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    Pre-treatment chest radiograph showing typical reticulonodular bilateral infiltrate of paracoccidioidomycosis. The diffuse micronodules have a miliary aspect in this patient co-infected with human immunodeficiency virus.

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    Lung paracoccidioidomycosis and co-infection with human immunodeficiency virus. Chest radiograph before treatment showing severe bilateral reticulonodular and alveolar infiltrate plus mediastinal lymphadenomegaly.

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Paracoccidioidomycosis in Patients Infected with and Not Infected with Human Immunodeficiency Virus: A Case-Control Study

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  • 1 Division of Infectious and Tropical Diseases, Hospital das Clínicas and Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil

Epidemiologic and clinical data for 53 patients with paracoccidioidomycosis and co-infected with human immunodeficiency virus (HIV) (cases) were compared with those for 106 patients with endemic paracoccidioidomycosis (controls). The prevalence of Paracoccidioides brasiliensis co-infection was estimated in 1.4% in cases of acquired immunodeficiency syndrome (AIDS). Patients co-infected with HIV were younger, less involved in agricultural occupations; 83.7% had CD4+ cell count < 200 cells/μL. Paracoccidioidomycosis in co-infected patients usually showed a rapid progression, with more fever, frequent involvement of the lungs, and multiple extrapulmonary lesions. The response to antifungal therapy and deaths caused by paracoccidioidomycosis were similar in the two patient groups, but late relapses were more common in co-infected cases. Paracoccidioidomycosis in HIV-infected patients shows epidemiologic and clinical characteristics differing from those of the endemic disease and should be considered an AIDS-defining opportunistic infection in Latin America.

INTRODUCTION

The fungus Paracoccidioides brasiliensis can infect persons by the respiratory route in those exposed to the rural environment of fungal-endemic areas. In general, the infection is controlled by the immune response and is asymptomatic. However, viable forms presumably persist within the healed primary lesion. Paracoccidioidomycosis, which is endemic in Brazil and a large part of Latin America can develop in some persons, particularly those working in agricultural occupations.1 This systemic mycosis can occur immediately or years after fungal infection and manifests as two major clinical forms. Almost all adults more than 30 years of age have the chronic form, which manifests as pulmonary lesions, often associated with ulcerations in the oral, nasal, or laryngeal mucosa, and eventually with other tegumentary and visceral lesions. The acute/subacute form is more common among children and young adults, who have generalized lymphadenopathy commonly associated with lesions suggestive of hematogenous dissemination of P. brasiliensis, such as hepatosplenomegaly, skin, intestinal, and bone lesions. 2,3 Itraconazole, trimethoprim-sulfamethoxazole, and amphotericin B are the antifungal agents most frequently used for treatment, leading to a cure in most patients.4 However, relapse can occur and the death rate for paracoccidioidomycosis has been estimated to be 3%.3

The first cases of paracoccidioidomycosis associated with acquired immunodeficiency syndrome (AIDS) were reported in 1989.57 Many co-infected patients lived in the southeastern and west-central regions of Brazil, where this fungal disease is hyperendemic. Three series of 7, 10, and 12 patients, respectively, have been reported,810 but other reports described only one or two cases of P. brasiliensis–human immunodeficiency virus (HIV) co-infection, in patients in Brazil 1113 and in patients in other Latin American countries. 14 The first cases were reviewed in 1995. 15 The relatively small number of cases of paracoccidioidomycosis associated with AIDS when compared with histoplasmosis and cryptococcosis among HIV-infected patients is intriguing because the prevalence of paracoccidioidomycosis is much higher in the non-immunosuppressed population. 14 Patients with P. brasiliensis-HIV co-infection usually have a low number of CD4+ cells and multiple fungal lesions, and this condition is associated with high death rates. 16 The small number of cases and the lack of complete data in various reports impair the characterization of the epidemiology and clinical spectrum of paracoccidioidomycosis in patients with HIV/AIDS.

