American Journal of Respiratory and Critical Care Medicine

Cases of paradoxical worsening of opportunistic infections shortly after the beginning of highly active antiretroviral therapy (HAART) prompted questions on the optimal timing of introduction of HAART in patients with inaugural AIDS-related opportunistic infections. We describe three cases of acute respiratory failure after early introduction of HAART in patients treated for Pneumocystis carinii pneumonia (PCP). The three patients had severe PCP that initially improved with anti-PCP and adjunctive steroid therapy. HAART was introduced 1 to 16 d after diagnosis of PCP, and steroids were stopped on Day 15. Seven to 17 d after HAART introduction, the three patients developed a second episode of severe acute respiratory failure with high-grade fever and patchy alveolar opacities on the chest roentgenogram. PCP resistant to cotrimoxazole, pulmonary superinfection, and drug-related pneumonitis were suspected but subsequently ruled out. Bronchoalveolar lavage and lung pathologic findings showed severe nonspecific pulmonary inflammatory foci surrounding a few persistent P. carinii cysts. All three patients recovered after HAART interruption or steroid reintroduction. We conclude that acute respiratory failure can recur after initiation of antiretroviral therapy in patients being treated for severe PCP. This phenomenon could result from rapid pulmonary recruitment of fully competent immune and inflammatory cells responding to a few persistent P. carinii cysts. A short course of steroid therapy may suppress this reaction.

Keywords: parodoxical worsening; HAART; Pneumocystis carinii pneumonia

Pneumocystis carinii pneumonia (PCP) was rapidly recognized as the most frequent and severe respiratory infection in human immunodeficiency virus (HIV)-infected patients. In the mid-1990s, PCP remained the first manifestation of acquired immunodeficiency syndrome (AIDS) in more than 15% of cases, with a 20% mortality rate at 3 mo despite effective PCP prophylaxis and adjunctive steroid therapy for patients with mild to severe hypoxemia (1). The recent advent of highly active antiretroviral therapy (HAART) has resulted in a marked decrease in the incidence and mortality of opportunistic infections. However, cases of paradoxical worsening of opportunistic infections shortly after the beginning of HAART prompted questions on the optimal timing of introduction of HAART in patients with inaugural AIDS-related opportunistic infections (2). We describe three cases of acute respiratory failure that recurred after early introduction of HAART during treatment of severe PCP.

Case 1

On January 21, 1997, a 37-yr-old man was admitted with severe (PaO2 = 59 mm Hg) PCP revealing HIV infection (Figure 1A). Chest radiograph showed diffuse granular opacities (Figure 2A). The CD4+ lymphocyte count was 7/mm3 and the plasma viral load 140,000 copies/ml. He improved on parenteral cotrimoxazole and methylprednisolone. On February 6, the PaO2 and chest radiograph were normal (Figure 2B); steroids were withdrawn, cotrimoxazole was given orally, and HAART (zidovudine, lamivudine, and indinavir) was introduced.

Eleven days later, he developed acute respiratory failure with high-grade fever. Chest radiograph examination disclosed patchy alveolar opacities in the two upper lobes (Figure 2C). The PaO2 was 69 mm Hg. Bronchoscopy with protected brushing, bronchoalveolar lavage (BAL), and bronchial and transbronchial biopsies were performed. Cytologic analysis of BAL fluid (BALF) showed 900,000 cells/ml, comprising 30% alveolar macrophages (0% siderophages), 59% lymphocytes, and 11% neutrophils. A few P. carinii cysts persisted, together with cytomegalovirus (CMV) inclusion cells. Microbiologic tests of respiratory, blood, and urinary specimens were negative, except for one blood sample and one BAL sample that yielded CMV. Bronchial and transbronchial biopsies showed no CMV inclusions in alveolar or endothelial cells. Other laboratory tests were normal. The CD4+ cell count was 38/mm3, and viral load was undetectable. Despite the absence of documented bacterial infection, the patient was treated with imipenem and amikacin with no improvement. Similarly, despite the absence of CMV retinitis or colitis, a 21-d course of foscavir was also given. On February 26, cotrimoxazole was continued at a prophylaxis dose and HAART was interrupted because of the elevation of serum transaminases. Surgical lung biopsy was performed on March 7 because of the persistence of fever and radiologic abnormalities, despite a partial improvement in respiratory function. Macroscopically, there was an inflammatory condensation of the right upper lobe. Histologic examination showed lesions of organizing pneumonia with alveolar necrosis and marked macrophage, neutrophil, lymphocyte, and plasma cell infiltration (Figures 3A through 3C). Almost all lung-infiltrating lymphocytes were of the T lineage as assessed by immunophenotyping (Figure 3D). By contrast to the low peripheral blood CD4/CD8 ratio (0.3), CD4 and CD8 lymphocyte subsets were equally represented in the lung tissue section (Figures 3E and 3F) There were no CMV inclusion cells. All tests for infectious agents were negative. The patient gradually became afebrile, and the X-ray films improved. HAART was reintroduced on March 9 with no further complications.

