Revision to this section proposed.
leave it as annual screening
no change
Page #
Line #
Comments
Suggestions
Type
Would include a frequency for screening of Public
BP; otherwise, this is confusing.
Discussion
make annual screening change already made
37
37
1 No panel recommendations for evaluation of HTN in children with SCD?
Invitedchange already made

Non
Disclosed
no change
37
1 How often do you recommend screening children or adolescents for

elevated BP?
1 what BP in children should warrant intervention or further work up?
Invited
change already made
no change
Invited
change already made
no change
Public
Public
possible change. Will review

Something can go into the background, before key question.
Panel will reference Chronic chapter and write a brief addition
to the background. See pages 156-157.
Revision to this section was submitted.

Revision submitted
37
37
38
38
20 The sentence is unclear

0 Screening for eye diseaseneed information presented on effectiveness
of treatment (for those identified through screening) p 38
3 Comments on "Screening for Retinopathy" section in Health Maintenance

chapter: The expert panel reports the prevalence of clinically significant
proliferative retinopathy to be 2.7 percent (Clarkson 1982). However, there
is no agreed terminology in the literature defining what type of proliferative
retinopathy is clinically significant versus not clinically significant. This
terminology is unique to Clarksons 1982 publication. Rather, all
proliferative sickle cell retinopathy should be considered visually
threatening and a more recent publication could be referenced. A more
recent study by Clarkson (1992) reviewed data from a specialty center in
Miami, FL over a 10-ywear period and reported the prevalence of any
proliferative retinopathy to be 18% in all sickle cell types (45% SC, 11%
SS, 17% S-thal). This higher rate may be attributed to referral bias. The
most recent data from the Childrens National Medical Center (Rosenberg,
2011) reviewed 258 patients and found that 4.3 percent had proliferative
sickle cell retinopathy. Clarksons 1982 review reporting a proportion of 2.7
percent may be an underestimate and Rosenbergs 2011 data may be
more accurate to reference.
Please clarify
One might consider earlier screening in

Public
young patients at higher risk of retinopathy,
from age 6, with yearly rather than biennial
exams in: males with pain or splenic crisis,
HbSC or beta-thal or G6PD deficiency
(Rosenberg, 2011). Although this evidence
was not reported elsewhere and no studies
specifically looked as this aspect of
screening, the expert panel may wish to
comment on screening at an earlier age
and Rosenbergs study results, even if the
expert panel does not wish to change the
screening recommendations. Given the
wide audience for the document, this
information warrants inclusion.
no change
Will add Rosenberg to the background, but no change to the

Revision submitted
rec is indicated. Also need to consult with panel members on
these comments "This screening requires a dialated eye exam
and the ability to do that will vary according to the child and the
resources available. Variability in resources...variability in the
ability to perform the exam and the available resources.
Page #
Line #
38
Comments
3 Comments on "Screening for Retinopathy section in Health Maintenance
ch., cont.: In regards to age at screening commencement, it must be
emphasized that children develop vision from birth to age 7 or slightly
beyond. During the period of visual development, any insult to the retina
has the potential to interfere with this process and may have lasting effects
on vision, such as amblyopia or strabismus, that would interfere with visual
development and cause a child to be permanently visually impaired.
Therefore, any non-proliferative sickle cell retinopathy can be considered
an important finding in a child, despite the low rate of vision loss from nonproliferative retinopathy. In the publication by Rosenberg (2011), the
youngest patient with sickle cell retinopathy was 6 years old. As such,
screening from age 6 may be warranted.
Suggestions
Type
Public
Discussion
This section being updated
Revision submitted
38
3 References
Clarkson J. The ocular manifestations of sickle-cell disease: a prevalence
and natural history study. Trop Amer Ophth Soc, 1982; 90:481-504.
Clarkson JG. The ocular manifestations of sickle-cell disease: a
prevalence and natural history study. Trans Am Ophthalmol Soc. 1992;90:
481504
Rosenberg JB, Hutcheson KA. Pediatric sickle cell retinopathy: correlation
with clinical factors. J AAPOS 2011 Feb;15(1):49-53.
Public
This section being updated. Adding Rosenberg. Dr. L will check Revision submitted
other references, as needed.
38
13 Please include HOW you recommend screening for hypertension on an

annual basis. Suggest referencing established hypertension treating
protocols (use of aneroid sphygmomanometer rather than automated, and
then referral for elevated values. A recommendation for referral to
nephrologist should be in this section at least for children.
Public
Revamping the HTN section (earlier section).
38
17 Educate patients on symptoms of retinopathy.
Public
This is a good suggestion. Acute vision loss, pain,the things Done. Added new rec. #1 on 1/10/13.
we usually try to tell patients. Maybe we can say "Screen for
and educate" NEW REC #1: Educate all patients about the
signs and symptoms of retinopathy. Consensus Panel Expertise
38
18 no rec as to who should do this? PCP, optometry, ophthalmology
Invited
refer to an opthalmologist for dialated eye exam (add this Done 1/10/13
to the current #1, new #2. Delete "perform or" Just have "refer
to an opthalmologist"
38
19 Recom #1 should be at 2-5 years esp. with tech for exam
38
19 How often do we screen for retinopathy (the literature review provided

would lead me to believe annually? Also, why age 10--again this seems
like an arbitrary number and I don't see age 10 mentioned anywhere in the
background/lit review
neonatal retinal screening is done with little InvitedThe recs are being revised
problems and should be use in 2-5 yr age Non
Disclosed
Invited
Already covered in a previous change.
Revision submitted
Revision submitted
No change
Page #
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39
Comments
0 Screening for risk of stroke using neuroimaging: ( Line 14
Recommendation) This is a strong personal statement based on clinical
practice experience : Young adults with history of abnormal TCD should
have a brain MRA to rule out severe vasculopathy with moyamoya. Adults
with no history of CVA or TIA who give a history of headache or "migraine
headache" should have an MRI/no contrast and a MRA to rule out cerebral
vasculopathy or cerebral aneuriym.
Suggestions
Type
Public
Discussion
There is no change based on this comment, the commenter is No change
not talking about asymptomatic individuals. We are addressing
screening of asymptomatic individuals.
The team did not agree that this change is necessary.
39
1 Consider stating, "... retinal specialist who is knowledgeable about ."
Invited
39
1 Implementing this recommendations may be difficult: who should do the

referring (the opthalmologist or other eye care provider or the primary care
person or does it matter), how does a patient or referring clinician identify
who is a retinal care specialist - are these providers self-identified or is
there a suggestion for certification/training one should look for.
Fed
39
3 Neurocognitive Testing: There is no discussion or section concerning the

efficacy of utilizing neurocognitive testing.
39
8 The presenting signs of stroke leave out headache, weakness, blindness,

cranial nerve palsies etc. The sentence could be modified to say "sudden
onset of neurological deficits such as weakness and aphasia etc."
39
18 The sentence should start with "In those who have had one stroke, stroke
recurs"
Neurocognitive testing is a valuable tool in Public

detecting patients with neuroischemic
injury who are at risk for stroke. This
should be discussed in the
recommendations and reviewed as to what
specific indications when neurocognitive
testing should be done. Clearly, patients
who have progressive problems in
cognitive functioning in school and adults
with memory loss would warrant testing
based on existing data.
No change
No change
This is outside of the scope of this chapter
No change
Invited
This is part of the background. Will expand the symptoms and

signs of stroke.
Rewritten to include: "sudden onset of weakness, numbness, or

other focal neurological signs such as visual disturbances,
dysarthria, aphasia, or ataxia. DONE 2/14/13
Invited
This is part of the background. Will work on this section of the

background, as well.
This sentence was deleted in the revision of this section. 2/14/13
Page #
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39
Comments
Suggestions
Type
21 The section on TCD screening and prevention of stroke is very short given The STOP study NeJM 1998 is not even Public
the massive high quality data--I cant believe more background and
referenced and must be. There are also
information cannot be provided here.
several other studies beyond the CHOP
clinic that show there has been a major
reduction in stroke almost certainly due to
TCD and Transfusion. This section should
be strengthened and amplified,
emphasizing the need to get ALL kids
regularly screened. --given the amount and
quality of the data, the numerous spin off
papers and teh $ 25,000,000 investment of
nhlbi.
Discussion
Will review the background and see if additional detail would
benefit the chapter. Consider indicating the quality of the
evidence by describing the number of RCTs.
Rewritten as follows: Transcranial Doppler (TCD) imaging of large
intracranial blood vessels to detect increased velocities secondary
to stenosis is now employed to can predict risk of stroke in children
with SCA (Adams 1992)(Adams et al. 1992). Primary stroke
prevention using regular blood transfusions in children with such
elevated velocities proved successful in the NIH-funded STOP trial
(Adams et al. 1998 ). This approachtransfusions for an
abnormal TLD velocity (>200 cm/sec)has resulted in a declining
incidence of primary overt stroke in children with SCD (EnninfulEghan et al. 2010 ). Unfortunately, discontinuation of such
transfusions was shown in the STOP-2 trial to result in a high rate
of reversion to increased TCD velocities or to overt stroke (Adams
et al. 2005 ). Therefore, such transfusions may be necessary
indefinitely. DONE 2/14/13
40
3 The sentence should be made more clear by saying ---markedly

