key: cord-0960135-7fdl1ebt
authors: Fukuda, Yuya; Tsugawa, Takeshi; Nagaoka, Yoshinobu; Ishii, Akira; Nawa, Tomohiro; Togashi, Atsuo; Kunizaki, Jun; Hirakawa, Satoshi; Iida, Junya; Tanaka, Toju; Kizawa, Toshitaka; Yamamoto, Dai; Takeuchi, Ryoh; Sakai, Yoshiyuki; Kikuchi, Masayoshi; Nagai, Kazushige; Asakura, Hirofumi; Tanaka, Rina; Yoshida, Masaki; Hamada, Ryo; Kawasaki, Yukihiko
title: Surveillance in Hospitalized Children with Infectious Diseases in Japan: pre- and post-Coronavirus Disease 2019
date: 2021-08-04
journal: J Infect Chemother
DOI: 10.1016/j.jiac.2021.07.024
sha: 88b6f6895ca1ce474bc02a8ede7a7597d8f803f7
doc_id: 960135
cord_uid: 7fdl1ebt

Introduction The epidemic of coronavirus disease 2019 (COVID-19) rapidly spread worldwide, and the various infection control measures have a significant influence on the spread of many infectious diseases. However, there have been no multicenter studies on how the number of hospitalized children with various infectious diseases changed before and after the outbreak of COVID-19 in Japan. Methods We conducted a multicenter, prospective survey for hospitalized pediatric patients in 18 hospitals in Hokkaido Prefecture, Japan, from July 2019 to February 2021. We defined July 2019 to February 2020 as pre-COVID-19, and July 2020 to February 2021 as post-COVID-19. We surveyed various infectious diseases by sex and age. Results In total, 5,300 patients were hospitalized during the study period. The number of patients decreased from 4,266 in the pre-COVID-19 period to 701 (16.4%) post-COVID-19. Patients with influenza and RSV decreased from 308 and 795 pre-COVID-19 to zero and three (0.4%) post-COVID-19. However, patients with adenovirus (respiratory infection) only decreased to 60.9% (46 to 28) of pre-COVID levels. Patients with rotavirus, norovirus, and adenovirus gastroenteritis decreased markedly post-COVID-19 to 2.6% (38 to 1), 27.8% (97 to 27) and 13.5% (37 to 5). The number of patients with UTIs was similar across the two periods (109 and 90). KD patients decreased to 31.7% (161 to 51) post-COVID-19. Conclusions We suggest that current infection control measures for COVID-19 such as wearing masks, washing hands, and disinfecting hands with alcohol are effective against various infectious diseases. However, these effects vary by disease.

The most common conditions seen in the field of pediatrics are infectious diseases, and there are a wide variety of epidemic diseases that are often difficult to manage. Infectious disease outbreaks vary greatly depending on the season, year, region and country, and it is important to understand the epidemiology. In Japan, the National Institute of Infectious Diseases (NIID) surveys the national trends in infectious diseases [1] . National surveillance in Hokkaido Prefecture reports weekly on infectious diseases including influenza, respiratory syncytial virus (RSV) and infectious gastroenteritis [2] . However, these data do not provide information on trends in patients who require hospitalization. Primary, junior high, and high schools and special support schools all closed from 28 February to 31 May 2020, to prevent the spread of COVID-19 among children [3, 4] . In pediatrics, we know that various infection control measures have a significant influence on the spread of many infectious diseases. However, to our knowledge, there have been no multicenter studies on how the number of hospitalized children with various infectious diseases changed before and after the outbreak of COVID-19. This paper therefore reports changes in the number and age distribution of pediatric patients with various infectious diseases, drawing on the results of surveillance up to 28 February 2021. 

We aggregated data from patients aged 0-15 years who were newly admitted to the 18 hospitals in Hokkaido Prefecture from 1 July 2019 to 28 February 2021. We defined the 8 months from 1 July 2019 to 28 February 2020 as "pre-COVID-19", and from 1 July 2020 to 28 February 2021 as "post-COVID-19". The staff of each hospital input the data every week using Microsoft Excel and emailed it to the central staff.

