Hand-foot-and-mouth disease (HFMD) is an infectious disease which mainly affects children under 5 years of age. HFMD is characterized by low-grade fever, general malaise, and vesicles or papulae on the palms, soles, and buttocks.
Since firstly reported in 1957 [
In 2008, HFMD characterized by onychomadesis in later phase was first reported in Finland [
We have also encountered atypical HFMD in Chongqing, China, in 2013. This disease had similar manifestations to chickenpox, impetigo, and measles. Thus, it is easy to be misdiagnosed, subsequently causing delayed therapy and subsequent epidemic. To date, no study has been conducted to report the clinical and epidemiological characteristics of atypical HFMD. Chongqing is a southwestern city of China with a large population, a relatively poor sanitary condition, and a high incidence of infectious diseases. Thus, we should pay more attention to the prevention of HFMD. This study aimed to summarize the epidemiological, clinical, and etiological characteristics of atypical HFMD diagnosed between September 2013 and August 2014 in Chongqing, China, which may be helpful for the diagnosis, differential diagnosis, and therapy of HFMD.
A total of 887 hospitalized children were diagnosed with HFMD in the Children’s Hospital of Chongqing University between September 2013 and August 2014. Of these patients, 64 children (7.2%, 64/887) with atypical HFMD were recruited into this study for further analysis. Informed consent was obtained. This study has been approved by the Ethics Committee related to the Children’s Hospital of Chongqing University.
HFMD patients with following characteristics were recruited into present study. Characteristics of atypical rashes were as follows: (1) distribution: papules and/or vesicles (diameter < 5 mm) being also found in other sites such as face, neck, perioral area, trunk, limbs, and externalia besides the palms, soles, and buttocks; and/or (2) morphology of rashes: large vesicles or bullae (diameter > 5 mm), erosive lesions, purpuric/petechial lesions, or “eczema coxsackium” at any site [
(1) Informed consent was not obtained from their parents or their parents withdraw from this study before the end of study; (2) stools were not collected, or the clinical information was incomplete; (3) there were skin lesions caused by other diseases (such as chickenpox, impetigo, and measles).
This study was approved by the Ethics Committee of Children’s Hospital of Chongqing University (number: 105/2014). Informed consent was obtained from parents of participants before study. Stools were collected from 64 children with atypical HFMD in acute phase (within 3 days after disease onset) and stored at −80°C for further detection. In addition, the rashes were photographed, and onychomadesis, desquamation, and sequelae were closely monitored during follow-up period. The patients’ characteristics and clinical manifestations were collected from the medical record. At the same time, the characteristics of all the patients with different types of HFMD were also recorded in the same period for the epidemiological comparisons.
RNA was extracted from stool samples by using QIAampH MinElute Virus Spin Kits (Qiagen, Hilden, Germany) and cDNA was synthesized by using Reverse Transcription System A3500 (Promega, Madison, WI, USA) according to the manufacturer’s instructions. Nested-PCR was performed to detect universal enteroviruses (EV-U), EV-A71, CV-A16, respectively, while ordinary PCR was performed to detect CV-A6. Primers for CV-A6 were 5′-TGGTAGGAGTTGTGGAGGT-3′ (forward) and 5′-CCTTCATAATCYGTAGTGGTT-3′ (reverse), which was constructed by ourselves. And primers for other genes were obtained from the study of Ge et al. [
Data with normal distribution were expressed as mean ± standard deviation (
During this study, a total of 887 hospitalized children were diagnosed with HFMD, of whom 7.2% (64/887) were atypical HFMD. Both total and atypical HFMD had two peaks in their incidences. The proportion of atypical HFMD varied over time and ranged from 1.9% to 30.4%. The proportion was the highest from January to March, a season transiting from winter to spring, in which atypical HFMD accounted for 30.4% (7/23), 17.6% (3/17), and 12.5% (4/32), respectively. From January to March, the highest proportion of atypical HFMD was found in January. Another peak was found from August to October in which the proportion of atypical HFMD was 12.1% (4/33), 7.8% (6/77), and 5.3% (6/114), respectively. Besides, atypical HFMD was also found in other seasons. However, total HFMD peaked from April to July, a season transiting from spring to summer, in which total HFMD accounted for about 52.2% in the study period (443/887). The second peak was found from September to November, a season transiting from autumn to winter, and total HFMD in these months accounted for 31.5% in the study period (279/887) (Figure
Proportion of atypical HFMD to total HFMD per month and number of total HFMD in each month. Black: proportion of atypical HFMD; white: number of total HFMD.
