INTRODUCTION

TOP ABSTRACT INTRODUCTION CASE REPORTS DISCUSSION REFERENCES

Highly active antiretroviral therapy (HAART) usually refers to the combination of an inhibitor of human immunodeficiency virus (HIV)-encoded protease in association with two nucleoside analog reverse transcriptase inhibitors (1). HAART has been shown to cause a profound and sustained suppression of viral replication, to reduce mortality, and to prolong life in patients with HIV infection (2, 3). According to current clinical guidelines HAART is recommended in most HIV-infected patients (1). Apart from reducing the viral load it also greatly increases the CD4 cell blood count. The origin and functions of these reappearing CD4 cells are still controversial. Studies performed on peripheral blood cells show a quantitative and qualitative immune restoration that may not be complete, or may be achieved only after a long period of time (4). HAART-induced immune recovery is in fact demonstrated by an increase in memory and naive T cells, an enhancement of lymphoproliferative responses with an increase in interleukin 2 (IL-2) receptor expression (CD25⁺), and a reduction in harmful cytokine plasma concentration, such as tumor necrosis factor (5, 6). On the other hand, dramatic improvement of opportunistic conditions, i.e., Kaposi's sarcoma (KS) (7), chronic intestinal cryptosporidiosis, and microsporidiosis (8) as well as exacerbation of latent infections, i.e., Mycobacterium avium-intracellulare (MAC) lymphadenitis (9), do suggest that a redistribution of memory T cells occurs rapidly in tissues, after institution of HAART. We report the occurrence of a newly diagnosed granulomatous pulmonary disorder mimicking sarcoidosis in two HIV-infected patients receiving HAART, which raises the question of its possible relationship with local lung immune restoration under such therapy.

	CASE REPORTS

TOP ABSTRACT INTRODUCTION CASE REPORTS DISCUSSION REFERENCES

Patient 1

A 45-yr-old homosexual white man presented, in June 1995, with a histologically proven mucocutaneous KS involving the lungs, revealing HIV seropositivity. The CD4 cell count at the time of diagnosis was 58/mm³. A purified protein derivative (PPD) test was negative despite BCG vaccine injection during childhood. The KS initially progressed in spite of chemotherapy with vinblastin (6 mg every 3 wk) and bleomycin (3 MU once a day, for 3 d every 3 wk). During this period, he received secondary Pneumocystis carinii pneumonia (PCP) prophylaxis with cotrimoxazole and antiretroviral therapy with zidovudine (250 mg twice a day) and didanosine (100 mg twice a day). In June 1996, new KS lesions were observed during bronchoscopic examination and bronchoalveolar lavage (BAL) analysis was normal (total cell count of 100,000/mm³, with 15 and 82% lymphocytes and macrophages, respectively). The CD4 cell count was 19/mm³ and the HIV RNA level was 17,000 copies/ml of plasma (Quantiplex HIV RNA branched DNA assay, lower limit of detection 500 copies/ml; Chiron, Emerville, CA). Antiretroviral therapy was changed to protease inhibitor-containing HAART (lamivudine, 150 mg twice a day; stavudine, 40 mg twice a day; and indinavir, 800 mg three times a day). In November 1996, chemotherapy was stopped after dramatic improvement in mucocutaneous and pulmonary KS. Chest X-ray and lung computed tomography (CT) scan were then considered normal.