decreases the risk of stroke in children with SCD who have an abnormal
TCD (>200 cm/sec). Not all recurrent strokes are preventable.
Invited
Will make this more clear.
This sentence was deleted in the revision of this section. 2/14/13
40
Public
No change
CHANGE: Page 40, line 9: Add a new paragraph following this section
that acknowledges the growing body of research on neuropsychological
outcomes, and the role of neuropsychological testing, in identifying,
diagnosing, describing, and precisely guiding management of
neurocognitive or psychosocial compromise among individuals with SCD
(see, for example, Berkelhammer 2007, Wang et al. 2001, and Wills 2011).
Acknowledge that the present review considered neuroimaging
technologies but did not evaluate the role of psychological or
neuropsychological testing as a screening tool or for clinical evaluation of
patients with SCD.
Page #
Line #
40
Comments
10 Screening for Risk of Stroke Using Neuroimaging: The key question is "In
asymptomatic individuals with SCD, what is the effect of screening on risk
of stroke with neuroimaging tests (CT scan, MRI or TCD)?" The
recommendations are to screen children with SS below 16 years of age
with TCD and not to do any testing in adults. These recommendations do
not address the complexity and risk categories in SCD. There are not 2
groups of patients totally asymptomatic who are under 16 years of age and
patients with overt symptoms over 16. The TCD and MRI are synergistic
and complimentary in several specific instances, and in many cases, the
MRI has specific indications.
Suggestions
Type
The recommendations section should
Public
define what asymptomatic means. Are
patients with headaches, deteriorating
school performance, severe sleep hypoxia,
neurologic soft signs, memory loss,
seizures, abnormal neurocognitive testing,
or IEPs in school asymptomatic or
symptomatic? There should be detailed
recommendations concerning when MRI
testing would be indicated.
In our opinion, there is sufficient evidence
to support screening for silent cerebral
infarction in general. However, in patients
with any soft signs, the data is even
stronger. Silent infarctions are correlated
with cognitive deficits and behavioral
problems that can be identified and allow
for additional educational resources and
assistance. In addition, close monitoring
and therapeutic options can be reviewed.
Discussion
Yes, we agree. Panel members will dicuss the extend that we
need to define asymptomatic.
Per revision, Background section revised to include: "transfusions
for an abnormal TCD velocity (>200 cm/sec). DONE 2/14/13
40
10 Consider adding MRA/MRV to list of neuroimaging in key question, or

provide information in the background on the challenges with using MRA/V
for screening
Invited
Will give consideration to putting this in the background - will

discuss with additional panel members.
This was not added in revised section. DONE
40
11 This is far from the "key question" as the effect of screening is clearly to
The key questions really are why these
Public
decimate the rate of first stroke, albeit at the price of tranfusions.
particular children develop vasculopathy
Neuroimaging is secondary to TCD and will likely always be as the first test and how it can be interupted with more
to establish treatment is often hard to improve upon with good evidence as discrete or small molecule approaches
the high risk individuals are no longer having outcomes nearly as often
short of transfusion. The other major issue
and surrogate measures, beyond TCD are not valid. TCD is easy to do
is the complete dearth of data on adults
and cheap but in cases where tcd cannot be done MRA or CTA should be with SCD and stroke and stroke risk. unlike
recommended.
in kids this risk is rising not falling and
there is no stategy even in the pipeline for
this.
The team will check to see if this is already addressed in the

gaps
Sectoin revised. No change to this language.
This is addressed in a recommendation to refer. Will consider

adding something to the background.
Section revised. No change to this language.
41
0 What is the panel's recommendation for perfomance of an MRI/MRA with

elevated TCD values to rule out unsuspected clinical stroke. THIS should
be discussed and added here.
Public
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41
41
Comments
1 Would consider "elevated cerebral blood flow velocity (CBFV >200
cm/sec) as an alternative to abnormal, sicne the strog evidence is just for
that group
Suggestions
Type
Discussion
InvitedChange to "elevated" instead of "abnormal" on line 17
Non
Disclosed
10 Change from Dr. Lottenberg and Joylene received 11/30/12 via e-mail
Done 1/10/13
Done 1/11/13
Information from a modeling and decision analysis (not a

clinical study) suggests that the optimal stroke prevention
strategy is annual TCD ultrasonography screening up to age 10
with transfusion for those at high risk until age 18. (Maxumdar
2007) No clinical trials have been published evaluating this
strategy.
41
41
12 Why stop transfusions at age 18? Data? Rationale.

need rationale
Public
Invited
No change
Done 1/10/13
Public
This is out of the scope of this chapter.

This is SCA. In children with SCA, screen annually... EDITOR
MAKE CHANGE.
This is a modelling study
41
15 This contrasts with the above text about doing it until age 10
need to be consistant
41
15 Should include information that some patients can not have a meaningful
TCD evaluation because of closure of bony windows, that this is more
common in older adolescents and adults. Also if known an estimate of this
number.
Public
Panel members will discuss
41
15 There has been at least one publication recommending stopping

performing routine TCDs after several normal ones
Invited
No specific change recommended. Panel does not feel a need No change

to change the document.
41
15 Recom#1 if neuro eval done at 2 yrs at same time do retinal exam
41
41
Establish 2 years age for most SCD

screens
InvitedThis is being handled in a previous section.

Non
Disclosed
No change
15 there is no recommendation given for Hb S B0 thal

15 "In children with SS, screen annually with TCD, beginning at age 2 and
continuing until age 16". This is the STOP data; however it is not clear why
16 based on the information provided in the preceding paragraphs. The
panel wrote up to age 10 in the preceding lines based on another
reference.
Public
Invited
Covered in previous change

This is being covered in a previous comment
No change
No change
41
15 what about sickle beta zero thal? May be better to consistently use
terminology that covers both SS and s-beta zero (?SCA)
Invited
This is covered in a previous change
No change
41
16 "at least age 16" is vague. If the statement is intentionally vague, please
state that explicitly. If there are known considerations for whether
screening should continue or discontinue starting with the 16th birthday,
please state those.
Fed
Panel members will discuss to determine if a change is needed Section revised. No change to this language.
41
17 what about imaging TCD (TCDi)? May need modifications of STOP cutoffs
Invited
Panel will address.
42
1 please expand or clarify that Sbzero and SOarab are at increased stroke
risk. Screening should follow recommendation for HbSS
Clarify wording and incorporate additional Public

information.
What should be do with Soarab?
No change since throughout the document HbSB0 and the rare

HbOArab are considered all clinical respects as SCA. DONE
42
1 sickle beta-0 thalassemia should be included with Hb SS
sickle beta-0 thalassemia should be

included with Hb SS
Before the parens, or hemoglobin S beta zero thalassemia (in Done 1/10/13
correct format).
Public
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42
Line #
Comments
1 How can a strong recommendation be made against screening, with very
low quality evidence? Is there a better way to word this-there is limited
evidence that screening is not effective/necessary/cost effective?
42
42
42
42
1 No mention of Sickle Beta zero thal

1 same issue as stated above about sickle beta zero
2 Avoid the phrase "do not perform"
3 Neuro - General
42
4 Is there any evidence to refute the utility of neuroimaging in adults ? A

recommendation against would seem to require some evidence against
and I do not believe any is cited
42
4 the evidence does not justify categorizing as strong recommendation.

Additional research is needed, especially in light of recent progress in
neuroimaging techniques.
Suggestions
In general, the sections on stroke

screening and management are concise
and informative. Below are suggestions to
clarify specific points. The guidelines do
not contain sufficient information or
recommendations addressing the other
neurological complications of SCD. In
particular, discussion on prevalence and
surveillance of neurocognitive deficits
seems necessary.
Clarify recommendation.
Type
Discussion
InvitedThe panel is comfortable with the grading of this
Non
recommendation. Should this be addressed in the Intro - what
Disclosed strong/very low means?
Yes, this will be revised in the Intro.
Public
Invited
Public
Public

The team does not agree with this.
We are not addressing neurocognitive evaluations in detail.
Further discussion is outside of the scope of this chapter.
No change
No change
No change
No change
Public
Will consider moving information from the background to the

summary of the evidence
Public
Will consider moving information from the background to the

summary of the evidence
Page #
42
Line #
Comments
6 Screening for Respiratory Disorders in SCD (Asthma, PFTs)
Suggestions
Type
Asthma is a critical problem and needs to Public
be included in the document. Relying on
the physician to obtain history of asthma
symptoms is unreliable and
underestimates the magnitude of the
problem. Given the morbidity of this
complication, this section underestimates
the importance of early diagnosis and
treatment of broncho-reactive lung
disease. A high degree of suspicion is
warranted for testing. Rather than exclude
pulmonary functions as an entire category,
we would recommend an expanded
section that outlines those patients who
should be tested if not all. In addition,
since so many of the patients with acute
chest syndrome have a broncho-reactive
component, the issue of treatment of acute
chest syndrome with broncho-reactive
medications needs to be included
somewhere in the text.
42
9 state background rate
Invited
43
3 COPD is a diagnosis that is made by pulmonary function testing and its

severity is graded by this testing so it is not clear to me how the authors
plan to identify these patients without PFTs.
Public
43
8 Should another key question be "Screening for asthma in all chidlren (+/-)
adutls with SCD?
InvitedThis is out of the scope of this section of the chapter.

