Aetiology of cavitary lung lesions in patients with HIV infection*

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1 DOI: /j x r 2009 British HIV Association HIV Medicine (2009), 10, ORIGINAL RESEARCH Aetiology of cavitary lung lesions in patients with HIV infection* C-Y Lin, w H-Y Sun, w M-Y Chen, S-M Hsieh, W-H Sheng, Y-C Lo, C-C Hung and S-C Chang Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan Background Although many studies have been carried out on pulmonary diseases in HIV-infected patients, studies specifically investigating the aetiologies of cavitary lung lesions are rare. Methods HIV-infected patients enrolled in a cohort study who presented with cavitary lung lesions by radiography were identified between June 1994 and March Medical records and radiological and microbiological data for these patients were retrospectively reviewed using a standardized case collection form. Results During the 14-year study period, 73 episodes of cavitary lung lesions were diagnosed in 66 of 1790 (3.7%) HIV-infected patients. At the diagnosis of cavitary lung lesions, the median CD4 count was 25 cells/ml (range cells/ml). Eighty-one pathogens were considered causative, with fungi being the most common aetiology (42.0%), followed by bacteria (29.6%) and mycobacteria (25.9%). Of the fungal pneumonias, 19 (55.9%) were caused by Penicillium marneffei, 11 (32.4%) by Cryptococcus neoformans, two (5.9%) by Pneumocystis jirovecii, and two (5.9%) by Aspergillus species. During the study period, 11 of 205 patients (5.4%) who were diagnosed as having tuberculosis presented with cavitary lung lesions, compared with 19 of 36 patients (52.8%) with penicilliosis and 11 of 64 patients (17.2%) with cryptococcosis (Po0.0001). The median CD4 count of patients with cavitary lung lesions resulting from tuberculosis (115 cells/ml) was significantly higher than that of patients with cavitary lung lesions resulting from penicilliosis (4 cells/ml) and cryptococcosis (29.5 cells/ml). Conclusions Our findings suggest that invasive infections attributable to endemic fungi were the leading cause of cavitary lung lesions among patients in the late stage of HIV infection, and were more common than infections attributable to bacteria and mycobacteria. Keywords: AIDS, cavitary pneumonia, HIV, invasive fungal infection, mycobacterial infection Accepted 16 September 2008 Introduction Although the introduction of highly active antiretroviral therapy (HAART) and primary and secondary antimicrobial prophylaxis have led to declines in the incidences of *Preliminary analyses of these data were presented as Abstract 1733_140 at the 17th European Congress of Clinical Microbiology and Infectious Diseases held in Munich, Germany, 31 March to 3 April w Drs C. Y. Lin and H. Y. Sun contributed equally to the paper. Correspondence: Dr Chien-Ching Hung, Department of Internal Medicine, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, Taiwan. Tel: , ext ; fax: ; hcc0401@ ntu.edu.tw opportunistic infections and AIDS- and HIV-related mortality, many HIV-infected patients still present to clinics with advanced stages of disease and opportunistic illnesses because of a lack of awareness of their HIV serostatus, delays in seeking HIV care, or poor compliance with therapies prescribed [1 3]. Of the wide variety of infectious and noninfectious complications that can occur in HIV-infected individuals, pulmonary diseases remain the major cause of morbidity and mortality. Up to 90% of patients with HIV infection experience pulmonary complications during the course of their illness and up to 65% of AIDS-defining opportunistic illnesses may involve the lung 191

2 192 C-Y Lin et al. [2,4]. The range of aetiologies of pulmonary diseases in HIV-infected patients is broad and aetiological diagnosis is often challenging for clinicians, given the variable and nonspecific clinical and radiological manifestations. Among the numerous HIV-associated pulmonary complications, cavitation can occur as the end result of the pathological process that leads to tissue necrosis [5 7]. The aetiologies of cavitary lung lesions may vary with immune status, comorbidity, risk factor for HIV transmission, and risk of exposure to pathogens that are prevalent in the areas the patients reside in or travel to. To our knowledge, there are only two reports in the literature that