Sarcoidosis Complicated by HIV Infection: Three Case Reports and a Review of the Literature"?
WILLIAM
s.
LOWERY, WARREN L. WHITLOCK, ROBERT A. DIETRICH, and JONATHAN M. FINE
Introduction
P resenting symptoms of sarcoidosis and HIV infection are similar. Developing HIV infection in a patient with sarcoidosis presents an immunologic paradox and a clinical dilemma. Whereas progression of HIV infection is characterized by a diminution of CD4+ lymphocyte counts, both in BAL and in peripheral blood, a hallmark of active sarcoidosis is the elevation of CD4 + lymphocyte counts in BAL, with normal or low peripheral blood lymphocyte counts. Clinical manifestations of these diseases overlap. In addition to sharing similar pulmonary symptoms, HIV and sarcoidosis also manifest similar immunologic features, including circulating lymphopenia, anergy, and a rise in gamma globulin levels. Data on the pulmonary aspects of both diseases, including bronchoalveolar lavage (BAL), is expanding; however, to date very little data exist on the interaction of these two diseases (1). Although corticosteroid therapy is used in AIDS-related pulmonary diseases (2, 3) and sarcoidosis, it may lead to precipitous complications in HIV-positivepersons (4), highlighting the importance of distinguishing between the two forms of alveolitis.
Case Reports Patient 1 A 37-yr-old homosexual white man was referred in June 1987 for evaluation of positive HIV serologic findings. His medical history included a diagnosis of Stage I sarcoidosis in 1977based on mediastinal lymph node biopsy findings. The patient displayed no symptoms of sarcoidosis on initial presentation and had received no therapy. Follow-up chest roentgenographic (CXR) findings in 1985were consistent with Stage I sarcoidosis and were unchanged from 1977. HIV-positive serology was detected on routine military screening in June 1987. Results of the patient's physical examination, at that time, were normal except for bilateral axillary lymphadenopathy. Laboratory evaluation revealed cutaneous anergy, a polyclonal gammopathy, and stable CXR findings. Pulmonary function tests (PFT) performed in June 1987 revealed a normal FVC of 4.62 L (89070 of predicted), a FEV 1 of 3.89 L (97070 of predicted), and a diffusion capacity for carbon monoxide (DLco) of 80070 of predicted. The patient presented 7 months later (February 1988) with increasing dyspnea on exertion and fatigue. Results of physical examination, CXR, and PFT were unchanged. He was referred for evaluation of HIV-related pulmonary disease versus progression of sarcoidosis. Staging workup revealed a peripheral white blood cell (WBC) count of 3.8 x 103/mm3 (total lymphocyte count, 1,100/mm 3 ) and a depressed concentration of CD4 + lymphocytes at 120/mm3 with a CD4 + ICD8 + ratio of
SUMMARY We report three cases of sarcoidosis complicated by human immunodeficiency virus (HIV) infection and review four other Isolated case reports In the literature. There is clinical overlap of both diseases, including symptoms, pulmonary function abnormalities, and lymphoCYtefunction. Bronchoalveolar lavage (BAL) in these patients showed a lymphoCYtic alveolltis without pathogens. BAL lymphoCYte subset analysis showed markedly depressed CD4 +/CDS + ratios in three patients. These data were clinically useful for distinguishing the CDS + alveolltis associated with HIV infection from the CD4 + alveolitis associated with sarcoidosis. Three patients improved with corticosteroid therapy. Two patients with BAL-documented COS + alveolitis tolerated discontinuation of steroids. One patient's sarcoidosis improved without therapy concurrent with the diagnosis of Kaposi's sarcoma. Another patient developed sarcoidosis 1 yr after manifesting HIV positive serology. BAL can be used to distinguish the lymphocytic alveolltis of sarcoidosis from that associated with HIV infection. Patients with active sarcoidosis complicated by HIV infection can be effectiveAM REV RESPIR DIS 1990; 142:887-889 ly treated with corticosteroid therapy.
0.49. Bronchoscopy with BAL was performed. BAL fluid showed 25070 lymphocytes with a CD4 + I CD8 + ratio of 0.34. Special stains and cultures for pathogens were negative. At 18 months, a repeat bronchoscopy with BAL showed 32070 lymphocytes with a CD4 + ICD8 + ratio of 0.28. The patient has received no specific therapy for a CD8 + alveolitis and has remained free of symptoms to date.
Patient 2 A 48-yr-old homosexual white man presented for evaluation of uveitis and interstitial infiltrates on CXR in February 1986. He had a history of Bell's palsy and a decrease in hearing acuity of the left ear in December 1985. Physical examination showed 1-to 2-cm cervical and axillary nodes and bilateral uveitis. Laboratory evaluation revealed a normocytic anemia, normal lymphocyte count, an angiotension-converting enzyme (ACE) level of25 lUlL (normal, 12 to 36), and a rise in polyclonal gamma globulin level to 4.7 gldl (normal, 1.9 to 3.4). An intermediate-strength tuberculin skin test (PPD) was not reactive. The PFT revealed a FVC of 4.1 L (83070), TLC of 6.8 L (93070), and a DLco of 73070 of predicted. The CXR findings were consistent with Stage III sarcoidosis. Bronchoscopy with transbronchial biopsy showed noncaseating granulomas. Special stains and cultures for pathogens were negative. After 1 month of prednisone therapy (40 mgl day), the patient had a partial resolution of lymphadenopathy and improvement in the pulmonary parenchymal infiltrates. His uveitis resolved completely. Repeat laboratory testing revealed an ACE level of 6 lUlL, a gamma globulin level of 3.5 gldl, and stable PFT and DLco. In February 1987, he presented with Kaposi's sarcoma and was found to be serologically positive for HIV. Three months later, the patient was reevaluated for dyspnea and increased interstitial infiltrates on CXR. He had received 15 mg of prednisone for worsening of hearing deficit on the left side, which was believed to be related to the sarcoidosis. Results of his physical examination and PFT were unchanged. Bronchoscopy with BAL showed a lymphocytosis of 21070 (CD4+/CD8+ ratio was not performed). Special stains and cultures again re-
vealed no pathogens, and the patient remained well. Corticosteroid therapy was tapered and discontinued. Evaluation in July 1988 showed spirometry and lung volumes to be unchanged; however, the DLcohad decreased to 56070 of predicted (concurrent with a 25070 decrease in the hemoglobin to 10.4g/dl). Serum gamma globulin levelwas 4.2 g/dl. Peripheral lymphocyte analysis revealed a CD4 + cell count of 187/mm3 and a CD4 + ICD8 + ratio of 0.10. Repeat CXR findings were unchanged. The patient has since been lost to follow-up.
