Viral Pathogenic Spectrum and Epidemiological Characteristics of Febrile Rash Illness in China From 2009 to 2021

Abstract

Objective:

The aim of this study was to monitor the spectrum of viral pathogens involved in febrile rash illness (FRI) and their epidemiology.

Methods:

A large-scale study was conducted in multiple provinces of China from 2009 to 2021. A total of 14,168 patients of all age groups were enrolled and tested for seven common viruses causing FRI: measles virus (MV), rubella virus (RuV), enterovirus (EV), varicella zoster virus (VZV), human parvovirus B19 (HPV B19), human herpes virus 6 (HHV6), and dengue virus (DENV).

Results:

Of 14,168 patients with FRI, 9,443 tested positive for a virus, thus yielding a viral positivity rate of 66.65%. Among the seven viruses detected, EV (61.04%), MV (23.32%), RuV (7.74%), and VZV (5.26%) had high detection rates and exhibited different age-specific positivity rates and seasonal prevalence patterns. Early in the Coronavirus Disease 2019 (COVID-19) pandemic, the number of EV, MV, RuV, and VZV cases significantly declined, and the seasonal patterns also changed in 2020, with delay or disappearance of traditional epidemic peaks.

Conclusions:

EV, MV, RuV, and VZV were found to be the main causal pathogens of FRI among patients in China, and their epidemic levels and seasonal patterns changed during the COVID-19 pandemic, because of large-scale implementation of non-pharmacological interventions.

Main article text

INTRODUCTION

Febrile rash illness (FRI) comprises a series of infectious diseases whose main clinical manifestations are fever, and skin or mucosal rash. These diseases include measles; rubella; hand, foot, and mouth disease (HFMD); varicella; dengue fever; dengue hemorrhagic fever; scarlet fever; typhoid fever; paratyphoid fever; and Lyme disease. These infectious diseases pose substantial threats to public health worldwide. A variety of pathogens, including viruses and bacteria, can cause FRI. Measles virus (MV), rubella virus (RuV), enterovirus (EV), varicella zoster virus (VZV), human parvovirus B19 (HPV B19), human herpes virus 6 (HHV6), and dengue virus (DENV) are common FRI-associated viruses. In general, the etiology of FRI is determined primarily according to the characteristics of the rash and other clinical manifestations. However, most FRI rashes are nonspecific; consequently, recognizing FRI-associated viruses is difficult. For example, even with typical clinical presentation, exanthem subitem caused by HHV-6 and clinical manifestations of infection with B19V are frequently misdiagnosed as measles or rubella [1–3]. Laboratory testing and surveillance are necessary to identify the pathogens causing FRI. Correct diagnosis of infectious viral FRI is essential for the proper treatment, prevention, and control of FRI. In 2020, the World Health Organization released the “Global Strategic Framework for Measles and Rubella 2021–2030,” which reaffirmed the goal of achieving and sustaining the elimination of measles and rubella in the next 10 years in six regions, and established a vision of “a world free of measles and rubella” [4]. The clinical presentation of some measles cases due to vaccine failure may no longer be typical. Therefore, distinguishing other pathogens causing FRI from MV and RV infections is also critical for the elimination and/or eradication of measles and rubella.

To clarify the viral pathogenic spectrum of FRI, etiological surveillance of FRI is important. Existing FRI-associated surveillance systems have been designed primarily for single diseases. For example, a surveillance system for measles and rubella was established to eliminate the diseases worldwide [5], and nationwide surveillance for HFMD has also been conducted in China since the 2008 outbreak in Fuyang city in Anhui Province [6]. In this study, FRI surveillance cases from 2009 to 2021 from ten sentinel provinces covering all geographical regions of China, including Anhui, Beijing, Guangdong, Hebei, Hunan, Shandong, Shanxi, Shaanxi, Shanghai, and Xinjiang, were selected to analyze the viral pathogenic spectrum and epidemiological characteristics of FRI cases in China, to gain insight into FRI-related viruses.

