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. 2021 Feb 23;7(2):157. doi: 10.3390/jof7020157

Paracoccidioidomycosis Diagnosed in Europe—A Systematic Literature Review

Gernot Wagner 1,*, Deddo Moertl 2, Anna Glechner 1, Verena Mayr 1, Irma Klerings 1, Casey Zachariah 1, Miriam Van den Nest 3,4, Gerald Gartlehner 1,5, Birgit Willinger 4
PMCID: PMC7926554  PMID: 33672212

Abstract

Paracoccidioidomycosis is a systemic mycosis that is endemic in geographical regions of Central and South America. Cases that occur in nonendemic regions of the world are imported through migration and travel. Due to the limited number of cases in Europe, most physicians are not familiar with paracoccidioidomycosis and its close clinical and histopathological resemblance to other infectious and noninfectious disease. To increase awareness of this insidious mycosis, we conducted a systematic review to summarize the evidence on cases diagnosed and reported in Europe. We searched PubMed and Embase to identify cases of paracoccidioidomycosis diagnosed in European countries. In addition, we used Scopus for citation tracking and manually screened bibliographies of relevant articles. We conducted dual abstract and full-text screening of references yielded by our searches. To identify publications published prior to 1985, we used the previously published review by Ajello et al. Overall, we identified 83 cases of paracoccidioidomycosis diagnosed in 11 European countries, published in 68 articles. Age of patients ranged from 24 to 77 years; the majority were male. Time from leaving the endemic region and first occurrence of symptoms considerably varied. Our review illustrates the challenges of considering systemic mycosis in the differential diagnosis of people returning or immigrating to Europe from endemic areas. Travel history is important for diagnostic-workup, though it might be difficult to obtain due to possible long latency period of the disease.

Keywords: paracoccidioidomycosis, Paracoccidioides spp., endemic systemic mycosis

1. Introduction

Paracoccidioidomycosis, also known as South American blastomycosis, is a systemic fungal infection [1] caused by the thermally dimorphic fungi of the species Paracoccidioides brasiliensis and the related species P. americana, P. restrepiensis, P. venezuelensis, and P. lutzii [2,3]. These fungi are endemic to certain geographic regions of Central and South America [4]. Most of the cases of paracoccidioidomycosis are reported in Brazil, followed by Colombia, Venezuela, Ecuador, and Argentina [5]. Based on estimates from epidemiological data, the number of cases of paracoccidioidomycosis in Brazil ranges from 3360 to 5600 per year [5]. The incidence of cases considerably varies among regions with low, moderate or high endemicity [5]. According to estimates, in regions with a stable endemic situation, the annual incidence of paracoccidioidomycosis ranges from 1 to 4 cases per 100,000 inhabitants [5].

People living in rural areas and working in agriculture are particularly at risk for this mycosis [1]. The risk of infection is higher for men than women [6]. The chronic form (adult type) accounts for the majority of cases [4]. This form of paracoccidioidomycosis is progressive over months or years and can be unifocal, if only one site is affected, or multifocal, in case of dissemination [7]. The organ most frequently affected is the lung [7]. Skin, oral mucosa, pharynx, larynx, lymph nodes, adrenal glands, central nervous system, bones, or joints may also be affected [8]. Symptoms of the disease can be systemic (e.g., weight loss, general weakness) or related to specific organ affection (e.g., cough, shortness of breath) [8]. In particular, pulmonary affection, lymphadenopathy, and B symptoms often lead to clinical signs similar to tuberculosis [8,9].

Paracoccidioidomycosis differential diagnosis is particularly challenging, because clinical signs and symptoms, as well as histopathological findings, resemble numerous other infections (e.g., tuberculosis) and noninfectious diseases (e.g., sarcoidosis) [8]. In addition, a long latency period [7] between exposure and manifestation of symptoms, as well as limited clinical experience, make adequate diagnosis difficult. In nonendemic areas, the history of travel and residency in endemic regions is a key to consider paracoccidioidomycosis for differential diagnosis.

Most physicians in nonendemic areas are unfamiliar with the clinical picture of endemic systemic mycoses because they are rarely presented to them. This in turn increases the risk that patients with paracoccidioidomycosis end up with misdiagnosis or remain undiagnosed. Subsequently, this results in no or inappropriate therapy. Therefore, it is important to provide information about the disease presentations in nonendemic regions.

A previously published review by Ajello et al. 1985 [10] comprehensively summarized internationally published cases of paracoccidioidomycosis from Africa, Asia, the Middle East, North America, and Europe [10]. However, this review is now 35 years old and needs to be updated.

The purpose of this systematic review is to summarize the evidence of paracoccidioidomycosis imported to nonendemic European countries. Thereby, we aim to increase awareness for this fungal infection and provide important information regarding its challenging diagnosis.

2. Materials and Methods

For reporting of this systematic review, we followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (PRISMA) [11].

2.1. Information Sources and Literature Search

An experienced information specialist searched PubMed and Embase (Embase.com ((accessed on 16 December 2020))) from inception to June 15 and 16, 2020 to identify relevant publications. We used a combination of subject headings and title and abstract free-text terms. We restricted our search to adults and humans. We have provided the detailed search strategy in Appendix A (Table A1 and Table A2). In addition to database searches, we used Scopus (Elsevier) on 16 June 2020 to perform forward and backward citation tracking of included publications and reviews. We also manually screened reference lists of these records, in case the reference lists available via Scopus were incomplete. To identify publications published prior to 1985, we used the previous review published by Ajello et al. [10]. We used references found by our search to identify relevant publications published in 1985 or later.

2.2. Eligibility Criteria and Study Selection

Our population of interest was adults of any age and origin diagnosed with paracoccidioidomycosis (South American blastomycosis) in geographic Europe. We considered any case description of an acute or chronic form of paracoccidioidomycosis as eligible for this review if authors provided sufficient clinical information on number of cases, country of exposure, and diagnosis. Publications were included regardless of language and type of publication. We included case series and case reports, observational studies, reviews providing information mentioned above and published as abstracts, full-articles, letters, and editorials. Table 1 provides a summary of eligibility criteria.