Patient 3 A'37-yr-old bisexual black man was evaluated for cough and dyspnea in January 1986. Physical examination was notable only for tachypnea. CXR findings were consistent with Stage II sarcoidosis. Additional studies included an elevated alkaline phosphatase, a rise in polyclonal gamma globulin level of 7.7 g/dl (normal, 1.9 to 3.~), and a normal differential blood count. The PFT showed a TLC of 4.3 L (63070), a FVC of 2.4 L (50070), and a DLco of 106070 of predicted. A bronchoscopy with transbronchial biopsies revealed poorly formed granulomas with no pathogens by special stains or cultures. Mediastinoscopy with node biopsy showed noncaseating granulomas. Cultures of lymph node specimens were positive for HIV.
(Received in original form October 24, 1989 and in revised form March 22, 1990) 1 From the Pulmonary Disease Service, Presbyterian Medical Center, the Pulmonary Disease Service, Letterman Army Medical Center, and the Chest Service, San Francisco General Hospital, San Francisco, California. 2 The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army, the Department of Defense, or the U.S. Government. 3 Correspondence and requests for reprints should be addressed to William S. Lowery, M.D., Alameda Hospital, Alameda, CA 94501.
887
888
CASE REPORT
TABLE 1 SUMMARY OF NEW CASE REPORTS AND LITERATURE REVIEW Patient No.
Age (yr)
HIV Diagnosis
Sarcoidosis Diagnosis Race
Year
Tissue Site
Stage
Year
Method
BAL
Treatment
Outcome
1*
37
White
1977
Mediastinal lymph node
1987
Serology
CD8+
None
Stable PFT/CXR
2*
48
White
1986
Lung biopsy
III
1987
Serology KS
Lymphocytic alveolitis
Steroid taper, 1987
Improved TLC/CXR
3*
38
Black
1986
Mediastinal lymph node
II
1986
HIV culture
CD8 + alveolitis
Steroid taper, 1987 Periodic, 1988
Improved TLC/CXR Died PCP in 1988
4 (5)
35
Black
1970
Liver/bone marrow
NA
1978
CNS Toxo CMV
ND
NA
Died, no granuloma at autopsy
5 (6)
46
NA
1974
Lung biopsy
III
1985
Serology
ND
Steroids Thymostimulin
Improved symptoms and CXR
6 (7)
29
Black
1987
Lung and lymph node biopsy
1986
Serology
ND
None
Stable at 1 yr
7 (8)
40
NA
1966
Lung biopsy
1986
Serology KS
CD8 + alveolitis
None
Improved TLC, CXR, and SACE (spontaneous)
Definition of abbreviations: CXR = chest roentgenogram; KS = Kaposi's sarcoma; CMV = cytomeglovirus; Toxo = toxoplasmosis; CNS = central nervous system; NA not done; PFT = pulmonary function tests; Steroid = corticosteroid; PCP = Pneumocystis carinii; SACE = serum angiotensin-converting enzyme. * Patients reported in this Case Report; numbers in parentheses are reference numbers for patients discussed in the literature.
After a 2-month trial of prednisone therapy (40 mg/day), the patient improved symptomatically. His TLC increased to 5.11 L (670/0), accompanied by partial clearing of infiltrates on CXR. In August 1986, he developed increased cough and dyspnea. A staging workup revealed a peripheral WBC count of 8.3 x 103/mm3 (total lymphocyte count, 4,150/mm 3 ) and a CD4+ cell count of 388/mm3 with a CD4+/CD8+ ratio of 0.10. Bronchoscopy with BAL showed a lymphocytic alveolitis of 250/0 and lymphocyte subsets revealing a CD8 + cell count of 860/0 of total lymphocytes with a CD4 + / CD8 + ratio of 0.07. Special stains and cultures were negative for opportunistic infections. The patient remained stable. Corticosteroid tapering was recommended, but the patient remained on therapy against medical advice until October 1987 when he was weaned. Follow-upstudies in February 1988showeda TLC of 5.36 L (780/0) and a DLco of 950/0 of predicted. The CXR findings remained unchanged. In August 1988,he complained of increased dyspnea, and CXR showed diffuse infiltrates and persistent hilar lymphadenopathy. Gamma globin level was 3.9 g/dl. Diagnostic bronchoscopy with BAL revealed Pneumocystis carinii. Despite therapy he died of respiratory failure. No autopsy was performed. We have presented three new cases of welldocumented sarcoidosis complicated by HIV infection with BAL results and lymphocyte subset
analysis. Four other isolated cases are reported in the literature, with only one patient undergoing BAL with T-cell subset analysis (table 1) (5-8). All patients were homosexual or bisexual men. In four of seven of them, sarcoidosis was diagnosed at least 8 yr before HIV infection was documented. In one patient, sarcoidosis and HIV infection were diagnosed concurrently, and, in another, HIV infection was found 1 yr before the detection of sarcoidosis. The spectrum of HIV disease ranged from asymptomatic early HIV infection to advanced HIV infection (AIDS) as defined by Kaposi's sarcoma or opportunistic infections. Kaposi's sarcoma was the initial AIDS diagnosis in two patients. Five of the seven patients had documented low circulating CD4 + lymphocyte counts at the time of detecting HIV-positive serology (table 2). At some time, all but one patient presented with systemic and respiratory symptoms consistent with either sarcoidosis or HIV-associatedpulmonary disorders. Four patients underwent bronchoscopy with BAL that revealed a lymphocytic alveolitis. Two patients were treated with corticosteroid therapy, and later weaned, before their diagnosis of Kaposi's sarcoma and Pneumocystiscariniipneumonia. Six of the seven patients remained stable or showed partial resolution of their sarcoidosis as evidenced by results of PFT and CXR findings at the time of initial serologic detection of HIV infection. Two of the patients eventually died of AIDS com plica-
TABLE 2 PERIPHERAL BLOOD AND BAL LYMPHOCYTE STUDIES Peripheral
Bronchoalveolar Lavage
Patient No.
