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Review

Paracoccidioidomycosis Diagnosed in Europe—A Systematic Literature Review

1
Department for Evidence-Based Medicine and Evaluation, Danube University Krems, Dr.-Karl-Dorrek-Strasse 30, 3500 Krems, Austria
2
Clinical Department of Internal Medicine III, University Hospital St. Poelten, Karl Landsteiner University of Health Sciences, Dunant-Platz 1, 3100 St. Poelten, Austria
3
Department for Infection Control and Hospital Epidemiology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
4
Division of Clinical Microbiology, Department of Laboratory Medicine, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
5
RTI International, 3040 East Cornwallis Road, P.O. Box 12194, Research Triangle Park, NC 27709-2194, USA
*
Author to whom correspondence should be addressed.
J. Fungi 2021, 7(2), 157; https://doi.org/10.3390/jof7020157
Received: 20 November 2020 / Revised: 10 February 2021 / Accepted: 11 February 2021 / Published: 23 February 2021

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.

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.
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.
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.

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.

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.
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.

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.

Acknowledgments

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

Conflicts of Interest

The authors declare no conflict of interest.

List of Abbreviations

PCRpolymerase chain reaction
PCMparacoccidioidomycosis
PRISMAPreferred Reporting Items for Systematic Reviews and Meta-Analyses