MATERIALS AND METHODS

Case sources and ethics statement

Active FRI surveillance among patients of all ages was conducted from January 2009 to June 2021 in ten provinces in China. Patients meeting the FRI case definition (clinical manifestation of fever >37.5°C for more than 1 day and generalized or localized skin or mucosal rash) were enrolled after they or their parents/guardians provided informed consent. On this basis, FRI cases were further classified as suspected cases of specific diseases. For example, cases with symptoms of cough, catarrhal rhinitis, or conjunctivitis were considered suspected measles cases; cases with enlarged cervical lymph nodes were considered suspected rubella cases; cases with a rash morphology of herpes were considered suspected varicella cases; cases with maculopapular blistering lesions on the oral mucosa, hands, and feet were considered suspected HFMD cases; cases with severe myalgia and arthralgia were considered suspected dengue fever cases; cases with infectious erythema were considered suspected human picornavirus B19 cases; and cases with a red maculopapular rash accompanied by a rash after fever relief were considered suspected exanthema subitem cases caused by HHV-6.

The standard operating protocol for surveillance developed by the China CDC, including guidelines for patient enrollment, specimen collection, laboratory testing, and data recording and management, was used in all participating hospitals and laboratories [7]. Detailed epidemiological information was collected through a uniform case reporting form by staff at sentinel hospitals [7]. This study was approved by the Ethics Committee of the National Institute for Viral Disease Control and Prevention, China Centers for Disease Control and Prevention, and all methods were performed in accordance with the relevant guidelines. Informed consent was obtained from the patients or their parents/guardians.

Specimen collection and laboratory testing

Different types of clinical specimens were collected from patients with FRI according to their clinical diagnoses (Table S1). Seven common viruses causing FRI, namely MV, RuV, VZV, EV, DENV, B19V, and HHV-6, were identified. Serum samples were tested for IgM antibodies to MV, RV, B19V, DENV, VZV, and HHV-6 with commercial enzyme-linked immunosorbent assay kits for the above six pathogens [7]. In addition, viral nucleic acid was extracted directly from clinical samples (throat swabs, feces, herpes fluid, and serum) with commercial kits (i.e., Invitrogen/Qiagen/Roche/Promega) or automated nucleic acid extraction equipment (i.e., from Qiagen/Roche/bioMerieux/Applied BioSystem company) [7]. Subsequently, MV, RuV, VZV, EV, DENV, B19V, and HHV-6 were identified through real-time reverse transcription polymerase chain reaction or polymerase chain reaction with commercial kits, according to the standard operating protocols for FRI surveillance [7].

Data collection and statistical analysis

A database of FRI cases, including epidemiological information and laboratory test results, was established and sorted in Excel 2016. Epidemiological characteristics were analyzed for only EV, MV, RuV, and VZV, because of the limited number of cases positive for B19V, HHV-6, and DENV. The patterns of age-specific positivity rates and seasonal trends in EV, MV, RuV, and VZV were analyzed through descriptive statistics. Patient age was described as median and interquartile range (IQR). On the basis of the age distribution, patients with FRI were divided into six age groups: <2, 2–4, 5–17, 18–39, 40–59, and ≥60 years. The months were seasonally divided into spring (March to May), summer (June to August), fall (September to November), and winter (December to February). Provinces in southern and northern China were divided by latitude: four regions (Anhui, Guangdong, Hunan, and Shanghai) were classified as southern China, whereas the other six provinces (Beijing, Hebei, Shandong, Shanxi, Shaanxi, and Xinjiang) were classified as northern China. Chi-squared tests and Cochran-Armitage trend tests were used to analyze significant differences in frequency data in SPSS 16.0, and P<0.05 was considered to indicate statistical significance.

RESULTS

Case detection profile

From January 2009 to June 2021, a total of 14,168 patients with FRI were enrolled in this study, including 12,495 from 2009 to 2019, and 1,673 from 2020 to June 2021 (Table 1). Of the 14,168 patients with FRI, 9,443 had a positive virus test, with a viral positivity rate of 66.65%. Among these positive patients, 5,849 were male, and 3,594 were female, and the detection rates were 67.62% (5,849/8,650) for males and 65.13% (3,594/5,518) for females. The viral detection rate among patients with FRI was significantly greater in males than females (χ²=9.368, P=0.002).

TABLE 1 |

Characteristics of enrolled patients with febrile rash illnesses (FRI) and laboratory-confirmed viral etiologies in China from 2009 to 2021.

