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    Topic review

    Pulmonary Histoplasmosis: Diagnosis

    Subjects: Microbiology
    View times: 12
    Submitted by: Nathan C. Bahr

    Definition

    Acute pulmonary histoplasmosis (APH) typically presents with fever, chills, shortness of breath, and resembles community acquired pneumonia. APH can range from a mild self-limiting illness to acute respiratory distress syndrome. Subacute pulmonary histoplasmosis (SPH) has a more insidious onset over at least one month and may develop after a smaller inoculum exposure. Chronic pulmonary histoplasmosis (CPH) is classically seen in older males with underlying lung disease. CPH has a similar presentation to tuberculosis with fever, night sweats, weight loss, cough, and dyspnea over at least three months. H capsulatum may also cause pulmonary nodules, mediastinal adenitis, mediastinal granulomas, and mediastinal fibrosis. Progressive disseminated histoplasmosis is a form of histoplasmosis that result from hematogenous spread and can impact multiple organ symptoms including the respiratory tract and cause severe disease.

    Pulmonary histoplasmosis: diagnosis1. Histoplasmosis

    Histoplasmosis is caused by Histoplasma capsulatum var capsulatum and Histoplasma capsulatum var. duboisii [1]. Classically, H capsulatum is thought of as endemic to the Ohio and Mississippi River Valleys in the United States, as well as parts of Central and South America [2][1][3][4][5]. More recently it has become clear that Histoplasma occurs frequently in many parts of the world including: Central and Eastern North America, the majority of Central and South America, much of sub-Saharan Africa, large portions of southeast Asia and small areas within Australia and Europe [1]. H duboisii has primarily been described in West Africa.
    Infection is acquired through inhalation of spores from soil that is contaminated with bird or bat droppings [4][5]. Histoplasma can cause a wide variety of clinical manifestations including a spectrum of pulmonary diseases ranging from acute to chronic presentations [4][6].

    2. Symptoms

    Acute pulmonary histoplasmosis (APH) typically presents with fever, chills, shortness of breath, and resembles community acquired pneumonia [2][7][4][6][8]. APH can range from a mild self-limiting illness to acute respiratory distress syndrome [2][4][6][9]. Subacute pulmonary histoplasmosis (SPH) has a more insidious onset over at least one month and may develop after a smaller inoculum exposure [2][7][4][6]. Chronic pulmonary histoplasmosis (CPH) is classically seen in older males with underlying lung disease [2][7][5][6]. CPH has a similar presentation to tuberculosis with fever, night sweats, weight loss, cough, and dyspnea over at least three months [4][5][6][8]. H capsulatum may also cause pulmonary nodules, mediastinal adenitis, mediastinal granulomas, and mediastinal fibrosis [10][2]. Progressive disseminated histoplasmosis is a form of histoplasmosis that result from hematogenous spread and can impact multiple organ symptoms including the respiratory tract and cause severe disease [6].
    In APH, imaging frequently shows diffuse bilateral patchy opacities with hilar and mediastinal adenopathy while diffuse reticulonodular or miliary infiltrates can be seen less commonly [2][7][6][9][11]. In CPH patchy infiltrates can progress to large, destructive cavities; hilar and mediastinal lymphadenopathy are uncommon compared to APH [5][6].

