Infectious diseases are the most common conditions seen in the field of pediatrics, and there are a wide variety of epidemic diseases that are often difficult to control. In December 2019, an outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing coronavirus disease 2019 (COVID-19), was reported in Wuhan, China, and rapidly spread all over the world.1
The first COVID-19 patient in Hokkaido Prefecture, Japan, was recognized on January 28, 2020, and the epidemic spread rapidly thereafter.2 3 4 5 Fig. 1 ).2
FIGURE 1.: The number of patients newly diagnosed with COVID-19 in Hokkaido Prefecture, Japan. This result is based on newly diagnosed COVID-19 patients reported to the Hokkaido government by public health centers and hospitals in Hokkaido Prefecture, and made publicly available on the Hokkaido government website. The data include both pediatric and adult patients, and there are no specific criteria for the diagnostic testing methods used. The vertical axis shows the number of patients, and the horizontal axis shows days. The red and yellow shaded areas indicate the period of “state of emergency” and “semi-state of emergency.” The arrow indicates a school closure period from February 28 to May 31, 2020.
Beginning July 1, 2019, we conducted the survey “Hokkaido Pediatric Infectious Diseases Surveillance” (HPIDS) to gather data about inpatient children with infectious diseases in the 18 hospitals in Hokkaido Prefecture, Japan (see Figure, Supplemental Digital Content 1, https://links.lww.com/INF/F85 6
In this study, we report the changes in the number and age distribution of various infectious diseases among children in Japan for the 3 years from July 2019 to June 27, 2022.
MATERIALS AND METHODS
Study Period and Institutions
We aggregated data from patients 0–15 years old who were newly admitted to the 18 hospitals in Hokkaido Prefecture, Japan, from July 1, 2019, to June 27, 2022. We defined the 8-month period from July 2019 to February 2020 as the “pre-COVID-19 period,” the 3-month period from March to May 2020 during the school closure period as the transition period, and the 25-month period from June 2020 to June 2022 as the “post-COVID-19 period.” The staff of each hospital entered the data every week using Microsoft Excel and emailed the data file to the central staff.
Diseases
We continued to investigate the 10 infectious diseases presented in the previous study.5 Mycoplasma pneumoniae , adenovirus (respiratory infection), norovirus gastroenteritis, rotavirus gastroenteritis, adenovirus gastroenteritis, and KD. We aggregated each disease by sex and by 6 age groups (0 years old, 1 year old, 2 years old, 3–6 years old, 7–12 years old, and 13–15 years old). In this study, we did not examine the number of patients with COVID-19.
Inclusion Criteria
For RSV, influenza virus, hMPV, M. pneumoniae , and adenovirus (respiratory infection), we included patients with positive rapid antigen detection tests or polymerase chain reaction (PCR) tests. For norovirus gastroenteritis, rotavirus gastroenteritis, and adenovirus gastroenteritis, we included patients with positive rapid antigen detection tests. When more than 2 types of pathogens were detected, if the attending physician determined it to be a coinfection, multiple items were counted. For KD, we included patients who met the diagnostic criteria outlined in the Japanese diagnostic guideline for KD (the 6th revised edition).7 8
Data Analysis
The hospitalization rates per 100,000 person-years were calculated using Poisson regression, with exact 95% confidence intervals based on the number of hospitalizations associated with each infectious disease and the size of the target population in the hospitals’ catchment areas.9 2 tests and residual analysis. We calculated the adjusted standardized residuals to identify significant cells after a statistically significant χ2 test. P values of <0.05 were considered significant. The statistical analyses were conducted in R Statistical Software (version 4.0.2; R Foundation for Statistical Computing, Vienna, Austria).
Ethical Approval
This study was approved by the Ethics Committee of Sapporo Medical University (Institutional ethical clearance number: 312-3349). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013).