Total T-Cells
CD4+
CD8+
CD4+/CD8+
(mm 3 )
(mm 3 ) '
(mm 3 )
(ratio)
1 2 3 4 5 6 7 Normal subjects
1,100 NA 3,755 588 2,080 646 1,375 1,340-2,400
Definition of abbreviations: NA
=
120 245 189 1,900 388 3,800 4 194 788 767 ND ND 384 928 490-1,080 225-529 not available; NO
=
not done.
0.49 0.10 0.10 0.02 1.0 0.15 0.41 1.2-3.4
Lymphocytes CD8+ (%) (%) 25 21 25 ND ND 70 ND 7-12
75 ND 86 ND ND 100 ND 30
CD4+/CD8+ 0.34 ND 0.07 ND ND 0.001 ND 1.5-1.8
= not
available; NO
=
tions 12and 30 months after positive serologic detection of HIV. One patient showed spontaneous improvement in the TLC and CXR findings concurrent with the diagnosis of Kaposi's sarcoma. In three cases, the patients showed a rise in polyclonal gamma globin levels,and two later normalized their gamma globulin levelsbecause of either progression of HIV infection or resolution of the sarcoidosis. One patient continued to relapse with sarcoidosis, which responded to steroids and thymostimulin. Twoof our three patients weresymptomatic from their sarcoidosis, even after diagnosis of HIV infection, and were continued on corticosteroid therapy. Four patients had a lymphocytic alveolitis. Patient 7 had improvement in lung volumes and a decrease in both serum and BAL ACE levels concurrent with serologic detection of HIV infection. Three of the seven patients had a CD8 + alveolitis and greaterthan 750/0 total lymphocytes with CD4 + / CD8 + ratios ranging from 0.001 to 0.34. Patient 2 had a lymphocytic alveolitis, although the CD4 + /CD8 + ratio was not determined.
Discussion The incidence of sarcoidosis complicated by HIV infection is unknown. Given the proportionally higher incidence of both diseases in the black population in the United States, a significant overlap likely exists. The current prevalence of sarcoidosis in the United States is 5 per 100,000 for whites and 40 per 100,000 for blacks (9). A conservative estimate for early HIV infection (asymptomatic, seropositive) in the United States is 1.5 million (10). White adults account for 590/0 and black adults for 260/0 of advanced cases of HIV infection (AIDS) in the U.S. (10). If the proportion of AIDS cases to early HIV infection is constant, then overlap of early HIV-infected populations with sarcoidosis populations would yield a total of 45 whites and 150blacks with combined disease in the United States. This may account for the small number of cases that have currently been reported. False positive HIV serologic findings do not appear to be a problem in sarcoidosis (11). Alternatively, immunosuppression and the development of
889
CASE REPORT
opportunistic infections are not part of the pathogenesis of sarcoidosis. It has been speculated that in a subset of patients, immunoincompetence may predispose an individual to a yet undefined sarcoidosis agent; however, this speculation is not supported by the current numbers of patients with HIV infection (12). The presenting clinical and immunologic features are similar for both diseases. Systemic symptoms of fever, weight loss, fatigue, and respiratory symptoms are common. Cutaneous anergy, peripheral lymphopenia, and a rise in polyclonal gamma globulin level are characteristic for both. A depressed circulating CD4 + cell count, and variable rise in CD8 + cellcount are typical for both sarcoidosis and HIV infection (9, 13). The sequestration of CD4 + lymphocytes in the lungs and other sites is responsible for the peripheral quantitative defects in sarcoidosis (6). HIV-related depression of CD4 + lymphocyte function is due to a total reduction of this population and to qualitative defects (13). The clinical features of our three new cases and the four previously reported cases of sarcoidosis and HIV infection are summarized in table 1. Variable degrees of immunosuppression were exhibited, which complicated the differential diagnosis of the predominant disease. Routine clinical, laboratory, and pulmonary function data were not helpful in differentiating these diseases. Bronchoalveolar lavage has shown utility in the staging and diagnosis of both diseases. Flow cytometric analysis of lymphocyte subsets has been helpful in characterizing lymphocytic alveolitis with high CD4 + /CD8 + ratios (such as sarcoidosis and berylliosis) or low CD4+/CD8+ ratios (such as hypersensitivity pneumonitis) (1).BAL has been helpful in the staging of sarcoidosis into high- and low-intensity lymphocytic alveolitis to determine those patients who will require corticosteroid therapy (14, 15).Recently BAL studies in HIV-infected patients have defined a lymphocytic alveolitis with a CD8 + lymphocyte predominance. The intensity of this alveolitis may represent a spectrum of lung disorders from minimal lymphocytic infiltration to fulminant lymphoid interstitial pneumonitis (LIP) (16,17).Lymphocyticalveolitishas been found in early and in advanced HIV infection in as much as 70070 of patients without an opportunistic infection or associated malignancy. It may be asymptomatic, but it often is associated with respiratory symptoms (16). The accumulation of CD8 + lymphocytes within the lung in HIV alveolitis may represent either an in situ clonal proliferation or a migration of CD8 + lymphocytes in response to the infected alveolar cells (17).Our BAL data (table 2) show a lymphocytic alveolitis (CD8 + predominant) in each case, which is characteristic of HIV infection and not of sarcoidosis. These data allowed a treatment plan of careful observation rather than the initiation or continuation of corticosteroids. Although patients with CD8 + alveolitis and LIP do present with symptoms, PFT, and CXR abnormalities consistent with