	No. of all patients with FRIs	No. of viral positive patients	EV	MV	RuV	VZV	DENV	B19V	HHV-6
Total	14,168	9,443	5,764	2,202	731	497	36	99	114
Sex
Male	8,650	5,849	3,615	1,341	450	309	23	50	61
Female	5,518	3,594	2,149	861	281	188	13	49	53
Age groups (M, IQR)	2 (1, 8)	2 (1, 5)	2 (1, 3)	1 (0.67, 18)	14 (10, 19)	10 (6, 17)	7 (2, 13.25)	6 (2, 15)	4 (2, 11.75)
<2 years	5,366	3,881	2,430	1,285	66	48	7	22	23
2–4 years	4,100	2,988	2,609	220	47	50	8	17	37
5–17 years	2,446	1,515	636	139	379	275	13	42	31
18–39 years	1,624	876	69	428	223	119	7	16	14
40–59 years	456	162	11	125	13	4	1	2	6
≥60 years	176	21	9	5	3	1	0	0	3
Region
Northern	9,438	6,426	3,538	1,600	625	466	33	98	66
Southern	4,730	3,017	2,226	602	106	31	3	1	48
Months
1	632	406	106	185	50	53	2	5	5
2	537	363	59	228	22	43	1	5	5
3	1,329	764	237	329	128	42	3	17	8
4	2,117	1,489	848	391	184	35	5	13	13
5	2,755	1,988	1,314	419	159	34	7	13	42
6	2,034	1,514	1,131	217	80	67	1	14	4
7	1,400	959	713	140	35	55	5	6	5
8	951	607	435	119	8	36	1	6	2
9	870	561	433	76	10	30	1	5	6
10	513	272	205	26	12	17	3	1	8
11	560	304	187	29	17	43	5	11	12
12	470	216	96	43	26	42	2	3	4
Rash type*
Maculopapules	3,506	2,322	822	1,076	336	17	6	11	43
Macula	504	311	149	114	38	2	2	5	1
Rose rash	50	26	3	3	18	2
Purulent herpes	28	18	16	1					1
Herpes	2,893	1,998	1,602	32	10	292		2	47
Papules	1,887	965	608	200	59	24	16	28	18

*Information on rash type was missing in some FRI cases.

FRI-associated viruses were detected in patients of all age groups, and the median age of virus-positive patients with FRI was 2 years (IQR, 1–5). A total of 6,869 patients were children under 5 years of age, accounting for 72.74% of the virus-positive patients with FRI. Further analysis revealed that the proportions of virus-positive FRI cases tended to decrease with age: 41.10%, 31.64%, 16.04%, 9.28%, 1.72%, and 0.22% of patients were <2, 2–4, 5–17, 18–39, 40–59, and ≥60 years of age, respectively. A significant difference in detection rates was observed among age groups (χ ²=727.558, P=0.001). Statistically significant differences were found between all age groups except between the <2 year and the 2–4 year age groups. The viral detection rates in FRI cases were high throughout the year, and the monthly positivity rate fluctuated between 45.96% and 74.43%. In terms of regional distribution, the viral detection rate was significantly greater (χ ²=26.236, P=0.001) in northern China (68.09%) than southern China (63.78%).

Viral detection rate and pathogenic spectrum

Among the 14,168 FRI cases, EV (5,764 cases, 40.68%) was the most frequently detected virus, and was followed by MV (2,202 cases, 15.54%), RuV (731 cases, 5.16%), VZV (497 cases, 3.51%), HHV-6 (114 cases, 0.80%), B19 (99 cases, 0.70%), and DENV (36 cases, 0.25%). These viruses accounted for 61.04%, 23.32%, 7.74%, 5.26%, 1.21%, 1.05%, and 0.38% of the 9,443 virus-positive FRI cases, respectively (Fig 1).

FIGURE 1 |

Viral spectrum in patients with FRI from 2009 to 2021.

A: Detection of seven viruses in patients with FRI. B: Proportions of EV serotypes among HFMD cases annually.

Data on rash types were collected from 8,868 FRI cases, including maculopapules, macula, rose rash, purulent herpes, herpes, and papules (Table 1). Among the virus-positive FRI cases, maculopapules, herpes, and papules were the predominant rash types, accounting for 41.17%, 35.43%, and 17.11%, respectively. The rash types caused by different viruses showed differing characteristics; for example, HFMD and varicella manifested primarily as herpes (accounting for 50.06% and 86.65%, respectively), whereas measles and rubella manifested primarily as maculopapules (accounting for 75.46% and 72.89%, respectively). Other viruses were not analyzed because of the limited data for other rash types.

