Changes in infant respiratory pathogens pre-during, and post-COVID-19 non-pharmacological interventions in Beijing

doi:10.21203/rs.3.rs-5177958/v1

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Changes in infant respiratory pathogens pre-during, and post-COVID-19 non-pharmacological interventions in Beijing

https://doi.org/10.21203/rs.3.rs-5177958/v1

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Objective: To explore the effect of non-pharmacological interventions (NPIs) on respiratory pathogens among hospitalized infants aged 0–3 months in Beijing during the coronavirus disease 2019 (COVID-19) pandemic.

Method: Respiratory specimens were collected from 1184 infants aged 0–3 months. The infants were hospitalized at the Children's Hospital affiliated with the Capital Institute of Pediatrics from January 2018 to December 2023 for acute respiratory infections. Based on the outbreak of COVID-19 and the implementation and termination of NPIs, the data were divided into three groups: the pre-epidemic group (January 2018 to December 2019), the epidemic prevention and control group (January 2020 to December 2022), and the post-epidemic group (January 2023 to December 2023). The specimens were tested for 14 respiratory pathogens, including influenza virus A (Flu A), influenza virus B (Flu B), respiratory syncytial virus (RSV), parainfluenza virus (PIV), adenovirus (ADV), human metapneumovirus (HMPV), human bocavirus (HBV), human rhinovirus HRV, coronavirus (CoV), Chlamydia trachomatis (Ct), Chlamydia pneumoniae (C.pn), Mycoplasma pneumoniae (MP), Bordetella pertussis (BP), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Result: A total of 1184 infants,including 649 men and 535 women,with acute respiratory infections were admitted. The positive detection rate for respiratory pathogens was 51.77% (N = 613). In 2023, the proportion of infants with respiratory infections after the epidemic was 19.4% (319/1646), the positive detection rate of respiratory pathogens was 68.3% (218/319), and the mixed infection detection rate of respiratory pathogens was 16.1% (35/218). Prior to the epidemic, these rates were 11.9% (431/3611), 37.1% (160/431), and 5.0% (8/160), respectively. During the epidemic prevention and control period, these rates significantly increased to 12.4% (434/3486), 54.1% (235/434), and 11.1% (26/235) (P<0.05), respectively. Post-epidemic, the proportion of newborns testing positive for respiratory pathogens decreased, whereas the number of infants aged 29–90 days significantly increased. The proportion of hospitalized weight and contact history with respiratory patients increased significantly compared to before and during the epidemic, with statistical significance (P<0.05). After the epidemic, a total of 13 respiratory pathogens were detected throughout the year. There were statistically significant differences in the detection rates of Flu A, PIV, SARS-COV-2, HRV, HMPV, ADV, and C.pn before, during, and after implementation of the NPI during the COVID-19 epidemic(P<0.05). Post-COVID-19 epidemic, the detection rates of Flu A, PIV, and SARS-COV-2 were significantly higher than those before and during the epidemic (P<0.017). The detection rates of HRV, HMPV, and ADV significantly increased after the epidemic compared to those before the epidemic (P<0.017). Before the COVID-19 epidemic, the positivity rate of respiratory pathogens was high in the first and fourth quarters. After the termination of NPIs, the positive detection rate decreased in the first quarter but increased in the second, third, and fourth quarters, with a statistically significant difference (P<0.05).

Conclusion: The implementation and lifting of COVID-19 NPIs have caused significant changes in the detection and seasonal distribution of respiratory pathogens in infants aged 0–3 months in Beijing. NPI temporarily reduced the detection rate of respiratory pathogens in infants during the prevalence of COVID-19. Understanding the prevalence of respiratory pathogens is particularly important for the prevention and control of respiratory diseases in infants.

Non-pharmacological interventions

Infants

Respiratory infections

pathogeny

Acute respiratory infections are common in infants, and their incidence and mortality have attracted global attention [1–3]. After the outbreak of coronavirus disease 2019 (COVID-19) at the end of 2019, countries adopted non-pharmacological intervention (NPI) measures, including closing schools, maintaining social distancing, wearing masks, paying attention to hand hygiene, and restricting outdoor activities. The implementation of these measures has effectively controlled the spread of COVID-19. In December 2022, China's NPI measures gradually relieved, and significant changes in the prevalence and spectrum of respiratory pathogens in infants were observed [4, 5]. However, few reports have documented respiratory pathogen changes in infants under 3 months of age who had minimal outdoor exposure, sporadic mask use, and difficulties maintaining hand hygiene before, during, and after the COVID-19 pandemic. This study retrospectively analyzed pathogenic respiratory tract infections among hospitalized infants in Beijing from January 2018 to December 2023. Changes in the pathogen spectrum in infants before, during, and after the implementation of NPIs during the COVID-19 pandemic were analyzed. This analysis offers clinical insights into the prevention and control of acute respiratory tract infections in local infants.

