(Chest. 2003;124:929-935.)
© 2003
American College of Chest Physicians
Sarcoidosis Following HIV Infection*
Evidence for CD4+ Lymphocyte Dependence
David G. Morris, MD;
Robert M. Jasmer, MD;
Laurence Huang, MD, FCCP;
Michael B. Gotway, MD;
Stephen Nishimura, MD and
Talmadge E. King, Jr, MD, FCCP
* From the Interstitial Lung Disease Program (Drs. Morris, Gotway, Nishimura, and King) and the Division of Pulmonary and Critical Care Medicine (Drs. Jasmer and Huang), Department of Medicine, San Francisco General Hospital, University of California, San Francisco, CA.
Correspondence to: David G. Morris, MD, Box 0854, University of California, San Francisco, San Francisco, CA 94143-0854; e-mail: dmorris{at}itsa.ucsf.edu
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Abstract
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Background: The chronic granulomatous inflammation of sarcoidosis has been hypothesized to depend on the CD4+ T-helper lymphocyte. HIV infection, which depletes these cells, has been reported to attenuate the manifestations of sarcoidosis.
Study objectives: We asked whether the development of symptomatic sarcoidosis in the context of preexisting HIV infection was dependent on the CD4+ lymphocyte count.
Design: We performed a retrospective standardized chart review of all patients who developed granulomatous inflammation following HIV infection at an urban academic referral center.
Measurements: We identified seven patients with sarcoidosis within this cohort and compared their CD4+ lymphocyte count to that in a cohort of 16 patients in whom similar granulomatous inflammation was found but who did not have sarcoidosis. We then compared our cases to all reported cases using a systematic literature review.
Results: The CD4+ lymphocyte count was > 200 cells/µL in all of our patients with HIV infection when they developed subsequent sarcoidosis. In contrast, specific etiologies for granulomatous inflammation were found in all 10 HIV-infected patients who presented with granulomatous inflammation and a CD4+ lymphocyte count of < 200 cells/µL, with infectious etiologies found in 8 patients. Similarly, there was relative preservation of the CD4+ lymphocyte count in previously reported cases, with 14 of 19 patients (74%) having an absolute CD4+ lymphocyte count of > 200 cells/µL.
Conclusions: We conclude that the development of the chronic granulomatous inflammation of sarcoidosis appears to depend on the preservation or restoration of the peripheral CD4+ lymphocyte count and that in most cases the CD4+ lymphocyte count exceeds 200 cells/µL. Furthermore, alternative specific etiologies of granulomatous inflammation are generally identifiable in HIV-infected patients with peripheral CD4+ lymphocyte counts of < 200 cells/µL.
Key Words: HIV infection • immune restoration • sarcoidosis
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Introduction
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Sarcoidosis is a multiorgan, inflammatory disorder that has a variable clinical course. A definitive diagnosis of sarcoidosis requires demonstration of the presence of characteristic epithelioid cell granulomas in a patient with an appropriate clinical history.1
Granulomatous diseases of known cause (eg, secondary to infectious, neoplastic, or chronic inflammatory conditions) must first be excluded. The specific etiology of sarcoidosis remains elusive, although infectious, environmental, and genetic factors all have been implicated.1
The concept that CD4+ lymphocytes are important to the pathogenesis of sarcoidosis originated with observations that, despite modest peripheral lymphopenia, patients with sarcoidosis had a preferential accumulation of CD4+ lymphocytes at sites of granulomatous inflammation.2
3
These CD4+ lymphocytes exhibit the T-helper type 1 profile of secreted cytokines (ie, interferon-
, interleukin-2).4
5
These findings led to the hypothesis that CD4+ lymphocytes, particularly those expressing the T-helper type 1 phenotype, are required for the development of sarcoidosis.
