Mycopathologia DOI 10.1007/s11046-014-9755-3
Epidemiology of Invasive Fungal Infections in Patients with Acquired Immunodeficiency Syndrome at a Reference Hospital for Infectious Diseases in Brazil Renata Buccheri de Oliveira • Jane Harumi Atobe • Simone Aparecida Souza Daniel Wagner de Castro Lima Santos
•
Received: 24 November 2013 / Accepted: 2 May 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract Invasive fungal infections (IFIs) represent one of the main causes of morbimortality in immunocompromised patients. Pneumocystosis, cryptococcosis and histoplasmosis are the most frequently occurring IFIs in patients with acquired immunodeficiency syndrome (AIDS). Fungi, such as Candida spp. and Aspergillus spp., may cause severe diseases during the course of an HIV infection. Following the introduction of highly active anti-retroviral therapy, there has been a marked reduction of opportunistic fungal infections, which today is 20–25 % of the number of infections observed in the mid-1990s. This study is an observational and retrospective study aimed at the characterising IFI incidence and describing the epidemiology, clinical diagnostic and therapeutic features and denouement in HIV/AIDS
patients. In HIV/AIDS patients, the IFI incidence is 54.3/1,000 hospitalisation/year, with a lethality of 37.7 %. Cryptococcosis represents the main opportunistic IFI in the population, followed by histoplasmosis. Nosocomial pathogenic yeast infections are caused principally by Candida spp., with a higher candidemia incidence at our institution compared to other Brazilian centres. Keywords Invasive fungal infections AIDS Cryptococcosis Histoplasmosis Candidemia Emerging opportunistic yeast infections
Introduction R. B. de Oliveira J. H. Atobe S. A. Souza D. W. de Castro Lima Santos Instituto de Infectologia Emı´lio Ribas, Sa˜o Paulo, SP, Brazil D. W. de Castro Lima Santos Laborato´rio Especial de Micologia - LEMI, Departamento de Infectologia, Universidade Federal de Sa˜o Paulo, Sa˜o Paulo, SP, Brazil Present Address: D. W. de Castro Lima Santos (&) Commission of Hospital Infection Control, Institute of Infectious Diseases Emı´lio Ribas, Avenida Doutor Arnaldo, 165, Cerqueira Ce´sar, Sa˜o Paulo, SP, Brazil e-mail: [email protected]
Invasive fungal infections (IFIs) represent one of the main causes of morbimortality in immunocompromised patients [1]. These infections generally occur in patients undergoing chemotherapy (with or without neutropenia) for neoplastic diseases, hematopoietic stem cell transplant (HSCT) or solid organ transplant and therapy with high or prolonged doses of corticoids as well as those with an advanced stage HIV infection who have not undergone retroviral therapy. IFIs also occur in gastrointestinal surgery patients, autoimmune disease patients receiving new immunobiological therapies, premature infants, the elderly and critical patients at an intensive care unit [2].
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Mycopathologia
In patients with AIDS, pneumocystosis, cryptococcosis and histoplasmosis are considered to be the most frequent IFIs. Other fungi, especially Candida spp. and Aspergillus spp., may cause severe diseases during the course of an HIV infection [3, 4]. However, there has been a marked reduction in the occurrence of opportunistic infections in the countries where highly active antiretroviral therapy (HAART) has been introduced, and following the introduction of HAART, opportunistic fungal infection-incidence has been reduced to 25–20 % of those reported in the mid1990s [5]. Because IFIs are increasingly recognised as the major cause of morbidity and mortality in immunocompromised patients and because these opportunistic diseases are often severe and fatal, epidemiological knowledge is essential for prompt diagnostic and therapeutic procedures. This study was aimed at the characterising the epidemiology of IFI incidence, clinical diagnostic and therapeutic features and denouement (mortality) in HIV/AIDS patients at the Institute of Infectious Diseases Emilio Ribas.
bacteriology/mycology department in a central laboratory and by pathological anatomy. Systematic sampling of clinical data was performed by reviewing the medical records accessed by a medical files service. The studied variables were: gender, age, CD4, CD8, viral load, previous opportunistic infection, hospitalisation time, treatment and mortality. The study criteria used for defining AIDS were according to the CDC norms [6]. Pneumocystosis cases were excluded. Presumptive diagnoses based on radiological and non-specific laboratory results (lactate dehydrogenase and PaO2) were according to the standards of most services, where microbiological confirmation is underused. HIV infection was diagnosed by the enzyme-linked immunosorbent assay and confirmed by Western blot. The data were stored in a data bank, and simple frequencies of the results were calculated. The present study was analysed and approved by the Ethics in Research Committee (CEP) at the IIER, protocol 19/2012 from September 27, 2012.
