doi: 10.1111/j.1600-0714.2009.00749.

J Oral Pathol Med (2009) 38: 481488

2009 John Wiley & Sons A/S All rights reserved
interscience.wiley.com/journal/jop

REVIEW ARTICLE

The Oral HIV/AIDS Research Alliance: updated case

definitions of oral disease endpoints
C. H. Shiboski1, L. L. Patton2, J. Y. Webster-Cyriaque2, D. Greenspan1, R. S. Traboulsi3, M. Ghannoum3,
R. Jurevic4, J. A. Phelan5, D. Reznik6, J. S. Greenspan1, The Oral HIV AIDS Research Alliance,
Subcommittee of the AIDS Clinical Trial Group
1

Department of Orofacial Sciences, School of Dentistry, University of California San Francisco, San Francisco, CA, USA;
Department of Dental Ecology, School of Dentistry, University of North Carolina, Chapel Hill, NC, USA; 3Center for Medical
Mycology, Department of Dermatology, Case Medical Center and Case Western Reserve University, Cleveland, OH, USA;
4
Department of Biological Sciences, School of Dental Medicine, Case Western Reserve University, Cleveland, OH, USA;
5
Department of Oral and Maxillofacial Pathology, Radiology and Medicine, New York University College of Dentistry, New York,
NY, USA; 6Emory University School of Medicine, Grady Health System Dental Service, Atlanta, GA, USA
2

The Oral HIV AIDS Research Alliance (OHARA) is part

of the AIDS Clinical Trials Group (ACTG), the largest
HIV clinical trials organization in the world. Its main
objective is to investigate oral complications associated
with HIV AIDS as the epidemic is evolving, in particular,
the effects of antiretrovirals on oral mucosal lesion
development and associated fungal and viral pathogens.
The OHARA infrastructure comprises: the Epidemiologic
Research Unit (at the University of California San Francisco), the Medical Mycology Unit (at Case Western
Reserve University) and the Virology Specimen Banking
Unit (at the University of North Carolina). The team
includes dentists, physicians, virologists, mycologists,
immunologists, epidemiologists and statisticians. Observational studies and clinical trials are being implemented
at ACTG-affiliated sites in the US and resource-poor
countries. Many studies have shared end-points, which
include oral diseases known to be associated with HIV
AIDS measured by trained and calibrated ACTG study
nurses. In preparation for future protocols, we have updated existing diagnostic criteria of the oral manifestations of HIV published in 1992 and 1993. The proposed
case definitions are designed to be used in large-scale
epidemiologic studies and clinical trials, in both US and
resource-poor settings, where diagnoses may be made by
non-dental healthcare providers. The objective of this
article is to present updated case definitions for HIVrelated oral diseases that will be used to measure standardized clinical end-points in OHARA studies, and that

Correspondence: Caroline H. Shiboski, Department of Orofacial

Sciences, Box 0422, Room S612, 513 Parnassus Avenue; University of
California San Francisco, San Francisco, CA 94143-0422. Tel:
+(415)476 5976, Fax: +(415)476 4204, E-mail: caroline.shiboski@
ucsf.edu
Sources of support: NIH NIDCR NIAID U01 AI 68636.
Accepted for publication January 4, 2009

can be used by any investigator outside of OHARA/ACTG

conducting clinical research that pertains to these endpoints.
J Oral Pathol Med (2009) 38: 481488
Keywords: AIDS; epidemiology; HIV; oral lesions

Introduction
Since the beginning of the AIDS epidemic, much has
been learned about HIV-related oral mucosal diseases.
The oral cavity has been found to play an important role
in monitoring the progression of HIV disease as the
occurrence of specic lesions, mainly oral candidiasis
and hairy leukoplakia, is strongly associated with a low
CD4 cell count (17) and a higher plasma viral load (6,
8). Furthermore, even though the prevalence of specic
oral lesions like candidiasis, hairy leukoplakia and
Kaposis sarcoma has been found to be lower among
patients on combination antiretroviral therapy (918),
other conditions such as oral warts (1921) and salivary
gland disease (19) have been found to be more prevalent
in this population. This suggests that some oral conditions may occur as part of the immune reconstitution
that results from antiretroviral therapy initiation, and
should be further explored.
The Oral HIV AIDS Research Alliance (OHARA) is
part of the AIDS Clinical Trials Group (ACTG), the
largest HIV clinical trials organization in the world. The
ACTG plays a major role in dening the standards of
care for treatment of HIV infection and opportunistic
diseases related to HIV AIDS (22). The OHARA was
created in 2006 in response to a request for applications
from the National Institute of Dental and Craniofacial
Research. One of its main objectives is to investigate the

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Shiboski et al.

