Advertisement
  • Loading metrics

The case for paracoccidioidomycosis to be accepted as a neglected tropical (fungal) disease

The case for paracoccidioidomycosis to be accepted as a neglected tropical (fungal) disease

  • Joshua Griffiths, 
  • Arnaldo Lopes Colombo, 
  • David W. Denning
PLOS
x

Introduction

The World Health Organization’s (WHO) neglected tropical disease (NTD) portfolio is a diverse group of diseases with profound impacts on affected populations. The diseases are recognised as being both a symptom of poverty and a powerful contributor to the ‘poverty trap’—a complex and self-perpetuating phenomenon of the interrelated burdens of disease, conflict, poverty, and low educational attainment [13]. In 2017, chromoblastomycosis was accepted as an NTD, following the example of mycetoma, by the Strategic and Technical Advisory Group for NTDs (STAG-NTD) and WHO Executive Board with ‘other deep mycoses’ [4].

Paracoccidioidomycosis (PCM) is a deep mycosis endemic to Latin America. Autochthonous cases are exclusive to the tropical and subtropical zone from Mexico (23° north) to Argentina (35° south) (Fig 1), and it is more common in areas with a high rainfall and subject to flooding [5]. It is caused by members of the Paracoccidioides genus, a dimorphic fungi found in soil that includes two different species: Paracoccidioides brasiliensis and P. lutzii. It predominantly affects males [6] from rural communities, or those who have had prolonged contact with a rural environment, aged between 30 and 60 years old [79].

thumbnail
Fig 1. Distribution of paracoccidioidomycosis in South America.

Image credit: with permission from Leading International Fungal Education (www.LIFE-worldwide.org).

https://doi.org/10.1371/journal.pntd.0007195.g001

The impact of this fungus in South America is widespread and devastating. Although already recognised by PLOS Neglected Tropical Diseases as a major NTD, we argue here that WHO and the Pan-American Health Organization (PAHO) should explicitly recognise PCM as an NTD.

Public health impact and association with poverty

Previous reviews of the epidemiology of PCM have attempted to estimate the incidence of the disease using case series [5,10]. Large series published from geographic areas with stable endemicity suggest incidence rates of 1–4 cases/100,000 inhabitants per year in Brazil and Colombia [8,11,12]. In hyperendemic areas from Brazil, annual incidence rates may be as high as 9–40 cases/100,000 inhabitants [10,13]. PCM caused 1,853 deaths in Brazil from 1996 to 2006 [14]. In two recent large epidemiological studies, the mortality of PCM was between 6.1% [13] and 7.6% [15].

Several of the predisposing factors for PCM may be related to poverty. First, as the conidia-producing form of Paracoccidioides spp. resides in soil and host-to-host transmission does not occur, PCM predominately affects those who have had prolonged contact with soil in endemic regions. This explains why the vast majority of cases are seen in patients who have lived or worked rurally—93.5% in a 1,000-case series published in 2011 [8]. It has been described as an occupational disease of farmers [10]. In addition to smoking, high alcohol intake predisposes to the progression of latent foci to active disease [16]. Malnutrition is also thought to be a contributor to the development of the disease [10].

