Open Access is an initiative that aims to make scientific research freely available to all. To date our community has made over 100 million downloads. It’s based on principles of collaboration, unobstructed discovery, and, most importantly, scientific progression. As PhD students, we found it difficult to access the research we needed, so we decided to create a new Open Access publisher that levels the playing field for scientists across the world. How? By making research easy to access, and puts the academic needs of the researchers before the business interests of publishers.
We are a community of more than 103,000 authors and editors from 3,291 institutions spanning 160 countries, including Nobel Prize winners and some of the world’s most-cited researchers. Publishing on IntechOpen allows authors to earn citations and find new collaborators, meaning more people see your work not only from your own field of study, but from other related fields too.
Early diagnosis of histoplasmosis is essential to establish a suitable antifungal therapy and reduce morbidity and mortality rates. However, laboratory diagnosis remains challenging due to the low availability of proper methods and the lack of clinical suspicion. Conventional diagnosis is still largely used even though limitations are well known. Isolating the fungus is time consuming and requires manipulation in BSL3 facilities, while direct visualization and histopathology techniques show low sensitivity and need skilled personnel. New approaches based on the detection of antibodies and antigens have been developed and commercialized last years. Although sensitivity and specificity of these methods is variable, antigen detection has been recently listed as an essential diagnostic test for AIDS patients due to its excellent performance. DNA detection methods are recognized as promising tools but there is still a lack of consensus among laboratories and there are not commercial tests available. Not all methods are widely available, thus most laboratories combine classical and other tests in order to overcome aforementioned limitations. In this chapter, we review the diagnostic pipeline currently available for the diagnosis of histoplasmosis in microbiological laboratories, from conventional to new developed tests. Most recent approaches are introduced and future perspectives are discussed.
Reference Laboratory in Mycology, National Center for Microbiology, Instituto de Salud Carlos III, Spain
Clara Valero
Reference Laboratory in Mycology, National Center for Microbiology, Instituto de Salud Carlos III, Spain
School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Brazil
*Address all correspondence to: buitrago@isciii.es
1. Introduction
Histoplasmosis is caused by the thermally dimorphic fungi Histoplasma capsulatum and encompasses a broad variety of clinical presentations ranging from asymptomatic infections to subacute, acute and chronic pulmonary infections [1]. In immunosuppressed patients, especially in HIV positive population, it causes a progressive disseminated disease [2]. Mortality rates in AIDS population have been reported as 30–50% when treated, and 100% in absence of treatment [3]. Although this fungus has a cosmopolitan distribution, there are some areas of high endemicity as Ohio and Mississippi basins in North America, several countries from Central and South America and different regions in the African continent [4, 5, 6]. Areas of medium-high endemicity have been reported in China and some sporadic cases have been described in other regions of Asia as North of India, Thailand and Philippines [7, 8, 9, 10]. The rest of the world is considered as non-endemic regions and reported cases are described as imported by travelers or immigrants [11]. It has been estimated that about a half million of people acquire the infection per year and around 100,000 develop a disseminated disease [3]. Certain regions of Brazil and Venezuela have been considered hotspots of the disseminated form of the disease [12]. However, in other regions as the African continent the incidence is probably underestimated due to lack of studies [6]. Diagnosis of histoplasmosis is challenging in both endemic and non-endemic regions due to its similarity to other diseases as tuberculosis, usually the first clinical suspicion, and the limitations and low availability of diagnostic tools. Consequently, many efforts have been recently made with the aim of improving diagnosis and combat histoplasmosis [3]. In this chapter, we describe the conventional methods used to diagnose histoplasmosis coupled with an update about the new tests available. The advantages and limitations of each method are detailed as well as their usefulness in the diagnosis regarding the diverse clinical presentations of the disease and their availability in the different regions. The need of continuous work on the development of new methods to achieve an early diagnosis and reduce histoplasmosis morbidity and mortality is also underlined.
Conventional diagnostic methods are still widely used for the diagnosis of histoplasmosis. The definite diagnosis is based on the isolation of the fungus in culture or the visualization of intracellular yeasts in tissues or other clinical samples. Thus, despite its known limitations, these methods are very useful and continue to be used in many laboratories, especially in low-resources settings.
2.1 Culture
The isolation of H. capsulatum in culture is the gold standard for the diagnosis of histoplasmosis. The recovery of the fungus by culture from clinical samples (blood culture, bronchoalveolar lavage fluid, etc.) is recognized as the criteria for the definition of proven histoplasmosis according to the consensus definitions of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium (EORTC-MSGERC) [13].