482

oral complications associated with HIV AIDS as the

epidemic is evolving, in particular, to explore the eects
of potent antiretrovirals on the development of oral
mucosal lesions, and associated fungal and viral pathogens. Another goal is to develop a comprehensive oral
infection and mucosal disease database with HIV
virologic and mycologic correlates and an HIV AIDS
oral specimen bank that will provide valuable material
for future epidemiologic and biological research questions.
The OHARA infrastructure comprises: the Epidemiologic Research Unit (at the University of California
San Francisco), the Medical Mycology Unit (at Case
Western Reserve University) and the Virology Specimen Banking Unit (at the University of North
Carolina). The team includes dentists specialized in
oral medicine, physicians, virologists, mycologists,
immunologists, epidemiologists and statisticians.
Shared use of key support services and of existing
research infrastructures is the hallmark of OHARA.
Observational studies and clinical trials are being
implemented at ACTG-aliated clinical research sites
in the US and in resource-poor countries. Many of
these studies have shared end-points, which include
oral mucosal diseases known to be associated with
HIV AIDS. At present, oral diseases, such as candidiasis, hairy leukoplakia, and at times necrotizing
ulcerative periodontitis, captured within some ACTG
studies, are measured by non-dental clinicians (nurses,
nurse practitioners or physicians) who have not
received a standardized training in the diagnosis of
these lesions. Even though the diagnosis of pseudomembranous candidiasis, routinely referred to as
thrush, is very familiar to HIV clinicians, the
diagnosis of erythematous candidiasis is more subtle,
and may be missed in the absence of a specialized
training. Therefore, to standardize the measurement of
oral mucosal outcomes associated with HIV AIDS
within the ACTG infrastructure the OHARA Clinical
Focus Group has developed an extensive training
module. A validation study of HIV-related oral
mucosal disease diagnoses made by ACTG clinicians
trained with this module as compared with oral
medicine trained dentists is currently being implemented. As part of this study, and in preparation for
future protocols, we have updated existing diagnostic
criteria of the oral manifestations of HIV published in
1992 (23) and 1993 (often referred to as EC-Clearinghouse or ECC criteria) (24) that have been used in
most studies of HIV oral diseases in the past decade
(39, 11, 13, 2533). The proposed case denitions are
designed to be used in large-scale epidemiologic
studies and clinical trials, in both US and resourcepoor settings, where diagnoses may be made by nondental healthcare providers. The objective of this
article is to present updated case denitions for
HIV-related oral diseases that will be used to measure
standardized clinical end-points in OHARA studies,
and that can be used by any investigator outside of
OHARA ACTG conducting clinical research that
pertains to these end-points.

J Oral Pathol Med

Revision of the 1992 and 1993 (ECC) criteria

In the present document, case denitions are organized by
etiology: fungal, viral, and bacterial infections, idiopathic
conditions, salivary gland disease and neoplasms. We
have found that when presenting our teaching modules to
both oral and non-oral health care providers, the organization by etiology is well-received and easy to understand
and remember. Furthermore, in addition to the clinical
descriptors that are observed by the clinician examiner
while performing a standardized oral mucosa examination, we have added descriptors of patient-reported
symptoms and duration of the condition if known. The
purpose of adding symptom and duration descriptors to
clinical descriptors is to improve diagnostic accuracy.
In addition to the inclusion of patient-reported
symptoms to the clinical descriptors of the 1992 and
1993 case denitions, we have made the following
modications and additions:
We have combined the 1993 denition of Ulceration
not otherwise specied (NOS), and Necrotizing
ulcerative stomatitis into one category, as it may be
difcult for non-dental examiners to determine if
bone is exposed or not. However, we recognize that
dental examiners may wish to make the distinction
between necrotizing ulcerative stomatitis related to
the periodontium and ulceration NOS elsewhere on
the mucosa. Therefore, the 1993 denition of necrotizing ulcerative stomatitis is provided within the
combined category, and can be extracted if desired.
We have combined necrotizing ulcerative gingivitis
and necrotizing ulcerative periodontitis, because
visual examination without radiographs and without
periodontal probing measurements would not permit
accurate differentiation between these conditions.
A case denition for oral squamous cell carcinoma
has been added. We recognize that oral squamous cell carcinoma has not yet been shown to
be associated with HIV AIDS. However, in the era
of highly potent antiretroviral therapy, patients with
HIV disease live longer, may use tobacco and or
alcohol, and therefore may be at risk of developing
this condition. Furthermore, several recent reports
in both the US and Europe have revealed an
increased risk of oral squamous cell carcinoma
among HIV-infected populations compared with the
general population (3436).
In the category of Salivary Gland Disease, salivary
gland enlargement and salivary hypofunction are
considered as two separate conditions as they may
occur separately.
We also provide an algorithm for HIV-related oral
lesion case denitions that summarizes clinical descriptors, symptoms and duration (Table 1).