Among the 64 children with atypical HFMD, there were 40 males and 24 females with the male to female ratio of 1.67 : 1. The age of children ranged from 6 months to 48 months (median: 15 months). Atypical HFMD mainly occurred in children younger than 3 years, which accounted for 93.8% (60/64), and 54.7% (35/64) of children were younger than 1 year. Most patients lived in the city (62.5%, 40/64). A majority of children lived scattered (79.7%, 51/64) and remaining children were on nursery care (15.6%, 10/64) and schooling (4.7%, 3/64) (Table
Demographic and clinical presentations of patients with atypical HFMD.
Variables | Atypical HFMD ( |
95% CI |
---|---|---|
|
||
Age (years) | ||
≤1 | 35 (54.7) | 53.7%~55.7% |
1–3 | 25 (39.1) | 37.9%~40.3% |
>3 | 4 (6.2) | 5.5%~6.9% |
Sex | ||
Male | 40 (62.5) | 61.6%~63.4% |
Female | 24 (37.5) | 36.3%~38.7% |
Residence | ||
Urban | 40 (62.5) | 61.6%~63.4% |
Rural | 24 (37.5) | 36.3%~38.7% |
Children care | ||
Home care | 51 (79.7) | 79.1%~80.3% |
Nursery care | 10 (15.6) | 14.6%~16.6% |
Schooling | 3 (4.7) | 4.1%~5.3% |
|
||
Fever | ||
≥37.5°C | 51 (79.7) | 79.1%~80.3% |
<37.5°C | 13 (20.3) | 19.2%~21.4% |
Cough | ||
Yes | 20 (31.3) | 30.1%~32.5% |
No | 44 (68.7) | 67.9%~69.5% |
Rhinorrhea | ||
Yes | 15 (23.4) | 22.3%~24.5% |
No | 49 (76.6) | 76.0%~77.2% |
Salivation | ||
Yes | 41 (64.1) | 63.2%~65.0% |
No | 23 (35.9) | 34.7%~37.1% |
Diarrhea | ||
Yes | 9 (14.1) | 13.1%~15.1% |
No | 55 (85.9) | 85.5%~86.3% |
Poor oral intake | ||
Yes | 43 (67.2) | 66.4%~68.0% |
No | 21 (32.8) | 31.6%~34.0% |
Vomiting | ||
Yes | 5 (7.8) | 7.0%~8.6% |
No | 59 (92.2) | 92.0%~92.4% |
Headache | ||
Yes | 2 (3.1) | 25.8%~36.2% |
No | 62 (96.9) | 96.8%~97.0% |
Febrile seizure | ||
Yes | 8 (12.5) | 11.6%~13.4% |
No | 56 (87.5) | 87.1%~87.9% |
Startle response | ||
Yes | 10 (15.6) | 14.6%~16.6% |
No | 54 (84.4) | 84.0%~84.8% |
Altered consciousness | ||
Yes | 1 (1.6) | 1.2%~2.0% |
No | 63 (98.4) | 98.3%~98.4% |
Limb trembling | ||
Yes | 2 (3.1) | 2.6%~3.6% |
No | 62 (96.9) | 96.8%~97.0% |
Unsteady gait | ||
Yes | 1 (1.6) | 1.2%~2.0% |
No | 63 (98.4) | 98.3%~98.4% |
HFMD, hand-foot-and-mouth disease. Statistical analysis was performed with SPSS version 17.0 (SPSS Inc., Chicago, IL, USA). A value of
Atypical HFMD children usually presented with fever (79.7%, 51/64), poor appetite (67.2%, 43/64), and salivation (64.1%, 41/64). In addition, 10 children had manifestations of neurologic involvement of whom the startle response (15.6%, 10/64), vomiting (7.8%, 5/64), and convulsion (12.5%, 8/64) had higher prevalences, but headache and limb trembling were found in only 2 patients, unconsciousness in 1 and unsteady gait in 1. Severe atypical HFMD was observed in 5 patients (7.8%, 5/64), of whom 4 had severe atypical HFMD (6.3%, 4/64) and 1 had critically severe atypical HFMD (1.5%, 1/64), but all these children recovered smoothly after therapy without any sequela (Table
Rashes of atypical HFMD were distributed not only in typical sites but on other sites (such as lower limbs
Rashes and complications of patients with atypical HFMD.
