A, Anterior trunk and arm. B, Back. C, Hands. D, Detail from dorsal
surface of hand showing excoriated papules.
A, Histopathological features characteristic of an arthropod bite or
sting that include a superficial and deep perivascular and interstitial infiltrate
of lymphocytes and eosinophils; a few neutrophils are also present (hematoxylin-eosin,
original magnification ×20). B, A punctum (arrowheads), represented
by a small intraepidermal vesicle, appears at the site at which mouth parts
or a stinger enters the skin (hematoxylin-eosin, original magnification ×40).
C, Dermis containing degranulated eosinophils; lymphocytes are also visible
(hematoxylin-eosin, original magnification ×400).
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Resneck JS, Van Beek M, Furmanski L, et al. Etiology of Pruritic Papular Eruption With HIV Infection in Uganda. JAMA. 2004;292(21):2614–2621. doi:10.1001/jama.292.21.2614
Author Affiliations: Departments of Dermatology
(Drs Resneck, LeBoit, Maurer, and Berger), Medicine (Dr Oyugi), Pathology
(Dr LeBoit), and Epidemiology and Biostatistics (Dr Pletcher), Institute for
Health Policy Studies (Dr Resneck), and Division of General Internal Medicine
(Dr Machtinger), University of California, San Francisco; Departments of Dermatology
and Epidemiology, University of Iowa, Iowa City (Dr Van Beek); Reach-Out Mbuya
Parish AIDS Initiative, Kampala, Uganda (Dr Furmanski); Academic Alliance
for AIDS Care and Prevention in Africa, Kampala (Drs Oyugi and Katabira);
and Makerere University, Kampala (Drs Katabira and Kambugu).
Context A frequent cause of human immunodeficiency virus (HIV)–related
morbidity in sub-Saharan Africa is a commonly occurring, intensely pruritic
skin rash. The resulting scars are disfiguring and stigmatizing. Despite the
substantial prevalence of pruritic papular eruption (PPE) among HIV-infected
Africans, the cause has been elusive.
Objective To determine the etiology of PPE occurring in HIV-infected individuals.
Design, Setting, and Patients Cross-sectional study of HIV-infected patients with active PPE from
clinics in Uganda conducted from May 19 through June 6, 2003. Enrollment occurred
in the month preceding May 19. Each participant was clinically examined by
2 dermatologists, had laboratory studies performed, was administered an epidemiologic
questionnaire, and had a skin biopsy of a new lesion evaluated by a dermatopathologist.
Main Outcome Measures Histological characteristics of new pruritic lesions. Other assessments
included CD4 cell count, eosinophil count, and physician-assessed rash severity.
Results Of 109 patients meeting inclusion criteria, 102 (93.6%) completed the
study. The CD4 cell counts in this study population were generally low (median,
46/μL) and inversely related to increasing rash severity (median CD4 cell
counts: 122 for mild, 41 for moderate, and 9 for severe; P<.001 for trend). Eighty-six patients (84%; 95% confidence interval,
77%-91%) had biopsy findings characteristic of arthropod bites. Patients with
arthropod bites on biopsy had significantly higher peripheral eosinophil counts
(median, 330 vs 180/μL; P = .02) and
had a trend toward lower CD4 cell counts (median, 40 vs 99/μL; P = .07) than those without histological evidence of arthropod
Conclusions Pruritic papular eruption occurring in HIV-infected individuals may
be a reaction to arthropod bites. We hypothesize that this condition reflects
an altered and exaggerated immune response to arthropod antigens in a subset
of susceptible HIV-infected patients.