2.1 Inclusion criteria

Infants aged 0–3 months who were hospitalized with acute respiratory infections at the Children's Hospital affiliated with the Capital Institute of Pediatrics between January 1, 2018, and December 31, 2023, were included in the study. These infants had fever (body temperature ≥ 37.3 ℃) or respiratory symptoms (cough, sputum, difficulty breathing, or shortness of breath) and developed digestive symptoms such as poor appetite and vomiting after contact with patients with respiratory infections. Additionally, they underwent testing for 14 respiratory pathogens.

2.2 Exclusion criteria

Infants with congenital immunodeficiency or congenital genetic metabolic diseases were excluded. Moreover, those who developed respiratory infections during hospitalization were also excluded.

2.3 Grouping

The COVID-19 epidemic began at the end of 2019, and strict NPIs were implemented in Beijing in January 2020. NPIs in Beijing gradually increased until the end of December 2022. The data were classified into three groups: the pre-epidemic group (January 1, 2018, to December 31, 2019), the epidemic prevention and control group (January 1, 2020, to December 31, 2022), and the post-epidemic group (January 1, 2023, to December 31, 2023). The infants were further divided into age groups: 0–28 days, 29–60 days, and > 60 days.

2.4 Specimen collection

Specimens, including throat swabs, sputum, or bronchoalveolar lavage fluid, were collected within 24 hours of admission to complete respiratory pathogen nucleic acid testing. Thirteen respiratory pathogen multiplex detection kits (PCR capillary electrophoresis fragment analysis method) (Ningbo Haier Shi Gene Technology Co., Ltd., National Machinery Injection Standard 20183400518) and pertussis bacteria nucleic acid detection kits (Shenzhen Yicubic Biotechnology Co., Ltd., National Machinery Injection Standard 20203400152) were used. Operating instructions were followed for detecting influenza A virus (Flu A), influenza B virus (Flu B), respiratory syncytial virus (RSV), parainfluenza virus (PIV), adenovirus (ADV), human metapneumovirus (HMPV), human bocavirus (HBoV), rhinovirus (HRV), coronavirus (CoV), Chlamydia trachomatis (Ct), Chlamydia pneumoniae (C.pn), Mycoplasma pneumoniae (MP), Bordetella pertussis (BP), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study was approved by the Ethics Committee of the Capital Institute of Pediatrics and did not require written informed consent (batch number: SHERLLM2024026).

2.5 Statistical analysis

Using SPSS 20.0 statistical software, econometric data that conform to normal distribution were represented by , and intergroup comparisons were made using the independent sample t-test. For data not conforming to a normal distribution, values were represented by M(P₂₅, P₇₅), and intergroup comparisons were conducted using the Wilcoxon rank sum/Kruskal Wallis test. Within-group comparisons of unified indicators were analyzed using one-way ANOVA. Count data were expressed in terms of examples (percentages), and intergroup comparisons were conducted using chi-square tests and Fisher's exact probability tests. Repeated measurement data were compared between groups using repeated measurement analysis of variance. A P-value of less than 0.05 indicated statistically significant differences.

3.1 General situation

From January 1, 2018, to December 31, 2023, a total of 8743 infants were hospitalized, of whom 1191 infants had acute respiratory infections. Among them, two premature infants had severe bronchopulmonary dysplasia, two had congenital developmental abnormalities, one had severe congenital heart disease, and two had hospital-acquired respiratory infections. These seven patients were excluded from this study, leaving a total of 1184 infants (13.5%) admitted for acute respiratory infections, including 649 males and 535 females. A total of 1184 throat swab specimens were collected, and 613 infants (51.8%) tested positive for at least one respiratory pathogen, with an average age of 35.0 ± 20.85 days.

The proportions of infants with acute respiratory infections per year from 2018 to 2023 were 15.0% (257/1708), 9.1% (174/1903), 12.0% (127/1057), 13.6% (165/1216), 11.7% (142/1213), and 19.4% (319/1646), respectively. The positive detection rates for respiratory pathogens were 36.6% (94/257), 37.9% (66/174), 41.7% (53/127), 62.4% (103/165), 55.6% (79/142), and 68.3% (218/319), respectively. The proportions of mixed infections caused by respiratory pathogens were 3.2% (3/94), 7.6% (5/66), 7.5% (4/53), 12.6% (13/103), 11.4% (9/79), and 16.1% (35/218), respectively. From 2018 to 2023, nine, six, 11, seven, nine, and 14 respiratory pathogens were detected, respectively. Sixty-five infants were simultaneously infected with two respiratory pathogens, three infants were infected with three respiratory pathogens, and one infant was infected with four respiratory pathogens. During the pandemic, the number of hospitalized infants significantly decreased, whereas the proportion of infants with respiratory infections, the positive detection rate of respiratory pathogens, the mixed infection detection rate of respiratory pathogens, and the diversity of respiratory pathogen types gradually increased, as shown in Fig. 1. With detection rates of 28.5% (338/613), 5.9% (70/613), and 5.8% (69/613), the top three pathogens primarily causing respiratory infections were RSV, SARS-COV-2, and PIV, respectively.

