Table_1_Elimination of Falciparum Malaria and Emergence of Severe Dengue: An Independent or Interdependent Phenomenon?.docx

The global malaria burden, including falciparum malaria, has been reduced by 50% since 2000, though less so in Sub-Saharan Africa. Regional malaria elimination campaigns beginning in the 1940s, up-scaled in the 1950s, succeeded in the 1970s in eliminating malaria from Europe, North America, the Caribbean (except Haiti), and parts of Asia and South- and Central America. Dengue has grown dramatically throughout the pantropical regions since the 1950s, first in Southeast Asia in the form of large-scale epidemics including severe dengue, though mostly sparing Sub-Saharan Africa. Globally, the WHO estimates 50 million dengue infections every year, while others estimate almost 400 million infections, including 100 million clinical cases. Curiously, despite wide geographic overlap between malaria and dengue-endemic areas, published reports of co-infections have been scarce until recently. Superimposed acute dengue infection might be expected to result in more severe combined disease because both pathogens can induce shock and hemorrhage. However, a recent review found no reports on more severe morbidity or higher mortality associated with co-infections. Cases of severe dual infections have almost exclusively been reported from South America, and predominantly in persons infected by Plasmodium vivax. We hypothesize that malaria infection may partially protect against dengue – in particular falciparum malaria against severe dengue – and that this inter-species cross-protection may explain the near absence of severe dengue from the Sub-Saharan region and parts of South Asia until recently. We speculate that malaria infection elicits cross-reactive antibodies or other immune responses that infer cross-protection, or at least partial cross-protection, against symptomatic and severe dengue. Plasmodia have been shown to give rise to polyclonal B-cell activation and to heterophilic antibodies, while some anti-dengue IgM tests have high degree of cross-reactivity with sera from malaria patients. In the following, the historical evolution of falciparum malaria and dengue is briefly reviewed, and we explore early evidence of subclinical dengue in high-transmission malaria areas as well as conflicting reports on severity of co-morbidity. We also discuss examples of other interspecies interactions.

自2000年以来，包括恶性疟（falciparum malaria）在内的全球疟疾负担已降低50%，但撒哈拉以南非洲的降幅相对较小。始于20世纪40年代、并于20世纪50年代得到升级推广的区域疟疾消除运动，于20世纪70年代成功在欧洲、北美、加勒比地区（海地除外）以及亚洲部分区域与南美、中美洲消除了疟疾。自20世纪50年代以来，登革热在整个泛热带地区呈暴发式增长，最初在东南亚出现大规模疫情，包括重症登革热病例，但基本未波及撒哈拉以南非洲。全球范围内，世界卫生组织（WHO）估计每年有5000万登革热感染病例，而其他研究则估计感染人数近4亿，其中包括1亿临床病例。令人费解的是，尽管疟疾与登革热的流行区域存在广泛的地理重叠，但直至近期，已发表的合并感染相关报告仍极为稀少。叠加的急性登革热感染本可能导致更严重的联合疾病，因为两种病原体均可引发休克与出血。然而，近期一项综述发现，尚无关于合并感染会加重发病或提高死亡率的报道。重症双重感染病例几乎仅见于南美地区，且主要集中在感染间日疟原虫（Plasmodium vivax）的人群中。我们提出假说：疟疾感染可能对登革热具有部分保护作用，尤其是恶性疟对重症登革热的保护作用；而这种种间交叉保护或许可以解释，直至近期，撒哈拉以南地区与南亚部分区域几乎未出现重症登革热病例的现象。我们推测，疟疾感染可诱导产生交叉反应性抗体或其他免疫应答，从而对有症状登革热与重症登革热提供交叉保护，或至少是部分交叉保护。已有研究表明，疟原虫可引发多克隆B细胞活化与嗜异性抗体产生，而部分抗登革热IgM检测试验与疟疾患者血清存在高度交叉反应性。下文将简要回顾恶性疟与登革热的历史演变，并探讨高传播疟疾流行区亚临床登革热的早期证据，以及关于合并发病严重程度的矛盾报道；同时还将讨论其他种间相互作用的案例。