specifically describe the aetiologies of cavitary lung diseases in HIVinfected patients with different demographic and clinical characteristics, one from Spain [8] and the other from the USA [9]. In this study, we aimed to investigate the aetiologies of cavitary lung lesions in individuals with HIV infection enrolled in an observational study, as well as to assess the correlation between the aetiologies and the immune status of the patients. Materials and methods Study population From June 1994 to March 2008, 1790 nonhaemophiliac HIV-infected patients aged 15 years or older were consecutively enrolled in the ongoing open cohort study at the National Taiwan University Hospital [10]. A computerized case report form was used to record the patients demographics, risk factors for HIV infection, CD4 and CD8 lymphocyte counts, plasma HIV RNA loads, HIV-related opportunistic illnesses, community-acquired and nosocomial pneumonia and bacteraemia, antiretroviral therapy prescribed, including HAART, antimicrobial therapy, and outcomes. The median CD4 count at baseline of the whole cohort was 130 cells/ml and 58.8% of the patients had a baseline CD4 count o200 cells/ml. Sexual contact was the leading risk factor for HIV transmission and injecting drug users (IDUs) accounted for 8.2% of all of the patients enrolled. Diagnostic investigations During the 14-year study period, stepwise investigations were performed as routine clinical care practice to identify the aetiology of any presenting symptoms [10]. For patients who presented with fevers, blood samples were obtained for bacterial, mycobacterial and fungal cultures. For lung lesions, cytological staining and microbiological cultures, including bacterial, mycobacterial and fungal cultures, were routinely performed, in addition to determinations of serum cryptococcal antigen. After 2006, an Aspergillus galactomannan assay using the Platelia enzyme-linked immunosorbent assay (ELISA; Bio-Rad, Marnes-la- Coquette, France) was added to facilitate earlier diagnosis of P. marneffei infection, an endemic fungal infection in Southeast Asia, Southwest China, Hong Kong and Taiwan, because of cross-reactions between P. marneffei and Aspergillus spp. in the Aspergillus antigen assay [11]. For lung lesions or mediastinal lymphadenopathy for which the aetiology remained unknown after noninvasive diagnostic tests, chest sonography or computed tomography (CT)-guided aspiration and biopsy were performed for those lesions that were accessible to aspiration and biopsy. Bronchoscopy was performed in patients with lesions that were considered inaccessible to CT- or sonography-guided aspiration and biopsy. In addition to histopathological examinations, clinical samples were routinely cultured for bacteria, fungi, mycobacteria and viruses. Definitions Cavitary lung lesions were retrospectively identified by a computerized search of the radiology database containing results for routine radiography and CT of the chest. A cavitary lung lesion was defined as any parenchymal lesion, with air content, visible in a plain X-ray or CT scan of the chest and 41 cm in diameter. Pathogens were considered definite if they were isolated from lung biopsy or aspirate specimens. Probable cases were defined as those in which organisms were isolated from sterile sites; those in which organisms were isolated from sterile sites and those in which Mycobacterium tuberculosis, P. marneffei or C. neoformans were identified or isolated from respiratory specimens and those with compatible clinical and radiographic findings and a response to specific antimicrobial therapy. Possible cases were those in which organisms were isolated from sputum specimens, and those in which there were episodes without specific isolates, but with compatible clinical and radiographic findings, plus a response to specific antimicrobial agents. If multiple microorganisms (definite, probable or possible) were considered responsible for cavitary lung lesions, such episodes were defined as polymicrobial episodes. Statistical analysis All statistical analyses were performed with SPSS version 12.0 (SPSS, Chicago, IL). Categorical variables were compared by w 2 analysis or Fisher s exact test. Noncategorical variables were compared by the Mann Whitney U-test. All comparisons were two-tailed and a P-value o0.05 was considered significant.

