Paracoccidioidomycosis disease (Lutz-Splendore-Almeida): etiology, epidemiology, and pathogenesis

Paracoccidioidomycosis (PCM) is a polymorphic systemic granulomatous mycosis determined by Paracoccidioides brasiliensis and P. lutzii and constitutes one of the 10 leading causes of morbidity and mortality by the parasitic diseases endemic in Brazil. The need for updates on the etiology, epidemiology, and pathogenesis is a for routinely including this disease in the differential diagnosis of current medical practice, recognizing it early and treating it properly, so as to avoid progression with sequelae and death.


INTRODUCTION
.2 It was named in various ways such as: South American blastomycosis, Lutz-Splendore-Almeida disease, paracoccidioides granulomatosis, paracoccidioides granuloma, tropical blastomycosis granuloma, and malignant ganglionic granuloma of blastomycosis origin. 3he disease can affect people of all ages, with acute-subacute or chronic evolution observed mainly in children-teenagers or adults 30 years and older, respectively; and clinical manifestations from benign to serious with risk of death.[6][7][8][9][10][11][12][13][14] Paracoccidioidomycosis disease (Lutz-Splendore-Almeida): etiology, epidemiology, and pathogenesis EPIDEMIOLOGY Endemic areas are located in regions of tropical or subtropical forests, with average temperatures between 14 and 20 °C, precipitation between 800 and 2,000 mm, and high relative air humidity.5][16] Their regional distribution is heterogeneous, with higher prevalence in the States of Rio Grande do Sul, Paraná, São Paulo, Rio de Janeiro, Espírito Santo, Minas Gerais, Goiás, Mato Grosso do Sul, Mato Grosso, and Amazon.[9][10]17 The actual prevalence of the PCM-disease is not established because its notification is not mandatory in most Brazilian States. 15,16,18 T.17 PCM composes the group of neglected infectious diseases because it does not receive the attention from institutions involved in public health policies and the pharmaceutical industry does not invest in the development of new antifungals..18 -23 ETIOLOGY PCM is caused by the fungi Paracoccidioides brasiliensis and P. lutzii (Onygenales, Onygenaceae, Paracoccidioides) dimorphic, which at room temperature (4 to 28 o C), presents the mycelial form and at 37 ºC develops as a yeast.The mycelial forms (multicellular) found in the environment, and mycelium in the yeast (unicellular) differentiate by giving the fungus increased resistance and pathogenicity in infected organisms, respectively.They present spherical shape in human tissues, double-walled refringent, measuring 2 to 30 micrometers or more in diameter.Its multiple sporulation results in the typical aspect of "wheel" or "boat wheel" considered as pathognomonic (Figure 1). 1, 3, 4 -14 The exocelular components of P. brasiliensis with more reactivity in immuno-diffusion tests are glycoproteins with molecular weights of 43 (gp43), 55, and 72 kDa.Gp43 is the component with the best reaction with specific rabbit antiserum.
The host immune response determines the evolution of the primary complex, from asymptomatic to intense symptoms and severe, affecting gateway organs or becoming systematized, depending on the extent and intensity of the inflammatory reaction, load of infective particles inhaled, and virulence of the P. brasiliensis strain.In most cases, spontaneous involution will occur, although fungemia can occur at any time with the development of metastatic focus in any organ.The scars resulting from the initial lesions may be sterile, with fungal destruction if the inflammatory response is effective.[11]13,[19][20][21][22][23] The fungal spread by lymphatic and hematogenous pathways (air and digestive ways) to various organs and systems occurs exceptionally after the initial contact with P. brasiliensis probably due to ineffective defense responses.The development of this type of evolution characterizes the acute or sub-acute form of PCM observed mainly in children and adults up to 30-year-olds and from both genders. 12,13,19,24 Thmajority of cases evolves, usually to prolonged latency, after involution of lesions of the primary complex, and can last for many years; the disease only appear in its chronic form, through reactivation of quiescent outbreaks (endogenous reactivation), when the fungi remained viable, spreading to other organs.The factors involved in reactivation of the residual or quiescent focus are not yet established.They may result from an imbalance of defense mechanisms responsible for the maintenance of fungal quiescence (endogenous reinfection)..13, 25-32 Every organ can be affected with often involvement of mucous-cutaneous (especially mouth and upper airways), pulmonary lymphatic, nervous, adrenal, spleen, liver, bones, and joints.
Studies based on intradermal reaction with paracoccidioidin reveal prevalences in endemic areas between 11.0 and 43.8% with contact with the fungus, being similar between genders.Among adults, there is involvement in the ratio of 5.4 to 10 men for each woman; however, a significant difference between genders does not occur in the childhood.Involvement in women over 50 years old is described as similar to that in childhood.
The severity of PCM has been linked to genetic factors in the host.It is more frequent in patients with HLA-B and in Asian descendants.The use of immuno-suppressants such as glucocorticoids, and immunosuppression such as in the acquired immunodeficiency syndrome (AIDS) relate to a higher frequency of PCM.][21][22] PCM is associated to professions and activities that involve soil management such as agriculture (rice, coffee, maize, and sugarcane crops), transport of plant products, earth-moving, and gardening.It mainly affects rural (44.3 to 76.2%) and construction workers (5 to 20%), who are in general, from rural areas.][23][24] The mortality rate stands at about 1.45 per 1,000,000 inhabitants, becoming the eighth cause of mortality among chronic infectious parasitic-chronic diseases.7][18][19][20][21] Social and economic costs are high when affecting individuals at productive stages, determining secondary permanent sequelae, and often preventing the patient to return to their original work. 12,25 -27

