Resurgence of common respiratory viruses and mycoplasma pneumoniae in children after ending the zero-COVID policy, Shanghai, China, 2023

doi:10.21203/rs.3.rs-4615735/v1

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Resurgence of common respiratory viruses and mycoplasma pneumoniae in children after ending the zero-COVID policy, Shanghai, China, 2023

https://doi.org/10.21203/rs.3.rs-4615735/v1

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Background

China has adhered to policies of zero-COVID for almost three years since the outbreak of COVID-19, which have remarkably affected the circulation of respiratory pathogens. However, China has begun to end the zero-COVID policies in late 2022. Here, we reported a resurgence of common respiratory viruses and mycoplasma pneumoniae with unique epidemiological characteristics among children after ending the zero-COVID policy in Shanghai, China, 2023.

Methods

Children hospitalized with acute respiratory tract infections were enrolled from January 2022 to December 2023. Nine common respiratory viruses and 2 atypical bacteria were detected in respiratory specimens from the enrolled patients using a multiplex PCR-based assay. The data were analyzed and compared between the periods before (2022) and after (2023) ending the zero-COVID policies.

Results

A total of 8550 patients were enrolled, including 6170 patients in 2023 and 2380 patients in 2022. Rhinovirus (14.2%) was the dominant pathogen in 2022, however, Mycoplasma pneumoniae (38.8%) was the dominant pathogen in 2023. Compared with 2022, the detection rates of pathogens were significantly increased in 2023 (72.9% vs. 41.8%, p < 0.001). An out-of-season epidemic of respiratory syncytial virus was observed during the spring and summer of 2023. The median age of children infected with respiratory viruses in 2023 was significantly greater than that in 2022. Besides, mixed infections were more frequent in 2023 (23.8% vs. 28.9%, p < 0.001).

Conclusions

China is now facing multiple respiratory pathogen epidemics with changing seasonality, altered age distribution, and increasing mixed infection rates among children in 2023. Our finding highlights the need for public health interventions to prepare for the respiratory pathogen outbreaks in the post-COVID-19 era.

COVID-19

NPIs

Children

Respiratory pathogens

Prevalence

To control the COVID-19 pandemic, China has adhered to policies of zero-COVID for almost three years with strictly enforced lockdowns and other aggressive restrictive measures such as social distancing, mask wearing, and case isolation since the outbreak of COVID-19 in late 2019 [1]. The implementation of these nonpharmaceutical interventions (NPIs) effectively cut off the respiratory transmission chain, which also resulted in a substantial reduction in the circulation of other common respiratory viruses and Mycoplasma pneumoniae (MP) in the early phases of the COVID-19 pandemic [2–5]. However, many viruses, such as respiratory syncytial virus (RSV), parainfluenza virus (PIV), human coronavirus (HCoV), rhinovirus (RV) and human bocavirus (HBoV) resurged after NPIs were relaxed, and schools reopened during September 2020 − January 2021, which raised concerns for a more significant rise in respiratory viruses when the COVID-19-related NPIs eventually lifted [6, 7].

Given the attenuated pathogenicity of SARS-CoV-2 omicron subvariants and increasing vaccination coverage, China has begun to end the zero-COVID policies, notably by announcing the 10 measures on 7 December 2022 [8]. After that, China experienced a nationwide outbreak of COVID-19 [9, 10]. Besides, the abrupt changes in NPIs may also contribute to outbreaks of other respiratory pathogens. Here, we reported a rebound of common respiratory viruses and MP with changing seasonality, altered age distribution, and increasing mixed infection rates among children in 2023 after ending the zero-COVID policy in Shanghai, China.

Study design

Children with acute respiratory tract infection (ARTI) admitted to the Children’s Hospital of Fudan University and receiving etiological tests in the entire years 2023 (after ending the zero-COVID) and 2022 (during the zero-COVID) were enrolled to explore the prevalence of respiratory pathogens in children after ending the zero-COVID policy. A patient was considered to have an ARTI if at least two of the following clinical manifestations occurred during the week prior to them presenting: fever, cough, nasal obstruction, expectoration, sneezing, and dyspnea. The decision as to whether an etiological test was necessary was made by the attending physician. Demographics and clinical data from the enrolled children were obtained from their electronic medical records.