interstitial lung disease, there is no clear consensus concerning the benefit of corticosteroids (3, 16, 18-21). Diseases traditionally requiring corticosteroid therapy complicated by HIV infection are reported in the literature (4, 22, 23). Nonetheless, corticosteroid therapy has led to precipitous and life-threatening opportunistic infections in some patients (4). Conclusions about the natural history and treatment strategies of sarcoidosis complicated by HIV infection are difficult. The CD4 + cell plays a central role in the initiation and maintenance of immune responses (24). Sarcoidosis has a tendency to improve spontaneously. An attractive theory is that selective destruction of CD4 + lymphocyte leads to spontaneous remission or stabilization of the sarcoidosis. One in vitro study demonstrated an increased susceptibility of the activated CD4+ lymphocyte, presumably through its surface receptors, to HIV infection (25). The natural history of sarcoidosis complicated by HIV infection may depend upon the number of activated CD4 + lymphocytes present. Active CD4 + lymphocytes present in the different stages of sarcoidosis may provide receptors for attachment by HIV and selective destruction of CD4 + lymphocytes. Other examples of CD4 + lymphocyte-modulated immune disease complicated by HIV infection with spontaneous remissions have been reported in the literature and include one case of Crohn's disease and two cases of systemic lupus erythematosus (22, 23). Complete remissions may not be possible because some CD4 + populations retain the ability to clonally expand in HIV infection (13). In all but one of the patients reported, the sarcoidosis remitted or remained quiescent. The decision to initiate corticosteroid therapy for active sarcoidosis may have long-term complications in the HIV-infected patient. Three of seven patients were treated with corticosteroid therapy without serious complications. One patient had a spontaneous improvement concurrent with HIV infection, and two others were able to be weaned from corticosteroid treatment as the HIV infection progressed. In sarcoidosis complicated by HIV infection, the decision to treat should reflect the type and activity of the alveolitis defined by BAL. Lack of a clear benefit for therapy of CD8 + alveolitis and evidence for potential infectious complications suggest corticosteroids should be reserved for patients with BAL-definedCD4+ high-intensity alveolitis. Sarcoidosis complicated by HIV is rare, but it is probably underreported. This diagnosis should be entertained in the workup of patients with HIV infection and intrathoracic lymphadenopathy. Diagnosis, staging, and management will require BAL with determination of lymphocyte subset populations. As with other CD4+ lymphocyte-modulated diseases, sarcoidosis may stabilize or even improve with HIV infection as a result of the progressive loss of activated CD4 + lymphocytes; however, corticosteroids may still be indicated for active sarcoidosis.
References 1. Reynolds HY. Bronchoalveolar lavage.Am Rev Respir Dis 1987; 135:250-63. 2. Montoner J. Acute respiratory failure secondary to Pneumocystis carinii pneumonia in the acquired immuno-deficiency syndrome: a potential role for corticosteroids. Chest 1989; 95:881-4. 3. Kornstein MJ, Pietra GG, Hoxie JA, Conley ME. The pathology and treatment of interstitial pneumonitis in two infants with AIDS. Am Rev Respir Dis 1986; 133:1196-8. 4. Shafer RW, Offit K, Macris NT, Horbar GM, Ancona L, Hoffman IR. Possible risk of steroid administration in patients at risk for AIDS. Lancet 1985; 1:934. 5. Kalter S. Acquired-immune deficiency syndrome in a patient with prior sarcoidosis. A case report with monocyte function studies. Tex Med 1985; 81:44-6. 6. Wurm K. Sarcoidosis complicated by HTLV II infection. Steroid therapy in combination with thymostimulin. Sarcoidosis 1987; 4:68-70. 7. Coots LE. Sarcoidosis diagnosed in a patient with known HIV infection. Chest 1989; 96:201-2. 8. Gormand F, Pacheco Y, Piperno D, et ale A case of sarcoidosis and AIDS association. Am Rev Respir Dis 1988; 137:425. 9. Thomas PD, Hunninghake GW. Current concepts of the pathogenesis of sarcoidosis. Am Rev Respir Dis 1987; 135:747-60. 10. Curran JW. The epidemiology of AIDS in the U.S. Sci Am 1988; 259:52-9. 11. Flint KC, Hudspith BN. Sarcoidosis is not associated with the HTLV-IIIvirus. Sarcoidosis 1985; 2:157. 12. Israel HL. Sarcoidosis, malignancy and immuno-suppressive therapy. Arch Intern Med 1978; 138:907-8. 13. Bowen DL, Lane HC, Fauci AS. Immunopathogenesis of the acquired immunodeficiency syndrome. Ann Intern Med 1985; 103:704-9. 14. Hollinger WM. Prediction of therapeutic response in steroid-treated pulmonary sarcoidosis. Am Rev Respir Dis 1985; 132:65-9. 15. Keogh BA. The alveolitis of pulmonary sarcoidosis. Am Rev Respir Dis 1983; 128:256-65. 