3.2 Comparison of positive respiratory pathogens in infants before, during, and after the implementation of NPIs

Before the epidemic, that is, between January 2018 and December 2019, 3611 infant patients were admitted, of whom 11.9% (431/3611) were diagnosed with acute respiratory infections. The positive detection rate of respiratory pathogens was 37.1% (160/431), and the mixed infection detection rate of respiratory pathogens was 5.0% (8/160). During the epidemic between January 2020 and December 2022, 3486 infants were admitted, of whom 12.4% (434/3486) were diagnosed with acute respiratory infections. The positive detection rate of respiratory pathogens was 54.1% (235/434), and the mixed infection detection rate of respiratory pathogens was 11.1% (26/235). Post epidemic from January to December 2023, 1646 infants were admitted, of whom 19.4% (319/1646) were diagnosed with acute respiratory infections, and the positive detection rate of respiratory pathogens was 68.3% (218/319). The detection rate for mixed respiratory pathogen infections was 16.1% (35/218). The proportion of infants with respiratory infections, positive detection rate of respiratory pathogens, and mixed infection detection rate of respiratory pathogens significantly increased after the 2023 epidemic compared to before and during the epidemic, with statistically significant differences (χ² = 59.428, 73.088, 34.468, P < 0.05). Additionally, the detection rates of respiratory and mixed respiratory pathogens in the epidemic significantly increased compared to those before the epidemic, with statistically significant differences (P < 0.05).

Among infants with positive respiratory pathogens before, during, and after the epidemic, no statistically significant differences (P > 0.05) in sex, delivery method, proportion of full-term infants, or infants requiring mechanical ventilation were observed. The proportions of infants testing positive for respiratory pathogens in the 0–28 days, 29–60 days, and > 60 days groups exhibited statistically significant differences before, during, and after the epidemic (P < 0.05). The proportions of newborns decreased, whereas the positive detection rates of infants aged 29–90 days during and after epidemic prevention and control significantly increased, with statistically significant differences (P < 0.05). The admission weight and contact history of patients testing positive for respiratory pathogens after the epidemic significantly increased compared with those before and during the epidemic (P < 0.05). The duration of pre-admission illness after the epidemic was shorter than that during the epidemic, with a statistically significant difference (P < 0.05). However, compared to before the epidemic, this difference was not statistically significant (P > 0.05). The hospitalization time of infants during and after the epidemic was longer compared with that before the epidemic, with a statistically significant difference (P < 0.05), as shown in Table 1.

Table 1

General information on infants testing positive for respiratory pathogens before, during, and after NPI implementation.
	Before NPI implementation (160)	During NPI implementation (235)	After NPI release (218)	χ²	P Value
gender				1.298	0.523
male	93 (58.1)	136 (57.9)	116 (53.2)
female	67 (41.9)	99 (42.1)	102 (46.8)
age
≤ 28d	93 (58.1)	91 (38.7)	68 (31.2)a	28.543	0.000
29ཞ60d	55 (34.4)	124 (52.8)a	107 (49.1)a	13.737	0.001
>60d	12 (7.5)	20 (8.5)	43 (19.7)ab	17.765	0.000
Full term or premature infants				5.509	0.064
Term Infant	153 (95.6)	212 (90.2)	194 (89.0)
premature	7 (4.4)	23 (9.8)	24 (11.0)
Respiratory patient contact history	78 (48.8)	114 (48.5)	150 (68.8)ab	23.241	0.000
Pre admission course	3 (2, 5)	4 (2, 6)	3 (1, 5)b	H = 6.659	0.036
Hospitalization days	6 (4, 7)	7 (5, 9)a	6 (5, 8)a	H = 13.328	0.001
Mechanical ventilation use	15 (9.4)	27(11.5)	14 (6.4)	3.513	0.173
NOTES: The difference between a and b was statistically significant compared to before and during the epidemic. NPI - Non-Pharmaceutical Interventions.

3.3 Annual distribution of 14 respiratory pathogens

Before the COVID-19 outbreak in 2018–2019, RSV accounted for 30.5% (53/174) of the pathogens in hospitalized infants with acute respiratory infections, followed by PIV (5.1%, 13/257) and MP (4%, 7/174). After the strict implementation of NPIs in Beijing at the end of January 2020, the annual detection rate of RSV in 2020 reduced to 18.1% (23/127). Moreover, the annual detection rates of BP, HRV, and C. pn were 0%, 10.3% (17/127), and 9.7% (16/127), respectively. The detection rates of HRV and C.pn demonstrated an increasing trend, rising from 0.6% (1/174) and 1.2% (3/257), respectively, prior to the COVID-19 outbreak. The top three respiratory pathogens in 2021 were RSV (38.2%, 63/165), HRV (10.3%, 17/165), and C.pn (9.7%, 16/165). The detection rates of Flu B (4.2%,6/142), MP (7.0%,10/142), and BP (0.7%,1/142) during the COVID-19 outbreak in Beijing in December 2022 exhibited a slight increase, whereas those of other respiratory pathogens exhibited a downward trend. After lifting the NPI in 2023, the positive detection rate of respiratory pathogens increased significantly to 68.3% (218/319), with all respiratory pathogens being detected. Thirteen respiratory pathogens were detected throughout the year. The numbers of positive cases of Flu A, PIV, RSV, SARS-COV-2, HRV, HMPV, ADV, and BP significantly increased compared to those before the epidemic and during epidemic prevention and control. The top three pathogens identified were RSV (28.8%, 92/319), SARS-COV-2 (17.9%, 57/319), and PIV (9.7%, 31/319), as shown in Table 2 and Fig. 2.

