Invasive Fungal Infections in People Living with HIV/AIDS

The increased incidence of invasive and opportunistic mycoses is probably related to the growth of the immunocompromised population, such as people living with HIV. This study is a literature review that aims to analyze the frequency of invasive fungal infections in people living with HIV. In most studies evaluated, Pneumocystis pneumonia was the most frequent invasive fungal infection among people living with HIV, and cryptococcosis was the second most frequent. Invasive fungal infections are associated with greater morbidity and mortality in people living with HIV. The most important highlighted information is that the lack of epidemiological data on fungal infections in the studied populations was reported by most studies. Therefore, there is a need for further studies to assess the frequency of invasive fungal infection in people living with HIV, which may serve as subsidies for the implementation of strategies for the prevention and management, with a consequent increase in the quality of life and reduction of morbidity/mortality in this population.

strategy for improving the quality of life of this population. The present study aimed to approach the frequency of IFI in people living with HIV and the main fungal species evolved.

Type of Study
This study consists of an integrative review of literature, that is a method of bibliographical research, which allows scientists to gather and summarize the scientific knowledge available on the subject in research. This type of study makes possible the evaluation and synthesis of the available scientific evidence that will contribute to the development of conclusions on the discussed thematic [11]. Six steps have been taken to prepare this study: establishing the guiding question and objectives of the research; definition of criteria for inclusion and exclusion of publications; search in the literature; analysis and categorization of studies; and presentation and discussion of results [11]. The question for this review was: "How frequent are invasive fungal infections in people living with HIV?" Based on the guiding question, the PRISMA flowchart model was used (Figure 1).

Course of the Selection of Articles
The search took place in May 2018 in the following databases and/or digital libraries: Virtual Health Library, Scientific Electronic Library Online (Scielo), and the PubMed portal; the Medical Literature Analysis and Retrieval System Online (Medline) from the association of descriptors in Health Sciences and Medical Subject Headings (MeSH) by means of the Boolean operator "AND": epidemiology; invasive fungal infections; and HIV. In the Medline/Pubmed search process, by the characteristics of this database, only the English descriptors were used. All the identified studies were initially evaluated by way of analysis of the titles and summaries. In the studies in which the reading of the title and summary was not sufficient for the application of the criteria of inclusion and exclusion, the article was read for inclusion or exclusion in the study.
The inclusion criteria were: publications that addressed invasive fungal infections in people living with HIV; published or available online in the period from January 2007 to April 2018 (10-years period); in the Portuguese, English, or Spanish languages; and were available free of charge for full Internet reading.
Studies were excluded that did not fill in the previous requirements; literature review papers, case reports, dissertations, theses, book chapters, supplements or editor comments; articles that did not address the search theme; and the duplicate articles should be considered for posting only once. A data collection instrument was developed that met the following inclusion criteria: 1) year of publication, 2) authors, 3) country where the study took place, 4) study type, and 5) IFI more frequent in people living with HIV.

Results
The path traveled in the identification and selection of study components was described in Figure 1. The selective reading of the 305 articles found in Medline and Virtual Health Library were initially made with review by title and summary. Thirty-seven studies were selected from Medline, according to titles and summaries. Then, the full and critical reading of these texts was conducted, and six articles were selected. From the search conducted at the Virtual Health Library, 72 articles were chosen after reading titles and summaries, which were read. Among the articles, 14 were selected. Of the 109 articles selected in the two databases, 89 were excluded when the pre-established exclusion criteria for the study were applied. So, 20 articles composed the corpus of work.
A. L. Sousa-Neto et al.  In the retrospective study conducted in North America, 159 (52.5%) of 303 HIV carriers presented with cryptococcosis. Of these, 77.9% showed a CD4+ count of less than 50 cells/mm 3 [10]. In research conducted in South Africa, where four (12.0%) of the 34 patients necropsied presented with cryptococcosis, the CD4+ count ranged from 1 cells/mm 3 to 56 cells/mm 3 , and in two of these patients, Cryptococcus neoformans was identified [12]. Identification of the Cryptococcus species was described by three (15.0%) studies [12] [13] [14]. In a study carried out in Mexico, 132 cases of fungal diseases were identified, of which 28 were caused by C. neoformans, one by C. laurentii, one by C. albidus, and one by C. uniguttulatus [13]. The studies carried out in Italy and South Africa identified only C. neoformans as the cryptococcal agent,