3 Cavitary pneumonia and HIV infection 193 Results Characteristics of patients with cavitary lung lesions From June 1994 to March 2008, routine chest radiography identified 73 episodes of cavitary lung lesions in 66 HIVinfected patients, and CT of the chest was subsequently performed in 63 (86.3%) episodes for further evaluation of the lesions. Only four patients with lesions inaccessible to CT- or sonography-guided aspiration underwent bronchoscopy. There were seven episodes of recurrence (9.6%) which occurred in four patients, and one patient had four recurrent episodes of the same pathogen which was classified as definite according to the definitions. The demographic and clinical characteristics of the patients are shown in Table 1. Most of the patients were men who have sex with men (57.6%). Their median age was 36 years (range years) at the time of diagnosis of cavitary lung lesions. Cavitary lung lesions were the initial presenting disease of HIV infection in 57.6% of the patients and more than two-thirds of them (69.7%) were naïve to HAART. At the time of diagnosis of cavitary lung lesions, Table 1 Demographics of HIV-infected patients with cavitary lung lesions Characteristic Data Number of patients 66 Male gender [n (%)] 61 (92.4) HIV risk factor [n (%)] Homosexual or bisexual 38 (57.6) Heterosexual 19 (28.8) Injecting drug user 7 (10.6) Other 2 (3.0) Data at enrolment of cohort CD4 count (cells/ml) [median (range)] 27.5 (1 575) CD8 count (cells/ml) [median (range)] 445 ( ) pvl (log 10 copies/ml) [median (range)] 5.4 ( ) Data at diagnosis of cavitary lung lesions Total number of episodes 73 Number of recurrence episodes 7 Number of polymicrobial episodes 11 Number of concurrent opportunistic infections 20 Age (years) [median (range)] 36 (23 81) Pre-HAART era [n (%)] 7 (10.6) Post-HAART era [n (%)] 59 (89.4) Naïve to HAART 46 (69.7) AIDS 63 (95.5) CD4 count (cells/ml) [median (range)] 25 (1 575) CD8 count (cells/ml) [median (range)] 322 ( ) pvl (log 10 copies/ml) [median (range)] 5.2 ( ) Episodes categorized by CD4 count [n (%)] o100 cells/ml 55 (75.3) cells/ml 6 (8.2) cells/ml 4 (5.5) 4350 cells/ml 4 (5.5) Unknown 4 (5.5) HAART, highly active antiretroviral therapy; pvl, plasma HIV RNA load. the median CD4 count and plasma HIV RNA load were 25 cells/ml (range cells/ml) and 5.2 log 10 HIV-1 RNA copies/ml (range log 10 copies/ml), respectively (Table 1). Aetiologies of cavitary lung lesions Discounting the eight episodes of unknown aetiology, there were 81 pathogens that could be considered responsible for the cavitary lung lesions (Table 2): 20 (24.7%) represented definite aetiologies, 46 (56.8%) probable aetiologies, and 15 (18.5%) possible aetiologies (Table 2). Fungi (42.0%) were the main causative micro-organisms, followed by bacteria (29.6%), mycobacteria (25.9%) and viruses (2.5%). Among the 34 fungi that were causative for pulmonary cavitation, P. marneffei caused 19 episodes (55.9%) (Figure 1), C. neoformans 11 (32.4%), Pneumocystis jirovecii two (5.9%), and Aspergillus spp. two (5.9%). Of the 24 bacterial isolates, seven (29.2%) were Staphylococcus aureus, six (25.0%) Rhodococcus equi (Figure 2), four (16.7%) Pseudomonas aeruginosa, three (12.5%) Streptococcus pneumoniae, two (8.3%) Klebsiella pneumoniae, one (4.2%) Nocardia spp., and one (4.2%) an unidentified Gramnegative bacterium (Table 2). There were 21 mycobacterial isolates that were considered responsible for cavitary lung lesions: M. tuberculosis was identified in 11 episodes (52.4%), Mycobacterium avium complex in nine (42.9%) and Mycobacterium kansasii in one (4.7%) (Table 2). Table 2 Aetiology of cavitary lung lesions in the 66 HIV-infected patients Pathogens Total Definite Probable Possible Fungi [n (%)]* 34 (42.0) Penicillium marneffei 19 (55.9) Cryptococcus neoformans 11 (32.3) Aspergillus spp. 2 (5.9) Pneumocystis jirovecii 2 (5.9) Bacteria [n (%)]* 24 (29.6) Staphylococcus aureus 7 (29.2) Rhodococcus equi 6 (25.0) Pseudomonas aeruginosa 4 (16.7) Streptococcus pneumoniae 3 (12.5) Klebsiella pneumoniae 2 (8.3) Nocardia spp. 1 (4.2) Other bacteria 1 (4.2) Mycobacteria [n (%)]* 21 (25.9) Mycobacterium tuberculosis 11 (52.4) Mycobacterium avium complex 9 (42.9) Mycobacterium kansasii 1 (4.7) Virus [n (%)]* 2 (2.5) Cytomegalovirus 2 (100) Total [n (%)]* 81 (100) *Percentage of total pathogens.