Pruritic papular eruption (PPE) is a substantial cause of human immunodeficiency
virus (HIV)–related morbidity in sub-Saharan Africa.1-7 Despite
2 decades of reports describing this condition, its etiology has not been
elucidated. Empirical therapies provide only minimal relief,5 and
the severe pruritus and subsequent scarred excoriations subject patients to
HIV-related stigma in their communities.1
Reports of PPE emerged early in the course of the HIV epidemic. Beginning
in 1983, studies in the Democratic Republic of the Congo,2 Mali,3 Zambia,4 Tanzania,5 Nigeria,6 Togo,7 and other African countries described an extremely
pruritic, diffuse skin eruption occurring in HIV-infected patients. The typical
primary lesion is a firm, discrete, erythematous, urticarial papule.8 The concentration of the lesions is highest on the
extremities, but the trunk and face are also involved in half of the patients.8 Most patients scratch the lesions because of the severe
pruritus, leading to excoriated papules, marked postinflammatory hyperpigmentation
and, eventually, scarred nodules.5 The persistent
pruritus is usually refractory to topical steroids and oral antihistamines.5 Cases have been reported with similar frequencies
in infected men, women, and children.2 While
numerous cases have also been described in Haiti,9 Brazil,10 and Thailand,11 the
eruption has rarely been reported in Europe and North America.2
The prevalence of PPE in Africans and Haitians with HIV varies from
12% to 46%, depending on the geographic area.2,4,8,9 It
is uncommon in immunocompetent patients,2,8 with
a reported positive predictive value of 82% to 87% for HIV infection.2,12 More than half of HIV-infected patients
in some countries (including Uganda and the Democratic Republic of the Congo)
may report the eruption as their initial disease manifestation.2,9 The
incidence of the rash increases with decreasing CD4 cell counts,11 but
it occurs even in early disease.2 In fact,
given the prevalence and positive predictive value of the rash, it has played
a role in diagnosing HIV infection in countries in which serologic testing
is not available or affordable.3
There have been scattered, inconsistent reports of the pathologic findings
from biopsy specimens2,4; in these
reports, most of the specimens showed a mild to moderate dermal perivascular
and periadnexal mononuclear infiltrate with variable intermixed eosinophils.2 Special stains for organisms have been negative, and
all efforts to implicate an opportunistic infection have been unsuccessful.2,8 Lower levels of interleukin 2 (IL-2)
and γ-interferon in HIV-infected patients with the eruption compared
with other HIV-infected patients have led some to argue for a role for immune
dysregulation.10 An increase in local and peripheral
eosinophilia as well as an increase in IgE levels has been reported, suggesting
hypersensitivity to arthropod bites.13 These
biopsy and laboratory studies, however, have been far too limited in scope
to provide any consensus as to the etiology of PPE.
A comprehensive review of PPE published in 1993 suggested that it “most
likely represents a spectrum of diseases, including HIV-associated eosinophilic
folliculitis, that have similar clinical and histologic findings.”8 Known dermatologic diseases with related clinical
presentations include staphylococcal folliculitis, Demodex folliculitis, drug eruption, exuberant reactions to arthropod bites,
and photodermatitis. Crusted scabies, secondary syphilis, onchodermatitis,
and papulonecrotic tuberculids can also resemble PPE.
We studied Ugandan HIV-infected patients with PPE, performing biopsies
on early lesions to gain insight into the etiology of the disease.
We performed a cross-sectional, descriptive, biopsy study of HIV-infected
patients with active clinical PPE enrolled as a consecutive convenience sample
from 2 clinics in Kampala, Uganda. To meet inclusion criteria, patients had
to be HIV-infected adults experiencing a pruritic skin eruption for greater
than 1-month duration, with evidence of multiple papular or nodular lesions.
The study was performed over a 3-week period from May 19 through June 6, 2003.
Analysis of biopsy specimens occurred in the United States after the 3-week
In the month leading up to the study, participants meeting inclusion
criteria and willing to participate were referred by physicians and nurses
from the 2 Ugandan clinics (each clinic was asked to recruit consecutive qualifying
patients until 75 were referred). One clinic was an HIV clinic in a large
public hospital (Mulago Hospital), and the other was a community-based, nongovernmental
organization providing care to nearby residents (Reach-Out Mbuya Parish HIV/AIDS
Community Initiative). The patient volume at each clinic was about 300 visits
per week. Together, these 2 clinics care for a broad spectrum of patients
living with HIV in urban Uganda. At the time of the study, both clinics were
offering treatment for opportunistic infections, but neither was providing
antiretroviral therapy due to lack of resources. Referring physicians indicated
that for the Mulago hospital clinic, where staff kept count, only 2 patients
who met inclusion criteria during the enrollment period declined to participate.