Table 2

Annual distribution of 14 respiratory pathogens (%).
	Number of respiratory tract infections (n = 1184)	2018 (n = 257)	2019 (n = 174)	2020 (n = 127)	2021 (n = 165)	2022 (n = 142)	2023 (n = 319)
Respiratory pathogen positive	613 (51.8)	94 (36.6)	66 (37.9)	53 (41.7)	103 (62.4)	79 (55.6)	218 (68.3)
mixed infection	69 (5.8)	3 (1.2)	5 (2.9)	4 (3.1)	13 (7.9)	9 (6.3)	35 (11.0)
Flu A	19 (1.6)	4 (1.6)	0	1 (0.8)	0	1 (0.7)	13 (4.1)
Flu B	9 (0.8)	1 (0.4)	0	1 (0.8)	0	6 (4.2)	1 (0.3)
PIV	69 (5.8)	13 (5.1)	2 (1.1)	8 (6.3)	12 (7.3)	3 (2.1)	31 (9.7)
RSV	338 (28.5)	64 (24.9)	53 (30.5)	23 (18.1)	63 (38.2)	43 (30.3)	92 (28.8)
SARS-COV-2	70 (5.9)	0	0	0	0	13 (9.2)	57 (17.9)
HRV	52 (4.4)	0	1 (0.6)	9 (7.1)	17 (10.3)	4 (2.8)	21 (6.6)
HMPV	15 (1.3)	0	0	1 (0.8)	5 (3.0)	0	9 (2.8)
ADV	8 (0.7)	0	0	2 (1.6)	0	0	6 (1.9)
C.pn	53 (4.5)	3 (1.2)	5 (2.9)	9 (7.1)	16 (9.7)	7 (4.9)	13 (4.1)
MP	34 (2.9)	5 (1.9)	7 (4.0)	2 (1.6)	2 (1.2)	10 (7.0)	8 (2.5)
Ct	4 (0.3)	3 (1.2)	0	1 (0.8)	0	0	0
BP	13 (1.1)	4 (1.6)	3 (1.7)	0	0	1 (0.7)	5 (1.6)
HBoV	6 (0.5)	3 (1.2)	0	1 (1.9)	1 (0.6)	0	1 (0.3)
CoV	1 (0.1)	0	0	0	0	0	1 (0.3)

ADV - Adenovirus; BP - Bordetella pertussis; C.pn - Chlamydophila pneumoniae; Ct - Chlamydia trachomatis; Flu A - Influenza A virus; Flu B - Influenza B virus; HBoV - Human Bocavirus; HMPV - Human Metapneumovirus; HRV - Human Rhinovirus; MP - Mycoplasma pneumoniae; n - Number; PIV - Parainfluenza Virus; RSV - Respiratory Syncytial Virus; SARS-COV-2 - Severe Acute Respiratory Syndrome Coronavirus 2.

3.4 Monthly and quarterly distributions of 14 respiratory pathogens

Before the epidemic, the number of cases of acute respiratory infections among infants exhibited a seasonal pattern resembling a "V" shape, typically peaking from November to February, as shown in Fig. 3. Quarterly distributions exhibited higher proportions of respiratory pathogens in the first and fourth quarters, as shown in Fig. 4.

After Beijing implemented NPIs by the end of January 2020, the proportion of hospitalized infants testing positive for respiratory pathogens reduced significantly from 14.4% (22/153) in January to 1.3% (1/76) in February. In December 2020, only 9.8% (11/112) of the hospitalized infants tested positive for respiratory pathogens, including two cases of PIV, four cases of RSV, four cases of HRV, and one case of RSV combined with C.pn, as shown in Fig. 3. The proportions of infants with respiratory infections in the first and fourth quarters of 2020 were lower than those before the epidemic.

In the first quarter of 2021, the proportion of respiratory-pathogen-positive hospitalizations in January was 13.1% (11/84), almost returning to pre-pandemic levels. By May 2021, there was a peak in respiratory-pathogen-positive hospitalizations, reaching 15.3% (19/124) primarily owing to RSV infection, which lasted for one month. From October 2021 to January 2022, respiratory infections, primarily caused by RSV, peaked at 25.3% (25/99), which continued until March. This proportion notably exceeded the peak levels observed before the pandemic. The detection rates of respiratory pathogens in October and November of the fourth quarters were at a relatively low level. From December 2022 until the relaxation of NPIs during the epidemic, a peak of respiratory infections dominated by SARS-COV-2 (13 cases, with a minimum age of 1 day, and nine cases aged ≤ 7 days) was observed, with 19.1% (13/68) patients being hospitalized, as shown in Fig. 3. The proportions of respiratory pathogens in the second and fourth quarters of the epidemic were significantly higher than those before the epidemic, with a statistically significant difference (P < 0.05) (Table 3 and Fig. 4).