Specimen collection and testing

Respiratory specimens (nasopharyngeal aspirates/bronchoalveolar lavage fluid) were obtained from all the enrolled children within 72 hours of admission by trained staff following standard operating procedures. The specimens were immediately transferred to the clinical laboratory for the detection of respiratory pathogens.

Respiratory specimens were tested for HCoV, RSV, HBoV, RV, PIV, general influenza virus A (IAV), influenza virus A H1N1 (2009) (H1N1), seasonal influenza virus A H3N2 (H3N2), influenza virus B (IBV), human adenovirus (ADV), human metapneumovirus (HMPV), Chlamydia (Ch), and MP by using the SureX 13 respiratory pathogen multiplex kit, a commercial multiplex PCR-based panel assay (Health Gene Technologies, Ningbo, China). Multiplex PCR products were separated and analyzed using an Applied Biosystems 3500 analyzer.

If any one of the targeted pathogens was detected in the specimens, the patient was considered positive for that pathogen. In cases where two or more pathogens were detected in the same clinical sample, the respective pathogens were counted individually.

Statistical analysis

Categorical variables (detection rates, sex) are expressed as numbers (%). As the continuous variable (age) in our study was not normal distributed, it was expressed as median (interquartile range). For comparisons between the periods before (2022) and after (2023) ending the zero-COVID policy, Chi-squared test was used for categorical data, and the Mann-Whitney U test was used for numeric data. All of the tests were two tailed, and a value of p < 0.05 indicated statistical significance. Statistical analyses were conducted with SPSS version 26.0 software (IBM, New York, USA).

Study population

A total of 8550 patients were enrolled in the study, including 6170 patients in 2023 and 2380 patients in 2022. The median age of patients in 2023 (3 years) was older than that in 2022 (0.5 years), and no significant differences in sex were observed between 2023 and 2022 (Table 1).

	Total	2022	2023	p value^#
Demographics
Total patients	8550	2380	6170
Male sex, n (%)	4728 (55.3)	1329 (55.8)	3399 (55.1)	0.531
Median age, years (IQR)	2 (0.17-6)	0.5 (0.08-4)	3 (0.5-7)	<0.001
Pathogen detection, n (%)
MP	2613 (30.6)	222 (9.3)	2391 (38.8)	<0.001
RV	1469 (17.2)	339 (14.2)	1130 (18.3)	<0.001
RSV	805 (9.4)	154 (6.5)	651 (10.6)	<0.001
PIV	640 (7.5)	153 (6.4)	487 (7.9)	0.021
IAV	573 (6.7)	22 (0.9)	551 (8.9)	<0.001
H1N1	169 (2.0)	0 (0.0)	169 (2.7)	<0.001
H3N2	404 (4.7)	22 (0.9)	382 (6.2)	<0.001
ADV	376 (4.4)	29 (1.2)	347 (5.6)	<0.001
HMPV	343 (4.0)	75 (3.2)	268 (4.3)	0.012
HBoV	257 (3.0)	62 (2.6)	195 (3.2)	0.178
HCoV	218 (2.6)	31 (1.3)	187 (3.0)	<0.001
IBV	88 (1.0)	49 (2.1)	39 (0.6)	<0.001
CP	58 (0.7)	39 (1.6)	19 (0.3)	<0.001
Total	5492 (64.2)	996 (41.8)	4496 (72.9)	<0.001
Mixed infection, n (%)
Dual	1335 (15.6)	130 (5.5)	1205 (19.5)	<0.001
Triple	240 (2.8)	20 (0.8)	220 (3.6)	<0.001
Quadruple	43 (0.5)	3 (0.1)	40 (0.6)	0.002
Quintuple	1 (0.0)	0 (0.0)	1 (0.0)	0.999
Total	1619 (18.9)	153 (6.4)	1466 (23.8)	<0.001

Table 1. Comparison of demographics and positive rates of respiratory pathogens between the year of 2023 (after ending the zero-COVID policy) and 2022 (before ending the zero-COVID policy)

#Comparison between the year of 2023 and 2022;

Abbreviations: IQR, interquartile range; RSV, respiratory syncytial virus; PIV, parainfluenza virus; HCoV, human coronavirus; RV, rhinovirus; HBoV, human Boca virus; IAV, influenza virus A; H1N1, influenza virus A H1N1 (2009); H3N2, influenza virus A H3N2, IBV, influenza virus B; ADV, human adenovirus; HMPV, human metapneumovirus; CP, Chlamydia pneumoniae; MP, Mycoplasma pneumoniae.