Staff at the Reach-Out clinic did not keep count but reported that fewer than
5 patients meeting inclusion criteria did not participate. The study provided
the opportunity for patients to access additional care at no cost, and the
2 sites did not experience significant difficulty in meeting recruitment goals.
This study was carried out with approval from institutional review boards
at the University of California, San Francisco, and Makerere University in
Uganda. Referred patients received information in their own language (including
English, Acholi, and Luganda) explaining that the study was an effort to determine
the cause of an itchy skin rash associated with HIV. Trained counselors reviewed
written consent forms that detailed all aspects of the study, as well as the
potential risks and benefits, with every referred patient in his/her preferred
language. Every patient willing to participate provided written informed consent
before undergoing any aspect of the study. The consent forms, approved by
both institutional review boards, indicated that no individual identities
would be used in published reports resulting from the study. The consent form
included sections on the purpose, background, procedures, risks, benefits,
and alternatives. The procedures section included paragraphs on the questionnaire,
blood tests, medical record reviews, skin examinations, skin biopsies, skin
cultures, suture removals, and receipt of test results. A section on confidentiality
stated that “Participation in research will mean some loss of privacy.
However, my research records will be handled as confidentially as possible.
All research records will be coded so that the laboratories and researchers
will not know which samples are mine. My clinic doctor will have access to
the codes so that I can be told the results of my specific diagnostic tests.
No individual identities will be used in any reports or publications that
result from this study.” An additional section on the voluntary nature
of the study stated that “If I agree to participate in this study, I
may stop participating at any time. I have the right to participate or withdraw
at any point in this study without the risk of losing my medical care.”
Those patients whose photographs were taken signed a separate consent form
giving permission for reproduction of images in published reports.
After the extensive consent process, enrollees were administered an
epidemiologic questionnaire by clinic nursing staff in 1 of 3 languages (English,
Acholi, and Luganda) preferred by the patient. The staff received training
in question administration prior to the study. The questionnaire included
items on patient demographics, history of the rash and attempted treatments,
environmental exposures, and medication history including traditional therapies.
All patients had medical charts available for review, and chart review was
used to ascertain past medical conditions including HIV-associated opportunistic
infections and tuberculosis, as well as to supplement information about medication
use. Patients were also asked about previous infections and medication use
during the physical examination, to supplement the chart review. A 12-month
cutoff was applied when eliciting use of medications.
Each participant received physical examinations by 2 US-based dermatologists
(J.S.R., M.V.) that included consensus subjective assessments of rash severity.
The rash of each participant was rated by both examining physicians (who were
blinded to the results of any laboratory or biopsy results) until verbal consensus
was reached. No accepted objective severity scale for PPE is in use, and the
authors did not develop one for use as a part of this study. Mild eruptions
consisted of sparse lesions (<20), usually limited to the distal extremities,
with only minimal scarring or pigmentary changes. Moderate eruptions were
characterized by approximately 20 to 60 lesions over the trunk and extremities,
usually with some degree of excoriation, pigmentary alteration, and scarring.
Patients with severe eruptions had high lesion counts (usually >60) with marked
excoriation, pigmentary alteration, and scarring and, occasionally, facial
Participants also had laboratory studies, including serologic testing
to confirm HIV infection, complete blood cell count with differential, and
CD4 cell count. The serologic tests for HIV were performed using parallel
testing with 2 kits (Thermo Labsystems HIV [Ani Labsystems Ltd, Vantaa, Finland]
and Abbott-Murex HIV [Abbott Laboratories, Abbott Park, Ill]) with tie-breaking
of discordant results using Western blot (though no tie-breaks were required).
CD4 cell counts were performed using FACSCount (Becton Dickinson, La Jolla,
Calif). Although serology results and CD4 cell counts were obtained on all
participants, specimen amounts were inadequate to report automated differential
blood counts in 16 patients. Viral loads were not obtained because of limited
resources and because, in the setting of the limited budget, we determined
that the CD4 cell counts were a more reliable marker of immunological status
and integrity, given that only a single laboratory measurement was being obtained
at a single point.
After local anesthesia, a 4-mm punch biopsy of a recent primary skin
lesion was performed. During the skin examination, patients were asked to
identify lesions that were new and that, based on their experience, would
develop into more advanced PPE lesions. Among these lesions, the investigators
selected 1 indurated papule without excoriation for biopsy.