Table 1.

Eligibility criteria.

Inclusion Exclusion
Population

  • Adults of any age and origin

  • Diagnosed with acute or chronic form of paracoccidioidomycosis (South American blastomycosis)

  • Children and adolescents

  • Any other infections

  • Sufficient clinical information on number of cases, country of exposure and diagnosis

  • Insufficient clinical information
Region

  • Diagnosis was made in geographic Europe

  • Diagnosis was made outside geographic Europe
Study design

  • Case reports and case series

  • Observational studies

  • Reviews

 -
Publication type

  • Any (e.g., abstract, full article, letters, and editorials)

 -
Language

  • Any

 -
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After a pilot round, two reviewers independently screened each title and abstract. Eligible publications subsequently underwent independent dual full-text assessment. We solved disagreements by consensus or involvement of a senior reviewer. Throughout the whole study selection process, we used the web-based software Covidence [12]. We organized search and screening results in an EndNote® X9 bibliographic database (Clarivate, PA, USA).

2.3. Data Collection Process and Evidence Synthesis

We extracted the following relevant information from each article into pilot-tested evidence tables: author, year, study design, language, country of diagnosis, country of exposure, number of cases, patient characteristics (age, gender, occupation, affected organ(s), systemic antimycotic therapy, and treatment response), and latency period. If the publication language was not English, we asked native speakers to translate or used the online tool DeepL (http://www.deepl.com (accessed on 15 January 2021)) for translations into German. We synthesized data of identified articles narratively.

3. Results

3.1. Study Selection and Characteristics

Overall, we identified 83 case reports from 11 European countries, published in 68 articles. Figure 1 shows details of the study selection process.

Figure 1.

Figure 1

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Modified Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram [11].

Table 2 summarizes the number of publications and reported cases by country. Spain reported most of the cases, followed by Italy and Germany. The majority of articles were written in English or Spanish. Other publication languages were German, Portuguese, Italian, Norwegian and French.

Table 2.

Number of identified publications and reported cases of paracoccidioidomycosis by country of diagnosis.

Country of
Diagnosis		 No. of
Publications		 No. of
Reported Cases
Austria 2 2
Bulgaria 1 1
France 5 5
Germany 8 9
Great Britain 5 6
Italy 15 15
Netherlands 1 1
Norway 1 1
Portugal 7 7
Spain 21 35 1
Switzerland 2 1
Total 68 83
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1 Based on number of cases reported by Vivancos et al. 1969 [13] (n = 1), Pereiro Miguens et al. 1974 [14] (n = 2), Simon Merchán, et al. 1970 [15] (n = 1), Pereiro Miguens et al. 1987 [16] (n = 1), Miguélez et al. 1995 [17] (n = 2), Molina-Morant et al. 2018 [18] (n = 25), Agirre et al. 2019 [19] (n = 2) and Chamorro-Tojeiro et al. 2020 [20] (n = 1). Abbreviation: No., number; n, number of patients.

3.2. Clinical Patient Characteristics

The age of the patients ranged from 24 to 77 years. The infection mainly affected men. In most cases, exposure to Paracoccidioides took place in Venezuela, followed by Brazil and Ecuador. The most common occupations were field and construction workers. Latency period, defined as the period from leaving the endemic region until occurrence of first symptoms or medical contact, ranged from six days to 50 years. Table 3 shows patient characteristics, country of exposure, latency period, affected organ(s), systemic antimycotic therapy and response to treatment grouped by countries in which the diagnosis was made.

Table 3.

Imported cases of paracoccidioidomycosis from Central and South America diagnosed in Europe.