Variables | Atypical HFMD ( |
95% CI |
---|---|---|
|
||
Palm/soles | ||
Yes | 51 (79.7) | 79.1%~80.3% |
No | 13 (20.3) | 19.2%~21.4% |
Oral ulcer | ||
Yes | 47 (73.4) | 72.7%~74.1% |
No | 17 (26.6) | 25.4%~27.8% |
Face | ||
Yes | 34 (53.1) | 52.1%~54.1% |
No | 30 (46.9) | 45.8%~48.0% |
Torso | ||
Yes | 27 (42.2) | 41.1%~43.3% |
No | 37 (57.8) | 56.8%~58.8% |
Arms | ||
Yes | 19 (29.7) | 28.5%~30.9% |
No | 45 (70.3) | 69.5%~71.1% |
Legs | ||
Yes | 36 (56.3) | 55.3%~57.3% |
No | 28 (43.7) | 42.6%~44.8% |
Buttocks | ||
Yes | 50 (78.1) | 77.5%~78.7% |
No | 14 (21.9) | 20.8%~23.0% |
Externalia | ||
Yes | 9 (14.1) | 13.1%~15.1% |
No | 55 (85.9) | 85.5%~86.3% |
|
||
Vesicle | ||
Yes | 41 (64.1) | 63.2%~65.0% |
No | 23 (35.9) | 34.7%~37.1% |
Papula | ||
Yes | 44 (68.8) | 68.0%~69.6% |
No | 20 (31.2) | 30.0%~32.4% |
Bulla | ||
Yes | 13 (20.3) | 19.2%~21.4% |
No | 51 (79.7) | 79.1%~80.3% |
Erosions | ||
Yes | 2 (3.1) | 2.6%~3.6% |
No | 62 (96.9) | 96.8%~97.0% |
|
||
Desquamation | ||
Yes | 15 (23.4) | 22.6%~24.5% |
No | 49 (76.6) | 76.0%~77.2% |
Onychomadesis | ||
Yes | 14 (21.9) | 20.8%~23.0% |
No | 50 (78.1) | 77.5%~78.7% |
HFMD, hand-foot-and-mouth disease. Statistical analysis was performed with SPSS version 17.0 (SPSS Inc., Chicago, IL, USA). A value of
Characteristics of rashes in atypical HFMD. (a) A boy aged 1 year, and papulae were mainly distributed on the perioral area and face; (b) a boy aged 1 year and 1 month, and papulae/vesicles were found at the back; (c) a girl aged 1 year and 6 months, and papulae were found on the hand; (d) a boy aged 1 year and 8 months, and erosions were noted in both feet.
All the children received follow-up after therapy. Of these patients, 14 (21.9%, 14/64) developed onychomadesis and 15 (23.4%, 15/64) had desquamation. In 14 children with onychomadesis, the most common virus in children with onychomadesis was CV-A6 (71.4%, 10/14), followed by nontypable enterovirus (14.3%, 2/14) and EV-A71 (14.3%, 2/14). The mean time to onychomadesis was 4.7 weeks after the acute phase of HFMD (range: 2–7 weeks), and onychomadesis was usually found at 5th week (5/14, 35.7%). Onychomadesis was mainly found in the right thumb (8/14, 57.1%) and with a mean of 4.7 fingers/toes (range: 1–20). The most common virus in children with desquamation was CV-A6 (80%; 12/15), followed by nontypable enterovirus (13.3%, 2/15) and EV-A71 (6.7%; 1/15). The mean time to desquamation was 4.3 weeks after the acute phase of HFMD (range: 2–8 weeks) and desquamation was usually found at 4th week (5/15, 33.3%). Of note, desquamation was often found at the sites with rashes (12/15, 80.0%) (Table
Incidences of onychomadesis and desquamation in atypical HFMD children at different time points.
