Reply to Wang et al. [Hepatitis E Virus–Associated Neurological Injury in China.]

To the Editor
We thank Wang et al for their interest in our recent findings on hepatitis E virus (HEV) infection in neurons and brains. As the authors have pointed out, in our study, HEV genotype 4 (HEV-4) was used in animal models, whereas patients were enrolled from countries where HEV genotype 3 (HEV-3) is predominant. Interestingly, Wang et al have investigated the association between neurological symptoms and HEV in China, where HEV-4 is predominant. They detected anti-HEV immunoglobulin G (IgG) positivity in 18 of 69 patients with Guillain-Barré syndrome (GBS) and 9 of 21 patients with encephalitis. One anti-HEV immunoglobulin M (IgM)–positive patient was found among the GBS patients, but viral RNA was not detected in the serum or cerebrospinal fluid.
So far, there is no unequivocal evidence that demonstrates HEV-4 in association with contemporaneous neurological disease in humans. Wang et al found serological evidence of HEV infection in a patient with GBS in an area where HEV-4 is known to predominate. A study in Japan by Fukae and colleagues showed that 3 of 63 (4.8%) patients with GBS/Miller Fisher syndrome had serological evidence of HEV infection, but none of the 60 controls did. In Japan, HEV-3 and HEV-4 co-circulate, but the Fukae et al study did not report which genotype was implicated in the 3 serologically confirmed cases. Therefore, whether HEV-4 infection can be sustained in human nervous tissues remains unresolved.
Although the prevalence rates of HEV infection varies among different cohorts of patients with neurological injury, collectively these studies unequivocally establish the relationship between HEV infection and neurological diseases. Whether this relationship is causal remains to be addressed. We agree with Wang et al that larger prospective multicenter cohort studies are warranted in HEV-4–predominant areas. However, in view of our own studies with genotype 4 and the results of others, we strongly suspect that such studies will reveal at least some degree of neuronal and brain infection by this viral variant.