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Abstract

Background:

Infection prevention and control (IPC) measures during the coronavirus disease 2019 (COVID-19) pandemic have led to a reduction in respiratory viral infections. However, these infections showed a resurgence in the post-COVID-19 era. Respiratory viral infections often exacerbate respiratory diseases.

Objectives:

This study aimed to determine how the relaxation of IPC measures affects the incidence of virus-related acute exacerbations in various respiratory diseases.

Design:

A retrospective study conducted at a tertiary care facility.

Methods:

This study retrospectively assessed data from adult patients aged 18 years and older who visited the emergency department (ED) of a tertiary medical centre in Kobe, Japan, from 1 October 2020 to 12 March 2024. We identified patients who visited because of chronic obstructive pulmonary disease (COPD) exacerbation, asthma exacerbation or acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) and classified them into two groups based on the pre-relaxation and post-relaxation of IPC measures. The detection rates and respiratory viruses identified using multiplex polymerase chain reaction were compared between the groups.

Results:

The total number of ED visits was 84,183 involving 129 cases of COPD exacerbation, 156 cases of asthma exacerbation and 68 cases of AE-IPF. Virus-related COPD exacerbations were significantly more frequent after the relaxation of IPC measures than before (7.7% vs 52.5%, p < 0.001). Similarly, virus-related asthma exacerbations occurred significantly more frequently after relaxation than before (39.7% vs 66.7%, p = 0.009). In contrast, no significant difference in the virus-associated AE-IPF was observed before and after relaxation (2.5% vs 5.0%, p = 0.61).

Conclusion:

Relaxation of IPC measures may increase virus-related exacerbations in COPD and asthma.

Plain language summary

COVID precautions and virus-related exacerbations

Relaxing COVID-19 infection control measures led to more virus-related exacerbations in COPD and asthma, but not in acute exacerbation of idiopathic pulmonary fibrosis. This study highlights the role of infection prevention in managing chronic respiratory diseases.

Keywords

asthma chronic obstructive pulmonary disease COVID-19 infection control respiratory virus

Introduction

Following the first reported case of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) in Japan on 16 January 2020, and the subsequent community transmission recognised from March 2020, the Japanese government strongly advocated for public health measures, including mask-wearing, hand hygiene and escaping 3Cs (closed spaces, crowded places and close-contact settings). These infection prevention and control (IPC) measures were enforced until they were relaxed on 13 March 2023, and the coronavirus disease 2019 (COVID-19) was legally downgraded under the Infectious Disease Control Law on 8 May 2023.¹ The implementation of stringent infection prevention and control measures during the COVID-19 pandemic has led to changes in the ecology of respiratory viruses. During the initial phase of COVID-19, the prevalence of rhinoviruses and enteroviruses (RV/EV) did not change, whereas the number of infections caused by influenza (Flu) and respiratory syncytial viruses (RSV) significantly decreased.^2–4 The RSV peak season shifted from autumn and winter to summer.⁵ A Japanese study indicated that cases of infection with the Flu virus and human metapneumovirus (hMPV) drastically declined in 2020 and 2021, respectively, with a trend towards recovery by 2022.⁶ Additionally, respiratory viruses have shown a trend towards resurgence in the post-COVID-19 era with the relaxation of IPC measures.^3,7

The exacerbation of respiratory diseases is strongly associated with viral respiratory infections. During the period of strict IPC measure implementation following the onset of the COVID-19 pandemic, the number of patients with chronic obstructive pulmonary disease (COPD) and asthma exacerbations decreased globally, which was attributed to a reduction in respiratory viral infections.^3,8–11 However, the resurgence of respiratory viral infections following the relaxation of IPC measures may have altered the aetiology of acute exacerbations in respiratory diseases, though such trends have not been reported in the literature.

In our facility, we routinely perform multiplex polymerase chain reaction (PCR) testing on most patients presenting to the emergency department (ED) with respiratory symptoms, both before and after the relaxation of IPC measures in Japan. This study aimed to determine how the relaxation of IPC measures affects the incidence of virus-related acute exacerbations in various respiratory diseases by analysing multiplex PCR data, thereby inferring the impact of IPC measures.

