Print version ISSN 0365-0596
An. Bras. Dermatol. vol.85 no.1 Rio de Janeiro Jan./Feb. 2010
Antônio de Deus FilhoI; Antônio Castelo Branco de DeusII; Alisson de Oliveira MenesesIII; Andressa Sobral SoaresIV; Aécio Lopes de Araújo LiraV
IDoctorate in Tropical Medicine from the Oswaldo Cruz Foundation (FIOCRUZ; RJ). Adjunct Professor of Pneumology, Grade IV, Federal University of Piauí (UFPI), Teresina, PI, Brazil
IIMedical student, School of Medicine, Federal University of Piauí (UFPI), Teresina, PI, Brazil
IIIMedical student, School of Medicine, Federal University of Piauí (UFPI), Teresina, PI, Brazil
IVMedical student, School of Medicine, Federal University of Piauí (UFPI), Teresina, PI, Brazil
VMedical student, School of Medicine, Federal University of Piauí (UFPI), Teresina, PI, Brazil
BACKGROUND: Coccidioidomycosis is a systemic mycosis that usually presents as a benign infection. Patients generally recover spontaneously; however, a small proportion of infected individuals develop progressive complications that may affect the skin in the form of disseminated pleomorphic lesions and may become fatal.
OBJECTIVES: To identify and describe skin and mucous membrane manifestations of coccidioidomycosis, to identify occupational hazards associated with the disease and to determine its associated clinical presentation.
METHODS: A study conducted between 2003 and 2006 involving 30 patients from the Brazilian states of Piauí and Maranhão with coccidioidomycosis diagnosed by direct microscopy, sputum culture or screening serology using agar gel double immunodiffusion, in association with anamnesis and physical examination.
RESULTS: Extrapulmonary lesions were found in 13 cases (43.3%), consisting predominantly of dermatological manifestations of hypersensitivity: erythema nodosum (26.6%), exanthema with erythematosquamous lesions (26.6%) and erythema multiforme (23.3%), as well as ulcerations of the tongue (13.3%), lip ulcers (6.6%) and subcutaneous abscess (3.3%). These manifestations were seen during the acute phase of the disease.
CONCLUSIONS: Skin manifestations associated with an acute respiratory infection reinforce the hypothesis of a diagnosis of coccidioidomycosis, particularly in individuals who hunt armadillos or in those exposed to soil excavation.
Keywords: Coccidioidomycosis; Diagnosis; Epidemiology; Erythema multiforme; Erythema nodosum; Exanthema
Systemic mycoses constitute a group of infections that are acquired by inhaling the spores of dimorphic fungi, resulting in a primary pulmonary lesion that tends to resolve spontaneously in the immunocompetent host. Pulmonary mycoses are defined as any fungal infection that presents with pulmonary symptoms. In addition to systemic mycoses, these also include pulmonary manifestations caused by species of: Aspergillus (aspergillosis), fungi of the order Mucorales (mucormycosis), hyaline and dematiaceous Hyphomycetes (hyalohyphomycosis and phaeohyphomycosis) and Candida (candidiasis). With the exception of the pulmonary manifestations caused by species of Candida, all the others are acquired by inhalation of an exogenous source, including dimorphic fungi (the agents of systemic mycoses) and saprophytic fungi (the agents of opportunistic mycoses).1-6
Up to the present date, few studies have been conducted on the occurrence of systemic mycoses in the semiarid regions of northeastern Brazil that could provide consistent data on the epidemiological indicators of the incidence, prevalence, morbidity and mortality related to this condition. The fact that pulmonary mycoses are not subject to compulsory notification further hampers understanding of the actual magnitude of the problem. Improving the survival of immunocompromised hosts requires better knowledge on fungal disease and access to accurate mycological diagnostic resources. Diagnosis of fungal lung infections is hampered by their varied and often uncharacteristic manifestations. The physician should consider the possibility of a fungal disease whenever faced with a subacute or chronic case of pneumonia that fails to respond to antibacterial antibiotics, and in which etiology by bacteria, mycobacteria or virus is unconfirmed.6
Lung manifestations caused by fungi are relatively common findings, particularly in the over-30s age-group. In Brazil, the mycoses that cause chronic lung disease or are associated with chronic pneumopathies of varied etiology include: coccidioidomycosis, paracoccidioidomycosis (PCM), aspergillosis, histoplasmosis and cryptococcosis.2,3,5,6
