Prevalence and Lethality Among Patients with Histoplasmosis and AIDS in the Midwest Region of Brazil

Received: 2 March 2016 | Revised: 30 May 2016 | Accepted: 19 July 2016 DOI: 10.1111/myc.12551

ORIGINAL ARTICLE

Prevalence and lethality among patients with histoplasmosis and AIDS in the Midwest Region of Brazil

1Institute of Tropical Pathology and Public Health, Federal University of Goiás, Goiania, Summary Goiás, Brazil Histoplasmosis is a systemic mycosis that is considered an important public health 2 Hospital of Tropical Diseases “Dr. Anuar problem. In this work, we performed a descriptive, observational, cross-sectional and Auad”, Goiania, Goiás, Brazil retrospective study with a secondary data analysis of medical records from 2000 to Correspondence 2012 at a tertiary hospital. The study sample consisted of 275 patients with laboratory- Thaísa C. Silva, Setor Universitário, Goiânia, confirmed Disseminated Histoplasmosis (DH)/AIDS. The results showed that the Goiás, Brazil. Email: [email protected] prevalence of DH associated with AIDS was 4.4%. The majority of patients were young adult men with fever in 84.2%, cough in 63.4%, weight loss in 63.1%, diarrhoea in 44.8% and skin manifestations in 27.6% of patients. In the overall cohort, the CD4 counts were low, but not significantly different in survivors and non-survivors. Higher levels of urea and lower levels of haemoglobin and platelets were observed in non- survivor patients (<.05). The global lethality was 71.3% (196/275). The results with high prevalence and lethality highlight the need to adopt measures to facilitate early diagnosis, proper treatment and improved prognosis.

KEYWORDS AIDS, histoplasmosis, prevalence

1 | INTRODUCTION The disease is endemic in South America; in Brazil, it has been reported in the south, southeast and northeast regions.5,8–10 In the Disseminated histoplasmosis (DH) is near the top of the list of AIDS- Midwest Region, there have been reports of 30 cases of histoplasmosis defining illnesses and AIDS-related deaths.1 The estimated incidence in the Mato Grosso do Sul State,8 and although there are frequent medi- of DH varies from 5% to 25% in persons with AIDS and residents of cal reports of large numbers of histoplasmosis in Goiás (Midwest Region), endemic areas,2,3 with variable lethality throughout the world that there are no epidemiological studies about its occurrence in this State. ranges from approximately 10% in developed countries to 30% in To assess the prevalence, clinical characteristics, and laboratory areas with limited financial resources.4,5 and evolutionary data of histoplasmosis associated with AIDS in the Infection is characterised by a wide spectrum of manifestations Goiania, Goiás State, we performed a retrospective study of disease ranging from asymptomatic illness to severe disseminated histoplas- from January 2000 to June 2012. mosis.6 Symptoms of patients include fever, chills, non-productive cough, headaches and general malaise. However, in AIDS patients, 2 | MATERIALS AND METHODS the disease has non-specific symptoms and usually occurs with unexplained fever and weight loss. Laboratory findings, such as serum 2.1 | Patients creatinine level >2.1 mg/dL and LDH level of >400 U/L, have been associated with an increased risk of severe manifestations, such as A retrospective study was conducted to analyse the cases of histo- septic shock, respiratory failure and death.7 plasmosis in HIV patients from a reference hospital from January