Results Materials and Methods This was an observational and retrospective study performed at the Institute of Infectious Diseases Emilio Ribas, which is a tertiary public health care institution that serves as a reference centre for infectious disease treatment in the Sao Paulo state and in Latin America. The institute has 199 active hospital beds; an intensive care unit with 17 beds and an emergency care unit. For this study, an IFI case was defined as any patient diagnosed between January 1 to December 31 with HIV/AIDS who had a suggestive clinical diagnosis of fungal infection that was confirmed by at least one of the following exams during hospitalization: positive culture of biological material collected from a normally sterile site (blood, liquor, pleural fluid, peritoneal fluid, etc.); positive culture of biological material collected from a normally non-sterile site (bronchoalveolar lavage, urine, etc.) associated with histopathology; confirmed presence of fungal elements; and inflammation and/or radiological changes suggesting infectious activity. The identification of IFIs was performed during the search for microbiological and histopathological information in
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In 2011, 24.482 medical care cases were seen at the IIER emergency unit, resulting in 2.611 (10.7 %) hospitalisations. An HIV/AIDS infection was the basic diagnosis in 1.692 (64.8 %) of these cases. The total number of HIV/AIDS patients admitted per day was 31.577, and lethality occurred in 262 cases (15.5 %). In biological material culture analyses, 126 patients presented a histopathological diagnosis and/or agent isolation, of which 104 were diagnosed with HIV/ AIDS. Three patients who had medical records that were not available, three patients who had only a superficial fungal infection, four patients who had pneumocystosis and four patients who had were believed to have sampling contamination were excluded from the analyses. In 122 patients, the diagnosis and empiric treatment for pneumocystosis was according to clinical, laboratory and radiological data, and four patients received a microbiological diagnosis by the direct detection of the agent by o-toluidine staining. In total, 90 HIV/AIDS patients presenting with an IFI diagnosis were considered. Two patients presented with an IFI episode during the studied year. There was a total of 92 IFI episodes in the cohort. The IFI incidence in the HIV/AIDS patients was 54.3/1.000
Mycopathologia
Fig. 1 Incidence rate of systemic fungal infections in HIV/ AIDS patients Table 1 Epidemiologic and demographic data as T CD4 and CD8 cells count, viral load, antiretroviral therapy and mortality in HIV/AIDS patients presenting IFI diagnostic at the Institute of Infectious Diseases Emilio Ribas Variables
Value
Age, mean (range)
32 (14–78)
Sex Male
63/90 (70 %)
Female
27/90 (30 %)
Risk factor for HIV infectiona Homosexual
17 (24 %)
Heterosexual
36 (50 %)
Injecting/inhalation drugs Blood transfusion
13 (18 %) 2 (2.0 %)
Vertical transmission
3 (4.0 %)
T cell count CD4b
89 (2–744)
Mean (cel/mm3), range T cell count CD8c
558 (9–2,545)
Mean (cel/mm3), range Viral loadd
81.603 (50–500.000)
Mean (copies/ml), range HAARTe Regular
22 (26,8 %)
Irregular
23 (28 %)
Abandonment
23 (28 %)
Not started
14 (17 %)
First opportunistic infection
12/90 (13.3 %)
Mortality
34/90 (37.7 %)
a c e
Evaluated in 71 patients; Evaluated in 86 patients; Evaluated in 82 patients
b d
Evaluated in 86 patients; Evaluated in 82 patients;
hospitalisations per year. IFI was considered the first opportunistic infection in 32 (35.5 %) patients, and AIDS was the defining illness in 12 patients (13.3 %). Of these, 90 patients, 34 (37.7 %) died during hospitalisation (Fig. 1). Epidemiologic and demographic data, such as CD4 and CD8 levels, T cell-count, viral load, anti-retroviral therapy and mortality are described in Table 1. Each IFI, including the mean age, incidence, mortality, CD4 level, viral load, time of HIV infection, treatment and time of hospitalisation, is described in Table 2. In 2011, cryptococcosis incidence in AIDS patients was 36/1.000 hospitalisations per year. The infectious agent was isolated from the cerebrospinal fluid (CSF) in 50 cases (82 %). In four cases (6.5 %), diagnosis was performed exclusively by agent isolation from a peripheral blood culture. In three cases (4.9 %), the agent was isolated exclusively from the respiratory material. Urine, synovial fluid and ascitic fluid were also used as isolation sites. Ten cases (16.3 %) showed neurocryptococcosis relapse, and only two patients used secondary prophylaxis with fluconazole. Fungal disease was considered as an AIDS-defining disease according to the CDC criteria in 10 cases (16.3 %). Global mortality for all of the cryptococcosis cases was 34.4 %. Of the 50 neurocryptococcosis cases, 15 (30 %) presented with a positive blood culture. The agent was identified as Cryptococcus neoformans in all cases through specific laboratory tests (Canavanine–glycine–bromothymol blue agar). The different varieties of the C. neoformans species were not assessed because our centre does not perform this test routinely. Specific treatment with antifungal drugs was given to 47 patients. Of these, 44 (93.6 %) patients began therapy with amphotericin B deoxycholate, in which 13 cases (29.5 %) where changed to lipid formulations due to nephrotoxicity induced by the first formulation. Three cases (6.3 %) were treated exclusively with the amphotericin B lipid formulation. Combination therapy was performed in 16 cases (34 %), with amphotericin B deoxycholate and fluconazole. The treatment data were not available for two patients, and another patient received the test result after discharge from the hospital. The global mortality rate for Neurocryptococcosis was 32 %.
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Mycopathologia Table 2 Specific data for each IFI, mean age, incidence, mortality, CD4, viral load, time of HIV infection, treatment and time of hospitalization Mycoses
N°
Incidence (cases/1.000 hospitalizationyear)
Mean age (years)
Time of HIV infection
CD4 (cel/mm3)
Viral load (copies/ ml)
Time of treatment (days)
Hospital stay (days)
Mortality
Cryptococcosis
61
36
38
8 years
83 (2–744)
89.309
31
33
34.3 % (21)
Histoplasmosis Paracoccidiodomycosis
12 1
7.1 0.5
36 45
7 years Diagnosis at admission
38 (2–170) 6
73.102 36.195
18 7
29 7
33,3 % (4) 100 % (1)
1
0.5
25
10 years
26
70.961
7
28
Lost follow up
Aspergillosis
Murcomycosis Invasive candidiasis
1
0.5
20
30 years
4
380
28
70
100 % (1)
14
8.3
36
8 years
126 (3–720)
100.175
16
52
50 % (7)
Trichosporonosis
1
0.5
26
1 months
55
64.051
21
21
–
Saccharomyces spp.