After the COVID-19 outbreak in 2023, the number of detected cases of respiratory pathogens in the first quarter was very low. From May of the second quarter, the number of positive cases of respiratory pathogens reached 12.8% (19/149), primarily owing to RSV (16/19). In June, the proportion of positive cases of respiratory pathogens reached 15.6% (22/141), primarily owing to SARS-COV-2 (21/22). By December, the proportion of hospitalized infants testing positive for respiratory pathogens reached a new peak of 42.2% (62/147) after the epidemic, with RSV infection being the primary cause of infection (49 cases). The number of RSV infections combined with BP, C. pn, MP, and ADV increased compared to before and during the epidemic. No SARS-COV-2 cases were detected between February and April or December after the epidemic, whereas cases were detected in all other months, as shown in Fig. 3. Compared to before and during the pandemic, the proportions and detection rates of respiratory pathogens after the epidemic decreased in the first quarter but increased in the third and fourth quarters, with a statistically significant difference (P < 0.05) (Table 3 and Fig. 4).

Table 3

Quarterly comparison of respiratory pathogens before, during, and after the epidemic
	Before NPI implementation (431)	During NPI implementation (434)	After NPI release (319)	χ² Value	P Value
The first quarter	88 (20.4)	87(20.0)	11(3.4)ab	12.336	0.002
The second quarter	19(4.4)	40(9.2)a	42(13.2)a	24.617	0.000
The third quarter	9(2.1)	18(4.1)	60(18.8)ab	45.785	0.000
The fourth quarter	44(10.2)	90(20.7)a	105(32.9)ab	35.651	0.000
NOTES: Statistical difference between a and b was observed during the epidemic compared to before and after the epidemic. NPI - Non-Pharmaceutical Interventions.

3.5 Changes in respiratory pathogens before, during, and after the epidemic

There were statistically significant differences in the detection rates of Flu A, PIV, SARS-COV-2, HRV, HMPV, ADV, and C.pn before, during, and after the implementation of NPIs during the COVID-19 pandemic (P < 0.05). After the epidemic, the detection rates of Flu A, PIV, and SARS-COV-2 were significantly higher than those before and during the epidemic, with a statistically significant difference (P < 0.017). The detection rates of HRV, HMPV, and ADV significantly increased after the epidemic compared to before, with a statistically significant difference (P < 0.017). However, the detection rate during the epidemic remained nearly unchanged, with a statistical significance of P > 0.017. The detection rate of C. pn during the epidemic increased compared to that before the epidemic, and the difference was statistically significant (P < 0.017); however, the change in the detection rate after the epidemic was not statistically significant (P > 0.017). The detection rates of Flu B, RSV, MP, Ct, BP, HBoV, and CoV exhibited no significant changes before, during, and after the outbreak, and the differences were not statistically significant, as shown in Table 4 and Fig. 5.

Table 4

Changes in respiratory pathogens before, during, and after the epidemic.
	Before NPI implementation (431)	During NPI implementation (434)	After NPI release (319)	χ² Value	P Value
Flu A	4 (0.9)	2 (0.5)	13 (4.1)ab	17.177	0.000
Flu B	1 (0.2)	7 (1.6)	1 (0.3)	5.448	0.065*
PIV	15 (3.5)	23 (5.3)	31 (9.7)ab	13.345	0.001
RSV	117 (27.1)	129 (29.7)	92 (28.8)	0.723	0.697
SARS-COV-2	0	13 (3.0)a	57 (17.9)ab	115.698	0.000
HRV	1 (0.2)	30 (6.9)a	21 (6.6)a	27.976	0.000
HMPV	0	6 (1.4)a	9 (2.8)a	11.739	0.003
ADV	0	2 (0.5)	6 (1.9)a	8.644	0.004*
C.pn	8 (1.9)	32 (7.4)a	13 (4.1)	15.558	0.000
MP	12 (2.8)	14 (3.2)	6 (1.9)	11.282	0.527
Ct	3 (0.7)	1 (0.2)	0	2.186	0.389*
BP	7 (1.6)	1 (0.2)	5 (1.6)	5.361	0.073*
HBoV	3 (0.7)	2 (0.5)	1 (0.3)	0.582	0.777*
CoV	0	0	1 (0.3)	2.274	0.269*
NOTES: Fisher's exact probability test: Statistically significant difference between a and b before and during the pandemic is observed. ADV - Adenovirus; BP - Bordetella pertussis; C.pn - Chlamydophila pneumoniae; CoV - Coronavirus; Ct - Chlamydia trachomatis; Flu A - Influenza A virus; Flu B - Influenza B virus; HBoV - Human Bocavirus; HMPV - Human Metapneumovirus; HRV - Human Rhinovirus; MP - Mycoplasma pneumoniae*; NPI - Non-Pharmaceutical Interventions; PIV - Parainfluenza Virus; RSV - Respiratory Syncytial Virus; SARS-COV-2 - Severe Acute Respiratory Syndrome Coronavirus 2; χ2 - Chi-squared.