Case 2

On January 13, 1998, a 47-yr-old man was admitted with severe (PaO2 = 69 mm Hg) PCP revealing HIV infection (Figure 1B). The chest radiograph showed diffuse granular opacities. The CD4+ lymphocyte count was 28/mm3 and the plasma viral load 100,000 copies/ml. He received parenteral treatment with cotrimoxazole and methylprednisolone. On January 14, HAART was started with viramune, stavudine, and didanosine. On January 26, cotrimoxazole was stopped and replaced by aerosolized pentamidine because of a skin rash. His clinical and radiologic condition normalized, and steroids were stopped after 15 d of treatment.

Seventeen days after initiation of HAART he developed acute respiratory failure with high-grade fever. The chest radiograph showed diffuse alveolar opacities. He was intubated and mechanically ventilated. Bronchoscopy with protected brushing, BAL, and bronchial and transbronchial biopsies were performed. Cytologic analysis of BALF showed 990,000 cell/ml, with 10% alveolar macrophages, 80% lymphocytes, and 10% neutrophils. All tests for infectious agents in respiratory, blood, and urinary specimens were negative. Transbronchial biopsies showed an alveolar inflammatory infiltrate composed of lymphocytes, macrophages, and neutrophils, with a few persistent P. carinii cysts. Echocardiography was normal. Other laboratory tests were normal. The CD4+ lymphocyte count was 50/mm3 and the plasma viral load 33,000 copies/ml. Despite the absence of documented bacterial infection, the patient was treated with ceftriaxone, ofloxacin, and amikacin, without improvement. As the respiratory distress persisted and pulmonary pathologic findings showed a histologic pattern of organizing pneumonia in the absence of demonstrable infection, methylprednisolone was introduced, and HAART was interrupted. The patient gradually improved and was extubated on February 21. HAART was reintroduced with no further complications.

Case 3

On October 26, 1999, a 50-yr-old woman was admitted with severe PCP (PaO2 = 32 mm Hg) revealing HIV infection (Figure 1C). The chest X-ray film showed diffuse granular opacities. The CD4+ lymphocyte count was 230/mm3 and the plasma viral load 565,000 copies/ml. She received treatment with parenteral cotrimoxazole and methylprednisolone. A transient rash occurred but did not necessitate cotrimoxazole withdrawal. Her clinical condition improved. On November 12, 1999, the PaO2 and chest radiograph were normal. Methylprednisolone was withdrawn, cotrimoxazole was given orally, and HAART was introduced (zidovudine, lamivudine, and indinavir).

One week later, the patient developed acute respiratory failure with high-grade fever. The chest radiograph showed patchy alveolar opacities of the two upper lobes. The PaO2 was 50 mm Hg. Bronchoscopy with protected brushing, BAL, and bronchial and transbronchial biopsies were performed. Cytologic analysis of BALF showed 530,000 cell/ml, with 70% alveolar macrophages, 21% lymphocytes, 3% neutrophils, 6.5% eosinophils, and 0.5% basophils and a few persistent P. carinii cysts. All tests for infectious agents in respiratory, blood, and urinary specimens were negative. Bronchial and transbronchial biopsies showed an intense inflammatory infiltrate composed of lymphocytes, plasma cells, and macrophages. Despite the absence of documented bacterial infection, the patient was treated with ceftriaxone and ofloxacin, without improvement. Although there was no new cutaneous rash or hematologic, hepatic, or renal abnormalities, cotrimoxazole was replaced by atovaquone and aerosolized pentamidine, and steroids were reintroduced. On December 7, when the patient's clinical status had markedly improved, all medications except HAART were withdrawn. Cotrimoxazole was subsequently reintroduced with no adverse effects. The CD4+ lymphocyte count was 564/mm3 and the plasma viral load 1,386 copies/ml.