Coccidioidomycosis is a systemic mycosis that affects humans and other vertebrates. Caused by the geophilic dimorphic fungus, Coccidioides immitis, it is acquired by inhaling the infectious arthroconidia present in soil. Based on molecular phylogeny, the existence of another species of the etiological agent was recently demonstrated to have been "hidden" with C. immitis, and was baptized Coccidioides posadasii after Alejando Posadas, who discovered it. Therefore, it is currently accepted that C. immitis corresponds to the fungi isolated in California, particularly in the San Joaquin Valley in the United States, while C. posadasii is prevalent in all the other endemic regions of the Americas; hence the coccidioidomycosis agent found in Brazil is presently known as C. posadasii.7
The condition usually presents as a benign infection that resolves spontaneously; however, in a small proportion of infected individuals it may develop into a serious and even fatal disease, and may affect other organs in addition to the lungs by hematogenous dissemination.8
Skin lesions are the most common extrapulmonary manifestations, the most common sites being the face or limbs. These generally present as maculopapular exanthema, erythema nodosa (EN), superficial abscesses, pustules and granulomatous lesions. One or several lesions of varying appearances, with or without the involvement of other organs, may be present in the same patient.9
This mycosis is found in the arid and semiarid regions of the Americas, the southwestern US and the north of Mexico being the largest contiguous area of high prevalence.10 It is also endemic in other areas of Central and South America.11 The semiarid region of northeastern Brazil has only recently been identified as an endemic area for coccidioidomycosis.12,13
The first case of coccidioidomycosis was identified in Argentina in 1891 by the then medical student Alejandro Posadas in a soldier from Chaco, who was suffering from chronic recurrent tumoral skin lesions.14 Posadas and a pathologist named Robert Wernicke described a parasite that was present in the lesions and that was similar in appearance to the coccidian protozoa, but had been unknown up to that time. In 1894, Rixford registered the first two cases occurring in the United States in Portuguese immigrants who had recently arrived in California and were working as farmers in the San Joaquin Valley, and in 1896 Rixford and Gilchrist identified a parasite in the lesions that was similar to that reported by Posadas. The actual nature of this agent was discovered in 1900 by Ophüls and Moffitt, who described a third case occurring in the United States, once again in a Portuguese immigrant. After observing the regularity with which mould appeared in the cultures, these investigators described the agent of the disease as a fungus. In Brazil, the first cases were reported in 1978 and 197915,16, but it was only in 1998 that Brazil was included in the map of geographical distribution of coccidioidomycosis,17 following the report of the first outbreaks of the acute pulmonary type that occurred in Piauí and Ceará.13,18
This mycosis has already been diagnosed in four Brazilian states: Piauí, Ceará, Maranhão and Bahia; Piauí being that in which prevalence has been greatest, with a total of 100 cases already having been identified there. 19 In addition, this mycosis has also been diagnosed in dogs and in the nine-banded armadillo (Dasypus novemcinctus), and C. immitis has been isolated from soil samples collected from armadillo burrows in the states of Piauí20,21 and Ceará.22
In view of the scarcity of data on this disease in Brazil, many cases are probably erroneously diagnosed as nonspecific pneumonias, tuberculosis or even pneumoconiosis/silicosis.
This study sample was composed of 30 patients originating from the states of Piauí and Maranhão with clinical pneumopathies of as yet unknown etiology, who attended the Pneumology Clinic of the Getulio Vargas Teaching Hospital of the Federal University of Piauí in the city of Teresina, Piauí, Brazil. An observational, prospective study was performed in full compliance with the regulations governing research in human beings, as defined in resolutions 196/96 and 251/97 of the National Health Council (Ministry of Health, Brazil, 1996).