Tissue samples were formalin-fixed and shipped to the United States
for analysis by a senior dermatopathologist (P.E.L.) with recognized expertise
in both dermatopathology and HIV pathology; this investigator was blinded
to any patient status that could have biased interpretation of the slides.
Six sections from each specimen were mounted on a slide and stained with hematoxylin-eosin
for primary light microscopic analysis. Additional level sections were obtained
if inflammatory infiltrates were not present in the initial sections or if
infiltrates were present around pilosebaceous units but the pilar canal of
the affected follicle was not adequately displayed. Only 1 specimen required
additional level sections. Special stains for organisms (including periodic
acid–Schiff [digested], Brown-Brenn, Fite, and Warthin-Starry) were
available for the study. These were not performed on any cases, however, as
none had histopathologic findings of an infection (eg, suppurative, suppurative
and granulomatous, or granulomatous dermatitis).
Statistical analyses were performed using SPSS version 11.5 (SPSS Inc,
Chicago, Ill) and Stata version 8.0 (StataCorp, College Station, Tex). We
used t tests and linear regression (assessing a linear
contrast of regression coefficients for trend) to evaluate differences in
age; χ2 tests (including tests of trend) to evaluate differences
in proportions such as sex, clinic, severity, and biopsy findings; and nonparametric
tests (including the Kruskal-Wallis test and the Cuzick extension to the Wilcoxon
rank-sum test for trend) to evaluate differences in CD4 cell and eosinophil
counts, which were abnormally distributed. We used logistic regression to
adjust for differences in the CD4 cell count when comparing the likelihood
of having certain biopsy findings between clinic sites. χ2 Tests
were used when comparing the frequency of absolute eosinophilia or the frequency
of certain biopsy findings among subgroups of patients. The only missing data
were eosinophil counts in the 16% (16/102) of patients with inadequate blood
samples, and those patients were excluded only from analyses involving peripheral
eosinophil counts. Also, 1 patient was missing data on rash distribution. P<.05 was used to determine statistical significance.
One hundred two (77.3%) of 132 patients referred completed the study
from May 19 through June 6, 2003. The other 30 were excluded because they
did not meet inclusion criteria when evaluated by the study dermatologists
(23 [17.4%]) or left the clinic before completing the study (7 [5.3%]). The
102 patients who finished the study represented 93.6% of the 109 meeting inclusion
criteria. The mean age of patients completing the study was 35 (SD, 8) years,
and the majority (83 [81%]) were women. Results of serologic testing to confirm
HIV infection were positive in all patients, and CD4 cell counts in this population
were low (median, 46/μL; interquartile range, 9-146/μL).
Fifty-two patients were from the hospital-based clinic, and 50 were
from the community-based clinic. Demographic characteristics of the 2 groups
were similar, including age and sex (Table 1).
The patients from Mulago Hospital, however, had significantly lower CD4 cell
counts (median, 33 vs 78/μL; P = .04).
On subjective global assessment by the investigators, patients were
described as having mild (30 [29%]), moderate (53 [52%]), or severe (19 [19%])
rashes. Mild eruptions consisted of fewer than 20 lesions, most commonly in
an acral distribution. Typical patients with moderate eruptions had approximately
20 to 60 excoriated, hyperpigmented papules and nodules on the trunk and extremities.
Those with severe eruptions had high lesion densities over larger body surface
areas, often including the face, trunk, and all 4 extremities. New lesions
were typically characterized by a 2- to 8-mm erythematous papule. Subacute
lesions were often excoriated papules, while chronic lesions were larger papules
to nodules (approximately 1 cm) with marked lichenification and hyperpigmentation
(Figure 1). Increasing rash severity
was significantly associated with lower CD4 cell counts (P<.001) and higher absolute peripheral eosinophil counts (P = .01) (Table 2).
