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Viral etiology of febrile respiratory syndrome among patients in Liaoning Province, China

BMC Infectious Diseases volume 24, Article number: 1060 (2024) Cite this article

Abstract

Background

Febrile respiratory syndrome (FRS) is often associated with viral infections. The aim of this study was to identify the viral pathogens responsible for FRS in Liaoning Province, China.

Methods

We tested eight respiratory viruses, namely, influenza virus (IFV), rhinovirus (RV), human adenovirus (HAdV), human bocavirus (HBoV), human parainfluenza virus (HPIV), human coronavirus (HCoV), respiratory syncytial virus (RSV), and human metapneumovirus (HMPV), using reverse transcription-polymerase chain reaction (RT-PCR). Statistical analyses were performed using SPSS version 25.0, and the data were plotted using RStudio 4.2.1 software.

Results

IFV was the most frequently identified pathogen, followed by RV, HAdV, HBoV, HPIV, HCoV, RSV, and HMPV. RSV/HBoV coinfection occurred most frequently among the mixed cases. The rate of respiratory virus detection was highest in children under one year of age and decreased significantly with age. Seasonal trends showed a peak in virus detection during the winter months.

Conclusions

IFV is the leading cause of FRS in Liaoning Province, China, with single-virus infections prevailing over coinfections. Observations indicate a differential virus detection rate across age groups and seasons, highlighting the need for focused preventive strategies to mitigate the transmission of respiratory viruses, particularly among susceptible populations in the colder season.

Peer Review reports

Background

Acute respiratory infections (ARIs) pose a substantial global health challenge and are linked to significant morbidity and mortality [1, 2]. ARIs impact both adults and children, ranking among the foremost causes of disability [3]. Empirical studies have demonstrated that viral pathogens constitute the primary etiological agents responsible for ARIs [4,5,6,7,8].

Despite the considerable burden of viral respiratory infections, vaccines for prevention remain scarce [7]. A comprehensive understanding of the causative viral agents is vital for the development of effective preventive, control, and therapeutic interventions. Given its vast territory, China exhibits a range of climatic conditions across different regions, which shapes the epidemiological profiles of ARIs. Several studies have addressed ARIs in various Chinese locales, including Beijing, Shanghai, Qinghai, and Huzhou, but these studies often present varying epidemic characteristics due to inconsistencies in inclusion criteria and regional climatic differences [7, 9, 10].

Liaoning Province, nestled in northeastern China and endowed with a temperate monsoon climate, enjoys proximity to Japan and South Korea. With a population of 41.97 million, the province experiences substantial population movement, enhancing the potential for increased respiratory virus transmission. A study in Shenyang, Liaoning Province, indicates that the influenza-like illness is notably prevalent in the winter [11], a characteristic similar to other areas in northern China [12, 13], but distinct from the southern regions that exhibit two peaks of prevalence in the summer and autumn [14, 15]. This difference may be caused by climatic or meteorological factors. The aim of this study was to determine the prevalence of respiratory viruses within Liaoning Province to inform prevention and management strategies for respiratory diseases.

Methods

Patients and specimens

Between January 2018 and December 2019, 730 patients with febrile respiratory syndrome (FRS) were identified from 18 sentinel hospitals in Liaoning Province, China. The inclusion criteria for patients encompassed recent onset of chills, fever, abnormal white blood cell counts (either elevated, reduced, or atypical), coupled with at least one respiratory symptom, such as coughing, expectoration, rhinorrhea, pharyngitis, dyspnea, chest pain, abnormal breath sounds, or inflammatory changes evident in lung imaging reports. Additional patient symptom, clinical diagnosis, and demographic data were gathered from case reports.

Reagents and equipment

EZ1 Virus Mini Kit V2.0 Nucleic Acid Extraction Kit (Qiagen, Germany, cat. No. 955134), Reverse Transcriptase Promega® Reverse Transcription System (Promega, USA, cat. No. A3500); Multiplex PCR Kit Seeplex® RV12 ACE Detection (Seegene, USA, cat. No. RV6C00Y); Agarose (Sigma, USA, LOT: WXBB1741V); EZ1 Advanced XL Automated Nucleic Acid Extractor, Gradient PCR Machine, Gel Imaging System (QIAGEN, USA).