Author,
Year		 Study Design
Language		 No. of Cases Age Years, Gender Suspected Country of Exposure Latency Period 1 Occupation Affected Organ(s) Systemic Antimycotic Therapy Treatment Response
AUSTRIA
Wagner et al. 2016 [21] Case report
English		 1 62, M Peru 6 years Construction worker Adrenal glands, brain, lung, lymph node Amphotericin B, itraconazole, posaconazole Clinical improvement during hospital stay
Mayr et al. 2004 [22] Case report
English		 1 43, F Brazil, Venezuela or Mexico 4 years Government employee Lung, lymph node Amphotericin B, voriconazole Clinical improvement
BULGARIA
Balabanov et al. 1964 [23] Case report *
French		 1 67, M Brazil 30 years Worked in the jungle Lung, oral mucosa Sulfonamide, trimethoprim Complete remission
GERMANY
Kayser et al. 2019 [24] Case report
English		 1 57, F Venezuela 1 year NR Lung Amphotericin B, itraconazole Clinical improvement during hospital stay, remained under control
Slevogt et al. 2004 [25] Case report
English		 1 31, F Brazil 10 years NR Lymph nodes Itraconazole Complete remission
Horré et al. 2002 [26] Case report
English		 1 61, M Brazil 10 years Legionnaire Lung, oral mucosa, skin Itraconazole Complete remission
Köhler et al. 1988 [27] Case report
German		 1 49, M Brazil 15 years Gold mine worker Brain, lung, oral and laryngeal mucosa Amphotericin B, ketoconazole, itraconazole Clinical improvement during hospital stay, remained under control
Neveling 1988 [28] Case series
German		 3 38, F Brazil 1 month Administrative employee Lung None Clinical improvement, remained under control
64, M Brazil 1 month Gardener Lung NR NR
45, M Brazil 1 month Librarian Lung NR NR
Braeuninger et al. 1985 [29], Hastra et al. 1985 [30] Case report
German		 1 32, M Peru 6 years NR Lung, lymph nodes, oral mucosa, skin Ketoconazole Clinical improvement
Altmeyer 1976 [31] Case report *
German		 1 69, M Paraguay 22 years Farm worker Lung, lymph nodes, oral mucosa, skin Imidazole Patient deceased
PORTUGAL
Ferreira et al. 2017 [32] Case report
English		 1 46, M Brazil 1 month NR Lung, lymph nodes, oral mucosa Itraconazole Clinical improvement
Coelho et al. 2013 [33] Case report (Abstract only)
English		 1 63, M Brazil 8 years Gardener Oral and pharyngeal mucosa NR NR
Alves et al. 2013 [34] Case report
Portuguese		 1 43, M Venezuela 6 years NR Lung, oral mucosa, skin Itraconazole Complete remission
Armas et al. 2012 [35] Case report
English		 1 43, M Venezuela NR Farm worker Lung, skin Itraconazole Clinical improvement
Carvalho et al. 2009 [36] Case report
Portuguese		 1 24, M Brazil 7 years Construction worker Lymph nodes, skin Itraconazole Clinical improvement
Villar et al. 1963 [37] Case report ** 1 - Brazil 37 years - - - -
Oliveira et al. 1960 [38] Case report **
Portuguese		 1 - Brazil 23 years - - - -
SPAIN
Chamorro-Tojeiro et al. 2020 [20] Case report
English		 1 42, M Mexico 6 days NR Lung Itraconazole Complete remission, remained under control
Agirre et al. 2019 [19] Case series
English		 2 29, F Peru 10 days NR Lung, lymph nodes Itraconazole Complete remission
31, M Peru 10 days NR Lung Itraconazole Complete remission
Molina-Morant et al. 2018 [18] Retrospective observational study
English		 25 2 Median 48 yrs (range
33 to 67),
M 16 (64%)		 This retrospective study reported 25 cases of paracoccidioidomycosis admitted to Spanish hospitals between 1 January 1997 to 31 December 2014.
Navascués et al. 2013 [39] Case report
Spanish		 1 47, M Ecuador 11 years NR Lung, lymph nodes, skin Amphotericin B, itraconazole Complete remission
Buitrago et al. 2011 [40] Case series
English		 6 67, M Ecuador NR
57, M Venezuela NR
44, M Paraguay NR
51, M Paraguay NR
31, M Ecuador NR
NR, M NR NR
Pujol-Riqué et al. 2011 [41] Case report
Spanish		 1 48, M Brazil 6 years Worked in the jungle Lung Amphotericin B, itraconazole Complete remission
Ramírez-Olivencia et al. 2010 [42] Case report
English		 1 56, M Venezuela 6 months NR Lung Itraconazole, amphotericin B Complete remission
Botas-Velasco et al. 2010 [43] Case report
Spanish		 1 43, M Ecuador NR NR Lung, oral and laryngeal mucosa Itraconazole Clinical improvement; disappearance of oral and laryngeal lesions
Mayayo et al. 2007 [44] Case report
English		 1 27, M Ecuador None Farmer Lymph nodes, skin Itraconazole Complete remission
López Castro et al. 2005 [45] Case report
Spanish		 1 63, M Venezuela 8 months Shoemaker Lung, skin Amphotericin B Patient deceased
Ginarte et al. 2003 [46] Case series English 3 72, M Venezuela 50 years NR Skin Fluconazole Remained under control
67, M Brazil 1 year NR Oral mucosa, teeth Itraconazole, sulfonamides Complete remission
65, M Venezuela 38 years NR Oral mucosa Fluconazole Remained under control
Garcia Bustínduy et al. 2000 [47] Case report
English		 1 59, M Venezuela 1 year Taxi driver Skin Itraconazole Complete remission
Del Pozo et al. 1998 [48] Case report
Spanish		 1 50, M Venezuela 13 years NR Skin, oral and nasal mucosa Itraconazole Complete remission
Garcia et al. 1997 [49] Case report
Spanish		 1 72, M Venezuela 50 years NR Lung, oral mucosa, skin Fluconazole Complete remission
Pereiro et al. 1996 [50] Case report
English		 This case was also described by Ginarte et al. 2003 [46] and is therefore not presented here again.
Miguélez et al. 1995 [17] Case report
Spanish		 2 44, M Venezuela 2 years NR Brain, lung, lymph nodes Itraconazole Patient deceased (tuberculosis coinfection)
53, M Venezuela 18 months NR Lung, lymph nodes, oral mucosa Itraconazole Clinical improvement
Pereiro Miguens et al. 1987 [16] Case report
Spanish		 1 51, M Venezuela 23 years Construction worker Oral mucosa, skin Ketoconazole Clinical improvement
Simon Merchán et al. 1970 [15] Case report ** 1 - Venezuela 2 years - - - -
Pereiro Miguens 1974 [14], Pereiro Miguens et al. 1972 [51] Case report *
Spanish		 2 44, M Venezuela 7 years NR Lung, oral mucosa Sulfonamide, trimethoprim Clinical improvement
49, M Venezuela 8 years Gardener Oral mucosa Sulfonamide, trimethoprim Clinical improvement
Vivancos et al. 1969 [13] Case report *
Spanish		 1 44, M Venezuela NR Farmer Oral mucosa Sulfamethoxazole/trimethoprim, amphotericin B Complete remission
GREAT BRITAIN
De Cordova et al. 2012 [52] Case report (Abstract only)
English		 1 52, M Venezuela NR Butcher Oral mucosa Itraconazole Complete remission
Sierra et al. 2011 [53] Case report (Abstract only)
English		 1 77, M Ecuador NR NR Lung, lymph nodes, oral mucosa, skin Itraconazole NR
Walker et al. 2008 [54] Case report
English		 1 51, M Venezuela None Accountant Lung, oral mucosa, skin Itraconazole Clinical improvement, cutaneous lesions cleared
Bowler et al. 1986 [55] Case report
English		 1 57, F Argentina, Venezuela 17 years Clerk Lung NR NR
Symmers 1966 [56] Case report *
English		 1 42, M Brazil NR Engineer Skin NR NR
1 46, M Brazil None Businessman Spleen (autopsy) No therapy Patient deceased (acute heart failure)
ITALY
Borgia et al. 2000 [57] Case report
English		 1 61, M Venezuela NR House-
painter		 Bones, lung Itraconazole Clinical improvement
Pecoraro et al. 1998 [58] Case report
Italian		 1 60, M Venezuela NR Coffee plantations worker Bones, lung Ketoconazole Clinical improvement
Solaroli et al. 1998 [59] Case report
Italian		 1 49, M Brazil NR NR Brain, lung, skin Itraconazole Clinical improvement
Fulciniti et al. 1996 [60] Case report
English		 1 60, M Venezuela NR NR Bones, lung Itraconazole Clinical improvement, remained under control
Cuomo et al. 1985 [61] Case report
Italian		 1 37, M Venezuela 2 years Butcher Lung, skin Ketoconazole Clinical improvement
Benoldi et al. 1985 [62] Case report *
English		 1 41, M Venezuela Few months Butcher Lung, lymph nodes, skin Ketconazole, sulfamethoxy-pyridazine Complete remission
Finzi et al. 1980 [63] Case report ** 1 - Brazil 14 years - - - -
Velluti et al. 1979 [64] Case report *
Italian		 1 52, M Venezuela 17 years Fabric retailer Lung Amphotericin B, miconazole Clinical improvement
Lasagni et al. 1979 [65] Case report **
Italian		 1 - Venezuela NR - - - -
Scarpa et al. 1965 [66] Case report *
Italian		 1 43, M Venezuela 5 years Farmer Lung, oral mucosa, skin Amphotericin B, sulfamethoxazole Patient deceased
Schiraldi et al. 1963 [67] Case report ** 1 - Venezuela None - - - -
Molese et al. 1956 [68] Case report *
Italian		 1 47, M Venezuela None Painter Lung, lymph nodes, oral mucosa Nystatin NR
Farris 1955 [69] Case report ** 1 - Brazil 7 years - - - -
Bertaccini 1934 [70] Case report ** 1 - Brazil None - - - -
Dalla Favera 1914 [71] Case report ** 1 - Brazil None - - - -
FRANCE
Heleine et al. 2020 [72] Case report English 1 48, M Brazil NR Farmer Lung, lymph nodes, oropharyngeal mucosa, skin Itraconazole Clinical improvement
Dang et al. 2017 [73] Case report
English		 1 54, M Columbia, Venezuela 12 years Journalist Lymph nodes, oropharyngeal mucosa Itraconazole Clinical improvement; almost complete resolution of the tongue lesion and lymhadenopathy
Sambourg et al. 2014 [74] Case report French 1 43, M Brazil NR NR Skin NR NR
Laccourreye et al. 2010 [75] Case report English 1 46, M Venezuela NR Engineer Laryngeal mucosa Itraconazole Complete remission
Poisson et al. 2007 [76] Case report
English		 1 70, M Paraguay 6 years NR Brain, lung Fluconazole, itraconazole Remained clinically stable
NETHERLANDS
Van Damme et al. 2006 [77] Case report
English		 1 60, M Peru, Ecuador 8 years Carpenter Lung, oral mucosa, urinary tract Itraconazole Clinical improvement, remained under control
NORWAY
Maehlen et al. 2001 [78] Case report
Norwegian		 1 51, F Brazil 23 years NR Brain - Patient deceased
SWITZERLAND
Stanisic et al. 1979
[79], Wegmann et al. 1959 [80]		 Case report *
German		 1 47, M Brazil 5 years Carpenter Lung, lymph nodes, oral mucosa Hydroxy-stilbamidine, amphotericin B, sulfonamide Patient deceased
(Cor pulmonale)
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Abbreviations: M, male; F, female; NR, not reported; yrs, years; 1 Latency period from leaving the endemic region until occurrence of first symptoms or medical contact; 2 We assume that most of 25 cases diagnosed in Spain between 1997 to 2014 and published by Molina-Morant et al. 2018 [18] are also described in case reports and case series presented in this table; * Included in the review by Ajello et al. 1985 [10]; ** Included in the review by Ajello et al. 1985, full-text not available, data extracted from Ajello et al. 1985 [10].