We report 53 cases of P. brasiliensis-HIV co-infection in an area of southeastern Brazil. This report represents the largest patients cohort from a single geographic area studied to date. Only three of the cases evaluated have been reported previously. 5,17,18 Epidemiologic, clinical, and laboratory data for patients with paracoccidioidomycosis-HIV co-infection were compared with those for HIV-negative patients with paracoccidioidomycosis. In our study, we analyzed a group of temporally related cases of endemic disease within the same geographic area to describe the particular aspects of paracoccidioidomycosis in patients with HIV/AIDS.

PATIENTS AND METHODS

A retrospective case-control study was conducted on two cohorts of patients with paracoccidioidomycosis during 1986–2004. All the patients included in the study received medical care at the University Hospital of the Faculty of Medicine of Ribeirão Preto, University of São Paulo, and lived in Ribeirão Preto, Brazil, or in nearby municipalities. During the same period, 3,744 patients with AIDS were admitted or received outpatient care in this hospital. Ribeirão Preto is located in the northeastern part of the state of São Paulo, Brazil (21°12′42″S, 47°48′24″W) and is the center of a geographic area with three million inhabitants and intense agricultural activity.

Fifty-three patients with paracoccidioidomycosis and HIV infection, most of then in the AIDS stage, were included in the paracoccidioidomycosis-HIV (Pbm-HIV) cohort. Paracoccidioides brasiliensis infection was diagnosed by mycologic and/or histologic methods in 45 patients. The diagnosis was made serologically in eight other patients by detection of antibodies to P. brasiliensis with an enzyme-linked immunosorbent assay (ELISA) and counterimmunoelectrophoresis test (antibodies titers ranged from 1:64 to 1:4,096); these eight patients did not have clinical or laboratory evidence of other opportunistic diseases. Six other patients with clinically presumed paracoccidioidomycosis were excluded from the Pbm-HIV cohort because of low titers (range = 1:16–1:32) in the counterimmunoelectrophoresis test as the only evidence of fungal disease and because they had been simultaneously treated with drugs against other infectious agents.

A total of 106 patients with paracoccidioidomycosis but not infected with HIV were included in the paracoccidioidomycosis control (Pbm-control) cohort, representing a sample of the 1,012 persons in whom fungal disease was diagnosed at our institution during 1986–2004. These patients were selected at random: for each case in the Pbm-cohort, two patients were selected by drawing lots from among those diagnosed with paracoccidioidomycosis in the same year as the patient co-infected with HIV. The Pbm-control cohort included only patients in whom the diagnosis of paracoccidioidomycosis had been confirmed through mycologic/histologic tests or counter-immunoelectrophoresis test (antibody titer to P. brasiliensis ≥ 1:64). Patients treated with potentially immunosuppressive drugs were excluded from the Pbm-control cohort. The acute/ subacute (juvenile) and chronic (adult) forms of paracoccidioidomycosis were identified in 27 (25.5%) and 79 (74.5%), respectively, of the 106 selected individuals. This finding was similar to the distribution of the two forms among the general population of paracoccidioidomycosis patients treated at the institution. Stored serum samples were obtained for 89 of the 106 Pbm-control group patients. All samples obtained were negative for serum antibodies against HIV in the ELISA.

Infection with HIV was diagnosed by detection of serum antibodies to HIV by using two serologic tests: an ELISA HIV 1/2 ® (Abbott Laboratories, Abbott Park, IL) and particle agglutination (Serodia HIV ®; Fujirebio Inc.). Western blot for antibodies to HIV (Genelabs Diagnostics, Singapore) and determination of HIV viral load by NASBA method (bio-Mérieux, Marcy l’Etoile, France) were also used to diagnose and evaluate HIV infection in cases diagnosed in more recent years. The two patient groups were compared by the following methods for diagnosis of paracoccidioidomycosis: direct mycologic examination of the samples treated with 10% KOH, culture on Sabouraud dextrose agar and Sabouraud-cycloheximide-chloramphenicol agar, histologic examination of biopsy samples (hematoxylin and eosin and Gomori staining), and serologic testing (counterimmunoelectrophoresis using a P. brasiliensis antigen obtained by yeast sonication). Antibody titers to P. brasiliensis ≥ 1: 64 in this test have a 100% predictive value for the diagnosis of paracoccidioidomycosis (data from our laboratory).