Non
Disclosed
44
0 If asthma rates high and serious why not do PFTs
44
0 Screening for Respiratory Disorders in SCD: - ( Line 16

Recommendations) I disagree. If we are doing comprehensive care in
patients with SCD, PFTs should be done in asymptomatic adults with
SCD. This chapter on Health Maintenance does not tell the primary care
physician about abdominal sonogram, hips and shoulders, which routine
Lab tests to do etc. Some of what I said is in subsequent chapters but they
should be summarized here.
Need to state approach fr screening for

asthma.
Discussion
Asthma guidelines have this information. Some of that
information might be helpful here. This could be in the
background. Asthma will be further addressed in the
background. We will review what has been included in ACS
specific to what has been addressed in broncho-reactive lung
disease.
Revised recommendations submitted for this section.
Can provide specific data. Editor - on line 8 remove "such as

asthma"
Panel members will collaborate on how to incorporate this into
the background of the document.
EDITOR: Removed "such as asthma."
No change
Public
We are going to add a recommendation about taking a

Submitted
thorough respiratory history and a broad recommendation about
how to proceed. 2 recommendations to be drafted.
Public
Recommendation being added to address this. In patients who Submitted

have respiratory symptoms, do appropriate evaluation,
including PFT and potentially CV evaluation. Goes with other
44/0 notes.
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44
44
Comments
4 Question: did not have clarity what asymptomatic means: several only
have headaches without any other neurological problesms and MRI shows
an anerysm. Where does the PCP go with this from such a blanket
statement?
17 There is no discussion here of asthma in SCD, other than to mention that
the prevalence is increased. There are no recommendations in this
document for the appropriate surveillance and treatment of asthma in
children with SCD; there is not even a reference to the standard NHLBI
guidelines for asthma care. Children with asthma are at increased risk of
vaso-occlusive episodes and ACS, particularly if the asthma is
inadequately controlled.
Suggestions
1. A review of systems for atopy and

asthma should be performed annually for
all children with SCD, starting at one year
of age. If the history is positive, they
should be referred to an allergist,
pulmonologist or other asthma specialist.
2. Treatment of chldren with SCD and
asthma should be undertaken according to
NHLBI guidelines. Once diagnosed,
children should be assessed at least every
6 months for persistent symptoms. We
recommend spirometry 2-4 times annually
for children with SCD and asthma, based
on the severity of the asthma and the level
of compliance with therapy and control of
symptoms. Children with asthma and SCD
should be seen by a pulmonologist,
allergist or other asthma specialist at least
annually if they have mild asthma and at
least every 6 months if they have
moderate to severe asthma.
Type
Invited
Discussion
This is out of scope fo this chapter
Public
There are no recommendations that are different for patients

Sent information to be incorporated into revision of Chronic
with SCD and asthma. The NHLBI asthma guidelines should be chapter.
used in this case. Also, this is a chronic condition, not a health
maintenance issue. Send note to Chronic to add a section on
referring to NHLBI asthma guidelines.
No change
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44
Comments
17 We are frankly dismayed by the lack of information regarding pulmonary
complications of SCD in this guideline. It is clear that nobody with a clinical
or research interest in this aspect of sickle cell care was asked to
participate in the generation of this report. While we concede that, again,
there is mostly poor quality evidence for any specific monitoring or
intervention for pulmonary complications of SCD in children, we absolutely
reject the defeatist tone that is implied in the single recommendation
provided in this document. Adult pulmonologists are increasingly familiar
with sickle cell chronic lung disease, an entity which is surely evolving
during childhood whether or not we recognize it. As the report indicates,
any number of observational studies have noted abnormalities of lung
function, both obstructive and restrictive in nature, in otherwise
asymptomatic children with SCD.
Suggestions
Type
1. We recommend that the Expert Panel
Public
Report call for the establishment of a
broad based registry for pulmonary
outcomes in children with SCD, which can
serve as the foundation for the urgently
needed prospective investigations of
clincial interventions for the treatment and
prevention of pulmonary complications.
Further, we recommend that this registry
be used for the institution of hypothesisdriven clinical investigation of therapies
and intervention to prevent many of the
pulmonary complications mentioned here.
2. Based on the recommendations of Drs.
Strunk and DeBaun in Kendig's textbook of
pediatric pulmonology, we believe that
children with SCD should have an
assessment of lung function by spirometry
annually after 6 years of age. Children with
asthma and SCD should have spirometry
with every visit, up to 4 times annually. A
bronchodilator challenge should be
performed for children who have an
obstructive pattern on baseline spirometry
(FEV1/FVC < 80%, or less than 95% CI).
3. Children with SCD should have an
assessment of possible defects in lung
function by lung volumes with
plethysmography starting at 6 years of age
(or first age at which they are able to
complete the test), and every 5 years
Discussion
This can be incorporated into the gaps section.
Revised Recommendations submitted. The gaps section was not
modified.
Page #
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44
44
Comments
17 Page 44, line 17 Cont'd - Our members do not believe that lack of proven
efficacy for treatment justifies recommendations against regular
surveillance with PFTs in children with SCD. Pulmonary complications
remain one of the leading causes of mortality and morbidity in this
poulation, and simple screening tests like spirometry may allow us to
identify those patients at particular risk for poor pulmonary outcomes.
Ongoing assessment of basic lung function is an essential prerequisite to
the urgently required evaluation of therapies commonly used in SCD
patients, including hydroxyurea, bronchodilators, inhaled steroids and
combinations of these drugs. In addition, we often identify patients who
lack (or fail to perceive) clinical signs of asthma, but who have reversible
bronchoconstriction which may respond to asthma medications. If we do
not look, we will not learn to identify signs of early lung damage in these
children.
Twenty-five years ago, there was almost no evidence to support
interventions that were used to treat cystic fibrosis, and most children died
in their teens. It was only through continued, aggressive observation of
interventions informed by expert clinical opinion that the current broad
base of knowledge was acquired, leading to rapid and dramatic changes in
CF care. Now the median age of survival for CF patients is 37-38 years,
but this would not have happened were clinicians advised to stop
screening for complications since there were then no available
interventions. Evidence based medicine is only an effective guide in the
presence of quality evidence. Where it does not exist, there needs to be a
strong call for MORE clinical observation, and more research, until this
type of evidence is acquired. In this setting, the input of clinicians with
experience and expertise in the area should weigh heavily in any
recommendations disseminated to the general medical community.
17 This is an over-simplification of the topic. The real issue is that of asthma

and airway hyper-reactivity in SCD. These are clear risk factors for
morbidity and mortality in SCD children and adolescents. PFTs are not the
only way to "screen" for these disorders but they are the only objective
measure of lung function available. Dyspnea is incredibly underrecognized in SCD and to mention that a respiratory evaluation is
necessary in one line of text really does not adequately address this issue.
Suggestions
Type
Public
Discussion
The reference provided will be reviewed and work with panel
members on this (and previous) comment. This may be
covered better in the revised recommendations that are
forthcoming. Research gaps may also be modified to address
this issue.
Revised recommendations for this section were submitted. The
Gaps section was not modified.
Public
Will look at the papers and attempt to address this comment
Revised recommendations for this section submitted.
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44
Comments
17 "Do not screen (asymptomatic) children and adults with SCDwith PFTS."
This recommendation is inconsistent with the cited data on pulmonary
dysfunction in SCD, and seems to be based on paucity of studies
evaluating "the utility of screening." However there are numerous studies
showing a high rate of reactive airway disease in the SCD population and
significant compromise of pulmonary function and decline with age in SCD
patients. Substantial restrictive lung disease is reported in adults with
SCD. Routine PFT screening is noninvasive and may guide therapies, in
particular, identifying reactive airway disease that may be amendable to
conventional standard of care asthma management. Indeed there are
clear guidelines (NIH) for asthma management. Given the difficulty in
defining "asymptomatic" in this population, the lack of sensitivity of
"symptoms" to predict abnormal PFT, and the critical role of pulmonary
function in the pathophysiology of SCD, it seems prudent and consistent
with good medical practice to assess pulmonary function in this group of
patients.
Suggestions
Type
Acknowledge the high incidence of lung
Public
disease in SCD and utility of routine PFT
screening in detecting dysfunction and
guiding therapy, especially for asthma.
Consider reference to NIH guidelines for
asthma management until more
information is available and asthma
studies specifically to SCD are performed.
Invited
Discussion
Will do some searching for review articles on this topic.
This is a closed issue - the group did not think a change was
warranted.
44
17 Would emphasize "asymptomatic" children and adults. This does not

apply to patients with h/o ACS (especially repeat ACS) who may have an
asthma component and should actually be evaluated by a pulmonologists
and with PFTs
Screening would imply "asymptomatic". Revision is being