Sequelae in different organs are frequently found as a result of late diagnosis of the fungal infection [15,17]. The sequelae of this disease during a sufferer’s economically most productive period can be significant. Combined with the potentially high cost of prolonged treatment, these factors contribute to this disease’s poverty-inducing potential. The sequelae of this disease are often the result of chronic inflammatory processes, leading to the accumulation of collagen in fibrosis—which may profoundly impact organ function and cannot be treated by antifungal medication [18]. Pulmonary involvement is common and may be confused with tuberculosis, leading to delayed diagnosis (Fig 2). PCM-associated pulmonary fibrosis is irreversible, and its restriction of patients’ activities of daily living can be profound [19]. Lung fibrosis occurs in up to 53% of treated patients with pulmonary PCM [20]. By using high-resolution computed tomography to evaluate 50 consecutive patients with PCM after successful treatment with antifungal drugs, residual radiological abnormalities were found in almost all patients, including architectural distortion (90%), reticulate and septal thickening (88%), centrilobular and paraseptal emphysema (84%), and parenchymal bands (74%) [20]. Adrenal involvement is also very common in PCM. At autopsy, P. brasiliensis has been demonstrated by direct visualisation of adrenal tissue in up to 90% of patients. In total, 14%–48% of patients with PCM have asymptomatic adrenal dysfunction, demonstrated by limited cortisol response to adrenocorticotropic hormone (ACTH) stimulation, and 3%–7% of patients develop Addison disease [21,22]. Neuroparacoccidioidomycosis (Fig 3) can be particularly disabling, and the risk of sequelae in this form of the disease is high. It may produce motor deficits, epilepsy, or significantly raised intracranial pressure requiring ventral shunting [23]. Dysphonia with vocal cord lesions [24], laryngeal obstruction necessitating tracheostomy, synechia of the buttocks following perianal lesions, and the particularly disfiguring microstomia following facial lesions are among the other sequelae described [25].

thumbnail
Fig 2. CT scan of pulmonary paracoccidioidomycosis with bilateral small nodules, ground glass changes, and a small cavity in the right upper lobe.

CT, computed tomography.

https://doi.org/10.1371/journal.pntd.0007195.g002

thumbnail
Fig 3. Centrally located neuroparacoccidioidomycosis in the posterior fossa measuring 2.4 × 1.8 cm.

https://doi.org/10.1371/journal.pntd.0007195.g003

Unlike other systemic mycoses such as histoplasmosis and cryptococcosis, an increased incidence of PCM in HIV-infected individuals has not been demonstrated, despite the epidemiological overlap of the two diseases [26]. The clinical course of the disease in patients coinfected with PCM and HIV tends to be more severe. Additionally, patients usually present with pulmonary lesions (a feature of the chronic form, which otherwise is almost the exclusive form affecting those over 30 years old) as well as generalised lymphadenopathy, splenomegaly, bone lesions, and skin lesions as a result of haematogenous dissemination (a feature of the acute/subacute form of the disease, which tends to affect children) [26]. In a 2009 retrospective case control study, the mortality in HIV-positive PCM patients was 12.2% (directly attributable to PCM, 24.4% all-cause mortality) compared with 6% in HIV-negative PCM patients [27]. The relapse rate is also usually higher in HIV-infected patients than that reported in normal hosts, and much longer treatment regimens are usually required.

Control and Prevention: Ongoing research and development needs

Diagnosis.

The ‘gold standard’ for the diagnosis of PCM is direct visualisation of the fungal yeast cells surrounded by multiple budding daughter cells (the ‘pilot’s wheel’) or isolation of the fungal agent in culture of clinical samples or tissue (Fig 4) [28]. The difficulties of demonstrating the fungus in clinical samples and the length of time that confirmation by culture requires means that serological tests have vital application in both the diagnosis of PCM and in monitoring treatment response (Table 1) [29]. Double immunodiffusion (DID) is the serological test of choice for the diagnosis of PCM. There are some key current problems in the serological diagnosis of PCM. The first is that the new insights into the complexity of the Paracoccidioides genus are shedding light on the wide variation in antigen production. For example, the antigenic 43-kDa glycoprotein gp-43 is the main antigen used in this test in the serological diagnosis of PCM, but some isolates in the Paracoccidioides spp. complex produce either very low levels of or no gp-43 antigens—particularly P. lutzii [29]. gp-43 is therefore not recommended as a single-antigen preparation for diagnosis. Furthermore, preparation of the antigens for serological diagnosis is not standardised with variations in production, resulting in substantial variation in immunogenicity. Mixtures of unidentified antigens are often used, which may impair the tests’ sensitivity and specificity because of cross-reactivity with the sera from patients with other mycoses [29].

thumbnail
Fig 4. Lung biopsy stained by methenamine silver (Gomori–Grocott) illustrating large yeast cells surrounded by multiple budding.

