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Letters to the Editor

A Fatal Case of Enterovirus 71 Infection With a Single Nucleotide Variation in Domain V of the 5′ Untranslated Region

Tong, C. Y. William MD; Bible, Jon M. PhD; Platt, Craig MB ChB, FRCPATH

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The Pediatric Infectious Disease Journal: November 2011 - Volume 30 - Issue 11 - p 1013-1014
doi: 10.1097/INF.0b013e318228ba24

To the Editors:

We report a fatal case of enterovirus 71 (EV71) infection with a single nucleotide variation within the internal ribosome entry site in the 5′ untranslated region of the viral genome.

A 22-month-old previously healthy white girl presented with a 1-week history of low-grade fever. Vesicular lesions were noted on her hands and feet. Her condition deteriorated 3 days later, and when examined in the emergency department, she was found to have shallow respiratory breathing, hypotension, and rolling of the eyes. She died within 30 minutes of transferral to a pediatric intensive care unit. The only laboratory tests performed before death showed hemoglobin of 10.2 g/dL, white blood cell count of 16 × 109/L (13 × 109 lymphocytes), and platelet count of 81 × 109/L.

At autopsy, vesicular lesions were found on her extremities consistent with hand-foot-and-mouth disease. Cervical and paratracheal lymphadenopathy and congestion of the lungs and liver were found on gross examination. Findings from the histologic examination showed pulmonary edema without consolidation and normal myocardial tissues. In the brain, there was histologic evidence of severe encephalitis, particularly affecting the brain stem with focal necrosis. The postmortem report of cerebrospinal fluid (CSF) sample showed 45 × 106 red cells/L and 1125 × 106 white cells/L (95% lymphocytes). CSF protein level was 1.3 g/L. Result of the bacterial culture was negative.

EV71 was isolated from the CSF and a stool sample. Sequencing of the VP1 and 3D polymerase sequences of the isolates confirmed the presence of EV71 subgenogroup C2 RNA (GenBank Accession number: AM939597).1

The secondary structures of each domain in the 5′ untranslated region of the isolates were analyzed.2 At position 526 within domain V, a uracil residue (526U) was noted. Position 526 is located at the base of a hairpin structure immediately following the main stem at the tip. A “C” at position 526 facilitates a strong GC bond with the “G” at position 515. By contrast, a “U” in position 526 causes disruption to the stem and loop structure (Fig., Supplemental Digital Content 1, This may reduce the stability of that particular part of the structure, and as this is part of the internal ribosome entry site it may affect replication efficiency.

This finding of 526U in an EV71 C2 isolate is unique and is not reported previously. It is also rarely found in other subgenogroups such as C1, C5, or B2 (n =1, 2, and 1, respectively, in Genbank sequences). In contrast, 48/68 (71%) of C4 sequences in Genbank had 526U. EV71 subgenogroup C4 recently caused large epidemics in China and has been associated with significant mortality and morbidity.3 Very little clinical information is available to determine whether 526U sequences in subgenogroup C4 are associated with more severe manifestations.

It is likely that multiple factors are involved in the virulence of EV71. Host and environmental factors are likely to be of greater significance.4 To evaluate our finding further, it is necessary to study the effect of sequence variations in domain V on efficiency of translation and viral replication.

C. Y. William Tong, MD

Department of Infectious Diseases Guy's and St. Thomas' NHS Foundation Trust Department of Infectious Diseases King's College London School of Medicine London, United Kingdom

Jon M. Bible, PhD

Department of Infectious Diseases Guy's and St. Thomas' NHS Foundation Trust London, United Kingdom

Craig Platt, MB ChB, FRCPATH

Department of Histopathology Bristol Royal Infirmary Bristol, United Kingdom


1.Bible JM, Iturriza-Gomara M, Megson B, et al. Molecular epidemiology of human enterovirus 71 in the United Kingdom from 1998 to 2006. J Clin Microbiol. 2008;46:3192–3200.
2.Mathews DH, Disney MD, Childs JL, et al. Incorporating chemical modification constraints into a dynamic programming algorithm for prediction of RNA secondary structure. Proc Natl Acad Sci USA. 2004;101:7287–7892.
3.Zhang Y, Tan XJ, Wang HY, et al. An outbreak of hand, foot, and mouth disease associated with subgenotype C4 of human enterovirus 71 in Shandong, China. J Clin Virol. 2009;44:262–267.
4.Bible JM, Pantelidis P, Chan PK, et al. Genetic evolution of enterovirus 71: epidemiological and pathological implications. Rev Med Virol. 2007;17:371–379.

Supplemental Digital Content

© 2011 by Lippincott Williams & Wilkins, Inc.