Title

Author(s)

Herpes simplex virus infection of respiratory tract in intensive

care unit

Lui, Mei-sze;

Citation

Issued Date

URL

Rights

2012

http://hdl.handle.net/10722/173733

Creative Commons: Attribution 3.0 Hong Kong License

Herpes Simplex virus infection of respiratory tract in

Intensive Care Unit - a single centre experience

By

Dr Lui Mei Sze

(No: 1998256815)

This work is submitted to

Faculty of Medicine of The University of Hong Kong
In partial fulfillment of the requirements for
The Postgraduate Diploma in Infectious Diseases, PDipID (HK)

Date: 10th August 2012

Supervisor: Dr VCC Cheng

Declaration

I, Lui Mei Sze, declare that this dissertation represents my own work and that it has
not been submitted to this or other institution in application for a degree, diploma or
any other qualifications.
I, Lui Mei Sze also declare that I have read and understand the guideline on What is
plagiarism? published by The University of Hong Kong (available at
http://www.hku.hk/plagiarism/) and that all parts of this work complies with the
guideline.

Candidate: Lui Mei Sze

Signature:
10th August 2012
Date:

Acknowledgement
The author would like to the acknowledge the guidance and supervision from Dr
Vincent Cheng and the Department of Microbiology, Queen Mary Hospital, The
University of Hong Kong, for undertaking the study project. The author would also
like to thank Dr Chan Wai Ming and the Department of Intensive Care Unit, Queen
Mary Hospital, for the support on the study project.

Abstract (word count: 342 )

Background
Herpes Simplex virus (HSV) is commonly isolated from the specimen of
respiratory tract in hospitalized patients.

It can indicate asymptomatic shedding

from respiratory epithelium, viral reactivation with macroscopic airway lesion, or

even pneumonia.

There are significant differences in the awareness, interpretation

and management strategies of the condition among departments and hospitals.

Objective
A retrospective case review of clinical features, management and outcomes of
hospitalized subjects from whom HSV is detected in the bronchoalveolar lavage
specimen
Method
The medical records of all the patients with pneumonia and bronchoalveolar
lavage (BAL) being positive for HSV culture, who were admitted between 2004 and
2011 to Queen Mary Hospital, were retrieved from the clinical management system or
record folders.

Their demographic data, laboratory results, progress and outcomes

were recorded.
Results
A total of 32 patients were identified over the period of seven years.

81.3% of

them were emergency admission while 18.8% were elective admission.

Most of

them (90.6%) required admission to the Adult Intensive Care Unit. 59.3% (n=19)
required intubation and mechanical ventilation during hospitalization. The mean age
was 57.1 (SD 13.8) year old.

71.9% were male patients. No patients with HSV

detected in BAL had macroscopic lesion on bronchoscopy. No cytological

examination on the BAL was performed.

HSV reactivation is commonly associated

other opportunistic pathogens such as Pneumocystis jivoreci (21.9%) and

cytomegalovirus antigenemia (18.8%).

Majority of the subjects (90.6%, n=29) with

HSV infection were lymphopenic (absolute lymphocyte count <1 x 109/L) which
could indicate underlying impairment in cell-mediated immunity related to
malnutrition, hematological disorders, use of immunosuppressants.

Similar

proportion in the surviving group received anti-viral treatment as compared to the

mortality group (53.8% versus 66.7%, respectively), implicating that treatment with
anti-viral medication might not have important impact on mortality rate.

Conclusion
The awareness of significance of HSV reactivation in lower respiratory tract is
highly variable.
pnemonitis.

Lymphopenic patients are at high risk of HSV reactivation or HSV

The presence of lymphopenia, or other immunocompromised state

should prompt the physicians to perform a thorough work-up for HSV infection even
in the absence of macroscopic lesions.

Body Text (Word count: 3109)

Background
Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), also known as Human herpes
virus 1 and 2 (HHV-1 and -2), are members of the herpes virus family, Herpesviridae,
that contains double-stranded DNA. Both HSV-1 and HSV-2 are ubiquitous in
environment and contagious among human. HSVs are predominantly neurotropic, and
possess genes associated with latency in neuronal tissues after primary infection.
Majority of human has been exposed to the virus early in life, which is commonly
asymptomatic or presented as non-specific febrile illness, and shed the virus in
secretions upon reactivation in later life.