In November 1997, routine physical examination was normal and KS was considered to be in complete remission. The CD4 cell count was 219/mm³ and the HIV RNA level was < 500 copies/ml. A chest X-ray, however, revealed diffuse interstitial micronodular lesions that were confirmed by CT scan (Figures 1A and 1B). There was no pleural effusion, and no mediastinal or hilar lymphadenopathy. There were no macroscopic KS lesions on bronchoscopy. BAL analysis showed a lymphocytic alveolitis (45% of total cells), mostly related to an increase in the CD4 cell subset (85% of lymphocytes) (Table 1). Bronchial biopsy (BB) and transbronchial biopsy (TBB) pathological findings revealed a well-formed noncaseating granuloma, located in the interstitium and bronchial mucosa. Special stainings performed on sputum, fibroaspiration, BAL, and tissue section specimens were negative for acid-fast bacilli, parasitic organisms, and fungi. Pulmonary tuberculosis was therefore first suspected, and a three-drug antituberculosis treatment regimen was initiated (isoniazid [300 mg], rifabutin [150 mg], and pyrazinamid [1,750 mg] once daily). Two months later, the patient presented a bilateral parotid gland enlargement. Cultures for mycobacteria, fungi, viral agents, and opportunistic bacteria performed on blood, sputum, fibroaspiration, BB, and TBB specimens remained negative, as was a PPD test. A second CT scan and a new bronchoscopy along with BAL, BB, and TBB did not show important changes. Immunostaining analysis of paraffin-embedded tissue sections demonstrated that the granuloma was predominantly infiltrated by T lymphocytes of the CD4 subset (Figure 2). A ⁶⁷Ga scan showed bilateral and strong gallium uptake in salivary glands. The serum angiotensin-converting enzyme (SACE) level was 2.5 times higher than the normal value. Sarcoid-like pulmonary disorder was then diagnosed and antituberculosis treatment was discontinued. Normal results of pulmonary function tests (PFTs) and absence of extrapulmonary life-threatening involvement did not indicate a need for steroids. At present, the patient remains asymptomatic regarding pulmonary disease and acquired immunodeficiency syndrome (AIDS), and HAART has been continued so far.

View larger version (126K): [in this window] [in a new window]   View larger version (127K): [in this window] [in a new window]   Figure 1.   Chest radiograph and CT scan from Patient 1 at the time of sarcoidosis diagnosis. (A) Chest radiograph, showing diffuse interstitial micronodular lesions; (B) CT scan, confirming the presence of micronodules with a diffuse and perilymphatic distribution.

View larger version (103K): [in this window] [in a new window]   Figure 2.   Histological findings of sarcoid granuloma from Patient 1. Left panel: typical aspect of noncaseating epithelioid and giant cell granuloma (hematein-eosin-safran staining; original magnification, ×200). Middle panel: CD4 expression of the T cells infiltrating the granuloma (Envision method [Dako, Trappes, France], using CD4 antibody from Novocastra [Tebu, Paris, France]; original magnification, ×200). Right panel: low CD8 expression of the T cells infiltrating the granuloma.

Patient 2

A 34-yr-old heavy-smoker white woman presented with an autoimmune thrombocytopenia purpura, revealing HIV seropositivity, in 1990. She had received a BCG vaccine during childhood and a PPD test was positive at initial evaluation of her HIV status. The CD4 cell count was 456/mm³. Thrombopenia rapidly resolved after zidovudine treatment (250 mg, three times a day), which was combined with zalcitabine (750 mg, three times a day) from September 1996 to October 1997. During this period, PCP and antituberculosis prophylaxies were not given and the patient remained asymptomatic. In October 1997, she was enrolled in a clinical trial of protease inhibitor-containing HAART (lamivudine, 150 mg twice a day; stavudine, 40 mg twice a day; and indinavir, 800 mg three times a day) associated with subcutaneous interleukin 2 (IL-2) immunotherapy (3.6 MU twice a day for 5 d, every month). At this time, the CD4 cell count was 275/mm³, the HIV RNA level was 3,500 copies/ml, and the chest X-ray was normal.