2000 to June 2012. This hospital is responsible for treating approxi- histoplasmosis, representing a prevalence of 4.4%, ranging from mately 90% of the HIV patients in Goiás. 0.9% in 2001 and 6.5% in 2011. The annual distribution of histo- The medical records of patients with AIDS (diagnosed according to plasmosis in AIDS patients showed an increased prevalence through the Brazilian Ministry of Health criteria) who had a diagnosis of histo- the years (Fig. 1). plasmosis were reviewed. Diagnosis of histoplasmosis was defined with Diagnostic confirmation occurred at a median of 10.5 days (per- standard mycologic examination methods from different fluids and tis- centiles 3–23) after admission, as defined by a positive culture in sues samples, including Giemsa stain and a positive culture in Sabouraud 64.1% of patients, cytology in 24.8% of patients and histopathology and Mycosel media, histoplasma antigen in urine and serum by immu- in 11.1% of patients. In this study, 40.1% (112/279) of patients were nological tests, or histopathologic consistent with H. capsulatum. diagnosed with DH and AIDS almost simultaneously, with interval less When available, the following information were collected: age, than 30 days. gender, occupation, residence area, clinical signs and symptoms, pres- The study population included 219 (78.5%) men and 60 (21.5%) ence of co-infections and treatment and evolution of the patients. women, with a median age of 37 years (range 30–49 years). Most of Laboratory data consisting of a full blood count, renal and hepatic func- the patients were born in the Goiás State (89.3%), came from urban tion tests and CD4+ cells count were recorded. Antifungal therapy for areas (82.1%), and did not have known risk activity for histoplasmosis, histoplasmosis was administered to 261 (93.6%) of the 279 patients. however, civil construction was the main activity for 23.3% ofpatients. Of the 279 patients study, four cases were excluded from the analysis because they had no record of the outcome death. 2.2 | Statistical analysis

Epi-Info, version 3.5.1 (Center for Disease Control and Prevention, 3.2 | Clinical findings Atlanta, GA, USA), was used for data entry. Descriptive statistics included the mean ± standard deviation (SD) or the median (range) for Clinical symptoms and/or signs of histoplasmosis began at a me- quantitative variables as well as the absolute and relative frequency dian of 26 days before the diagnosis (percentiles 9–70 days). The for categorical variables. We used Student t-test to compare means. most frequent clinical symptoms included: fever (84.2%), weight Univariate analyses were performed using Fisher’s Exact test or χ2 loss (63.1%), weakness (53.8%), cough (63.4%), dyspnoea (56.3%), methods for categorical variables. Multivariable analysis was per- hepatomegaly (47.7%), diarrhoea (44.8%), vomiting (36.3%), sple- formed using stepwise logistic regression to determine the association nomegaly (33%) and skin lesions (27.6%). Chest radiographies of the predictor variables with lethality. For all tests, statistical signifi- were available in 157 (56.3%) patients, of which 127 (80.9%) had cance level was determined at α=0.05. Statistical analysis was con- interstitial infiltrates. ducted using PASW Statistics 18® (version 18.0.0, SPSS Inc., Chicago, Illinois, USA). The study was approved by the Ethical Committee of 3.3 | Laboratory findings reference protocol no. 023/2011. Clinical laboratory findings were not available for all patients and ranged in completeness for each exam. A summary of the 3 | RESULTS demographic characteristics and laboratory findings of survivors and non-survivors can be found in Tables 1 and 2. In the over- 3.1 | Sociodemographic data all cohort, the chance of death was higher among female patients Out of 6330 AIDS cases found from January 2000 to June (OR=2.74 [95% CI 1.28–5.89]; P<.05) (Table 2); CD4 counts were 2012 at the studied hospital, 279 patients were diagnosed with low (range, 1–702 cells/mm3) with 85.9% <150 cells/mm3, but

FIGURE 1 Annual prevalence (2000– 2012 June) of histoplasmosis in patients with AIDS at Hospital of Tropical Diseases “Dr. Anuar Auad”. Goiânia, Goiás, Brazil Silva et al. | 61

TABLE 1 Demographic characteristics vs death of patients with disseminated histoplasmosis and AIDS attended at Hospital of Tropical Diseases “Dr. Anuar Auad”. Goiania, Goiás, Brazil, 2000–2012

Non-survivors Survivors

Demographic characteristics n=196 % n=79 % P-valuea Odds ratio (confidence interval 95%)