The majority of patients (n = 86 [84.3%; 95% confidence interval,
77%-91%]) had pathologic skin biopsy findings characteristic of arthropod
bites. Most of these (n = 53) had roughly wedge-shaped, moderately
dense to dense, superficial and deep, perivascular and interstitial infiltrates
of lymphocytes and many eosinophils beneath an epidermis that was slightly
hyperplastic (Figure 2). The infiltrates
often extended into the subcutis. Varying numbers of neutrophils were also
present. These are the features classically seen in arthropod bites or stings.14 Some (n = 11) also showed a punctum (a
small focus of spongiosis positioned in the epidermis over the center of the
dermal infiltrate) at the site of the bite, which is nearly pathognomonic.
Biopsy findings from the remaining 33 of the 86 patients were described as
having dermal perivascular and interstitial infiltrates of lymphocytes and
eosinophils—findings strongly suggestive of arthropod bites.
Most of the remaining biopsies (n = 10 [9.8%]) showed nonspecific
inflammatory changes (perivascular lymphocytes). The other 6 (5.9%) included
1 case each of a prurigo nodule, lichen simplex chronicus, scar, postinflammatory
pigmentary alteration, spongiotic dermatitis, and suppurative folliculitis.
There was not a single case of eosinophilic folliculitis.
There were differences between the groups of patients with and without
biopsy findings suggestive of arthropod bites. Compared with patients without
histological evidence of arthropod bites on biopsy, those with bites had significantly
higher peripheral eosinophil counts (median, 180 vs 330/μL, respectively; P = .02), and had a trend toward lower CD4 cell
counts (median, 99 vs 40/μL; P = .07).
Malaria and tuberculosis are prevalent in the area and some patients had been
treated for these conditions, but we did not believe that their prevalence
would have an effect on differences in eosinophilia among study groups. Also,
although we had the ability to obtain scrapings for dermatophytes and scabies,
none of the study patients had clinical findings supporting either of these
and so no scrapings were performed.
The physical distribution of the rash was not predictive of biopsy results
showing arthropod bites (arthropod bite on biopsy in 81% [13/16] of patients
with bites on extremities only, 85% [44/52] of those with bites on extremities
and trunk, and 88% [29/33] of those with bites on extremities, trunk, and
face; P = .82; missing distribution data
for 1 patient). The frequency of arthropod bites on biopsy was the same among
men (84% [16/19]) and women (84% [70/83]) in the study group (P = .99). Forty-four percent of patients had active or previously
treated pulmonary tuberculosis (TB), but TB status was not predictive of biopsy
results (arthropod bite on biopsy in 82% [47/57] of patients without known
TB, 88% [21 of 24] of those with successfully treated prior TB, and 86% [18/21]
of those with active TB; P = .83). Patients
from the public hospital clinic were more likely to have arthropod bites on
biopsy than were patients from the community-based clinic (92% vs 76%, P = .02), and there was a trend in this regard
even when controlling for CD4 cell count (P = .06).
The systemic medications most frequently prescribed within the previous
12 months, in descending order, were paracetamol/acetaminophen (59 patients),
trimethoprim/sulfamethoxazole (51), promethazine (38), ketoconazole (34),
amitriptyline (23), doxycycline (23), and pyrimethamine/sulfadoxine (16).
None of the patients was receiving antiretroviral therapy.
The topical medications most frequently prescribed within the prior
12 months included calamine (41 patients), clotrimazole (33), topical steroids
(21), salicylic acid (20), and Whitfield ointment (14). Systemic medication
history was not associated with clinical rash severity or biopsy results in
the study participants (P>.05 for all, by χ2 test). For topical steroids, however, users were more likely to have
an arthropod bite on biopsy (21/21 vs 65/81 [80%] for users vs nonusers, respectively; P = .03). We believe this may be due to chance,
because topical steroids are widely used on biopsied lesions and their effects
on histology are widely appreciated; if anything, they could mask the immune
cell response in the sections but would not likely increase the likelihood
of reactions to arthropod bites on biopsy. Also, most nonusers of topical
steroids had biopsy findings of arthropod bites. The use of Whitfield ointment
was also associated with biopsy findings. Nine (64%) of the 14 users had an
arthropod bite on biopsy, as did 77 (88%) of the 88 nonusers (P = .03). Pathologist investigators could not hypothesize
a way in which the ointment (benzoic acid and salicylic acid) could have affected
the likelihood of finding reactions to arthropod bites on biopsy and believed
the small numbers of users weighed against a statistically interesting finding.