16. Guillon JM, Autran B, Denis M, et ale Human immunodeficiency virus-related lymphocytic alveolitis. Chest 1988; 94:1264-322. 17. Agostini C. Human retrovirus and lung involvement. Am Rev Respir Dis 1989; 139:1317-22. 18. Morris JC, Rosen MJ, Marchevsky A, Teirstein AS. Lymphocyticinterstitial pneumonia in patients at risk for acquired immunodeficiency syndrome. Chest 1987; 91:63-7. 19. Solal-Celigny P, Couderc LJ, Herman D, et ale Lymphoid interstitial pneumonitis in acquired immunodeficiency syndrome-related complex. Am Rev Respir Dis 1985; 131:956-60. 20. Grieco MH, Chinoy-Acharya P. Lymphocytic interstitial pneumonia associated with the acquired immune deficiency syndrome. Am Rev Respir Dis 1985; 131:952-5. 21. Bach MC. Zidovudine for lymphocytic interstitial pneumonia associated with AIDS. Lancet 1987; 2:796. 22. James SP. Remission of Crohn's disease after human immunodeficiency virus infection. Gastroenterology 1988; 95:1667-9. 23. Furie R. SLE complicated by infection with HIV virus. Arthritis Rheum 1988; 31:556. 24. Behnken LS. Peripheral lymphocyte normal values, lymphocyte subpopulations. Drug Res 1985; 35:1311-6. 25. Gowda SD, Stein BS, Mohagheghapour N, Benike CJ, Engleman EJ. Evidence of T cell activation is required for HIV in CD4 + lymphocytes. J Immunol 1989; 142:773-80.
WILLIAM
s.
LOWERY, WARREN L. WHITLOCK, ROBERT A. DIETRICH, and JONATHAN M. FINE
Introduction
P resenting symptoms of sarcoidosis and HIV infection are similar. Developing HIV infection in a patient with sarcoidosis presents an immunologic paradox and a clinical dilemma. Whereas progression of HIV infection is characterized by a diminution of CD4+ lymphocyte counts, both in BAL and in peripheral blood, a hallmark of active sarcoidosis is the elevation of CD4 + lymphocyte counts in BAL, with normal or low peripheral blood lymphocyte counts. Clinical manifestations of these diseases overlap. In addition to sharing similar pulmonary symptoms, HIV and sarcoidosis also manifest similar immunologic features, including circulating lymphopenia, anergy, and a rise in gamma globulin levels. Data on the pulmonary aspects of both diseases, including bronchoalveolar lavage (BAL), is expanding; however, to date very little data exist on the interaction of these two diseases (1). Although corticosteroid therapy is used in AIDS-related pulmonary diseases (2, 3) and sarcoidosis, it may lead to precipitous complications in HIV-positivepersons (4), highlighting the importance of distinguishing between the two forms of alveolitis.
Case Reports Patient 1 A 37-yr-old homosexual white man was referred in June 1987 for evaluation of positive HIV serologic findings. His medical history included a diagnosis of Stage I sarcoidosis in 1977based on mediastinal lymph node biopsy findings. The patient displayed no symptoms of sarcoidosis on initial presentation and had received no therapy. Follow-up chest roentgenographic (CXR) findings in 1985were consistent with Stage I sarcoidosis and were unchanged from 1977. HIV-positive serology was detected on routine military screening in June 1987. Results of the patient's physical examination, at that time, were normal except for bilateral axillary lymphadenopathy. Laboratory evaluation revealed cutaneous anergy, a polyclonal gammopathy, and stable CXR findings. Pulmonary function tests (PFT) performed in June 1987 revealed a normal FVC of 4.62 L (89070 of predicted), a FEV 1 of 3.89 L (97070 of predicted), and a diffusion capacity for carbon monoxide (DLco) of 80070 of predicted. The patient presented 7 months later (February 1988) with increasing dyspnea on exertion and fatigue. Results of physical examination, CXR, and PFT were unchanged. He was referred for evaluation of HIV-related pulmonary disease versus progression of sarcoidosis. Staging workup revealed a peripheral white blood cell (WBC) count of 3.8 x 103/mm3 (total lymphocyte count, 1,100/mm 3 ) and a depressed concentration of CD4 + lymphocytes at 120/mm3 with a CD4 + ICD8 + ratio of
SUMMARY We report three cases of sarcoidosis complicated by human immunodeficiency virus (HIV) infection and review four other Isolated case reports In the literature. There is clinical overlap of both diseases, including symptoms, pulmonary function abnormalities, and lymphoCYtefunction. Bronchoalveolar lavage (BAL) in these patients showed a lymphoCYtic alveolltis without pathogens. BAL lymphoCYte subset analysis showed markedly depressed CD4 +/CDS + ratios in three patients. These data were clinically useful for distinguishing the CDS + alveolltis associated with HIV infection from the CD4 + alveolitis associated with sarcoidosis. Three patients improved with corticosteroid therapy. Two patients with BAL-documented COS + alveolitis tolerated discontinuation of steroids. One patient's sarcoidosis improved without therapy concurrent with the diagnosis of Kaposi's sarcoma. Another patient developed sarcoidosis 1 yr after manifesting HIV positive serology. BAL can be used to distinguish the lymphocytic alveolltis of sarcoidosis from that associated with HIV infection. Patients with active sarcoidosis complicated by HIV infection can be effectiveAM REV RESPIR DIS 1990; 142:887-889 ly treated with corticosteroid therapy.