In January 1998, the third course of IL-2 was not performed because of the occurrence of weight loss and exertional dyspnea, without fever. On admission, physical examination showed a few basal crackles. The CD4 cell count was 318/mm³ and the HIV RNA level was < 500 copies/ml. A chest X-ray and lung CT scan showed diffuse interstitial micronodular lesions (Figures 3A and 3B). There was no pleural effusion, and no mediastinal or hilar lymphadenopathy. There was no macroscopic abnormality on bronchoscopy. BAL analysis showed a lymphocytic alveolitis (46% of total cells), mostly related to an increase in the CD4 cell subset (80% of lymphocytes) (Table 1). Special stainings performed on sputum, fibroaspiration, BAL, and tissue section specimens were negative for acid-fast bacilli, parasitic organisms, and fungi. BB and TBB pathological findings revealed a well-formed noncaseating granuloma, located in the interstitium and bronchial mucosa. On the basis of these findings, pulmonary tuberculosis was first suspected and a three-drug antituberculosis treatment regimen was initiated (isoniazid [300 mg], rifabutin [150 mg], and pyrazinamid [1,750 mg] once daily). Two months later, the patient had not improved. Cultures for mycobacteria, fungi, viral agents, and opportunistic bacteria performed on blood, sputum, fibroaspiration, BB, and TBB specimens remained negative. A ⁶⁷Ga scan showed bilateral gallium uptake in both lung fields and salivary glands. A second CT scan and a new bronchoscopy along with BAL, BB, and TBB did not show important changes. Immunostaining analysis of paraffin-embedded tissue sections demonstrated that the granuloma was infiltrated predominantly by T lymphocytes of the CD4 subset (data not shown). Moreover, a PPD test became negative and the SACE level was twice the normal value. Sarcoid-like pulmonary disorder was diagnosed and antituberculosis treatment was discontinued. PFTs showed a total lung capacity (TLC) of 3.56 L (76% of predicted value), an FVC of 2.38 L (73%), an FEV₁ of 1.65 L (58%)with a 17% reversibility after -agonist inhalationand a diffusing capacity for carbon monoxide (DL_CO) of 45% of the predicted value. Measurements of blood gases in room air were normal. Extrapulmonary evaluation did not reveal life-threatening involvement and oral steroids were not given. During the next 6-mo follow-up after IL-2 immunotherapy discontinuation, dyspnea progressively improved and PFTs normalized while a chest X-ray was unchanged. At present, the patient remains asymptomatic regarding pulmonary disease and AIDS, while HAART has been continued so far.

View larger version (153K): [in this window] [in a new window]   View larger version (117K): [in this window] [in a new window]   Figure 3.   Chest radiograph CT scan from Patient 2 at the time of diagnosis. (A) Chest radiograph, showing diffuse interstitial micronodular lesions with a predominant left upper lung distribution; (B) CT scan, showing diffuse micronodules with a perilymphatic distribution.

	DISCUSSION

TOP ABSTRACT INTRODUCTION CASE REPORTS DISCUSSION REFERENCES

These two patients presented with similar clinical characteristics strongly suggesting the occurrence of granulomatous pulmonary disorder mimicking sarcoidosis (10). Indeed, chest X-ray and lung CT-scan features were compatible with stage III sarcoidosis. BB and TBB revealed noncaseating granuloma. They had bilateral parotid gland enlargement (Case 1), extrapulmonary ⁶⁷Ga uptake, and an increase of SACE level (Cases 1 and 2). The patients did not have a history of causative exposure to environmental or therapeutic agents that could have induced a sarcoid-like reaction in the lung: e.g, beryllium, silica, talc, and methotrexate or BCG therapy (10). All causes of infectious diseases usually associated with noncaseating granuloma (10), such as mycobacterial, viral, parasitic, and fungal infections, were excluded by negative results of direct examination and long-term cultures performed on sputum, fibroaspiration, BAL fluid, and lung tissue specimens. Blood cultures for mycobacteria and fungi were also negative and a 2-mo antituberculosis treatment did not improve clinical and radiological abnormalities. Finally, the diagnosis of lymphocytic interstitial pneumonitis (LIP) was unlikely in our patients. Indeed, although diffuse interstitial pneumonitis with a positive gallium scan in the eyes and parotids could reveal LIP, LIP is always associated with a CD8-lymphocytic alveolitis and usually improves during antiretroviral therapy (11, 12).