Appendix A

Table A1. Search Strategy Pubmed 15 June 2020.
Table A1. Search Strategy Pubmed 15 June 2020.
Search NumberQueryResults
1“Paracoccidioidomycosis” [Mesh]1833
2Paracoccidioidomycos* [tiab]1782
3Paracoccidioides brasiliensis [tiab]1611
4paracoccidioidal granuloma [tiab]9
5south american blastomycosis [tiab]272
6#1 OR #2 OR #3 OR #4 OR #52858
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
12europ* [tiab] OR immigrant* [tiab] OR travel* [tiab]383,712
13non endemic [tiab] OR nonendemic [tiab]4492
14#13 OR #12 OR #11 OR #10 OR #9 OR #8 OR #77,173,281
15#6 AND #14204
16(“Animals” [Mesh] NOT “Humans” [Mesh])4,707,502
17#15 NOT #16175
Table A2. Search Strategy Embase 16 June 2020.
Table A2. Search Strategy Embase 16 June 2020.
No.QueryResults
#1 ‘south american blastomycosis’/exp OR ‘paracoccidioides brasiliensis’/exp3026
#2 paracoccidioidomycos*:ab,ti OR ‘paracoccidioides brasiliensis’:ab,ti OR ‘paracoccidioidal granuloma’:ab,ti OR ‘south american blastomycosis’:ab,ti3075
#3 #1 OR #23620
#4 ‘europe’/exp OR ‘immigrant’/exp OR ‘travel’/exp1,695,885
#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,ti10,276,132
#6 europ* OR ‘non endemic’ OR nonendemic OR travel*:ab,ti OR imported:ti2,203,591
#7 immigrant*34,244
#8 #4 OR #5 OR #6 OR #711,651,119
#9 #3 AND #8457
#10 ‘animal’/exp NOT ‘human’/exp5,449,241
#11 #9 NOT #10405
#12 ‘groups by age’/exp NOT ‘adult’/exp2,775,185
#13 #11 NOT #12397
#14 ‘case report’/exp OR ‘case study’/exp OR ‘letter’/exp3,471,553
#15 case:ab,ti OR cases:ab,ti4,628,697
#16 ‘review’/exp OR ‘evidence based medicine’/exp3,575,830
#17 review:ab,ti OR systematic:ab,ti OR search*:ab,ti OR ‘meta analy*’:ab,ti OR metaanaly*:ab,ti2,588,995
#18 #14 OR #15 OR #16 OR #1710,847,515
#19 #13 AND #18256
Table A3. Signs and symptoms, differential diagnosis and diagnostic work-up.
Table A3. Signs and symptoms, differential diagnosis and diagnostic work-up.
Author,
Year
Symptoms and SignsDifferential DiagnosisSpecimen for HistopathologyHisto-Logy 1Micro-Biology 2Sero-LogyPCR
AUSTRIA
Wagner et al. 2016 [21]Chest and abdominal pain, weight loss, night sweats, coughTuberculosisLeft adrenal gland biopsy, extirpation of a right cervical lymph node++NR+
Mayr et al. 2004 [22]Cough, lymphadenopathy, weight lossTuberculosis, Wegener’s granulomatosis, sarcoidosis, mycosisLung biopsy+++NR
BULGARIA
Balabanov et al. 1964 [23]Ulcerous oral and cutaneous lesions, lymphadenopathyTuberculosisPeribuccal lesion biopsy ++NRNR
GERMANY
Kayser et al. 2019 [24]Cough, dyspneaSarcoidosis, histoplasmosisLung biopsy++++
Slevogt et al. 2004 [25]Bilateral cervical and axillary lymphadenopathy, weight lossTuberculosisCervical lymph node biopsy++NRNR
Horré et al. 2002 [26]Erythematous and swollen lips, mucocutaneous pustules and ulcerations, oral nodules, occasional night sweatsLeishmaniosis, tropical pulmonary mycosis, gammopathyOral lesion biopsy++++
Köhler et al. 1988 [27]Cheilitis, erosive stomatitis, loss of teeth, dysphagia, aphonia, cough, night sweats, weight lossTropical diseaseNRNR++NR
Neveling 1988 [28]Flue like symptoms,
dry cough
Coccidiosis, histoplasmosis, North American blastomycosisNRNRNR+NR
NRNRNRNRNR+
NRNRNRNRNR+
Braeuninger et al. 1985 [29], Hastra et al. 1985 [30]Flue like symptoms, cervical lymphadenopathy, skin lesions, cough, dyspnea, pain in the left legTuberculosis, sarcoidosisLymph node biopsy+++NR
Altmeyer 1976 [31]Respiratory insufficiency, cervical lymphadenopathy, painful infiltrations of the soft palate, hypersalivation, ulcerations of the feet, weight loss, dysphagia, dysphoniaTuberculosis, Wegner’s granulomatosisLung and skin lesion biopsy+NRNR
PORTUGAL
Ferreira et al. 2017 [32]Labial lesion, dry cough, inguinal and axillary lymphadenopathy, weight lossCryptococcosisLip lesion and lung biopsy, inguinal lymph node resection+NR+
Coelho et al. 2013 [33]Odynophagia, dysphagia, irregular and ulcerated oral mucosaNROropharyngeal mucosa biopsy+NRNRNR
Alves et al. 2013 [34]Skin lesion, oral mucosal ulcerationsCoccidioidomycosis, cutaneous tuberculosisSkin lesion and oral mucosa biopsy+ +NRNR
Armas et al. 2012 [35]Ulcerated skin and nasal mucosa lesionNRSkin lesion biopsy+ +NRNR
Carvalho et al. 2009 [36]Fever, epigastric pain, anorexia, fatigue, lymphadenopathy, skin lesions Skin biopsy and lymph node +NRNRNR
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 rashBacterial respiratory infectionNRNR+NR
Agirre et al. 2019 [19]Fever, productive cough, exertional dyspneaBacterial respiratory infectionNRNR+NR
Fever, myalgia, astheniaNRNRNR+NR
Molina-Morant et al. 2018 [18]NRNRNRNRNRNRNR
Navascués et al. 2013 [39]Productive cough, weight loss, asthenia, lymphadenopathy, skin lesionsNRLung biopsy+++
Buitrago et al. 2011 [40] 3Fever, asthenia, ulcerated pustular skin lesions, extremitiesNRSkin biopsy+NR++
Productive coughNRNR+NR++
NRNRCerebral biopsy+NR++
NRNRNR+NR++
NRNRLung biopsyNR+NR+