Resurgence of respiratory pathogens

One or more respiratory pathogens were detected in 4496/6170 (72.9%) specimens in 2023, which was significantly greater than that in 2022 (996/2380, 41.8%) (Table 1). Among all pathogens, MP (30.6%) had the highest detection rate, followed by RV (17.2%) and RSV (9.4%). RV (14.2%) was the most commonly detected pathogen in 2022, however, MP (38.8%) was the most common pathogen in 2023. Compared with those in 2022, the detection rates of MP, RV, RSV, PIV, IAV, ADV, HMPV and HCoV were significantly greater in 2023 (Table 1). However, the positive rates of IBV and CP were slightly lower in 2023 (Table 1). The positive rate of HBoV did not significantly differ between 2022 and 2023 (Table 1).

Altered age distribution

The age distribution of the children with virus infection between 2022 and 2023 varied. The median ages of children infected with RV, RSV, PIV, ADV, HMPV, HBoV, HCoV and IBV in 2023 were significantly greater than those in 2022 (Fig. 1). It means that more elder children tend to be susceptible to these viruses in 2023.

Changing seasonality

MP, IAV and ADV activities were extremely low in 2022(Fig. 2ABC). However, a large outbreak of IAV (H1N1) was firstly observed in March 2023, shortly after the end of the “zero-COVID” policy (Fig. 2B). After that, MP and ADV also resurged in August 2023 (Fig. 2AC). The detection rate of MP was nearly 60.0% in October 2023 (Fig. 2A). An out‐of-season epidemic of RSV was observed during the spring and summer (April to September) of 2023 (Fig. 2D). The activities of HCoV and PIV peaked during the summer of 2023. Besides, RV and HMPV also had a relatively high prevalence in 2023, especially in the second half of the year (Fig. 2EH).

Increasing of mixed infection

Among all the patients, 18.9% (1619/8550) had a mixed infection (at least two pathogens detected). Cases with mixed infections were more frequent in the year 2023 (23.8%, 1466/6170, p < 0.001) than in the year 2022 (6.4%, 153/2380) (Table 1). MP + RV was the most common mixed infection pattern in both 2022 and 2023 (Fig. 3AC). RV was the most frequently detected pathogen in mixed infection cases in 2022, followed by MP and PIV (Fig. 3B); however, MP became the top pathogen in mixed infection cases in 2023, followed by RV (Fig. 3D).

The nationwide “zero-COVID” policy was implemented for approximately 3 years in China, which was longer and stricter than the policies of many other countries. After the ending the “Zero‐COVID” policy, China is now facing multiple respiratory pathogen epidemics. Our study reports the high prevalence of multiple respiratory pathogens, changing seasonality, altered age distribution and increasing mixed infection rates among children in the first year after China fully exited the “Zero‐COVID” policy in 2023.

While NPIs limited the transmission of SARS-CoV-2, they also reduced the spread of other pathogens during and after lockdown periods, despite the re-opening of schools [2]. This positive collateral effect in the short term is welcome as it prevents additional overload of the healthcare system. The lack of immune stimulation due to the reduced circulation of microbial agents and to the related reduced vaccine uptake induced an “immunity debt”, which could have negative consequences when the pandemic is under control and NPIs are lifted [11]. The longer these periods of “viral or bacterial low-exposure” are, the greater the likelihood of future epidemics. In our study, the number of children hospitalized with ARTI at the Children’s Hospital of Fudan University largely increased with the resurgence of common respiratory viruses and MP in the year 2023. The surge of respiratory viruses such as IAV, MP, RSV, PIV, and ADV in children was also reported from other parts of the world after the relaxation of COVID-19 restrictions, such as Korean[12], Japan[13], Germany[14], Qatar[15], and the US[16]. These global epidemic trends were thought to be due in part to the reduced population-level immunity, antigenic drift and children’s re-engagement in social activities [17].