HSV-1 disease primarily involves the

mouth, eye and the central nervous system.

After anchoring to the receptor of

epithelial cells, the envelope of the virus fuses with the cell membrane, followed by
the transport of the viral nucleocapsids cross the cytoplasm to the nucleus of the
infected cells. Assembly of capsids and replication of viral DNA occur. Viral
glycoproteins are processed in the Golgi apparatus and incorporate into cell
membrane, from which the viral envelope is acquired as the virus buds out from the
nucleus.
Reactivation of latent HSV infection may be asymptomatic, though typically, it
gives vesicular lesions or ulcers.

DNA of herpes virus passes along nerve axon to

the nerve ending and epithelial cells, where it gives rise to visible lesions.
Occasionally, shedding of virus may occur without symptoms or visible lesions.
Reactivation can be triggered by diverse stimuli such as sunlight, febrile diseases,
local trauma or physical stress.

Common sites of HSV reactivation include

respiratory tract, eyes, oral or genital mucosa and the central nervous system.(1)
Regarding the respiratory tract, the virus could cause cold sore, gingivostomatitis,
tracheobronchitis and even pneumonia.(2) The diagnosis of HSV reactivation is
typically clinical when classical lesions are encountered, and supported by viral
detection or serological studies.

Viral detection by means of culture, electron

microscopy, antigen detection by immunofluorescence, or viral DNA amplification by

PCR technique allows earlier confirmation of diagnosis compared to antibody tests.
Herpes virus was reported to be the causative pathogen of pneumonia and erythema
multiforme since 1949 (3). In subsequent decades, Herpes infection has been
repeatedly reported in case report and series as the pathogens causing
tracheobronchitis or infection of lower respiratory tract.(4-8)

In intensive care

setting, HSV is commonly recognized in the respiratory tract specimen, regardless of

the presence or absence of macroscopic lesion, and the immune status of the host.(9)
Critically ill patients commonly possess risk factors for HSV reactivation, such as
systemic stress related to the critical illness, heightened stress hormone activity,

immunocompromised state due to organ failures or drugs, and local airway

trauma.(10) Local trauma as a result of intubation, instrumentation, mechanical
suction, burn could promote squamous metaplasia, which predispose to HSV
reactivation at the airway epithelium.(9) HSV can reach the lower respiratory tract by
aspiration of shed virus from upper respiratory tract, hematogenous spread, or
reactivation of latent infection within the vagal nerve with resultant spread to the
lung.(9) Cell mediated immunity is of paramount importance in controlling and
combating HSV reactivation, or in the other words, recurrent HSV infection could
represent underlying immunocompromised states, albeit subclinical.(11)
Simple isolation of HSV from respiratory tract specimen cannot differentiate true
disease from asymptomatic shedding.(12, 13) The shedding of HSV is convincingly
demonstrated to correlate with increased mortality in critically ill patients.(12, 14-16)
However, whether the viral shedding is simply a marker of the severity of underlying
illnesses, or per se a mediator of fulminant diseases, is still debatable.(10)

Of note,

another member of Herpes virus family, the Human Herpes virus 6 (HHV-6),
commonly reactivated in critically ill patients, but was not associated with adverse
outcomes.(17, 18)
The current study aims to review the clinical features, management and
outcomes of critically ill subjects from whom HSV is detected in the bronchoalveolar

lavage specimen in Queen Mary Hospital.

10

Methodology
The medical records of all the patients with pneumonia and bronchoalveolar
lavage being positive for HSV culture, who were admitted between 2004 and 2011 to
Queen Mary Hospital, were retrieved from the clinical management system or record
folders.

Demographic data including age, sex, medical illnesses, medication history,

laboratory data , length of hospital stay, and outcome were obtained and analyzed.
Variables were entered into Microsoft excel spreadsheet.

Variables are expressed as

mean +/- standard deviation if they are in normal distributions, or median and
interquartile range otherwise.

Results
A total of 32 patients were identified by retrospective review.

24 (75%) of them

were admitted under medical team, 6 (18.8%) were elective surgical admission while
2 (6.3%) were emergency surgical admission.