Among these 64 patients with atypical HFMD, RT-nested PCR showed all the samples were positive for EV-U, and the most common pathogen was CV-A6 (67.2%; 43/64), followed by nontypable enterovirus, EV-A71, and CV-A16 which were found in 26.6% (17/64), 4.7% (3/64), and 1.5% (1/64) of patients, respectively. Furthermore, sequencing was performed in 43 samples positive for CV-A6 and the fragment was 630 bp in length. After homology analysis of nucleotides and amino acids, results showed the homology of CV-A6 was 87.6%–100% and 94.5%–100% in the nucleotides and amino acids, respectively, as compared with the strain found in Spain, Finland, Japan, and Taiwan (Figure
Phylogenetic analysis of coxsackievirus A6 strains based on the partial VP1 gene sequence (nucleotide position: 254–864). ■: virus separated in the present study, and remaining viruses were from Genbank including 2011 Spain strains (JX845228, JX845232, KC431247, and KC431252), 2000–2011 Japan strains (AB114096, AB234336, AB234337, AB234338, AB649286, AB649287, AB649288, AB649289, and AB649291), 2010 Finland strains (HE572902, HE572930, and HE572939), and 2009–2011 Taiwan strains (JN582001, JQ946051, and JQ946054).
The clinical characteristics of atypical HFMD are usually atypical, which brings difficulty to the clinical diagnosis and therapy of HFMD, which may cause misdiagnosis and delayed therapy, resulting in regional or large-scale epidemic. To date, no study has been conducted to investigate the epidemiological and clinical characteristics of atypical HFMD. In the present study, we for the first time described the epidemiological, clinical, and etiological characteristics of atypical HFMD in Chongqing, China, between September 2013 and August 2014. Our findings may provide significant evidence for the clinical diagnosis, timely isolation, and therapy of atypical HFMD.
Results of this study showed that atypical HFMD had obviously seasonal prevalence, was often found in young children and in urban children, and usually predicted a good prognosis. In atypical HFMD children, rashes were widely distributed, skin lesions were severe, and the incidences of onychomadesis and desquamation were relatively high in late phase of atypical HFMD. Further etiological analysis showed CV-A6 was a major pathogen causing atypical HFMD, which had a high homology to the strain found in Finland, Taiwan, and other regions.
In the study period, the prevalence of atypical HFMD showed seasonal characteristics, and its incidence varied in different seasons. The incidence of atypical HFMD was high in the seasons transiting from winter to spring and from summer to autumn, but that of total HFMD was high in the seasons transiting from spring to summer and from autumn to winter. That is, the peak of atypical HFMD occurred in the troughs of total HFMD, but that of total HFMD occurred in the troughs of atypical HFMD. It is well known that the pathogenesis of HFMD is closely related to climatic factors such as temperature, humidity, and rainfall. The higher the humidity and temperature, the higher the possibility the presence of HFMD has within a certain range [
In our study, atypical HFMD was mainly found in children younger than 3 years old, and more than 50% children (54.7%) were younger than 1 year old. This was similar to findings in the study of Puenpa et al. [
In the present study, only 15.6% of children with atypical HFMD had manifestations of neurologic involvement. Further analysis showed 4 cases were severe HFMD and 1 was critically severe HFMD, but all of these children recovered smoothly after therapy without sequelae, suggesting a good prognosis. This was in agreement with findings reported by Huang et al. [
In children with atypical HFMD, the rashes were widely distributed and were diverse in morphology, which were in accordance with previously reported data in USA and Japan [
In late phase, the incidences of onychomadesis and desquamation were relatively high. A lot of pathogens may cause onychomadesis and desquamation, but CV-A6 is a major pathogen, which was in accordance with findings reported in Taiwan [
In early studies on the etiology of HFMD, results showed EV-A71 and CV-A16 were the major pathogens [
There were still limitations in the present study. First, not all the children with atypical HFMD were hospitalized for therapy, and thus the sample size of atypical children was still small. The clinical features collected from the hospitalized children with atypical HFMD might not represent the characteristics of all the children with atypical HFMD. In addition, some parents might neglect the onychomadesis and desquamation in late phase, which may underestimate the incidence of complications.
Taken together, the atypical HFMD has an obviously seasonal prevalence, special clinical manifestations, and a relatively good prognosis. Rashes in atypical HFMD are widely distributed and are diverse in morphology, the incidences of onychomadesis and desquamation are relatively high in late phase, and atypical HFMD is mainly caused by CV-A6 in Chongqing, China.
The authors declare that there is no conflict of interests regarding the publication of this paper.
Xiang Yan and Zhen-Zhen Zhang are equal contributors.
The authors are grateful to Mei-Hua Li and Hui-Yin Mao in Department of Infection in Children’s Hospital of Chongqing Medical University for providing and collecting samples and Fang-Fang Lai for providing excellent technical assistance.