We surveyed for measles, rubella, varicella, mumps, pertussis, influenza A, influenza B, respiratory syncytial virus (RSV), human metapneumovirus (hMPV), mycoplasma pneumoniae, adenovirus (respiratory infection), lower respiratory tract infection (LRTI), rotavirus gastroenteritis, norovirus gastroenteritis, adenovirus gastroenteritis, other gastroenteritis, aseptic meningitis, bacterial meningitis, encephalitis/encephalopathy, complex febrile seizure, urinary tract infection (UTI), and Kawasaki disease (KD). We aggregated each disease by sex and age (0-3 months, 4-6 months, 7-12 months, 1 year old, 2 years old, 3-6 years old, 7-12 years old and 13-15 years old).

For influenza, RSV, hMPV, adenovirus (respiratory infection), rotavirus gastroenteritis, norovirus gastroenteritis, and adenovirus gastroenteritis, we included patients with positive rapid antigen detection tests. For mycoplasma pneumoniae, we included patients with mycoplasma deoxyribonucleic acid (DNA) or antibodies in the blood, or J o u r n a l P r e -p r o o f 6 positive rapid antigen tests. We excluded patients whose symptoms or epidemiological associations suggested that they might be infected, but who either had a negative rapid test or were not tested. If the items overlapped, we aggregated both. For example, when RSV was detected in a patient with pneumonia, the patient was counted for both RSV and LRTI.

The data was only analyzed in a descriptive manner. Comparisons of number of patients between pre-COVID-19 and post-COVID-19 are reported as relative differences in percentages.

This study was approved by the Ethics Committee of Sapporo Medical University (Institutional ethical clearance number: 312-3349).

In total, 5,300 patients were hospitalized during the study period (1 July 2019 to 28 February 2021) ( Table 1) Table 1) . Influenza A increased from the end of November 2019, and the largest cluster of cases was at the beginning of December (Fig. 1) .

After that, incidence decreased sharply, and no patients were observed after May 2020.

Influenza B peaked in mid-February 2020, when influenza A cases tended to converge, but the number of hospitalizations was not as high as at the peak of influenza A. Influenza B also decreased during the school closure period (28 February to 31 May 2020), and there were no patients after April 2020.

In total, 795 patients had RSV, 201 hMPV and 158 mycoplasma pneumoniae pre-COVID-19. This decreased drastically to three (0.4%), zero and two (1.3%) post-COVID-19 (Table 1) . RSV and mycoplasma pneumoniae increased from June to November 2019. About five to ten patients with hMPV were detected every week from July 2019 to the end of the year. RSV, hMPV and mycoplasma pneumoniae all tended to decrease from the end of 2019 and were hardly seen after the school closure period (28 February to 31 May 2020) until 28

February 2021 (Fig. 1) .

There were 46 patients with adenovirus (respiratory infection) hospitalized pre-COVID-19 and 28 post-COVID-19, or 60.9% of the pre-COVID figure ( Table 1) . The number of patients with adenovirus (respiratory infection) was small in August-September but increased around November in both 2019 and 2020 (Fig. 1) . Unlike the other respiratory J o u r n a l P r e -p r o o f 8 infectious diseases surveyed, the incidence of adenovirus (respiratory infection) did not decrease drastically during the school closure period.

There were 38, 97, 37, and 232 patients with rotavirus, norovirus, adenovirus, and other gastroenteritis pre-COVID-19. This decreased to one, 27, five, and 127 post-COVID-19

( Table 1 ). The number of patients with rotavirus, norovirus, and adenovirus gastroenteritis decreased markedly post-COVID-19 to 2.6%, 27.8% and 13.5%. However, other forms of gastroenteritis decreased relatively little to 54.7%. Around 10-20 patients with gastroenteritis were hospitalized every week in July-August 2019, and rotavirus and adenovirus gastroenteritis were observed in about five patients/week during that period (Fig. 2) . The incidence tended to decrease slightly toward September-October 2019, then increased again from December during an epidemic of norovirus gastroenteritis. It decreased drastically after the school closure period, and almost never exceeded 10 patients/week until the end of 2020.