Most of them (90.6%) required

admission to the Adult Intensive Care Unit during hospitalization. 10 (31.2%) of

them had acute respiratory distress syndrome (ARDS). 59.3% (n=19) required
intubation and mechanical ventilation during hospitalization.
57.1 (SD 13.8) year old.

71.9% were male patients.

The mean age was

34.4% were ex-smokers or

active smokers. No patients with HSV detected in BAL had macroscopic lesion on

11

bronchoscopy, indicating that the reactivation was mostly asymptomatic.

HSV

reactivation is commonly associated other opportunistic pathogens such as

Pneumocystis jivoreci and cytomegalovirus antigenemia.

26.9% (n=7) of subjects in

the surviving group had CMV antigenemia concomitant with HSV reactivation.

All

of the 7 subjects with concomitant HSV infection and CMV antigenemia received
intravenous gancyclovir as treatment, as compared to intravenous acyclovir or enteral
valacyclovir for those with HSV infection.
Majority subjects (90.6%, n=29) with HSV infection were lymphopenic
(absolute lymphocyte count <1 x 109/L) which could be related to underlying
malnutrition, known hematological disorders, use of immunosuppressants or severe
infection.(Table 1)

Among the 32 subjects, 2 (6.2%) were HIV carrier, 18 (56.3%)

were taking steroid for long term indication or acute stress coverage, 17 (53.1%) were
on immunosuppressant other than steroid.
malignancy (hemic or solid organ).

11 (34.4%) of them had history of

Similar proportion in the surviving group

received anti-viral treatment as compared to the mortality group (53.8% versus 66.7%,
respectively), implicating that treatment with anti-viral medication might not have
important impact on mortality rate.(Table 1)

Surviving group was apparently

younger than the mortality group (Figure 1) (mean age 55.9 14.1 versus 62.0 11.8
respectively).

The group with HSV infection who died eventually had much longer

12

hospital stay compared to the surviving group (median length of stay LOS 40.0 days,
IQR 35.0, versus 17.5 days, IQR 39.0, respectively)

Discussion
The current retrospective study has found that immuno-deficient status, which
includes the use of immunosuppressants, underlying malignancy or HIV infection, is
an important risk factor for HSV reactivation. Concomittant infections by other
pathogens such as CMV or Pneumocystis jivoreci are relatively common. In the
dataset, HSV reactivation did not manifest as macroscopic lesion in tracheobronchial
trees.

Lymphopenia is almost universal among the subjects.

Anti-viral treatment

did not have overt bearing on overall mortality rate.

Bronchoscopy allows direct visualization of oropharyngeal and brochial
epithelium, and HSV infection typically manifests as edematous or erythematous
epithelium, ulcers or fibrinous purulent membrane, which are evidence of HSV
tracheo-bronchitis(9).

In the retrospective case series, no macroscopic lesions were

reported in the tracheo-bronchial tree of the study subjects. The presence or absence
of oropharyngeal lesions was not documented in majority of the records. Such finding
was consistent with published studies, which also found absence of gross lesion in
many subjects. In a prospective study on 201 nonimmunocompromised subjects

13

ventilated for at least 5 days, 42 subjects was diagnosed to have HSV

bronchopneumonitis, based on the fulfillment of all 3 diagnostic criteria: (1) clinical
deterioration, leading to the performance of BAL; (2) HSV detection in the lower
respiratory tract (PCR or culture); and

(3) HSV-specific nuclear inclusions in

cytology during BAL, endotracheal aspiration, and/ or bronchial biopsy. Among these
42 subjects, oral-labial lesions were noted in 23 (54%) and none of them had any
bronchial vesicular/ulcerated lesion.(19) Such finding arouses the awareness that HSV
pneumonia can manifest without upper respiratory involvement.

When there is no

gross lesion identified in orophargngeal region and tracheo-bronchial trees to

represent Herpes labialis or frank bronchitis, positive culture of HSV in lower
respiratory tract specimen can be a result of asymptomatic viral shedding,
contamination from mouth or upper respiratory tract, or genuine HSV pneumonia.(20,
21)
The diagnosis of HSV pneumonia is challenging, as both clinical features and
radiological findings are non-specific and can be confounded by concurrent infections
by other pathogens.

