Testing Practices for Fungal Respiratory Infections and SARS-Cov-2 Among Infectious Disease Specialists, United States

Journal of Fungi

Brief Report Testing Practices for Fungal Respiratory Infections and SARS-CoV-2 among Infectious Disease Specialists, United States

Kaitlin Benedict 1,* , Samantha Williams 1 , Susan E. Beekmann 2, Philip M. Polgreen 2, Brendan R. Jackson 1 and Mitsuru Toda 1

1 Mycotic Diseases Branch, Centers for Disease Control and Prevention, Atlanta, GA 30329, USA; [email protected] (S.W.); [email protected] (B.R.J.); [email protected] (M.T.) 2 Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; [email protected] (S.E.B.); [email protected] (P.M.P.) * Correspondence: [email protected]

Abstract: In an online poll, 174 infectious disease physicians reported that testing frequencies for coccidioidomycosis, histoplasmosis, blastomycosis, and cryptococcosis were similar before and during the COVID-19 pandemic, indicating that these physicians remain alert for these fungal infections and were generally not concerned about the possibility of under-detection.

Keywords: blastomycosis; coccidioidomycosis; cryptococcosis; histoplasmosis; SARS-CoV-2; COVID-19

Citation: Benedict, K.; Williams, S.; 1. Introduction Beekmann, S.E.; Polgreen, P.M.; Certain fungal infections can cause fever, cough, and shortness of breath, similar to Jackson, B.R.; Toda, M. Testing other respiratory illnesses including COVID-19, making them challenging to diagnose [1]. Practices for Fungal Respiratory Co-infection with fungi and SARS-CoV-2 is also a growing concern, particularly for COVID- Infections and SARS-CoV-2 among 19-associated pulmonary aspergillosis (CAPA) and mucormycosis [2,3]. The relationship Infectious Disease Specialists, United between COVID-19 and other fungal respiratory infections is less clear, with only a few States. J. Fungi 2021, 7, 605. https:// published case reports of coccidiomycosis, histoplasmosis, and cryptococcosis in COVID-19 doi.org/10.3390/jof7080605 patients [4–10]. In general, testing for fungal respiratory infections appears to be low among primary Academic Editor: David S. Perlin care providers, who are often the first point of care for patients with these diseases [11]. Consequently, these patients can experience long delays before being correctly diagnosed Received: 12 July 2021 by specialists such as infectious disease (ID) physicians. However, little is known about Accepted: 23 July 2021 fungal respiratory infection testing practices among this provider population, both gener- Published: 27 July 2021 ally and in the context of COVID-19. To inform strategies to reduce potential delayed and missed fungal diagnoses, we surveyed ID physicians to understand how the COVID-19 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in pandemic may have influenced their testing practices for coccidioidomycosis, histoplasmo- published maps and institutional affil- sis, blastomycosis, and cryptococcosis. iations. 2. Materials and Methods The Emerging Infections Network (EIN) is a provider-based surveillance network supported by CDC and IDSA [12]. EIN emailed a link to a 7-question poll three times during January–February 2021 to its >2700 member listserv (https://ein.idsociety.org/), Copyright: © 2021 by the authors. which includes the target audience of ~1500 ID physicians who see adult patients, pediatric Licensee MDPI, Basel, Switzerland. This article is an open access article ID physicians, and to other healthcare and public health professionals. distributed under the terms and 3. Results conditions of the Creative Commons Attribution (CC BY) license (https:// In total, 199 people responded; 6 were not practicing ID physicians and were excluded. creativecommons.org/licenses/by/ We further limited the analysis to the 174 (90%) ID physicians who had consulted on or 4.0/). treated any suspected or known COVID-19 patients (median 50 patients, interquartile

J. Fungi 2021, 7, 605. https://doi.org/10.3390/jof7080605 https://www.mdpi.com/journal/jof J. Fungi 2021, 7, x FOR PEER REVIEW 2 of 5