Age group 196 71.3 79 28.7 .387 10–29 48 24.5 17 21.5 1 30–49 118 60.2 54 68.4 0.77 (0.41–1.47) 50–72 30 15.3 8 10.1 1.33 (0.51–3.45) Sex .008b Female 51 26.0 9 11.4 2.74 (1.28–5.89) Male 145 74.0 70 88.6 1 Marital status .816 Single/divorced/separated/widowed 123 65.4 46 63.9 1.07 (0.61–1.89) Married/stable union 65 34.6 26 36.1 1 Educational level .959 ≤8 years 110 75.3 45 75.0 1.02 (0.51–2.04) >8 years 36 24.7 15 25.0 1 Place of origin .747 Goiânia/Metropolitan Region 86 44.6 34 43.6 1 Others Municipalities of Goiás 87 45.1 38 48.7 0.91 (0.52–1.57) Others States of Country 20 10.2 6 7.7 1.32 (0.49–3.56) Residence area .112 Urban 172 90.5 55 83.3 1.91 (0.85–4.29) Rural 18 9.5 11 16.7 1 aChi-square test. bP<.05. were not significantly different in survivors and non-survivors 1.1% (n=3), tuberculosis 1.1% (n=3), and 56 cases (20.3%) had no data (P=.602) (Table 2). Higher levels of urea and lower levels of hae- available in the records. moglobin and platelets were observed in non-survivor patients (P<.05) (Table 2). In addition to DH, others opportunistic fungal infections were 4 | DISCUSSION observed in 58.1% of patients (162/279), 87.0% showed only one concomitant fungal infection DH and 13.0% of patients with over one Histoplasmosis continues to be an important opportunistic mycosis fungal infection. The main concomitant infections were oral candidia- among AIDS patients.11,12 In endemic areas, the incidence of histo- sis (82.7%), pneumocystosis (25.9%) and cryptococcosis (2.5%). Three plasmosis occurs in 5 to 20% of these patients.2,13 This work confirms confirmed cases of tuberculosis after DH diagnosis. that histoplasmosis is largely associated with AIDS. We found high morbidity with a prevalence of histoplasmosis cases of 4.4%. Endemic areas with a high prevalence of histoplasmosis have been observed in 3.4 | Treatment and lethality Central America and in South America, including Brazil.8,9,14–16 Pontes Antifungal therapy for DH was administered to 261 patients et al.,5 in a study conducted in Ceará, reported a prevalence of histo- (93.6%). Amphotericin B (AmB) dexycholate (0.7–1.0 mg/kg daily plasmosis in patients with AIDS at 4.2%; in the study by Casotti et al.17 intravenously) alone was administered to 115 (44.1%) patients. carried out at Espírito Santo, the prevalence was 2.1%. However, Amphotericin B, as an initial therapy followed by maintenance ther- the prevalence of histoplasmosis may be underestimated, probably apy with itraconazole (400 mg for 6 months), was administered to due to the lack of effective diagnostic methods associated with the 146 patients (55.9%). Eighteen patient had never stated a specific lack of mandatory reporting of clinical and/or laboratory-confirmed treatment. cases.18,19 The 275 patients followed until the end of the study had an overall According to Brilhante et al.,20 the 21st century has witnessed lethality of 71.3% (196/275). The treatment was effective in 28.7% an increase in the number of histoplasmosis cases, in which they re- of patients, and 79 patients received hospital discharge. The primary ported 208 cases between 2006 and 2010 vs 164 cases from 1995 cause of death in certificate was confirmed to be DH in 9.2% of to 2004. The number of histoplasmosis found in our cases was higher patients (18/196), with a global lethality of 6.5% (18/275). AIDS was from 2007 to 2012 (184 cases) than that found from 2000 to 2006 basic cause of death in 44.7% (123/275) of patients, followed by other (95 cases). A possible explanation is the improvement of diagnosis in complications like pneumonia 1.4% (n=4), respiratory insufficiency the context of greater experience by health professionals. Throughout 62 | Silva et al.