MP is a common cause of lower and upper respiratory tract infections, especially in children and young adults. Although many common respiratory pathogens have resurged during the COVID-19 pandemic, the activity of MP remained in a low prevalence state before the end of the “Zero‐COVID” policy [18]. However, starting in late summer (August) 2023, we observed a rapid rise in MP detection, and many patients presented with coinfections of multiple pathogens. Up to now (June 2024), MP infections continue to occur at high rates based on our routine surveillance (data not shown). The current outbreak in late 2023 may be explained by the usual epidemic cycle of MP, which has shown outbreaks every 3–5 years [19]. However, it may also be related to host factors resulting from the COVID-19 related NPIs, which possibly led to a decline in population immunity, also known as “Immunity debt” [20].

NPIs significantly impacted RSV seasonality. In temperate countries, RSV activities generally started from late autumn or early winter peaked in winter, and ended in late winter or spring [21]. However, there was an absent RSV winter season in Shanghai in 2022, followed by a subsequent out‐of-season spring/summer surge in 2023. The out‐of-season spikes in RSV activity during the COVID-19 pandemic were also observed in China [22], France [23], Iceland [24], Israel [25], and the US [26] in spring/summer 2021, following the strict NPIs adopted in 2020. As the highly infectious Omicron variant rages in parts of China, strict and comprehensive NPIs were reimplemented between late February 2022 and the end of 2022 in Shanghai [27]. Similar to the out-of-season resurgence in 2021, the suppressed RSV circulation in the winter months of the 2022–2023 season was followed by a delayed RSV resurgence in spring/summer 2023. This resurgence was likely due to the accumulation of RSV-naïve population following a prolonged period of minimal RSV exposure in 2022.

Another interesting finding in our study is that the median age of children infected with respiratory viruses (except for IAV) after ending the “zero-COVID” policy was significantly greater than that in the prior period. The temporary shift in the age distribution of endemic viral infections may be due to the effects of delayed circulation and the resultant immunity gap, which makes the susceptible children be exposed for the first time at older ages [28].

Our study provides an overview of the distinct epidemiology of respiratory pathogens among children after ending the “zero-COVID” policy in Shanghai, including the atypical out-of-season circulations as well as the altered age profile of virus detection. The results highlight the need for health-care systems to prepare for the possibility of large outbreaks occurring out of season among older children in the post-COVID-19 era. Vaccines can be administered which can help to “repay” some of the immunity debt acquired over the past years. Future strategies such as strengthened implementation of routine childhood immunization programs, enhanced pathogen surveillance and improved health education are crucial.

NPIs: Nonpharmaceutical interventions

ARTI: Acute respiratory tract infection

MP: Mycoplasma pneumoniae

CP: Chlamydia pneumoniae

IAV: Influenza virus A

H1N1: Influenza virus A H1N1 (2009)

H3N2, Influenza virus A H3N2

IBV: Influenza virus B

ADV: Human adenovirus

RSV: Respiratory syncytial virus

RV: Rhinovirus;

HCoV: Human coronavirus

PIV: Parainfluenza virus

HMPV: Human metapneumovirus

HBoV: Human Boca virus

Ethics approval and consent to participate

Approval to conduct this study was granted by the Medical Research Ethics Committee of the Children’s Hospital of Fudan University.

Consent for publication

Not applicable

Availability of data and materials

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

Competing interests

The authors declare that they have no competing interests.

Fundings

This study was supported by the 3-Year Action Plan for Strengthening Public Health System in Shanghai (grant number: GWVI-11.2-YQ43), and the Key Development Program of Children's Hospital of Fudan University (grant number: EK2022ZX05).

Author contributions

PL and JX conceived and designed the study. MX, LL, XZ, RJ, ND, and LS performed the sampling. PL, MX, LL, and RJ analyzed the data. MX, XZ, ND, and LS conducted experiments. PL and JX prepared the manuscript draft and revised the manuscript. All authors provided comments on the manuscript and all authors accepted the final version.

Acknowledgements

Not applicable.

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No competing interests reported.

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Version 1

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You are reading this latest preprint version

Resurgence of common respiratory viruses and mycoplasma pneumoniae in children after ending the zero-COVID policy, Shanghai, China, 2023

Status:

Version 1

Abstract

Background

Methods

Results

Conclusions

Figures

Background

Methods

Study design

Specimen collection and testing

Statistical analysis

Results

Discussion

Conclusion

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1