Relapse of hand foot and mouth disease: are we at more risk?

Sir,

Hand, foot, and mouth disease (HFMD) is a form of viral exanthem caused by species- A human enteroviruses (HEVA), genus Enterovirus, family Picornaviridae. The members within HEVA are Coxsackievirus (CV) A10, A14 and -A16 and human enterovirus (HEV) 71; the last one being frequently associated with serious complications.

Little is known about the predictors of severe disease. HLA-A33 haplotype that is more common in Asian population than Caucasian is suggested as a risk factor for HEV71 infection.[1] Another proposed factor is glucose-6-phophate dehydrogenase deficiency.[2] Age in the range of 6 month to 3 years,[3] fever ≥ 3 days, fever peak ≥ 38.5°C and history of lethargy were also correlated with poor prognosis.[4] On the other hand, older age of the patient was associated with higher risk of EV71 infection.[4] There has been so far no attempt to explore the role of protective immunity and the correlation of the dermatological manifestation, the principal and most frequent expression of the disease, with disease prognosis.

After the small outbreak in 2004, first true epidemic of HFMD in India occurred in 2007.[5] Since then, clinical and epidemiological patterns of the disease appear to be changing. Significance of such changes remains to be elucidated.

The present author reported the previous epidemic and had been closely monitoring the epidemiological and clinical patterns of the disease since then. The changing pattern was quite evident. This report is to highlight some of these newly detected observations that came to notice since the last epidemic.

Total eighty-nine cases were detected by the author in a single centre from June to November 2010 (37 cases) and 2011 (52 cases). Reflecting a higher disease burden than 2007. Age ranged from 6 weeks to 32 years (median 8 years, mean 9.388 years ±7.2). Male slightly predominated (m-49, f-40). Involvement of wider age range was noticeable. Five patients were aged over 25 years and six were below 1 year. Incidentally the oldest patient had the most severe and extensive involvement [Figure 1].

Figure 1

A 32-year-old patient with HFMD. The left panel shows extensive and unusual areas of distribution. The right panel shows typical sites of involvement

Disease persisted for a longer period in the community. The last case was detected in the last week of November. It again indicated a higher disease burden and less effective immunity.

Family members were not affected in 73% of cases (n = 65). This was not in accordance with findings in many other countries but our previous report also suggested that involvement of family members was lesser than expected.

Disease severity was higher, involved larger body surface area [Figure 1] and persisted more than 10 days in many patients. Cloudy vesicle on an erythematous base was the typical presentation. Atypical presentation like erythematous and crusted papules, absence of vesicles, targetoid lesion and involvement of unusual sites like pinna was fairly common [Figure 2]. Disturbing dysphagia indicating pharyngeal involvement was noted in 39% (n = 14).

Figure 2

A four and half year old child with lesions of HFMD who had a previous attack 3 years back. Scattered lesions on trunk and pinna were noted

However, neurological or cardiological or other grave systemic complications were still not detected in any of the patients.

Possibly the most significant finding was four cases of relapse that affected children below 6 years age. [Figure 2]. Presumably, relapse of HFMD reflected absence of protective immunity. Infection by a different strain seems highly possible.

Relapse could be explained by infection by a different strain could have resulted from genetic recombination. Genetic recombination in HFMD is known to assist the virus to escape the existing immunity[67] and this mechanism has been proposed as an explanation for re-emergence of epidemics.[8] This changing pattern in genetic make up of the etiological organism could herald more number of relapses in near future.

HEV71 has been classified into four genogroups (A to D) on the basis of difference in the ‘highly variable sequence’ of the viral genome. Genogroup B and C each has 5 lineages whereas A and D each has a single strain. Genotype analysis of the HFMD viruses has hardly been attempted in India. The only strain isolated from India was the strain of genogroup D.[9] The above-mentioned cases showing a relapse were thus evidences to suggest the existence of multiple strains in this country at present.

Following the first identification in California in 1969, HEV 71 maintained a very low profile with only minor outbreaks. Following the prolonged quiescence the disease suddenly changed its character thereafter and caused repeated epidemic in many Asian countries. Severe and large epidemic occurred in Taiwan in 1998, Sarawakand then in China in 2008. In Taiwan, 78 children died and in China, 126 deaths were reported. After 18 years of presence in Taiwan, why did HEV71 suddenly became virulent to cause widespread epidemic with high fatality in 1998 is still a mystery.

Since 2004, each year the disease has been causing progressively larger outbreaks in India. Recent changes in clinico-epidemiological patterns including involvement of very young children and occurrence of relapses could be the causes for great concern in Indian perspective warranting urgent implementation of strict disease surveillance and notification policies as well as prevention strategies.