RESULTS
In total, 3417 patients with 10 infectious diseases were hospitalized during the study period (July 1, 2019, to June 27, 2022) (Table 1 ). The changes in the number of patients with each disease during the study period are shown in Figure 2A–H . Patients with RSV, influenza A, influenza B, hMPV, M. pneumoniae , and rotavirus gastroenteritis decreased drastically after the school closure period (February 28 to May 31, 2020). Among these, only RSV re-emerged in 2021.
TABLE 1. -
Patient Diagnoses During the Study Period
Diseases
Period
Total
Pre-COVID-19 (8 mo)*
Transition Period (3 mo)†
Post-COVID-19 (25 mo)‡
Total
1841
103
1473
3417
(1380.8 [1318.4–1445.3])
(206.0 [168.1–249.8])
(353.5 [335.7–372.0])
Respiratory infectious diseases
RSV
795
6
871
1672
(596.3 [555.5–639.2])
(12.0 [4.40–26.1])
(209.0 [195.4–223.4])
Influenza A
269
2
0
271
(201.8 [178.4–227.4])
(4.0 [2.2–20.5])
—
Influenza B
39
6
0
45
(29.3 [20.8–40.0])
(12.0 [4.4–26.1])
—
hMPV
201
7
5
213
(150.8 [130.6–173.1])
(14.0 [5.6–28.8])
(1.2 [0.4–2.8])
Mycoplasma pneumoniae
158
3
5
166
(118.5 [100.7–138.5])
(6.0 [1.2–17.5])
(1.2 [0.4–2.8])
Adenovirus (respiratory infection)
46
11
126
183
(34.5 [25.3–46.0])
(22.0 [11.0–39.4])
(30.2 [25.2–36.0])
Infectious gastroenteritis
Norovirus gastroenteritis
97
10
205
312
(72.8 [59.0–88.7])
(20.0 [9.6–36.8])
(49.2 [42.7–56.4])
Rotavirus gastroenteritis
38
3
2
43
(28.5 [20.2–39.1])
(6.0 [1.2–17.5])
(0.5 [0.1–1.7])
Adenovirus gastroenteritis
37
6
56
99
(27.8 [19.5–38.2])
(12.0 [4.4–26.1])
(13.4 [10.2–17.4])
Other
Kawasaki disease
161
49
203
413
(120.8 [102.8–140.9])
(98.0 [72.5–129.6])
(48.7 [42.2–55.9])
The numbers in parentheses indicate the hospitalization rates per 100,000 person-years, and the numbers in square brackets indicate the 95% confidence intervals.
* Pre-COVID-19 period refers to the 8 months from July 2019 to February 2020.
† Transition period refers to the 3 months from March to May 2020.
‡ Post-COVID-19 period refers to the 25 months from June 2020 to June 2022.
FIGURE 2.: Trends in the number of patients over the study period. A: RSV. B: Influenza. C: hMPV and
Mycoplasma pneumoniae . D: Adenovirus (respiratory infection). E: Norovirus gastroenteritis. F: Rotavirus gastroenteritis. G: Adenovirus gastroenteritis. H: Kawasaki disease. The vertical axis shows the number of patients, and the horizontal axis shows weeks. The red and yellow shaded areas indicate the period of “state of emergency” and “semi-state of emergency.” The arrow indicates a school closure period from February 28 to May 31, 2020. The gray shaded area indicates the trends in the number of patients newly diagnosed with COVID-19 in Hokkaido Prefecture (shown in
Fig. 1 ).
Only patients with RSV showed significant changes in the age distribution from the pre- to post-COVID-19 period [χ2 (5) = 17.311, P = 0.004, V = 0.102] (Fig. 3A ). There were no significant changes in the age groups of patients with adenovirus (respiratory infection), norovirus gastroenteritis, adenovirus gastroenteritis, or KD (P = 0.630, 0.248, 0.962, and 0.908, respectively) (Fig. 3B–E ).
FIGURE 3.: Age distribution of each infection. A: RSV. B: Adenovirus (respiratory infection). C: Norovirus gastroenteritis. D: Adenovirus gastroenteritis. E: Kawasaki disease. The percentages of patients 0 years old, 1 year old, 2 years old, 3–6 years old, 7–12 years old and 13–15 years old for each disease are shown. Vertical bars colored in red and blue are data in the pre-COVID-19 and post-COVID-19 period, respectively.
