In 2013 avian influenza virus A (H7N9) was detected in humans and according to figures from the World Health Organization has been fatal in over a quarter of those known to have been infected. A comprehensive understanding of the effects of this virus on the human immune system is still lacking. Lanjuan Li and colleagues from the Zhejiang University School of Medicine, China, sought to address this in their recent study in Critical Care, where they investigated the cytokine profiles and functional phenotypes of the immune cells of a cohort of infected patients compared to healthy controls. Here Li explains what insights they gained and how this may affect treatment of human H7N9 infection.
What is avian influenza A (H7N9)?
Influenza A (H7N9) is a subtype of influenza viruses that had not previously been seen in either animals or people until it was found in March 2013 in China. The new human H7N9 viruses are the product of reassortment of viruses that are of avian origin. Most of the cases rapidly developed into acute respiratory distress syndrome, with a mortality rate of roughly 30 percent. Fortunately, this virus does not appear to transmit easily from person to person, and sustained human-to-human transmission has not been reported. Now a vaccine developed independently by Chinese scientists has been tested in controlled clinical trials.
Why is it important to characterize the immunological characteristics of patients with H7N9?
In almost all cases of viral diseases, the viral-specific immune response is crucial for viral clearance, however, it usually amplifies the non-specific immune response to cause damage of normal host tissues. For example during chronic hepatitis B virus (HBV) infection, the immunological ‘complication’ is usually mild, limited but long-lasting (without treatment intervention), leading to persistent hepatic inflammation. Sometimes, such as during SARS-coronavirus infection, the response is rapid, profound and systemic. We believe, in viral diseases, the immunological characteristics of patients accurately reflect the clinical characteristics of patients. When it comes to H7N9 infection, clarifying the traits in host response to H7N9 infection would deepen our understanding of the clinical presentation of this disease.
What were your main findings?
As we expected, most H7N9-infected patients had rapid, profound and systemic immunological consequences as reflected by T lymphopenia, activation of innate and adaptive immune cells, as well as hyper-cytokinemia in their circulation. Accordingly, most patients clinically exhibited systemic inflammation response syndrome (SIRS). In addition, we observed a simultaneous presence of the anti-inflammatory response. This is derived from a feedback response to limit the detrimental effect of systemic inflammation. The consequence of this anti-inflammatory response is not clear, however, it may predispose patients to secondary infection.
You found that many patients with severe avian H7N9 influenza developed T lymphopenia. How does this compare to other respiratory viruses?
We found this condition was similar to those of other A subtype influenza, H5N1 and pH1N1. In fact lymphopenia when combined with other parameters was capable of being compiled into an early ‘diagnostic scoring system’ during the influenza pandemic of 2009. Other common respiratory viruses such as seasonal H3N2 influenza virus, human rhinovirus (HRV), and respiratory syncytial virus (RSV) had lymphopenia too. In fact lymphopenia is a common factor in viral upper respiratory infections in humans, but the degree and consistency of these changes varies from virus to virus.
What are the clinical implications of your findings?
As the aberrant immune response in H7N9-infected patients led to the rapid progression of the disease, therapy aimed to block the profound and uncontrolled immune reaction may be beneficial. Our findings will help alert clinicians to the condition worsening. A potential response would be the use of glucocorticoids to inhibit cellular and humoral immunity. Another possible approach is to remove the over-flowed circulating inflammatory cytokines by plasma exchange and continuous veno-venous hemofiltration (CVVH), one form of artificial liver system, which was proved to reduce cytokine levels.
What further research is needed?
Our study provides an overall perspective into the immune status of H7N9-infected patients but a number of key questions remained to be answered. First, as innate immunity is the first line of host defense, it is unknown what the key innate cells and cytokines/chemokines of the innate immune system are in initiating the response to H7N9 infection. We also still don’t know what the mutual regulation between various cytokines is. Second, humoral immunity is an important component of the adaptive immune system in response to viral infection; identifying neutralizing antibodies against H7N9 virus may therefore be beneficial for treatment. Third, the immunological status of patients may vary greatly during disease progression. Thus, a dynamic observation of the immunological status of patients would be necessary.