1
0.5
75
20 years
539
\50
21
56
100 % (1)
Pulmonary involvement by Cryptococcus spp. was confirmed by microbiological tests in five cases. The main symptoms were a cough and dyspnoea (66.6 % of cases). In four patients, pneumopathy caused by Cryptococcus ssp. was diagnosed by a transbronchial biopsy and in one case by a bronchoalveolar lavage culture. In all of the cases, no other infectious agents was isolated that would justify the involvement of respiratory; however, there was a single case with a concurrent Kaposi’s sarcoma diagnosis. Treatment was instituted in four cases, and in one case, the treatment information was not available in the records. Three of the four patients responded well to the treatment; however, one patient died due to the pulmonary involvement caused by Kaposi’s sarcoma. The global lethality of the pulmonary cases was 40 %. In two cases, C. neoformans was isolated from the ascitic fluid and synovial fluid, with no specific treatment during hospitalisation and a loss of followup after hospital discharge. C. neoformans was also isolated in blood and urine cultures from a patient hospitalised with symptoms of dysuria and fever who died 3 weeks after amphotericin B lipid formulation treatment, although the cause of death was related to sepsis caused by S. aureus. Histoplasmosis incidence in the AIDS patients was 7.1 cases/1.000 hospitalisations per year. The main symptoms were fever (58.3 %), headache (33.3 %)
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and cutaneous lesions (25 %). Histoplasmosis was considered as an AIDS-defining disease in two cases (17 %) and as the first opportunistic disease in one case. In six cases (50 %), Histoplasma capsulatum was isolated in peripheral blood culture. The agent was isolated or identified by specific staining of skin tissue (5 cases; 41.6 %), trachea biopsy (1 case; 8.3 %), epiglottis biopsy (1 case; 8.3 %), stomach biopsy (1 case; 8.3 %), bone marrow biopsy (1 case; 8.3 %) and pulmonary biopsy (1 case; 8.3 %). Amphotericin B treatment was given to 11 patients. In one case, the patient did not receive disease-specific treatment because he died before the results of the laboratory analyses were obtained. Four cases resulted in death (33.3 %). Paracoccidiodomycosis was diagnosed in one patient by a skin biopsy and due to agent growth in a blood culture. Double immunodiffusion serology was 1/128, and an AIDS diagnosis was concluded during hospitalisation. After receiving amphotericin B deoxycholate treatment, the patient developed respiratory insufficiency and died. There was one case of invasive pulmonary aspergillosis in a patient initially diagnosed with neurotoxoplasmosis who developed respiratory complaints during hospitalisation. Radiological lung exams revealed diffuse bilateral infiltrates; later, Aspergillus fumigatus was isolated by a bronchoscopy with a bronchoalveolar lavage. Aspergillosis was
Mycopathologia
diagnosed according to images, clinical, microbiological criteria and patient improvement upon treatment with itraconazole. There was a case of mucormycosis, which was detected via colonoscopy, in a patient who had an ulcer in the ascending colon, as revealed during a colonoscopy. A colon biopsy showed wide and coenocytic hyphae, invading mucosa and smooth muscles. Amphotericin B lipid formulation treatment was performed. However, during hospitalisation, lung and pulmonary Kaposi’s sarcoma were diagnosed, and the patient died. There was one case of fungemia caused by Trichosporon spp. The agent was isolated from two peripheral blood samples and was identified as Trichosporon asteroides by cistron sequencing of the ribosomal IGS region. The patient was already using an azole derivate, which was retained as a treatment for this IFI. The patient’s health improved, and the patient was discharged. Finally, there was one case of an invasive Saccharomyces cerevisiae infection in a patient at the intensive care unit. Following 7 days of hospitalisation, yeast growth was detected in a peripheral blood culture, and caspofungin therapy was initialised. However, when Saccharomyces cerevisiae was identified as the infectious species by sequencing the ITS region, the caspofungin treatment was changed to liposomal amphotericin, which resulted in improve patient health. However, the patient died from causes unrelated to fungal infection. The invasive candidiasis incidence was 8.3 cases/ 1.000 AIDS-patient hospitalisation-year. Candidemia was diagnosed in 12 cases. In two cases, the agent was isolated from the CSF and bone marrow. The isolated species were Candida albicans (4 cases; 28.5 %), C. tropicalis (5 cases; 35.7 %), C. parapsilosis (4 cases; 28.5 %), C. glabrata (1 case; 7 %) and C. krusei (1 case; 7 %). One patient sample showed the growth of two species (C. albicans and C. glabrata). Of all of the patients, seven (50 %) were admitted to the intensive care unit, four (28.5 %) were neutropenic, eight (57 %) had a central venous catheter and one underwent gastrointestinal surgery. The average time of hospitalisation was 24 days, varying from 2 to 27 weeks. Treatment was administered in 11 patients. Seven cases were initially treated with amphotericin B, which was replaced by caspofungin (four cases) or fluconazole (three cases) following agent identification. The other three cases were treated exclusively with caspofungin, and one case was treated with liposomal amphotericin. The three patients that did not
received treatment died before a partial and/or final culture result. Of the total number of patients, seven died.