No change
considered by the group at this time. Information about asthma
prevalence has also been sent around.
44
17 Recom 1 SCD with asthma risk should have PFT
need to make recom more inclussive,

much too short
44
17 these pulmonary recommendations are very minimal
it would be helpful to have some additional Public

recommendations, esp with restricitve
problems
This comment is being considered in a revision to this section.
No change
44
17 There is no discussion of sleep disturbed breathing in children with SCD in

this document. Children with SCD have a higher than typical incidence of
obstructive sleep apnea and associated hypoxemia. OSA in SCD patients
is associated with a higher incidence of stroke, and a recent report has
indicated that nocturnal oxygen desaturation and disordered sleep may
contribute to learning disorders and executive dysfunction in SCD patients
(Hollocks et all, J Int Neuropsychol Soc 2012; 18(1): 168-73.)
Children should be assessed annually by

history for symptoms of sleep disordered
breathing. If the history is positive, they
should be referred to a pulmonologist or
expert in sleep medicine for further
evaluation.)
This will be mentioned in a revision to the recommendations

that is underway, but this topic was not specifically part of our
evidence review and therefore we do not have evidence to
make specific recommendations.
No change
44
17 There should be some statement about screening with the history,

Add a suggestion here or have a separate Public
physical, and pulse ox with low threshold for complete evaluation for signs section for chronic pulmonary disease.
and symptoms if this is not addressed in a separate pulmonary section in
chronic disease.
There will be mention of this in the revision.
No change
44
17 Would consider changing recommendation to "Do not screen

ASYMPTOMATIC children and adults with SCD with PFTs
InvitedThis comment is being considered in a revision to this section.

Non
Disclosed
Public
InvitedThis is being addressed in a revision to the recommendations.

Non
Disclosed
No change
No change
Page #
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44
44
Comments
17 Add "asymptomatic" after "do not screen.." and before
".children"
17 I am surprised that the panel has reviewed the high incidence of airway
hyperreactivity, abnormal PFT, and studies have shown the associaiton of
asthma with mortality and ACS, and yet recommend not doing PFT. If
patients have airway hyperreactivity, they can be treated for asthma.
Asthma in SCD has been shown to be associated with increased mortality,
increased incidence of acute chest syndrome.
Suggestions
Type
Invited
Discussion
This is being addressed in a revision to the recommendations.
No change
Suggest "do not screen children and adults Public

with no prior history of asthma or
symptoms of asthma with PFT. However,
patients with history of reactive airway
disease or asthma should have PFT and
be treated for the asthma".
No change
44
17 add "asymptomatic" to this statement
Invited
No change
44
17 Add the word 'asymptomatic'
Invited
No change
44
18 any recommendation for baseline screening with pulse oximetry? Often

very useful in evaluating oxygen saturation with acute illnesses
Invited
There is no evidence to support making this recommendation

specific to SCD.
No change
Section lead needs to review and comment on this.
These data were not reviewed. No change.
EM
All options should be provided to individuals who are at risk.

Panel members will look at this and suggest some wording.
Out of scope. No change.
EM
Section lead needs to review and comment on this. May need

to pull in information from the STOP trial.
EDITOR- DELETE: In 1,814 patients with SCD who had been

transfused, the overall ..18.6 percent."
45
0 The only area I did not see covered (and it would be easy to miss amongst
the 225 pages of text) was men and women with sickle cell disease using
gene therapy. It seems to me a section on this area, similar to hydroxyurea
therapy and blood transfusion therapy, would be appropriate.
45
0 The section on heritability (page 45) is complete from a scientific

standpoint, but the clinical reality is that PGD, and in many places CVS are
not available due to cost constraints and few insurance companies cover
the former (it is really expensive).
45
0 The section on fetal anemia due to alloimmunization (page 45) should be

favored with references from several areas. The 18.6% seems to me to
be a high overall figure and there are specific references where the rate of
alloimmunization is much lower. Nevertheless, as noted on page 47, the
consensus recommendation is reasonable.
That being said, this alternative needs to

be revealed more strongly to patients in
perceptional counseling, particularly
women with SCD with partners who have
trait. The primary issue that should be
heavily emphasized now is testing the
father of the baby to assess
hemoglobinopathy status.
45
10 Would add "if their partners have SCD, B-thalassemia,or HbS, HbC, or
thalassemia trait.
InvitedSection lead needs to review and comment on this.

Non
Disclosed
OK to add this. EDITOR MAKE CHANGE.
45
13 add sentence on insurance coverage of these services
Invited
No change
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45
Comments
16 The practical lack of access to PGD and CVS for patients because of
insurance limitations (especially public insurance), a restriction that also
pertains to recommendations for genetic counselling by genetic
counsellors should be so stated. Recognition that this is not possible for
financial reasons or that this is costly should be included.
Suggestions
Type
Public
Discussion
No change
47
0 The section on contraception is well written and the recommendations are

excellent. I would insert a little more language and perhaps a reference on
page 49 as the IUDs are mainly associated with infectious risk due to the
patients defective immune system, particularly in the area of
opsonization. At any rate, counseling, particularly as it applies to people
who are thinking about becoming pregnant or who desires contraception is
paramount.
EM
Panel will draft a statement and revise the section: "There is no EDITOR: Insert this statement at the end of line 10: There is no
evidence of increased risk" into page 49, line 9.
evidence that IUDs pose an increased risk for women with SCD.
47
1 Consider renaming section since it includes both reproductive counselling

and management of pregnancy
Invited
This section does not cover management of pregnancy, so this No change

change is not warranted.
47
1 I am a R.N. and a patient with SCD. I am concerned about the lack of

information for the adult
patient. I believe the SS community would benefit from comparative
studies that would
determine the morbidity and mortality of the neonate and mother if there
were single person
allocated blood donors for transfusions in non acute settings to decrease
alloimmunization in
females before reproductive age versus multiple person donated units.
I know this is not the
form and will not be considered but I would have liked this addressed on
page 47 ore line 1. I
have sent this concern to SCDDA and no response. After my 1st child I
became unable to obtain
blood matches due to multiple antibodies; including Rh 46. I have met
many other young
mothers with the same alloimmunization problem. Thank you for your
time.
Public
These comments are very much appreciated. Changes

No change
mentioned are outside of the scope of this chapter. The
transfusion chapter does address the issue of alloimmunization.
47
9 What is "reproductive life plan" and what percentage of the general

populaion at childbearing age develop such a plan. With 55% of all
children (72% of African-American) born to women under 30yr being
children of unmarried parents, is this a realistic recommendation?
Invited
"Thinking about your goals for having or not having children and EDITOR INSERT ON Page 45, line 4 (after CDC 2010) They
how to achieve those goals is called a reproductive life plan."
recommend that women and couples think about their golas for
Figure out where this language can go - background?
having or not having children and how to achieve these goals,
known as a "reproductive life plan."
47
9 What is a "reproductive life plan?" Is there a template for this?
Invited
No change
47
9 "reproductive life plan" is vague
Fed
No change
Page #
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47
47
47
47
47
Comments
11 I would strongly suggest adding "or refer for risk assessment" in addition to
providing risk assessment and educational counseling. Most PCPs, even
if they had the time to devote to this single facet of counseling, probably do
not feel adequately prepared to counsel individuals with SCD on
reproductive issues. So if they don't want to/won't, then it is reasonable to
at least ask them to refer for this.
Type
Invited
Discussion
YES, change to "provide or refer to individuals with expertise in Done 1/17/13
these disciplines"
11 should this say all men and women or otherwise should this rec be listed in
the next section?
11 Consider adding clearer and more direct language to provide
contraceptive counseling, if desired, to prevent unintended pregancy, and
if pregnancy is desired, provide pre-conception counseling to reduce risks.
This could be connected to the subsequent section on contraception.
Invited
This is a very good suggestion and would have the consent of EDITOR - YES, CHANGE TO ALL WOMEN AND MEN.
the group.
We can insert the following between lines 12-13 on page 47.
Editor - change as indicated.
"Provide contraceptive counseling, if desired, to prevent
unintended pregancy, and if pregnancy is desired, provide
preconception counseling." However, I'm not sure it adds much.
12 Routine education about the reproductive issues should not be limited to

females of reproductive age.
14 This recommendation does not provide any direction for screening for
hemoglobinipathies and the phrasing is somewhat awkward.
Public
47
15 More useful if we specific recommended testing. Sickle prep is not

adequate for providing comprehensive counseling
47
16 This recommendation limits genetic counseling to couples at risk. All

people with SCD regardless of relationship status or whether the partner
knows carrier status should have access to genetic counseling. It also
gives no direction regarding where suitable genetic counseling services
can be obtained.
47
16 Genetic counselling by other than the hematologist is just not available to

publically insured patients. IT should not be listed as a specific
recommendation. Suggest couples at risk should be assisted in a
discussion of their specific risk by medical professionals
Suggestions
Fed
Refer partners of patients with SCD for

