PHWR Public Health Weekly Report

Influenza and seven respiratory viruses—respiratory syncytial virus, adenovirus, rhinovirus, parainfluenza virus, metapneumovirus, human coronavirus, and bocavirus—are classified as Class 4 infectious diseases. This implies that they are subject to sentinel surveillance rather than mandatory surveillance. The Division of Emerging Infectious Diseases of the Korea Disease Control and Prevention Agency (KDCA) operates the Korea Respiratory Virus Integrated Surveillance System (K-RISS). This system aims to analyze the prevalence and characteristics of respiratory pathogens. Over 150 healthcare institutions, including 77 clinic-level healthcare institutions, actively participate as sentinel surveillance institutions. Since January 2023, K-RISS has incorporated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a surveillance pathogen, anticipating the reclassification of coronavirus disease 2019 (COVID-19). Even after the downgrade to a Class 4 infectious disease on August 31, 2023, K-RISS has maintained stable monitoring of detection patterns. Among the 77 clinic-level sentinel surveillance institutions, 23 are internal medicine practices, 43 pediatric practices, 9 are family medicine practices, and 2 are otolaryngology practices. Additionally, 72 of these institutions participate in clinical surveillance of influenza. Samples collected from these sentinel surveillance institutions undergo genetic detection (real-time reverse transcription polymerase chain reaction, real-time RT-PCR) for nine different species: SARS-CoV-2, influenza virus, respiratory syncytial virus, adenovirus, rhinovirus, parainfluenza virus, metapneumovirus, human coronavirus, and bocavirus. Testing is conducted at the Public Health and Environment Research Institute of 18 cities and provinces. Our department collects and analyzes the weekly results of gene detection tests, which are subsequently shared on the Infectious Disease Portal on the KDCA website. For influenza, pathogen characteristics (vaccine strain homology, antiviral drug resistance, etc.) are monitored through genetic analysis. Viruses are also isolated from samples for antigenic and therapeutic phenotyping. As a World Health Organization (WHO)-designated National Influenza Center, our department shares weekly domestic detections and influenza isolates with the WHO. Furthermore, we actively participate in the global influenza surveillance and response system, contributing to international influenza epidemics, pandemic preparedness, and vaccine selection. This manuscript aims to present the detection patterns of influenza and respiratory viruses in the Republic of Korea (ROK) during the 2022–2023 season (from week 36 of 2022 to week 35 of 2023) and provide results of genotyping, antigenicity, and treatment resistance through the characterization of isolated influenza viruses.

1. Domestic and international influenza and respiratory virus detections

In the 2022–2023 season, a total of 15,009 samples collected in the ROK underwent genetic detection (real-time RT-PCR) for seven influenza and respiratory viruses at the Public Health and Environment Research Institute of 18 cities and provinces. The analysis of pathogen detection rates was based on the number of positive detections. Internationally, the influenza detection rates and subtype detection rates in the Northern Hemisphere were analyzed by considering the number of positive influenza detections and tests reported to WHO FluNet [1].

2. Influenza virus characterization

Hemagglutinin, a key gene in influenza viruses, was subjected to genotyping through phylogenetic analysis to confirm the virus’s phylogeny and its resemblance to that year’s vaccine strain. Additionally, the neuraminidase (NA) gene was sequenced to identify drug-resistant variants. Samples identified as influenza viruses were inoculated into Madin-Darby canine kidney (MDCK) cells for A(H1N1)pdm09 and type B and MDCK-SIAT1 cells for A(H3N2). The multiplied viruses were subsequently used for resistance phenotyping against antiviral drug agents (oseltamivir, zanamivir, and peramivir) and antigen typing using weasel antiserum immunized with the vaccine [2].

1. Influenza virus detections

During the 2022–2023 season, a total of 15,009 samples were collected, with 1,341 cases of influenza viruses, indicating a detection rate of 8.9%. The detection rate peaked in week 52, followed by a gradual decline, a minor fluctuation, and subsequent decreases from week 11 in 2023. In terms of influenza virus subtypes, A(H3N2) was the most prevalent at 80.9%, followed by A(H1N1)pdm09 at 15.7% and type B at 3.4% (Table 1).

Table 1 Number of influenza viruses detected in the Republic of Korea

Season	Number of specimen	Number of detection (%)		Number of detection by subtype (%)
		Total		A(H1N1)pdm09	A(H3N2)	B
2022–2023	15,009	1,341 (8.9)		211 (15.7)	1,085 (80.9)	45 (3.4)

In this season, influenza viruses were detected early on, with A(H3N2) identified as the predominant subtype. The first detection of type B occurred in week 43 while that of A(H1N1)pdm09 in week 53. A(H3N2) remained the predominant pandemic subtype until week 27 of 2023, following which A(H1N1)pdm09 was mainly detected (Figure 1).