The response to antifungal treatment was classified as follows: remission/improvement (disappearance of fever and of other signs of inflammation, together with regression of all or most fungal lesions); relapse (reappearance of lesions after a period of clinical cure); unchanged or worsened disease (fungal lesions unaltered or increased in number or intensity); death caused by paracoccidioidomycosis (death caused by organic and functional disorders caused by the fungal disease, with no other apparent cause); death from other causes (death attributed to another disease, regardless of the paracoccidioidomycosis status).

Epidemiologic and clinical data from patient medical records were organized into a database using Excel ® (Microsoft, Redmond, WA) and analyzed using the chi-square test and Fisher’s exact test. The study was reviewed and approved by the Ethics in Research Committee of the Hospital das Clínicas, Faculty of Medicine of Ribeirão Preto (Process no. 4857/2004 and no. 13982/2005).

RESULTS

At the hospital under study, the prevalence of paracoccidioidomycosis among AIDS patients was 1.4% (53 of 3,744) during 1986–2004. Highly active antiretroviral therapy (HAART) was introduced in Brazil in 1997. Therefore, we also analyzed the two periods (before and after the introduction of HAART) separately. The prevalence of paracoccidioidomycosis-HIV co-infection was 1.0% (16 of 1,539) during 1986–1996 (pre-HAART period) and 1.7% (37 of 2,205) during 1997–2004 (period after introduction of HAART). At the same hospital and during the same period (1986–2004), the prevalence of HIV infection among patients diagnosed with paracoccidioidomycosis was 5.2% (53 of 1,012). Of the 53 co-infected patients, 28 (52.9%) were unaware of the HIV infection.

Table 1 shows some aspects of HIV infection in the paracoccidioidomycosis-HIV group. Only 15 of the co-infected patients were taking antiretroviral drugs, 10 of whom were taking trimethoprim-sulfamethoxazole (80 mg of trimethoprim and 400 mg of sulfamethoxazole; two tablets a day) for prophylaxis against Pneumocystis jiroveci infection. Of the paracoccidioidomycosis-HIV co-infected patients for whom CD4+ cell counts were available, more than 80% had < 200 cells/mm3, which is consistent with a diagnosis of AIDS. Immunosuppression was severe (< 50 cells/mm3) in more than 50% of these patients. The viral load of HIV was quantified only in the more recent cases, 80% of which had a high level of viremia, suggesting uncontrolled retroviral infection.

As shown in Table 2, the mean ± SD age of the patients in the Pbm-HIV cohort was 33.5 ± 8.9 years (range = 16–57 years), which is significantly lower than that of those in the Pbm-Control group, which was 45.3 ± 13.6 years (range = 18–77 years). Males predominated in both groups, although the proportion of women among co-infected patients was greater than might be expected. In the Pbm-Control group, 59.4% of the patients were farmers or were engaged in some other type of occupation in a rural area, compared with only 27.5% of the Pbm-HIV cohort patients. Past exposure to the rural environment caused by either work or residence was reported by more persons in the Pbm-Control group than in the Pbm-HIV group (95.4% versus 64.3%). Smoking and alcohol use, both of which predispose to paracoccidioidomycosis, were present at a similar frequency in both groups. The frequency of comorbidities preceding or concomitant with paracoccidioidomycosis was, in general, comparable between the two groups. However, chronic liver disease was more common in the Pbm-HIV group (15.1% versus 3.8%) and was caused by hepatitis C virus (HCV) in the Pbm-HIV group patients and by chronic alcoholic liver disease in the Pbm-Control group.