3. Results

J. Fungi 2021, 7, 605 In total, 199 people responded; 6 were not practicing ID physicians and were2 of ex- 5 cluded. We further limited the analysis to the 174 (90%) ID physicians who had consulted on or treated any suspected or known COVID-19 patients (median 50 patients, interquartile range 20–200, range 3–2000). The highest proportion of respondents was from the West range(n = 55, 20–200, 32%), range followed 3–2000). by the The Midwest highest ( proportionn = 47, 27%), of South respondents (n = 46, was26%), from and theNortheast West (n(=n = 55 26,, 32%), 15%). followed by the Midwest (n = 47, 27%), South (n = 46, 26%), and Northeast (n = 26,The 15%). proportion of respondents who reported “sometimes” or “frequently” testing for fungalThe infections proportion among of respondents patients with who signs reported and symptoms “sometimes” of community-acquired or “frequently” testing pneu- for fungal infections among patients with signs and symptoms of community-acquired monia before the COVID-19 pandemic was similar to the proportion that reported doing pneumonia before the COVID-19 pandemic was similar to the proportion that reported so at the time of the survey for all four infections we surveyed: coccidioidomycosis (36% doing so at the time of the survey for all four infections we surveyed: coccidioidomycosis vs. 35%), histoplasmosis (58% vs. 53%), blastomycosis (35% vs. 31%), and cryptococcosis (36% vs. 35%), histoplasmosis (58% vs. 53%), blastomycosis (35% vs. 31%), and cryptococ- (52% vs. 49%) (Figure 1). In areas where each infection is typically most common, these cosis (52% vs. 49%) (Figure1). In areas where each infection is typically most common, proportions were the same before the pandemic vs. at the time of the survey for coccidi- these proportions were the same before the pandemic vs. at the time of the survey for oidomycosis (83% vs. 83%) in Arizona, California, New Mexico, Nevada, Texas, and Utah coccidioidomycosis (83% vs. 83%) in Arizona, California, New Mexico, Nevada, Texas, and combined; but they were higher before the pandemic vs. at the time of the survey for his- Utah combined; but they were higher before the pandemic vs. at the time of the survey for toplasmosis (85% vs. 70%) in the Midwest and for blastomycosis (65% vs. 53%) in the histoplasmosis (85% vs. 70%) in the Midwest and for blastomycosis (65% vs. 53%) in the Midwest [13]. Midwest [13].

100 9 10 90 20 13 14 25 26 31 80 33 70 35 37 37 60 44 40 40 50 38 40 Percent (%) 46 43 30 46 44 25 24 20 28 27 10 12 10 12 10 0 6 4 6 5 Pre- During Pre- During Pre- During Pre- During COVID- COVID- COVID- COVID- COVID- COVID- COVID- COVID- 19 19 19 19 19 19 19 19 Coccidioidomycosis (Valley fever) Histoplasmosis Blastomycosis Cryptococcosis

Frequently Sometimes Rarely Never

Figure 1. Infectious disease physicians’ reported testing frequency for coccidioidomycosis, histoplasmosis, blastomycosis, Figure 1. Infectious disease physicians’ reported testing frequency for coccidioidomycosis, histoplasmosis, blastomycosis, and cryptococcosis among patients with signs and symptoms of community-acquired pneumonia, before and during the and cryptococcosis among patients with signs and symptoms of community-acquired pneumonia, before and during the COVID-19COVID-19 pandemic, pandemic, United United States. States. Overall, most respondents (n = 124, 72%) said that their testing practices for fungal Overall, most respondents (n = 124, 72%) said that their testing practices for fungal infections had not changed since the pandemic began. Among the 9% (n = 15) who said infections had not changed since the pandemic began. Among the 9% (n = 15) who said they test for fungal infections less frequently since the pandemic began, the main reasons, they test for fungal infections less frequently since the pandemic began, the main reasons, captured as free-text responses, were that COVID-19 was believed to be a more likely captured as free-text responses, were that COVID-19 was believed to be a more likely ill- illness and reduced patient travel to regions where fungal infections are most common. ness and reduced patient travel to regions where fungal infections are most common. Among the 20% (n = 34) who said they test for fungal infections more frequently since Among the 20% (n = 34) who said they test for fungal infections more frequently since the the pandemic began, common reasons included: immunosuppression and steroid use pandemic began, common reasons included: immunosuppression and steroid use in in COVID-19 patients, suspicion for CAPA, and specific concern for patients with long hospitalizationsCOVID-19 patients, or failure suspicion to improve. for CAPA, and specific concern for patients with long hos- pitalizationsThe most influentialor failure to factors improve. in deciding to test possible COVID-19 patients for coccidioidomycosis,The most histoplasmosis, influential factors blastomycosis, in deciding andto test cryptococcosis possible COVID-19 included: patients exposure for coc- to a specificcidioidomycosis, environmental histoplasmosis source (n, blastomycosis,= 97, 56%), exposure and cryptoco to knownccosis endemic included: areas exposure (n = 92, to 53%),a specific and presence environmental of underlying source condition(s)(n = 97, 56%), that exposure predispose to known people endemic to fungal areas infections (n = 92, (n53%),= 91, and 53%) presence (Figure2 ).of Factorsunderlying less commonlycondition(s) noted that aspredispose extremely people influential to fungal were: infections abnormal imaging results (n = 41, 26%), lack of clinical improvement (n = 34, 20%), and two or more negative SARS-CoV-2 tests (n = 25, 15%). Most respondents (n = 94, 71%) were not concerned about underdiagnosis of these 4 fungal infections either at their institution or in general. The main reasons for lack of concern, captured as free-text responses, included: that patients are being appropriately tested for these infections, that these infections are J. Fungi 2021, 7, x FOR PEER REVIEW 3 of 5