From January 2021, the number of patients with norovirus gastroenteritis tended to increase, but remained lower than the same period in 2020.

Patients with UTIs were hospitalized during almost all weeks (96.6%, 85/88 weeks) during the study period, and the number of patients did not vary greatly pre-and post-COVID-19 (109 and 90 patients) ( Fig. 2 and Table 1 ).

Pre-COVID-19, 161 patients were hospitalized with KD, decreasing to 51 (31.7%) post-COVID-19 ( Table 1) . The number of patients with KD increased from November 2019, J o u r n a l P r e -p r o o f 9 and more than five patients were hospitalized almost every week before the school closure period (28 February to 31 May 2020) (Fig. 2) . The number of patients did not decrease markedly during the school closure period. However, there were rarely more than three patients/week hospitalized after the school closure period and this decreased further toward the end of the survey. Among all patients, almost all patients were ≤ 6 years old (97.4%, 263/270), and the number of patients under 1 year old, 1 year old, and 2 years old was almost the same (23.0%, 62/270; 25.2%, 68/270; and 21.9%, 59/270) (Fig. 3) . There were no deaths among anyone with KD and KD-like symptoms during the study period.

To the best of our knowledge, this is the first multicenter survey to comprehensively describe the trends in various infectious diseases among hospitalized children before and after the COVID-19 epidemic in Japan. We found that the number of children who needed hospitalization for infectious diseases decreased more than 80% post-COVID-19 in Hokkaido Prefecture, Japan. The figures for some diseases decreased more than 98%, but some decreased by less than half. SARS-CoV-2 is primarily transmitted between people through droplets, aerosols or contact, and the importance of wearing a mask, securing physical distance from others, washing hands, and disinfecting hands with alcohol has become well known [5] [6] [7] [8] . Nowadays in Japan, we wear masks when going out, and the installation and use of alcohol disinfectants is widespread in both homes and public places [9] . It seems that these infection control measures have affected not only COVID-19 but also many other infectious diseases.

Hokkaido Prefecture, which we surveyed in this study, is located in the northernmost part of Japan (Fig. 4) . The population of Hokkaido Prefecture is about 5.4 million, around J o u r n a l P r e -p r o o f 10 4.2% of the total population of Japan, and 11.4% of population is aged < 15 years old [10] .

According to information about infectious diseases from the national surveillance in Japan and Hokkaido Prefecture, the patterns of infectious disease outbreaks seen in Hokkaido

Prefecture are similar to those elsewhere, although RSV is most often seen nationwide around September, whereas there has been no fixed epidemic period for the past few years in Hokkaido Prefecture [1, 2] .

In December 2019, an outbreak of COVID-19-associated pneumonia was reported in Wuhan, China, and soon spread all over the world [11] . In Hokkaido Prefecture, Japan, the first COVID-19 patient was recognized on 28 January 2020, and the number of patients increased rapidly from around 20 February as shown in Figure 5 However, the decrease in the number of patients with infectious gastroenteritis was smaller than that for respiratory infectious diseases (overall gastroenteritis decreased to 39.6% post-COVID-19, while influenza, RSV, hMPV and mycoplasma pneumoniae decreased to almost none). This may be because of the different transmission routes for infectious gastroenteritis and respiratory infectious diseases. Influenza, RSV, hMPV and mycoplasma pneumoniae are mainly transmitted by droplets in the air from a person who coughs or sneezes [14] [15] [16] [17] [18] [19] . Infectious gastroenteritis including rotavirus, norovirus and adenovirus are mainly transmitted through the fecal-oral route [20] [21] [22] . This suggests that the current infection control measures for COVID-19 such as wearing a mask, securing physical distance from others, washing hands, and disinfecting hands with alcohol are more effective for droplet transmission than fecal-oral transmission. Another reason why respiratory infectious diseases decreased markedly might be that children who had even slight respiratory symptoms (e.g., coughing or sneezing) were not sent to schools or nurseries, because of the possibility of COVID-19 infection.

