Paracoccidioidomycosis in Mexico: clinical and epidemiological data from 93 new cases (1972-2012)

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mycoses

Diagnosis,Therapy and Prophylaxis of Fungal Diseases

Original article

Paracoccidioidomycosis in Mexico: clinical and epidemiological data from 93 new cases (1972–2012)  n Lo  pez-Martınez,1 Francisca Herna ndez-Herna ndez,1 Luis Javier Me ndez-Tovar,2 Rube 1 3 4 Patricia Manzano–Gayosso, Alexandro Bonifaz, Roberto Arenas, vez6 Marıa del Carmen Padilla-Desgarennes,5 Roberto Estrada6 and Guadalupe Cha 1 Departamento de Microbiologıa y Parasitologıa, Facultad de Medicina, Universidad Nacional Autonoma de Mexico, Mexico, D. F., Mexico, 2Laboratorio de Investigacion Medica en Dermatologıa y Micologıa, Hospital de Especialidades, Centro Medico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico, D. F., Mexico, 3Departamento de Micologıa, Servicio de Dermatologıa, Hospital General de Mexico “Dr. Eduardo Liceaga”, Mexico, D. F., Mexico, 4 Servicio de Dermatologıa y Micologıa, Hospital General “Manuel Gea Gonzalez”, Secretarıa de Salud, Mexico, D. F., Mexico, 5Laboratorio de Micologıa, Centro Dermatologico “Ladislao de la Pascua”, Secretarıa de Salud, Mexico, D. F., Mexico and 6Facultad de Medicina, Universidad Autonoma de Guerrero, Acapulco, Mexico

Summary

Paracoccidioidomycosis (PCM) is an endemic systemic infection in several countries of Latin America. The few registered cases in Mexico most likely do not reflect the real frequency. Disseminate the epidemiological and clinical data of unreported cases of PCM in Mexico from 1972 until 2012 is the aim of this work. Epidemiological and clinical information of non-published cases of PCM was requested from the principal mycological diagnosis centres in Mexico. A total of 93 cases were received. The infection was found predominantly in men (95.7%), peasants (88.5%) and individual between 31 and 60 years of age. Most of the cases were found in tropical areas of the Gulf of Mexico (54.84%) and the Pacific littoral (20.3%). The main sites of dissemination were the oral mucosa (39.38%) and skin (34.05%). The most effective treatments were itraconazole alone and the combination of itraconazole with sulfamethoxazole-trimethoprim. PCM is a subdiagnosed pathology in Mexico. Therefore, adequate training is necessary to determine the current status of this mycosis.

Key words: Paracoccidioidomycosis, Paracoccidioides brasiliensis, systemic mycosis.

Introduction Paracoccidioidomycosis (PCM) is a systemic mycosis caused by the inhalation of airborne Paracoccidioides brasiliensis conidia, a dimorphic fungus with an uncertain habitat that often cannot be isolated from the environment.1,2 This disease primarily affects the most pez-Martınez, Departamento de MicrobioCorrespondence: Dr Rub en Lo logıa y Parasitologıa, Facultad de Medicina, U.N.A.M. Av. Universidad 3000, Col. Universidad Nacional. Del. Coyoac an, C.P. 04510, M exico, D.F., Mexico. Tel.: +52 55 56 23 24 58. Fax: + 55 55 56 23 24 58. E-mail: [email protected] Submitted for publication 11 September 2013 Revised 15 January 2014 Accepted for publication 20 February 2014

© 2014 Blackwell Verlag GmbH Mycoses, 2014, 57, 525–530

vulnerable social and economic sectors. PCM presents two types of clinical manifestations: acute/subacute and chronic. The former type is more common in children and adolescents, its male–female distribution is similar, and the course of the disease is acute. The chronic form represents 90% of the total cases, and men between 30 and 50 years of age are the most affected. This form usually disseminates to the skin and mucosa, the course of the disease is slow and progressive, and it produces few symptoms.1 The diagnosis of PCM is based on the detection of fungal elements of P. brasiliensis through direct microscopic examination or histopathological examination. Culturing in Sabouraud dextrose agar makes it possible to obtain fungal colonies after incubation for 20–30 days at 25–28°C (mycelial phase) or for 10–12 days at 37 °C (yeast phase). Specific serological