Various respiratory viruses, including MP, C. pn, and other pathogens, are the main causes of respiratory infections in infants. Acute respiratory infections are a common cause of outpatient visits and hospitalization in infants. Before and after the COVID-19 pandemic, respiratory diseases in infants worldwide posed a huge burden on the global healthcare system, with hospitalizations accounting for 19.3%. Among infants with respiratory RSV infections, 59% were under 6 months of age, and those under 2 months are at a higher risk of hospitalization owing to acute respiratory diseases [6,7]. This study retrospectively analyzed the detection rates of and changes in respiratory pathogens in infants hospitalized in Beijing for less than 3 months before, during, and after the outbreak of COVID-19. The total positive detection rate of respiratory pathogens in this study was 51.8%, similar to the 48.4% detection rate of respiratory pathogens in infants reported previously [8].

By the end of 2019, the global implementation of NPIs resulted in a significant reduction in respiratory infections in infants [8-10]. The results of this study revealed that the number of hospitalized infants with respiratory infections during the 2020 epidemic prevention and control decreased, but the positive detection rate of pathogens did not decrease. This observation is consistent with previous reports' findings [8]. This may be owing to the implementation of strict NPIs that effectively block the transmission of other respiratory viruses. Efforts to minimize hospital visits and discourage seeking medical care for infants with milder symptoms have been implemented, yet they have not deterred parents from seeking medical attention for infants with more severe symptoms. This could contribute to the reduction in respiratory infections but may not lead to a decrease in the positive detection rate of respiratory pathogens.

Owing to the COVID-19 pandemic, different adjustments in global NPIs have been made. Respiratory pathogens rebounded, and younger infants were simultaneously infected with multiple respiratory pathogens [7, 9, 11]. The results of this study revealed that the number of hospitalized infants with respiratory infections in epidemic prevention and control was lower than that before the epidemic, but the proportion of respiratory cases, positive detection rate of respiratory pathogens, and mixed infection proportion have been increasing annually. After relaxing NPIs in 2023, 319 infants with acute respiratory infections were hospitalized, accounting for 19.4% of hospitalizations. The positive detection rate of respiratory pathogens was 68.3% (218/319), and the mixed infection rate of respiratory pathogens was 17.4% (38/218), which is significantly higher than those before and during the epidemic. The detection of respiratory pathogens reached a new peak, with 13 respiratory pathogens identified throughout the year and only 10 in November. Following the release of NPIs, the number of infants hospitalized for acute respiratory infections sharply increased, and the positive detection rate of respiratory pathogens exceeded the previous peak. The number of infants with mixed infections also increased significantly. This can be attributed to mothers not developing immunity to these respiratory pathogens during the epidemic prevention and control, potentially reducing infants' immune function at birth. Moreover, the increase in births during this period and the complete lifting of NPIs may have contributed to outbreaks of respiratory infections among infants [12,13]. Additionally, the population's reduced immune stimulation during NPI implementation could have led to greater susceptibility and lowered overall immunity compared to pre-epidemic levels, creating an "immune gap" [14,15]. These results indicate that the release of NPIs may lead to a resurgence of respiratory pathogens, as reported by Bobby et al. [3], suggesting a close relationship between the NPI release and changes in detection rates of respiratory pathogens. Before the new peak of respiratory infection occurs, we should apply prevention and control measures during COVID-19, such as wearing masks and paying attention to hand hygiene, to reduce respiratory infections in infants.

Ebba et al. [7] reported that infants under 1 year of age, particularly male infants <2 months of age, were more likely to be hospitalized for respiratory diseases. Our results showed that there was no statistical difference between the sexes of infants with positive respiratory pathogens before, during, and after the pandemic. On the other hand, the proportion of newborn infants among infants with positive respiratory pathogens after the pandemic decreased. The number of older infants aged 29–90 days increased significantly during the prevention and control of the epidemic and after the epidemic. This may be because, post-COVID-19 outbreak, newborns had minimal exposure to the outside world, hand hygiene for newborns was strictly followed, and protective isolation of respiratory infections was practiced. Older infants tend to go out more often than newborns do, which is related to the gradual weakening of protective isolation in older infants. This may also be owing to the presence of more maternal antibodies in the newborn's body, which reduces the risk of respiratory infection. Droplets and aerosols are common routes of respiratory virus transmission, and direct contact is an important route of transmission in young infants. The results of this study also confirm this assertion, revealing a contact transmission rate of 68.8% among infants positive for respiratory pathogens after the epidemic. This rate was significantly higher than that observed before and during the epidemic. The results of this study revealed that the course of illness in infants positive for respiratory pathogens after the pandemic significantly shortened before admission. This may be attributed to reduced public concern about COVID-19 following the relaxation of NPIs, leading to shorter observation periods at home after infants displayed respiratory infection symptoms. Conversely, the hospitalization time of infants after the pandemic was significantly prolonged compared to that before and during the pandemic. However, there was no increase in the incidence of respiratory tract infections requiring mechanical ventilation in critically ill infants before, during, and after the epidemic, consistent with the findings reported by Naishisha [16], in which mixed infections did not increase the proportion of critically ill infants. The longer hospitalization time of infants may be related to a higher number of pathogens and longer symptom duration after the epidemic.