The time between onset of disease and diagnosis of paracoccidioidomycosis was shorter in the Pbm-HIV cohort. Symptoms onset occurred until 90 days prior to diagnosis in 68.1% (32 of 47) of the Pbm-HIV group patients, compared with 37.3% (38 of 102) in the Pbm-Control group (P < 0.001). In 40.4% of the co-infected patients, there was rapid disease progression and a diagnosis was possible within 30 days after symptoms onset. Table 3 shows the frequency of the clinical manifestations of paracoccidioidomycosis. Signs and lesions suggestive of hematogenous dissemination of P. brasiliensis, including fever, cervical or generalized lymphadenomegaly, hepatomegaly, splenomegaly, and skin lesions, were more common in the Pbm-HIV group than in the Pbm-Control group. Among the patients with cutaneous paracoccidioidomycosis, the lesions were multiple and widely disseminated in 93.8% (30 of 32) of the co-infected patients, compared with 38.1% (16 of 42) of the Pbm-Control group patients (P < 0.001). The Pbm-HIV cohort patients typically had skin lesions in various stages of development, including papules, nodules, nodules with central ulceration, and ulcers. The aspect of the lesions resembled that observed in the endemic disease, particularly in the cases of acute or subacute paracoccidioidomycosis. With respect to mucosal involvement, fungal lesions were less common in Pbm-HIV group patients than in Pbm-Control group patients, affecting the mouth and nose (20.8% versus 50.9%) or the larynx (1.9% versus 23.6%), the latter finding as shown by chronic hoarseness (Table 3). Adrenal insufficiency was detected in only two of the Pbm-Control group patients and in none of the Pbm-HIV group patients.

Many patients in the Pbm-HIV and Pbm-Control groups had cough and dyspnea, (67.9% and 51.9% versus 26.1% and 27.1%, respectively; P > 0.05 for both). After excluding persons with other pulmonary comorbidities, we evaluated chest radiographs to identify pulmonary involvement. Fungal infection of the lungs was detected in most patients in both groups (Table 3). Diffuse bilateral infiltrate (reticulonodular or reticular) was the most common radiologic alteration, seen in 56.4% of the Pbm-HIV group patients and 70.1% of the Pbm-Control group patients (P > 0.05). Other radiologic findings included alveolar infiltrates in 25.6% and 11.9%, reticulonodular plus alveolar infiltrates in 15.4% and 13.4%, cavitation in 15.4% and 10.4%, mediastinal adenomegaly in 12.8% and 9.0%, and pleural effusion in 7.7% and 6.0% (P > 0.05 for all comparisons). The typical reticulonodular infiltrate of pulmonary paracoccidioidomycosis was frequently observed in the Pbm-HIV cohort. The co-infected patients with disseminated disease also had more intense alveolar infiltration that was occasionally accompanied by a miliary micronodular infiltrate and mediastinal adenomegaly (Figures 1 and 2).

Results of laboratory tests for the diagnosis of paracoccidioidomycosis are shown in Table 4. The diagnostic yield of the different methods (direct microscopic examination of the lesions and secretions, isolation of P. brasiliensis in culture, and histologic examination of the biopsy specimens) was comparable between the two groups. In the Pbm-HIV group, mycologic and histologic diagnosis of P. brasiliensis infection was made primarily through examination of skin samples, whereas the oral mucosa and lymph nodes were examined more often in the Pbm-Control group. Blood culture on brain heart infusion medium (prepared in-house) or tryptic soy broth (Bact Alert ®; bioMérieux) resulted in the isolation of P. brasiliensis in 5% (2 of 40) of the co-infected patients. Counterimmunoelectrophoresis showed that 76.0% and 96.1% of the Pbm-HIV and Pbm-Control group patients, respectively, were positive for serum antibodies to P. brasiliensis (P < 0.001).

The patients evaluated had been treated with antifungal therapy consisting of a single drug or a sequence of drugs. Treatment variations within and between the two groups were attributable to differences in clinical profiles, as well as in drug availability and patient access to drugs. In the Pbm-HIV group, the initial or secondary treatment included amphotericin B in 44.7% (21 of 47), trimethoprim-sulfamethoxazole in 59.6% (28 of 47), fluconazole in 25.5% (12 of 47), ketoconazole in 10.6% (5 of 47), and itraconazole in 6.4% (3 of 47). In the Pbm-Control group, the predominating treatment modality was monotherapy with trimethoprim-sulfamethoxazole, which was used in 81.1% (77 of 95) of the cases, followed by sul-fadiazine in 18.9% (18 of 95), amphotericin B in 9.5% (9 of 95), ketoconazole in 7.4% (7 of 95), and itraconazole in 2.1% (2 of 95). The duration of antifungal therapy ranged from a few months to 24 months or longer. A number of patients were lost to follow-up in the Pbm-HIV and Pbm-Control groups: at 6 months (4 and 6 patients, respectively); at 12 months (5 and 20 patients, respectively); and at 24 months (1 and 12 patients, respectively). For the patients not previously receiving antiretroviral treatment, HAART was started within the first three months after diagnosis of paracoccidioidomycosis, resulting in 83% (39 of 47) of the Pbm-HIV cohort patients receiving anti-retroviral and antifungal drugs concurrently.