Laboratory analysis

Nucleic acid detection is performed using the reverse transcription-polymerase chain reaction (RT-PCR) method. After pre-treatment of throat swab specimens, 200 µL of extracted nucleic acid is aspirated. The extracted nucleic acid should be used immediately or stored at -70 Â°C. RT-PCR and multiplex PCR are used for nucleic acid detection of influenza virus (IFV), respiratory syncytial virus (RSV), rhinoviruses (RV), human parainfluenza virus (HPIV), human adenovirus (HAdV), human coronavirus (HCoV), human bocavirus (HBoV), and human metapneumovirus (HMPV), and human metapneumovirus (HMPV). Results are detected using a 2% agarose gel electrophoresis method. These procedures adhered to the guidelines provided by the test manufacturers, and all personnel involved in medical and laboratory procedures underwent standardized training. The analytical methods complied with relevant directives and standards.

Statistical analyses

Statistical analyses were performed using IBM SPSS Statistics, Version 25, and RStudio Version 4.2.1. Plots were generated using the ggplot2 package in RStudio. Descriptive statistics were used to summarize the distributions of sex, age, season, and viral infection rate. Chi-square tests and Fisher’s exact tests were used to compare infection rates across sex, age groups, and month distributions. A P value < 0.05 indicated statistical significance.

Ethics statement

This study was approved by the Ethical Committee of Liaoning Provincial Centers for Disease Control and Prevention. Oral informed consent was obtained from each participant, and this form of consent was confirmed by the Ethical Committee.

Results

Patient characteristics and clinical diagnosis

Between January 2018 and December 2019, we amassed data from 730 patients with FRSs across 18 sentinel hospitals in eight urban centers within Liaoning Province. In terms of occupation, the greatest number of FRS patients were retired, accounting for 20.7% (151/730) of patients, followed by 135 patients with scattered children, accounting for 18.5% (135/730) of patients, and students, accounting for 18.1% (132/730) of patients (Table 1). The patients included 408 males and 322 females, yielding a sex ratio of approximately 1.3:1. Patient ages ranged from 0 months to 93 years. We divided the patients into six groups: 0–1 years old, 33 patients; 1–5 years old, 151 patients; 5–18 years old, 162 patients; 18–40 years old, 105 patients; 40–65 years old, 144 patients; and ≥ 65 years old, 135 patients. The most common clinical symptoms observed were fever (95.2%, 695/730) and cough (77.0%, 562/730) (Table 2).

Table 1 Occupation of patients
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Table 2 Clinical symptoms and diagnoses of patients
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Viral etiologies

Of the 729 tested patients, 213 (29.2%) were positive for at least one virus. Single infections were identified in 187 (25.7%) patients, while coinfections occurred in 26 (3.6%) patients. The detailed infection profile for each virus is depicted in Fig. 1. The IFV demonstrated the highest positivity rate, reaching 7.8%, surpassing the RV, which registered a positivity rate of 6.7%. The detection rates for HAdV, HBoV, HPIV, HCoV, RSV, and HMPV were 4.4%, 4.0%, 3.6%, 2.6%, 2.6%, and 1.1%, respectively (Table 3). Among the eight cities in Liaoning Province, Dandong exhibited the highest detection rate at 39.0%, succeeded by Dalian, Jinzhou, Shenyang, Panjin, Chaoyang, Benxi, and Fuxin, with detection rates of 37.4%, 35.6%, 28.1%, 27.8%, 19.2%, 23.5% and 15.8%, respectively (Table 4).

Fig. 1
figure 1

Detection rates for single and coinfections of respiratory viruses. Notes: IFV, influenza virus; RSV, respiratory syncytial virus; HPIV, human parainfluenza virus; HAdV, human adenovirus; HMPV, human metapneumovirus; HCoV, human coronavirus; HBoV, human bocavirus; RV, rhinovirus

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Table 3 Virus detection conditions in febrile respiratory syndrome patients
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Table 4 Detection of any virus in different cities in Liaoning Province
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Detection percentages of virus distribution from different sex and age groups

The virus detection rate among males was 30.5%, while that among females was 27.6%. Although a disparity in the rate of virus positivity was observed between males and females, this disparity was not deemed statistically significant (P = 0.405). IFV, RV, HAdV, and HBoV were the most frequently detected viruses in both sexes (Table 5).

Table 5 The results of viral etiology surveillance of febrile respiratory syndrome in different genders
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There was significant variance in virus positivity rates across age groups (P < 0.001) (Table 6). The 0–1 year age group had the highest detection rate at 56.3%, followed by the 1–5 years (47.7%), 5–18 years (31.5%), 18–40 years (20.0%), 40–65 years (18.8%), and ≥ 65 years (17.8%) age groups. The positive detection rates of the virus decreased with age. In the 0–1 year age group, the detection rates of various viruses, ranked from highest to lowest, are as follows: HBoV, RV, HAdV, RSV, HPIV, HCoV, IFV, and HMPV, with respective detection rates of 21.9%, 15.6%, 15.6%, 9.4%, 3.1%, 3.1%, 0.0%, and 0.0%. The younger the age group was, the more pronounced the viral diversity. All eight viruses were detectable in the 1–5 year age group, with the most prevalent viruses across age segments being HBoV (0–1 years), RV (1–5 years), IFV (5–18, 18–40, and 40–65 years), and HCoV (≥ 65 years).

