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Diagnosing atypical hand, foot, and mouth disease by routine microscopy

DII small banner By Warren R. Heymann, MD
Dec. 15, 2016

Hand, foot, and mouth (HFM) disease is childhood exanthem usually caused by Coxsackie A16; enterovirus 71 has been implicated in cases of HFM complicated by encephalitis, flaccid paralysis, myocarditis and pulmonary edema. Coxsackie A6 has recently been associated with severe, atypical episodes of HFM in children and adults. These cases are accompanied by fever, chills, myalgia, and diarrhea. Lesions tend to be vesiculobullous; they frequently appear as targetoid lesions easily mistaken for erythema multiforme. Eczema coxsackium may complicate patients with underlying atopic dermatitis (1). The differential diagnosis includes herpes infections (including zoster) and bullous impetigo. Arrested nail growth, resulting in Beau’s lines and/or onychomadesis may be noted, but are believed to be more common in those who infected with Coxsackie A6 (2).

We have seen multiple cases of presumed atypical HFM over the past several months in patients of all ages. The clinical pictures may be bewildering, often resembling bullous erythema multiforme or bullous pemphigoid.
Although the diagnosis is most specifically diagnosed by reverse transcriptase PCR derived from vesiculobullous lesions, other than sending a swab to the CDC, this test may not be readily available.

Given the atypical presentations, biopsies are often performed on bullous lesions. Could histology be useful in differentiating these disorders? The answer appears to be “yes.”

According to the Lever histopathology textbook, “Early vesicles are intraepidermal, whereas old vesicles may be subepidermal in location. There is pronounced reticular degeneration of the epidermis, resulting in multilocular vesiculation. In the deep layers of the epidermis, some ballooing degeneration may be found. Neither inclusion bodies or multinucleated giant cells are present.” (3) Presumably, most of the prior reports were from cases of typical HFM.

Laga et al presented 3 cases with clinical features suspicious for erythema multiforme or a disseminated herpesvirus infection. The histopathologic findings in all 3 were uniform, demonstrating intraepidermal vesiculation with a predominantly neutrophil-rich infiltrate. A characteristic feature was the specific involvement of the upper stratum spinosum and stratum granulosum, with relative sparing of the stratum corneum. In none of the cases was there evidence of herpesvirus. Molecular analysis performed on two of the cases showed involvement by Coxsackievirus A6. All three cases resolved spontaneously (4). On a histopathologic basis alone, perhaps one might consider nutritional deficiency (such as acrodermatitis enteropathica) or other viral processes (e.g. orf); with clinical-pathologic correlation, the diagnosis of atypical HFM disease becomes plausible in the absence of interface dermatitis that rules out erythema multifome and the lack of a subepidermal bulla ruling out bullous pemphigoid. I took the liberty of comparing Laga’s finding to the pathology published in a study of atypical HFM by Stewart et al. (5) The pathology is virtually identical in both papers. While further studies should be performed to confirm these findings, the histologic description provided by Laga et al is an important contribution allowing the reasonably precise diagnosis of atypical HFM when obtaining a sample for PCR is problematic.

1. Heymann WR. Diagnosing atypical hand, foot, and mouth disease while avoiding the foot in mouth syndrome. Skinmed 2014; 12: 46-7.
2. Feder HM, et al. Atypical hand, foot, and mouth disease: A vesiculbullous eruption caused by Coxsackie virus A6. Lancet Infect Dis 2014; 14: 83-6.
3. Xu X, et al. Diseases caused by viruses. In Elder DE, et al (eds). Lever’s Histopathology of the Skin, Eleventh Edition. Philadelphia 2015, pp781-815.
4. Laga AC, et al. Atypical hand, foot, and mouth disease in adults associated with coxsackie A6: A clinicopathologic study. J Cutan Pathol 2016; 43: 940-5.
5. Stewart CL, et al. Coxsackie A6-induced hand-foot-mouth disease. JAMA Dermatology 2014; 149: 1419.

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