An experiment of nature, which tests this hypothesis, occurs in the setting of infection with HIV because, under this hypothesis, patients who are infected with HIV and in whom CD4+ T-helper lymphocyte populations are dramatically reduced should not develop sarcoidosis. In fact, prior to the advent of highly active antiretroviral therapy (HAART), the development of sarcoidosis in patients previously infected with HIV was quite rare.6
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In the cases in which it occurred, the total peripheral CD4+ lymphocyte count was either normal or only modestly decreased.7
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Intriguingly, the increasing use of HAART among HIV-infected individuals, with associated immune restoration, seems to have coincided with an apparent increasing recognition of the coexistence of these two distinct disorders.12
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Nevertheless, the important clinical issues of whether, in fact, the development of sarcoidosis is dependent on the peripheral CD4+ lymphocyte count and whether the CD4+ lymphocyte count can be used as a tool in the evaluation of suspected sarcoidosis in HIV-infected patients remains unresolved. Therefore, in the present study, we asked what the peripheral CD4+ lymphocyte count was in patients with preexisting HIV when they developed symptomatic sarcoidosis and whether it was different from that found in patients with HIV who presented with other granulomatous diseases. We also compared our cases with all similar cases previously reported in the literature. Through this report and literature review, we propose a CD4+ lymphocyte count above which sarcoidosis typically presents and define the clinical features of sarcoidosis developing in the context of preexisting HIV infection.
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Materials and Methods
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San Francisco General Hospital (SFGH) is a referral center for the management of HIV infection, mycobacterial disease, and interstitial lung diseases. Using the SFGH Department of Pathology database, we defined a group of patients in whom the diagnosis of sarcoidosis was considered possible by retrospectively identifying those in whom a final pathologic diagnosis of any examined tissue included the word "granuloma" during the period of January 1994 to May 2002. These final pathologic diagnoses then were reviewed by one of the investigators (DM), and patients in whom another etiology of granulomatous inflammation was pathologically obvious were excluded. The remaining patients, with pathologically "idiopathic" granulomas, were considered possible sarcoidosis patients. A list of these patients then was cross-referenced against a contemporaneous list of all patients in the SFGH clinical laboratory database in whom either a CD4+ lymphocyte count or HIV viral load was measured. This database includes all patients within the SFGH referral network (ie, the Community Health Network) and is complete from 1996 through the present. Demographic and clinical data were obtained by standardized chart abstraction for all HIV-infected patients with possible sarcoidosis according to prospectively defined inclusion and exclusion criteria, including confirmation of HIV infection status (Table 1
). Four pulmonary medicine clinicians (DM, RJ, LH, and TK), a radiologist (MG), and a pathologist (SN) reviewed the clinical, radiographic, and pathologic features of each case and agreed either on a final diagnosis of sarcoidosis or on no diagnosis of sarcoidosis. HAART was defined as treatment with three or more antiretroviral agents including a protease inhibitor. The CD4+ lymphocyte counts used in the analysis all were obtained within the 3 months preceding the patients’ biopsies. The University of California, San Francisco Institutional Review Board and the SFGH General Clinical Research Center approved the protocol for the review of medical records.
We also reviewed all published case reports and case series up to May 2002. Articles were retrieved from PubMed (http://www.ncbi.nlm.nih.gov/PubMed/) using the keywords "sarcoidosis AND (HIV) OR (immune restoration)." The references of the retrieved articles also were reviewed to assure that no other case reports had been missed by the PubMed search. Only cases in which patients developed sarcoidosis either coincident with or subsequent to the diagnosis of HIV infection that fit the inclusion and exclusion criteria applied to our patients were included in this analysis. The authors of published studies were contacted directly to assess their reported patients for inclusion in cases in which such issues were not addressed in the published report. All cited reports had been peer-reviewed.
Statistical Analysis
The Mann-Whitney rank sum test was used for all analyses. A p value of < 0.05 was considered to be significant.