Public
hemoglobinopathy carrier screening when
status is unknown. Hemoglobin
electrophoresis or (HPLC for hemoglobins)
with a CBC are the best method for
detecting hemoglobinopathy carriers.
Sickle dex or solubility testing is not an
acceptable method for carrier detection.
Refer at risk couples or couples with an

unknown status for genetic counseling
regarding the chance to have an affected
pregnancy and to review preconception
and prenatal options. Refer people with
SCD who have questions about the
inheritance of the condition for genetic
counseling. Clinical genetic services can
be located through the NSGC, ABGC, or
ACMG.
Fixed by comment on page 47/11 "should this say all men and No change
women"
Here is how the sentence has been reworded this statement
Editor - change as indicated
without straying from our consensus, "If the partner of a man or
woman with SCD has unknown SCD or thalassemia status,
refer the partner for hemoglobinopathy screening. (Consensus
Adapted)" The Expert Panel did not discuss or develop
consensus around carrier screening and, therefore, we cannot
such make recommendations.
Invited
The group did not discuss or develop consensus around carrier No change
screening and, therefore, we cannot such make
recommendations.
Public
These are all good ideas, but while these recommendations

No change
recommend genetic counseling to couples at risk, they do not
limit genetic counseling to couples at risk. These
recommendations are by no means prohibitory. The additional
situations described should be considered optional, yet are
beyond what the Expert Panel recommended as a minimum.
Public
The Expert Panel agreed an this is why the section does not
specify by whom the genetic counseling should be performed.
No change
Page #
Line #
47
47
48
Comments
Suggestions
18 There is no statement of the burden of raising a young child and its
Add such a recommendation.
potential to reduce the ability of a young mother to care for her self and her
sickle cell disease. That she should have identified support systems
available before she becomes pregnant so she can take care of her own
health needs and so she has options for her child's care when she is
receiving health care for her sickle cell disease.
Type
Public
Discussion
This is an excellent point, but we actually found no literature
that supported our making such a recommendation.
18 there are recs for men in here too - confusing to have two sections here
that overlap
Invited
In this section on Specific Recommendations for Women with

SCD, the recs for men are for the partners of women with
SCD.
Invited
This document does not address the care of the woman once No change
she becomes pregnant. It would be appropriate to comment on
that in the introduction of the document.
Invited
Yes, but this document does not address the care of the woman No change
once she becomes pregnant.
7 what about antenatal diagnostic testing?
48
13 should pregnant women with SCD be referred to high risk Obs or MFM
specialists based on these complication risks?
48
16 Recom 4 d Not a recomandation just a risk statement
Infants born to women with SCD who

require narcotic meds for pain
management need to be observed for
withdrawl symptoms and managed
appropriatly.
48
17 Guidelines provided seem inadequate.
Pregnant SCD patients should be

Public
managed jointly by a hematologist and a
high risk pregnancy center based
gynecologist. Pregnant patients should
discontinue hydroxyurea once the
pregnancy is known or before a planned
pregnancy. Short term chronic transfusion
therapy should be considered during the
pregnancy.
49
49
1 very important section to include, well-written

11 no data on what types are selected most commonly by women with SCD?
- getting to pt preferences to guide conversations
50
4 duplicate of above couple sentences
No change
No change
InvitedWe make the statement that women should be counseled prior No change
Non
to pregnancy that, "For women who require chronic opioid
Disclosed therapy during pregnancy, there is an increased risk of neonatal
withdrawal in their newborns," however, this document does not
address the care of the woman once she becomes pregnant, let
alone the neonatal care of the infant after delivery
Invited
Invited
Invited
Yes, but this document does not address the care of the woman No change
once she becomes pregnant.
No data.
Actually not a duplicate. One section is about all women, one

section is about women with SCD. We'll fix the sentence on
lines 4-6 and make it explicit and also fix the error about
"progesterone-only," versus, "progestin-only." CHANGE: Page
49 line 20 should be "Progestin-only," not Progesterone-only.
No change
No change
DONE. Changed p. 49 line 20 to "progestin-only." 1/17/13
Page #
Line #
50
Comments
6 The sentence on lines 6-8 is a duplicate from the paragraph above and
should be omitted.
Suggestions
Type
Public
Discussion
The sentence in line 4 should read, "There were no episodes of Done 1/17/13
deep vein thrombosis (DVT) in women with SCD using
progestin-only contraceptives or IUDs" This will make the
sentence more explicit and should eliminate the confusion.
Public
The revised sentence shourld read,"...approximately 11 percent Done 1/17/13

of untreated women with SCD have had a clinically apparent
stroke"
50
10
Should indicate that 11% would be for

untreated patients
50
17 In non-SCD women with risk factors such as high VWF and ADAMTS13,
oral contraceptives increase MI and stroke risk (Blood 2012;119:1555). It
would be more prudent, in my opinion, to assume that SCD also
represents a risk factor to women exposed to oral contraceptives. Safer
alternatives to avoid pregnacy should be chosen: fertility-awareness
methods, which are as effective in preventing pregnancy as hormonal
contraceptives (Hum Reprod 2007;22:1310), would seem ideal for SCD
women.
Substitute Recommendations 1 and 2 with: Public

"Fertility awareness is the only family
planning option that does not expose
women to any potential risks and is
effective for planning or avoiding
pregnacy"
We used the CDC and WHO guidelines.
No change
50
17 Risk of venous thrombosis with progesterone containing contraceptives the conclusion that thrombosis is not increased is surprising and not
consistent with my understanding as there are a lack of comparative trials
with no intervention. There is reasonable evidence the risk is lower with
progesterone alone compared with combined.
Public
We summarized all of the available data.
No change
50
17 This sentence is a statement, not a recommendation. Would rephrase to

make the desired action (or inaction) clear.
Fed
The Expert Panel agreed to this language after considerable

deliberation.
No change
50
17 Should this recommendation be qualified, e.g., "unless there are risk

factors (other than SCD) for venous thromboembolism (VTE) present?"
(Specifically for oral and injectable formulations.)
Invited
Excellent point, but we used the CDC and WHO guidelines.
No change
50
20 should there be an exception excluding patients with prior stroke (or VTE)
from this rec as estrogens are not typically recommended with prior stroke
or VTE
Invited
Yes, and this is explicitly stated in these guidelines.
No change
50
20 add statement "and if no history of stroke" to the sentence about if the

benefits outweigh the risks then combined hormonal contraceptives may
be used. You have previously described h/o stroke as a contraindication
so to me this is not an issue of benefits outweighing risks at all if someone
has had a stroke.
Invited
We have used the CDC and WHO guidelines.
No change
50
20 Because of advice under Warnings/Precautions in the package insert to

discontinue use during periods of prolonged immobilization, and due to the
fact that SCD is considered by many to be a hypercoaguable state,
perhaps use of the contraceptive ring (NuvaRing ) should be
discouraged in all women with SCD.
Invited
Excellent point, but we used the CDC and WHO guidelines.
No change
Page #
51
Line #
Comments
1 Change to, "United States Preventive Services Task Force (USPSTF)
Recommendations" (This whole section inc. Exhitibit 4 should be in
accompanying Methodology/Reference volume.)
Suggestions
51
1 What does USPSTF stand for? Please spell out the complete name.
51
51
3
3 The USPSTF's report to Congress describes its recommendations as
"screening tests, counseling services and preventive medications"
51
4 The document uses the phrase "the average person" to describe the
population of interest for the Task Force. It might be more accurately
described as persons without signs or symptoms of the target condition.
However, recognizing how that might be confusing in this document could
you just say "children and adults" instead of "average person?" Or even
"general population" might capture the notion a little better.
51
5 Most primary care doctors do not test for trait in their patients who are in
childbearing years. Recent immigrants may never have been tested.
Test all young adults for trait and explain Public

consequences of having a child with SCD
This is misplaced and would actually go in the section on

womens' health.
No change
51
5 Most primary care doctors do not test for trait in their patients who are in
childbearing years. Recent immigrants may never have been tested.
Test all young adults for trait and explain Public

consequences of having a child with SCD
This is misplaced and would actually go in the section on

womens' health. A statement is being added to the intro do
discuss this an numerous other comments about pregnancy.
No change
51
13 Using the term "strong recommendations" may not be exactly right. Of all
its A and B recommendations the word "strongly" is only included in eight.
In addition, a few of the recommendations you listed include some C
recommendations. Could you use the term "positive recommendations?"
This would be more accurate. (As a reminder, the grade encompasses the
TF's assessment of both the magnitude of the potential net benefits and
certainty about the strength of evidence.) Another approach would be to
say, "We have only included A and B recommendations from the
USPSTF..." This is consistent with the ACA's approach as well.
Fed
ADD FOOTNOTE: "Please note, these include level A and level

B recomnendations of the USPSTF. For more information go
to..." and insert link to the recommendations. URL:
http://www.ahrq.gov/clinic/uspstfix.htm. Revision to one of the
sentences to be submitted.
Footnote added 1/17/13. Question: Is this the correct URL? The

URL provided as the source at the bottom of exhibit 4 is:
http://www.uspreventiveservicestaskforce.org/recommendations.ht
m. Use this instead?
51
15 The TF uses the phrase "clinical preventive services" as opposed to

