Pathogenesis, Treatment and Prevention of Emerging Infectious Diseases

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

Research in this project is currently focused on four areas. These are characterization of the survivors of the anthrax attacks of 2001; characterization of emerging respiratory infections including SARS and influenza; development of novel therapies for influenza; and evaluation of experimental vaccines and treatments for Ebola virus as well as characterizing the long-term sequelae of Ebola virus infection. The anthrax study has enrolled a cohort of volunteers who are currently undergoing an extensive diagnostic evaluation. To be ready to deal with emerging infectious diseases of the respiratory tract, an international protocol in in place to systematically study patients presenting with an influenza-like illness. This protocol has been complemented by the development of treatment protocols that study either hyperimmune plasma, intravenous immunoglobulin or a combination of antiviral chemotherapeutic agents. As part of the US government response to the 2014 Ebola outbreak in West Africa, a series of protocols have been initiated at the NIH Clinical Center and in West Africa to study the pathogenesis, treatment, long-term sequelae and prevention of Ebola virus disease. These include studies of the monoclonal antibody cocktail ZMapp, the candidate rVSV and ChAd3 platform Ebola vaccines and an observational cohort study of survivors of Ebola virus disease. Influenza causes substantial morbidity and mortality despite available treatments. Anecdotal reports have suggested that plasma with high antibody titers to influenza might be of benefit in the treatment of severe influenza but this hypothesis has never been rigorously tested. We conducted a randomized, open-label, multicenter, phase 2 trial to assess the safety and efficacy of anti-influenza plasma with hemagglutination inhibition antibody titers of 1:80 or more to the infecting strain. Hospitalized children and adults (including pregnant women) with severe influenza A or B (defined as the presence of hypoxia or tachypnea) were randomly assigned to receive either two units (or pediatric equivalent) of anti-influenza plasma plus standard care, versus standard care alone, and were followed up for 28 days. The primary endpoint was time to normalization of patients' respiratory status (respiratory rate of 20 breaths per min for adults or age-defined thresholds of 20-38 breaths per min for children) and a room air oxygen saturation of 93% or more. 113 participants were screened for eligibility and 98 were randomized to one of the two treatment arms. Of the 87 participants with confirmed influenza (by PCR), 28 (67%) of 42 in the plasma plus standard care group normalized their respiratory status by day 28 compared with 24 (53%) of 45 participants on standard care alone (p=0069). Six participants died, one (2%) in the plasma plus standard care group and five (10%) in the standard care alone group (HR 019 95% CI 002-165, p=0093). Participants in the plasma plus standard care group had non-statistically significant reductions in days in hospital (median 6 days IQR 4-16 vs 11 days 5-25, p=013) and days on mechanical ventilation (median 0 days IQR 0-6 vs 3 days 0-14, p=014). Fewer plasma plus standard care participants had serious adverse events compared with standard care alone recipients (nine 20% of 46 vs 20 38% of 52, p=0041). The most frequent serious adverse events were acute respiratory distress syndrome (one 2% vs two 4% patients) and stroke (one 2% vs two 4% patients). A health care worker from West Africa was evacuated to the National Institutes of Health Clinical Center on day 7 of documented Ebola virus disease. On arrival, he had symptoms of early Ebola virus disease including neuromuscular weakness, fever, hepatitis and coagulopathy. Over the next two weeks this evolved to diarrhea, skin rash, renal insufficiency and respiratory failure requiring mechanical ventilatory support. The was followed by meningoencephalitis and, as the patient began to recover from these manifestations of disease, the development of myocardial dysfunction and uveitis. This case study precisely depicts the course of a patient with Ebola virus disease who, despite never demonstrating a drop in blood pressure experienced a series of potentially life-threatening complications of infection that, with the use of standard supportive measures, began to resolve spontaneously. This highlights the fact that the high mortality figures previously reported for Ebola virus infection are likely due in large part to the lack of the type of supportive care available in tertiary medical centers.