H. capsulatum is a so-called fastidious fungus since it can take up to 4 weeks to grow and requires Biosafety level 3 (BSL-3) containment measures [2]. At 25–30°C, it grows as a white and cottony mycelium that evolves to brown, representing the invasive form of the disease. This mycelial form is the most dangerous, as spores could be inhaled causing infection. Some laboratory-acquired infections have been reported by culture manipulation [14]. Microscopically the mycelial form produces the typical tuberculate macroconidia, which are easily identified (Figure 1A). However, other species as Sepedonium spp., an environmental organism that is usually considered as a laboratory contaminant, produce similar structures. At 37°C (human body temperature), there is a conversion from the mycelial phase to the yeast form, which is the pathogenic form of the disease. These yeasts are easily recognized by their thick wall and ovoid form with a narrow base at the smaller end (Figure 1B).
Figure 1.
Photomicrograph of lactophenol cotton blue stains of both filamentous and yeast forms of H. capsulatum. (A) Culture at 30°C on potato dextrose agar (PDA) showing tuberculate macroconidia (63× magnification). (B) Culture at 37°C on ML-GEMA medium showing yeasts (20× magnification). Both images belong to the image library of the mycology reference laboratory (National Centre of Microbiology, Instituto de Salud Carlos III, Madrid, Spain).
The sensitivity of cultures depends on the clinical status of the patient and the origin of the sample. Cultures are negative in most cases of asymptomatic and mild disease, however they are useful in disseminated and chronic pulmonary histoplasmosis, although their sensitivity varies from 50 to 85% [2, 15].
The main limitation of cultures is the long turnaround time needed to reach a definite diagnosis. Moreover, the microscopical observation of the grown fungus requires further confirmation by other methods. Molecular identification by sequencing the internal transcribed spacer (ITS) region of ribosomal DNA is a powerful tool to confirm the presence of H. capsulatum, but extends the time response for the diagnosis even more. Alternatively, single-stranded DNA probes could also be used to detect the fungus in cultures (AccuProbe, Hologic, CA, USA), however the procedure is technically complex and time consuming [16]. In last years, matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-ToF MS) has started to be developed for the identification of H. capsulatum strains [17, 18, 19]. Although reports are still scarce, results in this area are promising since the system is able for recognizing different varieties (var. capsulatum, var. duboisii) and forms of the pathogen (yeast and mold), thus reducing response time and decreasing the risk of culture manipulation [19].
Since aforementioned limitations make culture useless for an early diagnosis of histoplasmosis, a great effort has been made for developing alternative diagnostic methods that could be used alone or in combination with cultures.
2.2 Histopathology and direct visualization
Direct examination of clinical samples or performing histopathological studies on tissues to detect yeast after staining with Gomori methenamine silver (GMS) or periodic acid-Schiff (PAS), are techniques largely used for the diagnosis of histoplasmosis. H. capsulatum could appear as a 2- to 4-μm (var. capsulatum) or 8- to 15-μm (var. duboisii) oval yeast. As yeasts are phagocytosed by macrophages, they could be found forming clusters, which can help the diagnosis. However, several fungi can be misled with H. capsulatum such as, among others, the small variant of Blastomyces dermatitidis, endospores of Coccidioides spp., Candida glabrata as well as the causal agents of leishmaniasis, toxoplasmosis, and Chagas’ disease [20]. The higher sensitivity could be obtained in respiratory specimens or bone marrow biopsy in patients with disseminated histoplasmosis [21]. However, the low specificity and the need of skilled personnel to achieve a presumptive diagnosis are the main limitations of this technique.
The detection of H. capsulatum antigens in clinical samples represented a breakthrough in the early diagnosis of histoplasmosis and has been included in the EORTC/MSG criteria for diagnosis of IFIs for almost 20 years [13, 22, 23]. The H. capsulatum polysaccharide antigen can be detected in both serum and urine samples with similar diagnostic value and has been recently listed as an essential diagnostic test for advanced AIDS patients [24, 25]. Two assays based on enzyme linked immunosorbent assay (ELISA) have been commercialized with good diagnostic performances (Table 1) although their availability is limited.