Respiratory Diseases
RSV
There were 1672 patients with RSV during the study period (Table 1 ). RSV tended to decrease from the end of 2019, and few patients were hospitalized during the time from April 2020 to March 2021 (Fig. 2A ). However, patients with RSV re-emerged from the end of April 2021, and gradually increased from May, reaching a notable peak of 50 patients/week in August 2021. After that, the number of patients gradually decreased to 2–3 patients/week toward June 2022.
Patients less than a year old were hospitalized the most in both pre- and post-COVID-19 periods (Fig. 3A ). The proportion of patients 3–6 years old was significantly lower in the pre-COVID-19 period and higher in the post-COVID-19 period (10.9% [87/795] and 17.0% [148/871], P = 0.001) (see Table, Supplemental Digital Content 2, https://links.lww.com/INF/F86
Influenza A and B
In total, 271 and 45 patients with influenza A and B were hospitalized during the study period (Table 1 ). Influenza A increased from the end of November 2019, and the largest cluster of patients was in December (Fig. 2B ). After that, incidence decreased sharply, and no patients were observed after May 2020. Influenza B peaked in mid-February 2020, but the incidence subsided in about a month, and there were no patients with influenza B after April 2020.
hMPV
There were 214 patients with hMPV during the study period (Table 1 ). About 5–10 patients with hMPV were hospitalized every week from July 2019 to February 2020 (Fig. 2C ). After the school closure period (March–May 2020), the incidence decreased drastically, and only 5 patients with hMPV were hospitalized from June 2020 to June 2022.
Mycoplasma pneumoniae
In total, 166 patients with M. pneumoniae were hospitalized during the study period (Table 1 ). M. pneumoniae increased from July 2019 and peaked in November with almost 10 patients per week (Fig. 2C ). After that, M. pneumoniae tended to decrease, and only 5 patients were hospitalized after the school closure period (March–May 2020).
Infectious Gastroenteritis
Norovirus Gastroenteritis
During the study period, 312 patients with norovirus gastroenteritis were hospitalized (Table 1 ). In 2020, norovirus gastroenteritis peaked in January and February, with 6–10 patients per week (Fig. 2E ). In 2021, there were only 1–2 patients per week in January, but a large peak exceeding 10 patients per week emerged in April. From July 2021 to June 2022, no major epidemic was observed, but at least 1 patient was hospitalized each week. The number of patients increased from February 2022 through July.
Rotavirus Gastroenteritis
In total, 44 patients with rotavirus gastroenteritis were hospitalized during the study period (Table 1 ). After the school closure period (March–May 2020), the incidence decreased, and only 2 patients were hospitalized from June 2020 to June 2022, both of whom had not been vaccinated against rotavirus (Fig. 2F ).