(n = 91, 53%) (Figure 2). Factors less commonly noted as extremely influential were: abnormal imaging results (n = 41, 26%), lack of clinical improvement (n = 34, 20%), and two or more negative SARS-CoV-2 tests (n = 25, 15%). Most respondents (n = 94, 71%) were not J. Fungi 2021, 7, 605 concerned about underdiagnosis of these 4 fungal infections either at their institution3 of or 5 in general. The main reasons for lack of concern, captured as free-text responses, included: that patients are being appropriately tested for these infections, that these infections are not present in their geographic area or the patient population they care for, and greater not present in their geographic area or the patient population they care for, and greater concern for CAPA than these infections. concern for CAPA than these infections.

Other Exposure to a specific environmental source or event (e.g., bird or bat guano, dust storm) Exposure to a geographic area where the fungi that cause these infections are known to be present Presence of an underlying condition(s) that predisposes to fungal infections Not at all Abnormal imaging result Rarely Slightly Lack of clinical improvement Extremely Two or more negative SARS-CoV-2 tests

One negative SARS-CoV-2 test

0 10203040506070 Percent (%)

Figure 2. Infectious diseases physicians’ responses to the question “When considering a patient with possible COVID-19, howFigure would 2. Infectious each of thediseases following physicians’ influence responses your decision to the toquesti teston for “When coccidioidomycosis, considering a histoplasmosis,patient with possible blastomycosis COVID-19, or cryptococcosis?”.how would each of the following influence your decision to test for coccidioidomycosis, histoplasmosis, blastomycosis or cryptococcosis?”. 4. Discussion 4. DiscussionID physicians reported similar rates of testing for coccidioidomycosis, histoplasmosis, blastomycosis,ID physicians and reported cryptococcosis similar beforerates of and testing during for thecoccidioidomycosis, COVID-19 pandemic, histoplasmo- relying primarilysis, blastomycosis, on epidemiologic and cryptococcosis exposures before and host and statusduring to the guide COVID-19 testing pandemic, decisions. relying These resultsprimarily indicate on epidemiologic that respondents exposures have continuedand host status to consider to guide these testing fungal decisions. infections These as a causeresults of indicate respiratory that illnessrespondents during have the COVID-19 continued pandemic.to consider these fungal infections as a causeOur of respiratory finding that illness most du respondentsring the COVID-19 were not pandemic. concerned about underdiagnosis of coccidioidomycosis,Our finding that histoplasmosis,most respondents blastomycosis, were not concerned and cryptococcosis about underdiagnosis in the context of coc- ofcidioidomycosis, COVID-19 may histoplasmosis, be justified by blastomyco the existencesis, ofand only cryptococcosis a few case reports in the ofcontext such co-of infections:COVID-19 4may histoplasmosis be justified casesby the in existence Latin America of only [5 ,a9 ,10few,14 case], 2 coccidioidomycosisreports of such co-infec- cases intions: a highly 4 histoplasmosis endemic area cases of California in Latin [Americ4,8], 2 cryptococcosisa [5,9,10,14], 2 casescoccidioidomycosis in immunocompromised cases in a patientshighly endemic [6,7], and area no publishedof California reports [4,8], of2 blastomycosis.cryptococcosis Togethercases in immunocompromised with the moderate-to- highpatients testing [6,7], frequencies and no published (depending reports on the of diseaseblastomycosis. and geographic Together area) with in the this moderate-to- survey, this suggestshigh testing that frequencies the overlap between(depending these on fungal the di infectionssease and and geographic COVID-19 area) may in not this be survey, widely overlookedthis suggests by that respondents. the overlap However, between delayed these fungal diagnosis infections of these and fungal COVID-19 infections may because not be ofwidely clinical overlooked similarities by respondents. to other respiratory However, infections delayed is diagnosis a potentially of these larger fungal issue infections than co- infections.because of IDclinical physicians similarities may to be other more respiratory likely to see infections patients withis a potentially fungal infections larger issue after failedthan co-infections. treatment for ID other physicians suspected may infections be more likely and are to see therefore patients probably with fungal more infections inclined toafter test failed for fungal treatment etiologies for other than suspected other healthcare infections providers. and are Nevertheless, therefore probably overwhelming more in- evidenceclined to indicatestest for fungal that these etiologies 4 fungal than infections other healthcare are under-detected providers. in Nevertheless, general, apart over- from COVID-19whelming evidence [15]. indicates that these 4 fungal infections are under-detected in general, apartIn from contrast COVID-19 to the few[15]. case reports of coccidioidomycosis, histoplasmosis, blastomycosis, and cryptococcosis associated with COVID-19, nearly 200 cases of CAPA have been described globally [16], and our results suggest that respondents were familiar with this emerging phenomenon, despite the survey’s intended focus on other infections. For ex- ample, our finding that 20% of respondents said they test for fungal infections overall more frequently now compared with pre-COVID-19 seems to contrast with the finding that testing rates were similar by time period for the 4 infections we asked about. However, this discrepancy appears to be attributable to providers including aspergillosis in their answers about overall testing. J. Fungi 2021, 7, 605 4 of 5