Discussion
The most common IFI among people living with HIV was Pneumocystis pneumonia. Despite the decline in mortality from HIV infection, Pneumocystis pneumonia is still a worrisome disease and, in most developing countries [27].
Pneumocystis pneumonia is caused by P. jirovecii and, in many cases, this disease defines AIDS in people living with HIV, occurring more often when the CD4+ count is less than 200 cells/mm 3 and when the patient was not using antiretrovirals [10] [21] [28] [29] [30].
Candidiasis was the fungal infection (although it is not invasive) that stood out in most studies evaluated due to its high prevalence. According to literature, oropharyngeal candidiasis is still a common problem in the people living with HIV, even with the availability of HAART [31]. Esophageal candidiasis affects about 20% of AIDS patients not using antiretrovirals and 5% of those who are under antiretroviral therapy [20]. Candidiasis can become severe when it spreads to deep organs and causes candidemia, increasing the mortality rate.
Cryptococcosis, the second most frequent IFI in people living with HIV, has a relevant role, because it is considered one of the most common mycoses, especially affecting the central nervous system [31]. Cryptococcal meningitis emerged firstly as one of the main causes of infectious morbidity and mortality in patients with AIDS, since the beginning of the spread of HIV in the world [32]. In the last two decades, there have been advances in the prevention, diagnosis, therapy, and results of patients with cryptococcal meningitis. However, efforts are still needed in order to implement these strategies, mainly in low-income populations [33]. The low incidence of cryptococcal meningitis found in some countries such as Romania, which has an estimated rate of 0.09/100,000 inhabitants, may have as a justification the broad coverage of HAART [25].
Histoplasmosis, an infection caused by H. capsulatum, first presents an acute pulmonary form, from where the fungus spreads through the hematogenic pathway. Disseminated histoplasmosis was rare until the emergence of AIDS, occurring only at extremes of age and in individuals immunocompromised by neoplastic diseases or by the use of immunosuppressant therapy [34]. However, the annual incidence of histoplasmosis is still unknown in many countries, even if endemic [35]. HAART have improved the cellular immunity of AIDS patients, and also the rate of response to the treatment of histoplasmosis, as observed in a study con-  [38]. In this study, all who received HAART responded to the antifungal treatment as well as the non-HIV patients, compared with 47% among those who did not receive antiretroviral therapy [38].
HAART has an important impact on reducing mortality, vertical transmission, and treatment of serious comorbidities [31]. For instance, a study carried out in China from 2014 to 2015 evaluated 954 HIV infected patients and concluded that the two most important factors for hospital mortality were the CD4+ count <100 cells/mm 3 and the non-use of HAART [39]. To promote restoration of the immune system is important for the treatment and prevention of all types of infection.
Early diagnosis of any type of infectious disease is extremely important for proper treatment. Delayed diagnostic of fungal diseases exacerbates the problem of empirical use of antimicrobials, with consequent risk of increased antimicrobial-resistant microorganisms [40]. The diagnosis of a fungal disease, especially in an immunocompromised patient, is not always obvious. It depends on the local epidemiology, the technical capacity of the healthcare team, the availability of diagnostic tests, whether serological, microscopic and culture, or molecular tests, such as PCR. The causes of death in patients with aids are tuberculosis and other associated infections, as fungal, bacterial or toxoplasmosis, and a team prepared for these diagnoses is not always available in all countries, especially in developing ones [41].
Most of the studies reported lack of reliable data and records on the frequency of IFI. Even with the limitation of epidemiological data, there is high mortality among people living with HIV related mainly to one of the following IFI: cryptococcosis, Pneumocystis pneumonia, histoplasmosis, or aspergillosis, which can be significantly reduced by investment in timely diagnosis and appropriate antifungal treatment [35].
Even in the current world effort scenario to increase access to HAART [1], it is necessary to improve the registration of IFI so that we can have access to actual data of these diseases in the population in addition to the greater availability of appropriate diagnostic and therapeutic methods. As a result, IFI can be identified early and have correct handling, which is important in preventing related mortality caused by fungi in people living with HIV [35].
In addition to the findings, opportunistic fungal infections affect not only HIV/AIDS patients, but also others who have immunocompromised, such as patients with hematological diseases, solid organ transplant and chronic obstructive pulmonary disease, among others [7]. Often infections by P. jirovecii are confused with other lung diseases, and as the microbiological diagnosis by culture is not performed, it can often not be confirmed, which may mask their real prevalence. Other fungi that affect HIV/AIDS-infected patients, such as Aspergillus species and Talaromyces marneffei species [7] [8] are often forgotten. We believe that studies on fungi that affect this population that is more susceptible to opportunistic fungal infections are poorly disseminated, or are restricted to Journal of Biosciences and Medicines regional publications. Thus, access to the literature is not possible, and the real prevalence of the different etiologic agents involved may remain unknown.

Conclusion
Invasive fungal infections are associated with greater morbidity and mortality in immunocompromised individuals. In most of the studies evaluated, the most frequent IFI in people living with HIV was caused by Pneumocystis jirovecii.
However, there is a lack of reliable data regarding its frequency, as well as for other fungal infections, like histoplasmosis. There is a need for further studies to assess the frequency of IFI in people living with HIV, which may serve as subsidies for the implementation of strategies for the prevention and management, in order to improve the quality of life and reduction of morbidity and mortality in this population.