The outbreak of COVID-19 and the implementation and lifting of NPIs led to certain changes in respiratory pathogens in infants before and after the epidemic. RSV was the main pathogen responsible for acute respiratory infections and hospitalization in infants [16-19]. This study demonstrates that the main pathogen causing acute respiratory infections in infants hospitalized between 0 and 3 months before the epidemic was RSV. During the COVID-19 pandemic, NPIs changed the proportion of respiratory viruses detected in preschool infants and reduced the infection rate of envelope viruses [3,5,20-22] but did not reduce the infection rate of non-envelope viruses [8,23-26]. This study shows that the RSV-positive detection rate in 2020 was only 18.1%, which is significantly lower than that of 24.9%–30.5% before the epidemic. HRV, ADV, and C. pn without the envelope virus showed increasing trends in 2020. This is because non-enveloped viruses exhibit superior thermal properties, can tolerate dry and acidic environments, and have a relatively low sensitivity to alcohol [27]. These features allow them to survive for longer periods in external environments and maintain their activity and infectivity under adverse conditions. Additionally, they have advantages in terms of transmission through aerosols and direct contact [28-29,30].

Robert et al. [14] reported that long-term exposure to low doses or lack of exposure to pathogens may lead to weakened immunity and that the population lacks immune stimulation from pathogens in the natural environment, increasing susceptibility. During the epidemic prevention and control, the detection of respiratory pathogens decreased or was not even detected, potentially leading to decreased population immunity against these pathogens. After the release of NPIs, a large portion of the population may easily be infected with these respiratory pathogens. The results of this study showed that the detection rates of RSV and HMPV returned to pre-pandemic levels in 2021, whereas those of PIV, HRV, and C. pn maintained remained high from 2020 to 2021. BP was not detected in 2020 or 2021. In 2022, the implementation of new prevention and control measures might result in cases of SARS-COV-2 in newborns and infants. The detection of RSV, PIV, HRV, and C.pn will slightly decrease, whereas ADV and HMPV will not be detected throughout the year. There was an increasing trend in MP and Flu B, and BP was detected again. Parsa et al. [31] reported that other non-COVID-19 respiratory pathogens proliferated after NPI relaxation. The results of this study show that the detection rates of Flu A, PIV, HRV, HMPV, and ADV in hospitalized infants after the release of NPIs were significantly higher than those before the epidemic. SARS-COV-2 has also become one of the main respiratory pathogens that cause hospitalization in infants aged 0–3 months. During the epidemic prevention and control, the detection rate of C. pn increased compared to that before the epidemic but has not continued to increase after the epidemic. The detection rates of Flu B, RSV, MP, Ct, BP, HBoV, and CoV did not show significant changes before, during, or after the outbreak. However, after the release of NPIs, multiple pathogens were detected simultaneously, and the number of mixed infections in infants increased significantly. The results of this study suggest that 9-10 respiratory pathogens will be detected every month from November to December 2023. The mixed infection rate of RSV with BP, C. pn, MP, and ADV reached 16.1%, which is more than three times that of mixed infections before the epidemic. The number of detected cases of Flu A, PIV, RSV, SARS-COV-2, HRV, HMPV, ADV, and BP in hospitalized infants reached its highest level in 6 years. In the future, upon lifting epidemic NPIs, could there be a further increase in these respiratory pathogens? We must remain vigilant, closely monitoring and implementing measures to prevent and manage these respiratory pathogens.