Discussion Over the past 10 years, the incidence of the main IFIs occurring with AIDS has progressively declined, as a result of routine prophylactic practices for Pneumocystis jiroveci (PCP) infections and HAART availability. Nevertheless, other IFI epidemiologic trends in the HIV-positive population are not well understood [7]. Antinori et al. [8] evaluated 1.630 AIDS patients in necropsy studies, observing IFIs in 297 (18.2 %) cases that were mostly in the advanced stage of the disease. Pneumocystosis had the highest frequency, followed by aspergillosis, cryptococcosis, candidiasis, histoplasmosis and mucormycosis. The incidence of IFI in autopsies has decreased significantly over time due to the wide use of HAART, decreasing from 25 % in the 1980s to 15.1 % in early 2000. In our study, we observed an incidence of 55.6 IFIs/ 1.000 AIDS patients hospitalisations-year. This is less than the total incidence estimated by Antinori et al. [8], where only the patients who died were analysed. Prado et al. [9] evaluated systemic mycosis as the primary cause of death in Brazil between 1998 and 2006. Systemic mycosis was recorded as cause of death on the death certificates in 5.898 (4.7 %) of patients with AIDS. Cryptococcosis was the cause of death in more than half of the cases, followed by candidiasis, histoplasmosis, aspergillosis, paracoccidiodomycosis, coccidiodomycosis and mucormycosis. Our study determined a global IFI mortality of 37.2 %, where the main cause of death was cryptococcosis, followed by invasive candidiasis, histoplasmosis, paracoccidiodomycosis, mucormycosis and Saccharomyces cerevisia fungemia. Therefore, the three main agents identified in this study are the same as those that were associated with AIDS patient-death in the study by Prado et al. [9]. Previous studies have shown a decline in mortality due to cryptococcosis in developed nations. Over the years, HAART has changed the demographic characteristics of patients with AIDS and cryptococcosis; previously these patients were older and unaware of their HIV infection at the time of diagnosis [10]. The
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Brazilian casuistry epidemiologic characteristics do not resemble the European and North American studies because 66 % of patients did not use or irregularly used HAART. Opportunistic infections are still frequent and cause an unacceptably high mortality in patients, despite treatment at a reference centre with a good infrastructure. However, when compared to the overall mortality of 55 % in Brazil, we realise that although the mortality is high, it is still better than in other regions [11]. Although we cannot assign cryptococcosis as the immediate cause of death to all cases because the cause of death in some cases was due to other infectious and/or pathological agents, in a recent study, an in-hospital mortality of 30 % was reported [12]. Therefore, many strategies for reducing mortality could be adopted by our institution, such as: (1) early HIV diagnosis and treatment; (2) screening and pre-emptive treatment for subclinical cryptococcosis; (3) optimised diagnosis of cryptococcal meningitis; and (4) optimised treatment of cryptococcal meningitis [13]. Because of advances in HAART, histoplasmosis incidence has decreased; however, the disease remains one of the most common opportunistic infections occurring in endemic areas [14]. Brazilian data are scarce, and the ability to estimate the real role of histoplasmosis in Brazil is limited. The disease can be severe and causes many deaths. In our study, the mortality rate was 33.3 %, similar to other studies in which this value varies between 30 and 65.2 % [15, 16]. It is possible that the present study may have several under-diagnosed cases because diagnostic resources, including molecular biological tools and antigen detection techniques, are not available for routine testing in Latin American countries. The case diagnoses in this study were performed mostly by agent isolation in conventional culture media or by pathological studies. The present casuistry had only one PCM case, with characteristics of a disseminated disease. PCM was detected by agent isolation in skin and blood cultures with a high serological titre of 1/128, suggesting that these tests may be useful, but they should not be used as the only methods to diagnose the disease. The literature shows that PCM diagnosis is performed by agent identification in biological samples (skin and sputum) or by serologic tests; however, these tests have a low sensitivity to low titration in immunosuppressed patients [17]. The relation between invasive
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aspergillosis (IA) and HIV infection has not been completely elucidated. In this study, the use of corticotherapy as an adjuvant therapy in neurotoxoplasmosis treatment may have been the reason for the development of aspergillosis. Moreover, the patients had presented with a positive diagnosis for AIDS for 10 years, indicating severe immunodepression. Interestingly, in a study in Italy, invasive aspergillosis was found to be the second most frequently occurring IFI [8]. However, the Italian study was performed postmortem, indicating that many aspergillosis cases in the present research may have been under-diagnosed. Mucormycosis is an aggressive disease and is often fatal. The scarcity of mucormycosis reports in HIV patients who do not use injected drugs indicates that HIV infection alone is not a significant risk factor to develop the disease [18, 19]. In the present study, there was only one case of mucormycosis, in which severe immunodepression, injected drugs usage and neutropenia were the main risk factors. Furthermore, intestinal involvement by cytomegalovirus and Kaposi’s sarcoma may have predisposed the patient to a local fungal invasion. Fungemia by Trichosporon spp. can occur due to an infected catheter and the breakdown of the cutaneous or digestive barrier [20]. The reports of this invasive infection in HIV patients are exceptional and the patient had only central venous catheter as a risk factor for this IFI [21]. Cases of fungemia by Saccharomyces cerevisiae have been related to usage of capsules containing yeasts, usually prescribed along with antibiotics and adjuvant therapy for diarrhoea caused by Clostridium difficile [22]. Other risk factors for the development of fungemia are permanent residence in an intensive care unit and using CVC, as in the case of a patient who did not use probiotics during hospitalisation. Candida is a pathogen of incontestable clinical relevance due to both increased disease incidence over the last few decades and the high morbid-mortality attributed to invasive disease episodes [23]. In the present study, the incidence of candidemia cases (7,1 cases/1.000 AIDS patients hospitalisation/year) is higher than the reports in the literature. In Brazil, Nucci et al. [23] reported an incidence of 1.38 cases every 1.000 hospitalisations, which is much lower than the incidence in the present study. As observed in other studies, HIV infection is not considered to be a high risk factor for candidemia. Characteristics with
Mycopathologia
respect to the use of invasive devices, previous antibiotics, parenteral nutrition and dialysis therapies are similar between the patients in the current study and the non-HIV patients. The distribution of Candida species showed a higher prevalence of non-albicans species (73 %) in many Brazilian and Latin American cases [23]. The limitations of this study include problems associated with retrospective studies, for example, the absence of a standardised history and others laboratory information. Moreover, although the number of patients studied here composed a representative sample, this study was performed for only 1 year. Therefore, a longer review is necessary to predict the actual incidence and mortality at our institution, which is responsible for the hospitalisation of 70 % of the patients with HIV/AIDS in Sa˜o Paulo. In conclusion, IFIs in HIV/AIDS patients remain an important cause of mortality in Brazil, despite the increasing availability of ATR. Cryptococcosis is the main IFI in our hospital, with a high mortality even in the postHAART (34.4 %) period. Other less common endemic IFIs are a rarity in our institute, as observed with paracoccidiodomycosis. Finally, nosocomial infections by pathogenic yeasts are mainly caused by Candida spp., with a higher incidence at our institute compared to other Brazilian centres. Acknowledgments This study was supported, in part, by the Centro de Estudos Emı´lio Ribas, Sa˜o Paulo, Brasil. Conflict of interest None of the authors have any potential conflict of interest or financial support in the subject matter.