3.3. Differential Diagnosis

Table A3 of Appendix A shows infectious and non-infectious diseases that were considered for differential diagnosis of cases in the included articles.

3.4. Diagnostic Work-up

The diagnostic workup varied across publications. Usually, Paracoccidioides spp. was identified from clinical specimens through microscopic visualization and/or culture. In addition, some of the authors reported results from serological tests and/or molecular biological techniques such as polymerase chain reaction (PCR). Table A3 provides information on diagnostic workup in individual cases of paracoccidioidomycosis.

In general, direct examination, using 10% potassium hydroxide applied to different samples, is effective and inexpensive. A histologic examination of tissue specimens using silver methenamine or periodic acid-Schiff stain is common and practical when patients present with oral or other skin lesions. In a clinical sample, Paracoccidioides spp. appear as globose yeast cells with multiple buds and a thick refractile wall [81].

4. Discussion

Our systematic review summarizes the evidence on published case reports of imported paracoccidioidomycosis diagnosed in Europe. To the best of our knowledge, this is the most recent and comprehensive review of published cases of this systematic mycosis endemic to geographical regions of Central and South America. While narrative reviews on patients with this disease often included a nonsystematic search, we followed a systematic approach with a much broader scope to identify all published cases of paracoccidioidomycosis imported to Europe. In addition, the last systematic assessment of case reports on paracoccidioidomycosis was published in 1985, almost four decades ago [10]. A more recent narrative review focused only on cases diagnosed in Spain [82].