"health maintenance recommendations."
Fed
CHANGE TO: "These clinical preventive services should be

provided to the person with SCD within the patient's principal
healthcare site."
Done 1/17/13
51
16 The recommendations are not really "applicable to everyone." Many are

for high risk groups, or children, or women, or pregnant women. We
understand the point, which is to say they apply equally to persons with
SCD as to those without. You might just say that - "These clinical
preventives services apply to persons with SCD as well as the general
population."
Fed
Define USPSTF
Type
Invited
Discussion
Spell out USPSTF in subheader
Changed to U.S. Preventive Services Task Force 1/17/13. The
USPSTF does not spell out "U.S."
Invited
Better definition is needed in this section. Where is USPSTF

defined? Will submit a sentence revision. Spell out USPSTF.
DONE
Public
Fed
Fed
No change
No change
Will look up exact wording and submit with her previous revision DONE
to first 1-2 lines of section.
No change
Page #
Line #
51
Comments
Suggestions
Type
17 What do we do about the numbers of people who don't have a primary
Encourage hospital staffs to go through
Public
care provider. They go to the emergency room where they are unlikely to mandatory training in treatment of SCD in
find a well-trained doctor.
order to be accredited.
Discussion
Training is beyond the scope of this panel.
No change
52
0 Recommendation for BP screening to begin at age 30 or 40 conflicts with

the recommendation on pg 36, line 12 - HTN screening. It probably should
be the latter.
InvitedDelete this statement (in the Adults section). It is with the Lipids Done 1/17/13. Note: This change was not part of revised Exhibit 4
Non
bullet. Please change BP to Blood Pressure. Add: "For Blood
received as separate Word file on 1/8/13.
Disclosed Pressure screening recommendations, see page X" (this is in
the HM chapter - currently p. 34, line 13, "Screening for
Hypertension in Individuals with SCD" ALSO: DELETE the
parens "(diabetes, lipids, and BP)
52
0 Exhibit 4 - in the section on Newborns: In the introductory sentence

"including those suspected or proven to have SCD" feels a little redundant
given the preceeding paragraphs and the first entry on the list.
Fed
Delete "Including those suspected or proven to have SCD"
52
0 Exhibit 4 - Adults "Depression screening" : I'm disappointed with the small

amount of psychosocial information in the Draft. Psychosocial dynamics
seem to have lost importance in the new edition when compared to the
old. In the 4th Edition there was a "Psychosocial Management" chapter
(see 4th edition-pgs 53-55; Adolescent Health Care and Transition pgs 3539; Adult Health Care Maintenance pgs 41-43; and Vocational Goals
-Counseling pgs 45-46). In this new document draft there are a few nonspecific mentions of "behavioral therapies" pg 137 line11;
"biopsychosocial" pg 139 lines 5-9; "social worker", "psychiatrist",
"neuropsychological deficits" pg 140, lines 9-12; Knowledge Gaps &
Opportunities for Research pg 158 Lines 10-11. I hope this is improved in
the next edit of this Draft.
Public
Without evidence, it is difficult to address this here. This should DONE -resubmitted
go into the gaps - specific to SCD. Also, check with Chronic
chapter on how this is handled in their gaps.
52
0 Exhibit 4 - Newborn section: The TF language is "screening for sickle cell

disease." The clinical considerations also suggest confirmatory testing
within 2 months.
Fed
Will submit wording regarding follow up in 2 months for

inclusion in the table.
Done. Revision to exhibit 4 submitted.
52
0 Exhibit 4 - Newborn section: For "prophylactic eye drops" the actual

recommendation is "prophylactic ocular topical medication for the
prevention of gonococcal ophthalmia neonatorum." In addition, the only
drug approved for this indication (as of 2011) was an ointment. They
suggest providing prophylaxis within 24 hours after birth.
Fed
Will submit revision.
Done 1/11/13. Revised Exhibit 4 submitted
52
0 Exhibit 4 - Newborns section: The TF does not recommend

"breastfeeding" per se but recommends interventions during pregnancy
and after birth to promote and support breast feeding" unless
contraindicated. The point about hydroxyurea as a contraindication is an
important one, however, the TF makes no statement about it. You might
include a parenthetical note that says something like this, "The Expert
Panel notes that hydroxyurea use is a contraindication to breastfeeding."
Fed
This change does need to be made. Please add, "The Expert

Panel notes" about HU in breastfeeding.
Done. Revised Exhibit 4 submitted
Done 1/17/13. These changes were included in the revised Exh 4

received on 1/8/13.
Page #
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52
Comments
0 Exhibit 4 - Newborns section: There are three positive TF
recommendations for newborns that you might consider adding: screening
for congenital hypothyroidism, screening for phenylketonuria, and
screening for hearing loss.
Suggestions
Type
Fed
Discussion
We can add hearing loss. Also will re-visit the recommendations Done 1/11/13. Revised Exhibit 4 submitted
to see if any further additions are needed. Also, remove
redundant language (see parens).
52
0 Exhibit 4 - Children Aged 3 Months to 12 Years: For the amblyopia

screening recommendation is different and much less specific than the
current text. "Vision screening for all children at least once between the
ages of 3 and 5 years, to detect the presence of amblyopia or its risk
factors." The TF provides no statement about the first baby check or
repeating at routine visits. There may be other groups that make this
recommendation and if so they should be referenced.
Fed
Will review the language and refer back to the TF language.
Done 1/11/13. Revised Exhibit 4 submitted
52
0 Exhibit 4 - Children Aged 3 Months to 12 Years: There are two other

recommendations that may be relevant for children with SCD: routine iron
supplmentation for asymptomatic children aged 6-12 months who are at
increased risk for iron deficiency anemia and screen children aged 6 years
and older for obesity, and offer or refer them to comprehensive intensive
behavioral interventions to promote improvement in weight status.
Fed
Will review the language and refer back to the TF language.
Done 1/11/13. Revised Exhibit 4
52
0 Exhibit 4 - Adolescents: For HIV screening the current recommendation is

to "screen for HIV in all adolescents at increased risk for HIV infection."
This recommendation is being updated and may change soon after
publication of these guidelines. One solution is to note this and reference
the CDC's HIV screening guidelines.
Fed
This is an update from when we did it. We will refer back to the Query from Editor: Pls clarify instruction in "discussion" column.
guidelines and ensure that this table is accurate.
Should we add, "for more information, please refer to the CDC"s
HIV screening guidelines at URL"? Or does it mean that we will
confirm that our recommendation is correct before these
guidelines are published by checking the CDC's guidelines to see
if they've changed?
52
0 Exhibit 4 - Adolescents: For tobacco use screening and counseling, the

current USPSTF recommendation for adolescents is an I
recommendation. It is currently being updated. This is another
recommendation where, depending on your timeframe, you might seek the
recommendations of others, like the CDC.
Fed
ADD: Screening and assessment recommendations are

frequently updated based on new available evidence. Please
continue to reference these guidelines directly for the latest
recommendations. Also - add language that these were
updated as of X date.
Editor added a footnote with this information, with the date TBD.
Page #
Line #
Type
Fed
Discussion
Will review and revise to include all applicable
recommendations.
0 Exhibit 4 - Adults: As noted in the sections above, these recommendations

do not apply to "all adults."
0 Exhibit 4 - Adults: For tobacco use the TF recommends asking about
tobacco use and "tobacco cessation interventions" not just counseling.
The TF recommends pharmacotherapy in addition to counseling and notes
that combining the two is more effective than either component alone. The
TF does not provide specific guidance on periodicity for rescreening, even
among smokers.
Fed
Will review and revise as needed
Revised Exhibit 4 submitted
Fed
52
0 Exhibit 4 - Adults: For depression screening, this is one of those

recommendations that does not apply to all adults. The specific language
of the recommendation is "screen adults for depression when staffassisted depression care supports are in place to assure accurate
diagnosis, effective treatment, and follow-up." The caveat is that care
supports need to be in place. Without those supports the likelihood of
benefit decreases substantially and the TF lowered the grade to a C
without support. The TF did not recommend a specific screening tool and
suggests clinicians may choose a method that is most consistent with their
personal preference, the patient population and the practice setting.
Fed
Done 1/17/13. Revised Exhibit 4 submitted.
52
0 Exhibit 4 - Adults: For alcohol misuse, the TF says "provide screening and
behavioral counseling interventions to reduce alcohol misuse." Not just
screening. Also, this might be included in the section for pregnant women
making the parenthetical redundant.
Fed
Revised Exhibit 4 submitted. Done
52
52
52
Comments
0 Exhibit 4 - Adolescents: There are four additional positive
recommendations for adolescents that you might consider adding to the
table (they may help emphasize the Panel's point about general
prevention):
Screen for chlamydial infection for all sexually active non-pregnant young
women aged 24 and younger.
Counsel children, adolescents and young adults aged 10-24 years who
have fair skin about minimizing their exposure to ultraviolet radiation to
reduce risk for skin cancer.
Offer high intensity behavioral counseling to prevent sexually transmitted
infections (STIs) for all sexually active adolescents at increased risk for
STIs.
Screen adolescents (12-18 years of age) for major depressive disorder
(MDD) when systems are in place to ensure accurate diagnosis,
psychotherapy (cognitive-behavioral or interpersonal), and follow-up.
Suggestions
Page #
Line #
52
Comments
0 Exhibit 4 - Adults: The obesity screening text seems both too vague and
too specific. The language from the TF is "screen all adults for obesity, and
offer or refer patients with a body mass index of 30kg/m*2 or higher to
intensive, multicomponent behavioral interventions. They do not specify a
periodicity for screening. "Diet and counseling" is too vague a description
of the intervention recommended by the TF.
Suggestions
Type
Fed
Discussion
52
0 Exhibit 4 - Adults: For cervical cancer screening the recently updated TF