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Epidemiology of Invasive Fungal Infections in Patients with Acquired Immunodeficiency Syndrome at a Reference Hospital for Infectious Diseases in Brazil Renata Buccheri de Oliveira • Jane Harumi Atobe • Simone Aparecida Souza Daniel Wagner de Castro Lima Santos
•
Received: 24 November 2013 / Accepted: 2 May 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract Invasive fungal infections (IFIs) represent one of the main causes of morbimortality in immunocompromised patients. Pneumocystosis, cryptococcosis and histoplasmosis are the most frequently occurring IFIs in patients with acquired immunodeficiency syndrome (AIDS). Fungi, such as Candida spp. and Aspergillus spp., may cause severe diseases during the course of an HIV infection. Following the introduction of highly active anti-retroviral therapy, there has been a marked reduction of opportunistic fungal infections, which today is 20–25 % of the number of infections observed in the mid-1990s. This study is an observational and retrospective study aimed at the characterising IFI incidence and describing the epidemiology, clinical diagnostic and therapeutic features and denouement in HIV/AIDS
patients. In HIV/AIDS patients, the IFI incidence is 54.3/1,000 hospitalisation/year, with a lethality of 37.7 %. Cryptococcosis represents the main opportunistic IFI in the population, followed by histoplasmosis. Nosocomial pathogenic yeast infections are caused principally by Candida spp., with a higher candidemia incidence at our institution compared to other Brazilian centres. Keywords Invasive fungal infections AIDS Cryptococcosis Histoplasmosis Candidemia Emerging opportunistic yeast infections
Introduction R. B. de Oliveira J. H. Atobe S. A. Souza D. W. de Castro Lima Santos Instituto de Infectologia Emı´lio Ribas, Sa˜o Paulo, SP, Brazil D. W. de Castro Lima Santos Laborato´rio Especial de Micologia - LEMI, Departamento de Infectologia, Universidade Federal de Sa˜o Paulo, Sa˜o Paulo, SP, Brazil Present Address: D. W. de Castro Lima Santos (&) Commission of Hospital Infection Control, Institute of Infectious Diseases Emı´lio Ribas, Avenida Doutor Arnaldo, 165, Cerqueira Ce´sar, Sa˜o Paulo, SP, Brazil e-mail: [email protected]
Invasive fungal infections (IFIs) represent one of the main causes of morbimortality in immunocompromised patients [1]. These infections generally occur in patients undergoing chemotherapy (with or without neutropenia) for neoplastic diseases, hematopoietic stem cell transplant (HSCT) or solid organ transplant and therapy with high or prolonged doses of corticoids as well as those with an advanced stage HIV infection who have not undergone retroviral therapy. IFIs also occur in gastrointestinal surgery patients, autoimmune disease patients receiving new immunobiological therapies, premature infants, the elderly and critical patients at an intensive care unit [2].
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In patients with AIDS, pneumocystosis, cryptococcosis and histoplasmosis are considered to be the most frequent IFIs. Other fungi, especially Candida spp. and Aspergillus spp., may cause severe diseases during the course of an HIV infection [3, 4]. However, there has been a marked reduction in the occurrence of opportunistic infections in the countries where highly active antiretroviral therapy (HAART) has been introduced, and following the introduction of HAART, opportunistic fungal infection-incidence has been reduced to 25–20 % of those reported in the mid1990s [5]. Because IFIs are increasingly recognised as the major cause of morbidity and mortality in immunocompromised patients and because these opportunistic diseases are often severe and fatal, epidemiological knowledge is essential for prompt diagnostic and therapeutic procedures. This study was aimed at the characterising the epidemiology of IFI incidence, clinical diagnostic and therapeutic features and denouement (mortality) in HIV/AIDS patients at the Institute of Infectious Diseases Emilio Ribas.
bacteriology/mycology department in a central laboratory and by pathological anatomy. Systematic sampling of clinical data was performed by reviewing the medical records accessed by a medical files service. The studied variables were: gender, age, CD4, CD8, viral load, previous opportunistic infection, hospitalisation time, treatment and mortality. The study criteria used for defining AIDS were according to the CDC norms [6]. Pneumocystosis cases were excluded. Presumptive diagnoses based on radiological and non-specific laboratory results (lactate dehydrogenase and PaO2) were according to the standards of most services, where microbiological confirmation is underused. HIV infection was diagnosed by the enzyme-linked immunosorbent assay and confirmed by Western blot. The data were stored in a data bank, and simple frequencies of the results were calculated. The present study was analysed and approved by the Ethics in Research Committee (CEP) at the IIER, protocol 19/2012 from September 27, 2012.