Table 5 shows the outcomes in the two groups. In both groups, the response to antifungal therapy was generally favorable, with regression of fever and of P. brasiliensis lesions within a few weeks. Skin papules and nodules regressed rapidly, and the ulcers became flat scars. Chest radiographs taken at the end of the follow-up period (after 24 months) were available for 32 Pbm-HIV group patients and 59 Pbm-Control group patients. When the initial (6 months), follow-up (12 months), and final (24 months) chest radiographs were compared, there was improvement, no change or worsening in 68.8%, 25.0% and 6.2%, respectively, of the Pbm-HIV group patients, compared with 45.8%, 52.5% and 1.7%, respectively, of the Pbm-Control group patients (P = 0.017). In both groups, remission of paracoccidioidomycosis was usually associated with persistence of a diffuse reticular infiltrate suggestive of fibrosis.

Death caused by diseases other than paracoccidioidomycosis was higher in the Pbm-HIV cohort (Table 5). After these cases were excluded, there was no difference between the two groups in terms of the response to treatment after 6 and 12 months of follow-up. However, after 24 months of treatment, the co-infected patients had a lower rate of sustained remission and a higher rate of relapse than the Pbm-Control group (P < 0.05). There was no difference between the two groups in terms of the number of deaths attributed to paracoccidioidomycosis. All deaths caused by complications of this fungal disease occurred early (before or during the initial phase of antifungal therapy).

Results of treatment were analyzed for some co-infected patients who received only one antifungal drug at the beginning of treatment. Amphotericin B deoxycholate (total dose = 290–4,160 mg, mean = 1,280 mg) was administered to 12 patients, 7 of whom later received consolidation therapy with additional drugs: fluconazole (n = 2), ketoconazole (n = 2), itraconazole (n = 1), or trimethoprim-sulfamethoxazole (n = 2). Improvement or remission of paracoccidioidomycosis was observed in 7 (58.3%) of those 12 patients, whereas 2 (16.7%) of the 12 relapsed during the follow-up period and the remaining 3 (25.0%) died of other diseases. Trimethoprim-sulfamethoxazole (160/800 mg 3–4 times a day until clinical improvement, followed by 160/800 mg twice a day) was used for 2–72 months to treat 19 patients with paracoccidioidomycosis in the Pbm-HIV cohort patients. Four of those patients received the drug intravenously (240 mg/1,200 mg four times a day) during the first days of antifungal therapy. Trimethoprim-sulfamethoxazole induced clinical improvement or prolonged remission in 7 (36.8%) of those 19 patients, whereas 5 (26.3%) experienced remission followed by recurrence 7–18 months after the beginning of treatment, 1 (5.3%) had persistence of fungal lesions, and 6 (31.6%) died of other diseases. Fluconazole (400–600 mg/day during the induction phase, and 200–400 mg/day during the consolidation and maintenance phases) was administered for 1–43 months to 7 Pbm-HIV group patients. Improvement or remission of paracoccidioidomycosis was observed in 5 (71.4%) of those patients, although one was lost to follow-up. The remaining 2 patients (28.6%) died of other diseases at 8 and 19 months, respectively, after the diagnosis of paracoccidioidomycosis. There were no differences among the three antifungal drugs in terms of the remission and improvement rates.