Cytological study can reveal multi-nucleated cells with

intra-nuclear changes and inclusion bodies in the infected tissues which are specific
features of HSV infection, but lacks sensitivity (30% only).(22) On the other hand,
lung biopsy, either by open surgery or transbronchial routes, is also unreliable or even

14

not practical, as a result of the risk of procedures, particularly in the setting of

critically ill subjects with respiratory failure on positive pressure ventilation.
According to previous studies, the identification of HSV by histology in lung biopsy
tissue was uncommon, even in subjects with other supportive evidence of HSV
infection.(23, 24)

Luyt and coworkers have demonstrated that among the 42

subjects requiring mechanical ventilation who showed clinical deterioration due to

HSV bronchopneumonitis, BAL cytological examination allows the identification of
the characteristic nuclear inclusion body in 30 subjects (71.4%), while such inclusion
body is present in only 7 (16.7%) bronchial biopsies and be present in both BAL and
bronchial biopsy in 5 subjects.(19)

Quantitative culture has been proposed to

differentiate between infection versus carrier state. Gooskens J and coworkers found
that quantitative HSV DNA by PCR assays on BAL of immunocompromised hosts
reflect clinical outcomes, with significant higher mortality within 28 days of sampling
if HSV DNA level is higher than 5.5 log.(25) However, the use of results of
quantitative culture to guide prescription of treatment still requires clarification by
further well-designed clinical trials. As a result of the difficulty in differentiating
true infection from carrier or asymptomatic shedding states, the management of
positive HSV culture without macroscopic lesion is still highly debatable.
Whether HSV infection is a true causative agent of pneumonia in critically ill

15

subjects is questionable.

Verheij and coworkers has demonstrated normal lung

permeability in 4 critically ill patients with persistent pulmonary infiltrates of

unknown origin and isolation of HSV-1 from tracheal aspirate or bronchoalveolar
lavage fluid, and all of them survived regardless of the use of anti-viral agents.(26)
Papazian and coworkers has performed open lung biopsy in subjects with acute
respiratory distress syndrome (ARDS) and in contrast to CMV pneumonia which was
identified in 50% (n=18) subjects, HSV was only found in 2.7% (n=1) subjects.(24)
From another point of view, HSV is believed to be a bystander indicating severity of
critical illness or be a prognostic markers, rather than true pathogen causing diseases.
HSV can be detected in saliva of normal subjects. In critically ill surgical patients,
Porteous and coworkers found HSV shedding in 40% of the subjects, which did not
affect the outcome.(27) For critical ill subjects with ARDS, HSV can be isolated in up
to 70% of the tracheo-bronchial specimens.(15, 21, 28) In previous studies, HSV was
commonly isolated from the upper and lower respiratory tract of ICU subjects, 22%
and 16% respectively. (6) (14)

Such findings indicate that HSV can be a normal

phenomenon in healthy subject, its shedding comes with physical stress and critical
illness, which suggests that it can be indicators of the severity of the stress , rather
than a real pathogen.
Whether HSV isolation in respiratory tract specimen is a prognostic marker is

16

still under debate.

Cook and coworkers have found that HSV-positive patients had

duration of hospital stay, lengths of intensive care unit admissions, and duration of
ventilator dependence comparable with patients without HSV infections in a
prospective study.(29) A recent case control study has found that HSV-positive
patients had shorted duration of mechanical ventilation than the HSV-negative group
(13 vs. 6 days, respectively; p = 0.002). Mortality did not differ between the HSV+
and HSV- groups, and treatment with acyclovir also did not affect mortality.(30)
However, such conclusions are not consistent in some other studies. Tuxen and
coworkers has found that the presence of HSV in the lower respiratory tract was
associated with prolonged mechanical ventilation and an increased late mortality.(15)
Similarly, De Vos and coworkers have reported the common occurrence of HSV in the
lower respiratory tract of critically ill patients on prolonged mechanical ventilation.
Detection of HSV was significantly associated with prolongation of mechanical
ventilation, ICU stay, and risk of ventilator-associated pneumonia.(31) In the
retrospective study by Linseen, higher HSV load was associated with increased
14-day in-hospital mortality.(32) Therefore, further large-scale prospective studies are
required to clarify the impact of HSV reactivation on the prognosis of hospitalized
and critically ill subjects.
Though studies have reported adverse effects of HSV reactivation on clinical

17

outcomes, evidence to support commencement of anti-viral treatment is still

controversial.