recommendation provides more specificity on intervals and screening
modalities. HPV is an option but not required. The language is "screen for
cervical cancer in women ages 21 to 65 years with cytology (Pap smear)
every 3 years or screen with a combination of cytology and human
papillomavirus (HPV) testing every 5 years." It does not apply to all adults the TF gave a D rec to adults 18-20 years of age and adults over 65.
Fed
Will review and revise as needed. Consider adding language

about how there are specific recommendations for all people,
and then specific recs for those with SCD.
52
0 Exhibit 4 - Adults: The TF HIV screening recommendation is currently

being updated. You may want to refer to the CDC's recommendations
instead.
Fed
52
0 Exhibit 4 - Adults: The TF recommends against routinely screening the

general asymptomatic population for chronic hepatitis B infection. There is
no recommendation on screening individuals on transfusion therapy. If this
references another guideline or the opinion of the Expert Panel it might be
best to note it as such.
Fed
52
0 Exhibit 4 - Adults: For breast cancer chemoprevention the TF recommends

clinicians "discuss chemoprevention with women at high risk for breast
cancer AND at low risk for adverse effects of chemoprevention."
Fed
52
0 Exhibit 4 - Adults: The USPSTF recommendation on breast cancer

screening has some nuances. The B recommendation is for "biennial
screening mammography for women aged 50 to 74 years." The TF does
not endorse a firm age to start screening but encourages individualized,
informed decision making about when to start mammography screening.
The recommendation for women less than 50 years of age is this, "the
decision to start regular, biennial screening mammography before the age
of 50 yars should be an individual one and take patient context into
account, including the patient's values regarding specific harms and
benefits." This is a C recommendation.
Fed
Page #
Line #
52
Comments
0 Exhibit 4 - Adults: Genetic risk assessment for breast and ovarian cancer The TF recommends that "women whose family history is associated with
an increased risk for deleterious mutations in BRCA1 or BRCA2 genes be
referred for genetic counseling and evaluation for BRCA testing." The TF
does not provide an age at which to begin assessing family history. It is
important to include first and second degree relatives on both maternal
and paternal side, in addition the TF notes several high risk patterns.
Suggestions
Type
Fed
Discussion
52
0 Exhibit 4 - Adults: CVD risk screening - For lipids or BP it might be good to

reference NHLBI's guidelines either in addition to or instead of the TF
recommendations.
Diabetes - the TF recommends "screening for type 2 diabetes in
asymptomatic adults with a sustained blood pressure greater than 135/80
mm Hg."
Lipids - the language in the document does not accurately describe the TF
recommendations. The TF "strongly recommends screening men aged 35
and older for lipid disorders" and "recommends screening men aged 20-35
for lipid disorders if they are at increased risk for coronary heart disease."
For women, the TF "strongly recommends screening women aged 45 and
older if they are at increased risk," and "recommends screening women
aged 20 to 45 if they are increased risk" but less strongly. The TF was
uncertain about the best screening interval but mentioned other guidelines
which suggest a five year interval.
Blood pressure - the TF recommendation is "screening for high blood
pressure in adults aged 18 and older." (Not beginning at age 30 or 40) The
TF did not say the BP should be measured at every visit but rather
deferred to the JNC 7 recommendation of screening every two years.
Fed
Revised Exhibit 4 submitted.
52
0 Exhibit 4 - Adults: The TF recommends "screening for colorectal cancer

using fecal occult blood testing, signmoidoscopy or colonoscopy, in adults,
beginning at age 50 years and continuing until age 75 years." The
screening interval depends on the modality used. The TF determined that
for population screening programs any of the three regimens they suggest
are approximately equal in effectiveness. FOBT should be done annually,
sigmoidoscopy every five years and colonoscopy at 10 year intervals.
Fed
52
0 Exhibit 4 - Adults: The AAA recommendation is to "screen for AAA by

ultrasonography in men aged 65 to 75 who have ever smoked."
Fed
52
0 Exhibit 4 - Pregnant women: For the asymptomatic bacteriuria

recommendation the TF rec is a little more specific, "screen for
asymptomatic bacteriuria with urine culture at 12 to 16 weeks gestation or
at the first prenatal visit if later."
Fed
Page #
Line #
52
Comments
0 Exhibit 4 - Pregnant women: The TF recommends that clinicians "screen
all sexually active women, including those who are pregnant, for gonorrhea
infection if they are at increased risk for infection." You might add the part
about increased risk.
Suggestions
Type
Fed
Discussion
52
0 Exhibit 4 - Pregnant women: One small suggestion for hepatitis B, the TF

recommends screening at the first prenatal visit.
Fed
52
0 Exhibit 4 - Pregnant women: The TF does recommend HIV screening but

does not make a statement about repeatedly offering testing.
Fed
52
0 Exhibit 4 - Pregnant women: Syphilis screening, no changes suggested
Fed
52
0 Exhibit 4 - Pregnant women: You may want to add screening and

counseling for alcohol misuse here.
0 Exhibit 4 - Pregnant women: The TF also has a positive recommendation
for chlamydia screening, specifically "screening all pregnant women aged
24 and younger and for older pregnant women who are at increased risk."
Fed
Fed
52
0 USPSTF Recommendations for people with SCD: Exhibit 4: To be added:

Hepatitis C screening to pediatric and adults patients on transfusion
therapy.
Public
52
0 It may be worth noting that the USPSTF guidelines contain no

recommendations on opioid misuse risk assessment.
Invited
So noted.
No change
52
0 You should comment about the addition of iron supplementation in the

exclusively breastfed infant as per normal guidelines at 6 months of age.
It is sad to see a breast fed SS child have severe anemia because they
become iron deficient.
Public
This is beyond the scope of the document.
No change
52
0 Exhibit 4 - General comment 1: The following comments focus on the

accuracy of the language and how closely it reflects the intent of the Task
Force's recommendations. We recognize that several recommendations
are more nuanced than can be accurately described in a brief table.
However, we wanted to share our suggestions with the Expert Panel on
how they might consider refining the table to capture as accurately as
possible the Task Force's recommendations on these important clinical
preventive services.
Fed
52
No change
Page #
Line #
52
Comments
0 Exhibit 4 - General comment 2: There are several recommendations that
are currently being updated, however, we can only provide the existing
approved language. For other recommendations it may be better to refer
to the guidelines of other organizations which might be more current, like
JNC8 for BP, ATP4 for lipids or the CDC for HIV screening. We will note
that in the specific comments on those recommendations below. Finally,
often for completeness sake we have added positive recommendations
excluded from the table. We offer them up for the Expert Panel's
consideration on whether to include them or not.
Suggestions
Type
Fed
Discussion
No change
52
0 Exhibit 4 - Children Aged 3 Months to 12 Years: The intro phrase "all

children (aged 3 months to 12 years) should have:" is not quite right
because some interventions are applicable only to high risk children or to
specific circumstances (i.e. flouride supplementation).
Fed
52
0 Exhibit 4 - Children Aged 3 Months to 12 Years: The exact language from

the TF is "oral fluoride supplementation at currently recommended doses
to preschool children older than 6 months of age whose primary water
source is deficient in fluoride." It is a minor difference.
Fed
52
0 Exhibit 4 - Adolescents: As noted in earlier sections the introductory

phrase "all adolescents should be assessed and offered" is not exactly
correct. And, it is probably not necessary.
Fed
The panel feels that adding the word "all" is reduntant and not
needed.
No change
52
1 colon ca risk - unless FMH then 10yrs before age of onset - think this is in
USPFT
1 bottom of table where discusses CV risk screening - duplicate entry of BP
Invited
Invited
This has been changed in a previous comment.
No change
52
52
2 why is there no mention of prophylactic Vitamin K?