Figure 1. Weekly detection status of influenza virus in the Republic of Korea during the 2022–2023 season

The influenza detection pattern in the Northern Hemisphere, sharing same seasonality with ROK, was similar to that of ROK itself. Influenza was detected from the first week of the season, with the detection number and rate peaking in week 49 of 2022, predominantly featuring influenza A. Subsequently, the detection rate decreased, followed by a slight increase. During this period, detection trend and influenza subtype distribution similar to those of ROK were observed, with A(H1N1)pdm09 being predominant subtype, albeit with a somewhat lower detection rate (Figure 2).

Figure 2. Weekly detection status of influenza virus in the Northern Hemisphere during the 2022–2023 season

2. Respiratory virus detections other than influenza

In the 2022–2023 season, among the seven respiratory viruses, rhinovirus demonstrated the highest prevalence, with a detection rate of 13.2%. It was followed by adenovirus at 10.4%, metapneumovirus at 9.7%, parainfluenza virus at 9.5%, respiratory syncytial virus at 7.6%, bocavirus at 5.3%, and human coronavirus at 4.9%. Since 2023, SARS-CoV-2 has been included as a surveillance pathogen, and its detection rate for weeks 1 through 35 in 2023 was calculated, revealing a rate of 9.2% (Table 2).

Table 2 Number of respiratory viruses detected in the Republic of Korea

Season	Number of specimena)	Number of detection (%)
		SARS-CoV-2b)	Rhinovirus	Adenovirus	Bocavirus	Metapneumovirus	Parainfluenza virus	Respiratory syncytial virus	Human coronavirus
2022–2023	15,009 (10,190)	936 (9.2)	1,978 (13.2)	1,564 (10.4)	794 (5.3)	1,456 (9.7)	1,430 (9.5)	1,139 (7.6)	742 (4.9)

^a)The number of cases in parentheses is the number of samples collected for 1 to 35 weeks in 2023, and it used to calculate the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection rate. ^b)The number of detection and detection rates from 1 to 35 weeks in 2023..

Among the respiratory viruses, bocaviruses remained detectable throughout the season, with detection rates consistently below 10%. Adenoviruses exhibited a sharp increase after week 29 in 2023, reaching their highest detection rate at 42.4% in week 33. Both rhinoviruses and SARS-CoV-2 displayed no seasonal trends, with outbreaks occurring consistently across the entire year. Metapneumoviruses reached their peak at 42 weeks, showing a detection rate of 39.0%, as the epidemic began in the fall at the start of the season. Subsequently, parainfluenza viruses and human coronaviruses spread sequentially. Respiratory syncytial virus was predominant in the fall, experienced a decrease, and then rose slightly from winter to spring, regaining prevalence (Figure 3).

Figure 3. Weekly detection status of respiratory virus during the 2022–2023 season
HRV=rhinovirus; HBoV=bocavirus; HAdV=adeno virus; HCoV=human coronavirus; HMPV=metapneumovirus; HPIV=parainfluenza virus; HRSV=respiratory syncytial virus; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2.

3. Domestic influenza virus characteristics for the 2022–2023 season

To characterize influenza detected in the ROK, both genetic and serotype analyses were conducted. The genetic analysis of the predominant A(H3N2) type in the 2022–2023 season revealed that the sublineage 3C.2a1b.2a.2a.3a.1, corresponding to the vaccine strain of the 2022–2023 season, had the highest detection rate of 61.4%. All other identified viruses were similar to the sublineage of the vaccine strain for the 2022–2023 season. In the case of A(H1N1)pdm09, two genotypes were identified, and similar to A(H3N2), both were traced back to the vaccine strain of the 2022–2023 season, confirming their genotypic similarity to the current year’s vaccine strain. During the 2022–2023 season, type B was identified as Victoria, except for one case, Yamagata. Type Victoria demonstrated a 100% V1A.3a.2 sublineage match to the vaccine strain (Table 3). For type Yamagata, genetic and serotype analyses could not be performed due to low viral titers.

Table 3 Analysis of influenza virus characteristics in the Republic of Korea during the 2022–2023 season

Virus	Clade of 2022–2023 season vaccine strain	Korea influenza virus in 2022–2023 season
		Genotype (%)	Drug resistance	Antibody titera)
A(H1N1)pdm09	6B.1A.5a.2	6B.1A.5a.2a (78.7)	Sensitive	160–640
		6B.1A.5a.2a.1 (21.3)
A(H3N2)	3C.2a1b.2a.2a	3C.2a1b.2a.2a.3a.1 (61.4)	Sensitive	80–320
		3C.2a1b.2a.2a.1 (26.0)
		3C.2a1b.2a.2b (10.6)
		3C.2a1b.2a.2a.1b (2.0)
B(Victoria)	1A.3a.2	V1A.3a.2 (100)	Sensitive	80–320

^a)Neutralization capacity effective when the titer is over the 40..