Acyclovir is the treatment of choice for HSV infection, while

Gancyclovir also possess activity against HSV in addition to CMV in spite of higher
risk of side effects. Large scale randomized controlled study about its effect on
patients outcome is still lacking.

Case reports or series have found potential

beneficial effects of acyclovir, including relief of bronchospasm (8) unresponsive to

other treatment, post-thoracotomy/cardiac surgery patients with pneumonia (33, 34),
interstitial pneumonia with ARDS (35), tracheobronchitis (36) or following liver
transplantation(20). However, such impact of treatment on outcomes is not consistent
in other studies.(29, 37) Tuxen and coworkers have undergone a double-blinded
randomized study on the use of intravenous acyclovir to prevent HSV reactivation and
assess its impact on outcome in seriously ill subjects with acute respiratory distress
syndrome. Acyclovir successfully prevented HSV reactivation in most subjects (HSV
reactivation was 6% in the acyclovir group versus 71% in the control group, p<0.001),
but it did not reduce the severity of respiratory failure, the duration of ventilator
support, or mortality.(28)

The benefits of prescription of anti-viral agents have to be

balanced against the possible side effects of treatment. At present, the use of anti-viral
agents in subjects with HSV reactivation in respiratory tract would likely be based on
(1)

any

unexplained

clinical

deterioration/visible

lesions,

(2)

underlying

18

immunocompromized state or risk factors, (3) evidence of lung parenchymal infection

by cytological or histological examination of specimen.(9)
The current study identified 32 subjects with positive BAL culture for HSV
over a period of 8 years. The study is limited by the retrospective design, and the
results might be prone to bias due to missing data.

The sample size of the current

study is relatively small, which could affect the interpretability and generalizability of
the results. The current study did not include subjects with burns.

The study has

reflected

were

the

fact

that

HSV

culture

positive

subjects

mostly

immunocompromised, with more than half being put on immunosuppressants. It is

plausible that HSV reactivation predominantly affects immuno-deficient group.
However, the finding can also reflect bias related to physician practice, as physicians
tend to request for more complete microbiological tests on BAL specimen of
immunocompromised subjects including viral culture, PCP tests, while less
comprehensive list of tests may be performed for non-/less immunocompromised
group.

The documentation of presence or absence of oro-labial lesions is also

incomplete in medical records, so despite that fact that bronchial lesions are not found
in the whole study sample, contamination from active lesion of upper aero-digestive
tract cannot be ruled out.

No cytological examination of the BAL specimen was

performed for the 32 samples, so whether the HSV comes from epithelial shedding or

19

true pneumonia is not confirmed.

The study is also limited by lacking a control

group for comparison, and being a retrospective study without blinding or

randomization.

Therefore, the findings of the current study cannot serve as a guide

for the indication of anti-HSV treatment or conclude on whether HSV reactivation is

an important prognostic marker particularly in critically ill subjects. On the other
hand, the almost universal finding of lymphopenia, which could reflect sub-clinical
impairment in cell-mediated immunity, among the affected subjects should prompt the
physicians in requesting the tests in appropriate clinical setting.
In the current study, over a period of eight years, only 32 specimens were found
positive for HSV in BAL and cytological examination was not routinely ordered,
which probably reflects low awareness among clinicians for HSV reactivation in
hospitalized subjects leading to low request rate for the tests.

The common

occurrence of HSV reactivation in non-immunocompromised subjects should arouse

more awareness among physicians for requesting the diagnostic tests in appropriate
setting.

In the current study, the mortality rate among the group receiving anti-viral

agent is similar to the group without treatment, which concur with previous studies.
After demonstrating HSV reactivation, the use of this piece of information in
prognostic stratification and guiding treatment requires further well-designed clinical
trials.

20

Reference
1.