Between April 1996 and April 2000, 65 cases of PCP were diagnosed in our institution. The patients were treated with cotrimoxazole (or aerosolized pentamidine in case of documented allergy to sulfa drugs) for 21 d. Two-thirds of patients also required adjunctive steroid therapy because of mild to severe hypoxemia. In three cases, an acute respiratory failure after early introduction of HAART was observed. The three patients had very similar features. All had severe PCP revealing HIV infection, which completely resolved after 15 d of parenteral therapy combining cotrimoxazole and steroids. All subsequently developed acute respiratory failure with high-grade fever shortly after starting HAART (7 to 17 d), which was introduced early after the diagnosis of PCP (1 to 16 d). Lung pathologic findings and BAL showed a severe immune and inflammatory reaction associated with the persistence of rare P. carinii cysts. All the patients improved after discontinuation of HAART or steroid reintroduction, or both.

Cotrimoxazole-resistant PCP was improbable for several reasons (3). First, the initial episode of PCP fully resolved after a 15-d course of cotrimoxazole. Second, these patients had not previously received sulfa drugs—the main risk factor for resistance to cotrimoxazole. Third, all the patients recovered, whereas resistant PCP is usually fatal. Pulmonary superinfection was ruled out. No parasites, fungi, bacteria, or mycobacteria were found in any lung, blood, or urine samples, with the exception of CMV in one patient. Moreover, broad-spectrum antibiotic therapy, given despite the absence of documented infection, did not lead to a clinical improvement. CMV detection in one blood and one BALF sample from Patient 1 was not considered indicative of CMV pneumonia, as there was no multiorgan CMV disease, anemia, or hemolytic syndrome, and symptoms failed to resolve on anti-CMV therapy (4, 5). Furthermore, open-lung biopsy showed no histologic signs of CMV pneumonia. Drug-related pulmonary toxicity was ruled out (6). The three patients had never previously received cotrimoxazole. In Case 1, cotrimoxazole was never discontinued, and the patient recovered on this therapy. Patients 2 and 3 developed a skin rash related to cotrimoxazole toxicity. However, in Case 2, cotrimoxazole was stopped before onset of the second episode of respiratory distress, and in Case 3, cotrimoxazole, discontinued during the second episode of respiratory distress, was subsequently reintroduced with no recurrence of respiratory symptoms. Finally, none of the HAART regimens contained abacavir, which was recently implicated in cases of acute respiratory distress syndrome and was pursued or reintroduced without relapse of pulmonary manifestation (7).

We conclude that the recurrence of acute respiratory failure resulted from an intense immune and inflammatory reaction after early HAART introduction and steroid withdrawal. Early steroid cessation may favor the relapse of steroid-controlled neutrophil alveolitis associated with PCP, resulting in a new episode of acute respiratory failure (8). Interestingly, this phenomenon has been described in patients in whom zidovudine was introduced during initial anti-PCP therapy (8). The improvement of neutrophil function observed during HAART may thus have contributed to the second episode of respiratory distress in our patients (9). Alternatively, it may have resulted from rapid pulmonary recruitment of fully competent immune cells responding to a few persistent P. carinii cysts acting as crude antigen. Paradoxical exacerbation of subclinical opportunistic infections such as viral hepatitis, CMV retinitis, and mycobacterial infection after HAART initiation has been well documented and might result from the rapid increase in competent antigen-specific memory T cells (10-15). Interestingly, studies of cellular immune reconstitution in animal models of PCP have shown similar paradoxical pulmonary inflammatory reactions (16-18). Severe combined immunodeficiency disease (SCID) mice with PCP developed acute respiratory failure related to a hyperinflammatory pulmonary reaction leading to P. carinii clearance after infusion of CD4+ cells (17). Histologic findings in these studies resembled those found in our patients, with an intense inflammatory infiltrate composed of lymphocytes, macrophages, and neutrophils, and a pattern of organizing pneumonia surrounding a few persistent P. carinii cysts. The efficacy of HAART in these patients was shown by the marked fall in plasma viral load. In contrast, circulating CD4+ cell counts did not increase in parallel, suggesting possible CD4+ cell sequestration in the lungs and their participation in the acute pulmonary reaction as also shown by the immunophenotyping of the lung tissue section from Case 1 (Figures 3D through 3F). This is supported by the observation that the reaction resolved after HAART discontinuation or steroid reintroduction, or both, as previously described in patients with paradoxical worsening of tuberculosis (11, 15).

These observations call for caution when introducing HAART early in patients with AIDS-inaugurating PCP, especially when adjunctive steroid therapy is indicated for mild to severe hypoxemia.

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Correspondence and requests for reprints should be addressed to Pr. J. Cadranel, Service de Pneumologie et de Réanimation Respiratoire, Hôpital Tenon, 4 rue de la chine, 75020, Paris, France. E-mail:

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