Furthermore, it would be difficult to argue that either of the topical treatments
caused the biopsy findings of arthropod bites, because most nonusers of each
ointment had biopsy findings consistent with arthropod bite.
Per questionnaire responses, 76% of study patients reported exposure
“to many bugs or insects at home/work,” and 56% reported sustaining
many bites. Of those reporting frequent bites, the majority (84%) listed mosquitoes
as the offending agent.
Our findings suggest that the PPE occurring in HIV-infected individuals
in Uganda may be a reaction to arthropod bites. Most of the biopsy specimens
of early lesions of PPE showed findings characteristic of arthropod bites—namely,
moderately dense to dense, superficial and deep, perivascular and interstitial
infiltrates of lymphocytes and eosinophils often extending into the subcutis,
with epidermal hyperplasia and, in some cases, accompanied by a punctum. We
thus suggest that “arthropod-induced prurigo of HIV” may be a
more specific and appropriate description of this clinical entity than PPE.
The lesions we identified as arthropod bites are not consistent with
any other diagnoses. The infiltrates were not centered around hair follicles,
arrector pili muscles, or sebaceous lobules (as in eosinophilic folliculitis).
Although drug eruptions can mimic almost every pattern of inflammatory skin
disease and have overlapping features with reactions to arthropod bites, we
do not believe that PPE is a drug reaction. The infiltrates in most drug eruptions
are not as dense as those seen in our cases and do not extend into the subcutis.
Puncta would not be seen in drug eruptions. The findings were not compatible
with conditions that can simulate PPE clinically, such as staphylococcal folliculitis
(suppurative folliculitis, demonstrated histologically), Demodex folliculitis (spongiotic infundibular folliculitis), phototoxic
or photoallergic dermatitis (many single necrotic keratinocytes or spongiotic
dermatitis, respectively), crusted scabies (mites, fecal deposits, or eggs
beneath the stratum corneum), secondary syphilis (a superficial and deep,
psoriasiform lichenoid pattern with lymphocytes, plasma cells, and histiocytes
predominating), onchodermatitis (a deep zone of fibrosis with microfilariae),
or papulonecrotic tuberculid (a necrotizing granulomatous reaction).
By aggressively seeking new primary lesions instead of older, scarred,
or excoriated nodules, we were able to obtain diagnostic biopsy results in
a majority of patients. The patients were adamant that the lesions biopsied
were representative of the initial presentation of all their PPE skin lesions.
We thus strongly doubt that the biopsied lesions represent a concurrent process
that was unrelated to the patients’ more advanced PPE lesions.
There are a number of possible explanations for the different findings
observed in the biopsies of the 16 patients without histopathological evidence
of arthropod bites. In 4 of these patients, the results suggested that an
older or secondary lesion was inadvertently selected for sampling. These 4
biopsies may represent prior arthropod bite reactions in later stages. Many
of the rest had highly nonspecific inflammatory changes. It is possible that
these lesions were also arthropod bites, as it is not uncommon to have these
nondiagnostic findings in known cases of arthropod-induced injuries.15
On the other hand, the patients without diagnostic biopsy findings might
have had some cause other than arthropod bites for their skin lesions. The
nonbite subgroup had a trend toward higher CD4 cell counts and had significantly
lower eosinophil counts. While these differences could suggest a different
etiology, they might also indicate an earlier stage of HIV in which lesions
diagnostic for arthropod bites are more difficult to detect. The different
laboratory profiles might also simply reflect a variation in the immunological
reaction pattern in response to the same causative insult.
The diffuse distribution of PPE lesions (most dense on the extremities,
but also in areas that are typically covered) raises the issue of whether
bites are the initiating event for every lesion. In our study patients, biopsies
from the trunk were no less likely to show primary arthropod bites than were
those from the extremities. In addition, many arthropods (including mosquitoes)
are known to bite through clothing and on the trunk. We believe that most
(if not all) PPE lesions do begin as arthropod bites. We did not, as part
of this study, attempt to identify the species responsible for the patients’
bites or stings. To do so would be difficult because patients usually do not
feel discomfort during the blood meal of certain arthropods (including mosquitoes)16-18 and because the histopathology
of bites and stings from different arthropods is generally indistinguishable.