TABLE 2 Laboratory findings vs death of patients with disseminated histoplasmosis and AIDS attended at Hospital of Tropical Diseases “Dr. Anuar Auad”. Goiânia, Goiás, Brazil, 2000–2012

Non-survivors Survivors

Laboratory findings n % n % P-valuea Odds ratio (confidence interval 95%)

Pancytopenia .683 Yes 19 67.9 9 32.1 1 No 176 71.5 70 28.5 1.19 (0.51–2.76) Haemoglobin (g/L) .007b <10 128 77.1 38 22.9 2.06 (1.21–3.51) ≥10 67 62.0 41 38.0 1 Leucocytes (cells/mL) .332 <3500 99 73.9 35 26.1 1.30 (0.77–2.19) ≥3500 96 68.6 44 31.4 1 Platelets (cells/mL) <.001b <100 000 90 84.1 17 15.9 3.16 (1.72–5.79) ≥100 000 104 62.7 62 37.3 1 Creatinine (mg/dL) .096 <1.5 130 68.4 60 31.6 1 ≥1.5 47 79.7 12 20.3 1.81 (0.89–3.65) Urea (mg/dL) <.001b ≥40 102 82.3 22 17.7 2.93 (1.63–5.26) <40 76 61.3 48 38.7 1 AST (IU/L) .258 <45 36 65.5 19 34.5 1 ≥45 132 73.3 48 26.7 1.45 (0.76–2.77) ALT (IU/L) .531 <43 74 69.2 33 30.8 1 ≥43 94 72.9 35 27.1 1.20 (0.68–2.11) DHL (IU/L) .361 <480 23 82.1 5 17.9 1.63 (0.56–4.73) ≥480 76 73.8 27 26.2 1 FA (IU/L) .527 <300 26 72.2 10 27.8 1 ≥300 26 78.8 7 21.2 1.43 (0.47–4.33) CD4+ (cells/mL) .602 ≤50 60 62.5 36 55.4 1.82 (0.73–4.55) 51–100 16 16.7 12 18.5 1.46 (0.48–4.41) 101–150 9 9.4 5 7.7 1.97 (0.50–7.69) >150 11 11.5 12 18.5 1 HIV viral load (cells/mL) 87 64.0 49 36.0 .394c – Mean 366 677.8 264 760.8 aChi-square test. bP<.05. cStudent t-test. the decade, the programme has intensified the surveillance of AIDS to descriptively analyse patients with histoplasmosis and AIDS in the patient monitoring and the reporting of cases, thus stimulating the state of Goiás. search for medical services and adherence to antiretroviral therapy. The ratio of males to females described in the literature varies from As have been reported, histoplasmosis is the first infection of 2 to 5.11,20,25,26 Data similar to this study was found to have a ratio of AIDS in 50 to 75% of HIV-positive patients in endemic areas.21,22 3.6:1. The greater participation of young adult males can be explained In this study, 40.1% of patients had histoplasmosis as the first man- by the fact that they represent the main cohort affected by HIV.9,25 ifestation of AIDS. Some workers showed rates of 34 to 100% in The high frequency of cases in urban areas with no history of the number of patients who had DH as the first manifestation of previous contact is a microfoci that is possibly found in our work AIDS.17,23,24 Despite frequent medical reports of large numbers of and enhances the aspect of histoplasmosis as an emerging disease histoplasmosis in Goiás (Central Midwest Region), there are no epi- that is essentially losing its rural character. Potential urban foci of demiological studies regarding its occurrence. This is the first study H. capsulatum should be investigated to assess the natural habitat Silva et al. | 63 of the fungus.27 These data also emphasise the need to investigate Brilhante et al.20 and Pontes et al.5 observed an elevation of LDH that symptomatic patients, even without a history of contact withan was two times higher than the normal range in individuals with histo- environmental risk factor.9 As this is a retrospective study, it was not plasmosis and AIDS. High LDH can be considered as a poor prognostic possible to assess the potential exposure to microfoci suspected of factor in histoplasmosis cases.38 causing infection because of the absence of information in the med- Advanced immunosuppression is the most important risk factor ical records. It is possible that these patients could have acquired for the development of histoplasmosis.11,39 Histoplasmosis patients the infection due to occupational risk for increased exposure to with CD4 counts of less than 150 cells/mL are at the highest risk conidia of H. capsulatum found in soils.28,29 Similar to the results for the severe disseminated form and often fatal conditions.40 At found by Mata-Essayag et al.,27 activities such as construction, farm diagnosis, most patients had CD4+ counts <150 cells/mL, and in work and domestic cleaners were the main occupations reported. some patients, this count