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Results
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SFGH
We found seven patients who developed sarcoidosis in the context of preexisting HIV infection. These cases were identified from a total pool of specimens from 474 patients who had granuloma listed as part of the final pathologic diagnoses. Of these patients, 324 had specific features noted in the pathologic diagnoses that were incompatible with sarcoidosis (pyogenic granuloma, 102 patients; granuloma annulare, 41 patients; granulomatous inflammation with visible organisms, 49 patients; and assorted other nonsarcoidal granulomatous reactions, 132 patients). Of the remaining 150 patients with possible sarcoidosis, 126 were not infected with HIV, leaving 24 patients who were HIV-infected with possible sarcoidosis. This group comprised our study population. The pathologic specimens of these 24 patients were reviewed, and the medical records were abstracted. The diagnosis of sarcoidosis was eliminated in 16 of these 24 patients either on the basis of clinical information indicating an infection or other etiologies for granulomatous inflammation (ie, Mycobacterium avium complex, 4 patients [CD4+ lymphocyte counts of 68, 93, 149, and 235 cells/µL]; Mycobacterium tuberculosis, 3 patients [CD4+ lymphocyte counts of 13, 58, and 190 cells/µL]; Mycobacterium fortuitum, 1 patient [CD4+ lymphocyte count of 9 cells/µL]; Mycobacterium leprae, 1 patient [CD4+ lymphocyte count of 320 cells/µL]; chronic Staphylococcus aureus lymphadenitis, 1 patient [CD4+ lymphocyte count of 6 cells/µL]; hypersensitivity pneumonitis, 1 patient [CD4+ lymphocyte count of 220 cells/µL]; and lymphoma, 2 patients [CD4+ lymphocyte counts of 137 and 18 cells/µL]), or on the basis of incompatible pathology noted at the time the biopsy specimen was reviewed (ie, nonsarcoidal granulomatous dermatitis, three patients [CD4+ lymphocyte counts of 329, 427, and 684 cells/µL]). One patient could not be classified on the basis of an uncertain diagnosis (isolated "sarcoid-like" dermal granulomas [CD4+ lymphocyte count of 720 cells/µL]) and was excluded from further analysis altogether. Seven HIV-infected patients were considered to have sarcoidosis. The CD4+ lymphocyte count in HIV-infected patients with sarcoidosis then was compared to the previously outlined group of 16 HIV-infected patients with granulomatous inflammation in whom the diagnosis of sarcoidosis had been eliminated. One patient in our cohort had been previously reported.13
This patient’s data were included in the analysis of our cohort and were excluded from the cohort of patients derived from the published literature.
The clinical characteristics of the seven patients with HIV infection and sarcoidosis are shown in Table 2
. The median age at the time of the diagnosis of sarcoidosis was 40.5 years (age range, 26 to 52 years). Four patients each had high-risk sexual behavior or IV drug use as their principal risk factor for acquiring HIV infection. Five patients were men. The CD4+ lymphocyte count at presentation with sarcoidosis was > 200 cells/µL in all patients. The median CD4+ lymphocyte count at presentation with sarcoidosis was 383 cells/µL (range, 210 to 916 cells/µL). In contrast, the median CD4+ lymphocyte count in the 16 patients with diseases other than sarcoidosis causing granulomatous inflammation was 143 cells/µL (range, 6 to 684 cells/µL; p = 0.005). All seven patients with sarcoidosis and HIV, five of whom were receiving HAART, had relatively well-preserved CD4+ lymphocyte counts at their clinical nadir, which exceeded 100 cells/µL in all cases (median, 364 cells/µL; range, 123 to 686 cells/µL). Five patients manifested chills, night sweats, fever, or fatigue (ie, the so-called constitutional symptoms). Three patients had either cough or shortness of breath as part of their initial presenting symptoms.
The pathologic features of the tissue biopsies are also shown in Table 2
. As expected, granulomatous inflammation was observed in affected tissues from all of the patients. The intensity of the inflammatory process varied from patient to patient but always included collections of epithelioid histiocytes with variable numbers of giant cells surrounded by a rim of mature lymphocytes. No foreign material was noted in the granulomatous foci, and no fungal or acid-fast organisms were found by silver or acid-fast stains in any case.