Results Materials and Methods This was an observational and retrospective study performed at the Institute of Infectious Diseases Emilio Ribas, which is a tertiary public health care institution that serves as a reference centre for infectious disease treatment in the Sao Paulo state and in Latin America. The institute has 199 active hospital beds; an intensive care unit with 17 beds and an emergency care unit. For this study, an IFI case was defined as any patient diagnosed between January 1 to December 31 with HIV/AIDS who had a suggestive clinical diagnosis of fungal infection that was confirmed by at least one of the following exams during hospitalization: positive culture of biological material collected from a normally sterile site (blood, liquor, pleural fluid, peritoneal fluid, etc.); positive culture of biological material collected from a normally non-sterile site (bronchoalveolar lavage, urine, etc.) associated with histopathology; confirmed presence of fungal elements; and inflammation and/or radiological changes suggesting infectious activity. The identification of IFIs was performed during the search for microbiological and histopathological information in
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In 2011, 24.482 medical care cases were seen at the IIER emergency unit, resulting in 2.611 (10.7 %) hospitalisations. An HIV/AIDS infection was the basic diagnosis in 1.692 (64.8 %) of these cases. The total number of HIV/AIDS patients admitted per day was 31.577, and lethality occurred in 262 cases (15.5 %). In biological material culture analyses, 126 patients presented a histopathological diagnosis and/or agent isolation, of which 104 were diagnosed with HIV/ AIDS. Three patients who had medical records that were not available, three patients who had only a superficial fungal infection, four patients who had pneumocystosis and four patients who had were believed to have sampling contamination were excluded from the analyses. In 122 patients, the diagnosis and empiric treatment for pneumocystosis was according to clinical, laboratory and radiological data, and four patients received a microbiological diagnosis by the direct detection of the agent by o-toluidine staining. In total, 90 HIV/AIDS patients presenting with an IFI diagnosis were considered. Two patients presented with an IFI episode during the studied year. There was a total of 92 IFI episodes in the cohort. The IFI incidence in the HIV/AIDS patients was 54.3/1.000
Mycopathologia
Fig. 1 Incidence rate of systemic fungal infections in HIV/ AIDS patients Table 1 Epidemiologic and demographic data as T CD4 and CD8 cells count, viral load, antiretroviral therapy and mortality in HIV/AIDS patients presenting IFI diagnostic at the Institute of Infectious Diseases Emilio Ribas Variables
Value
Age, mean (range)
32 (14–78)
Sex Male
63/90 (70 %)
Female
27/90 (30 %)
Risk factor for HIV infectiona Homosexual
17 (24 %)
Heterosexual
36 (50 %)
Injecting/inhalation drugs Blood transfusion
13 (18 %) 2 (2.0 %)
Vertical transmission
3 (4.0 %)
T cell count CD4b
89 (2–744)
Mean (cel/mm3), range T cell count CD8c
558 (9–2,545)
Mean (cel/mm3), range Viral loadd
81.603 (50–500.000)
Mean (copies/ml), range HAARTe Regular
22 (26,8 %)
Irregular
23 (28 %)
Abandonment
23 (28 %)
Not started
14 (17 %)
First opportunistic infection
12/90 (13.3 %)
Mortality
34/90 (37.7 %)
a c e
Evaluated in 71 patients; Evaluated in 86 patients; Evaluated in 82 patients
b d
Evaluated in 86 patients; Evaluated in 82 patients;
hospitalisations per year. IFI was considered the first opportunistic infection in 32 (35.5 %) patients, and AIDS was the defining illness in 12 patients (13.3 %). Of these, 90 patients, 34 (37.7 %) died during hospitalisation (Fig. 1). Epidemiologic and demographic data, such as CD4 and CD8 levels, T cell-count, viral load, anti-retroviral therapy and mortality are described in Table 1. Each IFI, including the mean age, incidence, mortality, CD4 level, viral load, time of HIV infection, treatment and time of hospitalisation, is described in Table 2. In 2011, cryptococcosis incidence in AIDS patients was 36/1.000 hospitalisations per year. The infectious agent was isolated from the cerebrospinal fluid (CSF) in 50 cases (82 %). In four cases (6.5 %), diagnosis was performed exclusively by agent isolation from a peripheral blood culture. In three cases (4.9 %), the agent was isolated exclusively from the respiratory material. Urine, synovial fluid and ascitic fluid were also used as isolation sites. Ten cases (16.3 %) showed neurocryptococcosis relapse, and only two patients used secondary prophylaxis with fluconazole. Fungal disease was considered as an AIDS-defining disease according to the CDC criteria in 10 cases (16.3 %). Global mortality for all of the cryptococcosis cases was 34.4 %. Of the 50 neurocryptococcosis cases, 15 (30 %) presented with a positive blood culture. The agent was identified as Cryptococcus neoformans in all cases through specific laboratory tests (Canavanine–glycine–bromothymol blue agar). The different varieties of the C. neoformans species were not assessed because our centre does not perform this test routinely. Specific treatment with antifungal drugs was given to 47 patients. Of these, 44 (93.6 %) patients began therapy with amphotericin B deoxycholate, in which 13 cases (29.5 %) where changed to lipid formulations due to nephrotoxicity induced by the first formulation. Three cases (6.3 %) were treated exclusively with the amphotericin B lipid formulation. Combination therapy was performed in 16 cases (34 %), with amphotericin B deoxycholate and fluconazole. The treatment data were not available for two patients, and another patient received the test result after discharge from the hospital. The global mortality rate for Neurocryptococcosis was 32 %.
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Mycopathologia Table 2 Specific data for each IFI, mean age, incidence, mortality, CD4, viral load, time of HIV infection, treatment and time of hospitalization Mycoses
N°
Incidence (cases/1.000 hospitalizationyear)
Mean age (years)
Time of HIV infection
CD4 (cel/mm3)
Viral load (copies/ ml)
Time of treatment (days)
Hospital stay (days)
Mortality
Cryptococcosis
61
36
38
8 years
83 (2–744)
89.309
31
33
34.3 % (21)
Histoplasmosis Paracoccidiodomycosis
12 1
7.1 0.5
36 45
7 years Diagnosis at admission
38 (2–170) 6
73.102 36.195
18 7
29 7
33,3 % (4) 100 % (1)
1
0.5
25
10 years
26
70.961
7
28
Lost follow up
Aspergillosis
Murcomycosis Invasive candidiasis
1
0.5
20
30 years
4
380
28
70
100 % (1)
14
8.3
36
8 years
126 (3–720)
100.175
16
52
50 % (7)
Trichosporonosis
1
0.5
26
1 months
55
64.051
21
21
–
Saccharomyces spp.