The patients selected for the study filled out a previously prepared questionnaire and were submitted to anamnesis, physical examination, serology by double immunodiffusion, direct microscopic examination and culture for fungi and acid-alcohol-fast bacilli in sputum and other samples suspected of containing the agent.
Patients with as yet unexplained pneumopathy. Referred cases or patients spontaneously attending the clinic with chest radiography or tomography findings indicative of processes that required diagnostic investigation, irrespective of whether respiratory symptoms were present or not. In addition, patients with extrapulmonary clinical manifestations, particularly in integuments (mucosa or skin), ganglia, in the central nervous system, adrenals, or others.
Patients with acute or chronic respiratory infections of bacterial or viral etiology.
Of the 30 patients studied, 28 (93.3%) had recently been exposed to the risk occupation of hunting armadillos or removing these animals from their burrows. One individual was employed in planting and harvesting cassava, while another worked in digging wells or water holes. Of the 30 patients, 29 were male. With respect to ethnicity, 13 were mulatto, 10 were white, 5 were black and 2 were native Indians. Age ranged from 15 to 82 years, with a mean of 37.9 years. Mean number of years of schooling was 2.9; however, nine patients were illiterate, while one had a university degree.
Four outbreaks were found in four different municipalities in the southwestern region of the state of Piauí, affecting 14 individuals. Nineteen isolated cases occurred and these were distributed throughout 15 municipalities; however, 17 of these patients were from the state of Piauí and the two native Indians were of the Guajajara tribe from the municipality of Arame in the state of Maranhão (Figure 1).
In the state of Piauí, 28 individuals became ill: 27 (96.4%) after hunting armadillos and/or removing them from their burrows and 1 after excavating wells. The other two patients who came from the state of Maranhão were native Indians of the Guajajara tribe from the municipality of Arame. One was an armadillo hunter and the other was employed in planting and harvesting cassava. Three of these patients died (10%).
There was a statistically significant correlation between the occupation of hunting armadillos and the onset of coccidioidomycosis. A cough was the most common symptom (100%), initially dry, then becoming productive with the elimination of phlegm after some days, accompanied by fever in 26 cases (86.7%) and chest pain in 22 (73.3%).
Among the methods used for laboratory diagnosis (Table 1), the most sensitive was sputum culture followed by direct microscopic examination (86.6%).
Extrapulmonary symptoms were present in 13 cases (43.3%), consisting of predominantly dermatological manifestations of hypersensitivity such as erythema nodosum (26.6%), exanthema with erythematosquamous lesions (26.6%) and erythema multiforme (23.3%) (Table 2, Figure 2, Figure 3, Figure 4 e Figure 5. Some patients had more than one skin or mucous membrane manifestation. With the exception of one case, all the extrapulmonary manifestations were found within the period of applicability of the diagnosis, i.e. during the acute phase of the disease.