MiraVista’s test presents great efficiency in serum and urine samples from patients with disseminated infection, but it is reduced in patients with pulmonary forms of the disease [26], in which BALF samples are more suitable for diagnosis [28]. This test is only performed in MVista’s facilities then is not accessible out of USA limiting their use. On the other hand, IMMY has recently released an Histoplasma GM ELISA test which shows great performance and reproducibility, but has only be tested in urine samples [27]. Despite the high degree of cross-reaction with other fungi, antigen detection assays are widely used to diagnose histoplasmosis and some reports indicate its capacity to monitor treatment response [29, 30]. Nevertheless, their use is restricted mainly to developed endemic areas but it is rarely used in non-endemic regions, probably due to its low cost-effectiveness out of endemic regions [24, 31].
In last years, point-of-care (POC) testing has been emerged as a new diagnostic methodology and immuno-chromatographic assays performed in lateral-flow devices (LFD) are good examples. These “pregnancy tests-like” assays are easy to use, have low turnaround time (less than an hour) and require minimal laboratory equipment which facilitate its implementation in low- and middle-income countries [32, 33]. This technology was first developed for Aspergillus GM detection with great results and MVista has recently released a similar test consisting of a dipstick sandwich immunochromatographic assay based on the recognition of H. capsulatum GM antigen. Although it has only been tested in serum samples from AIDS patients, its diagnostic performance was very promising (sensitivity of 96%, specificity of 90%) [34]. However, false positive and negative results still occurred due to cross-reactivity with other endemic fungi and antibiotic treatment, respectively, and a pre-treatment step was required extending turnaround times. Currently, a new LFD test is being developed and validated by using urine samples [35].
The main advantages of antibody detection tests are the requirement of minimally invasive samples and the achievement of results when culture is still negative reducing the need of handling potentially infectious fungi [36]. Serological techniques such as complement fixation or immunodiffusion are useful when testing samples from travelers coming from endemic regions for the first time. Both techniques are commercially available (Immuno Mycologics, Norman, OK, USA) and the sensitivity of these tests in acute and subacute pulmonary histoplasmosis has been reported as 95% [37]. However, sensitivity is very limited in immunosuppressed patients due to low or absent antibody titers. A recent meta-analysis described sensitivity and specificity values of 58% and 100%, respectively, in samples from HIV patients [38]. Finally, since seropositivity remains long time after disease, interpretation of serological results could be challenging [39, 40]. Despite the limitations previously described, antibody detection tests are still considered as valuable diagnostic tools and have been demonstrated to improve diagnostic yield when combined with other diagnostic methods [41, 42].
PCR methods based on the detection of fungal DNA directly from clinical samples are currently implemented in the routine of several laboratories for the diagnosis of main fungal infections, but there are considerably fewer PCR tests for the diagnosis of histoplasmosis. Their advantages rely on their simplicity, high specificity and short turnaround time with the bonus that real-time PCR (qPCR) formats allow for determining the fungal burden in patients by using non-specific DNA-binding dyes or fluorescently labeled probes [36, 43]. However, this technique also has some limitations as the moderate amount of DNA in low invasive samples, the lack of standardization and the low availability of widely validated commercial systems [44, 45]. Recently, PCR based methods have been included in the EORTC/MSG criteria for the diagnosis of some fungal infections such as invasive aspergillosis or candidiasis but not for endemic mycoses [13].
The majority of PCR tests for the diagnosis of histoplasmosis have been developed in house and none of them has been commercialized. They have been recently reviewed in several reports with different purposes [31, 38, 46]. Most developed methods targeted specific multicopy regions of the ribosomal DNA or the single-copy Hcp100 gene and were performed by using conventional, nested or qPCR formats. The sensitivity and specificity of these assays depends on the type of sample analyzed, the clinical characteristics of patients and the PCR format used for DNA detection. These tests showed an excellent analytical performance (overall sensitivity of 95% and specificity of 99%) when testing samples of HIV patients [38], but sensitivity decreased when testing blood and serum samples from immunocompetent patients [31, 46]. Panfungal or broad-range PCRs are used when there is not a clear suspicion of the fungus involved in the infection, since universal primers are used to detect any fungal DNA in the clinical sample. Although studies are scarce, several reports achieved the detection of H. capsulatum DNA in clinical samples by using this technique, which could be especially useful in non-endemic regions [47, 48, 49, 50, 51].