Chronological analysis indicated that the viral spectrum of FRI cases in 2009–2019 slightly differed from that in 2020–2021. The proportions of each virus among the virus-positive patients with FRI in 2009–2019 were, in descending order, EV (58.90%), MV (25.43%), RuV (8.46%), VZV (4.94%), B19 (1.19%), HHV-6 (0.65%), and DENV (0.43%). However, during 2020 to June 2021, the proportions of EV (76.79%), VZV (7.62%), and HHV-6 (5.31%) increased, whereas those of MV (7.79%) and RuV (2.48%) decreased, and the other two viruses (B19 and DENV) were not detected.

EV serotypes were further identified in 3,678 patients and were found to comprise 2,137 (56.10%) EVA71 cases, 751 (20.42%) CVA16 cases, 654 (17.78%) CVA6 cases, 104 (2.83%) CVA10 cases, and 32 (0.87%) cases of other enteroviruses. The chronological distribution patterns indicated that CVA6 and CVA10 have gradually replaced EV71 and CVA16 as the main pathogens causing HFMD since 2018 (Fig 1). Twenty-three patients (0.63%) were coinfected with at least two serotypes of EV, and the most common coinfecting viruses were EVA71 and CAV16 (ten patients), followed by EVA71 and CVA10 (six patients).

Patterns of age-specific positivity rates for EV, MV, RuV, and VZV

Because of the limited number of cases of B19, HHV-6, and DENV, follow-up analyses were conducted for four viruses: EV, MV, RuV, and VZV. Analysis of age-specific positivity rates revealed that the median age of patients with FRI varied among the four viral infections: 2 years (1–3 years) for EV, 1 year (8 months to 18 years) for MV, 14 years (10–19 years) for RuV, and 10 years (6–17 years) for VZV.

Further analyses of the age groups of individuals infected with the four viruses revealed that among the 5,764 EV-positive patients with HFMD, the main affected population comprised young children under 5 years of age, and the proportions of cases in children younger than 2 years and 2–4 years of age were 42.16% (2,430/5,764) and 45.26% (2,609/5,764), respectively. Among patients with FRI, the highest positivity rate for EV was found in patients 2–4 years of age (63.63%, 2,609/4,100), followed by those <2 (45.29%, 2,430/5,366), 5–17 (26.00%, 636/2,446), ≥60 (5.11%, 9/176), 18–39 (4.25%, 69/1,624), and 40–59 (2.41%, 11/456) years of age.

Among the 2,202 MV-positive patients, infections occurred primarily in infants younger than 2 years (58.36%, 1,285/2,202) and in adults 18–39 years of age (19.44%, 428/2,202). Among infants younger than 2 years, 41.56% (534/1,285) were younger than 8 months. Higher positivity rates were found in infants younger than 2 years (23.95%, 1,285/5,366), adults 18–39 years of age (26.35%, 428/1,624), and adults 40–59 years of age (27.41%, 125/456).

In contrast to EV and MV infections, RuV infection was concentrated primarily in children and adolescents 5–17 years of age (51.85%, 379/731) and adults 18–39 years of age (30.51%, 223/731). Higher positivity rates were also observed in children and adolescents 5–17 years of age (15.49%, 379/2,446) and adults 18–39 years of age (13.73%, 223/1,624).

Similarly to the observations of RuV infection, VZV infection was concentrated in patients 5–17 years of age (55.33%, 275/497); this age group also had the highest positivity rate (11.24%, 275/2,446). For the above four viruses, significant differences in positivity rates were observed among age groups (P<0.05). Notably, the trend in age-specific positivity rates for each virus in 2009–2019 was generally consistent with that in 2020–2021.

Seasonal epidemic pattern

EV, MV, RuV, and VZV were detected throughout the year and showed differing seasonal epidemic patterns in patients with FRI. During the 2009–2019 period, HFMD cases infected with EVs were concentrated between April and July, and the overall rate of EV positivity peaked around June. However, during early stages of the Coronavirus Disease 2019 pandemic (COVID-19) (January to June 2020), the number of HFMD cases was significantly lower than that in the same period during 2009–2019, and the previous spring-summer peak was delayed until autumn (September) 2020 and returned to the spring (May) peak thereafter, in 2021 (Fig 2).