Whitley RJ. Herpes simplex virus infection. Semin Pediatr Infect Dis. 2002

Jan;13(1):6-11.
2.

Herout V, Vortel V, Vondrackova A. Herpes simplex involvement of the lower

respiratory tract. Sb Ved Pr Lek Fak Karlovy Univerzity Hradci Kralove.

1966;9(1):25-34.
3.

Morgan HR, Finland M. Isolation of herpes virus from a case of atypical

pneumonia and erythema multiforme exudativum with studies of four additional cases.
Am J Med Sci. 1949 Jan;217(1):92-5.
4.

Herout V, Vortel V, Vondrackova A. Herpes simplex involvement of the lower

respiratory tract. Am J Clin Pathol. 1966 Oct;46(4):411-9.

5.

Nash G, Foley FD. Herpetic infection of the middle and lower respiratory tract.

Am J Clin Pathol. 1970 Dec;54(6):857-63.

6.

Buss DH, Scharyj M. Herpesvirus infection of the esophagus and other visceral

organs in adults. Incidence and clinical significance. Am J Med. 1979

Mar;66(3):457-62.
7.

Ramsey PG, Fife KH, Hackman RC, Meyers JD, Corey L. Herpes simplex virus

pneumonia: clinical, virologic, and pathologic features in 20 patients. Ann Intern Med.
1982 Dec;97(6):813-20.

21

8.

Sherry MK, Klainer AS, Wolff M, Gerhard H. Herpetic tracheobronchitis. Ann

Intern Med. 1988 Aug 1;109(3):229-33.

9.

Simoons-Smit AM, Kraan EM, Beishuizen A, Strack van Schijndel RJ,

Vandenbroucke-Grauls CM. Herpes simplex virus type 1 and respiratory disease in

critically-ill patients: Real pathogen or innocent bystander? Clin Microbiol Infect.
2006 Nov;12(11):1050-9.
10. van den Brink JW, Simoons-Smit AM, Beishuizen A, Girbes AR, Strack van
Schijndel RJ, Groeneveld AB. Respiratory herpes simplex virus type 1
infection/colonisation in the critically ill: marker or mediator? J Clin Virol. 2004
May;30(1):68-72.
11. Nash AA. T cells and the regulation of herpes simplex virus latency and
reactivation. J Exp Med. 2000 May 1;191(9):1455-8.
12. Bruynseels P, Jorens PG, Demey HE, Goossens H, Pattyn SR, Elseviers MM, et
al. Herpes simplex virus in the respiratory tract of critical care patients: a prospective
study. Lancet. 2003 Nov 8;362(9395):1536-41.
13. Corey L, Spear PG. Infections with herpes simplex viruses (2). N Engl J Med.
1986 Mar 20;314(12):749-57.
14. Ong GM, Lowry K, Mahajan S, Wyatt DE, Simpson C, O'Neill HJ, et al. Herpes
simplex type 1 shedding is associated with reduced hospital survival in patients

22

receiving assisted ventilation in a tertiary referral intensive care unit. J Med Virol.
2004 Jan;72(1):121-5.
15. Tuxen DV, Cade JF, McDonald MI, Buchanan MR, Clark RJ, Pain MC. Herpes
simplex virus from the lower respiratory tract in adult respiratory distress syndrome.
Am Rev Respir Dis. 1982 Sep;126(3):416-9.
16. Cook CH, Yenchar JK, Kraner TO, Davies EA, Ferguson RM. Occult herpes
family viruses may increase mortality in critically ill surgical patients. Am J Surg.
1998 Oct;176(4):357-60.
17. Desachy A, Ranger-Rogez S, Francois B, Venot C, Traccard I, Gastinne H, et al.
Reactivation of human herpesvirus type 6 in multiple organ failure syndrome. Clin
Infect Dis. 2001 Jan 15;32(2):197-203.
18. Razonable RR, Fanning C, Brown RA, Espy MJ, Rivero A, Wilson J, et al.
Selective reactivation of human herpesvirus 6 variant a occurs in critically ill
immunocompetent hosts. J Infect Dis. 2002 Jan 1;185(1):110-3.
19. Luyt CE, Combes A, Deback C, Aubriot-Lorton MH, Nieszkowska A, Trouillet
JL, et al. Herpes simplex virus lung infection in patients undergoing prolonged
mechanical ventilation. Am J Respir Crit Care Med. 2007 May 1;175(9):935-42.
20. Liebau P, Kuse E, Winkler M, Schlitt HJ, Oldhafer K, Verhagen W, et al.
Management of herpes simplex virus type 1 pneumonia following liver

23

transplantation. Infection. 1996 Mar-Apr;24(2):130-5.