After the COVID-19 outbreak and the implementation of NPIs, the seasonality of infant respiratory pathogens was disrupted, and the infection of seasonal respiratory pathogens such as RSV in young infants also changed. The results of this study showed that before the COVID-19 epidemic began, the epidemic season of RSV infection in hospitalized infants aged 0–3 months in Beijing began in November or December and ended in February of the following year, lasting for 3-4 months. This observation is consistent with previous reports' results [16, 32, 33]. The RSV epidemic ended after implementing a strict NPI at the end of January 2020. The adjustment and lifting of NPIs may lead to the resurgence of seasonal viruses such as PIV and RSV, potentially occurring at different times compared to pre-epidemic periods [31]. This study observed no peak in RSV prevalence during the winter of 2020-2021 compared to pre-pandemic levels, with a decreased positive detection rate of respiratory pathogens in the first quarter. However, an RSV outbreak occurred in May 2021, aligning with previously reported peak incidences in infants [16, 33-37]. This may be related to the relaxation of prevention and control measures and the opening of schools. At the same time, it may also be owing to the lack of natural immunity to RSV in infants born during the winter of that year. The delay or cancellation of vaccinations owing to prevention and control measures may also explain the low immunity of the population. In 2021, the NPI measures were slightly relaxed, and a peak of respiratory pathogens (25.3%), mainly RSV, began to emerge in October. Simultaneously, pathogens, including HRV, HMPV, C. pn, and MP, were detected for 5 months. The positive hospitalization rate for respiratory pathogens exceeded pre-epidemic levels. NPI measures were gradually lifted starting in December 2022, coinciding with a peak in SARS-COV-2 infections and an increase in RSV prevalence observed in May 2023. In June, there was another peak of SARS-COV-2 infection, and the positive detection rate of respiratory pathogens gradually increased. Off-season outbreaks of respiratory pathogens occurred in the second and third quarters. Until December, the peak of RSV infection in the main respiratory tract reached the highest level in 6 years, and the hospitalization of pathogen-positive infants reached a new peak of 42.2% (62/147), which was three times higher than before the epidemic. One year after lifting the NPIs, the respiratory pathogen epidemic lasted for up to 8 months. As reported by Rachel et al. [5], the lifting of the NPIs, the increase in susceptible populations, and the overlap of respiratory pathogen epidemic seasons may be the reasons for the sharp increase in patients with respiratory infections. In the years following the lifting of the NPIs, the seasonality of respiratory pathogens in young infants may have gradually recovered before the COVID-19 pandemic, and the dynamics of respiratory pathogens in young infants need to be closely monitored. Preventive measures for respiratory infections in infants

In this study, we summarized the changes in respiratory pathogens in infants under 3 months old between 2018 and 2023. The COVID-19 outbreak and the implementation and lifting of NPIs have increased the hospitalization rate, positive detection rate of respiratory pathogens, proportion of mixed infections, and types of pathogens detected in infants with respiratory infections. Respiratory pathogens in hospitalized infants are still mainly caused by RSV infection; however, SARS-COV-2, PIV, and HRV have significantly increased compared to before the epidemic. Within 1 year following the relaxation of NPIs, respiratory pathogens among infants under 3 months old exhibited seasonal disruptions, resulting in off-season epidemics. Respiratory pathogens in infants under 3 months old have shown an off-season outbreak. For infants under 3 months old, particular attention should be given to preventing respiratory infections during periods of heightened respiratory pathogen activity.

Our study has some limitations, the first of which was its retrospective, single-center design. For various reasons, before and during the epidemic prevention and control, there may not have been a focus on monitoring some pathogens, which may have impacted the research results. In summary, in the years following the release of NPIs, respiratory pathogens should be monitored in infants, and preventive and response measures should be implemented.

Ethics approval

This study was approved by the Ethics Committee of the Capital Institute of Pediatrics. All methods were performed by relevant guidelines and regulations. (batch number: SHERLLM2024026).

Consent for publication

All authors approved the final manuscript and the submission to this journal.

Availability of data and materials

Further information and requests for resources should be directed to and will be fulfilled by

the lead contact, Yajuan Wang. The data reported in this paper may be shared by the contact on request and pending approval from ethics and regulatory committees where relevant. This study didn’t report original code. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

Declaration of Competing Interest

The authors declare no conflict of interest.

Funding

This work was funded by Natural Science Foundation of Beijing - Haidian Original Innovation Fund Joint Project (Grant No. L202022) and High-level Public Health Technical Personnel Construction Project of Beijing Municipal Health Commission (Grant No.Academic leader -03-02).

CRediT authorship contribution statement:

Tongying Han: Data curation, Formal analysis, Investigation, Methodology, Validation, Writing–original draft. Di Zhang, Ying Li, Li Zhang, Jin Yan, Chi Li, Shengnan Yang: Data acquisition, Data curation, Investigation, Validation, Resources. Litao Guo and Huijuan Yan: Formal analysis, Validation, Supervision. Yajuan Wang: Conceptualization, Funding acquisition, Methodology, Project administration, Resources, Writing–review & editing.

Acknowledgments

We would like to thank Editage (www.editage.cn) for English language editing.

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Changes in infant respiratory pathogens pre-during, and post-COVID-19 non-pharmacological interventions in Beijing

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Abstract

Figures

1. Introduction

2. Methods

2.1 Inclusion criteria

2.2 Exclusion criteria

2.3 Grouping

2.4 Specimen collection

2.5 Statistical analysis

3. Results

3.1 General situation

3.2 Comparison of positive respiratory pathogens in infants before, during, and after the implementation of NPIs

3.3 Annual distribution of 14 respiratory pathogens

3.4 Monthly and quarterly distributions of 14 respiratory pathogens

3.5 Changes in respiratory pathogens before, during, and after the epidemic

4. Discussion

Declarations

References

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