doi:10.1111/myc.12190

R. L opez-Martınez et al.

tests (such as complement fixation and double immunodiffusion) are necessary tools to establish the diagnosis and monitor the disease course.3 Over the past few years, molecular techniques that enable faster and more reliable diagnosis have been developed.4,5 The selection of the treatment for PCM depends on the severity of the disease, the condition of the patient’s immune system and drug availability. For a mild infection, itraconazole is the best choice.1,6 Despite their low efficiency and high index of relapse, sulphonamides are still frequently used because of their low cost, good tolerability and availability in endemic regions. Amphotericin B is recommended in severe cases and for immunosuppressed patients.7 This mycosis is endemic to South America, and the countries with the highest percentages of cases are Brazil (80% of the reported cases), Colombia, Venezuela and Argentina. No cases have been reported in Chile, Guyana, Suriname, Belize or Nicaragua.2,8,9 Cases have been reported outside the endemic regions, but these are observed in migrants or in people who have travelled to or remained for a long period in the endemic areas.10 The first case in Mexico was reported by Gonz alezOchoa and Esquivel-Medina in 1950. The patient was a 30-year-old man, from Veracruz State who suffered from chronic pulmonary disease; he was treated with sulphapyridine and exhibited initial remission of the illness.11 However, 6 years later, he presented with a reactivation and lesions in the oral mucosa.12 Since then, only sporadic cases have been reported,13–18 including a case of PCM-mimicking squamous cell carcinoma.19 An additional case with insidious evolution has been diagnosed postmortem.20 The aim of this work was to present the most relevant epidemiological and clinical information on non-published cases of PCM in Mexico between 1972 and 2012.

Patients and methods Information on unpublished PCM cases was requested from mycologists at seven mycological diagnosis centres in Mexico: (i) Facultad de Medicina, Universidad Nacional Aut onoma de Mexico; (ii) Servicio de Dermatologıa y Micologıa, Hospital General de Mexico “Dr. Eduardo Liceaga”; (iii) Instituto Nacional de Referencia Epidemiol ogica, Secretarıa de Salud; (iv) Secci on de Micologıa, Servicio de Dermatologıa, Hospital General “Dr. Manuel Gea Gonz alez”, Secretarıa de Salud; (v) Servicio de Dermatologıa y Micologıa Medica, Hospital de Especialidades, Centro Medico Nacional, Instituto Mexicano del Seguro Social; (vi) Laboratorio de Micologıa, Centro Dermatol ogico “Ladislao de la Pascua”,

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Secretarıa de Salud and (vii) Hospital General de Acapulco, Guerrero, Secretarıa de Salud. The period considered for this study was from 1972 to 2012. The recorded demographic information included sex, age, occupation and geographical origin, as well as clinical manifestations, anatomic location, time of evolution, therapeutic drugs used and the treatment outcome.

Results In the past 40 years, 93 cases of PCM have been diagnosed through mycological study. It was not possible to obtain the epidemiological and clinical data for all of the cases. Sex

Of the 93 patients, 89 were men (95.7%), and four were women (4.3%); the male-to-female ratio was 22 : 1. Age

In 89 cases, the age was recorded. The age group including 31- to 60-year-old patients exhibited the highest frequency of disease diagnosis, with 61 cases (78.47%) (Table 1). The age of women affected by PCM ranged from 32 to 42 years. Geographical distribution

Figure 1 shows the geographical distribution of the recorded cases of PCM. In this study, three regions were considered: (i) Although the littoral region of the Gulf of Mexico includes five states with a tropical climate (Tamaulipas, Veracruz, Tabasco, Campeche and Yucatan), only Veracruz had recorded cases, and these accounted for the majority of the total number of cases, i.e. 51 cases (54.84%). (ii) The Pacific littoral Table 1 Distribution of 89 cases of paracoccidioidomycosis according to age group. Age (years)

Number

%

11–20 21–30 31–40 41–50 51–60 61–70 71–80 Total

8 10 19 25 17 8 2 89

8.98 11.23 21.36 28.10 19.11 8.98 2.24 100.00

Most of the cases of paracoccidioidomycosis were observed in patients between 31 and 60 years old.

© 2014 Blackwell Verlag GmbH Mycoses, 2014, 57, 525–530

Paracoccidioidomycosis in Mexico

Reported cases of paracoccidioidomycosis Tropic of Cancer

Aquismon 5 9

4

6 8 10

Pacific Ocean

State

Figure 1 Geographical distribution of 93

paracoccidioidomycosis cases in Mexico. The most northern case of paracoccidioidomycosis was found in a patient from the town of Aquismon in San Luis Potosi State.