However, the figures never dropped as low as for the other respiratory diseases. One reason may be that the adenovirus (respiratory infection) is spread by both droplet infection and by touching surfaces or objects that an infected person has touched [23] . It is also possible to be an asymptomatic carrier of adenovirus, and its incubation period is relatively long, at 2 days to 2 weeks [24, 25] . Children might therefore have gone to nursery without knowing they were infected and spread the infection by touching other children, desks, doors, or toys.

Another reason might be that adenovirus is a non-enveloped virus. SARS-CoV-2 is an enveloped virus and is susceptible to alcohol disinfectants. The importance and effectiveness of disinfection using alcohol is now widely known [26] [27] [28] . Influenza, RSV, and hMPV are also enveloped viruses and can be expected to be inactivated by alcohol [29] . However, adenovirus, as a non-enveloped virus, is generally considered to be more resistant to disinfectants including alcohol [29, 30] . It may therefore be difficult to control adenovirus Table 1) . This suggests that UTIs were not affected by the current infection control measures, and that they are not spread directly from child to child.

The cause of KD is still unknown, but epidemiology strongly suggests the involvement of infectious factors in triggering its onset [32] . In Japan, the number of patients peaks in January every year, decreases in February, increases from spring to summer, and decreases again in September-October [33] . A similar trend was seen from HPIDS during the study period, but the number of hospitalizations after the school closure period in 2020 was lower than during the same period in 2019 (Fig. 2) . Many infectious diseases decreased after the school closure period suggesting that infectious diseases may indeed be involved in During the COVID-19 epidemic worldwide, there have been several reports of critically ill patients with symptoms like KD [34] [35] [36] . This was described and understood as a disease different from KD, called multisystem inflammatory syndrome in children (MIS-C) [37] . Compared with KD, MIS-C often presents with severe abdominal pain and myocardial dysfunction, and requires intensive care [38, 39] . The median age for MIS-C was 9-10 years. This is in marked contrast to KD, which occurs predominately in children ≤ 5 years old [37, 39] . KD is often seen in Asian children, including in Japan, but MIS-C is rarely reported in Asian children, and is recorded predominantly as an issue among African children [37] .

Not all the 270 patients with KD in this study underwent COVID-19 tests, but there were no reports of the severe symptoms or characteristics associated with suspected MIS-C. There had been almost no reports of MIS-C in Japan, despite many worldwide. However, Fukuda et al. reported the first case of MIS-C in a Japanese boy in April 2021 [40] . The Japanese Pediatric Society and Japanese Society of Kawasaki Disease also published notification that there have been a few patients who may be MIS-C in Japan from mid-February 2021 [41] . It is therefore likely that MIS-C may become apparent in Japan when the number of children with COVID-19 has increased.

We have therefore found that many infectious diseases decreased after the outbreak of COVID-19. We targeted patients who needed to be hospitalized, so is likely to show relatively little effect of patients refraining from seeing a medical institution for fear of being infected with COVID-19. Doctors may also have performed rapid tests (e.g., influenza, RSV, and rotavirus/norovirus/adenovirus gastroenteritis) more actively on admission than among outpatients, to improve infection control. Our study is therefore considered to be able to detect rapid test positive patients more accurately. Our findings may not only reflect changes in awareness and behavior associated with COVID-19. For example, viral interference, which J o u r n a l P r e -p r o o f 14 is a phenomenon where one virus out-competes and suppresses the replication of other coinfecting viruses, may also be happening [42] [43] [44] . Certainly, the decrease in the number of children with many infectious diseases post-COVID-19 is surprising.

Several limitations of this study should be highlighted. First, we started the HPIDS survey from 1 July 2019, so we have only 8 months of data pre-COVID-19. It is therefore not possible to compare the post-COVID-19 period with data from several years before the pandemic. Second, to compare the number of patients between pre-COVID-19 and post-COVID-19 in the same months, we omitted patients from March to June 2020, the period shortly after COVID-19 spread. Third, for several diseases such as influenza, mycoplasma, and rotavirus/norovirus/adenovirus gastroenteritis, we included patients with positive rapid tests. Rapid antigen tests or antibody tests have problems of sensitivity and specificity, so may not be reliable for diagnosis. We also did not specify rapid tests and the 18 hospitals may therefore not have used the same products. This could have resulted in some detection bias.