Our results show that respondents rely more frequently on epidemiologic exposures, geography, and host factors, rather than negative SARS-CoV-2 testing or lack of clinical improvement, to guide testing decisions for certain fungal infections. Although the survey did not ask about factors inﬂuencing testing decisions for patients without COVID-19, it is critical for clinicians to remember when considering testing that many patients with these fungal infections do not have clear epidemiologic exposures, that the regions where these infections can occur are wider than are often appreciated, and that severe disease can occur among people without underlying conditions [17]. Our results are based on a convenience sample and might not reﬂect the experiences and opinions of all U.S. ID physicians. Much remains to be learned about coccidioidomycosis, histoplasmosis, blastomycosis, and cryptococcosis and their relationship to COVID-19. It is important for clinicians to continue considering fungal pneumonias as a possible cause of respiratory illness during the COVID-19 pandemic, to reduce diagnostic delays and prevent severe outcomes.

Author Contributions: Conceptualization, K.B., S.W., S.E.B., P.M.P., B.R.J. and M.T.; data curation, S.E.B. and P.M.P.; formal analysis, K.B.; writing—original draft preparation, K.B.; writing—review and editing, K.B., S.W., S.E.B., P.M.P., B.R.J. and M.T.; supervision, B.R.J. and M.T. All authors have read and agreed to the published version of the manuscript. Funding: This work was supported by Cooperative Agreement Number 1 U50 CK00477, funded by the Centers for Disease Control and Prevention. Conflicts of Interest: The authors declare no conflict of interest. Disclaimer : The findings and conclusions in this report are those of the authors and do not neces- sarily represent the official position of the Centers for Disease Control and Prevention. Preliminary results from this study were presented at the 65th annual Coccidioidomycosis Study Group meeting in April 2021.