Materials and methods

Study design and participants

This single-centre retrospective study was conducted at the Kobe City Medical Centre General Hospital. Our hospital serves as a regional hub and tertiary care facility, accommodating over 20,000 emergency visits and approximately 8000 ambulance calls annually. The inclusion criteria were as follows: (1) age ⩾18 years; (2) diagnosis of COPD exacerbation, asthma exacerbation or acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) according to established guidelines;^12–15 and (3) presentation to the ED between 1 October 2020 and 12 March 2024. Patients were excluded if clinical evaluation revealed a confirmed diagnosis unrelated to the target respiratory diseases. Patients who presented between 1 October 2020 and 12 March 2023 were classified into the pre-relaxation group, whereas those who presented between 13 March 2023 and 12 March 2024 were classified into the post-relaxation group. COPD exacerbation was diagnosed according to the Global Initiative for Chronic Obstructive Lung Disease guidelines 2024,¹² asthma exacerbation according to the Global Initiative for Asthma Global Strategy for Asthma Management and Prevention guidelines 2024,¹³ and AE-IPF according to the ATS/ERS/JRS/ALAT Clinical Practice Guidelines and Collard et al.’s definition; each condition was diagnosed by at least two emergency physicians and one or more respiratory physicians.^14,15 We classified asthma-COPD overlap syndrome exacerbation as a COPD exacerbation. Among these patients, those who underwent multiplex PCR testing in the ED were analysed to assess viral pathogen detection. In our hospital, patients who exhibit respiratory symptoms, such as increased sputum secretion, purulent sputum production and dyspnoea, are considered for testing. However, the attending emergency physician may opt to not perform the testing if a patient declines, prefers an alternative diagnostic approach or had previously undergone similar testing at another facility. This study was reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement (Supplemental Table 1).¹⁶

Data collection

Viral detection was performed using nasopharyngeal swabs and the BioFire Respiratory Panel 2.1, which detects SARS-CoV-2, adenovirus (AdV), coronavirus (HCoV) HKU1/NL63/OC43/229E, parainfluenza virus (PIV) 1/2/3/4, Flu A/B, RSV, RV/EV, hMPV, Bordetella pertussis, Bordetella parapertussis, Chlamydia pneumoniae and Mycoplasma pneumoniae. Regardless of whether patients were intubated or underwent bronchoscopy, all viral specimens for multiplex PCR testing were nasopharyngeal swabs, collected at the time of presentation to the ED. These samples were obtained by attending emergency physicians during the patients’ stay in the ED and were promptly subjected to multiplex PCR testing regardless of the time of day. RVs and EVs, which are genetically similar, cannot be differentiated using this method.^17,18 Two previous prospective trials have shown that for all viruses, except HCoV OC43, both the positive and negative predictive values exceeded 90%.^19,20 Given multiplex PCR testing’s high sensitivity and ability to rapidly detect multiple viruses simultaneously, this approach is deemed valuable for diagnosing pneumonia during the COVID-19 pandemic in emergency hospitals, where quick intervention for critical patients is crucial. In patients with COPD or asthma exacerbations, nasopharyngeal swabs are considered an appropriate specimen type for viral detection, with diagnostic accuracy comparable to that of sputum samples.²¹ In AE-IPF cases, although previous studies have suggested the potential utility of nasopharyngeal swabs, their diagnostic accuracy remains to be fully established.^22,23 All sputum specimens were also collected in the ED. A sputum sample was considered to be of high quality if it contained fewer than 10 squamous epithelial cells and more than 25 polymorphonuclear cells per low-power field (Geckler class IV or V). Bacterial growth of +1 or greater on semi-quantitative culture after 24–48 h of incubation was considered indicative of pathogenicity. Bacterial and fungal cultures were routinely performed, but mycobacterial testing was not conducted. Blood tests were conducted at the time of the emergency visit, and Krebs von den Lungen-6 (KL-6) levels were measured within 7 days of the visit.

Outcomes

The primary outcomes were the comparison of viral detection rates and types of viruses detected before and after the relaxation of IPC measures for COPD exacerbation, asthma exacerbation and AE-IPF.