Case definitions
Fungal infections
Pseudomembranous candidiasis

Clinical descriptors: White or yellow creamy spots or

plaques that may be located in any part of the oral

Red
White
Red
White

Oral non-Hodgkins
lymphoma

Oral squamous cell

carcinoma

Red
White
Yellow
Red
Purple

White
Yellow

Ulceration NOS
necrotizing
ulcerative stomatitis
Necrotizing ulcerative
gingivitis or
periodontitis
Oral Kaposi sarcoma

Red
Mucosal

Recurrent intraoral
herpes simplex
White
Yellow

Red
Mucosal

Herpes labialis

Recurrent aphthous
stomatitis

White
Mucosal

Oral wart

Hairy leukoplakia

NOS, not otherwise specied.

Neoplasms

Bacterial
Infections

Idiopathic
Conditions

Viral
Infections

Red
White
White

Angular cheilitis

Erythematous
candidiasis

White
Yellow
Creamy
Red

Pseudomembranous
candidiasis

Fungal
Infections

Color

Oral Lesion Condition

Etiology

Flat macular
Raised
Nodular
Ulcerated
Raised
Ulcerated
Indurated
Raised
Ulcerated
Indurated

Necrotic
Fetid odor

Ulcerated
Necrotic

Raised
Smooth
Spiky
Cauliower-like
Vesicular
(vesicles)
Ulcerated
Vesicular
(vesicles)
Ulcerated
Ulcerated

Fissured
Ulcerated
Corrugated

Plaques
(usually
removable)
Flat
Patchy

Character

Solitary

Solitary

Solitary

Solitary (> 1
ulcer may
be present)
Localized
or generalized

Solitary or
Multiple

Clustered

Solitary or
Clustered

Unilateral or
Bilateral
Unilateral or
Bilateral
Solitary or
Multiple
Clustered

Localized or
Generalized

Localized or
Generalized

Extent

Anywhere
Predilection
for palate
and gingiva
Anywhere
Predilection for fauces,
palate, gingiva
Anywhere
Predilection for tongue

Gingiva and
underlying bone

Labial mucosa
Buccal mucosa
Ventral tongue
Floor of mouth
Soft palate
Anywhere

Gingiva
Hard palate

Vermillion border
(lip)

Anywhere

Lateral tongue

Palate
Dorsum of tongue
Buccal mucosa
Lip commissures

Anywhere

Location

None to severe

None to moderate

None to moderate

Severe

Severe

Moderate to severe

Mild to moderate

Mild to moderate

None

None

None to mild

None to mild

None to mild

Symptoms

Table 1 Case denition algorithm summarizing clinical descriptors, symptoms, and duration for common HIV-related oral mucosal lesions

Longstanding

Longstanding

Longstanding

Sudden onset

Longstanding

Intermittent Minor:
7)10 days
Major: weeks
History of recurrence

Intermittent
7)10 days episode

Intermittent
7)10 days episode

Longstanding

Longstanding

Intermittent

Intermittent

Intermittent

Duration

Yes

Yes

Yes

No

Yes

No

No

No

Yes

No

No

No

No

Biopsy
Required

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cavity and can usually be wiped o to reveal an

erythematous surface (Fig. 1a).
Patient-reported symptoms: None or possible mild-tomoderate burning pain.
Patient-reported duration: Lesions symptoms usually
intermittent, but may be long-standing.

(a)

Erythematous candidiasis

Clinical descriptors: Patchy erythema or red areas

usually located on the palate and dorsum of the tongue,
but occasionally on the buccal mucosa. At times, white
spots or plaques of pseudomembranous candidiasis may
also be present (Fig. 1b).

(b)

Figure 1 Fungal infections: (a) Pseudomembranous candidiasis on the lower labial mucosa; (b) erythematous candidiasis on the dorsum of the
tongue and angular cheilitis at the corners of the mouth.