Table 6 The results of viral etiology surveillance of febrile respiratory syndrome in different age groups
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Detection percentages of viruses from different seasons

The virus detection rates varied greatly among months (P < 0.001). March recorded the highest prevalence of positive virus detection at 58.3%, trailed by December (49.1%) and January (47.1%). The monthly virus distribution details are shown in Figs. 2 and 3. The highest number of viruses was observed in November (n = 55) and December (n = 52). All viruses were detected in November and December. HBoV was the most commonly detected virus in November, and IFV was the most commonly detected virus in December. Although the monthly trend was not discernible, detection of viruses was notably higher during these two months.

Fig. 2
figure 2

Distribution of febrile respiratory syndrome patients from January to December. Notes: IFV, influenza virus; RSV, respiratory syncytial virus; HPIV, human parainfluenza virus; HAdV, human adenovirus; HMPV, human metapneumovirus; HCoV, human coronavirus; HBoV, human bocavirus; RV, rhinovirus

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Fig. 3
figure 3

Monthly distribution of febrile respiratory syndrome

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Coinfection with viruses

Coinfection was found in 26 out of 729 patients, for a detection rate of 3.6% (26/729). Among the positive patients, 12.2% (26/213) were positive. Coinfection was not significantly (P = 0.846) different in male patients (15/407, 3.7%) than in female patients (11/322, 3.4%). The coinfection rate varied significantly among age groups (P < 0.001). The highest detection rate was observed in the 0–1 years old group, at 12.5%, while the lowest detection rate was recorded in the 40–65 years old group, at 0.7%. All the patients with coinfections had dual infections. The RSV/HBoV combination was the most commonly encountered coinfection (Table 7).

Table 7 Detection of multiple viruses in febrile respiratory syndrome patients
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The study revealed that children and students had higher detection rates in coinfection. In terms of case types, the detection rate was higher among hospitalized patients compared to those in outpatient and emergency departments. All patients exhibited fever, and another common symptom was cough (Table 8).

Table 8 Coinfection patient characteristics and clinical presentation
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Among the viruses, IFV (50/57, 87.1%), RSV (13/19, 68.4%), HPIV (20/26, 76.9%), HAdV (26/32, 81.3%), HMPV (7/8, 87.5%), HCoV (15/19, 78.9%) and RV (42/49, 85.7%) were frequently detected as single viruses, with proportions above 50%, particularly in IFV and HMPV. However, HBoV (15/29, 51.7%) was primarily detected in coinfections (Fig. 4).

Fig. 4
figure 4

The quantity of single infections and coinfections for each virus. Notes: IFV, influenza virus; RSV, respiratory syncytial virus; HPIV, human parainfluenza virus; HAdV, human adenovirus; HMPV, human metapneumovirus; HCoV, human coronavirus; HBoV, human bocavirus; RV, rhinovirus

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Discussion

Globally, ARIs are a major cause of illness and fatality. In severe cases, ARIs can progress to acute respiratory distress syndrome (ARDS), a life-threatening condition [16]. In recent years, there has been a discernible shift in the etiology of respiratory illnesses, favoring atypical bacteria and viral pathogens, largely attributed to the overuse of antibiotics [17, 18]. Viruses, noted for their high transmissibility, extended incubation periods, and nonspecific clinical presentations, pose substantial challenges in disease prevention and control. As a result, timely and accurate identification of the virus causing acute respiratory infections is vital for preventing the inappropriate use of antibiotics and ensuring the use of suitable antiviral therapies.

In this study, at least one virus was detected in 729 patients in the FRS, 29.2% of whom tested positive for at least one virus. This percentage is lower than that in Shandong (35.75%) [7] and higher than that in Shenzhen (14.55%) [19]. This demonstrates the diversity and complexity of the etiology of FRS. IFV and RV were the most frequently detected respiratory viruses in our study, consistent with previous research [20, 21] but differing from other studies [22, 23]. In our investigation, fever and cough emerged as the predominant symptoms in FRS patients, aligning with previous research [9]. Therefore, it is necessary to strengthen this aspect of attention. In cases of fever and cough, patients should promptly seek medical advice.