Statistical analysis

Quantitative variables are reported as medians (interquartile range), and qualitative variables are reported as counts (percentages [%]). Comparisons between the two groups were performed using the Mann–Whitney U test for non-normally distributed data and the chi-squared test for categorical data. The association between the two groups and virus detection was assessed using the logistic regression analysis. Statistical analyses were conducted using JMP 17 (SAS Inst, NC, USA) with a significance level set at p < 0.05. Post hoc power analysis was performed using G*Power software (version 3.1.9.7; Heinrich Heine University Düsseldorf, Düsseldorf, Germany) to evaluate the adequacy of statistical power for the chi-squared test, using a two-sided test with a significance level of α = 0.05.

Results

Patient demographics and testing protocols

Between 1 October 2020 and 12 March 2024, 84,183 patients visited the ED, including 129 patients with COPD exacerbations, 156 with asthma exacerbations and 68 with AE-IPF. In total, 86 patients with COPD exacerbation were in the pre-relaxation group and 43 were in the post-relaxation group, with 78 and 40 patients receiving multiplex PCR testing, respectively. SARS-CoV-2 antigen testing was performed in seven patients in the pre-relaxation group and three in the post-relaxation group, with only one positive result in the latter group. There were 94 and 62 patients with asthma exacerbations in the pre- and post-relaxation groups, respectively, with 68 and 36 patients undergoing multiplex PCR testing, respectively. Antigen testing for SARS-CoV-2 and Flu A/B was conducted in three patients in the pre-relaxation group and 14 in the post-relaxation group, yielding one positive result for SARS-CoV-2 and one for Flu A in the pre-relaxation group, and one positive result for SARS-CoV-2 in the post-relaxation group. In total, 46 patients with AE-IPF were in the pre-relaxation group and 22 were in the post-relaxation group, with 40 and 20 patients undergoing multiplex PCR testing, respectively. Two patients in the pre-relaxation group were tested for SARS-CoV-2 using PCR and antigen testing, and all results were negative (Figure 1).

Figure 1.

Patient selection flowchart.

Baseline characteristics

In the pre-relaxation group, patients with COPD exacerbations were significantly more likely to be men (p = 0.006) and users of home oxygen therapy (p = 0.003). Although the difference was not significant, a lower incidence of severe exacerbation was observed in the pre-relaxation group than that in the post-relaxation group (39.5% vs 51.2%, p = 0.057). Patients with asthma exacerbations in the pre-relaxation group showed a significantly lower trend in CRP levels than that in the post-relaxation group (p = 0.025), with no significant differences in other parameters. For patients with AE-IPF, no significant difference in any of the parameters was observed between the groups. For each disease category, the proportions of patients with sputum cultures or high-quality sputum cultures obtained did not differ significantly between the pre-relaxation and post-relaxation groups (Table 1).

Table 1.

Baseline characteristics of the study patients.

