History and Perspective of Immunotherapy for Pythiosis

Abstract

The fungus-like microorganism Pythium insidiosum causes pythiosis, a life-threatening infectious disease increasingly reported worldwide. Antimicrobial drugs are ineffective. Radical surgery is an essential treatment. Pythiosis can resume post-surgically. Immunotherapy using P. insidiosum antigens (PIA) has emerged as an alternative treatment. This review aims at providing up-to-date information of the immunotherapeutic PIA, with the focus on its history, preparation, clinical application, outcome, mechanism, and recent advances, in order to promote the proper use and future development of this treatment modality. P. insidiosum crude extract is the primary source of immunotherapeutic antigens. Based on 967 documented human and animal (mainly horses) pythiosis cases, PIA immunotherapy reduced disease morbidity and mortality. Concerning clinical outcomes, 19.4% of PIA-immunized human patients succumbed to vascular pythiosis instead of 41.0% in unimmunized cases. PIA immunotherapy may not provide an advantage in a local P. insidiosum infection of the eye. Both PIA-immunized and unimmunized horses with pythiosis showed a similar survival rate of ~70%; however, demands for surgical intervention were much lesser in the immunized cases (22.8% vs. 75.2%). The proposed PIA action involves switching the non-protective T-helper-2 to protective T-helper-1 mediated immunity. By exploring the available P. insidiosum genome data, synthetic peptides, recombinant proteins, and nucleic acids are potential sources of the immunotherapeutic antigens worth investigating. The PIA therapeutic property needs improvement for a better prognosis of pythiosis patients.

Global Distribution and Clinical Features of Pythiosis in Humans and Animals

“…Surgery is the primary treatment for pythiosis. Additional therapies included antimicrobial drugs (mostly ineffective) [48] and immunotherapy (limited availability and efficacy) [52]. The mortality of pythiosis depended on animal species and clinical forms (i.e., vascular, ocular, cutaneous/subcutaneous, gastrointestinal, pulmonary, and disseminated infections; Table 4), which may involve microbial pathogenicity and host susceptibility or immune status.…”

“…Surgical intervention to remove an infected tissue is the primary treatment for pythiosis [50,51]. Immunotherapy using P. insidiosum antigens has been implemented to treat pythiosis, but its curative efficacy needs improvement [52].…”

Pythium insidiosum Keratitis: Past, Present, and Future

“…Since then, 168 ocular pythiosis cases have been reported in the literature until 2021 [ 5 ]. PI keratitis has been sparsely reported due to varied reasons such as lack of knowledge about the microscopic and colony morphology of the organisms among the microbiologists, falsely labeling it as an unidentified fungus, absence of growth in the culture, lack of high clinical suspicion among the clinicians, delayed diagnosis, and its clinical resemblance to fungus [ 6 ]. The common systemic and ocular risk factors identified for Pythium infection are thalassemias, sickle cell trait, swimming with contact lenses, exposure to farm animals, and swampy areas [ 7 ].…”

Secretome Profiling by Proteogenomic Analysis Shows Species-Specific, Temperature-Dependent, and Putative Virulence Proteins of Pythium insidiosum

“…Definitive diagnosis of pythiosis can be made by using various techniques (i.e., microbiological methods, serological tests, immunohistology, molecular detection, and proteomic analysis), many of which are not widely available [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. Conventional antimicrobial drugs usually fail in treating pythiosis [ 3 , 4 , 23 , 24 ]. An affected organ (i.e., leg, arm, and eye) is typically removed to prevent disease progression and recurrence.…”

“…An affected organ (i.e., leg, arm, and eye) is typically removed to prevent disease progression and recurrence. Many patients die from aggressive and uncontrollable pythiosis [ 4 , 24 ].…”