Cases

11 1

2

State

7

Cases

3 State

Cases

1) Veracruz

51

5) San Luis Potosi

6

9) Colima

1

2) Guerrero

12

6) Guanajuato

3

10) State of Mexico

1

3) Chiapas

9

7) Oaxaca

2

11) Puebla

1

4) Michoacan

6

8) Queretaro

1

Table 2 Occupation held by 90 paracoccidioidomycosis patients in Mexico. Occupation

Number

%

Peasant Housewives Gardener Employee Policeman Building worker Total

79 5 3 1 1 1 90

87.78 5.56 3.33 1.11 1.11 1.11 100.00

The main group of patients affected were peasants.

region had 30 recorded cases (32.25%), most of which were from Guerrero (12 cases) and Chiapas (nine cases). (iii) In the Central Zone, only 12.91% of the cases were recorded. The most northerly case corresponded to a patient who was a resident of the village of Aquismon, in the state of San Luis Potosi (21°370 North Latitude, slightly south of the Tropic of Cancer). Occupation

The highest percentage of cases was observed in peasants (87.78%). The five housewife cases reported were peasant’s wives who also took an active part in agricultural activities (5.56%) (Table 2).

© 2014 Blackwell Verlag GmbH Mycoses, 2014, 57, 525–530

Gulf of Mexico

Clinical manifestations

In 56 cases the clinical manifestations were reported. All of the cases presented the chronic form of the disease, and the age of the patients ranged from 15 to 65 years. Only three cases did not exhibit extra-pulmonary disseminations; the remaining 53 cases were reported as disseminated PCM. In several cases, more than one organ was involved. The oral mucosa (66.07%) and skin (57.14%) were the most frequently affected organs (Table 3). In the pulmonary form documented by chest X-ray, the clinical manifestations included cough with white or haemoptoic sputum production, dyspnoea, fever, and, in some cases, chest pain. The respiratory signs were of variable intensity. The predominant mucocutaneous lesions consisted of ulcers with elevated and indurated margins, stomatitis, periodontitis, nodes and verrucous and vegetative lesions. Evolution time

The elapsed years from the onset of the disease to the diagnosis of PCM were recorded for 57 patients. The diagnosis was made in the early stages in only three cases (5.26%), and the diagnosis in these cases was based on the initial symptoms and signs of pulmonary disease or dissemination to the skin or mucosa. In 32

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R. L opez-Martınez et al.

Table 3 Organs affected in 56 cases of paracoccidioidomycosis. Organs Lung only Disseminations (n = 53) Oral mucosa Skin Nasal mucosa Eyelid mucosa Lymph nodes

Cases

%

3

5.35

37 32 18 2 2

66.07 57.14 32.14 3.57 3.57

Mouth, skin and nose were the most frequently infected tissues.

cases (56.14%), the diagnosis was made within 1 or 2 years of disease evolution. In 22 cases (38.6%), the diagnosis was made within 3–9 years. Laboratory diagnosis

In all 93 cases, the diagnosis was established by one or more of the following three mycological procedures: (i) direct microscopy examination, (ii) culture in Sabouraud dextrose agar (SDA) and SDA with antibiotics (chloramphenicol and cycloheximide) and (iii) histopathological examination with haematoxylin–eosin, periodic acid-Schiff, or Gomori–Grocott staining. The frequency of positive diagnosis by each study was as follows: histopathology in 86 cases (92.47%), direct microscopy examination in 81 cases (87.09%) and culture in 73 cases (78.5%). Treatment

The treatment and its result were recorded in only 46 of 93 cases (49.46%). The treatment period was variable and drug dependent: an improvement was observed after 4 months, and cure was observed after 6 months to 2 years. Cure was determined based on the absence of symptoms and a negative mycological study. The patients were treated with a variety of different drugs, either singly or in combination, which produced different results. The best treatment was the combination of itraconazole with sulfamethoxazole-trimethoprim (SMX-TMP), which cured 7/7 cases. Amphotericin B with SMX-TMP was effective in 4/5 cases. The most efficient drug administered as a monotherapy was itraconazole (14/15), followed by SMX-TMP (3/4). Of the 46 cases, only 25 (54.34%) were cured. The remaining 21 patients were not cured and subsequently lost.