Non-PCR based methods are also able to amplify and detect H. capsulatum DNA from clinical samples. Loop-mediated isothermal amplification (LAMP) rests on the use of a DNA polymerase with high displacement strand activity and a set of specifically designed primers to amplify targeted DNA [52]. Some reports described the implementation of this technique for the molecular diagnosis of histoplasmosis showing great results [53, 54]. The high efficiency, sensitivity, specificity and cost-effectiveness of these assays make them good candidates to be implemented in the diagnostic routine of resource-limited laboratories.
Early diagnosis of histoplasmosis is essential to establish a suitable antifungal therapy, which results in the reduction of mortality rates [55, 56]. This becomes especially important in certain hyper-endemic regions since they usually are disfavored areas where patients develop the disease in its disseminated form. While culture and histopathological examination are considered the gold standards methods for histoplasmosis diagnosis, these techniques show moderate sensitivity. In addition, culture is time consuming, requiring handling fungi in BSL-3 facilities. New approaches as MALDI-ToF MS technology allow for a rapid identification, but studies are still scarce. Antibody and antigen detection are useful tools for an early detection of the pathogen in low invasive clinical samples such as serum and urine. Despite limitations concerning sensitivity in certain populations and specificity have been widely reported, H. capsulatum antigen detection has been recently included in the second edition of the list of essential in vitro diagnostics (https://www.who.int/medical_devices/diagnostics/selection_in-vitro/selection_in-vitro-meetings/sage-ivd2nd-meeting/190318-2ndEditionofEDL-open-session.pdf?ua=1). Regarding molecular methods, in the last decade a great effort has been made on the development of PCR tests for the detection of H. capsulatum DNA in a broad spectrum of clinical samples showing excellent diagnostic performance. However, a consensus among laboratories about the best samples, targets and procedures is mandatory. Consequently, no commercial tests are available to date limiting the use of this technique. To date, only an inter-laboratory study focused on molecular techniques for the diagnosis of histoplasmosis has been published [57]. In this work, authors concluded that qPCR targeting a multicopy genomic region was the best option for a suitable sensitivity. A European initiative is being launched to carry out multicenter studies in this regard.
All these problems have gained attention thanks to different initiatives coming from researchers from hyper-endemic regions [58] or international foundations as the Global Action Fund for Fungal Infections (GAFFI). As a result, proposals such as the Manaus declaration have been launched, specifically to get access to rapid testing for histoplasmosis in the Americas and Caribe until 2025 (https://www.gaffi.org/the-manaus-declaration-on-histoplasmosis-in-the-americas-and-caribbean-100-by-2025/). However, in addition to these excellent initiatives further work is required to improve diagnosis. In this sense, novel techniques as next generation sequencing (NGS) have been found to be useful in the diagnosis of several infections. Sequences obtained from clinical samples through NGS can be compared against reference databases enabling their identification to the genus and species level [59]. This technique has been used recently to identify H. capsulatum as the causal agent of a case of chronic meningitis [60] and for the differential diagnosis among histoplasmosis, leishmaniosis and talaromycosis [61]. Another approach in constant development is based on determining host and fungal biomarkers that could indicate the presence of H. capsulatum in human body fluids. Recent advances in antibody detection are related to the refinement of antibody detection platforms (Histoplasma antibody IgG IgM EIA, MiraVista Diagnostics), while most efforts in antigen detection are focused on improving diagnostic yields of POC methods [35].
In summary, the aim of this chapter was to summarize the diagnostic pipeline currently available for the diagnosis of histoplasmosis in microbiological laboratories (Figure 2). Although so much progress has been made in the area, much certainly remains to be done to improve the early diagnosis of histoplasmosis, allowing the establishment of a prompt antifungal therapy and consequently reducing morbidity and mortality rates of this infection.
Figure 2.
Diagnostic pipeline currently available for the microbiological diagnosis of histoplasmosis. aHistopathological preparation showing a H. capsulatum yeast budding [62]. bDirect visualization of fine needle aspiration cytology showing intra- and extracellular yeasts of H. capsulatum [63]. MALDI-ToF MS: matrix-assisted laser desorption/ionization-fime of flight mass spectrometry; ID: identification; EIA: enzyme immunoassay; LFD: lateral flow device; POC: point of care; qPCR: quantitative PCR; NGS: next generation sequencing.