Photomicrograph provided by Prof Rimarcs Gomes Ferreira, Department of Pathology-Escola Paulista de Medicina-UNIFESP. UNIFESP, Universidade Federal de São Paulo.

https://doi.org/10.1371/journal.pntd.0007195.g004

thumbnail
Table 1. Diagnostic methods for PCM and evaluation of value and drawbacks.

https://doi.org/10.1371/journal.pntd.0007195.t001

These two factors combined help explain the large interlaboratory variations in diagnosis recently demonstrated. In 2014, Vidal and colleagues compared serological diagnosis between six major Brazilian reference centres. It was found that there was a high rate of major discordance (20%), which can affect clinical decision-making. Those centres using antigens from pooled isolates performed better [30].

New PCM serum markers and a standardization of the diagnostic approach are required in order to effectively diagnose PCM and thereby manage it at a public health level. Past attempts at standardisation have foundered, as reference centres have used ‘in-house’ methodologies for many years, often with little feedback from clinicians, and there is little impetus for change [30]. Using standardised, purified, cloned antigens may be a way forward, rather than standardising ‘in-house’ antigen production. Using purified antigens reduces the risk of cross-reactivity, thereby increasing specificity, and their use, particularly in combination, can lead to high levels of sensitivity and specificity [29]. Otherwise, ‘point-of-care’ tests would certainly be more suitable for providing early diagnosis in endemic regions.

Education at all levels of the healthcare system is also required, and a free online course on microscopy and histology has recently been launched by Leading Fungal Education International in four languages (www.microfungi.net).

Treatment

There is a lack of a high-quality body of evidence guiding the treatment of PCM. It is responsive to many antifungal medications. In mild to moderate disease, a 200-mg dose of itraconazole was recommended as the first-line choice in the 2017 Brazilian consensus guidelines [31]. In severe PCM, the use of intravenous amphotericin B preparations, either as deoxycholate or in a lipid formulation, or alternatively intravenous cotrimoxazole was recommended, although there are very few data published [31]. Only two randomised trials of treatment regimens for PCM have been conducted, one comparing itraconazole and voriconazole [31] and the other comparing itraconazole, ketoconazole, and sulfadiazine [32]. Neither had the statistical power to demonstrate superiority of one treatment over the other. The most recent guidelines are based on numerous noncomparative studies and expert opinions and two studies comparing itraconazole and cotrimoxazole.

The first dual-cohort, nonrandomised study compared itraconazole (200 mg once daily) and cotrimoxazole (1,440 mg every 12 hours) in 177 patients in the induction and maintenance phases of treatment. Although no difference was found in efficacy and effectiveness of reaching either clinical cure in the induction phase or serological cure in the maintenance phase, itraconozole induced cure more quickly in both phases (105 days versus 159 days to clinical cure [p = 0.001], 161 days versus 495 days [p = 0.02]). It was also associated with fewer side effects (6.4% versus 20% [p = 0.03]) [33]. Another comparative cohort study of 200 patients was performed comparing once-daily itraconazole and twice-daily cotrimoxazole [34]. Itraconazole was significantly superior, and the time to cure was 11 months shorter with itraconazole (12 months versus 23 months). Adherence to treatment could be one factor responsible for better outcomes [34].

Generic itraconazole is only 1.6 times more expensive than cotrimoxazole in Brazil when this shortened treatment regime is taken into account. Given a better side effect profile and probable superiority, it is recommended as a first-line therapy [33]. However, sulfamethoxazole-trimethoprim is currently distributed free of charge by the Brazilian Ministry of Health [35] and, as such, is much more commonly used. This anomaly should be modernised.

There are other research areas requiring considerable development and funding that have the potential to benefit from a WHO NTD disease status. Prolonged treatment is currently required for the recovery of cell-mediated immunity. There has been some promising work on the development of a therapeutic vaccine that would induce immunity in experimental models and in vitro, which might eventually allow significantly shorter treatment regimes [36]. There is also some evidence in the literature that PCM patients with severe inflammation may benefit from adjunctive therapy with corticosteroids [37].