was not performed because there was no It is well known that histoplasmosis in an immunosuppressed host suspicion of histoplasmosis/HIV at admission. Although most patients may develop reinfection or foci reactivation.25 Because agricul- (85.7%) in our work had CD4 cells counts <150 per mm3, this factor tural activity in the state of Goiás is intense, it is possible that many did not significantly contribute to death, as shown in Table 1. The cases reflect the reactivation of endogenous infection acquired from CD4+ cells count is considered a fundamental parameter for moni- previous contact with the soil. toring the evolution of antiretroviral therapy in AIDS patients41 and The clinical features of histoplasmosis tend to be non-specific.30 provides prophylactic treatment with itraconazole in patients with This work confirms the profile of patients with histoplasmo- histoplasmosis in specific areas of endemicity.42 sis and AIDS where clinical features were similar to other reports Histoplasmosis associated with AIDS involves different organs characterised mainly by fever, weight loss, acute renal failure and and systems and, if untreated, can reach a lethality of up to 80%; respiratory.10,17,26,31 Due to the non-specific symptoms, histoplas- however, when antifungal therapy is used, this may reduce the mosis may be confused with acute lung disease, chronic pulmonary percentage to 25% or less.14,43 Treatment of AIDS associated with forms of aspergillosis and tuberculosis, disseminated forms of acute histoplasmosis, according to protocols, has an induction phase of miliary tuberculosis, leucosis and lymphomas, carcinomas, cutaneous 12 weeks and maintenance therapy varies according to the immu- leishmaniasis, tertiary syphilis, leukoplakia and lichen planus.32 The nity of patients.25,42,44 In this study, most of the patients received difficulty of a differential diagnosis compromises treatment and may treatment with amphotericin B, which was used as the primary lead to patient death. Cutaneous lesions, such as umbilicated papules, antifungal induction therapy followed by maintenance therapy with pustulas, nodules and folliculitis, can lead to early diagnostic suspi- itraconazole. The lethality rate of 6.5%, considering histoplasmosis cion.33,34 In this work, the skin lesions resulting from the haematog- as the underlying cause, was lower than that observed in other stud- enous spread of H. capsulatum were described in 27.6% of patients. ies where the percentages ranged from 32% to 42.3%.10,11,20 It is In Brazil, Mora et al.24 also reported the occurrence of skin injury in possible that the rate found in our work was a consequence of the 43.9% of patients. investigational work-up on each patient allowing for an appropriate Patients with histoplasmosis and AIDS are often concurrently diagnosis and timely treatment. infected with other opportunistic pathogens. According to the In conclusion, this study has demonstrated that DH is a com- Ministry of Health of Brazil,35 candidiasis, pneumocystosis and mon disease in the Midwest Region of Brazil and causes high cryptococcosis were reported co-infections in histoplasmosis/AIDS lethality in patients with HIV/AIDS. Thus, our study suggests that patients. At diagnosis of histoplasmosis, 58.1% of patients studied DH should be promptly recognised in these patients to provide in the present work had opportunistic infections, especially those clinical treatment. with CD4+ counts <150 cells/mL; oral candidiasis was the most com- mon clinical manifestation. These data indicate the need for a careful ACKNOWLEDGEMENTS search of co-infection. Among laboratory abnormalities, such as anaemia, increasedlevels The authors are grateful to Reginaldo Teixeira Nunes for assisting in of liver enzyme ALT/AST, lactate dehydrogenase (LDH), creatinine, data collection from medical records and to Dr. João Bosco Siqueira urea and CD4+ counts <150 cells/mL were observed in our work. Júnior for important contributions in data analysis. These data demonstrated that at the time of hospital admission, non- specific