Is severe visceral leishmaniasis a systemic inflammatory response syndrome? A case control study

Abstract

Introduction: The objective of the study is to identify the main risk factors for death by New World visceral leishmaniasis and establish a coherent pathogenic substrate of severe disease based on clinical findings. Methods: Seventy-six deceased inpatients and 320 successfully treated inpatients with VL were studied in a case control study. Results: Bacterial infection and bleeding were mutually exclusive events leading to death. Five risk factors were unique for death by bacterial infection (malnutrition, pulmonary rales, severe anemia, severe absolute neutropenia and higher neutrophil count), while another six were unique for death by bleeding (jaundice, severe relative neutropenia, severe thrombocytopenia, liver injury, kidney failure, higher bone marrow parasite load). Bacterial infection, bleeding, severe anemia, diarrhea, dyspnea, edema, jaundice and bone marrow parasite load were the main syndromes of visceral leishmaniasis among successfully treated patients. Conclusions: The data support the idea that bacterial infections are due to immune paralysis. Broad organ and system involvement is plausibly due to the high production of proinflammatory cytokines, whose actions fit well with visceral leishmaniasis. The syndromes and causative mediators are typical of a slowly developing systemic inflammatory response syndrome. Keywords: Visceral leishmaniasis. Kala-azar. Severe inflammatory response syndrome. AIDS. Bleeding. RESUMO Introdução: O objetivo do estudo foi identificar os principais fatores de risco para morte na leishmaniose visceral do Novo Mundo e estabelecer um substrato patogênico baseado nos achados clínicos coerente para doença grave. Métodos: Em um estudo caso-controle, foram estudados 76 pacientes internados que faleceram e 320 pacientes internados tratados com sucesso. Resultados: Infecção bacteriana e sangramento foram eventos que levaram à morte, mutuamente exclusivos. Cinco fatores de risco foram únicos para morte por infecção bacteriana (desnutrição, estertores pulmonares, anemia grave, neutropenia absoluta grave e número de leucócitos aumentados), enquanto outros seis foram exclusivos para morte por sangramento (icterícia, neutropenia relativa grave, trombocitopenia grave, lesão hepática, insuficiência renal, maior carga de parasitas na medula óssea). Entre os pacientes tratados com sucesso, as principais síndromes de leishmaniose visceral foram infecções bacterianas, sangramento, anemia grave, diarreia, dispneia, edema, icterícia e carga de parasitas na medula óssea. Conclusões: Os dados apoiam a ideia de que as infecções bacterianas são secundárias a imunoparalisia. O amplo envolvimento de órgãos e sistemas é de forma plausível devido a elevada produção de citocinas pró-inflamatórias, cujas ações se encaixam com a leishmaniose visceral. As síndromes e os mediadores causais são típicos da síndrome de resposta inflamatória sistêmica, desenrolando-se lentamente. Palavras-chaves: Leishmaniose visceral. Calazar. Síndrome da resposta inflamatória sistêmica. AIDS. Sangramento.

HIV/AIDS-related visceral leishmaniasis: a clinical and epidemiological description of visceral leishmaniasis in northern Brazil

“…Considering that other opportunistic diseases frequently develop during VL episodes in VL/HIV patients 33 , there was a highly accentuated death rate due to other causes in the VL/HIV group (12.9%) in comparison to the VL group (0.7%). It has been suggested that knowledge regarding the laboratory and clinical profi les of patients and their association with death from VL could assist in clinical management and reduce lethality [39][40][41] . Therefore, since 2011, the Brazilian Health Ministry (Ministério da Saúde do Brasil) has recommended the differential diagnosis of opportunistic infections and the use of serological tests for HIV in patients with VL in VL-endemic regions such as Tocantins.…”

Severe visceral leishmaniasis in children: the relationship between cytokine patterns and clinical features

“…The occurrence of death from VL is associated with several factors, including young age and the presence of comorbidities such as infections, malnutrition, and AIDS. The following features have been cited as markers of poor prognosis: fever lasting for more than 60 days, bacterial infection, jaundice, dyspnea, hemorrhage, severe anemia, severe neutropenia, and thrombocytopenia [3][4][5][6][7][8][9][10][11] . In addition, diffi culties in early diagnosis and appropriate treatment administration in many endemic areas are other determining factors of lethality; these issues are mainly caused by restricted access to health services 4 .…”

Genes that encodes NAGT, MIF1 and MIF2 are not virulence factors for kala-azar caused by Leishmania infantum

“…Factors such as other parasitic genes 10,20,37 and host determinants including host genetics 15 , immune status 8 , and nutrition 2 should be investigated 10 . Because of a likely polygenic infl uence on the phenotype of the disease, as suggested by the multiple molecular mechanisms associated with Leishmania survival in vertebrate hosts 38,39 , and the crucial involvement of the host response, additional kala-azar patients and other genes should be observed before a defi nitive conclusion is reached on the role of virulence factors in the pathogenesis of severe kala-azar.…”

“…With these classic manifestations, clinical presentations including bleeding and bacterial infections are present in the most severe forms of the disease and are associated with mortality 8 .…”

“…The existence of two distinct patient profi les (classic and severe) might be a consequence of several factors such as the infective strength level 11 , host immunosuppression 8,12,13 , and the genetic background of the host 14,15 , or it might be genetically determined by parasitic virulence factors 16 . The identifi cation of genetic changes in the pathogenic target genes is a starting point in the search for virulence factors 17 .…”