Risk Factors Associated with Severe Clinical Outcomes of Pandemic H1N1 Infection

Abstract

The clinical outcome of pandemic H1N1 influenza infection is dependent on the interplay of virus and host factors. Influenza virus infections can range from relatively mild infections of the upper respiratory tract to fatal disease of the lower respiratory tract. A range of host factors play a role in the severity of clinical disease in pdm(H1N1)09 infection. With the exception of neonates age was directly proportional to the severity of clinical outcome; obesity, COPD and pregnancy play a key role in clinical outcome of infection. An important determinant in the pathogenesis of influenza infection is the tissue tropism of the influenza virus. The D222G and D222N mutations of pdm(H1N1)09 influenza appear to have an increased tropism for the tissues of the lower respiratory tract and are disproportionally associated with severe clinical disease. These α2-3 salicylic acid tropic mutations, which have been associated with fatal cases of influenza infection, have also been preferentially selected for during sequential passage in embryonated eggs and viruses of avian origin. KeywordsInfluenza; Pandemic; H1N1; pdm(H1N1)09; Oseltamivir IntroductionThe current H1N1 influenza vaccine strain A/ California/7/2009 has a surprisingly high no detectable antibody (NDA) rate of approximately 52% in a population of 200 subjects screened (unpublished data). Studies have shown that the A/California/7/2009 strain of pandemic H1N1 influenza causes alveolar haemorrhage in the ferret model [1,2]; similar "swine flu" viruses A/Mexico/4482/2009 and A/ Netherlands/602/2009 also presented severe pathology in the ferret model [3,4]. As a consequence it is clear that infection with this group of viruses represents a significant risk of a severe clinical outcome. Furthermore, the severe symptoms that are associated with a subset of A/California/7/2009 infections are atypical for previous seasonal influenza infections. Co-morbidities and their impact on clinical outcome of infectionThe clinical outcomes of infection by pdm(H1N1)09 are considerably affected by one or more host factors and comorbidities. Here we discuss these co-morbidities and the impact that they have on clinical consequences to infection. Case fatality ratiosBy July 2009 63,479 cases of influenza like illness were reported in Mexico; of these cases 11% (6,945) were confirmed as H1N1 influenza; 92% of confirmed positive cases (6,407) were treated as outpatients, 7% (475) were admitted to hospital and survived and <1% died (63) [5]. During the early phase of the pandemic the case fatality ratio (CFR) was calculated to be approximately 0.4-0.6% [6]. In the UK an estimated 540,000 people had symptomatic H1N1 infection during a study period with a CFR of (0.026%) 26 deaths per 100,000 [7]. There is little published information for the CFRs of seasonal H1N1 or H3N2 influenza. However using data from the Health Protection Agency (HPA) we were able to determine the CFR for influenza infections admitted to intensive care units (ICU). 2/7 SymptomsA meta-analysis of H1N1...

The manufacturing of human viral challenge agents for use in clinical studies to accelerate the drug development process

“…As an example; (H1N1) A/California/7/2009-like (pdm09-like) influenza virus isolates may have two key mutations in the Haemagglutinin receptor binding site, D222G and D222N. Both lead to greater tropism for the lower respiratory tract and are associated with severe clinical outcome [ 6 ]. Viral genome sequencing ensures that mutations affecting pathogenicity and virulence, or those that may confer resistance to antiviral therapy are not present in the CA.…”