Nevertheless, most study patients reporting frequent arthropod bites did list
mosquitoes as the source of their bites.
The association between arthropod bites and PPE raises many pathophysiological
issues. Patients with PPE may lose the well-described desensitization19,20 most people develop after repeated
exposure to arthropod bites. The experience of increasing hypersensitivity
to previously tolerated medications in HIV-infected patients as CD4 cell counts
decline21 provides one possible model. Some
have hypothesized that this profound increase in drug hypersensitivity22 could be secondary to polyclonal B-cell activation23 or T-cell activation24 seen
with AIDS. These same hypothesized phenomena could be involved as patients
with PPE become hypersensitive to arthropod antigens they may have previously
The idea that arthropod bite hypersensitivity might account for the
pruritus observed in some HIV-infected patients has been raised previously,
though the literature on this subject is sparse. One study of 7 AIDS patients
in Florida with pruritus (though not classic PPE) found that 5 had increased
antibody titers to antigens in the saliva of a common local mosquito.25 The authors hypothesized that the pruritus in some
patients with AIDS might be a form of chronic “recall” reaction
to mosquito salivary antigens in the setting of nonspecific B-cell activation.
Another study found that patients with PPE in Brazil had lower IL-2 and γ-interferon
levels than did HIV-infected patients without dermatitis,10 raising
the possibility of a potential role of TH2-dominant humoral immunity.
A shift from TH1 to TH2 cytokine predominance has been
associated with advancing HIV.26-28 A
subset of patients with pronounced TH2 dominance may be more predisposed
to the development of the arthropod hypersensitivity leading to PPE.
The HIV-infected patients in industrialized nations who have intractable
pruritus29 and who have prurigo nodularis30 frequently have accompanying hypereosinophilia. Prurigo
nodularis, which can clinically resemble mild PPE, is an idiopathic condition
in which nodular lesions result from repetitive picking or scratching. Though
it may occur in some HIV-infected patients, it may also be associated with
renal failure and hepatic dysfunction and may be seen in some patients without
other medical problems. In our study population, higher eosinophil counts
were associated with more severe clinical PPE eruptions. Since the IL-4 and
IL-5 produced by TH2 lymphocytes promote IgE production and eosinophil
differentiation,31 this further supports the
idea that a subset of patients with advanced HIV infection and hyperactive
TH2 immune response may be more likely to experience exaggerated
immunological phenomena in the skin.
Another question remains unanswered, ie, why is this condition more
prevalent in Africa (and possibly southeast Asia) than in North America and
Europe? One possibility is that arthropod antigens on those continents are
simply different—ie, more likely to cause this reaction pattern. Another
possibility is that host factors predispose certain populations. One study
of HIV-infected patients with rashes in the southern United States found that
eosinophilia and skin rashes were more common in African Americans.30
Some researchers are suggesting that PPE be added to the list of conditions
qualifying patients for initiation of HIV medications in settings that rely
on clinical indicators of immune suppression.32 Many
of our patients were enrolled in trials of antiretroviral therapy after completing
the skin study, and anecdotal follow-up suggests that their symptoms of PPE
are improving. More formal work is under way to establish the course of this
eruption after initiation of antiretroviral agents. Determining the effectiveness
of HIV therapy for the symptoms of PPE might also provide additional information
on the immunological basis of this condition.
Follow-up studies may be required to determine whether these results
are generalizable to other places where this eruption has been reported (eg,
other African countries, southeast Asia, and the Caribbean). This study, however,
provides evidence to support the hypothesis that PPE is actually an arthropod-induced
prurigo representing an exaggerated immune response to arthropod antigens
in predisposed HIV-infected patients.
Corresponding Author: Jack S. Resneck, Jr,
MD, Department of Dermatology and Institute for Health Policy Studies, University
of California, San Francisco, School of Medicine, Box 0363, San Francisco,
CA 94143-0363 (firstname.lastname@example.org).