Epidemiology and prevention

The 2017 Brazilian guidelines for the management of PCM called for the development of a national registry of cases and the institution of compulsory notification [31]. Such a registry would be beneficial in many ways, giving a more accurate understanding of the size and spread of the problem and allowing more effective strategic healthcare provision planning and commensurate allocation of resources.

Prevention of PCM is a challenge given the very high rates of infection and the apparent ease of exposure to the fungus in rural areas. Current recommendations advise avoiding exposure to soil dust in endemic areas if possible (particularly in children and the immunocompromised) and the use of N95 respirators or well-sealed cabins in agricultural machinery for rural workers otherwise unable to avoid exposure in hyperendemic areas. Health education programmes, particularly in hyperendemic areas, could tackle both exposure to the fungus and the usual delayed presentation of the chronic disease to medical attention. These programmes could also be extended to urban centres receiving high volumes of migrants from these areas. No efforts to treat latent PCM, as for tuberculosis, are published. Much more work is needed to develop such effective public health interventions and assess their value.

Conclusion

PCM fulfils WHO NTD criteria and would benefit from such a classification. PCM is endemic to the tropical regions of Latin America. PCM is an important cause of mortality in Brazil [14,38]. PCM causes significant morbidity and predominately affects poor rural workers or people living in urban slums at their most economically productive stage of life and requires very long treatment regimes. Lung sequelae are frequent, reducing work productivity and quality of life of a large number of patients, and other complications can also be very disabling.

PCM is neglected by research, and the care of patients with the disease is underdeveloped when it comes to new diagnostics, medicine, and other control tools. There are currently significant problems in the diagnosis of PCM, with a great need to standardise diagnostics and find new serum markers, as well as to develop useful point-of-care tests. In addition, more research is required to optimise treatment—particularly through randomised control trials—and to address latency. Though itraconazole is the first-line recommended drug, it is currently not provided free of charge in most medical centres in Brazil and Latin America. The creation of a national registry of the cases of the disease across all states in Brazil and in other countries in which the fungus presents a public health problem would greatly aid the public health effort.