tests were requested in an attempt to diagnose the infection CONFLICTS OF INTEREST because there was no standardised protocol for investigation. Low levels of haemoglobin as well as high levels of AST/ALT in patients None of the authors report conflicts of interest. with histoplasmosis and AIDS may be aggravated by the use of antiretroviral therapy.5,11,17,30,31,36 AUTHOR CONTRIBUTIONS Lactic dehydrogenase (LDH) is a non-specific enzyme that is widely distributed throughout the lymphoid, hepatic, kidney, lung, Thaísa C. Silva: study concept and design, data collection, entry, brain tissue as well as cardiac muscle, skeletal, and in erythrocytes.37 analysis, and manuscript preparation, editing, writing, and review. This study showed that most patients had LDH levels over 480 IU/L. Carolina M. Treméa and Carolina R. Costa: data collection, entry, 64 | Silva et al. and manuscript review. Ana Laura S. A. Zara: data entry, analysis, clinical-laboratory study of 12 cases (1999-2001). Braz J Infect Dis. manuscript preparation, writing, editing, and review. Ana Flávia 2006;10:327–330. 18. Vicentini-Moreira AP, Kohara VS, Passos AN, et al. Microepidemia Mendonça: data collection and manuscript review. Cássia S. M. de histoplasmose no munícipio de Arapeí, São Paulo. Bepa. Godoy: study concept and design, and manuscript review. Lúcia K. 2008;5:8–11. H. Souza: study concept and design, manuscript writing, editing, 19. Prado M, Silva MB, Laurenti Luiz RR, Travassos LR, Taborda CP. and review. Maria R. R. Silva: study concept and design, manuscript Mortality due to systemic mycoses as a primary cause of death or in association with AIDS in Brazil: a review from 1996 to 2006.Mem Inst writing, editing, and review. Oswaldo Cruz. 2009;104:513–521. 20. Brilhante RS, Fechine MA, Mesquita JR, et al. Histoplasmosis in REFERENCES HIV-positive patients in Ceará, Brazil: clinical-laboratory aspects and in vitro antifungal susceptibility of Histoplasma capsulatum isolates. 1. Nacher M, Adenis A, Adriouch L, et al. What is AIDS in the Amazon Trans R Soc Trop Med Hyg. 2012;106:484–488. and the Guianas? Establishing the burden of disseminated histoplas- 21. Marshall BC, Cox JK, Carroll KC, Morrison RE. Histoplasmosis as a mosis. Am J Trop Med Hyg. 2011;84:239–240. cause of pleural effusion in the acquired immunodeficiency syn- 2. Wheat LJ, Kauffman CA. Histoplasmosis. Infect Dis Clin North Am. drome. Am J Med Sci. 1990;300:98–101. 2003;17:1–19. 22. Wheat LJ, Connolly-Stringfield PA, Baker RL, et al. Disseminated 3. Panel on Opportunistic Infections in HIV-Infected Adults and histoplasmosis in the acquired immune deficiency syndrome: clin- Adolescents. Guidelines for the prevention and treatment of oppor- ical findings, diagnosis and treatment, and review of the literature. tunistic infections in HIV-infected adults and adolescents: recom- Medicine. 1990;69:361–374. mendations from the Centers for Disease Control and Prevention, 23. Goldman M, Zackin R, Fichtenbaum CJ, et al. Safety of discontin- the National Institutes of Health, and the HIV Medicine Association uation of maintenance therapy for disseminated histoplasmosis of the Infectious Diseases Society of America. Available at http:// after immunologic response to antiretroviral therapy. Clin Infect Dis. aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. (Accessed on 2004;38:1485–1489. 19 Nov 2012). 24. Mora DJ, dos Santos CT, Silva-Vergara ML. Disseminated histoplas- 4. Karimi K, Wheat LJ, Connolly P, et al. Differences in histoplasmosis mosis in acquired immunodeficiency syndrome patients in Uberaba, in patients with acquired immunodeficiency syndrome in the United MG, Brazil. Mycoses. 2008;51:136–140. States and Brazil. J Infect Dis. 2002;186:1655–1660. 25. Pedroza BEP. Histoplasmose associada a HIV/aids. Estudo descritivo de 5. Pontes LB, Leitão TM, Lima GG, Gerhard ES, Fernandes TA. Clinical causuística em um centro de pesquisa no Rio de Janeiro (1987-2002). and evolutionary characteristics of 134 patients with disseminated Medicina Tropical. Rio de Janeiro: Instituto Oswaldo Cruz; 2003. histoplasmosis associated with AIDS in the State of Ceará. Rev Soc 26. Huber F, Nacher M, Aznar C, et al. AIDS-related Histoplasma capsula- Bras Med Trop. 2010;43:27–31. tum var. capsulatum infection: 25 years experience of French Guiana. 