Our systematic review of case reports and case series emphasizes the clinical challenges and pitfalls of paracoccidioidomycosis. Most of the physicians in non-endemic regions such as Europe are unfamiliar with systemic mycosis. They struggle with the diagnostic work-up and management due to several reasons. In general, depending on the type, clinical presentation of patients with paracoccidioidomycosis is variable [4]. A major issue is the clinical similarity to several other infectious and non-infectious diseases [81]. Paracoccidioidomycosis is commonly misdiagnosed as tuberculosis [83]. The clinical picture of tuberculosis resembles the chronic progressive form of paracoccidioidomycosis [9]. The differential diagnosis of chronic paracoccidioidomycosis with lung involvement also includes coccidioidomycosis, histoplasmosis, sarcoidosis, pneumoconiosis, interstitial pneumonia, and malignancy [84]. Inappropriate treatment could have harmful consequences for the patient, without any prognostic impact on systemic mycosis. In addition, the latency period from pathogen exposure to development of symptoms is highly variable and might comprise several decades when patients might already have left the endemic region [7]. Therefore, clinicians must inquire about any short- and long-term stay (travel and residency) in endemic areas and even time abroad many years preceding presentation. Figure 2 summarizes important aspects that have to be considered for diagnosis of paracoccidioidomycosis, including signs and symptoms, travel history, and imaging.

Figure 2.

Figure 2

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Summary of important aspects for the diagnosis of paracoccidioidomycosis.

If paracoccidioidomycosis is considered for differential diagnosis, clinicians should provide this information to the microbiologist, pathologist and other laboratory personnel to ensure that adequate methods for direct and indirect identification of the pathogen are applied. In addition, laboratory personnel need to apply safety precautions when collected specimens are handled.

The strengths of our work are the systematic literature search and screening. However, this systematic review has several limitations. First, we have not included cases that may have been diagnosed but never published. Second, because translation methods varied, we might have missed relevant information in the articles. A native speaker translated Spanish texts into German but online electronic translation tools provided translations for all other languages (11 publications) except texts published in English and German. Third, our findings rely on not uniformly structured case reports and cases series that are considered as low-level evidence. Finally, although we conducted comprehensive additional literature searches, we might have missed studies not cited in previous reviews and not indexed in electronic databases due to very early publication dates or non-indexed journals.

5. Conclusions

In conclusion, this review highlights the importance of considering systemic mycosis in the differential diagnosis of people with symptoms of tuberculosis who have either returned to Europe from endemic areas or were natives of endemic countries who immigrated to Europe. In light of systemic mycosis’s potentially long latency period, extensive evaluation of travel history is an essential key for a quick and correct diagnosis of systematic endemic mycosis such as paracoccidioidomycosis.

Acknowledgments

We would like to thank Edith Kertesz from Danube University for administrative support.

List of Abbreviations

PCR polymerase chain reaction
PCM paracoccidioidomycosis
PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses
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Appendix A

Table A1.

Search Strategy Pubmed 15 June 2020.

Search Number Query Results
1 “Paracoccidioidomycosis” [Mesh] 1833
2 Paracoccidioidomycos* [tiab] 1782
3 Paracoccidioides brasiliensis [tiab] 1611
4 paracoccidioidal granuloma [tiab] 9
5 south american blastomycosis [tiab] 272
6 #1 OR #2 OR #3 OR #4 OR #5 2858
7 “Europe” [Mesh] 1,408,827
8 “Emigrants and Immigrants” [Mesh] 12,277
9 “Travel” [Mesh:NoExp] 24,916
10 (Albania* [tiab] OR Andorra* [tiab] OR Armenia* [tiab] OR Austria* [tiab] OR Azerbaijan* [tiab] OR Belarus* [tiab] OR Belgi* [tiab] OR Bosnia* [tiab] OR Herzegov* [tiab] OR Bulgaria* [tiab] OR Croatia* [tiab] OR Cypr* [tiab] OR Czech [tiab] OR Denmark [tiab] OR danish [tiab] OR Estonia* [tiab] OR Finland [tiab] OR finnish [tiab] OR France [tiab] OR french [tiab] OR Georgia* [tiab] OR German* [tiab] OR Greece [tiab] OR greek [tiab] OR Hungar* [tiab] OR Iceland* [tiab] OR Ireland [tiab] OR irish [tiab] OR Italy [tiab] OR italian [tiab] OR Kazak* [tiab] OR Kosov* [tiab] OR Latvia* [tiab] OR Liechtenstein* [tiab] OR Lithuania* [tiab] OR Luxembourg* [tiab] OR Macedonia* [tiab] OR Malta [tiab] OR maltese [tiab] OR Moldov* [tiab] OR Monac* [tiab] OR Montenegr* [tiab] OR Netherlands [tiab] OR dutch [tiab] OR Norway [tiab] OR norwegian [tiab] OR Poland [tiab] OR polish [tiab] OR Portug* [tiab] OR Romania* [tiab] OR Russia* [tiab] OR San Marino [tiab] OR Serbia* [tiab] OR Slovakia* [tiab] OR Slovenia* [tiab] OR Spain [tiab] OR spanish [tiab] OR Sweden [tiab] OR swedish [tiab] OR Switzerland [tiab] OR swiss [tiab] OR Turkey [tiab] OR turkish [tiab] OR Ukrain* [tiab] OR United Kingdom [tiab] OR britain [tiab] OR british [tiab]) 1,082,126
11 (Albania* [ad] OR Andorra* [ad] OR Armenia* [ad] OR Austria* [ad] OR Azerbaijan* [ad] OR Belarus* [ad] OR Belgi* [ad] OR Bosnia* [ad] OR Herzegov* [ad] OR Bulgaria* [ad] OR Croatia* [ad] OR Cypr* [ad] OR Czech [ad] OR Denmark [ad] OR danish [ad] OR Estonia* [ad] OR Finland [ad] OR finnish [ad] OR France [ad] OR french [ad] OR Georgia* [ad] OR German* [ad] OR Greece [ad] OR greek [ad] OR Hungar* [ad] OR Iceland* [ad] OR Ireland [ad] OR irish [ad] OR Italy [ad] OR italian [ad] OR Kazak* [ad] OR Kosov* [ad] OR Latvia* [ad] OR Liechtenstein* [ad] OR Lithuania* [ad] OR Luxembourg* [ad] OR Macedonia* [ad] OR Malta [ad] OR maltese [ad] OR Moldov* [ad] OR Monac* [ad] OR Montenegr* [ad] OR Netherlands [ad] OR dutch [ad] OR Norway [ad] OR norwegian [ad] OR Poland [ad] OR polish [ad] OR Portug* [ad] OR Romania* [ad] OR Russia* [ad] OR San Marino [ad] OR Serbia* [ad] OR Slovakia* [ad] OR Slovenia* [ad] OR Spain [ad] OR spanish [ad] OR Sweden [ad] OR swedish [ad] OR Switzerland [ad] OR swiss [ad] OR Turkey [ad] OR turkish [ad] OR Ukrain* [ad] OR United Kingdom [ad] OR britain [ad] OR british [ad]) 5,875,438
12 europ* [tiab] OR immigrant* [tiab] OR travel* [tiab] 383,712
13 non endemic [tiab] OR nonendemic [tiab] 4492
14 #13 OR #12 OR #11 OR #10 OR #9 OR #8 OR #7 7,173,281
15 #6 AND #14 204
16 (“Animals” [Mesh] NOT “Humans” [Mesh]) 4,707,502
17 #15 NOT #16 175
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Table A2.