An analysis of NA gene sequencing and resistance phenotyping for treatment resistance indicated the absence of treatment-resistant variants. The NA inhibitors oseltamivir (Tamiflu), zanamivir (Relenza), and peramivir (Peramiflu) were all found to be drug resistant. In the serotyping of influenza virus isolates in the ROK using a neutralization reaction with immune weasel antiserum of the vaccine strain, the neutralizing ability of the viruses was within a 4-fold range of the vaccine strain titer (A(H1N1)pdm09 and B were 320 and A(H3N2) was 640). This confirmed that the vaccine serum effectively neutralized the domestic isolates.

During the 2021–2022 season in the ROK, the detection of influenza viruses remained low at 0.6%, attributed to the ongoing COVID-19 pandemic. However, in the subsequent 2022–2023 season, the overall detection rate significantly increased to 8.9%. This rise was particularly evident late fall, indicating the first occurrence of an epidemic pattern since the onset of COVID-19 outbreak [3]. Similarly, in North America, the commencement of the seasonal influenza epidemic was noted during the 2022–2023 season [4]. In the Northern Hemisphere, which has a similar season to that of the ROK, influenza tended to show a high prevalence in winter, predominantly with detection of A(H3N2) influenza viruses, followed by a decline in early spring, primarily featuring A(H1N1)pdm09 viruses [1]. Analyzing the weekly data, a peak was observed in week 49 of 2022, followed by a subsequent decline, a minor resurgence, and a continuous decrease from week 9 of 2023, resulting in less than 5% of detections in the summer. Notably, ROK demonstrated a similar detection pattern to the global Northern Hemisphere, with the peak of the epidemic occurring 3 weeks later in week 52. Additionally, the second wave’s peak was 20 weeks later than the international epidemic, indicating a prolonged epidemic with unusually high detection rates even in the summer. In the ROK, type B influenza was confirmed in week 7 of 2023, exhibiting a very low detection rate. In contrast, overseas, consistent detection rate was observed from the beginning of the season, reaching a rate of 24.3% of positive influenza tests in 2023. The domestically detected influenza demonstrated a genotype similar to the vaccine strain, with validated neutralization ability, indicating a high compatibility with the vaccine strain. Unlike in other countries, ROK reported four cases of resistance against the drugs oseltamivir, zanamivir, and peramivir; however, no genetic variation was observed, confirming susceptibility of all phenotypes. This indicated that all influenza virus drugs are effective [5]. During COVID-19 outbreak, respiratory viruses exhibited different detection times compared to traditional seasonal trends. Parainfluenza, typically peaking from April to August, exhibited increased detection rates during winter and persisted through the summer. In the 2021-2022 season, high rates of parainfluenza viruses were detected during the fall season, attributed to increased face-to-face activities due to relaxed quarantine measures. Given the evolving patterns observed this season, continuous monitoring is crucial to comprehend outbreak developments [6]. Metapneumoviruses, typically prevalent in early spring, experienced a sharp surge in detection rates during late summer and fall. Adenoviruses, usually detected at low levels throughout the year, showed a sharp increase from week 29 in 2023, followed by a decline from week 34.

The 2022–2023 season in the ROK marked the confirmation of influenza epidemic for the first time since the COVID-19 outbreak, persisting through the summer. Changes in the overall detection of respiratory viruses and pathogen prevalence occurred at different times than in previous seasons. This shift may be attributed to reduced exposure to respiratory viruses during the COVID-19 pandemic due to social distancing and strict personal hygiene. Subsequently, a rapid return to normal life, increased face-to-face contact, and various forms of social interaction may have facilitated a non-specific epidemic of respiratory viruses even during non-prevalent seasons. Some countries reported outbreaks of respiratory viruses at unusual times [7,-9]. These non-specific outbreaks are complicating the prediction of future respiratory virus outbreaks [10].

The significance of national respiratory virus surveillance has become even more critical, and our department is committed to supporting point-of-care responses for effective patient management in community-acquired respiratory infections. Through continuous close surveillance of influenza and respiratory viruses and the dissemination of results, we aim to share influenza epidemiology and characteristics with the WHO, contributing to the selection of the next seasonal vaccine and pandemic preparedness.

Ethics Statement: Ethics approval for the study protocol and analysis of the data was obtained from the Institutional Review Board of the KDCA (2022-02-05-C-A).

Funding Source: This study was supported by intramural funds (grant NO. 6300-6332-304) from the KDCA.

Acknowledgments: We thank 18 Public Health and Environment Research Institutes for support.

Conflict of Interest: The authors have no conflicts of interest to declare.

Author Contributions: Data curation: SHW, NJL. Formal analysis: SHW, NJL, JHL, JER. Investigation: SHW, JHL. Resources: NJL, JHL. Supervision: JER, EJK. Visualization: SHW, NJL, EJK. Writing - original draft: SHW. Writing - review & editing: JER, EJK.