NRNROral mucosa biopsy+NR++
Pujol-Riqué et al. 2011 [41]Productive cough, hemoptysis, night sweats, skin lesionsSarcoidosisLung and skin biopsy+NRNR
Ramírez-Olivencia et al. 2010 [42]Fever, dyspnea, productive cough, hemoptysis, night sweats, loss of appetite, weight lossNRLung biopsyNR++
Botas-Velasco et al. 2010 [43]Cough, fever, weight loss, retromolar massSarcoidosisRetromolar mass and laryngeal biopsy+++NR
Mayayo et al. 2007 [44]Skin lesionsBlastomycosisSkin lesion biopsy+NRNRNR
López Castro et al. 2005 [45]Dyspnea, dry cough, fever,
weight loss, skin lesions
SarcoidosisLung and skin biopsy+NRNR
Ginarte et al. 2003 [46]Ulcerative lesions from upper left jaw to labial mucosa and nasal graveSquamous cell carcinomaLesion biopsy+++NR
Ulcerative lesions left cheek mucosa, periodontitis with loss of several teethTuberculosis, squamous cell carcinomaLesion biopsy++NRNR
Mass and ulcerative lesions in cheek mucosaSquamous cell carcinomaLesion biopsy++NRNR
Garcia Bustínduy et al. 2000 [47]Ulcerative skin lesionNRSkin lesion biopsy+++NR
Del Pozo et al. 1998 [48]Lesions upper labial mucosa and nasal fossaNRLesion biopsy++NRNR
Garcia et al. 1997 [49]Lesions of labial and palatal mucosaNRLesion 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 graveEpidermoid carcinomaLesion biopsy+++NR
Miguélez et al. 1995 [17]Fever, weight loss, dyspnea, ulcerated mass right tonsil, lymphadenopathyPulmonary fibrosisUlcerated mass biopsy++NRNR
Palatal mass, cervical lymphadenopathyNRPalatal mass biopsy++NRNR
Pereiro Miguens et al. 1987 [16]Oral mucosal lesions, gingivitisTuberculosisMucosa 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
TuberculosisEpididymis and oral lesion biopsy+++NR
Asthenia, ulcerative oral lesions,
labial edema
NROral lesion biopsy++NRNR
Vivancos et al. 1969 [13]Oral mucosal lesionsPseudoneoplasiaOral lesion biopsy++NRNR
GREAT BRITAIN
De Cordova et al. 2012 [52]Submandibular mass,
oral ulcerative lesions
NROral lesion and submandibular mass biopsy++NRNR
Sierra et al. 2011 [53]Dyspnea, lip lesion,
ulcer on tonsil and uvula
Malignancy, sarcoidosis, squamous cell carcinomaLip 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 lossNRSkin biopsy+++NR
Bowler et al. 1986 [55]Cough, dyspnea, and wheeze on exertionLymphangitis carcinomatosaLung biopsy+NR+NR
Symmers 1966 [56]AsymptomaticNRSpleen (autopsy)+NRNRNR
Skin ulcerationNRSkin lesion excision+NRNRNR
ITALY
Borgia et al. 2000 [57]Fever, pain, and inflammation of left kneeMalignancyLeft femur biopsy++NRNR
Pecoraro et al. 1998 [58]Weight loss, night sweat, pain left kneeNRLeft femur biopsy+NRNRNR
Solaroli et al. 1998 [59]Skin lesion, asthenia, fever, loss of visionNRSkin lesion excision + +NRNR
Fulciniti et al. 1996 [60]Weight loss, night, sweats, pain in left kneeMetastatic lung cancerLeft femur biopsy++NRNR
Cuomo et al. 1985 [61]Productive cough, weight loss, asthenia, skin lesionsTuberculosis, lupus vulgarisLung and skin lesion biopsy+++NR
Benoldi et al. 1985 [62]Ulcerative skin lesions, cough, fatigue, malaise, weight lossTuberculosis, lupus vulgarisSkin lesion biopsy+++NR
Finzi et al. 1980 [63]Full-text not available
Velluti et al. 1979 [64]Cough, dyspneaBronchitis, tuberculosisLung 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 lesionsTuberculosisLymph node and lung biopsy++NRNR
Schiraldi et al. 1963 [67]Full-text not available
Molese et al. 1956 [68]Oral mucosa lesions, cervical lymphadenopathy, fever, coughTuberculosis, leishmaniosis, pneumoconiosis, lues, malignancyOral mucosa and tonsillar biopsy+NRNRNR
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 lossHIV, tuberculosisSkin biopsy+NRNR
Dang et al. 2017 [73]Nodular slightly painful, nonulcerated lesion of the tongue, cervical lymphadenopathyNRLingual lesion biopsy+NRNR+
Sambourg et al. 2014 [74]Partially ulcerous and crusted erythematous lesion left auricle extending to the pre-auricular regionLeishmaniosisSkin lesion biopsy+++
Laccourreye et al. 2010 [75]Dysphonia, laryngitisChronic laryngitisLaryngeal biopsy, removed mucosa ++NRNR
Poisson et al. 2007 [76]SeizuresBrain tumorSingle cerebral lesion surgically excised+++NR
NETHERLANDS
Van Damme et al. 2006 [77]Dyspnea, cough, wheezing, weight loss, tiredness, fever, night sweats, periodontitis, oral ulceration, macrohematuriaSarcoidosis, bronchiolitis obliterans organizing pneumonia, oral carcinomaLung and oral mucosa biopsy+++NR
NORWAY
Maehlen et al. 2001 [78]Dizziness, nausea,
headache, hearing loss, hemiplegia
Cerebral tuberculosisBrain biopsy++NRNR
SWITZERLAND
Stanisic et al. 1979
[79], Wegmann et al. 1959 [80]
Submandibular and cervical lymphadenopathy, oral ulcerationTuberculosis, Morbus Wegener, lues, bartonellosis, Morbus Hodgkin, neoplasma, blastomycosis, sporotrichosis, cryptococcosisOral mucosa and cervical lymph node biopsy++NRNR
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].