Search Strategy Embase 16 June 2020.

No. Query Results
#1 ‘south american blastomycosis’/exp OR ‘paracoccidioides brasiliensis’/exp 3026
#2 paracoccidioidomycos*:ab,ti OR ‘paracoccidioides brasiliensis’:ab,ti OR ‘paracoccidioidal granuloma’:ab,ti OR ‘south american blastomycosis’:ab,ti 3075
#3 #1 OR #2 3620
#4 ‘europe’/exp OR ‘immigrant’/exp OR ‘travel’/exp 1,695,885
#5 albania*:ca,ab,ti OR andorra*:ca,ab,ti OR armenia*:ca,ab,ti OR austria*:ca,ab,ti OR azerbaijan*:ca,ab,ti OR belarus*:ca,ab,ti OR belgi*:ca,ab,ti OR bosnia*:ca,ab,ti OR herzegov*:ca,ab,ti OR bulgaria*:ca,ab,ti OR croatia*:ca,ab,ti OR cypr*:ca,ab,ti OR czech:ca,ab,ti OR denmark:ca,ab,ti OR danish:ca,ab,ti OR estonia*:ca,ab,ti OR finland:ca,ab,ti OR finnish:ca,ab,ti OR france:ca,ab,ti OR french:ca,ab,ti OR georgia*:ca,ab,ti OR german*:ca,ab,ti OR greece:ca,ab,ti OR greek:ca,ab,ti OR hungar*:ca,ab,ti OR iceland*:ca,ab,ti OR ireland:ca,ab,ti OR irish:ca,ab,ti OR italy:ca,ab,ti OR italian:ca,ab,ti OR kazak*:ca,ab,ti OR kosov*:ca,ab,ti OR latvia*:ca,ab,ti OR liechtenstein*:ca,ab,ti OR lithuania*:ca,ab,ti OR luxembourg*:ca,ab,ti OR macedonia*:ca,ab,ti OR malta:ca,ab,ti OR maltese:ca,ab,ti OR moldov*:ca,ab,ti OR monac*:ca,ab,ti OR montenegr*:ca,ab,ti OR netherlands:ca,ab,ti OR dutch:ca,ab,ti OR norway:ca,ab,ti OR norwegian:ca,ab,ti OR poland:ca,ab,ti OR polish:ca,ab,ti OR portug*:ca,ab,ti OR romania*:ca,ab,ti OR russia*:ca,ab,ti OR ‘san marino’:ca,ab,ti OR serbia*:ca,ab,ti OR slovakia*:ca,ab,ti OR slovenia*:ca,ab,ti OR spain:ca,ab,ti OR spanish:ca,ab,ti OR sweden:ca,ab,ti OR swedish:ca,ab,ti OR switzerland:ca,ab,ti OR swiss:ca,ab,ti OR turkey:ca,ab,ti OR turkish:ca,ab,ti OR ukrain*:ca,ab,ti OR ‘united kingdom’:ca,ab,ti OR britain:ca,ab,ti OR british:ca,ab,ti 10,276,132
#6 europ* OR ‘non endemic’ OR nonendemic OR travel*:ab,ti OR imported:ti 2,203,591
#7 immigrant* 34,244
#8 #4 OR #5 OR #6 OR #7 11,651,119
#9 #3 AND #8 457
#10 ‘animal’/exp NOT ‘human’/exp 5,449,241
#11 #9 NOT #10 405
#12 ‘groups by age’/exp NOT ‘adult’/exp 2,775,185
#13 #11 NOT #12 397
#14 ‘case report’/exp OR ‘case study’/exp OR ‘letter’/exp 3,471,553
#15 case:ab,ti OR cases:ab,ti 4,628,697
#16 ‘review’/exp OR ‘evidence based medicine’/exp 3,575,830
#17 review:ab,ti OR systematic:ab,ti OR search*:ab,ti OR ‘meta analy*’:ab,ti OR metaanaly*:ab,ti 2,588,995
#18 #14 OR #15 OR #16 OR #17 10,847,515
#19 #13 AND #18 256
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Table A3.

Signs and symptoms, differential diagnosis and diagnostic work-up.