1.Kauffman CA. Histoplasmosis. Clinics in Chest Medicine. 2009;30(2):217-225. DOI: 10.1016/j.ccm.2009.02.002
2.Wheat LJ, Azar MM, Bahr NC, Spec A, Relich RF, Hage C. Histoplasmosis. Infectious Disease Clinics of North America. 2016;30(1):207-227. DOI: 10.1016/j.idc.2015.10.009
3.Bongomin F, Kwizera R, Denning DW. Getting histoplasmosis on the map of international recommendations for patients with advanced HIV disease. Journal of Fungi. 2019;5(3). DOI: 10.3390/jof5030080
4.Benedict K, Mody RK. Epidemiology of histoplasmosis outbreaks, United States, 1938-2013. Emerging Infectious Diseases. 2016;22(3):370-378. DOI: 10.3201/eid2203.151117
5.Colombo AL, Tobon A, Restrepo A, Queiroz-Telles F, Nucci M. Epidemiology of endemic systemic fungal infections in Latin America. Medical Mycology. 2011;49(8):785-798. DOI: 10.3109/13693786.2011.577821
6.Oladele RO, Ayanlowo OO, Richardson MD, Denning DW. Histoplasmosis in Africa: An emerging or a neglected disease? PLoS Neglected Tropical Diseases. 2018;12(1):e0006046. DOI: 10.1371/journal.pntd.0006046
7.Antinori S. Histoplasma capsulatum: More widespread than previously thought. The American Journal of Tropical Medicine and Hygiene. 2014;90(6):982-983. DOI: 10.4269/ajtmh.14-0175
8.Bulmer AC, Bulmer GS. Incidence of histoplasmin hypersensitivity in the Philippines. Mycopathologia. 2001;149(2):69-71. DOI: 10.1023/a:1007277602576
9.Kathuria S, Capoor MR, Yadav S, Singh A, Ramesh V. Disseminated histoplasmosis in an apparently immunocompetent individual from North India: A case report and review. Medical Mycology. 2013;51(7):774-778. DOI: 10.3109/13693786.2013.777166
10.Rangwala F, Putcharoen O, Bowonwatanuwong C, Edwards-Jackson N, Kramomthong S, Kim JH, et al. Histoplasmosis and penicilliosis among HIV-infected Thai patients: A retrospective review. The Southeast Asian Journal of Tropical Medicine and Public Health. 2012;43(2):436-441
11.Molina-Morant D, Sanchez-Montalva A, Salvador F, Sao-Aviles A, Molina I. Imported endemic mycoses in Spain: Evolution of hospitalized cases, clinical characteristics and correlation with migratory movements, 1997-2014. PLoS Neglected Tropical Diseases. 2018;12(2):e0006245. DOI: 10.1371/journal.pntd.0006245
12.Denning DW. Minimizing fungal disease deaths will allow the UNAIDS target of reducing annual AIDS deaths below 500,000 by 2020 to be realized. Philosophical Transactions of the Royal Society of London Series B, Biological Sciences. 2016;371(1709). DOI: 10.1098/rstb.2015.0468
13.Donnelly JP, Chen SC, Kauffman CA, Steinbach WJ, Baddley JW, Verweij PE, et al. Revision and update of the consensus definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium. Clinical Infectious Diseases. 2019;ciz1008 (online ahead of print). DOI: 10.1093/cid/ciz1008
15.Azar MM, Hage CA. Laboratory diagnostics for histoplasmosis. Journal of Clinical Microbiology. 2017;55(6):1612-1620. DOI: 10.1128/JCM.02430-16
16.Gómez BL. Molecular diagnosis of endemic and invasive mycoses: Advances and challenges. Revista Iberoamericana de Micología. 2014;31(1):35-41. DOI: 10.1016/j.riam.2013.09.009
17.Lau AF, Drake SK, Calhoun LB, Henderson CM, Zelazny AM. Development of a clinically comprehensive database and a simple procedure for identification of molds from solid media by matrix-assisted laser desorption ionization-time of flight mass spectrometry. Journal of Clinical Microbiology. 2013;51(3):828-834. DOI: 10.1128/JCM.02852-12
18.Rychert J, Slechta ES, Barker AP, Miranda E, Babady NE, Tang YW, et al. Multicenter evaluation of the Vitek MS v3.0 system for the identification of filamentous fungi. Journal of Clinical Microbiology. 2018;56(2):e01353-17. DOI: 10.1128/JCM.01353-17