DISCUSSION
This is a multicenter survey to comprehensively describe the trends in various infectious diseases among hospitalized children before and after the COVID-19 epidemic in Japan, from July 1, 2019, to June 27, 2022. There are several reports showing the reduction of various infectious diseases immediately after the COVID-19 epidemic,10–14 6
First, RSV, which had decreased drastically after the school closure period (March–May 2020) and had hardly been seen for a year, formed a marked epidemic, reaching 50 patients/week in August 2021 (Fig. 2A ). In the pre-COVID-19 era, RSV was seen almost year-round in Hokkaido Prefecture from 2017, and there had not been a major epidemic in August like that of 2021 in the last decade.15 16 10 , 11 17–20 21–23 24 25
Another interest is the change in age group of patients with RSV (Fig. 3A ). The re-emergence of RSV in the post-COVID-19 period included more older children (3–6 years old) than in the pre-COVID-19 period (17.0% and 10.9%, respectively). The above reports from China and Australia also mentioned that patients in the RSV re-emergence were significantly older than in pre-COVID-19.19 , 20 24 , 26
Influenza, hMPV, and M. pneumoniae , which also decreased dramatically after the school closure period (March–May 2020), were rarely seen for more than 2 years until June 2022 in our survey (Fig. 2B , C ). Similar observations have been reported from different countries, highlighting the remarkable decrease in these respiratory infections in the post-COVID-19 era.10 , 11 27 28 29 25 M. pneumoniae mainly presents in school-age children who can partake in NPIs properly, which may have resulted in the reduced number of patients.30 M. pneumoniae epidemics occur in 3- to 7-year cycles, and Hokkaido Prefecture recently had epidemics in 2016 and 2019.15
In our previous study conducted between July 2019 and February 2021, we reported that the incidence of norovirus gastroenteritis decreased drastically to 27.8% of its former level post-COVID-19.6 Fig. 2E ). It was reported that norovirus gastroenteritis also decreased sharply in the post-COVID-19 era in various countries, but most of the survey period was until December 2020.12–14 14
Unlike norovirus gastroenteritis, patients with rotavirus gastroenteritis were rarely seen for more than 2 years, until June 2022 (Fig. 2F ). In many countries, the number of patients with rotavirus gastroenteritis also decreased sharply in the post-COVID-19 era.13 , 14 , 19 , 31 14 32–34 35 36 37 38
There are several limitations to this study. First, we started the HPIDS survey from July 1, 2019, meaning that we only have 8 months of pre-COVID-19 data available. Therefore, it is not possible to compare the post-COVID-19 period with data from several years prior to the pandemic. Second, there were no established protocols for conducting pathogen testing. The decision on conducting testing for each patient was made by the attending physician at each hospital, based on the individual needs of the patient. This could have resulted in a selection bias. Third, for several diseases, such as influenza and norovirus/rotavirus/adenovirus gastroenteritis, we included patients with positive rapid tests. Rapid antigen tests have lower sensitivity and specificity, and may therefore be less reliable for diagnosis.39 , 40 41 , 42
In conclusion, our findings indicate that the trends in common infectious diseases have changed from the immediate post-COVID-19 era toward 2022 in Japan. RSV, which had been reduced markedly in the post-COVID-19 era, re-emerged dramatically, including among older children, in August 2021. Norovirus gastroenteritis does not appear to be sufficiently inactivated by current NPIs for COVID-19 and has spread without significant change from the pre-COVID-19 era. However, influenza, hMPV, M. pneumoniae , and rotavirus gastroenteritis are still strongly suppressed as of June 2022. Nonetheless, in several countries, these infectious diseases have already re-emerged after relaxing COVID-19 restrictions. Therefore, we should be cautious of a possible resurgence of these diseases in Japan after easing infection control measures against COVID-19.
ACKNOWLEDGMENTS
We thank all the pediatricians who participated in this survey. We thank John Daniel from Edanz ( https://jp.edanz.com/ac ) for editing a draft of this article .
REFERENCES
1. Centre for Health Protection of the Hong Kong Special Administrative Region Government.
CHP closely monitors cluster of pneumonia cases on Mainland . Dec 31, 2019. Available at:
https://www.info.gov.hk/gia/general/201912/31/P2019123100667.htm . Accessed February 9, 2023.
2. Hokkaido government. Data for COVID-19 in Hokkaido Prefecture (in Japanese). Available at:
http://www.pref.hokkaido.lg.jp/ss/dtf/opendata/covid19.htm . Accessed August 17, 2022.
3. World Health Organization. Transmission of SARS-CoV-2: implications for infection prevention precautions. Available at:
https://www.who.int/news-room/commentaries/detail/transmission-of-sars-cov-2-implications-for-infection-prevention-precautions . Accessed February 9, 2023.
4. Hokkaido government. Efforts to control COVID-19 (in Japanese).
https://www.pref.hokkaido.lg.jp/covid-19/koronasengen.html . Accessed April 11, 2023.
5. Hokkaido Government Board of Education. Information about COVID-19 (in Japanese). Available at:
http://www.dokyoi.pref.hokkaido.lg.jp/hk/ktk/corona.htm . Accessed February 9, 2023.