Author,
Year		 Symptoms and Signs Differential Diagnosis Specimen for Histopathology Histo-Logy 1 Micro-Biology 2 Sero-Logy PCR
AUSTRIA
Wagner et al. 2016 [21] Chest and abdominal pain, weight loss, night sweats, cough Tuberculosis Left adrenal gland biopsy, extirpation of a right cervical lymph node + + NR +
Mayr et al. 2004 [22] Cough, lymphadenopathy, weight loss Tuberculosis, Wegener’s granulomatosis, sarcoidosis, mycosis Lung biopsy + + + NR
BULGARIA
Balabanov et al. 1964 [23] Ulcerous oral and cutaneous lesions, lymphadenopathy Tuberculosis Peribuccal lesion biopsy + + NR NR
GERMANY
Kayser et al. 2019 [24] Cough, dyspnea Sarcoidosis, histoplasmosis Lung biopsy + + + +
Slevogt et al. 2004 [25] Bilateral cervical and axillary lymphadenopathy, weight loss Tuberculosis Cervical lymph node biopsy + + NR NR
Horré et al. 2002 [26] Erythematous and swollen lips, mucocutaneous pustules and ulcerations, oral nodules, occasional night sweats Leishmaniosis, tropical pulmonary mycosis, gammopathy Oral lesion biopsy + + + +
Köhler et al. 1988 [27] Cheilitis, erosive stomatitis, loss of teeth, dysphagia, aphonia, cough, night sweats, weight loss Tropical disease NR NR + + NR
Neveling 1988 [28] Flue like symptoms,
dry cough		 Coccidiosis, histoplasmosis, North American blastomycosis NR NR NR + NR
NR NR NR NR NR +
NR NR NR NR NR +
Braeuninger et al. 1985 [29], Hastra et al. 1985 [30] Flue like symptoms, cervical lymphadenopathy, skin lesions, cough, dyspnea, pain in the left leg Tuberculosis, sarcoidosis Lymph node biopsy + + + NR
Altmeyer 1976 [31] Respiratory insufficiency, cervical lymphadenopathy, painful infiltrations of the soft palate, hypersalivation, ulcerations of the feet, weight loss, dysphagia, dysphonia Tuberculosis, Wegner’s granulomatosis Lung and skin lesion biopsy + − NR NR
PORTUGAL
Ferreira et al. 2017 [32] Labial lesion, dry cough, inguinal and axillary lymphadenopathy, weight loss Cryptococcosis Lip lesion and lung biopsy, inguinal lymph node resection + − NR +
Coelho et al. 2013 [33] Odynophagia, dysphagia, irregular and ulcerated oral mucosa NR Oropharyngeal mucosa biopsy + NR NR NR
Alves et al. 2013 [34] Skin lesion, oral mucosal ulcerations Coccidioidomycosis, cutaneous tuberculosis Skin lesion and oral mucosa biopsy + + NR NR
Armas et al. 2012 [35] Ulcerated skin and nasal mucosa lesion NR Skin lesion biopsy + + NR NR
Carvalho et al. 2009 [36] Fever, epigastric pain, anorexia, fatigue, lymphadenopathy, skin lesions Skin biopsy and lymph node + NR NR NR
Villar et al. 1963 [37] Full-text not available
Oliveira et al. 1960 [38] Full-text not available
SPAIN
Chamorro-Tojeiro et al. 2020 [20] Fever, arthralgia, myalgia, dyspnea, dry cough, sweating, general cutaneous rash Bacterial respiratory infection NR NR − + NR
Agirre et al. 2019 [19] Fever, productive cough, exertional dyspnea Bacterial respiratory infection NR NR − + NR
Fever, myalgia, asthenia NR NR NR − + NR
Molina-Morant et al. 2018 [18] NR NR NR NR NR NR NR
Navascués et al. 2013 [39] Productive cough, weight loss, asthenia, lymphadenopathy, skin lesions NR Lung biopsy + − + +
Buitrago et al. 2011 [40] 3 Fever, asthenia, ulcerated pustular skin lesions, extremities NR Skin biopsy + NR + +
Productive cough NR NR + NR + +
NR NR Cerebral biopsy + NR + +
NR NR NR + NR + +
NR NR Lung biopsy NR + NR +
NR NR Oral mucosa biopsy + NR + +
Pujol-Riqué et al. 2011 [41] Productive cough, hemoptysis, night sweats, skin lesions Sarcoidosis Lung and skin biopsy − + NR NR
Ramírez-Olivencia et al. 2010 [42] Fever, dyspnea, productive cough, hemoptysis, night sweats, loss of appetite, weight loss NR Lung biopsy NR − + +
Botas-Velasco et al. 2010 [43] Cough, fever, weight loss, retromolar mass Sarcoidosis Retromolar mass and laryngeal biopsy + + + NR
Mayayo et al. 2007 [44] Skin lesions Blastomycosis Skin lesion biopsy + NR NR NR
López Castro et al. 2005 [45] Dyspnea, dry cough, fever,
weight loss, skin lesions		 Sarcoidosis Lung and skin biopsy + NR − NR
Ginarte et al. 2003 [46] Ulcerative lesions from upper left jaw to labial mucosa and nasal grave Squamous cell carcinoma Lesion biopsy + + + NR
Ulcerative lesions left cheek mucosa, periodontitis with loss of several teeth Tuberculosis, squamous cell carcinoma Lesion biopsy + + NR NR
Mass and ulcerative lesions in cheek mucosa Squamous cell carcinoma Lesion biopsy + + NR NR
Garcia Bustínduy et al. 2000 [47] Ulcerative skin lesion NR Skin lesion biopsy + + + NR
Del Pozo et al. 1998 [48] Lesions upper labial mucosa and nasal fossa NR Lesion biopsy + + NR NR
Garcia et al. 1997 [49] Lesions of labial and palatal mucosa NR Lesion biopsy + + + NR
Pereiro et al. 1996 [50] Tumoral mass of the upper jaw, ulcerated lesion in the upper left jaw, extended to the lip mucosa and the nasal grave Epidermoid carcinoma Lesion biopsy + + + NR
Miguélez et al. 1995 [17] Fever, weight loss, dyspnea, ulcerated mass right tonsil, lymphadenopathy Pulmonary fibrosis Ulcerated mass biopsy + + NR NR
Palatal mass, cervical lymphadenopathy NR Palatal mass biopsy + + NR NR
Pereiro Miguens et al. 1987 [16] Oral mucosal lesions, gingivitis Tuberculosis Mucosa biopsy + + + NR