19.Valero C, Buitrago MJ, Gago S, Quiles-Melero I, García-Rodríguez J. A matrix-assisted laser desorption/ionization time of flight mass spectrometry reference database for the identification of Histoplasma capsulatum. Medical Mycology. 2018;56(3):307-314. DOI: 10.1093/mmy/myx047
20.Guarner J, Brandt ME. Histopathologic diagnosis of fungal infections in the 21st century. Clinical Microbiology Reviews. 2011;24(2):247-280. DOI: 10.1128/CMR.00053-10
21.Kauffman CA. Histoplasmosis: A clinical and laboratory update. Clinical Microbiology Reviews. 2007;20(1):115-132. DOI: 10.1128/CMR.00027-06
22.Ascioglu S, Rex JH, de Pauw B, Bennett JE, Bille J, Crokaert F, et al. Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: An international consensus. Clinical Infectious Diseases. 2002;34(1):7-14. DOI: 10.1086/323335
23.De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T, et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/invasive fungal infections cooperative group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clinical Infectious Diseases. 2008;46(12):1813-1821. DOI: 10.1086/588660
24.Bongomin F, Govender NP, Chakrabarti A, Robert-Gangneux F, Boulware DR, Zafar A, et al. Essential in vitro diagnostics for advanced HIV and serious fungal diseases: International experts’ consensus recommendations. European Journal of Clinical Microbiology & Infectious Diseases. 2019;38(9):1581-1584. DOI: 10.1007/s10096-019-03600-4
25.Fandiño-Devia E, Rodríguez-Echeverri C, Cardona-Arias J, González A. Antigen detection in the diagnosis of histoplasmosis: A meta-analysis of diagnostic performance. Mycopathologia. 2016;181(3-4):197-205. DOI: 10.1007/s11046-015-9965-3
26.Hage CA, Azar MM, Bahr N, Loyd J, Wheat LJ. Histoplasmosis: Up-to-date evidence-based approach to diagnosis and management. Seminars in Respiratory and Critical Care Medicine. 2015;36(5):729-745. DOI: 10.1055/s-0035-1562899
27.Cáceres DH, Samayoa BE, Medina NG, Tobon AM, Guzmán BJ, Mercado D, et al. Multicenter validation of commercial antigenuria reagents to diagnose progressive disseminated histoplasmosis in people living with HIV/AIDS in two Latin American countries. Journal of Clinical Microbiology. 2018;56(6). DOI: 10.1128/JCM.01959-17
28.Hage CA, Wheat LJ. Diagnosis of pulmonary histoplasmosis using antigen detection in the bronchoalveolar lavage. Expert Review of Respiratory Medicine. 2010;4(4):427-429. DOI: 10.1586/ers.10.36
29.Cáceres DH, Scheel CM, Tobon AM, Ahlquist Cleveland A, Restrepo A, Brandt ME, et al. Validation of an enzyme-linked immunosorbent assay that detects Histoplasma capsulatum antigenuria in Colombian patients with AIDS for diagnosis and follow-up during therapy. Clinical and Vaccine Immunology. 2014;21(9):1364-1368. DOI: 10.1128/CVI.00101-14
30.Hage CA, Kirsch EJ, Stump TE, Kauffman CA, Goldman M, Connolly P, et al. Histoplasma antigen clearance during treatment of histoplasmosis in patients with AIDS determined by a quantitative antigen enzyme immunoassay. Clinical and Vaccine Immunology. 2011;18(4):661-666. DOI: 10.1128/CVI.00389-10
31.Buitrago MJ, Martin-Gomez MT. Timely diagnosis of histoplasmosis in non-endemic countries: A laboratory challenge. Frontiers in Microbiology. 2020;11:467. DOI: 10.3389/fmicb.2020.00467
32.Kozel TR, Burnham-Marusich AR. Point-of-care testing for infectious diseases: Past, present, and future. Journal of Clinical Microbiology. 2017;55(8):2313-2320. DOI: 10.1128/JCM.00476-17
33.Prattes J, Heldt S, Eigl S, Hoenigl M. Point of care testing for the diagnosis of fungal infections: Are we there yet? Current Fungal Infection Reports. 2016;10:43-50. DOI: 10.1007/s12281-016-0254-5
