Elsevier

The Lancet

Volume 381, Issue 9885, 29 June–5 July 2013, Pages 2273-2279
The Lancet

Articles
Association between adverse clinical outcome in human disease caused by novel influenza A H7N9 virus and sustained viral shedding and emergence of antiviral resistance

https://doi.org/10.1016/S0140-6736(13)61125-3Get rights and content

Summary

Background

On March 30, a novel influenza A subtype H7N9 virus (A/H7N9) was detected in patients with severe respiratory disease in eastern China. Virological factors associated with a poor clinical outcome for this virus remain unclear. We quantified the viral load and analysed antiviral resistance mutations in specimens from patients with A/H7N9.

Methods

We studied 14 patients with A/H7N9 disease admitted to the Shanghai Public Health Clinical Centre (SPHCC), China, between April 4, and April 20, 2013, who were given antiviral treatment (oseltamivir or peramivir) for less than 2 days before admission. We investigated the viral load in throat, stool, serum, and urine specimens obtained sequentially from these patients. We also sequenced viral RNA from these specimens to study the mutations associated with resistance to neuraminidase inhibitors and their association with disease outcome.

Findings

All patients developed pneumonia, seven of them required mechanical ventilation, and three of them further deteriorated to become dependent on extracorporeal membrane oxygenation (ECMO), two of whom died. Antiviral treatment was associated with a reduction of viral load in throat swab specimens in 11 surviving patients. Three patients with persistently high viral load in the throat in spite of antiviral therapy became ECMO dependent. An Arg292Lys mutation in the virus neuraminidase (NA) gene known to confer resistance to both zanamivir and oseltamivir was identified in two of these patients, both also received corticosteroid treatment. In one of them, wild-type sequence Arg292 was noted 2 days after start of antiviral treatment, and the resistant mutant Lys292 dominated 9 days after start of treatment.

Interpretation

Reduction of viral load following antiviral treatment correlated with improved outcome. Emergence of NA Arg292Lys mutation in two patients who also received corticosteroid treatment led to treatment failure and a poor clinical outcome. The emergence of antiviral resistance in A/H7N9 viruses, especially in patients receiving corticosteroid therapy, is concerning, needs to be closely monitored, and considered in pandemic preparedness planning.

Funding

National Megaprojects of China for Infectious Diseases, Shanghai Municipal Health and Family Planning Commission, the National Key Basic Research Program of China, Ministry of Science and Technology, and National Natural Science Foundation of China.

Introduction

Pandemic influenza arises from influenza viruses of birds or swine.1 Recently, we and others reported a novel avian-origin influenza virus subtype (A/H7N9) from patients with severe and fatal respiratory disease in eastern China.2, 3 The virus has so far caused disease in 132 human beings in nine provinces and municipalities in China, leading to 33 deaths. Poultry seem to be the source of human infections.3 Although other avian influenza viruses (eg, subtypes H5N1, H9N2, H7N7, and H7N3) have infected man before, such transmission has remained exceedingly inefficient, possibly because avian viruses are inefficient at binding to the sialic acid receptors located in the human upper airways. By comparison, the novel A/H7N9 virus, which has mammalian adaptation mutations in the receptor binding site of the haemagglutinin gene and in the polymerase basic 2 (PB2) gene (E627K)2, 4 of the virus, seems to cross species from poultry to man more easily, raising concern about its pandemic potential.

The genes of this A/H7N9 virus were of avian origin, with six internal genes from avian influenza A (H9N2) viruses whereas the haemagglutinin (HA) and neuraminidase (NA) gene segments derive from viruses from ducks or wild birds.2, 3 Human beings infected with A/H7N9 are of older age and many of them have underlying diseases.5 Since A/H7N9 is resistant to the M2-ion channel blockers amantadine and rimantadine, the neuraminidase inhibitors oseltamivir, zanamivir, and peramivir have been the main drugs used for antiviral treatment of patients with A/H7N9.

The viral and host factors associated with the unusual severity of this disease are poorly understood. In this study, we quantified the viral load in sequentially obtained throat swabs, serum, urine, and stool specimens from A/H7N9 patients. We also looked for mutations associated with resistance to neuraminidase inhibitor treatment.

Section snippets

Patients and specimens

We included in the study 14 patients who were diagnosed with A/H7N9 infection at the Shanghai Municipal Centre for Disease Control and Prevention (CDC), Shanghai, China, and had had oseltamivir treatment for less than 2 days before admission to the Shanghai Public Health Clinical Centre (SPHCC) between April 4, and April 27, 2013. Table 1 outlines the demographic details, comorbidities, antiviral, and corticosteroid treatment received, and final disposition of these patients. Most patients

Results

The 14 patients in our study group had a median age of 74 years (IQR 60–78), ten of them (71%) were male (table 1). None of the patients were epidemiologically linked. Seven (50%) patients developed pneumonia and were oxygen-dependent but did not require ventilator support or ECMO; they constitute the pneumonia group. Four other patients further deteriorated with acute respiratory distress syndrome (ARDS) and required mechanical ventilation (those constitute the mechanical ventilation group).

Discussion

We investigated the relation of clinical and virological factors associated with adverse clinical outcome in A/H7N9 infection in a cohort of 14 patients admitted to the Shanghai Public Health Clinical Centre, China. We noted that oseltamivir treatment was associated with falling viral load in the respiratory tract in most patients with A/H7N9 infection. We also report that the emergence of mutations associated with resistance to neuraminidase inhibitors in some patients with A/H7N9 infection is

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