By: Davidta Brown, Staff Editor
When the seasons transition from winter into spring every year, healthcare providers brace for a shift into a time of increased sneezes, requests for cough medication, and vaccinations, otherwise known as flu season. The rounds of illness that pass each year are usually more of an annoyance than a cause for serious concern, and typically only pose a threat to the very young, the elderly, and those of compromised immune systems. However, during some years, the strain of influenza virus is more dangerous and requires more than the usual surveillance. For example, the influenza A, subtype H7N9 virus that appeared in China this past spring proved to be virulent enough to warrant international concern and investigation, and provided an opportunity for the public health defenders of the world to put protocol and procedure to the test.
The first introduction to a new flu virus came in March of this year, with the hospital admission of three individuals – two from the city of Shanghai, and one from the Anhui province – in eastern China.1,2 Throat-swab samples were collected from the patients and were put through the reverse-transcription polymerase chain reaction where they were then tested with probes for the H1 to H16 and N1 to N9 influenza subtypes.3 These tests proved that the flu variety that had caused severe sickness, and eventually death for the three patients, was an avian H7N9 virus. While H7 viruses are common in birds, they had never before been observed among the human population in Asia.1 The N9 classification was even more unusual, as human infection with this subtype had previously never been documented. As more and more cases appeared across eastern China, and with the median time between symptom onset and death at most twenty days, it soon became clear that this new influenza outbreak warranted decisive action; Chinese authorities therefore took the first step by closing markets that sold live birds.2, 4
After the identification of the new type of viral threat, the next course of action was sequencing the genetic material of H7N9. The viral sequences obtained from the original three cases first needed to be tested for similarity. This was achieved as the sequences were shown to be 97.7% to 100% identical.2 Next, phylogenetic analysis needed to be performed in order to trace the avian origins of H7N9. It was found that the gene coding for hemogluttin in this viral strain was most similar to H7N9 subtype KO14, found in a duck in Zhejiang in 2011. Furthermore, six internal genes in the new virus were closest to influenza A (H9N2), found in a brambling (a small bird) in Beijing.3 The observed variation in genetic origins made it clear that H7N9 was the result of reassortment between several bird flu viruses.
Further genetic analysis indicated traits in the new virus that proved to be of great significance in understanding its transmission and virulence. The absence of certain key insertion and deletion mutations in the genetic sequence for hemagglutinin revealed that H7N9 is actually a “low-pathogenic” virus for many bird species, including chickens.2 This means that the pathogen could be spread across avian populations without detection because of its nearly asymptomatic nature in birds, while still posing serious risk to people who come into contact with the infected poultry. Also of clinical importance was a mutation identified in the PB2 proteins of some of the viral samples collected from human cases reported later; single amino-acid substitutions at positions 627 or 701 suggested enhanced viral replication at temperatures similar to those found in the upper airways of humans and other mammals.1,2 Curiously, these mutations were not observed in H7N9 samples collected from birds, suggesting that they were selected for in the human host.2 With the obvious significance of these genetic discoveries, the full genome sequences of influenza A (H7N9) were deposited into the Global Initiative on Sharing Avian Influenza Data database on March 29th of this year.3
While most confirmed cases of influenza A (H7N9) could be traced to contact with live birds such as those found in open markets, one patient had no known experience of such contact in the two weeks prior to the onset of symptoms.1 Consequently, transmission of the virus through the air has not been ruled out, nor has the possibility of another mammalian reservoir, pigs being the most likely candidates.1 Additionally, the lack of known contact between the confirmed cases, as well as a phylogenetic distinction between one of the original three H7N9 patients and the other two, indicate the likelihood that the virus has had at least two introductions into human populations.2, 3
Confirmed cases of the H7N9 virus were studied for their clinical implications, such as symptoms and typical treatments, the information likely of most interest to both healthcare providers and the general public. A case of H7N9 was considered “confirmed” upon diagnosis of pneumonia with H7N9 viral RNA, or upon isolation of the virus itself from a patient’s respiratory specimens.3 Among all of the cases identified, the most common symptoms were the most typically “flu-like”, namely high fever and cough.3 However, the complications of infection were usually more serious, consisting of septic shock, respiratory failure, or bacterial and fungal infections.2 Acute respiratory distress syndrome was also a common result.3 It should be noted that the majority of confirmed cases were in patients with underlying chronic conditions, and that those hospitalized with pneumonia and with a history of systemic, high-dose steroid use appeared susceptible to increased viral replication and the emergence of antiviral resistance.2
The median time span between the onset of influenza symptoms and hospitalization among all of the cases observed to date is four-and-a-half days, and as mentioned before, the time between symptom onset and death ranges from seven to twenty days.2 Clearly, prompt diagnosis and treatment are of the utmost importance in dealing with H7N9. A substitution mutation in the M2 protein of the virus indicated resistance to adamantane antiviral drugs, but the influenza strain did display sensitivity to neuraminidase inhibitors, leading experts to suggest that oral oseltamivir or inhaled zanamivir be used as soon as possible in confirmed or suspected cases.1, 5
At present, there have been a total of 132 human cases of H7N9 infection, and 37 reported deaths.5 The potential for an even more widespread epidemic prompted the World Health Organization to suggest the use of the viral sample isolated from the patient in Anhui in the preparation of vaccines, in case of a future pandemic.5 In addition, WHO is still on watch for events considered “high significance”, such as new cases of H7N9, or evidence of human-to-human transmission.2 While the number of detected cases fell sharply after April of this year, perhaps due to containment measures and the change of seasons,public health officials continue to keep a watchful eye on the pathogen that could potentially become an international crisis when cold weather returns.4
- Brown, T. H7N9 Human Infection of ‘Public Health Significance’. Medscape Medical News. 2013 Apr [cited 2013 Jul 22] http://www.medscape.com/viewarticle/782489
- World Health Organization. Overview of the emergence and characteristics of the avian influenza A (H7N9) virus. http://www.who.int/influenza/human_animal_interface/influenza_h7n9/WHO_H7N9_review_31May13.pdf. Accessed July 23, 2013
- Rongbao G, Bin C, Yunwen H, et al. Human Infection with a Novel Avian-Origin Influenza A (H7N9) Virus. N Eng J Med 2013; 368:1888-1897
- Centers for Disease Control and Prevention. Avian Influenza A (H7N9) Virus. 2013 Jul 10 [cited 2013 Jul 23] http://www.cdc.gov/flu/avianflu/h7n9-virus.htm
- World Health Organization. WHO provisional recommendation on influenza A (H7N9) vaccine virus. http://www.who.int/influenza/human_animal_interface/influenza_h7n9/ProvisionalRecommendation_H7N9_31May13.pdf. Accessed July 23, 2013