4 194 C-Y Lin et al. Relationship between aetiologies and CD4 cell count The relationship between aetiologies and CD4 cell count for cavitary lung lesions is shown in Table 3. For the 55 episodes (75.3%) of cavitary lung lesions that occurred in patients with CD4 counts o100 cells/ml, 65 pathogens were isolated and aetiology was unknown for five episodes. Of the 65 pathogens, 33 (50.8%) were fungi, with P. marneffei (29.2%) and C. neoformans (16.9%) being Table 3 Correlation between pathogens and CD4 cell count of HIVinfected patients with cavitary lung lesions Pathogens CD4 count (cells/ll) o Unknown Fungus [n (%)]* 33 (50.8) 0 (0) 0 (0) 0 (0) 1 (25.0) Penicillium marneffei Cryptococcus neoformans Aspergillus spp Pneumocystis jirovecii Bacteria [n (%)]* 15 (23.1) 1 (25.0) 2 (40.0) 3 (100) 3 (75.0) Staphylococcus aureus Pseudomonas aeruginosa Streptococcus pneumoniae Klebsiella pneumoniae Nocardia spp Rhodococcus equi Other bacteria Mycobacteria [n (%)]* 15 (23.1) 3 (75.0) 3 (60.0) 0 (0) 0 (0) Mycobacterium tuberculosis Mycobacterium avium complex Mycobacterium kansasii Virus [n (%)]* 2 (3.0) 0 (0) 0 (0) 0 (0) 0 (0) Cytomegalovirus *Percentage of total pathogens within each CD4 cell count category. predominant, 15 (23.1%) were bacteria, 15 (23.1%) were mycobacteria, and two (3.1%) were viruses. Of the six episodes (8.2%) in patients with CD4 counts between 100 and 200 cells/ml, mycobacteria were the causative microorganisms in three cases and bacteria in one case, and two episodes had unknown aetiology. Mycobacteria (in three cases) and bacteria (in two cases) were the main causative pathogens in the four episodes (5.5%) in patients with CD4 counts between 200 and 350 cells/ml. In the four episodes (5.5%) in patients with CD4 counts 4350 cells/ml, bacteria were identified in three episodes and one episode had unknown aetiology (Table 3). Eleven (15.1%) episodes of cavitary lung lesions were considered to be polymicrobial. The demographics of the patients, the micro-organisms, and the specimens from which the micro-organisms were isolated for these 11 polymicrobial episodes are shown in Table 4. Twenty-five pathogens were involved in these episodes, with eight episodes each caused by two pathogens and three episodes by three pathogens. One of these polymicrobial episodes occurred in an HIV-infected patient with a CD4 lymphocyte count of 268 cells/ml, but all the others (10; 90.9%) occurred in patients with CD4 counts o50 cells/ml. Of the 25 pathogens, six (24.0%) were definite, 15 (60.0%) probable and four (16.0%) possible. Moreover, the most common combinations of pathogens responsible for cavitary lung lesions were fungi and mycobacteria, which occurred in patients in the late stage of HIV infection (Table 4). The propensity to produce cavitary lung lesions may vary with the infecting agent. During the study period, 11 of 205 patients (5.4%) diagnosed with tuberculosis presented with cavitary lung lesions, compared with 19 of 36 patients (52.8%) with P. marneffei infection and 11 of 64 patients (17.2%) with cryptococcosis (Po0.0001). The Table 4 Characteristics of HIV-infected patients with cavitary lung lesions defined as polymicrobial episodes Episode Age (years) HIV risk factor CD4 count (cells/ll) Micro-organism (specimen) 1 34 Heterosexual 4 Penicillium marneffei (sputum, lung biopsy); Pneumocystis jirovecii (lung biopsy) 2 45 Heterosexual 4 Penicillium marneffei (blood, bronchial washing); Streptococcus pneumoniae (bronchial washing); Haemophilus parainfluenzae (bronchial washing) 3 33 Homosexual 10 Penicillium marneffei (lung aspirate, blood, skin); Mycobacterium avium complex (blood); Mycobacterium kansasii (blood) 4 81 Heterosexual 15 Penicillium marneffei (blood); Mycobacterium avium complex (blood, sputum) 5 62 Heterosexual 10 Cryptococcus neoformans (lung biopsy); cytomegalovirus (lung biopsy) 6 48 Homosexual 25 Pseudomonas aeruginosa (blood, sputum); Mycobacterium avium complex (blood) 7 57 Bisexual 43 Mycobacterium tuberculosis (sputum); Cryptococcus neoformans (blood) 8 33 Bisexual 1 Penicillium marneffei (blood, sputum); Mycobacterium avium complex (lung biopsy, sputum) 9 48 Injecting drug user 9 Penicillium marneffei (bronchial washing); Mycobacterium avium complex (blood, sputum); cytomegalovirus (bronchial washing) Homosexual 26 Pseudomonas aeruginosa (sputum); Pneumocystis jirovecii (response to treatment) Heterosexual 268 Mycobacterium tuberculosis (response to treatment); Klebsiella pneumoniae (sputum)

5 Cavitary pneumonia and HIV infection 195 median CD4 count of the patients with cavitary lung lesions attributable to tuberculosis (115 cells/ml) was significantly higher than that of patients with cavitary lung lesions attributable to P. marneffei infection (4 cells/ml) and cryptococcosis (29.5 cells/ml). Discussion In this study of cavitary lung lesions in patients in the late stage of HIV infection who acquired HIV infection mainly through sexual transmission, we found that pulmonary cavitation was not a common pulmonary complication (3.8%), and the most common causative pathogens of cavitary lung lesions were fungi (41.9%), followed by bacteria (29.6%) and mycobacteria (25.9%). Our findings are quite different from those of two previous studies by Rodríguez Arrondo et al. [8] and Aviram et al. [9]. The aetiologies of cavitary lung lesions found in the two previously published studies and in ours are summarized in Table 5. In the studies by Rodríguez Arrondo et al. [8] and Aviram et al. [9], bacteria were the predominant causative pathogens. Such differences in the aetiologies of cavitary lung lesions in HIV-infected patients among the three studies may be related to differences in the study populations and in the endemicity of infectious diseases. In our study, most of the patients were severely immunocompromised at the time of diagnosis of cavitary lung lesions; 95.5% of them had AIDS; and only 10.6% of our patients were IDUs. In contrast, in the study by Rodríguez Arrondo et al., [8] IDUs constituted 93% of the patients. As bacterial Table 5 Comparisons of three studies of aetiologies of cavitary lung lesions in HIV-infected patients Rodríguez Arrondo et al. [8]* Aviram et al. [9] Present study Country Spain USA Taiwan Study design; Retrospective; January 1989 December 1994 Retrospective; April 1996 March 1998 Retrospective; June 1994 March 2008 study period Prospective; January 1995 December 1996 Definitions Any parenchymal lesion, with air content, Chest CT: a gas-containing space Any parenchymal lesion, with air content, visible in a simple X-ray and 41 cm in diameter within the lung surrounded by a visible in a simple X-ray and 41 cm in diameter wall with thickness 41mm Number of patients and cases/episode 73 patients; 78 cases Confirmed: 54 (69.2%); probable: 15 (19.2%); possible: 9 (11.5%) 8 cases with more than one pathogen Demographics and Median age: 30 years (range years) clinical characteristics Homosexual: 2 (2.7%) Heterosexual: 3 (4%) IDU: 68 (93%) Median CD4 count: 30 cells/ml (range cells/ml) Pathogens Fungi 15 cases (19.2%) Pneumocystis jirovecii, 11; Cryptococcus neoformans, 2; Aspergillus fumigatus, 2 Bacteria 33 cases (42.3%) Staphylococcus aureus, 14; Pseudomonas aeruginosa, 13; Rhodococcus equi, 6; anaerobes, 