References 1. CDC. Fungal Diseases and COVID-19. 2020. Available online: https://www.cdc.gov/fungal/covid-fungal.html (accessed on 10 May 2021). 2. Beer, K.D.; Jackson, B.R.; Chiller, T.; Verweij, P.E.; Van de Veerdonk, F.L.; Wauters, J. Does Pulmonary Aspergillosis Complicate Coronavirus Disease 2019? Crit. Care Explor. 2020, 2, e0211. [CrossRef][PubMed] 3. John, T.M.; Jacob, C.N.; Kontoyiannis, D.P. When Uncontrolled Diabetes Mellitus and Severe COVID-19 Converge: The Perfect Storm for Mucormycosis. J. Fungi 2021, 7, 298. [CrossRef][PubMed] 4. Shah, A.S.; Heidari, A.; Civelli, V.F.; Sharma, R.; Clark, C.S.; Munoz, A.D.; Ragland, A.S.; Johnson, R.H. The Coincidence of 2 Epidemics, Coccidioidomycosis and SARS-CoV-2: A Case Report. J. Investig. Med. High Impact Case Rep. 2020, 8.[CrossRef] [PubMed] 5. Messina, F.A.; Marin, E.; Caceres, D.H.; Romero, M.; Depardo, R.; Priarone, M.M.; Rey, L.; Vázquez, M.; Verweij, P.E.; Chiller, T.M.; et al. Coronavirus Disease 2019 (COVID-19) in a Patient with Disseminated Histoplasmosis and HIV-A Case Report from Argentina and Literature Review. J. Fungi 2020, 6, 275. [CrossRef][PubMed] 6. Khatib, M.Y.; Ahmed, A.A.; Shaat, S.B.; Mohamed, A.S.; Nashwan, A.J. Cryptococcemia in a Patient with COVID-19: A case report. Clin. Case Rep. 2020, 9, 853–855. [CrossRef][PubMed] 7. Howard, M.; Heller, H.M.; Gonzalez, R.G.; Edlow, B.L.; Ard, K.L.; Gogakos, T. Case 40-2020: A 24-Year-Old Man with Headache and Covid-19. N. Engl. J. Med. 2020, 383, 2572–2580. [CrossRef] 8. Chang, C.C.; Senining, R.; Kim, J.; Goyal, R. An Acute Pulmonary Coccidioidomycosis Coinfection in a Patient Presenting with Multifocal Pneumonia With COVID-19. J. Investig. Med. High Impact Case Rep. 2020, 8.[CrossRef][PubMed] 9. Bertolini, M.; Mutti, M.F.; Barletta, J.A.; Falak, A.; Cuatz, D.; Sisto, A.; Ragusa, M.; Fernandez Claros, N.O.; Rolón, M.J. COVID-19 associated with AIDS-related disseminated histoplasmosis: A case report. Int. J. STD AIDS 2020, 31, 1222–1224. [CrossRef] [PubMed] 10. Basso, R.P.; Poester, V.R.; Benelli, J.L.; Stevens, D.A.; Zogbi, H.E.; Vasconcellos, I.; Comarú Pasqualotto, A.; Orzechowski Xavier, M.O. COVID-19-Associated Histoplasmosis in an AIDS Patient. Mycopathologia 2020, 186, 109–112. [CrossRef][PubMed] 11. Benedict, K.; Li, Y.; Molinari, N.A.M.; Jackson, B.R. Healthcare Providers’ Testing Practices for Coccidioidomycosis and Histo- plasmosis in Patients with Community-Acquired Pneumonia—United States, 2020. Open Forum Infect. Dis. 2021, 8.[CrossRef] [PubMed] J. Fungi 2021, 7, 605 5 of 5

12. Pillai, S.K.; Beekmann, S.E.; Santibanez, S.; Polgreen, P.M. The Infectious Diseases Society of America Emerging Infections Network: Bridging the Gap Between Clinical Infectious Diseases and Public Health. Clin. Infect. Dis. 2014, 58, 991–996. [CrossRef] [PubMed] 13. Centers for Disease Control and Prevention (Atlanta, GA, USA). Infectious disease physicians’ reported testing frequency for coccidioidomycosis, histoplasmosis, blastomycosis, and cryptococcosis among patients with signs and symptoms of community- acquired pneumonia, before and during the COVID-19 pandemic, United States, by disease and region. 2020. 14. Stasiak, C.E.S.; Nigri, D.H.; Cardoso, F.R.; de Almeida Rezende de Mattos, R.S.; Martins, P.A.G.; Carvalho, A.R.S.; de Almeida, S.A.; Rodrigues, R.S.; Rosado-de-Castro, P.H. Case report: Incidental Finding of COVID-19 Infection after PET/CT Imaging in a Patient with Diagnosis of Histoplasmosis and Recurring Fever. Am. J. Trop. Med. Hygiene 2021, 104, 1651–1654. [CrossRef][PubMed] 15. CDC. Burden of Fungal Diseases in the United States. 2020. Available online: https://www.cdc.gov/fungal/cdc-and-fungal/ burden.html (accessed on 10 May 2021). 16. Salmanton-García, J.; Sprute, R.; Stemler, J.; Bartoletti, M.; Dupont, D.; Valerio, M.; Garcia-Vidal, C.; Falces-Romero, I.; Machado, M.; de la Villa, S.; et al. COVID-19–Associated Pulmonary Aspergillosis. Emerg. Infect. Dis. 2021, 27, 1077–1086. [CrossRef][PubMed] 17. Lockhart, S.R.; Toda, M.; Benedict, K.; Caceres, D.H.; Litvintseva, A.P. Endemic and Other Dimorphic Mycoses in the Americas. J. Fungi 2021, 7, 151. [CrossRef]