In view of the wide variation in its clinical presentation, coccidioidomycosis has been classified within the group of "great imitator diseases", together with hanseniasis, tuberculosis and syphilis.23 This fact further emphasizes the importance of taking skin and mucous membrane manifestations into consideration in forming a diagnostic hypothesis when the patient has a clinical history compatible with this condition. In view of the lack of available knowledge on the disease in this country, many cases are probably diagnosed erroneously as nonspecific pneumonias, tuberculosis or even pneumoconiosis/silicosis, principally in patients exposed to soil excavation.19
The easy availability and low cost of performing direct microscopic examination and culture mycological tests reinforces the priority that must be given to these methods, while respecting the appropriate biosafety procedures. Other diagnostic techniques such as serology should also be used, as well as molecular techniques that may perhaps become available in some referral centers, notably in the northeastern region of Brazil, where the disease is endemic.22
The involvement of integumentary structures in coccidioidomycosis may be organic or reactive. Organic lesions contain microorganisms, specimens of which are identifiable by histopathological examination or culture. These lesions result from hematogenic dissemination to the skin or, less commonly, from a primary skin infection. Eruptive reactions, which do not contain viable organisms, most commonly include erythema nodosum, acute generalized exanthema, erythema multiforme and interstitial granulomatous dermatitis.24
Erythema nodosum is considered to represent the skin reaction most characteristic of coccidioidomycosis,24 a fact that was confirmed in the present study (26.6% of cases, a similar proportion to that of exanthema) (Table 2). All the patients with this manifestation reported concomitant arthralgia. Between one and three weeks following onset of the disease, the patient develops red and painful subcutaneous nodules, typically on the lower limbs (Figure 2). The diagnosis is often based on these clinical characteristics. Excisional biopsy reveals a histopathological pattern of granulomatous panniculitis. Other known causes of erythema nodosum include sarcoidosis, streptococcal and other infections, inflammatory bowel disease, pregnancy and the use of oral contraceptives. In patients with erythema nodosum, the onset of the eruption coincides with the beginning of late hypersensitivity reaction.25 Erythema nodosum appears to reflect the presence of a vigorous cell-mediated immune response that may offer additional protection against the microorganism. 26 In fact, none of the patients who died in this study (10%) had erythema nodosum.
Acute exanthema appears at the onset of coccidioidomycosis, typically 48 hours after the appearance of the first symptoms.27 In some of the present cases, the skin eruption constituted the principal complaint. Its appearance may precede the development of detectable serum antibodies. The skin lesions are described clinically as macules, papules (Figure 3), urticarial exanthema or target lesions, resulting in a clinical appearance that resembles allergic contact dermatitis or erythema multiforme. Exanthema may persist for various weeks and is occasionally followed by palmar desquamation and, in some cases, by oral involvement.24
For more than sixty years, erythema multiforme has been associated with coccidioidomycosis.27 The clinical condition of erythema multiforme appears to superimpose that of acute exanthema. In both cases, the manifestations occur at the onset of the disease and appear as target lesions, with oral involvement, pruritus and palmar desquamation.28 In the present study, lesions were found principally on the thoracic dorsal region and around the neck and face Figure 4 e Figure 5. Acute exanthema may clinically mimic erythema multiforme although the two conditions differ histopathologically.
Of the 30 patients, 28 worked as armadillo hunters, while one excavated wells for a living and one was an agricultural worker. The association between risk occupations and coccidioidomycosis, analyzed using the chi-square exact test, showed a high risk for coccidioidomycosis in armadillo hunters. Therefore, a diagnosis of coccidioidomycosis should be considered when an acute or chronic infection is present together with various clinical or radiological findings, and when the onset of the disease occurred following exposure to soil, either as a result of the activity of armadillo hunting or of excavating soil in other types of occupation.
Descriptive studies and clinical case reports have identified other indicators of risk, such as: living in rural environments in endemic areas, exposure to soil, being male and having migrated to an endemic area. Risk factors for dissemination of the disease include belonging to a black or Asian ethnic group.
The present cases, since they represented acute forms of the disease in which the patients were exposed to intense inoculation as reflected by manifestations of hypersensitivity,29 triggered skin lesions in a greater percentage of cases than previously reported in the literature (26.6%). Corroborating this hypothesis, the four patients involved in the outbreak that occurred in the town of Elesbão Veloso in the state of Piauí19 all had skin and mucous membrane manifestations. In 2006, Macêdo, who was studying the fungal agent in the soil at this same location, found the highest rate of contamination in samples obtained from armadillo burrows in the state of Piauí.
Greater knowledge on this disease, including identification of risk occupations, transmission of the disease, its clinical characteristics and radiological abnormalities, have permitted pneumologists and infectious disease specialists, when provided with adequate laboratory support, to confirm diagnosis in a growing number of cases, as highlighted by the fact that in the period between August 2003 and July 2006 the number of known cases in the state of Piauí doubled. It is very probable that this mycosis is underdiagnosed and that its geographical distribution indeed extends into other northeastern states or even other regions of Brazil.13,18,30
Since this type of mycosis is systemic, the wide variation in clinical findings may hamper the diagnosis of coccidioidomycosis in low prevalence areas. Knowledge with respect to the relationship between the skin and mucous membrane lesions and this disease may help physicians correctly diagnose "suspect" patients with acute respiratory infections who have been exposed to soil excavation (such as armadillo hunters).