    3. Diagnosis

    Identification of H capsulatum on histopathology and culture is the classical diagnostic standard [2][5][12]. The narrow based budding ovoid Histoplasma yeast (2–4 μM in diameter) is visualized via direct microscopic examination or the use of Gomori methenamine silver, Giemsa, periodic acid-Schiff, or hematoxylin eosin stains of specimens such as respiratory samples, lymph node tissue, or lung tissue (Figure 1A) [10][2][3][4][6][13][14][15]. Cytopathologic examination of bronchoalveolar lavage (BAL) fluid is positive in up to 50% of cases [2][7][3]. Histopathologic examination can reveal both caseating and non-caseating granulomas [3][4]. Despite the potential to improve diagnosis, pathological examination is not feasible in most patients as it requires invasive procedures, such as bronchoscopy or biopsies [3]. In general, it is more useful in disseminated histoplasmosis compared to pulmonary histoplasmosis and is more likely to be positive in SPH or CPH compared to APH [6][16]. Histoplasma can take 2–8 weeks to grow on culture which is similarly more likely to be positive in SPH or CPH compared to APH [2][7][3][4][5][13][16]. Overall sensitivity of culture of sputum or bronchoscopy specimens is 48–75% in pulmonary histoplasmosis [7][6].
    Antigen detection can provide rapid diagnosis of pulmonary histoplasmosis. Numerous commercial and in-house tests are available, however, agreement between tests is not uniform [8][12][17]. Most though not all antigen tests use an enzyme immunoassay (EIA) [8][12][18]. Antigen is generally more likely to be positive in APH compared with SPH and CPH although CPH commonly yields positive results as well [2][7][6][16]. In a multicenter evaluation by Hage et al., antigenuria was detected in 83% of acute cases, 30% of subacute cases, and 87.5% of chronic pulmonary histoplasmosis, with the highest antigen concentrations in acute cases—combined urine and serum antigen testing improved yield [16]. In another large study of APH, antigen was detected in serum and urine in 65% and 69% of cases, respectively [9]. This same study found that antigen was more likely to be detected in patients who require hospitalization, likely reflecting higher fungal burden in more severe disease [9]. Antigen testing of BAL can further aid in diagnosis of pulmonary histoplasmosis, particularly in CPH or diffuse pulmonary disease complicating disseminated histoplasmosis. Hage et al. found that among 31 patients with histoplasmosis and pulmonary involvement, antigen detection in BAL had 93.5% sensitivity, 97.8% specificity, 68.8% positive predictive value, and 99.6% negative predictive value [19]. Overall, 21 of the 31 patients in this study were immunocompromised with disseminated histoplasmosis including disseminated pulmonary disease [19]. One limitation of Histoplasma antigen testing is its cross reactivity with other mycoses, such as Blastomyces spp, Talaromyces marneffei, Paracoccidioides, Coccidioides, and Aspergillus spp. [2][7][5][6][8][11][12][16][18][20][17]
    The IMMY Histoplasma EIA, is a commercially available, FDA approved EIA for detection of Histoplasma antigen in urine [8][12]. In a study by Theel et al. the IMMY EIA had 97.6% agreement with MiraVista Diagnostic’s EIA and a specificity and sensitivity of 99.8% and 64.5%, respectively [12]. As opposed to MiraVista’s EIA which is done at a central laboratory, health centers can perform IMMY’s test given its FDA approval. MiraVista recently developed a lateral flow assay (LFA) for serum antigen detection [21]. In patients with HIV and disseminated histoplasmosis, sensitivity was 96% and specificity 94% [21]. This test is not FDA approved.
    Antibody testing is also used to diagnose histoplasmosis. Because antibodies take time to develop after acute infection, they are more useful in SPH and CPH than APH and negative initial antibody testing should be repeated in one to two months if suspicion is high [2][7][3][4][5][6][9][11][14]. Additionally, antibody testing may be negative in immunocompromised patients and may cross react with other endemic mycoses such as Blastomyces, Paracoccidioides, and Coccidioides [2][3][4][6]. Common methodologies include immunodiffusion (ID), complement fixation (CF), or EIA [2][3][4][6]. ID detects H and M bands, H bands are more rare but when found indicate acute infection whereas M bands are more common and may persist for years [2][3][6]. A fourfold rise in CF titers or a single titer of 1:32 or higher is indicative of active infection [2][3][6]. Compared to CF, ID is slightly more specific and less sensitive [5]. One multicenter evaluation found 67% seropositivity (by CF or ID) in APH, compared to 95% in SPH and 83% in CPH [16]. In one study of patients with APH, MiraVista Diagnostics’ IgM, and IgG EIA exhibited 89% sensitivity and 92% specificity [11]. Combining antigen and antibody testing may improve sensitivity for diagnosis of APH, potentially as high as 96% [9][11]. Similar sensitivity has been found using the combination of BAL antigen detection and BAL cytopathology [7].
    Nucleic acid amplification tests (NAAT) such as polymerase chain reaction (PCR) or loop-mediated isothermal amplification (LAMP) have been utilized for the identification of H. capsulatum, however these have variable sensitivities and none are commercially available [2][22][23][24][25][26][27][28][29]. NAATs are less likely to have false positive results due to other endemic fungi compared to antigen and antibody testing [22]. A reference database has been created to identify H. capsulatum via matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) but little data on performance is available [30][31]. Similarly, while metagenomic next generation sequencing (mNGS) has been used on BAL fluid to diagnose H. capsulatum causing chronic progressive pulmonary lesions and epiglottis lesions, broader performance data are not available [32][33]. Finally, there may be a role for panfungal PCR to diagnose histoplasmosis, but so far use has been exploratory [34].
    Pulmonary infection is more common due to H. capuslatum var capsulatum than H. capsulatum var. duboisii [1]. In a summary of 94 reported cases, only 10 were suspected to have pulmonary involvement [35]. H capsulatum var. duboisii frequently causes lymphadenopathy, bone, cutaneous, sub-cutaneous, and disseminated disease, and may occur decades after leaving the endemic area [35]. H capsulatum var. duboisii diagnosis has not been well studied and so diagnostic test performance characteristics are less well understood. Histopathology, cytology are commonly used while confirmation with culture or PCR are less common and antibody testing is even more rare [35]. Histoplasma antigen testing has not been utilized [35].