FIGURE 2 |

Seasonal epidemic patterns of EV, MV, RuV, and VZV in patients with FRI from 2009 to 2021.

Note: The number of cases per month from 2009 to 2019 was the average number of cases per month from 2009 to 2019.

The seasonal epidemic patterns of MV and RuV in China were similar, occurring primarily in winter and spring during the 2009–2019 period, with cases concentrated between March and May. However, the number of both measles and rubella cases decreased significantly and remained relatively low during the COVID-19 pandemic, and the original winter-spring pattern was interrupted (Fig 2). In January 2020, the numbers of both measles and rubella cases were abnormally high, because of clusters of measles and rubella cases reported in the cities of Handan and Tangshan, respectively, in Hebei Province.

For varicella, a two-peak epidemic pattern (June to July, and November to January) was found in 2009–2019. In contrast, during the COVID-19 epidemic, the number of varicella cases markedly decreased in the first half of 2020, and the original first peak of the epidemic was delayed by 1 or 2 months, to August, and subsequently returned to June 2021 (Fig 2).

Notably, the seasonal pattern of the HFMD epidemic differed between southern and northern China. In southern China, two epidemic peaks were observed, from April to July and from September to November. However, in northern China, only one epidemic peak occurred, primarily from April to September. However, differences between northern and southern China were not observed for the other three viruses.

DISCUSSION

In this study, we described the common viral infections in patients with FRI from ten provinces of China, on the basis of 13 consecutive years of FRI surveillance data from 2009 to 2021. Overall, 66.65% of the patients tested positive for a virus, in agreement with data reported from other regions of China [8–11]. Among the FRI cases, EV was the most commonly detected virus, and was followed by MV, RuV, and VZV. Similar results have been found in other provinces or regions in China. For example, the four most common FRI-related viruses were EV, MV, VZV, and RuV, in that order, in Gansu Province from 2009 to 2019 [8]; EV, MV, RuV, and VZV in the Pudong New Area of Shanghai from 2010 to 2017 [9]; and MV, RuV, EV, and VZV in Shanxi Province from 2009 to 2015 [10]. Therefore, although the order of predominant viruses in patients with FRI varied slightly among regions, EV, MV, RuV, and VZV were considered the main causal pathogens of FRI in China. In comparison, in a population-based study of infectious FRI etiologies in Campinas, Brazil, low measles and rubella virus transmission and HHV-6, EBV, B19, and RuV were the most frequent causes of infection [12]. Thus, the composition of the FRI viral spectrum was closely associated with the prevalence of different FRI diseases, as well as geographical and climatic conditions in different geographical areas.

HFMD is an important public health problem in many countries, particularly in the Asia-Pacific region [13,14]. In China, HFMD is a highly prevalent infectious disease and has been the most common notifiable infectious disease in China since 2010 [15]. In recent years, HFMD in China has been characterized by a wide distribution, high incidence, and long peak duration, and has become a serious public health problem endangering health among infants and young children [15]. Cases of the most common FRI, HFMD, were concentrated in children under 5 years of age, and epidemic peaks occurred in spring and summer in China. However, the seasonal pattern showed regional characteristics, with a single peak (April to September) in northern China and a double peak (April to July, and September to November) in southern China, in agreement with previous descriptions in the literature [16–18]. Thus, region-targeted strategies for the prevention and control of HFMD are essential. The viral spectrum of HFMD in China showed dynamic changes over the years; for example, in 2008–2012, the main pathogens causing HFMD were EV71 and CVA16 [19,20]; after 2013, CVA-6 caused HFMD outbreaks and epidemics in many areas, and was followed by high incidence of non-EV71 and non-CVA16, and a decreasing trend in the proportion of EV71 [20,21]; since 2018, the intensity of the EV71 epidemic has further declined, probably because of vaccination, whereas other EVs, such as CVA6 and CVA10, have continued to be prevalent [22]. Because these viruses can also cause severe and fatal cases, continuous etiological surveillance of HFMD-associated viruses is critical for HFMD prevention and control.