DISCUSSION

The results of the present study demonstrate that in patients with HIV/AIDS, paracoccidioidomycosis has the characteristics of an opportunistic disease. The inclusion of a large number of patients co-infected with P. brasiliensis and HIV was the result of the increased endemicity of paracoccidioidomycosis in the northeastern region of the state of São Paulo, Brazil, where more densely populated cities have also been severely affected by the HIV/AIDS epidemic.19 Approximately 5% of the patients with paracoccidioidomycosis seen at our institution were infected with HIV. The number of cases of P. brasiliensis-HIV co-infection was not reduced after HAART became available in Brazil in 1996–1997. However, our study was not designed to assess the impact of HAART on the number of new cases of co-infection within the population of HIV/AIDS patients. Many HIV patients diagnosed with paracoccidioidomycosis after 1996 were not receiving HAART, principally because they were not aware of being infected with HIV, and because they refused antiretroviral treatment or did not fully comply with the treatment. Our findings suggest that in areas most affected by the HIV/AIDS epidemic, patients with disseminated paracoccidioidomycosis should be tested for HIV infection.

The estimated prevalence of paracoccidioidomycosis in HIV-infected persons (1.4%) is comparable to the 1.5% reported for the state of Mato Grosso do Sul, 10 another region of Brazil in which this fungal infection is endemic. In patients with AIDS in Brazil, as well in other regions of South America, the prevalence of paracoccidioidomycosis is lower than that of histoplasmosis and cryptococcosis. 14,20 This finding is in contrast to what is seen in the general population and might be a consequence of the epidemiologic differences between HIV infection and P. brasiliensis infection, the former predominating in larger urban centers and the latter primarily affecting small agricultural communities. 1,19 In patients with other causes of immunosuppression, paracoccidioidomycosis is less prevalent than is histoplasmosis or cryptococcosis, also suggesting a lower capacity of P. brasiliensis to reactivate from a latent primary focus. In the present study, 40% of the co-infected patients previously known to be HIV-infected were taking low doses of trimethoprim-sulfamethoxazole, which would seem to contradict the hypothesis that this medication protects against P. brasiliensis infection when used for prophylaxis of Pneumocystis jiroveci infection in AIDS patients. 21

In our study, the mean age of the patients with P. brasiliensis-HIV co-infection was lower than that of HIV-negative patients with paracoccidioidomycosis and was comparable to the demographic profile of AIDS cases in general. The typically age range of HIV-infected patients (20–40 years) is intermediate between the two age ranges commonly seen in cases of endemic paracoccidioidomycosis (< 25 years for those with the acute/subacute form and > 30 years for those with the chronic form). 2,3 Although not confirmed in the present study, a greater proportion of women has already been observed among the first reported cases of paracoccidioidomycosis associated with AIDS. 15 An increase in the rate of co-infected women is predictable as the consequence of the increasing involvement of women in the HIV/AIDS epidemic in Brazil. 19

Most of the P. brasiliensis-HIV co-infected patients evaluated in the present study worked in urban areas, suggesting that the epidemiology of paracoccidioidomycosis is changing. However, many patients reported they had been extensively exposed to rural environments in the past, when they might have been infected with P. brasiliensis. Therefore, we can presume that in those cases, paracoccidioidomycosis resulted from reactivation of a latent fungal infection, 22,23 as observed in cases of immunosuppression caused by use of cytotoxic drugs. 24

At the time of paracoccidioidomycosis diagnosis, HIV-infected patients commonly have low CD4+ cell counts 23,25 and high HIV viral loads, characterizing an immunosuppression status. This condition suggests P. brasiliensis opportunism. Reduction in the CD4+ cell count was also observed in endemic paracoccidioidomycosis, particularly in patients with the acute/subacute form. 26 Hypothetically, the fungal disease could intensify the HIV infection by further reducing the CD4+ cell count. Cases of co-infection in which the patient had a CD4+ cell count > 200 cells/mm3 and disseminated disease has been reported.9 In such cases, the role that HIV plays in the development of P. brasiliensis infection is unknown. In our study, no difference was observed between HIV-infected patients and HIV-negative patients regarding other factors predisposing to paracoccidioidomycosis, such as smoking and alcohol use. Although chronic liver disease caused by HCV was more common among the HIV-infected patients, liver disease has not been shown to predispose to paracoccidioidomycosis.