1. Andrade JAF. Avaliação da freqüência de micoses sistêmicas e oportunistas em pacientes com doenças pulmonares: estudo clínico e sorológico no Hospital Otávio Mangabeira [dissertação]. Salvador: Universidade Federal da Bahia; 1987. [ Links ]
2. Chagas PRS. Pesquisa de agentes e anticorpos fúngicos em pacientes com pneumopatia a esclarecer dissertação]. São Paulo: Universidade de São Paulo; 1982. [ Links ]
3. Ferreira-da-Cruz MF. A importância das técnicas de imunoprecipitação na triagem e no diagnóstico da aracoccidioidomicose, histoplasmose e aspergilose. Estudo em população hospitalar do Rio de Janeiro [dissertação]. Rio de Janeiro: IOC-Fiocruz; 1984. [ Links ]
4. Londero AT, Wanke B, Lacaz CS et al. Proposta de iagnóstico e tratamento das micoses profundas com manifestações pulmonares da Comissão de Peritos em Micoses da CNCT e da Comissão Científica da SBPT. Boletim CNCT. 1987;1:53-57. [ Links ]
5. Tarantino AB, Gonçalves AJR, Capone D, Aidé MA, Lazéra MS, Wanke B. Micoses pulmonares. In: Tarantino AB. Doenças pulmonares. 5 ed. Rio de Janeiro: Guanabara Koogan; 2002. p.416-50. [ Links ]
6. Wanke B, Monteiro PCF, Lazéra MS, Capone D, Bethlem EP, Rego AP. Micoses pulmonares. In: Bethlem NM. Pneumologia. 4 ed. Rio de Janeiro: Atheneu; 1996. p.449-77. [ Links ]
7. Fisher MC, Koenig GL, White TJ, Taylor JT. Molecular and phenotypic description of Coccidioides posadasii sp. nov., previously recognized as the non-California population of Coccidioides immitis. Mycologia. 2002;94:73-84. [ Links ]
8. Rippon JW. Coccidioidomycosis. In: Medical Mycology. The pathogenic fungi and the pathogenic actinomycetes. 3th ed. W.B. Philadelphia: Saunders Co; 1988. p.443-73. [ Links ]
9. Chiller TM, Galgiani JN, Stevens DA. Coccidioidomycosis. Infect Dis Clin North Am. 2003;17:41-57. [ Links ]
10. Pappagianis D. Epidemiology of coccidioidomycosis. In: McGinnis MR. Current topics of medical mycology. New York: Springer-Verlag; 1988. p.199-238. [ Links ]
11. Mayorga RP, Espinoza H. Coccidioidomycosis in Mexico and Central America. Mycopathol Mycol Appl. 1970;41:13-23. [ Links ]
12. Wanke B, Lazéra MS, Nucci M. Fungal infections in the immunocompromised host. Mem Inst Oswaldo Cruz. 2000;95(Suppl1):153-8. [ Links ]
13. Sidrim JJC, Silva LCI, Nunes J, Rocha MFG, Paixão GC. Le nord-est brésilien, région d'endémie de occidioidomycose? A propos dune micro-épidémie. J Mycol Méd. 1997;7:37-9. [ Links ]
14. Posadas A. Un nuevo caso de micosis fungoidea con psorospermias. An Circ Med Argent. 1892;15:585-97. [ Links ]
15. Gomes OM, Serrano RRP, Pradel HOV, Moraes NLTB, Varella ALB, Fiorelle AI et al. Coccidioidomicose pulmonar. Primeiro caso nacional. Rev Assoc Med Bras. 1978;24:167-168. [ Links ]
16. Vianna H, Passos HV, Sant'Ana AV. Coccidioidomicose. Relato do primeiro caso ocorrido em nativo do Brasil. Rev Inst Med Trop. 1979;21:51-5. [ Links ]
17. Pappagianis D. Coccidioides immitis. In: Collier L, Balows A, Sussman M. Microbiology and microbial infections. 9th ed. London: Ajello L & Hay; 1998. v.4. p.357-71. [ Links ]