5; Salmonella enteritidis, 3; Streptococcus pneumoniae, 2; Streptococcus milleri, 1; Serratia marcescens, 1 Mycobacteria 23 cases (29.5%) Mycobacterium tuberculosis, 22; Mycobacterium kansasii, 1 25 patients 66 patients; 73 episodes; 81 pathogens Definitive: 20 patients Definite: 20 (24.7%); probable: 46 (56.8%); 17 patients with more than one pathogen possible: 15 (18.5%) Polymicrobial: 11 cases 18 men, 7 women Mean age: 44 years (range years) AIDS: 23 patients (92%) Mean CD4 count: 106 cells/ml (range cells/ml) 4 patients (16.0%) Candida albicans, 2; Aspergillus spp., 1; Pneumocystis jirovecii, 1 17 patients (68.0%) Staphylococcus aureus, 5; Pseudomonas aeruginosa, 5; Klebsiella spp., 4; Nocardia asteroids, 3; Enterobacter spp., 2; Escherichia coli, 2; Rhodococcus equi, 1 8 patients (32.0%) Mycobacterium tuberculosis, 4; Mycobacterium avium complex, 3; Mycobacterium kansasii, 1; Mycobacterium fortuitum, 1 Virus 3 patients (12.0%) Cytomegalovirus, 3 *In the study by Rodríguez Arrondo F et al., seven cases (8.9%) were due to infective endocarditis. CT, computed tomography; IDU, injecting drug user. 5 women, 61 men Median age: 36 years (range years) AIDS: 63 patients (95.5%) Homosexual: 38 (57.6%) Heterosexual: 19 (28.8%) IDU: 7 (10.6%) Median CD4 count: 25 cells/ml (range cells/ml) 34 cases (42.0%) Penicillium marneffei, 19; Cryptococcus neoformans, 11; Pneumocystis jirovecii, 2; Aspergillus spp., 2 24 cases (29.6%) Staphylococcus aureus, 7; Pseudomonas aeruginosa, 4; Rhodococcus equi, 6; Streptococcus pneumoniae, 3; Klebsiella pneumoniae, 2; Nocardia spp., 1; other, 1 21 cases (25.9%) Mycobacterium tuberculosis, 11; Mycobacterium avium complex, 9; Mycobacterium kansasii, 1 2 cases (2.1%) Cytomegalovirus, 2

6 196 C-Y Lin et al. Fig. 1 Computed tomography (a) and chest X-ray (b) of a 26-year-old HIV-infected male patient with a lung abscess. His CD4 count was 30 cells/ml at diagnosis of the cavitary lung lesion. Cultures of the CT-guided lung aspiration sample of the lung abscess yielded Penicilium marneffei. Fig. 2 Chest X-ray (a) and computer tomography (b) of a 44-year-old HIV-infected male patient with a lung abscess. His CD4 count was 12 cells/ml at diagnosis of the cavitary lung lesion. Rhodococcus equi as isolated from blood and sputum cultures. infections and infective endocarditis frequently occur in IDUs, these complications with cavitation of the lung were more commonly identified in their study. The risks of environmental exposure to infectious agents endemic in these three study locations (Taiwan, Spain and the USA) may also be responsible for the differences in the

7 Cavitary pneumonia and HIV infection 197 aetiologies of cavitary lung lesions. In Southeast Asia and Taiwan, fungi, especially P. marneffei and C. neoformans, and mycobacteria are important endemic pathogens in HIVinfected patients who are severely immunocompromised [12 15]. In our study, P. marneffei and C. neoformans were the two predominant fungi responsible for cavitary lung lesions in the HIV-infected patients. In contrast, P. marneffei was not identified in the other two studies [8,9]. In this study, we found that the propensity to cause cavitary lung lesions was different among the three most commonly identified infectious agents, and M. tuberculosis was less likely to cause pulmonary cavitation than P. marneffei and C. neoformans. The reason for the difference remains unclear and may be related to interactions between the immune status of the host and the virulence of the infecting agent. In our study, HIV-infected patients with cavitary lung lesions caused by M. tuberculosis had higher CD4 lymphocyte