Chronic granulomatous disease

Juliette L. Wohlrab, MD, C.A. Read, MD, A.E. O'Donnell, MD--Pulmonary and Critical Care Medicine, Georgetown University Medical Center, Washington, D. C., USA

Introduction. Highly active antiretroviral therapy (HAART) has become the standard of care for viral suppression and immune reconstitution in patients infected with the human immunodeficiency virus (HIV). It has been shown to induce immune recovery by increasing both naive and memory T cells. It also increases interleukin 2-receptor expression and decreases cytokine concentration. Granulomatous disorders, such as sarcoidosis, are characterized by proliferation of activated T helper 1 lymphocytes bearing the CD4 phenotype, which release inflammatory mediators such as interleukin 2, and interferon-[Gamma].

Case Series: Patient 1 is a 42 year old white male with HIV on therapy with Combivir, Delavirdine, and Saquinavir. His most recent CD4 count was 419/[mm.sup.3] and viral load 2476 copies/ml. He presented with a two week history of dyspnea, fever, and a nonproductive cough. Physical exam was significant for fever to 101.7 [degrees] F, a clear chest, and axillary lymphadenopathy. Cell count, chemistry and liver, including lactate dehydrogenase, panels were normal. Chest roentgenogram demonstrated bilateral interstitial infiltrates and a chest computed tomograph (CT) confirmed a micronodular interstitial pattern with upper lobe predominance. No evidence of pleural effusions or lymphadenopathy was seen. Purified protein derivative (PPD) was negative. Arterial blood gas (ABG) showed a pH 7.5, p[CO.sub.2] 21 mm Hg, p[O.sub.2] 111 mm Hg on room air. Pulmonary function tests (PFT's) demonstrated a decreased diffusion capacity (55%) without evidence for obstructive or restrictive disease. Bronchoalveolar lavage with transbronchial biopsies was performed. Noncaseating granulomas were seen on pathology. Cultures were negative for bacterial, fungal, and mycobacterial pathogens. Special stains were negative for pneumocystis. The patient was started on prednisone and had clinical and radiographic improvement with recrudescence when steroids were discontinued. Patient 2 is a 50 year old female with HIV on therapy with Lamivudine, Stavudine, and Nevirapine. Her latest CD4 count was 398/[mm.sup.3] and viral load of [is less than] 400 copies/ml. She also presented with dyspnea on exertion and a nonproductive cough. Physical exam and laboratories were unrevealing. PPD was negative. Room air ABG showed a pH 7.38, p[CO.sub.2] 40 mm Hg, p[O.sub.2] 77 mm Hg. Pulmonary function tests revealed a severe restrictive defect with a total lung capacity of 1.83 liters (34% predicted) with a diffusion capacity of 81%. Chest roentgenogram showed bilateral interstitial infiltrates and a CT scan confirmed an interstitial process with upper lobe predominance. Bronchoscopy was performed with transbroncnial biopsies, which again demonstrated noncaseating granulomas with no evidence for the above-mentioned infectious etiologies. Her symptoms also improved after the initiation of prednisone.

Discussion: The use of HAART has greatly improved prognosis in HIV positive patients with the of slowing disease progression by effectively suppressing viral replication and reducing susceptibility to opportunistic infections. It may, however, also allow a paradoxical susceptibility to diseases that are usually attenuated in the setting of HIV via an enhanced lymphoproliferative response. Sarcoidosis is unusual in patients with HIV. Several cases of the two co-existent diseases were reported in 1989 and 1992, but the sarcoidosis was either a pre-existent process or was diagnosed at the same time as the HIV. A review of the literature disclosed only a few case reports of the development of sarcoidosis in patients with known HIV after initiation of HAART. These cases include both pulmonary and skin involvement. Several cases have also been reported which describe exacerbation of latent infections such a mycobacterial disease, cytomegalovirus, and cryptococcus. Our two patients help support the recently observed "immune reconstitution syndrome" with the development of sarcoid-like pulmonary disease. Whether this truly represents the development of active sarcoidosis or if it is an idiosyncratic reaction to HAART remains yet to be determined. Bronchoscopy with transbronchial biopsies is important in the investigation of any patient with HIV and pulmonary symptoms, as the diagnosis would have been missed with bronchoalveolar lavage alone.

Conclusion: Two cases are presented that illustrate the development of sarcoid-like pulmonary disease in patients with HIV after the initiation of HAART and reconstitution of their immune systems. Highly active antiretroviral therapy has improved survival in patients with HIV, but it may also unmask diseases that are less common in the HIV population, such as sarcoidosis.

References

[1] Coots, LE, Lazarus, AA. Sarcoidosis Diagnosed in a patient with known HIV Infection. Chest 1989; 96:201-2.

[2] Dam Nielson, S et al. Highly Active Antiretroviral Therapy Normalizes the Function of Progenitor Cells in HIV infected Patients. J Infect Dis 1998; 178:1299-305.

[3] Mirmirani, P et al. Sarcoidosis in a patient with AIDS: a manifestation of immune restoration syndrome. J Am Acad Deem 1999; 41:285-6.

[4] Naccache, JM et al. Sarcoid-Like Pulmonary Disorder in HIV Infected Patients Receiving Antiretroviral Therapy. Am J Respir Crit Care Med 1999; 159:2009-13.

[5] Newman, TG et al. Coexistent Sarcoidosis and HIV Infection. Chest 1992; 102:1899-901.

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