Measles and rubella are viral infectious diseases targeted for elimination worldwide. With the implementation of immunization with two doses of measles and rubella-containing vaccine (1^st dose: 8 months of age; 2^nd dose: 18 months of age) in China, the incidence of measles and rubella has gradually decreased in recent years and has remained low since 2020 (<1 per million) [23,24]. Moreover, the seasonal distribution characteristics are no longer clear. Nevertheless, recent serological surveys in several provinces have indicated relatively low overall antibody levels in the population [25,26], and most regions have not reached the threshold for herd immunity required by the WHO (measles, >92%; rubella, >85%) [27,28]. Additionally, in agreement with previous reports [29], the age of measles onset showed a bidirectional shift: unvaccinated infants younger than 8 months and adults 18–39 years of age with low antibody levels were the main groups with MV infection, whereas rubella cases in China were concentrated primarily in children and adolescents 5–17 years of age and adults 18–39 years of age. Accordingly, vigilance remains necessary to prevent potential recurrence risks of measles and rubella despite the current low incidence, because effective immune barriers for measles and rubella have not been established, and susceptible populations continue to exist.

Varicella is a highly contagious respiratory disease with a high disease burden in China. According to the 2019 National Infectious Disease Reporting System, varicella is the third most common vaccine-preventable infectious disease after tuberculosis and influenza and thus has become a great public health concern in China [30]. Studies, including ours, have indicated that varicella-zoster viral infections are concentrated primarily in children and adolescents 5–17 years of age [31]. Because varicella is currently not a notifiable infectious disease in China, and the virus is prone to cause outbreaks in places where people gather, such as schools and kindergartens, sufficient attention to this disease and further improvement in the emergency response capacity are warranted to prevent the spread of the virus.

In the early stages of the COVID-19 pandemic, the number of patients with FRI infected with viruses such as EV, MV, RuV, and VZV declined significantly, because of the massive implementation of nonpharmaceutical interventions (NPIs); therefore, NPIs appear to have effectively decreased viral transmission. In 2020, seasonal changes were observed for EV, MV, RuV, and VZV, wherein previous epidemic peaks were delayed or disappeared, then returned to their original peaks in the following year, in agreement with findings from published studies [32,33].

Notably, during the COVID-19 pandemic, fewer gathering activities, and increased personal hygiene and health awareness, decreased the risk of viral exposure. Moreover, the above measures might have resulted in the accumulation of susceptible populations and a decline in herd immunity [34], thus potentially increasing the likelihood of future epidemics of infectious disease. Respiratory infectious diseases such as influenza and respiratory syncytial virus were affected by the COVID-19 pandemic: their incidence first declined sharply and subsequently markedly rebounded [35–38]. In late 2022, an unprecedented epidemic occurred in several American and European countries, with simultaneous circulation of SARS-CoV-2, influenza virus, and respiratory syncytial virus in children, thus further burdening already strained health care systems [39]. A similar situation occurred in some cities in China in 2023, when cocirculation of multiple respiratory pathogens led to a substantial decrease in medical resources [40,41]. FRI-associated viruses must be continually monitored, and appropriate intervention measures should be taken to prevent the resurgence of related infections and potential outbreaks.

In addition, regular vaccination programs against infectious diseases should be maintained to protect children against FRI-associated viruses and further prevent the community spread of diseases [34]. Measles, rubella, and varicella are vaccine-preventable diseases. However, routine immunization might be challenging, because mass vaccination with the SARS-CoV-2 vaccine has increased the pressure on already strained health resources. Consequently, a decline in routine vaccination coverage for these viral diseases might occur. People who do not receive timely vaccination face elevated risk of viral infection when NPIs are relaxed. Therefore, intensifying routine immunization should be prioritized to strengthen immunity and protect susceptible populations against viral infection.

This study has several limitations. Many pathogens can cause rashes, including viruses, bacteria, and fungi. Because of limited surveillance data on the etiology of FRS cases, only seven of the most common viruses were analyzed in this study. Therefore, ongoing and wider pathogenetic surveillance of rash cases will be essential.

CONFLICTS OF INTEREST

The authors have no competing interests to declare.

SUPPLEMENTARY MATERIAL

Supplementary Material can be downloaded from https://zoonoses-journal.org/wp-content/uploads/2024/09/zoonoses20240024_Suppl.pdf

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