34.Cáceres DH, Gómez BL, Tobon AM, Chiller TM, Lindsley MD. Evaluation of a Histoplasma antigen lateral flow assay for the rapid diagnosis of progressive disseminated histoplasmosis in Colombian patients with AIDS. Mycoses. 2020;63(2):139-144. DOI: 10.1111/myc.13023
35.Myint T, Leedy N, Villacorta Cari E, Wheat LJ. HIV-associated histoplasmosis: Current perspectives. HIV/AIDS. 2020;12:113-125. DOI: 10.2147/HIV.S185631
36.Kozel TR, Wickes B. Fungal diagnostics. Cold Spring Harbor Perspectives in Medicine. 2014;4(4):a019299. DOI: 10.1101/cshperspect.a019299
37.Hage CA, Knox KS, Wheat LJ. Endemic mycoses: Overlooked causes of community acquired pneumonia. Respiratory Medicine. 2012;106(6):769-776. DOI: 10.1016/j.rmed.2012.02.004
38.Cáceres DH, Knuth M, Derado G, Lindsley MD. Diagnosis of progressive disseminated histoplasmosis in advanced HIV: A meta-analysis of assay analytical performance. Journal of Fungi. 2019;5(3). DOI: 10.3390/jof5030076
39.Ramanan P, Wengenack NL, Theel ES. Laboratory diagnostics for fungal infections: A review of current and future diagnostic assays. Clinics in Chest Medicine. 2017;38(3):535-554. DOI: 10.1016/j.ccm.2017.04.013
40.Richardson M, Page I. Role of serological tests in the diagnosis of mold infections. Current Fungal Infection Reports. 2018;12(3):127-136. DOI: 10.1007/s12281-018-0321-1
41.Bloch KC, Myint T, Raymond-Guillen L, Hage CA, Davis TE, Wright PW, et al. Improvement in diagnosis of Histoplasma meningitis by combined testing for Histoplasma antigen and immunoglobulin G and immunoglobulin M anti-Histoplasma antibody in cerebrospinal fluid. Clinical Infectious Diseases. 2018;66(1):89-94. DOI: 10.1093/cid/cix706
42.Richer SM, Smedema ML, Durkin MM, Herman KM, Hage CA, Fuller D, et al. Improved diagnosis of acute pulmonary histoplasmosis by combining antigen and antibody detection. Clinical Infectious Diseases. 2016;62(7):896-902. DOI: 10.1093/cid/ciw007
43.Arvanitis M, Anagnostou T, Fuchs BB, Caliendo AM, Mylonakis E. Molecular and nonmolecular diagnostic methods for invasive fungal infections. Clinical Microbiology Reviews. 2014;27(3):490-526. DOI: 10.1128/CMR.00091-13
44.Alanio A, Bretagne S. Performance evaluation of multiplex PCR including Aspergillus-not so simple! Medical Mycology. 2017;55(1):56-62. DOI: 10.1093/mmy/myw080
45.Khot PD, Fredricks DN. PCR-based diagnosis of human fungal infections. Expert Review of Anti-Infective Therapy. 2009;7(10):1201-1221. DOI: 10.1586/eri.09.104
46.Vasconcellos I, Dalla Lana DF, Pasqualotto AC. The role of molecular tests in the diagnosis of disseminated histoplasmosis. Journal of Fungi. 2019;6(1). DOI: 10.3390/jof6010001
47.Ala-Houhala M, Koukila-Kahkola P, Antikainen J, Valve J, Kirveskari J, Anttila VJ. Clinical use of fungal PCR from deep tissue samples in the diagnosis of invasive fungal diseases: A retrospective observational study. Clinical Microbiology and Infection. 2018;24(3):301-305. DOI: 10.1016/j.cmi.2017.08.017
48.Buitrago MJ, Bernal-Martínez L, Castelli MV, Rodríguez-Tudela JL, Cuenca-Estrella M. Performance of panfungal and specific PCR based procedures for etiological diagnosis of invasive fungal diseases on tissue biopsy specimens with proven infection: A 7-year retrospective analysis from a reference laboratory. Journal of Clinical Microbiology. 2014;52(5):1737-1740. DOI: 10.1128/JCM.00328-14
49.Gómez CA, Budvytiene I, Zemek AJ, Banaei N. Performance of targeted fungal sequencing for culture-independent diagnosis of invasive fungal disease. Clinical Infectious Diseases. 2017;65(12):2035-2041. DOI: 10.1093/cid/cix728