0.49. Bronchoscopy with BAL was performed. BAL fluid showed 25070 lymphocytes with a CD4 + I CD8 + ratio of 0.34. Special stains and cultures for pathogens were negative. At 18 months, a repeat bronchoscopy with BAL showed 32070 lymphocytes with a CD4 + ICD8 + ratio of 0.28. The patient has received no specific therapy for a CD8 + alveolitis and has remained free of symptoms to date.
Patient 2 A 48-yr-old homosexual white man presented for evaluation of uveitis and interstitial infiltrates on CXR in February 1986. He had a history of Bell's palsy and a decrease in hearing acuity of the left ear in December 1985. Physical examination showed 1-to 2-cm cervical and axillary nodes and bilateral uveitis. Laboratory evaluation revealed a normocytic anemia, normal lymphocyte count, an angiotension-converting enzyme (ACE) level of25 lUlL (normal, 12 to 36), and a rise in polyclonal gamma globulin level to 4.7 gldl (normal, 1.9 to 3.4). An intermediate-strength tuberculin skin test (PPD) was not reactive. The PFT revealed a FVC of 4.1 L (83070), TLC of 6.8 L (93070), and a DLco of 73070 of predicted. The CXR findings were consistent with Stage III sarcoidosis. Bronchoscopy with transbronchial biopsy showed noncaseating granulomas. Special stains and cultures for pathogens were negative. After 1 month of prednisone therapy (40 mgl day), the patient had a partial resolution of lymphadenopathy and improvement in the pulmonary parenchymal infiltrates. His uveitis resolved completely. Repeat laboratory testing revealed an ACE level of 6 lUlL, a gamma globulin level of 3.5 gldl, and stable PFT and DLco. In February 1987, he presented with Kaposi's sarcoma and was found to be serologically positive for HIV. Three months later, the patient was reevaluated for dyspnea and increased interstitial infiltrates on CXR. He had received 15 mg of prednisone for worsening of hearing deficit on the left side, which was believed to be related to the sarcoidosis. Results of his physical examination and PFT were unchanged. Bronchoscopy with BAL showed a lymphocytosis of 21070 (CD4+/CD8+ ratio was not performed). Special stains and cultures again re-
vealed no pathogens, and the patient remained well. Corticosteroid therapy was tapered and discontinued. Evaluation in July 1988 showed spirometry and lung volumes to be unchanged; however, the DLcohad decreased to 56070 of predicted (concurrent with a 25070 decrease in the hemoglobin to 10.4g/dl). Serum gamma globulin levelwas 4.2 g/dl. Peripheral lymphocyte analysis revealed a CD4 + cell count of 187/mm3 and a CD4 + ICD8 + ratio of 0.10. Repeat CXR findings were unchanged. The patient has since been lost to follow-up.
Patient 3 A'37-yr-old bisexual black man was evaluated for cough and dyspnea in January 1986. Physical examination was notable only for tachypnea. CXR findings were consistent with Stage II sarcoidosis. Additional studies included an elevated alkaline phosphatase, a rise in polyclonal gamma globulin level of 7.7 g/dl (normal, 1.9 to 3.~), and a normal differential blood count. The PFT showed a TLC of 4.3 L (63070), a FVC of 2.4 L (50070), and a DLco of 106070 of predicted. A bronchoscopy with transbronchial biopsies revealed poorly formed granulomas with no pathogens by special stains or cultures. Mediastinoscopy with node biopsy showed noncaseating granulomas. Cultures of lymph node specimens were positive for HIV.
(Received in original form October 24, 1989 and in revised form March 22, 1990) 1 From the Pulmonary Disease Service, Presbyterian Medical Center, the Pulmonary Disease Service, Letterman Army Medical Center, and the Chest Service, San Francisco General Hospital, San Francisco, California. 2 The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army, the Department of Defense, or the U.S. Government. 3 Correspondence and requests for reprints should be addressed to William S. Lowery, M.D., Alameda Hospital, Alameda, CA 94501.
887
888
CASE REPORT
TABLE 1 SUMMARY OF NEW CASE REPORTS AND LITERATURE REVIEW Patient No.
Age (yr)
HIV Diagnosis
Sarcoidosis Diagnosis Race
Year
Tissue Site
Stage
Year
Method
BAL
Treatment
Outcome
1*
37
White
1977
Mediastinal lymph node
1987
Serology
CD8+
None
Stable PFT/CXR
2*
48
White
1986
Lung biopsy
III
1987
Serology KS
Lymphocytic alveolitis
Steroid taper, 1987
Improved TLC/CXR
3*
38
Black
1986
Mediastinal lymph node
II
1986
HIV culture
CD8 + alveolitis
Steroid taper, 1987 Periodic, 1988
Improved TLC/CXR Died PCP in 1988
4 (5)
35
Black
1970
Liver/bone marrow
NA
1978
CNS Toxo CMV
ND
NA
Died, no granuloma at autopsy
5 (6)
46
NA
1974
Lung biopsy
III
1985
Serology
ND
Steroids Thymostimulin
Improved symptoms and CXR
6 (7)
29
Black
1987
Lung and lymph node biopsy
1986
Serology
ND
None
Stable at 1 yr
7 (8)
40
NA
1966
Lung biopsy
1986
Serology KS
CD8 + alveolitis
None
Improved TLC, CXR, and SACE (spontaneous)
Definition of abbreviations: CXR = chest roentgenogram; KS = Kaposi's sarcoma; CMV = cytomeglovirus; Toxo = toxoplasmosis; CNS = central nervous system; NA not done; PFT = pulmonary function tests; Steroid = corticosteroid; PCP = Pneumocystis carinii; SACE = serum angiotensin-converting enzyme. * Patients reported in this Case Report; numbers in parentheses are reference numbers for patients discussed in the literature.