counts than those with lesions caused by P. marneffei and C. neoformans. Similarly, cavitary lung lesions caused by M. tuberculosis occurred more frequently in patients with higher CD4 cell counts than those caused by M. avium complex. This finding is compatible with previous reports that manifestations of tuberculosis vary considerably in HIV-infected patients according to their immune status. Patients in the late stage of HIV infection may have atypical radiographic findings attributable to tuberculosis, and cavitary lung lesions in such cases are uncommon, with the exception of reports of cavitation caused by multi-drug-resistant M. tuberculosis [16 18]. Immune reconstitution inflammatory syndrome (IRIS) may cause cavitary lung lesions in HIV-infected patients with low CD4 cell counts after initiation of antiretroviral therapy [19]. Of the 66 patients with cavitary lung lesions in this study, 46 (69.7%) were naïve to antiretroviral therapy at the diagnosis of lung lesions. For the remaining 20 patients, who had received antiretroviral therapy, the symptomatology and clinical course were mainly consistent with the diagnosed infectious diseases rather than IRIS (data not shown). The clinical course in one patient whose CD4 count increased from 15 to 69 cells/ml after 1 month of HAART when tuberculosis was diagnosed was consistent with IRIS according to the newly proposed consensus definitions for IRIS of tuberculosis [20]. Although we were not able to exclude the possibility of IRIS because of the limitations of the retrospective study design, IRIS appeared to be a rare cause of cavitary lung lesions in this study. Our study had several limitations. Firstly, the sample size was small. Secondly, this was not a multicentre study and all of the data came from our cohort which was recruited at a referral university hospital. Thirdly, because of difficulties in obtaining tissue for definite diagnosis in every case, several episodes were regarded as probable or possible, and Table 6 Aetiologies of cavitary lung lesions in HIV-infected patients after exclusion of those defined as possible aetiologies Pathogens Definite Probable Total Fungus (n) Penicillium marneffei Cryptococcus neoformans Aspergillus spp Pneumocystis jirovecii Bacteria (n) Staphylococcus aureus Pseudomonas aeruginosa Streptococcus pneumoniae Klebsiella pneumoniae Nocardia spp Rhodococcus equi Mycobacteria (n) Mycobacterium tuberculosis Mycobacterium avium complex Mycobacterium kansasii Virus (n) Cytomegalovirus Total number the roles of different pathogens in episodes with polymicro-organisms could not be defined precisely. However, our findings concerning the frequencies of the different causative micro-organisms and the correlation between CD4 cell count and aetiologies did not change after we excluded those episodes attributable to pathogens that were defined as possible (Table 6). Fourthly, we performed a literature search to identify the studies that were specifically designed to provide detailed aetiological diagnoses for patients with cavitary lung lesions by radiography. We did not include those studies in which cavitary lung lesions were part of the radiographic spectra of lung lesions in HIV-infected patients. In conclusion, our findings suggest that invasive infections attributable to endemic fungi were the leading cause of cavitary lung lesions among patients in the late stage of HIV infection in Taiwan, and were more common than infections attributable to bacteria and mycobacteria. Conflicts of interest: The authors have no conflicts of interest to declare. 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