Respiratory complications of Plasmodium vivax malaria: systematic review and meta-analysis

Background: Malaria, a major global public health problem, is mainly caused by Plasmodium falciparum and P. vivax, and is responsible for nearly half a million deaths annually. Although malaria due to P. vivax was not believed to cause severe disease, recent robust studies have proved otherwise. However, the clinical spectrum and pathogenesis of severe vivax malaria and, especially, its respiratory complications remain poorly understood. Materials and Methods: We searched for articles reporting respiratory complications associated with vivax malaria in Lilacs, Cochrane, Scielo, Web of Science, and Medline/Pubmed with no date or language restrictions. Frequency of acuterespiratory distress syndrome (ARDS) and associated case fatality rate (CFR) were calculated from cross-sectional and longitudinal studies, whereas risk factors associated with death were calculated from data pooled from case reports. Results: A total of 101 studies were included (49 cross-sectional or longitudinal and 52 case reports). Frequency of ARDS was 2.8% and 2.2% in children and adults presenting to hospital, respectively, with nearly 50% CFR. A total of 67 cases were analyzed with the female gender (p=0.013), having any comorbidity (p=0.036), lower admission values of body temperature (p=0.032), hemoglobin (p=0.043), and oxygenation (p=0.053) being significantly associated with mortality. Furthermore, non-survivors were kept on oxygen support for less time (p=0.026), required invasive oxygen delivery strategies (p=0.076), and had shorter hospitalizations (p=0.007). Histopathology reports included bronchiolitis obliterans/organizing pneumonia, presence of monocytes, lymphocytes and neutrophils in pulmonary microvasculature along with phagocytosed pigment and diffuse alveolar damage accompanied by hyaline membrane formation, severe alveolar edema and congestion with infiltrates containing mononuclear cells and also images suggesting adhesion of infected red cells to lung microvasculature. Conclusions:P. vivax malaria respiratory complications included ARDS and were associated with high mortality. Demographics and clinical characteristics were associated with mortality among patients with respiratory complications in vivax malaria. Histopathology reports resembled those found in the literature in P. falciparum cases. New multicenter studies are needed using standardized protocols with exclusion of confounding factors in order to better characterize vivax clinical spectrum and, specifically, respiratory impairment.