Coxsackievirus A6-Induced Central Nervous System Injury and Limb Paralysis

To the Editors: In recent years, the pathogen spectrum of hand, foot and mouth disease (HFMD) has changed, with coxsackievirus (CV) A6 emerging as the primary pathogen. Currently, CVA6 represents one of the most widespread enteroviruses globally, and it’s a novel variant that has experienced genetic recombination and evolution. Genetic recombination and progression of CVA6 may cause changes in clinical manifestations and could potentially heighten pathogenicity because of the accumulation of nucleotide mutations.1 Notably, CVA6 appears to have a broader impact, affecting a wider age range of children and leading to more severe and prolonged sickness compared to other enteroviruses. Although HFMD is mostly a self-limiting illness, a significant number of patients develop neurological and/or cardiopulmonary complications, such as encephalitis, aseptic meningitis, encephalomyelitis, acute flaccid paralysis and fatal cardiopulmonary complications.2 Here, we reported the central nervous system injury and limb paralysis caused by CVA6. A boy of 1 year and 11 months presented to our hospital with worsening fever for a week, oral herpes for 5 days and weakness of the limbs for 2 days. On June 16, 2023, the patient was admitted to a local orthopedic hospital and was diagnosed with herpes pharyngitis, and was given intravenous ceftriaxone 1.0 g and feverfew 7 mL once a day; acyclovir 0.1 g and metronidazole sodium chloride 40 mL every 12 h for 5 consecutive days. During hospitalization, the parents found a red rash on both feet, and on 19 June, the patient’s condition worsened, with inability to hold up his head, weakness in all 4 limbs, inability to walk, and poor mental status (Fig. 1A). Cranial magnetic resonance imaging scan showed uneven distribution of bilateral cerebellar cortex with irregular margins, and multiple punctate pieces of long T1 and long T2 signal were seen in the cortex and subcortex (Fig. 1B). The patient complained of no significant abnormality in the full epigenetic test and DMD gene report, and no abnormality in the electromyography and muscle-related gene test. Targeted sequencing of multiple pathogens in the respiratory tract indicated CVA6 D3a subtype infection (Fig. 1C). We performed a supportive treatment by giving the patient intravenous ceftriaxone for controlling bacterial infections, and spraying interferon for antiviral therapy. One week after hospitalization, the rash had resolved, but achilles and knee tendon reflexes were still not restored. Considering the severe clinical presentation of the patient, we analyzed the strain for nucleotide and amino acid mutations. The VP1 of this CVA6 strain displayed a nucleotide similarity of 82.4% and a difference rate of 20.7% compared to reference strain Gdula (AY421764.1). And this strain showed 94.8% amino acid similarity and 5.1% difference with the VP1 of Gulda (AY421764.1) (Fig. 1D,E). Compared to the reference strain (AY421764.1), A total of 15 loci (S5T, I8V, N10S, S13K, T14A, A30D, S32T, Q98L, N137S, G160S, I174V, S194T, F261L, S279T and F305S) were mutated in the strain isolated in this study (Fig, 1F).FIGURE 1.: The clinical manifestations of the case and the evolutionary characteristics of the isolated CVA6 strain. A: Clinical manifestations of limb paralysis in the patient. Photographs were taken with the patient’s informed consent. B: Cranial magnetic resonance imaging scan showed uneven distribution of bilateral cerebellar cortex with irregular margins, and multiple punctate pieces of long T1 and long T2 signal were seen in the cortex and subcortex. C: Phylogenetic analysis based on the VP1 region of CVA6. The blue triangles marked the EVA71 prototype strain. The prototype strain of CVA6 is labeled with a red star. Yellow circles marked representative strains that cause atypical HFMD. D: Nucleotide sequence comparison and homology analysis of the VP1 region of CVA6 strain. E: Amino acid sequence comparison and homology analysis of the VP1 region of strain CVA6. F: Amino acid mutation sites in the VP1 region of CVA6 strain.The CVA6 was originally discovered during a large outbreak of HFMD in Finland, in 2008. Since then, CVA6 outbreaks have occurred all over the world. The globally prevalent CVA6 strains can be categorized into 6 genotypes, labeled from A to F. The genotype D manifests further differentiation into D1~D3. Our study found that the isolate strain was the D3 subgenotype. The D3 subgenotype appears to be more adapted to local environments and exhibits a greater capacity for transmission.3 Numerous mutations have been observed at amino acid sites within the VP1 region of this isolate. These substitutions occurring in regions of the VP1 protein are believed to play a significant role in altering the virulence of CVA6.4 As the virus evolves, these changes could potentially impact the severity of the disease and the contagion’s spread, consequently posing challenges for public health and disease prevention. We identified that the CVA6 strain from Zhengzhou City was evolved and simultaneously present with CVA6 strains from other parts of China. Moreover, due to the vastness of China, different regions have different climates and environments, leading to possible differences in the transmission and replication capacity of CVA6. The current isolate has mutations in several amino acid sites in the VP1 region and substitutions in this region are vital for shifts in CVA6 virulence.4 Apart from the genetic recombination and evolution of viral strains, other aspects like environmental conditions, host factors (age, nutrition, previous vaccination, etc.) can also play a role in leading to different clinical manifestations.5 The study describes the clinical features of the case and performs a pathogenic analysis of the disease. In future clinical work, the CVA6 pathogen should be considered when diagnosing unknown causes of red rash and limb paralysis. And timely antiviral and rehabilitation treatment should be provided.