Although males are often more susceptible to viral respiratory infections [24], our study revealed no significant sex difference in the incidence of respiratory viruses (P = 0.405), suggesting a lack of sex bias in viral respiratory infections, a finding corroborated by research from Qinghai Province in China [20].

There were no substantial differences in the detection rate of respiratory viruses between sexes; however, significant discrepancies were observed across various age groups (P < 0.001). In this study, infants under the age of one had the highest percentage of virus-positive individuals, while older adults (≥ 65 years) had the lowest percentage. Notably, virus positivity decreased with increasing age. This finding is consistent with previous studies [24, 25]. This trend could be ascribed to the comparatively weaker immune responses in infants or due to the higher likelihood of infants being presented to hospitals upon symptom manifestation. Empirical research indicates that infancy is a pivotal developmental window, during which environmental exposures, encompassing viral respiratory infections, have the potential to shape the remodeling of the airways and the functionality of the immune system [26]. The innate immune system in infants undergoes development and exhibits distinct characteristics compared to adults, such as attenuated interferon reactions, which could account for their heightened vulnerability to viral pathogens [27, 28]. Furthermore, the absence of immunological memory to invading pathogens in infants leads to a protracted viral clearance and an exacerbation in the severity of disease [29]. Different regions may have varying virus prevalence. Our study identified RV as the most prevalent virus in children aged 0–5 years, which contrasts with findings from the United States, where HBoV is more common [30], and Guangdong Province, where RSV dominates [31]. A study conducted in Japan has demonstrated that HBoV is a pathogen to which there is a widespread susceptibility during the early stages of life, a conclusion that is corroborated by our research [32]. One study revealed that IFV was the most common virus among those aged 5 ∼ 65 years, echoing research from India [33]. Furthermore, not only was IFV the most frequent virus detected within this particular age group, but it was also the most prevalent of all viruses detected. Influenza viruses can induce substantial lung damage [34] and may even precipitate severe or fatal complications [35]. Thus, enhancing IFV detection and vaccination rates is imperative. HCoV and RV were the viruses most commonly detected in the ≥ 65 age group. RV and HCoV are prone to occur in elderly individuals, infants and other immunocompromised populations.

Seasonality is a common feature of ARIs, especially in areas with temperate climates [20]. Typically, respiratory viruses are most active during the months of November through March in the Northern Hemisphere [30]. Our study’s findings mirrored this pattern, with peak virus positivity noted in March, trailed by December and January, possibly owing to environmental conditions like reduced humidity and cooler temperatures, conducive to viral longevity. Studies have indicated that under low-temperature conditions, the viability of viruses is enhanced, particularly for lipid-enveloped viruses. Furthermore, temperature and humidity can modulate the antiviral functions of the respiratory tract, including epithelial integrity, mucociliary clearance, and tissue repair capabilities, thereby influencing the host’s innate and adaptive immune responses [36, 37]. Moreover, the prevalence of FRS may be subject to the interactive effects of various meteorological factors, a complexity that poses challenges for prediction and intervention. Peaks for HCoV and HMPV occurred in May, while those for RV, HAdV, HBoV, and HPIV peaked in November. The incidences of IFV and RSV peaked in December, consistent with US data [38] but not with findings from Qingdao, China [20], indicating that there might be regional variations in the prevalence of the virus.

In our analysis, single infections predominated over coinfections, with the latter constituting merely 3% of instances, a figure lower than those documented in prior research [20, 39, 40]. However, coinfections were observed for all of the pathogens, and the number of coinfections with HBoV was greater than that of single infections. All the patients with coinfections had dual infections, with RSV/HBoV and HBoV/RV being the two most common types of coinfections, a finding consistent with studies from Changsha, China, as well as numerous other countries and regions around the world [41,42,43]. Coinfections likely result from initial viral damage to the respiratory mucosa, facilitating subsequent viral entry. Immune system dysfunctions linked to viral infections may raise the likelihood of contracting further viral infections [44]. Research has found that influenza A particles might evade the immune system by employing RSV surface proteins as a form of disguise [45]. Our study revealed a greater incidence of coinfections among young children and elderly individuals, indicating a greater susceptibility to coinfections in immunocompromised individuals. In our study, all patients with coinfections exhibited fever symptoms, and a higher detection rate was observed in pediatrics and the ICU. This is consistent with previous research findings that children with mixed viral infections are more likely to have fever, hypoxemia, and longer hospital stays, and that the risk of admission to the ICU due to dual respiratory virus coinfections is increased compared to single viral infections [46, 47].