    This entry is adapted from 10.3390/diagnostics11050856

    References

    1. Ashraf, N.; Kubat, R.C.; Poplin, V.; Adenis, A.A.; Denning, D.W.; Wright, L.; McCotter, O.; Schwartz, I.S.; Jackson, B.R.; Chiller, T.; et al. Re-drawing the Maps for Endemic Mycoses. Mycopathologia 2020, 185, 843–865.
    2. Azar, M.M.; Hage, C.A. Clinical Perspectives in the Diagnosis and Management of Histoplasmosis. Clin. Chest Med. 2017, 38, 403–415.
    3. Hage, C.A.; Azar, M.M.; Bahr, N.; Loyd, J.; Wheat, L.J. Histoplasmosis: Up-to-Date Evidence-Based Approach to Diagnosis and Management. Semin. Respir. Crit. Care Med. 2015, 36, 729–745.
    4. McKinsey, D.S.; McKinsey, J.P. Pulmonary histoplasmosis. Semin. Respir. Crit. Care Med. 2011, 32, 735–744.
    5. Baker, J.; Kosmidis, C.; Rozaliyani, A.; Wahyuningsih, R.; Denning, D.W. Chronic Pulmonary Histoplasmosis-A Scoping Literature Review. Open Forum Infect. Dis. 2020, 7, ofaa119.
    6. Wheat, L.J.; Azar, M.M.; Bahr, N.C.; Spec, A.; Relich, R.F.; Hage, C. Histoplasmosis. Infect. Dis. Clin. N. Am. 2016, 30, 207–227.
    7. Hage, C.A.; Knox, K.S.; Davis, T.E.; Wheat, L.J. Antigen detection in bronchoalveolar lavage fluid for diagnosis of fungal pneumonia. Curr. Opin. Pulm. Med. 2011, 17, 167–171.
    8. Couturier, M.R.; Graf, E.H.; Griffin, A.T. Urine antigen tests for the diagnosis of respiratory infections: Legionellosis, histoplasmosis, pneumococcal pneumonia. Clin. Lab. Med. 2014, 34, 219–236.
    9. Swartzentruber, S.; Rhodes, L.; Kurkjian, K.; Zahn, M.; Brandt, M.E.; Connolly, P.; Wheat, L.J. Diagnosis of acute pulmonary histoplasmosis by antigen detection. Clin. Infect. Dis. 2009, 49, 1878–1882.
    10. Salzer, H.J.F.; Burchard, G.; Cornely, O.A.; Lange, C.; Rolling, T.; Schmiedel, S.; Libman, M.; Capone, D.; Le, T.; Dalcolmo, M.P.; et al. Diagnosis and Management of Systemic Endemic Mycoses Causing Pulmonary Disease. Respiration 2018, 96, 283–301.
    11. Richer, S.M.; Smedema, M.L.; Durkin, M.M.; Herman, K.M.; Hage, C.A.; Fuller, D.; Wheat, L.J. Improved Diagnosis of Acute Pulmonary Histoplasmosis by Combining Antigen and Antibody Detection. Clin. Infect. Dis. 2016, 62, 896–902.
    12. Theel, E.S.; Jespersen, D.J.; Harring, J.; Mandrekar, J.; Binnicker, M.J. Evaluation of an enzyme immunoassay for detection of Histoplasma capsulatum antigen from urine specimens. J. Clin. Microbiol. 2013, 51, 3555–3559.
    13. Fandino-Devia, E.; Rodriguez-Echeverri, C.; Cardona-Arias, J.; Gonzalez, A. Antigen Detection in the Diagnosis of Histoplasmosis: A Meta-analysis of Diagnostic Performance. Mycopathologia 2016, 181, 197–205.