(a)

(b)

(c)

(d)

Figure 2 Viral infections: (a) Hairy leukoplakia on the right lateral border of tongue; (b) herpes labialis (arrows show ulcers that have coalesced at
a later stage of recurrent herpes infection); (c) recurrent intraoral herpes simplex on left hard palate; (d) multiple warts seen on upper labial mucosa.

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485

(a)

(b)

Figure 4 Bacterial infections: Necrotizing ulcerative periodontitis in

the lower anterior segment.

(c)

Figure 5 Salivary gland disease: Bilateral parotid enlargement.

Patient-reported duration: Lesions symptoms usually

intermittent, but may be long-standing.
Viral infections
Hairy leukoplakia

Figure 3 Idiopathic conditions: (a) Minor aphthous ulcer on lower

labial mucosa (note red hallo); (b) major aphthous ulcers on lower
labial mucosa (note red hallo); for both minor and major aphthous
ulcers, patient reports longterm history recurrence; (c) ulceration not
otherwise specied (NOS); patient reports no history of recurrence.

Patient-reported symptoms: None or possible mild-tomoderate burning pain.

Patient-reported duration: Lesions symptoms usually
intermittent, but may be long-standing.
Angular cheilitis

Clinical descriptors: Red or white ssures or linear ulcers

located at the lip commissures or corners of the mouth
(Fig. 1b).
Patient-reported symptoms: None or possible mild
pain when opening mouth.

Clinical descriptors: Whitish grey lesions on the lateral

margins of the tongue. They are not removable and
may exhibit vertical corrugations. Lesions range in
size as they may be <1 cm, or may extend onto the
ventral and dorsal surfaces of the tongue where they
are usually at. May be bilateral or unilateral
(Fig. 2a).
Patient-reported symptoms: Asymptomatic.
Patient-reported duration: Lesion(s) usually longstanding.
Herpes labialis

Clinical descriptors: Single or multiple vesicles or ulcers

with crusting on vermillion portion of lips and adjacent
facial skin (Fig. 2b).
Patient-reported symptoms: Usually mild-to-moderate
pain.
Patient-reported duration: Lesion(s) usually present
for at most 1014 days. Prior history of (or recurrent)
lesion(s).
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486

(a)

(b)

(c)

(d)

Figure 6 Neoplasms: (a) Early stage Kaposis sarcoma on upper left gingiva; (b) advanced stage Kaposis sarcoma on upper right hard palate;
(c) non-Hodgkins lymphoma on right soft palate; (d) squamous cell carcinoma on right lateral posterior tongue.

Recurrent intra-oral herpes simplex

Clinical descriptors: Solitary, or cluster of multiple or

conuent ulcers that may be noted together with vesicles
on keratinized mucosa, including hard palate, attached
gingiva and dorsum of tongue. Exceptionally, nonkeratinized tissue may be involved. Round to slightly
irregular (map-like) margins with minimal to no erythematous halos are present. The base of the ulcers is
usually pink (Fig. 2c).
Patient-reported symptoms: Usually mild-to-moderate
pain.
Patient-reported duration: Lesion(s) usually present
for at most 1014 days. Prior history of (or recurrent)
lesion(s).
Oral warts

Clinical descriptors: Mucosal color or white, solitary

or multiple (often clustered) raised lesions that range
in texture as they may be smooth, spiky, or cauliower-like, and located in any part of the oral cavity
(Fig. 2d).
Patient-reported symptoms: Usually asymptomatic.
Note: Warts on the buccal or labial mucosa or tongue
along the lines of occlusion may become traumatized by
biting, and thus may be painful.
J Oral Pathol Med

Patient-reported duration: Lesion(s) usually longstanding.

Denitive diagnosis (required): Biopsy and routine
histopathologic analysis to dierentiate wart from
papilloma not otherwise specied.
Idiopathic conditions
Recurrent aphthous stomatitis

Clinical descriptors: Single or multiple, white yellow

well circumscribed ulcer(s) on non-keratinized
tissue. A red hallo is usually present around each
ulcer. Minor aphthous ulcers may be 0.20.5 cm in
diameter (Fig. 3a), while major aphthous ulcers are
>0.5 cm (may be as large as 2 cm in diameter;
Fig. 3b).
Patient-reported symptoms: Moderate-to-severe pain,
especially upon eating.
Patient-reported duration: Each minor ulcer usually
lasts 710 days, while major aphthous ulcers may last
for weeks. Patient reports a long-term history of
recurrent ulcers.
Ulcerations NOS necrotizing ulcerative stomatitis