6. Fukuda Y, Tsugawa T, Nagaoka Y, et al. Surveillance in hospitalized children with infectious diseases in Japan: Pre- and post-coronavirus disease 2019. J Infect Chemother. 2021;27:1639–1647.
7. Kobayashi T, Ayusawa M, Suzuki H, et al. Revision of diagnostic guidelines for Kawasaki disease (6th revised edition). Pediatr Int. 2020;62:1135–1138.
8. Japan Pediatric Society. Pediatric COVID-19-Associated Multisystem Inflammatory Syndrome (MIS-C/PIMS) Clinical Consensus Statement (in Japanese). Available at:
http://www.jpeds.or.jp/uploads/files/202105120_mis-c_st.pdf . Accessed April 10, 2023.
9. Hokkaido Government. Overview of population and number of households in Hokkaido (in Japanese). Available at:
https://www.pref.hokkaido.lg.jp/fs/4/8/5/1/3/4/8/_/2020kekkanogaiyou1.pdf . Accessed April 10, 2023.
10. Olsen SJ, Azziz-Baumgartner E, Budd AP, et al. Decreased Influenza Activity During the COVID-19 Pandemic — United States, Australia, Chile, and South Africa, 2020. Am J Transplant. 2020;20:3681–3685.
11. Groves HE, Piché-Renaud P, Peci A, et al. The impact of the COVID-19 pandemic on influenza, respiratory syncytial virus, and other seasonal respiratory virus circulation in Canada: A population-based study. Lancet Reg Health Am. 2021;1:100015.
12. Eigner U, Verstraeten T, Weil J. Decrease in norovirus infections in Germany following COVID-19 containment measures. J Infect. 2021;82:276–316.
13. Wang LP, Han JY, Zhou SX, et al.; Chinese Centers for Disease Control and Prevention (CDC) Etiology of Diarrhea Surveillance Study Team. The changing pattern of enteric pathogen infections in China during the COVID-19 pandemic: a nation-wide observational study. Lancet Reg Health West Pac. 2021;16:100268.
14. Chan MC. Return of norovirus and rotavirus activity in winter 2020–21 in city with strict COVID-19 control strategy, Hong Kong, China. Emerg Infect Dis. 2022;28:713–716.
15. Hokkaido Infectious Disease Surveillance Center. Sentinel weekly reporting diseases (in Japanese). Available at:
https://www.iph.pref.hokkaido.jp/kansen/weekunitinfection.html . Accessed February 9, 2023.
16. National Institute of Infectious Diseases, Japan. Infectious diseases weekly report (in Japanese). Available at:
https://www.niid.go.jp/niid/images/idsc/idwr/IDWR2021/idwr2021-51-52.pdf . Accessed February 9, 2023.
17. Agha R, Avner JR. Delayed seasonal RSV surge observed during the COVID-19 pandemic. Pediatrics. 2021;148:e2021052089.
18. Opek MW, Yeshayahu Y, Glatman-Freedman A, et al. Delayed respiratory syncytial virus epidemic in children after relaxation of COVID-19 physical distancing measures, Ashdod, Israel, 2021. Euro Surveill. 2021;26:2100706.
19. Liu P, Xu M, Lu L, et al. The changing pattern of common respiratory and enteric viruses among outpatient children in Shanghai, China: two years of the COVID-19 pandemic. J Med Virol. 2022;94:4696–4703.
20. Foley DA, Phuong LK, Peplinski J, et al. Examining the interseasonal resurgence of respiratory syncytial virus in Western Australia. Arch Dis Child. 2022;107:e7.
21. Paynter S. Humidity and respiratory virus transmission in tropical and temperate settings. Epidemiol Infect. 2015;143:1110–1118.
22. Otomaru H, Sornillo JBT, Kamigaki T, et al. Risk of transmission and viral shedding from the time of infection for respiratory syncytial virus in households. Am J Epidemiol. 2021;190:2536–2543.
