Treatment of yellow fever.
Yellow fever (YF) is a life-threatening mosquito-borne flaviviral hemorrhagic fever (VHF) characterized by severe hepatitis, renal failure, hemorrhage, and rapid terminal events with shock and multi-organ failure. A live, attenuated vaccine (YF 17D), in wide use for over 60 years, causes a disease identical to wild-type virus at an incidence of 2.5x10(-6). Our current understanding of the pathogenesis and treatment of YF (described in this brief review) is derived from studies of animal models (macaques, hamsters) that reproduce the features of human YF and from descriptive studies of human cases of naturally acquired and vaccine-associated VHF. The least understood, but potentially most important terminal events appear to be due to 'cytokine storm' and represent a potential target for therapeutic interventions. Areas for future study include dissection of cytokine-mediated events in animal models, the pathogenic role of the profound neutrophilia that occurs pre-terminally, the (pathological) role of adaptive immune clearance in pathogenesis, and treatments directed at cytokine storm. Antibody, interferon-alpha, polyICLC and other immune modulators are highly effective when administered before or within a narrow time window after infection, but are ineffective when given after the infection is established. A few antivirals have been evaluated (ribavirin, tiazofurin, carboxamide, pyrazoline compounds). Ribavirin has been used successfully to treat hamsters when the drug is given at high doses up to 2 days after virus infection (shortly before liver infection), but has not shown promise in nonhuman primate models. Future work should focus on evaluating higher doses of ribavirin alone or in combinations with potentially synergistic drugs, including interferons. Also specific inhibitors against other flaviviruses such as dengue virus should be investigated for potential pan-flavivirus activity since recent studies have shown that specific targets such as the flavivirus proteases and helicases are very similar in structure.
Kleiner Perkins Caufield & Byers, Menlo Park, CA, United States. tmonath@kpcb.com
Thomas P
TP
Monath
D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D006224:Cricetinae; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D006801:Humans; D007372:Interferons / Q000627:therapeutic use; D012254:Ribavirin / Q000627:therapeutic use; D015004:Yellow Fever / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology / Q000821:virology; D015005:Yellow fever virus / Q000276:immunology / Q000472:pathogenicity*
D000998:Antiviral Agents; D016207:Cytokines; D012254:Ribavirin; D007372:Interferons