Clinical descriptors: Large (> 0.5 cm and sometimes up

to 3 cm) ulceration(s) with white yellow necrotic base

HIV-related oral disease case definitions

Shiboski et al.

that may be located on either keratinized or nonkeratinized mucosa (Fig. 3c; Note: clinical appearance
may be similar to that of major aphthous ulcer, but
there is no history of recurrent lesions). Necrotizing
ulcerative stomatitis presents as localized, painful ulceronecrotic lesions of the oral mucosa that exposes
underlying bone or penetrates or extends into contiguous tissues. These lesions may extend from areas of
necrotizing periodontitis.
Patient-reported symptoms: Severe pain may be a
prominent feature.
Patient-reported duration: Sudden onset, but may be
long-standing.
Denitive diagnosis (required): Histologic features are
those of non-specic ulceration. Microbiologic studies
fail to identify a specic etiologic agent.
Bacterial infections
Necrotizing ulcerative gingivitis or periodontitis

Clinical descriptors: Destruction of one or more interdental gingival papillae. In the acute stage of the process
ulceration, necrosis and sloughing may be seen with
ready hemorrhage and characteristic fetid odor. In the
case of necrotizing ulcerative periodontitis, the condition is characterized by soft tissue loss as a result of
ulceration or necrosis with exposure, destruction or
sequestration of alveolar bone. The teeth may become
loosened (Fig. 4).
Patient-reported symptoms: Moderate-to-severe pain
may be a prominent feature.
Patient-reported duration: Usually sudden onset and
rapidly worsening.
Salivary gland disease
Parotid enlargement

Clinical descriptors: Enlargement of the parotid glands,

usually bilateral (Fig. 5).
Patient-reported symptoms: Usually asymptomatic
enlargement. Patient may report xerostomia (perception
of dry mouth).
Patient-reported duration: Usually long-standing.
Salivary hypofunction

Dened as unstimulated whole salivary ow rate

<0.1 ml min)1 (3739).
Neoplasms
Oral Kaposis sarcoma

Clinical descriptors: Early lesions are typically at (or

macular) with color ranging from red to purple. At a
later stage, lesions become nodular, raised and or
ulcerated. Predominantly present on the palate and
gingiva (Fig. 6a,b).
Patient-reported symptoms: At early stage, lesions are
asymptomatic. Mild-to-moderate pain may develop as
lesions become nodular and ulcerated. Local trauma to
more advanced lesions may induce bleeding.
Patient-reported duration: Nodular lesions are longstanding.
Denitive diagnosis (required): Characteristic histologic appearance on biopsy.

487

Oral non-Hodgkins lymphoma

Clinical descriptors: A rm elastic, often somewhat reddish

swelling, with or without ulceration. The gingiva, palatal
mucosa, and fauces are sites of predilection (Fig. 6c).
Patient-reported symptoms: At early stage, lesions are
usually asymptomatic. Moderate-to-severe pain may
develop as lesions become ulcerated.
Patient-reported duration: Ulcerated lesions and swellings are long-standing.
Denitive diagnosis (required): Characteristic histologic
appearance on biopsy, supported by appropriate immunocytochemical or molecular biological investigations.
Oral squamous cell carcinoma
Clinical descriptors: Non-healing ulcer with rolled borders or margins. An advanced stage ulcer may be
indurated or located on a rm mass (Fig. 6d).
Patient-reported symptoms: At early stage, lesions are
usually asymptomatic. Moderate to severe pain may
develop as lesions enlarge and become ulcerated.
Patient-reported duration: Ulcerated lesions and swellings are long-standing.
Denitive diagnosis (required): Characteristic histologic appearance on biopsy.

Conclusion
Epidemiologic studies of disease outcomes rely on case
denitions that can easily be measured with a clinical
examination when a diagnostic test is not feasible. Such
case denitions need to be both accurate (i.e. they
measure what is intended to be measured) and precise
(i.e. reproducible). We have expanded upon previously
established diagnostic criteria for HIV-related oral
diseases by adding patient-reported symptoms and
duration to existing sets of clinical descriptors for each
lesion. We anticipate that these updated case denitions
will become the new standardized tool for the clinical or
presumptive diagnosis of HIV-related oral lesions in
epidemiologic studies, by both dental and non-dental
clinician examiners. As our intent is to standardize these
denitions across studies, our training module is available from the corresponding author upon request.

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