21. Connolly MG, Jr., Baughman RP, Dohn MN, Linnemann CC, Jr. Recovery of
viruses other than cytomegalovirus from bronchoalveolar lavage fluid. Chest. 1994
Jun;105(6):1775-81.
22. Prellner T, Flamholc L, Haidl S, Lindholm K, Widell A. Herpes simplex
virus--the most frequently isolated pathogen in the lungs of patients with severe
respiratory distress. Scand J Infect Dis. 1992;24(3):283-92.
23. Francois-Dufresne A, Garbino J, Ricou B, Wunderli W. ARDS caused by herpes
simplex virus pneumonia in a patient with Crohn's disease: a case report. Intensive
Care Med. 1997 Mar;23(3):345-7.
24. Papazian L, Thomas P, Bregeon F, Garbe L, Zandotti C, Saux P, et al. Open-lung
biopsy in patients with acute respiratory distress syndrome. Anesthesiology. 1998
Apr;88(4):935-44.
25. Gooskens J, Templeton KE, Claas EC, van Bussel MJ, Smit VT, Kroes AC.
Quantitative detection of herpes simplex virus DNA in the lower respiratory tract. J
Med Virol. 2007 May;79(5):597-604.
26. Verheij J, Groeneveld AB, Beishuizen A, van Lingen A, Simoons-Smit AM, van
Schijndel RJ. Herpes simplex virus type 1 and normal protein permeability in the
lungs of critically ill patients: a case for low pathogenicity? Crit Care. 2004

24

Jun;8(3):R139.
27. Porteous C, Bradley JA, Hamilton DN, Ledingham IM, Clements GB, Robinson
CG. Herpes simplex virus reactivation in surgical patients. Crit Care Med. 1984
Aug;12(8):626-8.
28. Tuxen DV, Wilson JW, Cade JF. Prevention of lower respiratory herpes simplex
virus infection with acyclovir in patients with the adult respiratory distress syndrome.
Am Rev Respir Dis. 1987 Aug;136(2):402-5.
29. Cook CH, Martin LC, Yenchar JK, Lahm MC, McGuinness B, Davies EA, et al.
Occult herpes family viral infections are endemic in critically ill surgical patients. Crit
Care Med. 2003 Jul;31(7):1923-9.
30. Scheithauer S, Manemann AK, Kruger S, Hausler M, Kruttgen A, Lemmen SW,
et al. Impact of herpes simplex virus detection in respiratory specimens of patients
with suspected viral pneumonia. Infection. 2010 Oct;38(5):401-5.
31. De Vos N, Van Hoovels L, Vankeerberghen A, Van Vaerenbergh K, Boel A,
Demeyer I, et al. Monitoring of herpes simplex virus in the lower respiratory tract of
critically ill patients using real-time PCR: a prospective study. Clin Microbiol Infect.
2009 Apr;15(4):358-63.
32. Linssen CF, Jacobs JA, Stelma FF, van Mook WN, Terporten P, Vink C, et al.
Herpes simplex virus load in bronchoalveolar lavage fluid is related to poor outcome

25

in critically ill patients. Intensive Care Med. 2008 Dec;34(12):2202-9.