References

  1. 1. Hotez PJ, Fenwick A, Savioli L, Molyneux DH. Rescuing the bottom billion through control of neglected tropical diseases. Lancet. 2009;373(9674):1570–5. pmid:19410718
  2. 2. World Health Organization. Working to overcome the global impact of neglected tropical diseases. First WHO report on neglected tropical diseases. Geneva: World Health Organization; 2010.
  3. 3. World Health Organization. Recommendations for the Adoption of Additional Disease as Neglected Tropical Diseases. Geneva: World Health Organization; 2016.
  4. 4. World Health Organization. Report of the Tenth Meeting of the WHO Strategic and Technical Advisory Group for Neglected Tropical Diseases. Geneva: World Health Organization; 2017.
  5. 5. Martinez R. Epidemiology of Paracoccidioidomycosis. Rev Inst Med Trop Sao Paulo. 2015;57:11–20. pmid:26465364
  6. 6. Shankar J, Restrepo A, Clemons K V. Hormones and the resistance of women to paracoccidioidomycosis. Clin Microbiol Rev. 2011;24(2):296–313. pmid:21482727
  7. 7. de Oliveira HC, Assato PA, Marcos CM, Scorzoni L, de Paula E Silva ACA, Da Silva JDF, et al. Paracoccidioides-host Interaction: An Overview on Recent Advances in the Paracoccidioidomycosis. Front Microbiol. 2015;6:1319. pmid:26635779
  8. 8. Bellissimo-Rodrigues F, Machado AA, Martinez R. Paracoccidioidomycosis epidemiological features of a 1,000-cases series from a hyperendemic area on the southeast of Brazil. Am J Trop Med Hyg. 2011;85(3):546–50. pmid:21896820
  9. 9. Delboni Nunes NE, Schmidt EB, Massaroni Peçanha MA, Zanotti RL, Gonçalves Ferreira CU, Lamas de Araújo M, et al. Paracoccidioidomycosis: Epidemiological and Clinical Aspects in 546 Cases Studied in the State of Espírito Santo, Brazil. Am J Trop Med Hyg. 2017 Sep 7;97(3):836–44. pmid:28749757
  10. 10. Martinez R. New Trends in Paracoccidioidomycosis Epidemiology. J Fungi. 2017;1(3).
  11. 11. Calle D, Rosero DS, Orozco LC, Camargo D, Castaneda E, Restrepo A. Paracoccidioidomycosis in Colombia: an ecological study. Epidemiol Infect. 2001;126(2):309–15. pmid:11349982
  12. 12. Greer DL, Restrepo M. La epidemiologia de la paracoccidioidomicosis. Boletín la Of Sanit Panam. 1977;(82):428–445.
  13. 13. Vieira Gde D, Alves Tda C, Lima SM, Camargo LM, Sousa CM. Paracoccidioidomycosis in a western Brazilian Amazon State: Clinical-epidemiologic profile and spatial distribution of the disease. Rev Soc Bras Med Trop. 2014;47(1):63–8. pmid:24603739
  14. 14. Prado M, Silva MB, Laurenti R, Travassos LR, Taborda CP. Mortality due to systemic mycoses as a primary cause of death or in association with AIDS in Brazil: a review from 1996 to 2006. Mem Inst Oswaldo Cruz. 2009;104(3):513–21. pmid:19547881
  15. 15. Paniago AM, Aguiar JI, Aguiar ES, da Cunha RV, Pereira GR, Londero AT, et al. Paracoccidioidomycosis: A clinical and epidemiological study of 422 cases observed in Mato Grosso do Sul. Rev Soc Bras Med Trop. 2003;36(4):455–9. pmid:12937721
  16. 16. dos Santos WA, da Silva BM, Passos ED, Zandonade E, Falqueto A. Association between smoking and paracoccidioidomycosis: a case-control study in the State of Espirito Santo, Brazil. Cad saude publica / Minist da Saude, Fund Oswaldo Cruz, Esc Nac Saude Publica. 2003;19(1):245–53.
  17. 17. Colombo AL, Tobon A, Restrepo A, Queiroz-Telles F, Nucci M. Epidemiology of endemic systemic fungal infections in Latin America. Med Mycol. 2011;49(8):785–98. pmid:21539506
  18. 18. Brummer E, Castaneda E, Restrepo A. Paracoccidioidomycosis: an update. Clin Microbiol Rev. 1993 Apr;6(2):89–117. pmid:8472249
  19. 19. Alvarez M, Pina DR, de Oliveira M, Ribeiro SM, Mendes RP, Duarte SB. Objective CT-based quantification of lung sequelae in treated patients with paracoccidioidomycosis. Med (United States). 2014;93(25):e167.
  20. 20. Costa AN, Benard G, Albuquerque ALP, Fujita CL, Magri ASK, Salge JM, et al. The lung in paracoccidioidomycosis: new insights into old problems. Clinics (Sao Paulo). 2013;68(4):441–8.