18. Wanke B, Lazéra MS, Monteiro PC, Lima FC, Leal MJ, Ferreira Filho PL et al. Investigation of an outbreak of endemic coccidioidomycosis in Brazil's northeastern state of Piauí with a review of the occurrence and istribution of Coccidioides immitis in three other Brazilian states. Mycopathologia. 1999;148:57-67. [ Links ]
19. Deus Filho A. Manifestações respiratórias das micoses. Estudo em população com pneumopatia no estado do Piauí [tese]. Rio de Janeiro: Instituto Osvaldo Cruz (Fiocruz); 2007. [ Links ]
20. Eulálio KD. Contribuição ao estudo da coccidioidomicose: identificação de infecção natural de tatus Dasypus novemcintus por Coccidioides immitis [dissertação]. Rio de Janeiro: Instituto Osvaldo Cruz (Fiocruz); 2000. [ Links ]
21. Macêdo RCL. Isolamento e identificação de Coccidioides immitis de amostras do solo relacionadas a surtos de coccidioidomicose [dissertação]. Rio de Janeiro: Instituto Osvaldo Cruz (Fiocruz); 2006. [ Links ]
22. Cordeiro RA. Fenotipagem de cepas de Coccidioides posadasii e desenvolvimento de novas estratégias para o diagnóstico da coccidioidomicose - uma doença emergente no nordeste brasileiro [tese]. Fortaleza: Universidade Federal do Ceará; 2006. [ Links ]
23. Huntington RW Jr. Coccidioidomycosis: a great imitator disease. Arch Pathol Lab Med. 1986;110:182. [ Links ]
24. DiCaudo DJ. Coccdidioidomycosis: a review and update. J Am Acad Dermatol. 2006;55:929-42. [ Links ]
25. Smith CE. Epidemiology of acute coccidioidomycosis with erythema nodosum ("San Joaquin" or "Valley Fever"). Am J Public Health Nations Health. 1940;30:600-11. [ Links ]
26. Braverman IM. Protective effects of erythema nodosum in coccidioidomycosis. Lancet. 1999;353:168. [ Links ]
27. Richardson HB Jr, Anderson JA, McKay BM. Acute pulmonary coccidioidomycosis in children. J Pediatr. 1967;70:376-82. [ Links ]
28. DiCaudo DJ, Yiannias JA, Laman SD, Warschaw KE. The exanthem of acute pulmonary coccidioidomycosis: clinical and histopathologic features of 3 cases and review of the literature. Arch Dermatol. 2006;142:744-6. [ Links ]
29. Pappagianis D. Coccidioidomycosis. Semin Dermatol. 1993;12:301-9. [ Links ]
30. Wanke B. Coccidioidomicose no Brasil. Infocus América Latina - II Fórum de Infecções Fúngicas na Prática Clínica, São Paulo, Livro de Resumos, 2003. p.55. [ Links ]
Mailing Address: Recebido
em 11.08.2008. *
Study conducted at the Pneumology Clinic, Getulio Vargas Teaching Hospital, Federal
University of Piauí (UFPI), Teresina, PI, Brazil.
Av. Marechal Castelo Branco, 400 - Apto 1600 Cristo Rei
64014 058 Teresina PI
Tel.:/Fax: 86 3217 8406 / 9982 2065 / 99419233
Aprovado pelo Conselho Consultivo e aceito para publicação em 17.12.08.
Conflicts of interest: None
Financial support: The cost of the supplementary tests performed in this study was covered by the Brazilian National Health System (SUS). The remaining expenses were paid by the authors themselves
* Study conducted at the Pneumology Clinic, Getulio Vargas Teaching Hospital, Federal University of Piauí (UFPI), Teresina, PI, Brazil.