The radiographic features of sarcoidosis in patients with HIV infection are shown in Table 3
. High-resolution CT scans of the chest showed perilymphatic or subpleural nodules characteristic of sarcoidosis in three of five patients. Chest imaging was obtained in all seven patients and showed thoracic lymphadenopathy that was consistent with sarcoidosis in four patients.
Previously Published Reports
The PubMed database search identified 207 articles. From this list, we retrieved 12 articles containing original case reports of 22 patients in whom sarcoidosis developed either coincident with or subsequent to a diagnosis of HIV infection. From this group, three patients had previous infections with microbes known to commonly cause granulomatous inflammation (M avium complex, two patients; Torulopsis glabrata, one patient) prior to their diagnosis of sarcoidosis and were excluded (L. Haramati; personal communication; October 2, 2002). We restricted our analysis of CD4+ lymphocyte counts to the 19 remaining patients so as to more accurately estimate the minimum CD4+ lymphocyte count required for the development of clinically apparent sarcoidosis. The clinical characteristics of those patients are shown in Table 4
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The majority of these HIV-infected patients were symptomatic at the time of their presentation with sarcoidosis (18 of 19 patients; 95%), a finding similar to that of our case-series. Two previously published case reports16
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also noted skin findings (erythema nodosum), as in our series. The median peripheral CD4+ lymphocyte count in all previously reported patients who developed clinical manifestations of sarcoidosis either following or coincident with receiving a diagnosis of HIV infection was 250 cells/µL (range, 25 to 550 cells/µL).
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Discussion
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The main finding of this study was that in all patients at SFGH who developed symptomatic sarcoidosis in the context of HIV infection, the peripheral CD4+ lymphocyte count was > 200 cells/µL at the time of their clinical presentation with granulomatous inflammation. The second major finding of this study was that specific alternative causes of granulomatous inflammation were found in all HIV-infected patients with granulomatous inflammation and a peripheral CD4+ lymphocyte count of < 200 cells/µL in our series. The observation of a dependence of sarcoidosis on the peripheral CD4+ lymphocyte count is further strengthened by a comparison to all other reported cases of sarcoidosis developing in the context of HIV infection. In 89% of those cases (17 of 19 cases), the CD4+ lymphocyte count was > 100 cells/µL, and in 74% of cases (14 of 19 cases) the CD4+ lymphocyte count was > 200 cells/µL. These results are consistent with the hypothesis that circulating CD4+ lymphocytes are central to the development of the persistent granulomatous inflammation that characterizes sarcoidosis.2
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The clinical, radiographic, and pathologic features of sarcoidosis in the context of preexisting HIV infection were similar to the well-known features of sarcoidosis in non-HIV-infected individuals. Respiratory symptoms occurred in three of eight patients (38%), and constitutional complaints (ie, fevers, night sweats, or chills) were seen in half of the patients in the present case series. This is similar to the frequency of these manifestations in the absence of HIV infection.1
Interestingly, a similar clinical syndrome of constitutional complaints is occasionally observed as part of immune restoration (typically, in the setting of an underlying opportunistic infection) following the initiation of HAART.20
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The radiographic findings in our series included parenchymal nodules (typically, in a perilymphatic distribution), as well as hilar and mediastinal lymphadenopathy. Although adenopathy is well-known to be characteristic of sarcoidosis, parenchymal and subpleural nodules also are frequently noted. In fact, in a retrospective study of 15 patients with biopsy-proven sarcoidosis, Lynch and colleagues23
demonstrated nodules by high-resolution chest CT scan in 13 patients (87%) with sarcoidosis in the absence of HIV infection. Although no patients in that series showed ground-glass opacities by high-resolution chest CT scan, Haramati and coworkers,17
in a retrospective review of patients with sarcoidosis and HIV infection, have reported ground-glass opacities in 50% in addition to the finding of nodules and lymphadenopathy. Ground-glass opacities were not noted in our series.