    14. Azar, M.M.; Malo, J.; Hage, C.A. Endemic Fungi Presenting as Community-Acquired Pneumonia: A Review. Semin. Respir. Crit. Care Med. 2020, 41, 522–537.
    15. Azar, M.M.; Hage, C.A. Laboratory Diagnostics for Histoplasmosis. J. Clin. Microbiol. 2017, 55, 1612–1620.
    16. Hage, C.A.; Ribes, J.A.; Wengenack, N.L.; Baddour, L.M.; Assi, M.; McKinsey, D.S.; Hammoud, K.; Alapat, D.; Babady, N.E.; Parker, M.; et al. A multicenter evaluation of tests for diagnosis of histoplasmosis. Clin. Infect. Dis. 2011, 53, 448–454.
    17. Zhang, C.; Lei, G.S.; Lee, C.H.; Hage, C.A. Evaluation of two new enzyme immunoassay reagents for diagnosis of histoplasmosis in a cohort of clinically characterized patients. Med. Mycol. 2015, 53, 868–873.
    18. Connolly, P.A.; Durkin, M.M.; Lemonte, A.M.; Hackett, E.J.; Wheat, L.J. Detection of histoplasma antigen by a quantitative enzyme immunoassay. Clin. Vaccine Immunol. 2007, 14, 1587–1591.
    19. Hage, C.A.; Davis, T.E.; Fuller, D.; Egan, L.; Witt, J.R., 3rd; Wheat, L.J.; Knox, K.S. Diagnosis of histoplasmosis by antigen detection in BAL fluid. Chest 2010, 137, 623–628.
    20. Swartzentruber, S.; LeMonte, A.; Witt, J.; Fuller, D.; Davis, T.; Hage, C.; Connolly, P.; Durkin, M.; Wheat, L.J. Improved detection of Histoplasma antigenemia following dissociation of immune complexes. Clin. Vaccine Immunol. 2009, 16, 320–322.
    21. Caceres, D.H.; Gomez, B.L.; Tobon, A.M.; Chiller, T.M.; Lindsley, M.D. Evaluation of a Histoplasma antigen lateral flow assay for the rapid diagnosis of progressive disseminated histoplasmosis in Colombian patients with AIDS. Mycoses 2020, 63, 139–144.
    22. Babady, N.E.; Buckwalter, S.P.; Hall, L.; Le Febre, K.M.; Binnicker, M.J.; Wengenack, N.L. Detection of Blastomyces dermatitidis and Histoplasma capsulatum from culture isolates and clinical specimens by use of real-time PCR. J. Clin. Microbiol. 2011, 49, 3204–3208.
    23. Gago, S.; Esteban, C.; Valero, C.; Zaragoza, O.; Puig de la Bellacasa, J.; Buitrago, M.J. A multiplex real-time PCR assay for identification of Pneumocystis jirovecii, Histoplasma capsulatum, and Cryptococcus neoformans/Cryptococcus gattii in samples from AIDS patients with opportunistic pneumonia. J. Clin. Microbiol. 2014, 52, 1168–1176.
    24. Zatti, M.D.S.; Arantes, T.D.; Fernandes, J.A.L.; Bay, M.B.; Milan, E.P.; Naliato, G.F.S.; Theodoro, R.C. Loop-mediated Isothermal Amplification and nested PCR of the Internal Transcribed Spacer (ITS) for Histoplasma capsulatum detection. PLoS Negl. Trop. Dis. 2019, 13, e0007692.
    25. Dantas, K.C.; Freitas, R.S.; da Silva, M.V.; Criado, P.R.; Luiz, O.D.C.; Vicentini, A.P. Comparison of diagnostic methods to detect Histoplasma capsulatum in serum and blood samples from AIDS patients. PLoS ONE 2018, 13, e0190408.