There were still some limitations to this study. First, this study focused solely on viral pathogens in the respiratory tracts of FRS patients, omitting bacterial pathogen exploration. Consequently, our findings do not fully encompass the pathogens responsible for FRS. Future research should delve into the epidemiology of respiratory infections, the pathogenesis of coinfections, and their impact on clinical outcomes to achieve a more comprehensive understanding. Second, although we collected case data from 18 sentinel hospitals across Liaoning Province, the uneven distribution of hospitals implies that our data may not fully represent the actual situation across the entire study area. In future research, the number of sentinel hospitals could be increased to enhance the representativeness of the sample source. Third, PCR detection necessitates specialized equipment and highly skilled personnel, with demanding requirements for the technical proficiency of operators, which may impact the accuracy and reliability of the detection results. However, we believe that technicians who have undergone standardized training will minimize these concerns.

Conclusions

In summary, IFV was identified as the leading cause of FRS in Liaoning Province, China. Single viral infections were more common than coinfections, and detection rates for viruses diminished progressively with increasing age. The study also revealed distinctions in virus distribution across age groups and seasonal variations, with the highest detection rates occurring during November and December and different peak months for various viruses. Based on the epidemiological characteristics of FRS in Liaoning Province, we recommend the following public health policy suggestions to strengthen prevention and treatment strategies. Implement age-specific vaccination programs, prioritizing high-risk groups such as the elderly and infants during the influenza season. Encourage ongoing research into virus evolution and the development of more effective vaccines and antiviral treatments. Foster collaboration between local health departments, educational institutions, and community organizations to implement these strategies and share best practices. This research provides valuable epidemiological insights into FRS in Liaoning Province and could guide effective prevention and treatment strategies to curb virus transmission among vulnerable populations during peak seasons.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

FRS:

Febrile respiratory syndrome

IFV:

Influenza virus

RV:

Rhinovirus

HAdV:

Human adenovirus

HBoV:

Human bocavirus

HPIV:

Human parainfluenza virus

HCoV:

Human coronavirus

RSV:

Respiratory syncytial virus

HMPV:

Human metapneumovirus

RT-PCR:

Reverse transcription-polymerase chain reaction

ARIs:

Acute respiratory infections

ARDS:

Acute respiratory distress syndrome

ICU:

Intensive care unit

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Acknowledgements

We are very grateful to all staff at Liaoning Provincial Centers for Disease Control and Prevention for providing the data and all medical staff members and field workers who are working on the frontline of caring for patients and collecting the data.

Funding

This study was sponsored by the Major National Science and Technology Projects (grant no. 2017ZX10103007) and Liaoning Provincial Department of Science and Technology Support Fund Project for High-Quality Development of China Medical University (grant no. 2023JH2/20200054).

Author information

Author notes

  1. Baihong Sun and Yuzhu Qiu contributed equally and should be considered co-first authors.

Authors and Affiliations

  1. Liaoning Provincial Center for Disease Control and Prevention, Shenyang, Liaoning, China

    Baihong Sun, Lulu Wang, Haibo Sun & Lingling Mao

  2. Department of Epidemiology, School of Public Health, China Medical University, Shenyang, Liaoning, China

    Yuzhu Qiu & Wei Wu

  3. Research Center for Universal Health, School of Public Health, China Medical University, Shenyang, Liaoning, China

    Zhiqian Wang

Authors
  1. Baihong Sun
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  2. Yuzhu Qiu
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  3. Lulu Wang
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  4. Haibo Sun
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  5. Zhiqian Wang
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  6. Lingling Mao
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  7. Wei Wu
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Contributions

YQ participated in the design of the study, collected the data, performed the statistical analysis and drafted the manuscript. BS participated in the design of the study, collected the disease data, participated in the statistical analysis and helped to draft the manuscript. LW, HS and ZW collected data, contributed data analysis and helped to draft the manuscript. LM and WW conceived of the study and participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Lingling Mao or Wei Wu.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the Ethical Committee of Liaoning Provincial Center for Disease Control and Prevention. The oral informed consent was obtained from each participant and this form of consent was confirmed by the Ethical Committee.

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Not applicable.

Competing interests

The authors declare no competing interests.

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Sun, B., Qiu, Y., Wang, L. et al. Viral etiology of febrile respiratory syndrome among patients in Liaoning Province, China. BMC Infect Dis 24, 1060 (2024). https://doi.org/10.1186/s12879-024-09956-z

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Keywords

BMC Infectious Diseases

ISSN: 1471-2334

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