PATHOGENESIS
The paracoccidioidomycosis infection is acquired by inhalation or inoculation of spores in solution of continuity in the skin or mucous membranes, especially in the oral or anal region.[9][10][11]13 The spores or infective particles easily reach the bronchiole alveolar units, where they transform into yeasts and multiply by multiple budding.Next, the fungus can cause alveolitis with migration of neutrophils, which are later replaced by lymphocytes and macrophages (parenchymal pole).][35][36][37][38] Neutrophils and macrophages, once reaching the infectious focus, cannot digest the fungus and prevent its multiplication, however, they are able to promote fungal debugging if they are activated by interferongamma (IFN-γ) and alpha tumor necrosis factor (TNF-α).TNF-α is able to activate T lymphocytes (L); and IFN-γ, through NK cells and LTCD4 + , activates macrophages, which results in the inhibition of P. brasiliensis replication.The antibodies do not appear to protect against infection by P. brasiliensis.Worsened PCM is observed associated with impaired cellular immunity and presence of elevated serum A, E, and G immunoglobulin titers, possibly associated with a predominance of LTh2 stimulation.LTh1, which produces IL-2, TNF-α, and INF-γ promotes macrophages activation.LTh2 releases IL-4, IL-5, IL-6, and IL-10, which inhibits cellular immunity.These interleukins can inhibit LTh1 activity through the suppressor cytokines IL-4 and IL-10, and promote the synthesis of antibodies.[35][36][37][38]

PATHOLOGY
The initial contact of the host with the fungus is reflected by nonspecific inflammation around one or more fungi, characterized by vascular congestion, edema, and the predominance of polymorphonuclear cells (neutrophils and eosinophils).Subsequently, mononuclear cells, macrophages, auxiliary LTs, and histiocytes replace many of the polymorphonuclear cells.[9][10]13 Granulomas can present different forms, from compact and with few fungi (hyperergic pole) to loose and suppurative with extensive necrosis and many fungi The evolution of PCM may be to healing, sequel, or death.4][25][26] The initial establishment period of P. brasiliensis is asymptomatic, although the development of humoral and cellular immune response is observed.
Humans are a host that is resistant to P. brasiliensis because the number of people exposed (PCMinfection) to the fungus is much higher than that of patients with PCM (PCM-disease).Some factors such as age, gender, or genetics can relate to the process of reactivation of the initial infection.The higher prevalence among men seems associated with the female protection afforded by estrogen, which inhibits the transformation of mycelium into yeast.This conception is reaffirmed by the similar prevalence between genders in the first and after the sixth decades of life.The inhibitory action of estrogen on the transformation of mycelium into yeasts can be associated with the apparent female resistance to PCM. [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] P. brasiliensis, despite being pathogenic, sometimes acquires an opportunistic character associated with the severe forms and disseminates with immunodeficiency factors such as leukemia, lymphoma, drugrelated immunosuppression, post-transplant occurrences, and acquired immunodeficiency syndrome.8][9][10]

IMMUNOPATHOGENESIS
The factors involved in the rupture of the hostparasite balance, favorable to the parasite, are not yet identified.The evolution of paracoccidioidomycosis infection into the disease in individuals living in endemic areas seems to depend on factors in the parasite and the host's immune response against P. brasiliensis.[10][34][35][36][37][38][39][40][41][42][43] The immune response in the P. brasiliensis host seems to be at the origin of these differences, being mainly cellular and under the influence of the cytokines involved (humoral response).The fungus anti-(anergic pole), which are, respectively, associated to effective immune defense or compromised.

Figure 2 -
Figure 2 -Geographic distribution of paracoccidioidomycosis.Source: Brazilian Ministry of Health.