“If names are not correct, language will not be in accordance with the truth of things.”
- Confucius
“The term “tomato flu” is a misnomer that should no longer be used because both HFMD and its enteroviral causes, such as Coxsackie A16, are well known.”
Donald R. Lucey, M.D., MPH, Clinical Professor of Medicine, Dartmouth Geisel School of Medicine
On August 17, 2022, the Lancet Respiratory Medicine reported an outbreak in Kerala, India of 82 children younger than 5 who had what appeared to be a new viral illness called “tomato flu.” (The children had reddish skin lesions that gradually enlarged to the size of a tomato.) By the end of the month, it became clear that the illness had nothing to do with either tomatoes or influenza, and it wasn’t a new viral illness. Instead, it was an outbreak of hand, foot, and mouth disease (HFMD), a common viral infection in children caused, in this case, by the enterovirus Coxsackievirus A16.
While it was unfortunate that this outbreak occurred, it was fortunate that the enterovirus Coxsackievirus A16 caused this outbreak of mild HFMD in Kerala rather than Enterovirus 71 (EV71), also known as Enterovirus A71 (EV-A71). The latter, which can invade the central nervous system provoking a fatal brain infection, has been associated with past outbreaks of HFMD in East and Southeast Asia. In this Germ Gems post, I provide a brief description HFMD and draw attention to EV71, another more ominous etiology for HFMD.
What is HFMD? HFMD is a common infection occurring mainly in children that is caused by a group of enteroviruses. While Coxsackievirus A16 is the most common cause of HFMD in the U.S., more severe cases of HFMD caused by Coxsackievirus A6 are on the rise.
HFMD occurs in all areas of the world and is highly contagious. As its name suggests, the telltale clinical manifestation is a rash of flat discolored spots, bumps, and vesicular sores with blisters on the palms of the hands and soles of the feet, along with painful ulcers, blisters, or lesions in and around the mouth or nose. Fever, nausea, and vomiting occur at the outset of disease with skin lesions appearing three to six days after exposure to the virus. For cases of HFMD caused by the Coxsackieviruses there is no specific therapy. Instead, all the symptoms and signs generally resolve on their own.
HFMD and EV71. Like Coxsackievirus A16-caused HFMD, EV71 HFMD is also highly contagious and frequently affects young children under five years old. EV71 infection can be asymptomatic or manifest as self-limited HFMD, but it can also be a much bigger worry.
EV71 is one of the most important “neurotropic” viruses known. It triggers hundreds of thousands of hospitalizations annually throughout the world with many patients experiencing severe or fatal neurological consequences. The basis of its neurotropism (predilection for the nervous system) isn’t completely clear.
In 1969, researchers in California first identified EV71 when they isolated it from a stool sample of a child suffering from encephalitis. By the 1990s, EV71 became endemic in the Asia-Pacific region where it precipitated major outbreaks of HFMD every three to four years in East and Southeast Asia, with substantial morbidity and mortality due to encephalitis (infection and inflammation of the brain).
For example, during Taiwan’s largest epidemic in 1998, there were approximately 130,000 cases, of which 405 were severe and 78 were fatal. Subsequently, other outbreaks of EV71 HFMD cropped up in children in Taiwan causing neurological complications including the often fatal brainstem encephalitis.
A promising EV71 vaccine. Given this backdrop of outbreaks of severe EV71 infections throughout the Asia-Pacific region, a focal point to prevent disease has been the development of safe and effective vaccines. Three EV71 vaccines have been licensed in China for use in children. To me, the most promising is a vaccine called EV71vac.
In its April 30, 2022 issue, the Lancet published the results of a randomized, placebo-controlled trial of EV71vac carried out in children aged 2-23 months at five hospitals in Taiwan and two in Vietnam. The results showed a vaccine efficacy of 96.8% with no adverse events.
The results of this study—showing a life-saving vaccine against EV71—received little media attention in the U.S. In contrast, the news of the non-entity “tomato flu,” an outbreak of self-limited HFMD caused by Coxsackievirus A16, quickly found its way to various news sources. Perhaps this is because EV71 is not, at present, found in the U.S. and therefore this life-saving vaccine has been of no direct importance to U.S. patients. Yet, our failure to more widely recognize the importance of this vaccine is short sighted.
We must all remember that EV71 was first recognized in California in 1969 where it became endemic. It may well rear its ugly head again in the U.S. If it does, you can be sure that Pediatric Infectious Diseases doctors will be conferring with public health officials as well as vaccine experts at the U.S. Food and Drug Administration and in the pharmaceutical industry about generating an EV71 vaccine for use here as quickly as possible. In fact, the moral of the clinical story of EV71 (“out of sight, out of mind”) is “timing is everything,” so let’s hope those discussions of an EV71 vaccine are already underway.