The pathologic features of sarcoidosis in our series of patients with HIV infection were largely indistinguishable from the pathologic findings of well-formed, distinct, noncaseating granulomas observed in non-HIV-infected patients, although one patient (patient A) manifested relatively poorly formed granulomas. Interestingly, this patient also had the lowest CD4+ lymphocyte count at presentation. Conceivably, this may reflect the threshold of cellular immune function (as reflected by the CD4+ lymphocyte count) that is required by the host to manifest clinically apparent sarcoidosis.
Such CD4+ lymphocyte-dependent granulomatous inflammation also has been seen in animal models of another common granulomatous disease, tuberculosis. In this disease, the successful formation of granulomas is critical to controlling the pathogen. In fact, mice that lack CD4+ lymphocytes fail to develop such a protective granulomatous response to M tuberculosis infection and show increased mortality.24
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Similarly, in humans the CD4+ lymphocyte depletion of HIV infection also is associated with accelerated progression of M tuberculosis infection.26
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Our results further reinforce this concept that granuloma formation (in this case, in response to the as-yet-unidentified "sarcoid agent") is critically dependent on the maintenance of sufficient numbers of circulating CD4+ lymphocytes.
Certain methodological issues and limitations of this present study should be addressed. The first and major limitation of this study is its retrospective design. However, given the relative scarcity of patients with both diagnoses, a retrospective design was essential. The second limitation is that our inclusion criteria were quite rigorous in eliminating patients with prior granulomatous opportunistic infections, although others have included such patients in their series.17
In doing this, we may have reduced our ability to detect some patients with both resolved opportunistic infections and low CD4+ lymphocyte counts who subsequently developed sarcoidosis. However, we considered making a confident diagnosis of sarcoidosis in the setting of any prior infection with organisms known to cause granulomatous inflammation, such as fungi or atypical mycobacteria, to be impossible. Furthermore, and more importantly, our exclusion criteria would not have eliminated patients with a low CD4+ lymphocyte count who presented with granulomatous inflammation in whom all other causes were excluded by careful clinical and microbiological evaluation.
Notably, although our series suggested that a peripheral CD4+ lymphocyte count of > 200 cells/µL was necessary to develop sarcoidosis in the setting of HIV infection, five patients have been reported previously who apparently developed sarcoidosis at peripheral CD4+ lymphocyte counts of < 200 cells/µL, and fulfilled our inclusion and exclusion criteria (Table 4)
.10
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Of these patients, two in a single series had CD4+ lymphocyte counts of < 100 cells/µL (CD4+ lymphocyte counts of 25 and 60 cells/µL).17
Although the timing of these cell counts relative to the development of sarcoidosis is not clear from these reports, the results suggest that although preservation or restoration of a CD4+ lymphocyte count of > 200 cells/µL is observed in the majority of cases, and > 100 cells/µL in virtually all cases, there may still be occasional exceptions.
Nevertheless, our study, which is the largest series to date from a single hospital, when combined with others from the published literature strongly suggested that a higher level of cellular immune function is necessary for HIV-infected individuals to manifest granulomatous inflammation in response to the sarcoid agent (whether it is an endogenous or exogenous antigen) than is required to respond similarly to other agents such as mycobacteria or chronic infection. Interestingly, although SFGH has large populations of patients with either HIV infection or sarcoidosis, we were able to identify only a small number of patients with both diseases despite an exhaustive search. We believe that the infrequency with which these two otherwise common disorders actually coexist further emphasizes the centrality of a preserved immune response to the development of sarcoidosis.
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Footnotes
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Abbreviations: HAART = highly active antiretroviral therapy; SFGH = San Francisco General Hospital
This research was supported by National Heart, Lung, and Blood Institute grant K08 HL04465-01 (to DGM).
Received for publication November 22, 2002.
Accepted for publication February 18, 2003.
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J. Clin. Pathol.,
September 1, 2005;
58(9):
996 - 997.
[Abstract]
[Full Text]
[PDF]
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Abstract
Introduction