    26. Lopez, L.F.; Munoz, C.O.; Caceres, D.H.; Tobon, A.M.; Loparev, V.; Clay, O.; Chiller, T.; Litvintseva, A.; Gade, L.; Gonzalez, A.; et al. Standardization and validation of real time PCR assays for the diagnosis of histoplasmosis using three molecular targets in an animal model. PLoS ONE 2017, 12, e0190311.
    27. Vasconcellos, I.; Dalla Lana, D.F.; Pasqualotto, A.C. The Role of Molecular Tests in the Diagnosis of Disseminated Histoplasmosis. J. Fungi (Basel) 2019, 6, 1.
    28. Caceres, D.H.; Knuth, M.; Derado, G.; Lindsley, M.D. Diagnosis of Progressive Disseminated Histoplasmosis in Advanced HIV: A Meta-Analysis of Assay Analytical Performance. J. Fungi (Basel) 2019, 5, 76.
    29. Scheel, C.M.; Zhou, Y.; Theodoro, R.C.; Abrams, B.; Balajee, S.A.; Litvintseva, A.P. Development of a loop-mediated isothermal amplification method for detection of Histoplasma capsulatum DNA in clinical samples. J. Clin. Microbiol. 2014, 52, 483–488.
    30. Panda, A.; Ghosh, A.K.; Mirdha, B.R.; Xess, I.; Paul, S.; Samantaray, J.C.; Srinivasan, A.; Khalil, S.; Rastogi, N.; Dabas, Y. MALDI-TOF mass spectrometry for rapid identification of clinical fungal isolates based on ribosomal protein biomarkers. J. Microbiol. Methods 2015, 109, 93–105.
    31. Valero, C.; Buitrago, M.J.; Gago, S.; Quiles-Melero, I.; Garcia-Rodriguez, J. A matrix-assisted laser desorption/ionization time of flight mass spectrometry reference database for the identification of Histoplasma capsulatum. Med. Mycol. 2018, 56, 307–314.
    32. Chen, J.; Li, Y.; Li, Z.; Chen, G.; Liu, X.; Ding, L. Metagenomic next-generation sequencing identified Histoplasma capsulatum in the lung and epiglottis of a Chinese patient: A case report. Int. J. Infect. Dis. 2020, 101, 33–37.
    33. Wang, J.; Zhou, W.; Ling, H.; Dong, X.; Zhang, Y.; Li, J.; Zhang, Y.; Song, J.; Liu, W.J.; Li, Y.; et al. Identification of Histoplasma causing an unexplained disease cluster in Matthews Ridge, Guyana. Biosaf. Health 2019, 1, 150–154.
    34. Frickmann, H.; Loderstaedt, U.; Racz, P.; Tenner-Racz, K.; Eggert, P.; Haeupler, A.; Bialek, R.; Hagen, R.M. Detection of tropical fungi in formalin-fixed, paraffin-embedded tissue: Still an indication for microscopy in times of sequence-based diagnosis? Biomed. Res. Int. 2015, 2015, 938721.
    35. Develoux, M.; Amona, F.M.; Hennequin, C. Histoplasmosis caused by Histoplasma capsulatum var. duboisii: A comprehensive review of cases from 1993 to 2019. Clin. Infect. Dis. 2020, ciaa1304.
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