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Figure 1. Modified Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram [11].
Figure 1. Modified Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram [11].
Jof 07 00157 g001
Figure 2. Summary of important aspects for the diagnosis of paracoccidioidomycosis.
Figure 2. Summary of important aspects for the diagnosis of paracoccidioidomycosis.
Jof 07 00157 g002
Table 1. Eligibility criteria.
Table 1. Eligibility criteria.
InclusionExclusion
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
-
Table 2. Number of identified publications and reported cases of paracoccidioidomycosis by country of diagnosis.
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
Austria22
Bulgaria11
France55
Germany89
Great Britain56
Italy1515
Netherlands11
Norway11
Portugal77
Spain2135 1
Switzerland21
Total6883
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.
Table 3. Imported cases of paracoccidioidomycosis from Central and South America diagnosed in Europe.
Table 3. Imported cases of paracoccidioidomycosis from Central and South America diagnosed in Europe.
Author,
Year
Study Design
Language
No. of CasesAge Years, GenderSuspected Country of ExposureLatency Period 1OccupationAffected Organ(s)Systemic Antimycotic TherapyTreatment Response
AUSTRIA
Wagner et al. 2016 [21]Case report
English
162, MPeru6 yearsConstruction workerAdrenal glands, brain, lung, lymph nodeAmphotericin B, itraconazole, posaconazoleClinical improvement during hospital stay
Mayr et al. 2004 [22]Case report
English
143, FBrazil, Venezuela or Mexico4 yearsGovernment employeeLung, lymph nodeAmphotericin B, voriconazoleClinical improvement
BULGARIA
Balabanov et al. 1964 [23]Case report *
French
167, MBrazil30 yearsWorked in the jungleLung, oral mucosaSulfonamide, trimethoprimComplete remission
GERMANY
Kayser et al. 2019 [24]Case report
English
157, FVenezuela1 yearNRLungAmphotericin B, itraconazoleClinical improvement during hospital stay, remained under control
Slevogt et al. 2004 [25]Case report
English
131, FBrazil10 yearsNRLymph nodesItraconazoleComplete remission
Horré et al. 2002 [26]Case report
English
161, MBrazil10 yearsLegionnaireLung, oral mucosa, skinItraconazoleComplete remission
Köhler et al. 1988 [27]Case report
German
149, MBrazil15 yearsGold mine workerBrain, lung, oral and laryngeal mucosaAmphotericin B, ketoconazole, itraconazoleClinical improvement during hospital stay, remained under control
Neveling 1988 [28]Case series
German
338, FBrazil1 monthAdministrative employeeLungNoneClinical improvement, remained under control
64, MBrazil1 monthGardenerLungNRNR
45, MBrazil1 monthLibrarianLungNRNR
Braeuninger et al. 1985 [29], Hastra et al. 1985 [30]Case report
German
132, MPeru6 yearsNRLung, lymph nodes, oral mucosa, skinKetoconazoleClinical improvement
Altmeyer 1976 [31]Case report *
German
169, MParaguay22 yearsFarm workerLung, lymph nodes, oral mucosa, skinImidazolePatient deceased
PORTUGAL
Ferreira et al. 2017 [32]Case report
English
146, MBrazil1 monthNRLung, lymph nodes, oral mucosaItraconazoleClinical improvement
Coelho et al. 2013 [33]Case report (Abstract only)
English
163, MBrazil8 yearsGardenerOral and pharyngeal mucosaNRNR
Alves et al. 2013 [34]Case report
Portuguese
143, MVenezuela6 yearsNRLung, oral mucosa, skinItraconazoleComplete remission
Armas et al. 2012 [35]Case report
English
143, MVenezuelaNRFarm workerLung, skinItraconazoleClinical improvement
Carvalho et al. 2009 [36]Case report
Portuguese
124, MBrazil7 yearsConstruction workerLymph nodes, skinItraconazoleClinical improvement
Villar et al. 1963 [37]Case report **1-Brazil37 years----