In conclusion, the number of children who needed hospitalization for infectious diseases decreased markedly after the COVID-19 epidemic in Japan. We suggest that current infection control measures for COVID-19 such as wearing masks, washing hands, and disinfecting hands with alcohol are effective against various infectious diseases. However, these effects vary by disease and the result of our survey may not only reflect infection control measures for COVID-19. Further surveys are required to evaluate whether the outbreak of many infectious diseases can be suppressed in the long term.

All authors meet the ICMJE authorship criteria. 

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

None.

The authors declare that they have no conflicts of interest. 

Hokkaido Infectious Disease Surveillance Center. Sentinel weekly reporting diseases

Hokkaido government. Data for COVID-19 in Hokkaido Prefecture

Hokkaido Government Board of Education

World Health Organization. Transmission of SARS-CoV-2: implications for infection prevention precautions

SARS-CoV-2 and Potential Airborne Transmission

How to Protect Yourself & Others

Masks Do More Than Protect Others During COVID-19: Reducing the Inoculum of SARS-CoV-2 to Protect the Wearer

Statistics Bureau of Japan. Final report of 2015 "Population and households of Japan

Centre for Health Protection of the Hong Kong Special Administrative Region Government. CHP closely monitors cluster of pneumonia cases on Mainland

Ministry of Health, Labour and Welfare. COVID-19 outbreak situation in Japan

Declaration of State of Emergency in Response to COVID-19. Hokkaido government

Inactivation of influenza A viruses in the environment and modes of transmission: A critical review

Humidity and respiratory virus transmission in tropical and temperate settings

Respiratory Syncytial Virus: Infection, Detection, and New Options for Prevention and Treatment

Human metapneumovirus infection

Community Outbreak of Mycoplasma pneumoniae Infection: School-Based Cluster of Neurologic Disease Associated with Household Transmission of Respiratory Illness

Rotavirus overview

Molecular Epidemiology of Enteric Adenovirus Gastroenteritis in under-Five-Year-Old Children in Iran

Adenovirus Infection and Outbreaks: What You Need to Know

Adenovirus: Epidemiology, Global Spread of Novel Serotypes, and Advances in Treatment and Prevention

Rates of asymptomatic respiratory virus infection across age groups

COVID-19: Discovery, diagnostics and drug development

Inactivation of Severe Acute Respiratory Syndrome Coronavirus 2 by WHO-Recommended Hand Rub Formulations and Alcohols

Hand Hygiene Recommendations. Guidance for Healthcare Providers about Hand Hygiene and COVID-19

Efficacy of ethanol against viruses in hand disinfection

Investigation of the efficacy of alcohol-based solutions on adenovirus serotypes 8, 19 and 37, common causes of epidemic keratoconjunctivitis, after an adenovirus outbreak in hospital

Urinary Tract Infection in Children

The Epidemiology and Pathogenesis of Kawasaki Disease

Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: prospective observational study

Multisystem Inflammatory Syndrome in U.S. Children and Adolescents

An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study

Multisystem Inflammatory Syndrome in Children and Kawasaki Disease: Two Different Illnesses with Overlapping Clinical Features

Multi-System Inflammatory Syndrome in Children (MIS-C) Following SARS-CoV-2 Infection: Review of Clinical Presentation, Hypothetical Pathogenesis, and Proposed Management

Multisystem Inflammatory Syndrome in Children Related to SARS-CoV-2

A case of multisystem inflammatory syndrome in children in a japanese boy: with discussion of cytokine

About severe pediatric cases of COVID-19 in Japan

Interference between rhinovirus and influenza A virus: a clinical data analysis and experimental infection study

Virus-virus interactions impact the population dynamics of influenza and the common cold

Human Rhinovirus Infection Blocks Severe Acute Respiratory Syndrome Coronavirus 2 Replication Within the Respiratory Epithelium: Implications for COVID-19

We would like to thank all the pediatricians who participated in this survey. We thank Melissa Leffler, MBA, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript. We thank Shiro Hinotsu for supervising data analysis of this manuscript.J o u r n a l P r e -p r o o f