33. Camazine B, Antkowiak JG, Nava ME, Lipman BJ, Takita H. Herpes simplex
viral pneumonia in the postthoracotomy patient. Chest. 1995 Sep;108(3):876-9.
34. Shimokawa S, Watanabe S, Taira A, Eizuru Y. Herpes simplex virus pneumonia
after cardiac surgery: report of a case. Surg Today. 2001;31(9):814-6.
35. Lheureux P, Verhest A, Vincent JL, Lienard C, Levivier M, Kahn RJ. Herpes
virus infection, an unusual source of adult respiratory distress syndrome. Eur J Respir
Dis. 1985 Jul;67(1):72-7.
36. Legge RH, Thompson AB, Linder J, Woods GL, Robbins RA, Moulton AL, et al.
Acyclovir-responsive herpetic tracheobronchitis. Am J Med. 1988 Oct;85(4):561-3.
37. Schuller D, Spessert C, Fraser VJ, Goodenberger DM. Herpes simplex virus
from respiratory tract secretions: epidemiology, clinical characteristics, and outcome
in immunocompromised and nonimmunocompromised hosts. Am J Med. 1993
Jan;94(1):29-33.

26

Table 1:

Characteristics of study subjects

All (N=32)

Survival

Mortality

group

group (N=6)

(N=26)
Demographics
Age [mean, SD]

57.1, 13.8

55.9, 14.1

62.0, 11.8

Male

23 (71.9%)

19 (73.1%)

4 (66.7%)

Female

9 (28.1%)

7 (26.9%)

2 (33.3%)

Active smoker

4 (12.5%)

4 (15.4%)

0 (0%)

Ex-smoker

7 (21.9%)

6 (23.1%)

1 (16.7%)

Non-smoker

21 (65.6%)

16 (61.5%)

5 (83.3%)

Chronic drinker

5 (15.6%)

4 (15.4%)

1 (16.7%)

Non-drinker

27 (84.4%)

22 (84.6%)

5 (83.3%)

Post-operative pneumonia

6 (18.8%)

5 (19.2%)

1 (16.7%)

ARDS

14 (43.8%)

9 (34.6%)

5 (83.3%)

8.1, 12.1

8.1, 7.0

0.54, 0.36

0.61, 0.81

Gender

Smoking status

Drinking status

Clinical presentation

Blood WCC on day of HSV sample 8.0, 10.8

(x 109/L)
[median, IQR]
Blood Lymphocyte on day of HSV 0.54, 0.42

27

sample (x 109/L)
[median, IQR]
Absolute lymphocyte count < 1 x 29 (90.6%)

25 (96.2%)

4 (66.7%)

0 (0%)

0 (0%)

109/L
Macroscopic bronchial lesions on 0 (0%)
bronchoscopy
CMV antigenemia

7 (21.9%)

7 (26.9%)

0 (0%)

Pneumocytis jivoreci pneumonia

6 (18.8%)

5 (19.2%)

1 (16.7%)

Chronic respiratory diseases *

6 (18.8%)

6 (23.1%)

0 (0%)

Diabetes mellitus

5 (15.6%)

2 (7.7%)

3 (50%)

Cirrhosis

7 (21.9%)

4 (15.4%)

3 (50%)

Chronic renal failure

8 (25%)

6 (23.1%)

2 (33.3%)

Acute renal failure

11 (34.4%)

8 (30.8%)

3 (50%)

On long term steroid

14 (43.8%)

12 (46.2%)

2 (33%)

Acute steroid use

4 (12.5%)

4 (15.4%)

0 (0%)

On immunosuppressant

17 (53.1%)

15 (57.7%)

2 (33%)

HIV carrier

2 (6.2%)

2 (7.7%)

0 (0%)

Malignancy

11 (34.4%)

10 (38.5%)

1 (16.7%)

8 (30.8%)

0 (0%)

3 (9.4%)

2 (7.7%)

1 (16.7%)

8 (25%)

7 (26.9%)

1 (16.7%)

4 (12.5%)

3 (11.5%)

1 (16.7%)

Medical comorbidities

Hemic

maglinancy

myeloproliferative disease

/ 8 (25%)

Solid organ malignancy

Post liver/renal transplantation
Liver transplantation

28

Renal transplantation

4 (12.5%)

4 (15.4%)

0 (0%)

Yes

18 (56.2%)

14 (53.8%)

4 (66.7%)

No

14 (43.8%)

12 (46.2%)

2 (33.3%)

17.5, 39.0

40.0, 35.0

--

--

Treatment and outcome

Treated with Antiviral

LOS in acute hospital, in days 34.4, 39.0

[median, IQR]
Mortality

6 (18.8%)

29

Figure 1: The association of age and mortality

30