Oliveira et al. 1960 [38]Case report **
Portuguese
1-Brazil23 years----
SPAIN
Chamorro-Tojeiro et al. 2020 [20]Case report
English
142, MMexico6 daysNRLungItraconazoleComplete remission, remained under control
Agirre et al. 2019 [19]Case series
English
229, FPeru10 daysNRLung, lymph nodesItraconazoleComplete remission
31, MPeru10 daysNRLungItraconazoleComplete remission
Molina-Morant et al. 2018 [18]Retrospective observational study
English
25 2Median 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
147, MEcuador11 yearsNRLung, lymph nodes, skinAmphotericin B, itraconazoleComplete remission
Buitrago et al. 2011 [40]Case series
English
667, MEcuador NR
57, MVenezuela NR
44, MParaguay NR
51, MParaguay NR
31, MEcuador NR
NR, MNR NR
Pujol-Riqué et al. 2011 [41]Case report
Spanish
148, MBrazil6 yearsWorked in the jungleLungAmphotericin B, itraconazoleComplete remission
Ramírez-Olivencia et al. 2010 [42]Case report
English
156, MVenezuela6 monthsNRLungItraconazole, amphotericin BComplete remission
Botas-Velasco et al. 2010 [43]Case report
Spanish
143, MEcuadorNRNRLung, oral and laryngeal mucosaItraconazoleClinical improvement; disappearance of oral and laryngeal lesions
Mayayo et al. 2007 [44]Case report
English
127, MEcuadorNoneFarmerLymph nodes, skinItraconazoleComplete remission
López Castro et al. 2005 [45]Case report
Spanish
163, MVenezuela8 monthsShoemakerLung, skinAmphotericin BPatient deceased
Ginarte et al. 2003 [46]Case series English372, MVenezuela50 yearsNRSkinFluconazole Remained under control
67, MBrazil1 yearNROral mucosa, teethItraconazole, sulfonamidesComplete remission
65, MVenezuela38 yearsNROral mucosaFluconazoleRemained under control
Garcia Bustínduy et al. 2000 [47]Case report
English
159, MVenezuela1 yearTaxi driverSkinItraconazoleComplete remission
Del Pozo et al. 1998 [48]Case report
Spanish
150, MVenezuela13 yearsNRSkin, oral and nasal mucosaItraconazoleComplete remission
Garcia et al. 1997 [49]Case report
Spanish
172, MVenezuela50 yearsNRLung, oral mucosa, skinFluconazole 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
244, MVenezuela2 yearsNRBrain, lung, lymph nodesItraconazolePatient deceased (tuberculosis coinfection)
53, MVenezuela18 monthsNRLung, lymph nodes, oral mucosaItraconazoleClinical improvement
Pereiro Miguens et al. 1987 [16]Case report
Spanish
151, MVenezuela23 yearsConstruction workerOral mucosa, skinKetoconazole Clinical improvement
Simon Merchán et al. 1970 [15]Case report **1-Venezuela2 years----
Pereiro Miguens 1974 [14], Pereiro Miguens et al. 1972 [51]Case report *
Spanish
244, MVenezuela7 yearsNRLung, oral mucosaSulfonamide, trimethoprimClinical improvement
49, MVenezuela8 yearsGardenerOral mucosaSulfonamide, trimethoprimClinical improvement
Vivancos et al. 1969 [13]Case report *
Spanish
144, MVenezuelaNRFarmerOral mucosaSulfamethoxazole/trimethoprim, amphotericin BComplete remission
GREAT BRITAIN
De Cordova et al. 2012 [52]Case report (Abstract only)
English
152, MVenezuelaNRButcherOral mucosaItraconazoleComplete remission
Sierra et al. 2011 [53]Case report (Abstract only)
English
177, MEcuadorNRNRLung, lymph nodes, oral mucosa, skinItraconazoleNR
Walker et al. 2008 [54]Case report
English
151, MVenezuelaNoneAccountantLung, oral mucosa, skinItraconazoleClinical improvement, cutaneous lesions cleared
Bowler et al. 1986 [55]Case report
English
157, FArgentina, Venezuela17 yearsClerkLungNRNR
Symmers 1966 [56]Case report *
English
142, MBrazilNREngineerSkinNRNR
146, MBrazilNoneBusinessmanSpleen (autopsy)No therapyPatient deceased (acute heart failure)
ITALY
Borgia et al. 2000 [57]Case report
English
161, MVenezuelaNRHouse-