After a 2-month trial of prednisone therapy (40 mg/day), the patient improved symptomatically. His TLC increased to 5.11 L (670/0), accompanied by partial clearing of infiltrates on CXR. In August 1986, he developed increased cough and dyspnea. A staging workup revealed a peripheral WBC count of 8.3 x 103/mm3 (total lymphocyte count, 4,150/mm 3 ) and a CD4+ cell count of 388/mm3 with a CD4+/CD8+ ratio of 0.10. Bronchoscopy with BAL showed a lymphocytic alveolitis of 250/0 and lymphocyte subsets revealing a CD8 + cell count of 860/0 of total lymphocytes with a CD4 + / CD8 + ratio of 0.07. Special stains and cultures were negative for opportunistic infections. The patient remained stable. Corticosteroid tapering was recommended, but the patient remained on therapy against medical advice until October 1987 when he was weaned. Follow-upstudies in February 1988showeda TLC of 5.36 L (780/0) and a DLco of 950/0 of predicted. The CXR findings remained unchanged. In August 1988,he complained of increased dyspnea, and CXR showed diffuse infiltrates and persistent hilar lymphadenopathy. Gamma globin level was 3.9 g/dl. Diagnostic bronchoscopy with BAL revealed Pneumocystis carinii. Despite therapy he died of respiratory failure. No autopsy was performed. We have presented three new cases of welldocumented sarcoidosis complicated by HIV infection with BAL results and lymphocyte subset
analysis. Four other isolated cases are reported in the literature, with only one patient undergoing BAL with T-cell subset analysis (table 1) (5-8). All patients were homosexual or bisexual men. In four of seven of them, sarcoidosis was diagnosed at least 8 yr before HIV infection was documented. In one patient, sarcoidosis and HIV infection were diagnosed concurrently, and, in another, HIV infection was found 1 yr before the detection of sarcoidosis. The spectrum of HIV disease ranged from asymptomatic early HIV infection to advanced HIV infection (AIDS) as defined by Kaposi's sarcoma or opportunistic infections. Kaposi's sarcoma was the initial AIDS diagnosis in two patients. Five of the seven patients had documented low circulating CD4 + lymphocyte counts at the time of detecting HIV-positive serology (table 2). At some time, all but one patient presented with systemic and respiratory symptoms consistent with either sarcoidosis or HIV-associatedpulmonary disorders. Four patients underwent bronchoscopy with BAL that revealed a lymphocytic alveolitis. Two patients were treated with corticosteroid therapy, and later weaned, before their diagnosis of Kaposi's sarcoma and Pneumocystiscariniipneumonia. Six of the seven patients remained stable or showed partial resolution of their sarcoidosis as evidenced by results of PFT and CXR findings at the time of initial serologic detection of HIV infection. Two of the patients eventually died of AIDS com plica-
TABLE 2 PERIPHERAL BLOOD AND BAL LYMPHOCYTE STUDIES Peripheral
Bronchoalveolar Lavage
Patient No.
Total T-Cells
CD4+
CD8+
CD4+/CD8+
(mm 3 )
(mm 3 ) '
(mm 3 )
(ratio)
1 2 3 4 5 6 7 Normal subjects
1,100 NA 3,755 588 2,080 646 1,375 1,340-2,400
Definition of abbreviations: NA
=
120 245 189 1,900 388 3,800 4 194 788 767 ND ND 384 928 490-1,080 225-529 not available; NO
=
not done.
0.49 0.10 0.10 0.02 1.0 0.15 0.41 1.2-3.4
Lymphocytes CD8+ (%) (%) 25 21 25 ND ND 70 ND 7-12
75 ND 86 ND ND 100 ND 30
CD4+/CD8+ 0.34 ND 0.07 ND ND 0.001 ND 1.5-1.8
= not
available; NO
=
tions 12and 30 months after positive serologic detection of HIV. One patient showed spontaneous improvement in the TLC and CXR findings concurrent with the diagnosis of Kaposi's sarcoma. In three cases, the patients showed a rise in polyclonal gamma globin levels,and two later normalized their gamma globulin levelsbecause of either progression of HIV infection or resolution of the sarcoidosis. One patient continued to relapse with sarcoidosis, which responded to steroids and thymostimulin. Twoof our three patients weresymptomatic from their sarcoidosis, even after diagnosis of HIV infection, and were continued on corticosteroid therapy. Four patients had a lymphocytic alveolitis. Patient 7 had improvement in lung volumes and a decrease in both serum and BAL ACE levels concurrent with serologic detection of HIV infection. Three of the seven patients had a CD8 + alveolitis and greaterthan 750/0 total lymphocytes with CD4 + / CD8 + ratios ranging from 0.001 to 0.34. Patient 2 had a lymphocytic alveolitis, although the CD4 + /CD8 + ratio was not determined.
