diagnostics Review Diagnosis of Pulmonary Infections Due to Endemic Fungi Victoria Poplin 1, Clarissa Smith 2 , Dominique Milsap 3, Lauren Zabel 3 and Nathan C. Bahr 1,* 1 Department of Internal Medicine, Division of Infectious Diseases, University of Kansas, Kansas City, KS 66160, USA; [email protected] 2 Department of Internal Medicine, University of Kansas, Kansas City, KS 66160, USA; [email protected] 3 School of Medicine, University of Kansas, Kansas City, KS 66160, USA; [email protected] (D.M.); [email protected] (L.Z.) * Correspondence: [email protected]; Tel.: +1-(913)-588-6035; Fax: +1-(913)-945-6916 Abstract: Endemic mycoses including Histoplasma, Blastomyces, Coccidioides, Paracoccidioides, and Ta- laromyces are dimorphic fungi that can cause a variety of clinical manifestations, including respiratory infections. Their pulmonary presentations are variable, and diagnosis is often delayed as they can mimic other infectious and non-infectious causes of pulmonary disease. Delay in diagnosis can lead to unnecessary antibiotic use, repeat hospitalizations, and increased morbidity and mortality. The diagnosis of endemic fungal pulmonary infections often relies on multiple diagnostic tests including culture, tissue histopathology, antigen assays, and antibody assays. Due to the increased use of immunosuppressive agents and the widening geographic ranges where these infections are being found, the prevalence of endemic fungal infections is increasing. Physicians need to be aware of the clinical manifestations of pulmonary infections due to endemic fungal in order to ensure that the proper diagnostic work up is obtained promptly. A high index of suspicion is particularly important in patients with suspected pulmonary infections who have failed to improve despite antibiotics in the appropriate setting. We present a review diagnostic testing for pulmonary infections due to endemic mycoses. Citation: Poplin, V.; Smith, C.; Milsap, D.; Zabel, L.; Bahr, N.C. Keywords: endemic fungi; diagnostic tests; histoplasmosis; blastomycosis; coccidioidomycosis; Diagnosis of Pulmonary Infections paracoccidioidomycosis; talaromycosis; pulmonary infection Due to Endemic Fungi. Diagnostics 2021, 11, 856. https://doi.org/ 10.3390/diagnostics11050856 1. Introduction Academic Editor: Byeong-Ho Jeong Fungal pneumonia caused by endemic fungi including Histoplasma, Blastomyces, Coc- cidioides, Paracoccidioides, and Talaromyces can be challenging to diagnose. These mycoses Received: 5 March 2021 are termed endemic as they classically occur in particular geographic regions [1]. Endemic Accepted: 30 April 2021 Published: 10 May 2021 fungi are dimorphic, existing as molds at cooler environmental temperatures and yeast within the warmer temperatures of the human body. The endemic fungi can cause a variety Publisher’s Note: MDPI stays neutral of syndromes, but all carry the potential to cause respiratory infections since inhalation with regard to jurisdictional claims in is a major mode of disease acquisition in humans. Furthermore, rates of pneumonia due published maps and institutional affil- to endemic fungi are increasing due to increased use of immunosuppressive therapies [2]. iations. Diagnosis of pneumonia due to endemic fungi can be challenging as the clinical presen- tations are varied and non-specific, meaning this type of pneumonia may be mistaken for a variety of infectious or non-infectious causes of lung disease [1,3]. The diagnosis is frequently delayed, particularly when occurring outside of traditional endemic areas as physicians may not be familiar with the disease manifestations [1]. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. Multiple diagnostic tests may be required for diagnosis including tissue histopathol- This article is an open access article ogy, culture, or specific fungal antigen or antibody detection assays in the appropriate distributed under the terms and clinical scenario. One non-specific fungal diagnostic test may be useful in the diagnosis of conditions of the Creative Commons Coccidioides, Histoplasma, Talaromyces, and Paracoccidioides is detection of 1,3-β-D-glucan, a Attribution (CC BY) license (https:// component of the cell wall of many fungi [4–6]. The 1,3-β-D-glucan assay is less useful to creativecommons.org/licenses/by/ detect Blastomyces given its yeast phase produces low levels of 1,3-β-D-glucan [4]. 