Re: Probable person to person transmission of novel avian influenza A (H7N9) virus in Eastern China, 2013: epidemiological investigation
Since late February 2013, more than 130 laboratory-confirmed cases of human infections by the novel avian influenza A(H7N9) have been reported in China . Although the number of cases has been declining since April, the latest confirmed case reported in Guangdong  shows that A(H7N9) still merits close attention. Whereas the severity of A(H7N9) disease appears higher than for seasonal influenza viruses , transmissibility between humans has been low to date with a small number of family clusters , and among 2,554 traced close contacts of confirmed H7N9 cases, only 4 (<0.2%) potential secondary infections were detected .
Qi et al.  reported an investigation into possible human-to-human transmission from a 60-year old father to his 32-year old daughter (the Jiangsu family cluster reported in ). By stating that they believe their investigation supports ‘probable’ human-to-human transmission, the authors give the impression that they believe there is more than a 50% chance that the daughter was infected by the father. The authors have conceded that there is an absence of certainty over the chain of transmission that led to infection of the daughter . There is certainly a ‘possibility’ (i.e. a probability between 0 and 1) that (1) the daughter was infected directly by the father, but there is also a possibility that (2) the daughter and father were both infected from a common source, and furthermore a possibility that (3) the daughter and father were infected from separate sources. The third scenario is very unlikely given the close genetic relationship of the viruses isolated from the father and the daughter . However, the authors did not demonstrate that scenario (1) had higher probability than scenario (2), or that scenario (1) had a probability above 50%.
There is support for scenario (1) from the epidemiologic investigation, where the daughter had no known poultry exposure and had prolonged close contact with the father while he was ill. In addition, sequencing of all eight genes from the three H7N9 strains isolated separately from the father and daughter demonstrated a high level of sequence similarity (99.6 – 99.9%). However, evidence against scenario (1) includes the relatively long apparent incubation period, if infection occurred during the period of greatest unprotected exposure. Moreover,while the viral genomes are very similar, this does not in itself imply transmission: we have previously reported 99.99% average sequence identity between human influenza viruses in index and secondary cases in households  and the rate with which sequence variation arises within infection and is transmitted to subsequent hosts is unknown. Additional mutations could have occurred during passaging in cell culture, and it would have been preferable if possible to sequence the virus directly from the original clinical specimens. The significance of the sequence similarity between the virus isolated from the father and daughter is unclear without further information and notably expanded sampling, as such observations may readily arise via alternative transmission scenarios. The single environmental isolate provides inadequate context, and as such, the genomic data do not add a great deal to the evidence for direct transmission.
This work highlights the need for a formal quantitative framework for the analysis of epidemiological and virus sequence data, allowing investigators to test formal hypotheses such as comparing the probability of scenario (1) vs (2) described above. Such a framework could be particularly valuable when assessing any future changes in transmissibility of H7N9.
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Competing interests: BJC has received research funding from MedImmune Inc. and consults for Crucell NV.