Simon Merchán et al. 1970 [15] Full-text not available
Pereiro Miguens et al. 1974 [14], Pereiro Miguens et al. 1972 [51] Epididymitis, gingivitis,
oral ulcerative lesion		 Tuberculosis Epididymis and oral lesion biopsy + + + NR
Asthenia, ulcerative oral lesions,
labial edema		 NR Oral lesion biopsy + + NR NR
Vivancos et al. 1969 [13] Oral mucosal lesions Pseudoneoplasia Oral lesion biopsy + + NR NR
GREAT BRITAIN
De Cordova et al. 2012 [52] Submandibular mass,
oral ulcerative lesions		 NR Oral lesion and submandibular mass biopsy + + NR NR
Sierra et al. 2011 [53] Dyspnea, lip lesion,
ulcer on tonsil and uvula		 Malignancy, sarcoidosis, squamous cell carcinoma Lip lesion excision, ulcer biopsy + NR + NR
Walker et al. 2008 [54] Cough, dyspnea, plantar pruritus, painful skin lesions on his legs, face and feet, hepatomegaly, weight loss NR Skin biopsy + + + NR
Bowler et al. 1986 [55] Cough, dyspnea, and wheeze on exertion Lymphangitis carcinomatosa Lung biopsy + NR + NR
Symmers 1966 [56] Asymptomatic NR Spleen (autopsy) + NR NR NR
Skin ulceration NR Skin lesion excision + NR NR NR
ITALY
Borgia et al. 2000 [57] Fever, pain, and inflammation of left knee Malignancy Left femur biopsy + + NR NR
Pecoraro et al. 1998 [58] Weight loss, night sweat, pain left knee NR Left femur biopsy + NR NR NR
Solaroli et al. 1998 [59] Skin lesion, asthenia, fever, loss of vision NR Skin lesion excision + + NR NR
Fulciniti et al. 1996 [60] Weight loss, night, sweats, pain in left knee Metastatic lung cancer Left femur biopsy + + NR NR
Cuomo et al. 1985 [61] Productive cough, weight loss, asthenia, skin lesions Tuberculosis, lupus vulgaris Lung and skin lesion biopsy + + + NR
Benoldi et al. 1985 [62] Ulcerative skin lesions, cough, fatigue, malaise, weight loss Tuberculosis, lupus vulgaris Skin lesion biopsy + + + NR
Finzi et al. 1980 [63] Full-text not available
Velluti et al. 1979 [64] Cough, dyspnea Bronchitis, tuberculosis Lung biopsy + + + NR
Lasagni et al. 1979 [65] Full-text not available
Scarpa et al. 1965 [66] Cough, asthenia, weight loss, night sweats, lymphadenitis, ulcerative oral lesions Tuberculosis Lymph node and lung biopsy + + NR NR
Schiraldi et al. 1963 [67] Full-text not available
Molese et al. 1956 [68] Oral mucosa lesions, cervical lymphadenopathy, fever, cough Tuberculosis, leishmaniosis, pneumoconiosis, lues, malignancy Oral mucosa and tonsillar biopsy + NR NR NR
Farris 1955 [69] Full-text not available
Bertaccini 1934 [70] Full-text not available
Dalla Favera 1914 [71] Full-text not available
FRANCE
Heleine et al. 2020 [72] Skin lesions, ulcero-nodular lesions lips and mouth, cough, fever, inguinal lymphadenopathy, asthenia, weight loss HIV, tuberculosis Skin biopsy − + NR NR
Dang et al. 2017 [73] Nodular slightly painful, nonulcerated lesion of the tongue, cervical lymphadenopathy NR Lingual lesion biopsy + NR NR +
Sambourg et al. 2014 [74] Partially ulcerous and crusted erythematous lesion left auricle extending to the pre-auricular region Leishmaniosis Skin lesion biopsy + + − +
Laccourreye et al. 2010 [75] Dysphonia, laryngitis Chronic laryngitis Laryngeal biopsy, removed mucosa + + NR NR
Poisson et al. 2007 [76] Seizures Brain tumor Single cerebral lesion surgically excised + + + NR
NETHERLANDS
Van Damme et al. 2006 [77] Dyspnea, cough, wheezing, weight loss, tiredness, fever, night sweats, periodontitis, oral ulceration, macrohematuria Sarcoidosis, bronchiolitis obliterans organizing pneumonia, oral carcinoma Lung and oral mucosa biopsy + + + NR
NORWAY
Maehlen et al. 2001 [78] Dizziness, nausea,
headache, hearing loss, hemiplegia		 Cerebral tuberculosis Brain biopsy + + NR NR
SWITZERLAND
Stanisic et al. 1979
[79], Wegmann et al. 1959 [80]		 Submandibular and cervical lymphadenopathy, oral ulceration Tuberculosis, Morbus Wegener, lues, bartonellosis, Morbus Hodgkin, neoplasma, blastomycosis, sporotrichosis, cryptococcosis Oral mucosa and cervical lymph node biopsy + + NR NR
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Abbreviations: NR, not reported or not performed; +, positive for Paracoccidioides spp.; −, negative for Paracoccidioides spp.; 1 Fungal structures were identified in at least one of the biopsy/excision specimen; 2 Microbiology includes microscopy and/or culture; 3 Signs and symptoms obtained for case 1 and case 2 obtained from Buitrago et al. 2009 [85].

Author Contributions

Conceptualization, B.W. and G.W.; methodology, G.W., A.G. and G.G.; literature search, I.K.; literature screening, A.G., V.M, C.Z., and G.W.; data extraction, A.G., V.M., M.V.d.N., C.Z. and G.W.; writing—original draft preparation, G.W.; writing—review and editing, A.G, B.W., D.M., V.M., I.K., M.V.d.N., C.Z., and G.G.; supervision, B.W., D.M. and G.G. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by internal funds from the Department of Evidence-based Medicine and Evaluation, Danube University Krems, Austria.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflict of interest.

Footnotes

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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