1,3-β- 4.0/). D-glucan assay is a nonspecific test, therefore additional testing is needed to differentiate Diagnostics 2021, 11, 856. https://doi.org/10.3390/diagnostics11050856 https://www.mdpi.com/journal/diagnostics Diagnostics 2021, 11, 856 2 of 18 between fungi when the test is positive. Accordingly, the main role for 1,3-β-D-glucan testing in the diagnosis of endemic fungal pneumonia is as a screening test, or a non-specific test to help one further narrow the planned workup. We present a review of diagnostic testing for pneumonia due to endemic fungi. Given that geographic location and clinical presentations are crucial to proper diagnosis, these factors are described as well. 2. Histoplasmosis Histoplasmosis is caused by Histoplasma capsulatum var capsulatum and Histoplasma capsulatum var. duboisii [7]. 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 [2,7–10]. 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 [7]. 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 [9,10]. Histoplasma can cause a wide variety of clinical man- ifestations including a spectrum of pulmonary diseases ranging from acute to chronic presentations [9,11]. Table1 describes signs, symptoms, imaging and lab findings, and epidemiology of histoplasmosis and other endemic fungi. Table 1. Signs, symptoms, imaging and lab findings, and epidemiology of pulmonary infections due to endemic mycoses *. Clinical Presentation Imaging Laboratory Epidemiology Histoplasmosis Fevers, chills, malaise, Diffuse patchy dyspnea ranging from Pancytopenia in opacities self-limited illness to disseminated disease Hilar/mediastinal Acute Pulmonary ARDS Narrow based budding adenopathy. Histoplasmosis Painful compressive ovoid Histoplasma yeast, Miliary pattern in adenopathy. 2–4 µM in diameter on severe and Rheumatologic pathology disseminated disease manifestations Central and Eastern North America, much Pancytopenia in of Central and South Hilar and mediastinal disseminated disease Mild respiratory and America, Sub-Saharan Subacute pulmonary Adenopathy Narrow based budding constitutional Africa, large portions of Histoplasmosis Focal/patchy airspace ovoid Histoplasma yeast, symptoms, >1 month Southeast Asia, small disease 2–4 µM in diameter on areas of Australia and pathology Europe Patchy infiltrates, cavities that may Fever, night sweats, Narrow based budding enlarge over time Chronic Pulmonary weight loss, cough, ovoid Histoplasma yeast, Calcified lymph nodes. Histoplasmosis shortness, chest pain of 2–4 µM in diameter on Typically no breath, >3 months pathology mediastinal lymphadenopathy Acute: fevers, chills, Consolidation productive cough with Mass like infiltrates or without sputum Miliary pattern production severe cases Nodules Midwestern United can develop ARDS. Reticular infiltrates Broad-based budding States and Eastern Blastomycosis Subacute/chronic: Often no mediastinal yeast North America, much 2–6 months: lymphadenopathy on pathology of Africa and India fever, night sweats, Chronic disease cough, typically hemoptysis, weight upper lobe loss predominant Diagnostics 2021, 11, 856 3 of 18 Table 1. Cont. Clinical Presentation Imaging Laboratory Epidemiology Histoplasmosis Lobar consolidation (more common), Peripheral eosinophilia Nodular opacities Spherules range in Fatigue, cough, fever, Mediastinal, hilar, diameter from 10 to dyspnea, night sweats, and/or C immitis: Central 200 µm, are filled with myalgias, paratracheal California, Washington 2–5 µm diameter symptoms onset adenopathy C posadasii: South and Coccidiomycosis endospores 1–3 weeks after Pleural effusion Central America, Endospores may be exposure (typically unilateral) Mexico, Arizona, Texas, outside Rheumatologic Cavities Utah of spherules and phenomena Miliary pattern in misidentified as other immunosuppressed fungi Migratory (phantom) infiltrates Acute/subacute: fever, Reticular, nodular, weight loss, interstitial or mixed Characteristic yeast lymphadenopathy, opacities. Referred to resembling “pilot Parts of Central and signs of disseminated as ‘bat’ or ‘butterfy’ Paracoccidiomycosis wheel” or “Mickey South America, most disease wing in median zone mouse” head on commonly in Brazil Chronic/adult: cough, Nodules pathology dyspnea, weight loss, Cavities. Interlobular anorexia septal thickening Fever, weight loss, cutaneous lesions, hepatosplenomegaly, lymphadenopathy, Patchy exudates respiratory signs (both Anemia, Nodular infiltrates in thrombocytopenia, South and Southeast Talaromycosis Pleural effusions HIV positive and HIV elevated liver function Asia Cavitary lesions negative individuals) tests Miliary pattern Arthritis, spondylodiskitis, osteomyelitis (more common in HIV negative individuals) ARDS: Acute