Financial Disclosures: Dr Resneck owns stock
in several pharmaceutical companies (none of which has products mentioned
in the study herein); has received educational grants from health care–related
manufacturers Connetics and the Galderma Foundation, training and research
grants from a nonprofit foundation (The Dermatology Foundation), and a research
grant from the University of California, San Francisco (UCSF); has received
honoraria from Connetics; has consulted for the Gerson Lehman group; has been
an advisor to Connetics and Novartis; has received a training grant from the
Health Resources and Services Administration; and has consulted in liability
cases with skin involvement. Dr Van Beek has conducted research on treatment
of psoriasis for Genentech and Fujisawa; was a consultant for IQ Solutions,
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
contract 04-1, Core Measure of the Burden of Skin Disease; and has received grants or funding from the F32 Herzog Award, National
Research Service Award (Public Health Service) regarding nevi and melanoma,
from NIAMS, National Institutes of Health (NIH)—National Cancer Institute
(R03 CA099520-01A1) regarding tanning bed use in University of Iowa students,
from the American Cancer Society regarding cumulative sun exposure and melanoma,
and from the NIH (K12 Mentored Clinical Research Award) regarding health-related
quality of life in inflammatory skin disease; and has served as an advisor/consultant
receiving honoraria from Amgen and Genentech (neither of which has products
mentioned in the study herein). Dr LeBoit owns stock in several pharmaceutical
companies (none of which has products mentioned in the study herein), has
received honoraria from lectures and publishers (but none from pharmaceutical
companies), has given expert medical testimony (but not related to the study
herein or to pharmaceutical companies or products), and has received honoraria
from book publishers (but unrelated to pharmaceutical companies or products).
Dr Maurer was a consultant for Abbott Laboratories for omnicef, Celgene for
thalidomide, and Vaxgen for smallpox vaccine; has received honoraria/lectureships
from Contemporary Forums, Symposia Medicus, and Fujiyama; had an advisory
position as a dermatology consultant for smallpox vaccine and served on a
drug safety monitoring board and Advisory Committee on Immunization Practices;
and has received grants from the AIDS Clinical Research Center, UCSF, for
research on the effects of HAART therapy on HIV skin disease and from UCSF
for the study herein. Dr Berger has had prior or current pharmaceutical company
support as a consultant/advisor to Gilead Sciences, Novartis, and Doak Dermatologics,
and was on the speakers bureau for Gilead Sciences, Novartis, Dermik, and
3M. Dr Machtinger has received an unrestricted educational grant from Ortho
Biotech, honoraria from GlaxoSmithKline and Savient, was a consultant for
GlaxoSmithKline, and served on the advisory board of GlaxoSmithKline and Abbott.
Author Contributions: Dr Resneck had full access
to all of the data in the study and takes responsibility for the integrity
of the data and the accuracy of the data analyses.
Study concept and design: Resneck, Furmanski,
Oyugi, Berger, Machtinger.
Acquisition of data: Resneck, Van Beek, Furmanski,
Oyugi, Katabira, Kambugu.
Analysis and interpretation of data: Resneck,
Furmanski, LeBoit, Maurer, Berger, Pletcher, Machtinger.
Drafting of the manuscript: Resneck, Van Beek,
Critical revision of the manuscript for important
intellectual content: Resneck, Van Beek, Furmanski, Oyugi, LeBoit,
Katabira, Kambugu, Maurer, Berger, Pletcher, Machtinger.
Statistical analysis: Resneck, Pletcher.
Obtained funding: Resneck, Machtinger.
Administrative, technical, or material support:
Resneck, Van Beek, Furmanski, Oyugi, LeBoit, Kambugu, Machtinger.
Study supervision: Resneck, Oyugi, Katabira,
Maurer, Berger, Machtinger.
Funding/Support: This study was primarily supported
by a grant from the Research Evaluation and Allocation Committee, Office of
the Dean, University of California, San Francisco. An additional travel grant
was provided by the Donald Marion Pillsbury Fund of the Dermatology Foundation.
Role of the Sponsor: The organizations funding
this study had no role in the study design, data collection, data analysis,
data interpretation, manuscript creation, or decision to publish.
Previous Presentation: These data have not
been published elsewhere. Preliminary data were presented as an oral abstract
at the 11th Conference on Retroviruses and Opportunistic Infections; Februrary
8-11, 2004; San Francisco, Calif.
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