Discussion Paracoccidioidomycosis is a primary pulmonary infection that is restricted to Latin America; it has severe

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respiratory repercussions, such as residual fibrosis, and a mortality rate in endemic zones of up to 59.9%.21,22 The frequency of disease in endemic countries is variable. In Brazil, 4,000 cases have been reported over a period of 5 years.23 In 1998, Severo et al. [24] reported 627 Brazilian cases over a period of 31 years, and in 2011, Loth et al. [25] detected 102 cases in an endemic region over a period of 1 year. This information demonstrates that Brazil tops the list of the countries that are most affected by PCM. The second most affected country is Venezuela, where 686 cases have been reported over a period of 21 years (1951–1972); in Colombia, 561 cases have been reported over a period of 4 years,21 and the annual incidence proportion is 0.1–0.4 cases per one million people.26 In Mexico, a relatively low number of cases of PCM have been recorded. From 1950, when Gonz alez-Ochoa and Esquivel-Medina [11] reported the first case, to 2012, there have been 123 known cases, of which 30 have been published.13–20 The remaining 93 are non-reported cases and are included in the present work. This number of cases may reflect only the patients who had symptoms that were sufficiently severe to prompt referral to a mycological diagnosis centre in Mexico, but the reality is unknown. However, it is also likely that only some states in Mexico present the ideal conditions for the development of the mycelial infective form of P. brasiliensis in nature, which constitutes the infection source. This hypothesis is based on observations such as that of Burstein (2002), who found that some cases of PCM in Peru originated only in rainforest zones.27 Silva-Vergara proposed a relationship between coffee cultivation and PCM.28 In this study, most of the cases were found in Veracruz, Guerrero, and Chiapas, which are states that have tropical rainforest zones and where coffee is cultivated; in addition to these three states, coffee is also cultivated in Oaxaca, Puebla and San Luis Potosi, which are states in which some cases were also reported. The absence of cases in the northern region may be associated with the more arid climate above the Tropic of Cancer. Although many studies have investigated the ecological niche of P. brasiliensis, the source of infection has not been satisfactorily determined.29 Another possible reason for the low number of cases presented in this study is that the epidemiological reporting of PCM cases is not mandatory in Mexico. The demographic variables presented in this report of Mexican cases of PCM are similar to data from other endemic countries in Latin America: men and peasants of productive ages constitute the most

© 2014 Blackwell Verlag GmbH Mycoses, 2014, 57, 525–530

Paracoccidioidomycosis in Mexico

commonly affected populations.2,27 This sex difference is primarily explained by the inhibitory influence of 17 b-estradiol on the conidia and the mycelium transformation to the invasive phase, which consist in multiple budding yeast.30,31 Paracoccidioidomycosis occurs frequently in rural areas, where the primary pulmonary form is rarely diagnosed because it is usually confused with other pathologies, such as tuberculosis.25 As in other reports, we found that the oral mucosa and the skin are the most frequently affected extra-pulmonary organs. However, in contrast to other studies in which the lymph nodes were affected in 13.3–35.2% of cases,27 we found adenopathy in only 2.12% of the cases. In the present work, histopathology was the most effective diagnostic method and yielded the highest number of positive results, whereas culture was the least efficient method. These results are similar to those of other reports in the literature.32 In Mexico, immunological and molecular studies are not usually performed to diagnose this infection. The drugs that have been most often used to treat PCM are itraconazole, amphotericin B and SMXTMP.33 In the last 10 years, other azoles have also been used (fluconazole and voriconazole),34,35 along with echinocandins (micafungin) 36 and allylamines (terbinafine);37 however, these compounds are not considered to be the first option in PCM therapy. In the patients analysed in this study, the best response to treatment was obtained using either itraconazole alone or the combination of SMX-TMP with itraconazole. In Mexico, as in other Latin American countries, PCM is most likely underdiagnosed, which results in severe consequences, such as high rates of morbidity and mortality. In this context, it is necessary to increase interest in this disease within the medical and paramedical communities in endemic zones, to create an adequate professional training programme to develop the skills necessary for mycological diagnosis and to search for infection sources. Accomplishing these goals will help prevent the establishment of P. brasiliensis and will favour the early diagnosis and prompt treatment of PCM in the at-risk population.

Conflict of interest The authors declare that they have no conflicts of interest.

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Acknowledgments The authors thank Dr. Oscar Velasco-Castrej on, Dr. Amado Sa ul and Dr. Jorge Cazarın-Barrientos for sending some of the patient data that were used in this study.

© 2014 Blackwell Verlag GmbH Mycoses, 2014, 57, 525–530

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