Discussion The incidence of sarcoidosis complicated by HIV infection is unknown. Given the proportionally higher incidence of both diseases in the black population in the United States, a significant overlap likely exists. The current prevalence of sarcoidosis in the United States is 5 per 100,000 for whites and 40 per 100,000 for blacks (9). A conservative estimate for early HIV infection (asymptomatic, seropositive) in the United States is 1.5 million (10). White adults account for 590/0 and black adults for 260/0 of advanced cases of HIV infection (AIDS) in the U.S. (10). If the proportion of AIDS cases to early HIV infection is constant, then overlap of early HIV-infected populations with sarcoidosis populations would yield a total of 45 whites and 150blacks with combined disease in the United States. This may account for the small number of cases that have currently been reported. False positive HIV serologic findings do not appear to be a problem in sarcoidosis (11). Alternatively, immunosuppression and the development of
889
CASE REPORT
opportunistic infections are not part of the pathogenesis of sarcoidosis. It has been speculated that in a subset of patients, immunoincompetence may predispose an individual to a yet undefined sarcoidosis agent; however, this speculation is not supported by the current numbers of patients with HIV infection (12). The presenting clinical and immunologic features are similar for both diseases. Systemic symptoms of fever, weight loss, fatigue, and respiratory symptoms are common. Cutaneous anergy, peripheral lymphopenia, and a rise in polyclonal gamma globulin level are characteristic for both. A depressed circulating CD4 + cell count, and variable rise in CD8 + cellcount are typical for both sarcoidosis and HIV infection (9, 13). The sequestration of CD4 + lymphocytes in the lungs and other sites is responsible for the peripheral quantitative defects in sarcoidosis (6). HIV-related depression of CD4 + lymphocyte function is due to a total reduction of this population and to qualitative defects (13). The clinical features of our three new cases and the four previously reported cases of sarcoidosis and HIV infection are summarized in table 1. Variable degrees of immunosuppression were exhibited, which complicated the differential diagnosis of the predominant disease. Routine clinical, laboratory, and pulmonary function data were not helpful in differentiating these diseases. Bronchoalveolar lavage has shown utility in the staging and diagnosis of both diseases. Flow cytometric analysis of lymphocyte subsets has been helpful in characterizing lymphocytic alveolitis with high CD4 + /CD8 + ratios (such as sarcoidosis and berylliosis) or low CD4+/CD8+ ratios (such as hypersensitivity pneumonitis) (1).BAL has been helpful in the staging of sarcoidosis into high- and low-intensity lymphocytic alveolitis to determine those patients who will require corticosteroid therapy (14, 15).Recently BAL studies in HIV-infected patients have defined a lymphocytic alveolitis with a CD8 + lymphocyte predominance. The intensity of this alveolitis may represent a spectrum of lung disorders from minimal lymphocytic infiltration to fulminant lymphoid interstitial pneumonitis (LIP) (16,17).Lymphocyticalveolitishas been found in early and in advanced HIV infection in as much as 70070 of patients without an opportunistic infection or associated malignancy. It may be asymptomatic, but it often is associated with respiratory symptoms (16). The accumulation of CD8 + lymphocytes within the lung in HIV alveolitis may represent either an in situ clonal proliferation or a migration of CD8 + lymphocytes in response to the infected alveolar cells (17).Our BAL data (table 2) show a lymphocytic alveolitis (CD8 + predominant) in each case, which is characteristic of HIV infection and not of sarcoidosis. These data allowed a treatment plan of careful observation rather than the initiation or continuation of corticosteroids. Although patients with CD8 + alveolitis and LIP do present with symptoms, PFT, and CXR abnormalities consistent with
interstitial lung disease, there is no clear consensus concerning the benefit of corticosteroids (3, 16, 18-21). Diseases traditionally requiring corticosteroid therapy complicated by HIV infection are reported in the literature (4, 22, 23). Nonetheless, corticosteroid therapy has led to precipitous and life-threatening opportunistic infections in some patients (4). Conclusions about the natural history and treatment strategies of sarcoidosis complicated by HIV infection are difficult. The CD4 + cell plays a central role in the initiation and maintenance of immune responses (24). Sarcoidosis has a tendency to improve spontaneously. An attractive theory is that selective destruction of CD4 + lymphocyte leads to spontaneous remission or stabilization of the sarcoidosis. One in vitro study demonstrated an increased susceptibility of the activated CD4+ lymphocyte, presumably through its surface receptors, to HIV infection (25). The natural history of sarcoidosis complicated by HIV infection may depend upon the number of activated CD4 + lymphocytes present. Active CD4 + lymphocytes present in the different stages of sarcoidosis may provide receptors for attachment by HIV and selective destruction of CD4 + lymphocytes. Other examples of CD4 + lymphocyte-modulated immune disease complicated by HIV infection with spontaneous remissions have been reported in the literature and include one case of Crohn's disease and two cases of systemic lupus erythematosus (22, 23). Complete remissions may not be possible because some CD4 + populations retain the ability to clonally expand in HIV infection (13). In all but one of the patients reported, the sarcoidosis remitted or remained quiescent. The decision to initiate corticosteroid therapy for active sarcoidosis may have long-term complications in the HIV-infected patient. Three of seven patients were treated with corticosteroid therapy without serious complications. One patient had a spontaneous improvement concurrent with HIV infection, and two others were able to be weaned from corticosteroid treatment as the HIV infection progressed. In sarcoidosis complicated by HIV infection, the decision to treat should reflect the type and activity of the alveolitis defined by BAL. Lack of a clear benefit for therapy of CD8 + alveolitis and evidence for potential infectious complications suggest corticosteroids should be reserved for patients with BAL-definedCD4+ high-intensity alveolitis. Sarcoidosis complicated by HIV is rare, but it is probably underreported. This diagnosis should be entertained in the workup of patients with HIV infection and intrathoracic lymphadenopathy. Diagnosis, staging, and management will require BAL with determination of lymphocyte subset populations. As with other CD4+ lymphocyte-modulated diseases, sarcoidosis may stabilize or even improve with HIV infection as a result of the progressive loss of activated CD4 + lymphocytes; however, corticosteroids may still be indicated for active sarcoidosis.
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