2 First section of the table HYDROXYUREA USE BY THE
BREASTFEEDING MOTHER, sentence should be modified to so indicate
that the mother can not use
Public
Public


52
2 Is cholesterol screening (routine every 5 years) appropriate for people with

HbSS that usually have very low cholesterol and CVD risk?
InvitedWill review and revise as needed

Non
Disclosed
52
2 Table: for adolescents and adults, would be helpful to include ages (ie do
you count adolescents from ages 13 to 18 or 13 to 21??)
Invited
Added age for adolescents only (age 12 to 18 years), not for

adults.
52
These nuances are indicated in the table already. It is stated

that fluoride is only for those with a water supply deficient in
fluoride.
No change
No change
Page #
Line #
52
52
54
Comments
2 Good idea to summarize in a table but would expand beyond USPSTF or
make a second table to include the recommendations across the lifespan
recommended in the guidelines. Under newborn, should clarify screening
versus disease confirmation; the PCP needs to follow up screening with
appropriate confirmatory testing in most states (some are reflexive). All
other SCD-specific preventive measures at every age should be
incorporated (Newborn: start penicillin, get immunizations, etc)
Suggestions
Table Recommendations for Newborns - should vitamin K be

recommended? For age 9-24 months, screening for iron deficiency?
Same for adolescents.
Type
Invited
Discussion
Public
0 Page 54 : KNOWLEDGE GAPS AND OPPORTUNITIES FOR

RESEARCH.
1 it would be useful to list out the recs on immunization and reimmunization
for Strep, pneumococcus, HIB, and flu as this is a frequent ? Also IN
ADDITION consider linking to the ACIP recs, but as the sickle cell specific
recs are buried within this, I would still list separately in our document
Public
Invited
Will work on this. The link will be included in the text for
updates.
Added information about immunization recommendations as

adopted from the Advisory Committee on Immunization Practices
in a new exhibit 5. DONE
54
1 Immunizations: The CDC's recent recommendations on hepatitis C

screening is to include all individuals within an age category. It is likely that
most sickle cell anemia patients would have received a transfusion by
adulthood, even if it's not recorded. Routine screening for hepatitis C is
warranted. Liver failure and cirrhosis is a growing problem in sickle cell
disease, and treatment with hepatitis therapy offers a high chance of cure.
Details and recommendations concerning hepatitis C treatment in SCD
should be mentioned since many of the GI community do not treat sickle
cell anemia patients because of their over concern about ribavirin-induced
anemia.
Public
Yes, this will be added in a statement in the background section

about the screening for Hep C. This needs to be crossreferenced with what is in the Transfusion chapter. ..."alll blood
since that time has been screened for Hep C"
Exhibit 4 revised to include the following recommendation for

children agred 3 months to 12 years: Hepatitis C screening for
pediatric patients on transfusion therapy. Also revised the Adults
section of exhibit 4 with the following recommendation: Hepatitis
C screening to adult patients on transfusion therapy. Is this
sufficient to address this query?
54
1 any consideration of recommendations for influenza vaccines?
Invited
Exhibit 5 addresses the ACIP recommendations - new submission.
54
4 Known by some physicians and patients that Influenza vaccine may cause
VOC in some sickle cell patients (significant numbers of people Ive polled
in our support group, approx 30%). This needs immediate RCTs. [Noted
as an SS patient and Clinical Lab Scientist.]
Public
This is consistent with ACIP recs, which will be added to the

chapter.
Will add wording about influenza vaccine in the gaps section.
54
4 addtl sentence specifying that adults with SCD qualify as high risk group
for pneumovax and mening due to functional asplenia (included in ACIP
recs but worth calling out)
Invited
No change
54
7 Recommendations for PPSV23 vaccination are not consistent with 2012

CDC/ ACIP guidelines
Public
We will include URLs so readers can get updated information.
Revised exhibit 5 includes a link to the ACIP immunization

schedule: http://www.cdc.gov/vaccines/schedules. Done
54
Update recommendations to reflect these

new guidelines. First dose PPSV23 at 2
years followed by single revaccination 5
years later
No change
This is done.
Page #
Line #
Comments
Suggestions
7 Need clarification of when to give boosters (or not). Reccomendations are Need a summary table of normal
changing
immunization needs including boosters
Type
Public
Discussion
The table in the chapter is being updated.
No change
54
7 specific recommendation fo "13-valent conjugate pneumococcal vaccine".

It is likely that in the near future the valency of this vaccine will increase;
could the recommendation be made for the "prevailing approved conjugate
pneumococcal vaccine (currently the 13-valent vaccine)"?
Invited
URL will be included for reference per previous comment.
No change
54
9 the 23-valent pneumococcal polysaccharide vaccine is not a conjugate

vaccine, ie, not conjugated to diphtheria toxoid.
Invited
Will review to make sure we don't say that it is.
54
9 What, if any, proof exists for benefit of 23 valents polysaccharide vaccine

in children with SCD who are already receiving penicillin prophylaxis?
Invited
This is outside the scope of this chapter.
54
10 2nd Pneumovax has historically been given age 5 years in patients with
sickle cell disease, but most recent ACIP Dec 2010 recommendation is to
give 2nd dose 5 years after the 1st dose for children with sickle cell
disease. I personally have had some health departments not give 2nd
Pneumovax until age 7 years due to this. Based on the above mentioned
articles and ACIP guidelines, I've started continuing penicillin prophylaxis
beyond 5 years age and giving 2nd Pneumovax age 7 years. Since I'm
continuing penicillin, I don't feel as nervous having an unprotected gap
between 5 and 7 years age. Also, I think recommendation should be
made to give PCV13 to children age 6-18 years who've not been
previously vaccinated? This is also discussed in the ACIP 2010
recommendation.
Public
Please see the URL that will be provided. No further change will No change
be needed.
54
10 second dose of PPV should be given 5 years after 1st dose per recent
AAP and CDC guidelines
0 I agree that studies are needed for pulmonary hypertension,
TCD in adults, renal disease, screening for asthma, natural history of
sickle cell retinopathy, Hypertension, needs of PFTs, natural history of
osteopenia and osteoporosis in SCD. However, one has to be cautious
regarding optimal management of pain crisis in pregnancy. Transfusion
should the treatment of choice. Avoidance of dependency or addiction is
important. In my experience the few patients with pain difficult to manage
are patients on habit forming opiates prescribed by theirs providers in
huge amount for years. The use of adjunctive non pharmacologic
approaches including psychosocial support are important.
Public
Public
Please see the URL that will be provided. No further change will No change
be needed.
No change
Public
This is being tweaked per another comment.
54
55
55
4 1. Should influenza vaccine be specifically mentioned (worth mentioning

separate from the ACIP schedule)
Clarify recommendation.
No change
No change
Page #
Line #
55
Comments
15 Adult TCD trials. Should be omitted because of issues about ability to
screen all adults due to closed bone windows. See above.
Suggestions
Type
Public
Discussion
TCD in adults should be addressed. Neuroimaging.
Neurocognitive testing. This could be combined. Neuroimaging
and neurocognitive evaluationNeurocognitive assessment
56
4 Is there a reason checking Vitamin D levels & screening for osteoporosis

in those with low levels is not addressed in this section? There is
significant evidence in literature of low Vitamin D levels in the SCD
population (far higher than in the general population), even in pediatric
patients.
InvitedWe would do the same as with any other patient.

Non
Disclosed
No change
56
4 Change this sentence to read"screening for osteoporosis and its therapy

as well as studies to evaluate factors leading to osteoporosis."
Invited
No change
We would do the same as with any other patient.

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Page # Line #

Revision subitted to this section. Done.

The team discussed the issue of breakthrough pain.

Nociceptive pain is a hallmark of acute pain (see

13 Only the Ficat classification is mentioned

Broaden definition of therapeutic outcomes to be

Included references to other classification systems Public

This is correct, we use only the Ficat classification.

The study was evaluated by the panel. WILL

In the background, wound care specialist can be

Include the severity index in a statement to address

define microalbumin and macroalbumin precisely

On page 149 line 17 add:

Get references and see exactly what has been

Modest expansion of the description of the study

Error; this comment doesn't apply to this line, but

0 Renal Complications: Recommendations - Good chapter.

10 Not clear if this includes individualized treatment plans

InvitedRecommendation based on low quality

Add a brief discussion of realities and principles of Public

Recommendations have been revised. This comment is resolved.

The principles of acute pain are discussed in the

Change to "partnership agreement leading to a

4 not sure about use of stimulant laxatives chronically

7 "HbS-a-thalassemia", missing another "S"

18 Leg ulcers: there are no recommendations on local therapy

Note from Editor: This should be page 141, line 7.

CHANGE: After increase fluid intake to right after

We cannot make it congruent because we said it is

Add New Recommendation #5: For persistent leg

2 Syncope is the medical term for "passing out suddenly"

1 Important to have a hematogist and urologist consulted for priapism.

Given that recurrent prolonged priapism results in

Done. This is actually page 141, line 7.

Initially treat leg ulcers in patients with SCD with

The team agrees to use this term

Recommendation on page 155, lines 1-3, should

Local ulcer/wound therapy, cultures should be done Public

Table of staging will be included. Already answered

1 These are TWO separate issues to investigate. Separate and rephrase.

Yes, separate out the topics with separate bullets.

15 These are TWO separate issues to investigate. Separate and rephrase.

Yes, separate out the topics with separate bullets.

15 No recommendation is made for evaluation and/or treatment of co-morbid mood disorders in

This is a serious and potentially misleading

However, need to add that the study was stopped Public

We should remove all screening from this chapter.

This is outside our evidence report timeframe. Will

2/19/13: Walk-PHaSST added to the background. DONE

Will look at the whole seciton and see if there is a

Insufficient information to develop consensus

1 Chronic Complications - Stuttering Priapism: This section makes no recommendations other

The panel has considered this during the

Revision submitted. Done.

17 Managing Chronic Pain

Re-looking at rec #10 to consider an adjustment.

Revision submitted (to rec. #11). Done.

There should be a consensus recommendation

The comments concerning referring patients for

Will be made consistent in the health mantenance

This is defined in the document. "After being unable

Change in research gaps.

Revision submitted to this section. Done