  21. 21. Tobón AM, Agudelo CA, Restrepo CA, Villa CA, Quiceno W, Estrada S, et al. Adrenal Function Status in Patients with Paracoccidioidomycosis after Prolonged Post-Therapy Follow-Up. Am J Trop Med Hyg. 2010 Jul 20;83(1):111–4. pmid:20595488
  22. 22. Colombo AL, Faical S, Kater CE. Systematic evaluation of the adrenocortical function in patients with paracoccidioidomycosis. Mycopathologia. 1994;127(2):89–93. pmid:7984218
  23. 23. Francesconi F, da Silva MTT, Costa RLB, Francesconi VA, Carregal E, Talhari S, et al. Long-term outcome of neuroparacoccidioidomycosis treatment. Rev Soc Bras Med Trop. 2011;44(1):22–5. pmid:21340402
  24. 24. da Costa AD, Vargas AP, Lucena MM, Ruas ACN, Braga F da SS, Bom-Braga MP, et al. Voice disorders in residual paracoccidioidomycosis in upper airways and digestive tract. Rev Iberoam Micol. 2017;34(3):180–4. pmid:28583268
  25. 25. Shikanai-Yasuda MA, Telles Filho F de Q, Mendes RP, Colombo AL, Moretti ML. [Guidelines in paracoccidioidomycosis]. Rev Soc Bras Med Trop. 2006;39(3):297–310. Portuguese. pmid:16906260
  26. 26. Almeida FA de, Neves FF, Mora DJ, Reis TA Dos, Sotini DM, Ribeiro BDM, et al. Paracoccidioidomycosis in Brazilian Patients With and Without Human Immunodeficiency Virus Infection. Am J Trop Med Hyg. 2017;96(2):368–72. pmid:27895278
  27. 27. Morejon KML, Machado AA, Martinez R. Paracoccidioidomycosis in patients infected with and not infected with human immunodeficiency virus: a case-control study. Am J Trop Med Hyg. 2009;80(3):359–66. pmid:19270282
  28. 28. Marques SA. Paracoccidioidomycosis. Clin Dermatol. 2012;30(6):610–5. pmid:23068148
  29. 29. da Silva J de F, de Oliveira HC, Marcos CM, Assato PA, Fusco-Almeida AM, Mendes-Giannini MJS, et al. Advances and challenges in paracoccidioidomycosis serology caused by Paracoccidioides species complex: An update. Diagn Microbiol Infect Dis. 2016;84(1):87–94. pmid:26494541
  30. 30. Vidal MSM, Del Negro GMB, Vicentini AP, Svidzinski TIE, Mendes-Giannini MJ, Almeida AMF, et al. Serological diagnosis of paracoccidioidomycosis: high rate of inter-laboratorial variability among medical mycology reference centers. PLoS Negl Trop Dis. 2014;8(9):e3174. pmid:25211336
  31. 31. Shikanai-Yasuda MA, Mendes RP, Colombo AL, de Queiroz-Telles F, Kono ASG, Paniago AMM, et al. Brazilian guidelines for the clinical management of paracoccidioidomycosis. Rev Soc Bras Med Trop. 2017 Jul 12;50(5):715–40. pmid:28746570
  32. 32. Shikanai-Yasuda MA, Benard G, Higaki Y, Del Negro GMB, Hoo S, Vaccari EH, et al. Randomized trial with itraconazole, ketoconazole and sulfadiazine in paracoccidioidomycosis. Med Mycol. 2002;40(4):411–7. pmid:12230222
  33. 33. Cavalcante R de S, Sylvestre TF, Levorato AD, de Carvalho LR, Mendes RP. Comparison between itraconazole and cotrimoxazole in the treatment of paracoccidiodomycosis. PLoS Negl Trop Dis. 2014;8(4):e2793. pmid:24743230
  34. 34. Borges SRC, Silva GMS da, Chambela M da C, Oliveira R de VC de, Costa RLB, Wanke B, et al. Itraconazole vs. trimethoprim-sulfamethoxazole: A comparative cohort study of 200 patients with paracoccidioidomycosis. Med Mycol. 2014;52(3):303–10. pmid:24577007
  35. 35. Shikanai-Yasuda MA. Paracoccidioidomycosis treatment. Rev Inst Med Trop Sao Paulo. 2015;57:31–7. pmid:26465367
  36. 36. Taborda CP, Uran ME, Nosanchuk JD, Travassos LR. Paracoccidioidomycosis: Challenges in the development of a vaccine against an endemic mycosis in the Americas. Rev Inst Med Trop Sao Paulo. 2015;57 Suppl 19:21–4.
  37. 37. Benard G, Campos AF, Netto LC, Goncalves LG, Machado LR, Mimicos EV, et al. Treatment of severe forms of paracoccidioidomycosis: Is there a role for corticosteroids? Med Mycol. 2012;50(6):641–8. pmid:22309459
  38. 38. Coutinho ZF, Silva D da, Lazera M, Petri V, Oliveira RM de, Sabroza PC, et al. Paracoccidioidomycosis mortality in Brazil (1980–1995). Cad Saude Publica. 2002;18(5):1441–54. pmid:12244377