Chronic necrotizing pulmonary aspergillosis after tuberculosis in an HIV-positive woman: an unusual immune reconstitution phenomenon?

Abstract

Chronic necrotizing pulmonary aspergillosis (CNPA) is characterized by fungal invasion of the lung parenchyma causing local destruction [1–5]. It usually occurs in elderly patients with underlying lung disease and in association with diabetes mellitus, low-dose corticosteroids or poor nutrition. Herein, we report on a woman with AIDS and tuberculosis who developed CNPA in the area of an upper lobe cavitary lesion when she was on combined tuberculostatic and highly active antitretroviral therapy (HAART). The role of immune restoration by HAART as a possible, so far unreported, risk factor for CNPA is discussed. Case report A formerly healthy 23-year-old female immigrant from Cameroun presented with a one month history of productive cough, fever and a 10 kg weight loss over a 2-month period. Chest radiograph showed a cavitary lesion in her right upper lobe, and in her sputum acid fast bacilli were found that proved to be Mycobacterium tuberculosis by culture, which were treated accordingly. Because she tested positive for HIV, primary prophylaxis against Pneumocystis carinii pneumonia (trimethoprim/sulphamethoxazole) was started. Pulmonary symptoms subsided completely and the patient was discharged. After 3 months, tuberculostatic therapy was simplified, and antiretroviral therapy with efavirenz, lamivudine and tenofovir was initiated. At this time the CD4 cell count was 90 × 106/l and viral load was 720 000 HIV-RNA copies/ml. Six weeks later, the CD4 cell count had risen to 110 × 106/l and viral load had dropped to 9100 HIV-RNA copies/ml. She was in a stable condition and had regained approximately 5 kg body weight. Another 6 weeks later, a productive cough developed with abundant brownish sputum. On chest X-ray,the cavitary lesion of the right upper lobe was unchanged (Fig. 1a). Broncho-alveolar lavage showed signs of inflammation with giant cells and cultures from the lavage fluid grew ample Aspergillus fumigatus. Neither acid fast bacilli nor Pneumocystis carinii were detected. The right upper lobe was removed by surgery. Histological examination presented with areas of necrosis with a rim of eosinophilic granulocytes, histiocytes, giant cells and lymphocytes, followed by adjacent fibroplastic demarcation. In these necrotic zones, fungi arranged in septate hyphae (Aspergillus species) were seen (Fig. 1b). Angioinvasion was not found. Tissue cultures remained negative for M. tuberculosis. Fungistatic therapy with itraconazole 400 mg/day was started and continued for 4 weeks. The patient recovered completely.Fig. 1: (a) Chest X-ray at second admission: cavitary lesion of the right upper lobe. (b) Methenamine-silver stain (Grocott) reveals invasive hyphae of Aspergilli (original magnification ×200).The lung parenchyma of this patient had been altered by M. tuberculosis infection, resulting in a cavitary lesion in an upper lobe that created an ideal environment for Aspergillus colonization. In this patient, instead of a fungus ball, CNPA developed, which raises important questions about the pathogenesis of aspergillosis in individuals infected with HIV. Aspergillosis is uncommon among patients infected with HIV [6–10]. This rarity is explained by the natural defence against Aspergillus provided by macrophages and neutrophils, which is not thought to require T cells. Therefore, it is not surprising that in these isolated cases, in which pulmonary aspergillosis develops in HIV-infected patients, concomitant neutropenia or corticosteroid use is frequently found. Occasionally, however, aspergillosis has been observed in the absence of these two classic risk factors. A common feature in most cases of aspergillosis in HIV patients is that it occurs as a late complication of AIDS when CD4 cell counts are less than 50 cells/mm3, which suggests that CD4 lymphocytopenia constitutes an independent risk. The mechanism by which the CD4 lymphocytic defect compromises the defence against Aspergilli and whether phagocytic dysfunction is involved remains unclear. A remarkable feature in this patient is that her immune system was in recovery when invasive aspergillosis developed. The desired improvement of immunocompetence leads to more potent inflammatory responses, which unmasks prevalent subclinical infections in individuals treated with HAART, causing considerable morbidity [11,12]. So far, invasive pulmonary aspergillosis has not been reported as a complication of immune reconstitution in HIV infection. One major factor that paved the way for fungal infection in this patient was the destruction of the lung parenchyma by tuberculosis, because lung cavities are ideal niches for Aspergillus colonization. Most commonly, this colonization results in ball-like structures that do not exhibit invasive behaviour as long as the host defence lines are intact. We suggest that immune reconstitution may have promoted fungal invasiveness in this patient leading to CNPA. Therefore, antifungal therapy was initiated until immune recovery was completed. Acknowledgement The authors would like to thank the patient who agreed to have her case published. There are no conflicts of interest to declare. There was no financial support for this work.