50.Lindner AK, Rickerts V, Kurth F, Wilmes D, Richter J. Chronic oral ulceration and lip swelling after a long term stay in Guatemala: A diagnostic challenge. Travel Medicine and Infectious Disease. 2018;23:103-104. DOI: 10.1016/j.tmaid.2018.04.009
51.Valero C, de la Cruz-Villar L, Zaragoza Ó, Buitrago MJ. New panfungal real-time PCR assay for diagnosis of invasive fungal infections. Journal of Clinical microbiology. 2016;54(12):2910-2918. DOI: 10.1128/JCM.01580-16
52.Wong YP, Othman S, Lau YL, Radu S, Chee HY. Loop-mediated isothermal amplification (LAMP): A versatile technique for detection of microorganisms. Journal of Applied Microbiology. 2018;124(3):626-643. DOI: 10.1111/jam.13647
53.Scheel CM, Zhou Y, Theodoro RC, Abrams B, Balajee SA, Litvintseva AP. Development of a loop-mediated isothermal amplification method for detection of Histoplasma capsulatum DNA in clinical samples. Journal of Clinical Microbiology. 2014;52(2):483-488. DOI: 10.1128/JCM.02739-13
54.Zatti MDS, Arantes TD, Fernandes JAL, Bay MB, Milan EP, Naliato GFS, et al. Loop-mediated isothermal amplification and nested PCR of the internal transcribed spacer (ITS) for Histoplasma capsulatum detection. PLoS Neglected Tropical Diseases. 2019;13(8):e0007692. DOI: 10.1371/journal.pntd.0007692
55.Adenis AA, Aznar C, Couppie P. Histoplasmosis in HIV-infected patients: A review of new developments and remaining gaps. Current Tropical Medicine Reports. 2014;1:119-128. DOI: 10.1007/s40475-014-0017-8
56.Scheel CM, Gómez BL. Diagnostic methods for histoplasmosis: Focus on endemic countries with variable infrastructure levels. Current Tropical Medicine Reports. 2014;1(2):129-137. DOI: 10.1007/s40475-014-0020-0
57.Buitrago MJ, Canteros CE, Frías De León G, González Á, Marques-Evangelista De Oliveira M, Muñoz CO, et al. Comparison of PCR protocols for detecting Histoplasma capsulatum DNA through a multicenter study. Revista Iberoamericana de Micología. 2013;30(4):256-260. DOI: 10.1016/j.riam.2013.03.004
58.Nacher M, Adenis A, Mc Donald S, Do Socorro Mendonca Gomes M, Singh S, Lopes Lima I, et al. Disseminated histoplasmosis in HIV-infected patients in South America: A neglected killer continues on its rampage. PLoS Neglected Tropical Disease. 2013;7, 11:e2319. DOI: 10.1371/journal.pntd.0002319
59.Kidd SE, Chen SC, Meyer W, Halliday CL. A new age in molecular diagnostics for invasive fungal disease: Are we ready? Frontiers in Microbiology. 2019;10:2903. DOI: 10.3389/fmicb.2019.02903
60.Wilson MR, O’Donovan BD, Gelfand JM, Sample HA, Chow FC, Betjemann JP, et al. Chronic meningitis investigated via metagenomic next-generation sequencing. JAMA Neurology. 2018;75(8):947-955. DOI: 10.1001/jamaneurol.2018.0463
61.Zhang HC, Zhang QR, Ai JW, Cui P, Wu HL, Zhang WH, et al. The role of bone marrow metagenomics next-generation sequencing to differential diagnosis among visceral leishmaniasis, histoplasmosis, and talaromycosis marneffei. International Journal of Laboratory Hematology. 2020;42(2):e52-e54. DOI: 10.1111/ijlh.13103
62.Pakasa N, Biber A, Nsiangana S, Imposo D, Sumaili E, Muhindo H, et al. African histoplasmosis in HIV-negative patients, Kimpese, Democratic Republic of the Congo. Emerging Infectious Diseases. 2018;24(11):2068-2070. DOI: 10.3201/eid2411.180236
63.Mahajan VK, Raina RK, Singh S, Rashpa RS, Sood A, Chauhan PS, et al. Case report: Histoplasmosis in Himachal Pradesh (India): An emerging endemic focus. The American Journal of Tropical Medicine and Hygiene. 2017;97(6):1749-1756. DOI: 10.4269/ajtmh.17-0432
Written By
María J. Buitrago and Clara Valero
Submitted: November 6th, 2019Reviewed: July 1st, 2020Published: September 16th, 2020
Open access peer-reviewed chapter