painter
Bones, lungItraconazoleClinical improvement
Pecoraro et al. 1998 [58]Case report
Italian
160, MVenezuelaNRCoffee plantations workerBones, lungKetoconazoleClinical improvement
Solaroli et al. 1998 [59]Case report
Italian
149, MBrazilNRNRBrain, lung, skinItraconazoleClinical improvement
Fulciniti et al. 1996 [60]Case report
English
160, MVenezuelaNRNRBones, lungItraconazoleClinical improvement, remained under control
Cuomo et al. 1985 [61]Case report
Italian
137, MVenezuela2 yearsButcherLung, skinKetoconazoleClinical improvement
Benoldi et al. 1985 [62]Case report *
English
141, MVenezuelaFew monthsButcherLung, lymph nodes, skinKetconazole, sulfamethoxy-pyridazineComplete remission
Finzi et al. 1980 [63]Case report **1-Brazil14 years----
Velluti et al. 1979 [64]Case report *
Italian
152, MVenezuela17 yearsFabric retailerLung Amphotericin B, miconazoleClinical improvement
Lasagni et al. 1979 [65]Case report **
Italian
1-VenezuelaNR----
Scarpa et al. 1965 [66]Case report *
Italian
143, MVenezuela5 yearsFarmerLung, oral mucosa, skinAmphotericin B, sulfamethoxazolePatient deceased
Schiraldi et al. 1963 [67]Case report **1-VenezuelaNone----
Molese et al. 1956 [68]Case report *
Italian
147, MVenezuelaNonePainterLung, lymph nodes, oral mucosaNystatinNR
Farris 1955 [69]Case report **1-Brazil7 years----
Bertaccini 1934 [70]Case report **1-BrazilNone----
Dalla Favera 1914 [71]Case report **1-BrazilNone----
FRANCE
Heleine et al. 2020 [72]Case report English148, MBrazilNRFarmerLung, lymph nodes, oropharyngeal mucosa, skinItraconazoleClinical improvement
Dang et al. 2017 [73]Case report
English
154, MColumbia, Venezuela12 yearsJournalistLymph nodes, oropharyngeal mucosaItraconazoleClinical improvement; almost complete resolution of the tongue lesion and lymhadenopathy
Sambourg et al. 2014 [74]Case report French143, MBrazilNRNRSkinNRNR
Laccourreye et al. 2010 [75]Case report English146, MVenezuelaNREngineerLaryngeal mucosaItraconazoleComplete remission
Poisson et al. 2007 [76]Case report
English
170, MParaguay6 yearsNRBrain, lung Fluconazole, itraconazoleRemained clinically stable
NETHERLANDS
Van Damme et al. 2006 [77]Case report
English
160, MPeru, Ecuador8 yearsCarpenterLung, oral mucosa, urinary tractItraconazoleClinical improvement, remained under control
NORWAY
Maehlen et al. 2001 [78]Case report
Norwegian
151, FBrazil23 yearsNRBrain-Patient deceased
SWITZERLAND
Stanisic et al. 1979
[79], Wegmann et al. 1959 [80]
Case report *
German
147, MBrazil5 yearsCarpenterLung, lymph nodes, oral mucosaHydroxy-stilbamidine, amphotericin B, sulfonamidePatient deceased
(Cor pulmonale)
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].
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Wagner, G.; Moertl, D.; Glechner, A.; Mayr, V.; Klerings, I.; Zachariah, C.; Van den Nest, M.; Gartlehner, G.; Willinger, B. Paracoccidioidomycosis Diagnosed in Europe—A Systematic Literature Review. J. Fungi 2021, 7, 157. https://doi.org/10.3390/jof7020157

AMA Style

Wagner G, Moertl D, Glechner A, Mayr V, Klerings I, Zachariah C, Van den Nest M, Gartlehner G, Willinger B. Paracoccidioidomycosis Diagnosed in Europe—A Systematic Literature Review. Journal of Fungi. 2021; 7(2):157. https://doi.org/10.3390/jof7020157

Chicago/Turabian Style

Wagner, Gernot, Deddo Moertl, Anna Glechner, Verena Mayr, Irma Klerings, Casey Zachariah, Miriam Van den Nest, Gerald Gartlehner, and Birgit Willinger. 2021. "Paracoccidioidomycosis Diagnosed in Europe—A Systematic Literature Review" Journal of Fungi 7, no. 2: 157. https://doi.org/10.3390/jof7020157

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