Patients infected with HIV commonly have rapidly progressive febrile disease and develop multiple lesions caused by hematogenous dissemination of the fungus and involvement of the monocyte-macrophage system. 10,25 In general, the clinical manifestations of paracoccidioidomycosis in co-infected patients are comparable to those seen in patients with the acute/subacute form of endemic paracoccidioidomycosis, in which the cellular immune response is also inadequate. 23 However, in some cases, the dissemination is quite extensive, as shown by diffuse skin and bone lesions. 18 In addition, many P. brasiliensis-HIV co-infected patients have lung lesions, sometimes showing atypical infiltrates, probably resulting from reactivation of the primary focus and from hematogenous dissemination. 25,27,28 This finding is in contrast to the pulmonary normality seen in the acute/subacute form of endemic paracoccidioidomycosis.2 The multiple extrapulmonary fungal lesions caused by hematogenous dissemination, together with the frequent and occasionally more intense pulmonary involvement, characterize a unique form of opportunistic paracoccidioidomycosis in persons with AIDS-related immunosuppression. Interestingly, lesions of the oral mucosa and of the respiratory airway mucosa were less common among the HIV co-infected patients. Such lesions are typical of the chronic form of endemic paracoccidioidomycosis and develop slowly after secondary involvement of the lymphatic tissue of the submucosa. Involvement of the adrenal glands and adrenal insufficiency are also more characteristic of the chronic form of paracoccidioidomycosis and were not observed in the Pbm-HIV cohort.

The diagnosis of paracoccidioidomycosis was established through histologic detection of P. brasiliensis, particularly in skin lesions, in a great percentage of the HIV co-infected patients. Many of those patients also had positive results for the mycologic examination, although the rate of isolation of P. brasiliensis in culture was lower than that reported for Histoplasma capsulatum isolation in cases of disseminated histoplasmosis in AIDS patients. 29 Cases of P. brasiliensis fungemia have been reported in HIV-infected patients. 30 The low rate of P. brasiliensis isolation from the blood of patients with HIV/AIDS in the present study was probably caused by the use of bacterial culture flasks, which were not appropriate for use with dimorphic fungi. Detection of antibodies to P. brasiliensis has been widely used for the diagnosis of paracoccidioidomycosis in persons not infected with HIV or in persons infected with HIV. Although false-negative results for this and other opportunistic infections have been observed in AIDS patients, 23,25 eventual failure of tests for antibodies will be overcome by detection of P. brasiliensis antigens.31

Antifungal treatment was more successful than in previous studies of P. brasiliensis-HIV co-infection. Most patients, including those who had not previously started HAART, showed full remission of fungal lesions during the first weeks of treatment. The immediate response to the antifungal agents was usually good, but the prognosis was less favorable for patients in the advanced stages of AIDS. During the 24-month follow-up period, 38% of the patients in the Pbm-HIV group died of causes other than paracoccidioidomycosis. Treatment with amphotericin B was prescribed more often in co-infected patients, but remission was also obtained with trimethoprim-sulfamethoxazole and with azole drugs. Although itraconazole is the drug recommended for treatment of paracoccidioidomycosis,4 a greater number of patients were treated with fluconazole, which can be obtained free of charge in Brazil. In controlling this fungal disease in patients with HIV/AIDS, fluconazole was as effective as was amphotericin B and trimethoprim-sulfamethoxazole. In a study with immunocompetent patients, fluconazole resulted in improvement or remission of paracoccidioidomycosis in 27 (93%) of the 29 cases at the end of treatment. 32 Trimethoprim-sulfamethoxazole elicited a satisfactory response during the first months of treatment of the co-infected patients but failed in more cases on long-term evaluation. The results related to the use of the three principal drugs used for primary antifungal therapy in the Pbm-HIV cohort should be compared with caution because the distribution of patients treated with the different drugs was not controlled.

Recurrence of paracoccidioidomycosis was more common in HIV co-infected patients, demonstrating that antifungal agents do not eradicate P. brasiliensis from the injured tissues. Therefore, it is advisable to continue maintenance treatment against the fungus in patients with CD4+ cell counts < 200 cells/mm3, even if those patients meet the criteria proposed for cure of the mycosis.4 Except for one case, all co-infected patients who were still alive had received antifungal treatment for more than 24 months. In HIV co-infected patients, the cure of paracoccidioidomycosis requires prolonged anti-fungal treatment and regular use of the drugs in combination with the antiretroviral agents. Even in patients with an initial CD4+ cell count > 200 cells/mm3 or in patients who achieve immunologic recovery, 18–24 months of treatment might be needed to prevent relapse.