Concomitant HIV infection and sarcoidosis have rarely been reported and may represent the occurrence of two independent conditions in the same patient (13). In the few reported cases, sarcoidosis was diagnosed before (4 mo to 20 yr) or at the same time as HIV infection. The immunodeficiency level at the time of HIV diagnosis was variable (CD4 cell count ranged from 4 to 900/mm³). Clinical and radiological presentation of sarcoidosis, in these previously reported cases, did not differ from those usually observed in non-HIV-infected patients. In a few cases, patients were also able to form a positive Kveim test (16). Some patients were asymptomatic (13, 14) whereas others had respiratory symptoms (15) or extrapulmonary involvement (15), sometimes requiring steroid therapy. The influence of immune deficiency and antiretroviral therapy on sarcoidosis evolution cannot be evaluated on the basis of these few case reports with a short-term follow-up. Our two cases differed strongly from those previously reported. Sarcoid-like pulmonary disorder occurred long after HIV diagnosis, i.e., 2.5 yr for the first case and 8 yr for the second case, under HAART. Furthermore, BAL cell analysis showed an intense CD4⁺ lymphocytic alveolitis (Table 1) whereas previous reports of HIV-associated sarcoidosis (15, 18) described a CD8⁺ lymphocytic alveolitis related to HIV infection itself (11).

HAART has an important effect on the natural history of AIDS. Some reports have described a dramatic improvement of AIDS-related conditions, i.e., Kaposi's sarcoma (7), as in our first patient, or chronic intestinal cryptosporidiosis and microsporidiosis (8). In contrast, others have reported an exacerbation of latent infections, probably related to an antigen-specific T cell response, induced by HAART and mediated by CD8⁺ cells (hepatitis B virus infection) (19) or CD4⁺ cells (mycobacterial infection) (9). In our two patients, the development of a pulmonary granulomatous reaction, after peripheral blood CD4⁺ cell recovery, could suggest a possible causative relationship between HAART introduction and the occurrence of a "sarcoid-like" process. The relationship between HAART introduction and exacerbation of another granulomatous disease, i.e., MAC infection, has in fact been previously described after HAART introduction (9). Moreover, the intense CD4⁺ lymphocytic alveolitis (with an increased proportion of cells of the CD25⁺ subtype) with a dramatic increase in the CD4/CD8 ratio, compared with the peripheral blood ratio (Table 1), as well as the CD4⁺ granulomatous infiltration shown on pathological sections (Figure 2), suggest that the recovered T cells may produce a local pulmonary effective immune response, leading to a sarcoid-like pulmonary disorder in our patients. On the other hand, the delay between HAART introduction and pulmonary manifestation in our cases (1.5 yr and 3 mo, respectively) is longer then that observed for the patients who suffered from lymph node granuloma inflammation associated with MAC infection (1 to 3 wk) (9). This suggests that the occurrence of sarcoid-like granuloma most probably involved naive and IL-2 receptor-positive CD4⁺ T cells rather than memory T cells, which have been thought to be implicated in MAC exacerbation (9). This hypothesis is supported by peripheral blood immune recovery kinetics previously described in patients treated by HAART. Indeed, recovery of naive or IL-2 receptor-positive CD4⁺ T cells is delayed from 3 to 6 mo after HAART introduction whereas memory T cell recovery appears with a delay of 3 wk (5, 6). The earlier occurrence of pulmonary manifestation in our second case may be related to a lesser immune deficiency at the time of HAART introduction or to the concomitant administration of IL-2, a cytokine that has been demonstrated to play a pivotal role in the pathophysiology of sarcoid lesions (20). In fact, the increase in CD4⁺ cells (Table 1), related to HAART, associated to their activation by IL-2 treatment may together have led to an earlier and more acute presentation in this patient. We cannot exclude an IL-2 therapy toxicity per se, but such complication has never been described. Moreover, the absence of chest X-ray improvement after IL-2 discontinuation suggests that IL-2 acts on granuloma formation rather like a triggering factor than as a causative factor.

In conclusion, the introduction of protease inhibitor-containing HAART could be responsible for the occurrence of sarcoid-like pulmonary disorder. Furthermore, this diagnosis should be considered in patients with pulmonary infiltrates occurring after immune recovery related to HAART. However, the exact frequency of such a complication needs to be evaluated further. The description of this particular manifestation may contribute to a better understanding of local immune reconstitution observed in HIV-infected patients receiving HAART.