6. Cano MV, Hajjeh RA. The epidemiology of histoplasmosis: a review. AIDS. 2008;22:1047–1053. Semin Respir Infect. 2001;16:109–118. 27. Mata-Essayag S, Colella MT, Rosello A, et al. Histoplasmosis: a study 7. Wheat LJ, Chetchotisakd P, Williams B, Connolly P, Shutt K, Hajjeh of 158 cases inVenezuela, 2000-2005. Medicine. 2008;87:193–202. R. Factors associated with severe manifestations of histoplasmosis in 28. Deepe GS. Histoplasma capsulatum. In: Mandell GL, Douglas AIDS. Clin Infect Dis. 2000;30:877–888. RG, Bennett JE, eds. Principles and practice of infectious diseases. 8. Borges AS, Ferreira MS, Silvestre MT, Nishioka Sde A, Rocha A. Philadelphia: Churchil Livingstonr; 2010:3305–3318. Histoplasmosis in immunodepressed patients: study of 18 cases seen 29. Colombo AL, Tobon A, Restrepo A, Queiroz-Telles F, Nucci M. in Uberlândia, MG. Rev Soc Bras Med Trop. 1997;30:119–124. Epidemiology of endemic systemic fungal infections in Latin America. 9. Unis G, Oliveira FM, Severo LC. Histoplasmose disseminada no Rio Med Mycol. 2011;49:785–798. Grande do Sul. Rev Soc Bras Med Trop. 2004;37:463–468. 30. Fredricks DN, Rojanasthien N, Jacobson MA. AIDS-related dis- 10. Chang MR, Taira CL, Paniago AMM, Taira DL, Cunha RV, Wanke B. seminated histoplasmosis in San Francisco, California. West J Med. Study of 30 cases of histoplasmosis observed in the Mato Grosso do 1997;167:315–321. Sul State, Brazil. Rev Inst Med Trop Sao Paulo. 2007;49:37–39. 31. Baddley JW, Sankara IR, Rodriquez JM, Pappas PG, Many WJ. 11. Daher EF, Barros FAS, Silva-Jr GB, et al. Risk factors for death in Histoplasmosis in HIV- infected patients in a southern regional med- acquired immunodeficiency syndrome-associated disseminated his- ical center: poor prognosis in the era of highly active antiretroviral toplasmosis. Trop Med Hyg. 2006;74:600–603. therapy. Diagn Microbiol Infect Dis. 2008;62:151–156. 12. Damasceno LS, Novaes AR, Alencar CHM, et al. Disseminated his- 32. Ministério da Saúde, Secretaria de Vigilância em Saúde, Departamento toplasmosis and aids: relapse and late mortality in endemic area in de Vigilância Epidemiológica. Doenças infecciosas e parasitárias: guia de North-Eastern Brazil. Mycoses. 2013;56:520–526. bolso. 8th edn. Brasília-DF, Brazil: Ministério da Saúde; 2010. 13. Burke DG, Emancipator SN, Smith MC, Salata RA. Histoplasmosis and 33. Reyes M, Arenas LR, Pichardo P, Vick R, Torres A, Zacarias R. Cutaneous kidney disease in patients with AIDS.Clin Infect Dis. 1997;25:281–284. histoplasmosis and AIDS. Gac Med Mex. 2003;139:270–275. 14. Wheat LJ, Sarosi G, McKinsey D, et al. Practice guidelines for the 34. Orsi AT, Nogueira L, Chrusciak-Talhari A, et al. Coinfecção histoplas- management of patients with histoplasmosis. Infectious Diseases mose e Aids. An Bras Dermatol. 2011;86:1025–1026. Society of America. Clin Infect Dis. 2000;30:688–695. 35. Ministério da Saúde, Secretaria de Vigilância em Saúde, Departamento 15. Leimann BC, Pizzini CV, Muniz MM, et al. Histoplasmosis in a de Vigilância Epidemiológica. Guia de Vigilância Epidemiológica. Brasília Brazilian center: clinical forms and laboratory tests. Rev Iberoam Micol. – DF, Brazil: Ministério da Saúde, 2009. 2005;22:141–146. 36. Gutierrez ME, Canton A, Sosa N, Puga E, Talavera L. Disseminated his- 16. Oliveira MF, Unis G, Severo LC. An outbreak of histoplasmo- toplasmosis in patients with AIDS in Panama: a review of 104 cases. sis in the city of Blumenau, Santa Catarina. J Bras Pneumol. Clin Infect Dis. 2005;40:1199–1202. 2006;32:375–378. 37. Motta VT. Bioquímica Clínica: Princípios e Interpretações. In: Motta 17. Casotti JA, Motta TQ, Ferreira CU Jr, Cerutti C Jr. Disseminated his- VT, ed. Bioquímica clínica para o laboratório, 5th edn. Rio Grande do toplasmosis in HIV positive patients in Espirito Santo state, Brazil: a Sul: Medbook; 2009:215–233. Silva et al. | 65