The lethality attributed to paracoccidioidomycosis in the present study was relatively low compared with that seen among the first reported cases of P. brasiliensis co-infection.15,16 This finding might be explained by the earlier diagnosis and initiation of antifungal treatment and use of HAART. Deaths from paracoccidioidomycosis occurred before or at the beginning of antifungal therapy among HIV-infected patients and HIV-negative patients.

In patients with HIV/AIDS, the epidemiologic and clinical characteristics of paracoccidioidomycosis differed from those of the recognized forms of the endemic disease. Therefore, it should be classified as opportunistic paracoccidioidomycosis and included among the diseases that define AIDS in HIV-infected patients living in Latin America.

Table 1

Characteristics of human immunodeficiency virus-infected patients at the time of diagnosis of paracoccidioidomycosis*

Table 1
Table 2

Epidemiologic data and comorbidities of paracoccidioidomycosis patients co-infected (Pbm-HIV) or not co-infected (Pbm-Control) with human immunodeficiency virus (HIV)*

Table 2
Table 3

Clinical manifestations of paracoccidioidomycosis in patients co-infected (Pbm-HIV) or not co-infected (Pbm-Control) with human immunodeficiency virus (HIV)*

Table 3
Table 4

Diagnosis of paracoccidioidomycosis in patients co-infected (Pbm-HIV) or not co-infected (Pbm-Control) with human immunodeficiency virus (HIV), by laboratory method used

Table 4
Table 5

Response to treatment by paracoccidioidomycosis patients co-infected (Pbm-HIV) or not co-infected (Pbm-Control) with human immunodeficiency virus (HIV) at different times during follow-up

Table 5
Figure 1.
Figure 1.

Pre-treatment chest radiograph showing typical reticulonodular bilateral infiltrate of paracoccidioidomycosis. The diffuse micronodules have a miliary aspect in this patient co-infected with human immunodeficiency virus.

Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 80, 3; 10.4269/ajtmh.2009.80.359

Figure 2.
Figure 2.

Lung paracoccidioidomycosis and co-infection with human immunodeficiency virus. Chest radiograph before treatment showing severe bilateral reticulonodular and alveolar infiltrate plus mediastinal lymphadenomegaly.

Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 80, 3; 10.4269/ajtmh.2009.80.359

*

Address correspondence to Roberto Martinez, Divisão de Moléstias Infecciosas e Tropicais, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Avenida Bandeirantes 3900, 14049-900, Ribeirão Preto, SP, Brazil. E-mail: rmartine@fmrp.usp.br

Authors’ addresses: Karen M. Loro Morejón, Departamento de Clínica Médica, Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, SP, Avenida Bandeirantes 3900, 14048-900, Ribeirão Preto, SP, Brazil, E-mail: karenmorejon@uol.com.br. Alcyone Artioli Machado and Roberto Martinez, Divisão de Moléstias Infecciosas e Tropicais, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Avenida Bandeirantes 3900, 14049-900, Ribeirão Preto, SP, Brazil, E-mails: aamachado@fmrp.usp.br and rmartine@fmrp.usp.br.

Acknowledgments: We thank Lúcia Helena Vitali for technical assistance; Drs. Gleusa de Castro, Maria Janete Moya, Marta Peinado, and Jeova Keny Collares for professional support; and Viviane Cunha Cardoso and Edson Zangiacomi Martinez for assistance in performing statistical analysis.

Financial support: This study was supported by the Brazilian National Ministry of Health (Unidade de Pesquisa e Desenvolvimento Tecnológico) Research and Technological Development Unit)/ National STD/AIDS Program, and the Fundação de Apoio ao Ensino, Pesquisa e Assistência of the Hospital das Clínicas, Faculty of Medicine of Ribeirão Preto, University of São Paulo.

Disclosure: None of the authors have any conflicts of interest.

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