1
0.5
75
20 years
539
\50
21
56
100 % (1)
Pulmonary involvement by Cryptococcus spp. was confirmed by microbiological tests in five cases. The main symptoms were a cough and dyspnoea (66.6 % of cases). In four patients, pneumopathy caused by Cryptococcus ssp. was diagnosed by a transbronchial biopsy and in one case by a bronchoalveolar lavage culture. In all of the cases, no other infectious agents was isolated that would justify the involvement of respiratory; however, there was a single case with a concurrent Kaposi’s sarcoma diagnosis. Treatment was instituted in four cases, and in one case, the treatment information was not available in the records. Three of the four patients responded well to the treatment; however, one patient died due to the pulmonary involvement caused by Kaposi’s sarcoma. The global lethality of the pulmonary cases was 40 %. In two cases, C. neoformans was isolated from the ascitic fluid and synovial fluid, with no specific treatment during hospitalisation and a loss of followup after hospital discharge. C. neoformans was also isolated in blood and urine cultures from a patient hospitalised with symptoms of dysuria and fever who died 3 weeks after amphotericin B lipid formulation treatment, although the cause of death was related to sepsis caused by S. aureus. Histoplasmosis incidence in the AIDS patients was 7.1 cases/1.000 hospitalisations per year. The main symptoms were fever (58.3 %), headache (33.3 %)
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and cutaneous lesions (25 %). Histoplasmosis was considered as an AIDS-defining disease in two cases (17 %) and as the first opportunistic disease in one case. In six cases (50 %), Histoplasma capsulatum was isolated in peripheral blood culture. The agent was isolated or identified by specific staining of skin tissue (5 cases; 41.6 %), trachea biopsy (1 case; 8.3 %), epiglottis biopsy (1 case; 8.3 %), stomach biopsy (1 case; 8.3 %), bone marrow biopsy (1 case; 8.3 %) and pulmonary biopsy (1 case; 8.3 %). Amphotericin B treatment was given to 11 patients. In one case, the patient did not receive disease-specific treatment because he died before the results of the laboratory analyses were obtained. Four cases resulted in death (33.3 %). Paracoccidiodomycosis was diagnosed in one patient by a skin biopsy and due to agent growth in a blood culture. Double immunodiffusion serology was 1/128, and an AIDS diagnosis was concluded during hospitalisation. After receiving amphotericin B deoxycholate treatment, the patient developed respiratory insufficiency and died. There was one case of invasive pulmonary aspergillosis in a patient initially diagnosed with neurotoxoplasmosis who developed respiratory complaints during hospitalisation. Radiological lung exams revealed diffuse bilateral infiltrates; later, Aspergillus fumigatus was isolated by a bronchoscopy with a bronchoalveolar lavage. Aspergillosis was
Mycopathologia
diagnosed according to images, clinical, microbiological criteria and patient improvement upon treatment with itraconazole. There was a case of mucormycosis, which was detected via colonoscopy, in a patient who had an ulcer in the ascending colon, as revealed during a colonoscopy. A colon biopsy showed wide and coenocytic hyphae, invading mucosa and smooth muscles. Amphotericin B lipid formulation treatment was performed. However, during hospitalisation, lung and pulmonary Kaposi’s sarcoma were diagnosed, and the patient died. There was one case of fungemia caused by Trichosporon spp. The agent was isolated from two peripheral blood samples and was identified as Trichosporon asteroides by cistron sequencing of the ribosomal IGS region. The patient was already using an azole derivate, which was retained as a treatment for this IFI. The patient’s health improved, and the patient was discharged. Finally, there was one case of an invasive Saccharomyces cerevisiae infection in a patient at the intensive care unit. Following 7 days of hospitalisation, yeast growth was detected in a peripheral blood culture, and caspofungin therapy was initialised. However, when Saccharomyces cerevisiae was identified as the infectious species by sequencing the ITS region, the caspofungin treatment was changed to liposomal amphotericin, which resulted in improve patient health. However, the patient died from causes unrelated to fungal infection. The invasive candidiasis incidence was 8.3 cases/ 1.000 AIDS-patient hospitalisation-year. Candidemia was diagnosed in 12 cases. In two cases, the agent was isolated from the CSF and bone marrow. The isolated species were Candida albicans (4 cases; 28.5 %), C. tropicalis (5 cases; 35.7 %), C. parapsilosis (4 cases; 28.5 %), C. glabrata (1 case; 7 %) and C. krusei (1 case; 7 %). One patient sample showed the growth of two species (C. albicans and C. glabrata). Of all of the patients, seven (50 %) were admitted to the intensive care unit, four (28.5 %) were neutropenic, eight (57 %) had a central venous catheter and one underwent gastrointestinal surgery. The average time of hospitalisation was 24 days, varying from 2 to 27 weeks. Treatment was administered in 11 patients. Seven cases were initially treated with amphotericin B, which was replaced by caspofungin (four cases) or fluconazole (three cases) following agent identification. The other three cases were treated exclusively with caspofungin, and one case was treated with liposomal amphotericin. The three patients that did not
received treatment died before a partial and/or final culture result. Of the total number of patients, seven died.