38. Couppie P, Sobesky M, Aznar C, et al. Histoplasmosis and acquired em Adultos Infectados pelo HIV. 7th edn. Brasília-DF, Brazil: Ministério immunodeficiency syndrome: a study of prognostic factors.Clin Infect da Saúde; 2008. Dis. 2004;38:134–138. 42. Wheat LJ, Freifeld AG, Kleiman MB, et al. Clinical practice guide- 39. McLeod DS, Mortimer RH, Perry-Keene DA, et al. Histoplasmosis lines for the management of patients with histoplasmosis: 2007 in Australia: report of 16 cases and literature review. Medicine. update by the Infectious Diseases Society of America. Clin Infect Dis. 2011;90:61–68. 2007;45:807–825. 40. Tobon AM, Agudelo CA, Rosero DS, et al. Disseminated histoplasmo- 43. Roy D, Guha P, Bandyopadhyay D, Sardar P, Chatterjee SK. sis: a comparative study between patients with acquired immunode- Pancytopenia with hemophagocytic syndrome associated with his- ficiency syndrome and non-human immunodeficiency virus-infected toplasmosis in acquired immundeficiency syndrome: description of individuals. Am J Trop Med Hyg. 2005;73:576–582. 2 case studies and literature review. J AIDS Clin Res. 2011;2:115. 41. Ministério da Saúde, Secretária de Vigilância em Saúde, Programa 44. Kauffman CA. Histoplasmosis: a clinical and laboratory update. Clin Nacional de DST e AIDS. Recomendações para Terapia Anti–retroviral Microbiol Rev. 2007;20:115–132.