23. Moreira LP, Watanabe ASA, Camargo CN, et al. Respiratory syncytial virus evaluation among asymptomatic and symptomatic subjects in a university hospital in Sao Paulo, Brazil, in the period of 2009-2013. Influenza Other Respir Viruses. 2018;12:326–330.
24. Noble M, Khan RA, Walker B, et al. Respiratory syncytial virus-associated hospitalisation in children aged ≤5 years: a scoping review of literature from 2009 to 2021. ERJ Open Res. 2022;8:00593–02021.
25. Galanti M, Birger R, Ud-Dean M, et al. Rates of asymptomatic respiratory virus infection across age groups. Epidemiol Infect. 2019;147:e176.
26. Glezen WP, Taber LH, Frank AL, et al. Risk of primary infection and reinfection with respiratory syncytial virus. Am J Dis Child. 1986;140:543–546.
27. Department of Health and Aged Care, Australian Government. Australian Influenza Surveillance Reports. Available at:
https://www.health.gov.au/resources/collections/aisr?language=en . Accessed February 9, 2023.
28. Centers for Disease Control and Prevention. The National Respiratory and Enteric Virus Surveillance System (NREVSS): Human Metapneumovirus Surveillance. Available at:
https://www.cdc.gov/surveillance/nrevss/hmpv/index.html . Accessed February 9, 2023.
29. Takeuchi H, Kawashima R. Disappearance and re-emergence of influenza during the COVID-19 pandemic: association with infection control measures. Viruses. 2023;15:223.
30. Sauteur PMM, Unger WWJ, Nadal D, et al. Infection with and carriage of Mycoplasma pneumoniae in children. Front Microbiol. 2016;7:329.
31. Burnett E, Parashar UD, Winn A, et al. Trends in rotavirus laboratory detections and Internet search volume before and after rotavirus vaccine introduction and in the context of the COVID-19 pandemic—United States 2000–2021. J Infect Dis. 2022;226:967–974.
32. Burnett E, Parashar UD, Tate JE. Global impact of rotavirus vaccination on diarrhea hospitalizations and deaths among children <5 years old: 2006–2019. J Infect Dis. 2020;222:1731–1739.
33. Ito M, Higashigawa M. Effectiveness of self-financed rotavirus vaccination in Ise City, Japan. Hum Vaccin Immunother. 2021;17:5650–5655.
34. Fujii Y, Noguchi A, Miura S, et al. Effectiveness of rotavirus vaccines against hospitalisations in Japan. BMC Pediatr. 2017;17:156.
35. Tsugawa T, Akane Y, Honjo S, et al. Rotavirus vaccination in Japan: efficacy and safety of vaccines, changes in genotype, and surveillance efforts. J Infect Chemother. 2021;27:940–948.
36. Saitoh A, Okabe N. Changes and remaining challenges for the Japanese immunization program: Closing the vaccine gap. Vaccine. 2021;39:3018–3024.
37. Number of people who received routine vaccination. Ministry of Health, Labour and Welfare, Japan (in Japanese). Available at:
https://www.mhlw.go.jp/topics/bcg/other/5.html . Accessed February 9, 2023.
38. Yeung KHT, Lin SL, Clark A, et al. Economic evaluation of the introduction of rotavirus vaccine in Hong Kong. Vaccine. 2021;39:45–58.
39. Gonzalez MD, McElvania E. New developments in rapid diagnostic testing for children. Infect Dis Clin North Am. 2018;32:19–34.
40. Centers for Disease Control and Prevention. Information for Clinicians on Rapid Diagnostic Testing for Influenza. Available at:
https://www.cdc.gov/flu/professionals/diagnosis/rapidclin.htm . Accessed February 9, 2023.
41. Antalis E, Oikonomopoulou Z, Kottaridi C, et al. Mixed viral infections of the respiratory tract; an epidemiological study during consecutive winter seasons. J Med Virol. 2018;90:663–670.
42. Lin CY, Hwang D, Chiu NC, et al. Increased detection of viruses in children with respiratory tract infection using PCR. Int J Environ Res Public Health. 2020;17:564.