Discussion Over the past 10 years, the incidence of the main IFIs occurring with AIDS has progressively declined, as a result of routine prophylactic practices for Pneumocystis jiroveci (PCP) infections and HAART availability. Nevertheless, other IFI epidemiologic trends in the HIV-positive population are not well understood [7]. Antinori et al. [8] evaluated 1.630 AIDS patients in necropsy studies, observing IFIs in 297 (18.2 %) cases that were mostly in the advanced stage of the disease. Pneumocystosis had the highest frequency, followed by aspergillosis, cryptococcosis, candidiasis, histoplasmosis and mucormycosis. The incidence of IFI in autopsies has decreased significantly over time due to the wide use of HAART, decreasing from 25 % in the 1980s to 15.1 % in early 2000. In our study, we observed an incidence of 55.6 IFIs/ 1.000 AIDS patients hospitalisations-year. This is less than the total incidence estimated by Antinori et al. [8], where only the patients who died were analysed. Prado et al. [9] evaluated systemic mycosis as the primary cause of death in Brazil between 1998 and 2006. Systemic mycosis was recorded as cause of death on the death certificates in 5.898 (4.7 %) of patients with AIDS. Cryptococcosis was the cause of death in more than half of the cases, followed by candidiasis, histoplasmosis, aspergillosis, paracoccidiodomycosis, coccidiodomycosis and mucormycosis. Our study determined a global IFI mortality of 37.2 %, where the main cause of death was cryptococcosis, followed by invasive candidiasis, histoplasmosis, paracoccidiodomycosis, mucormycosis and Saccharomyces cerevisia fungemia. Therefore, the three main agents identified in this study are the same as those that were associated with AIDS patient-death in the study by Prado et al. [9]. Previous studies have shown a decline in mortality due to cryptococcosis in developed nations. Over the years, HAART has changed the demographic characteristics of patients with AIDS and cryptococcosis; previously these patients were older and unaware of their HIV infection at the time of diagnosis [10]. The
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Brazilian casuistry epidemiologic characteristics do not resemble the European and North American studies because 66 % of patients did not use or irregularly used HAART. Opportunistic infections are still frequent and cause an unacceptably high mortality in patients, despite treatment at a reference centre with a good infrastructure. However, when compared to the overall mortality of 55 % in Brazil, we realise that although the mortality is high, it is still better than in other regions [11]. Although we cannot assign cryptococcosis as the immediate cause of death to all cases because the cause of death in some cases was due to other infectious and/or pathological agents, in a recent study, an in-hospital mortality of 30 % was reported [12]. Therefore, many strategies for reducing mortality could be adopted by our institution, such as: (1) early HIV diagnosis and treatment; (2) screening and pre-emptive treatment for subclinical cryptococcosis; (3) optimised diagnosis of cryptococcal meningitis; and (4) optimised treatment of cryptococcal meningitis [13]. Because of advances in HAART, histoplasmosis incidence has decreased; however, the disease remains one of the most common opportunistic infections occurring in endemic areas [14]. Brazilian data are scarce, and the ability to estimate the real role of histoplasmosis in Brazil is limited. The disease can be severe and causes many deaths. In our study, the mortality rate was 33.3 %, similar to other studies in which this value varies between 30 and 65.2 % [15, 16]. It is possible that the present study may have several under-diagnosed cases because diagnostic resources, including molecular biological tools and antigen detection techniques, are not available for routine testing in Latin American countries. The case diagnoses in this study were performed mostly by agent isolation in conventional culture media or by pathological studies. The present casuistry had only one PCM case, with characteristics of a disseminated disease. PCM was detected by agent isolation in skin and blood cultures with a high serological titre of 1/128, suggesting that these tests may be useful, but they should not be used as the only methods to diagnose the disease. The literature shows that PCM diagnosis is performed by agent identification in biological samples (skin and sputum) or by serologic tests; however, these tests have a low sensitivity to low titration in immunosuppressed patients [17]. The relation between invasive
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aspergillosis (IA) and HIV infection has not been completely elucidated. In this study, the use of corticotherapy as an adjuvant therapy in neurotoxoplasmosis treatment may have been the reason for the development of aspergillosis. Moreover, the patients had presented with a positive diagnosis for AIDS for 10 years, indicating severe immunodepression. Interestingly, in a study in Italy, invasive aspergillosis was found to be the second most frequently occurring IFI [8]. However, the Italian study was performed postmortem, indicating that many aspergillosis cases in the present research may have been under-diagnosed. Mucormycosis is an aggressive disease and is often fatal. The scarcity of mucormycosis reports in HIV patients who do not use injected drugs indicates that HIV infection alone is not a significant risk factor to develop the disease [18, 19]. In the present study, there was only one case of mucormycosis, in which severe immunodepression, injected drugs usage and neutropenia were the main risk factors. Furthermore, intestinal involvement by cytomegalovirus and Kaposi’s sarcoma may have predisposed the patient to a local fungal invasion. Fungemia by Trichosporon spp. can occur due to an infected catheter and the breakdown of the cutaneous or digestive barrier [20]. The reports of this invasive infection in HIV patients are exceptional and the patient had only central venous catheter as a risk factor for this IFI [21]. Cases of fungemia by Saccharomyces cerevisiae have been related to usage of capsules containing yeasts, usually prescribed along with antibiotics and adjuvant therapy for diarrhoea caused by Clostridium difficile [22]. Other risk factors for the development of fungemia are permanent residence in an intensive care unit and using CVC, as in the case of a patient who did not use probiotics during hospitalisation. Candida is a pathogen of incontestable clinical relevance due to both increased disease incidence over the last few decades and the high morbid-mortality attributed to invasive disease episodes [23]. In the present study, the incidence of candidemia cases (7,1 cases/1.000 AIDS patients hospitalisation/year) is higher than the reports in the literature. In Brazil, Nucci et al. [23] reported an incidence of 1.38 cases every 1.000 hospitalisations, which is much lower than the incidence in the present study. As observed in other studies, HIV infection is not considered to be a high risk factor for candidemia. Characteristics with
Mycopathologia
respect to the use of invasive devices, previous antibiotics, parenteral nutrition and dialysis therapies are similar between the patients in the current study and the non-HIV patients. The distribution of Candida species showed a higher prevalence of non-albicans species (73 %) in many Brazilian and Latin American cases [23]. The limitations of this study include problems associated with retrospective studies, for example, the absence of a standardised history and others laboratory information. Moreover, although the number of patients studied here composed a representative sample, this study was performed for only 1 year. Therefore, a longer review is necessary to predict the actual incidence and mortality at our institution, which is responsible for the hospitalisation of 70 % of the patients with HIV/AIDS in Sa˜o Paulo. In conclusion, IFIs in HIV/AIDS patients remain an important cause of mortality in Brazil, despite the increasing availability of ATR. Cryptococcosis is the main IFI in our hospital, with a high mortality even in the postHAART (34.4 %) period. Other less common endemic IFIs are a rarity in our institute, as observed with paracoccidiodomycosis. Finally, nosocomial infections by pathogenic yeasts are mainly caused by Candida spp., with a higher incidence at our institute compared to other Brazilian centres. Acknowledgments This study was supported, in part, by the Centro de Estudos Emı´lio Ribas, Sa˜o Paulo, Brasil. Conflict of interest None of the authors have any potential conflict of interest or financial support in the subject matter.
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