(a) COPD exacerbation.
Variables	Pre-relaxation group (n = 86)	Post-relaxation group (n = 43)	p-Value
Age (years)	76.0 (71.0–82.3)	77.0 (72.0–81.0)	0.93
Male sex	78 (90.7)	31 (72.1)	0.006
BMI (kg/m²)	20.1 (18.3–22.8)	20.7 (18.6–23.1)	0.67
Smoking index (pack-year)	59 (40–83)	60 (40–88)	0.61
Home oxygen therapy	34 (39.5)	6 (14.0)	0.003
Controller inhalers			0.53
LAMA	3 (3.5)	3 (7.0)
ICS	0	1 (2.3)
LABA	2 (2.3)	1 (2.3)
LAMA/LABA	27 (31.4)	11 (25.6)
ICS/LABA	6 (7.0)	4 (9.3)
ICS/LAMA/LABA	29 (33.7)	11 (25.6)
No inhalers	19 (22.1)	12 (27.9)
Severity of COPD exacerbation			0.057
Mild	14 (16.3)	1 (2.3)
Moderate	38 (44.2)	20 (46.5)
Severe	34 (39.5)	22 (51.2)
Admission	77 (89.5)	39 (90.7)	0.84
WBC count (cells/µL)	9,550 (7,300–12,775)	9,600 (7,400–14,200)	0.58
Eosinophil count (cells/µL) (n = 82 vs 41)	80 (0–216)	44 (0–848)	0.23
LDH (U/L)	229 (178–287)	228 (196–297)	0.44
CRP (mg/dL)	1.37 (0.27–6.78)	3.70 (0.41–10.52)	0.14
Sputum culture obtained	51 (59.3)	28 (65.1)	0.41
High-quality sputum culture obtained	16 (18.6)	10 (23.3)	0.39
(b) Asthma exacerbation.
Variables	Pre-relaxation group (n = 94)	Post-relaxation group (n = 62)	p-Value
Age (years)	48.0 (29.8–62.8)	52.0 (36.8–62.3)	0.42
Male sex	33 (35.1)	25 (40.3)	0.51
Smoking status (ex/current smoker)	40 (42.6)	23 (39.7)	0.72
Controller inhalers			0.89
ICS	3 (3.2)	1 (1.6)
ICS/LABA	39 (41.5)	22 (35.5)
ICS/LAMA/LABA	10 (10.6)	8 (12.9)
No inhalers	39 (41.5)	29 (46.8)
Unknown	3 (3.2)	2 (3.3)
Severity of asthma exacerbation			0.25
Mild	48 (51.1)	25 (40.3)
Moderate	31 (33.0)	21 (33.9)
Severe	15 (16.0)	16 (25.8)
Admission	34 (36.2)	23 (37.1)	0.91
WBC count (/µL) (n = 65 vs 40)	9,100 (7,400–11,150)	9,650 (7,425–12,250)	0.36
LDH (U/L) (n = 65 vs 38)	199 (169–239)	204 (171–258)	0.63
CRP (mg/dL) (n = 65 vs 39)	0.46 (0.14–1.86)	1.4 (0.42–3.60)	0.025
Sputum culture obtained	17 (18.1)	10 (16.1)	0.75
High-quality sputum culture obtained	8 (8.5)	3 (4.8)	0.77
(c) AE-IPF.
Variables	Pre-relaxation group (n = 46)	Post-relaxation group (n = 22)	p-Value
Age (years)	77.5 (71.8–85.0)	78.0 (69.0–83.0)	0.99
Male sex	37 (80.4)	20 (90.9)	0.27
Smoking status (ex/current smoker)	37 (80.4)	19 (86.4)	0.55
BMI (kg/m²)	23.1 (20.1–25.5)	20.9 (18.4–23.6)	0.12
Home oxygen therapy	17 (37.0)	5 (22.7)	0.24
Admission	45 (97.8)	21 (95.5)	0.59
WBC count (cells/µL)	10,750 (8550–13,425)	8700 (6675–15,025)	0.51
LDH (U/L)	298 (255–411)	384 (304–431)	0.091
KL-6 (U/mL) (n = 39 vs 20)	1328 (856–2313)	1120 (653–2190)	0.39
CRP (mg/dL)	6.84 (2.62–12.31)	7.85 (3.73–12.40)	0.73
Sputum culture obtained	24 (52.2)	16 (72.7)	0.11
High-quality sputum culture obtained	5 (10.9)	3 (13.6)	0.74

Quantitative variables are reported as medians (interquartile range), and qualitative variables are reported as counts (%).

AE-IPF, acute exacerbation of idiopathic pulmonary fibrosis; BMI, body mass index; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; ICS, inhaled corticosteroid; KL-6, Krebs von den Lungen-6; LABA, long-acting beta-agonist; LAMA, long-acting muscarinic antagonist; LDH, lactate dehydrogenase; WBC, white blood cell.

Detection of pathogens

In the COPD exacerbation cohort, viruses were detected in 7.7% (6/78) of the patients in the pre-relaxation group and 52.5% (21/40) in the post-relaxation group, with RV/EV at 10% (4/40), RSV at 12.5% (5/40) and Flu A at 10% (4/40), demonstrating a significantly higher detection rate in the latter group (p < 0.001). In the univariate logistic regression analysis, patients in the post-relaxation group had significantly higher odds of testing positive for respiratory viruses (odds ratio (OR) 13.26, 95% confidence interval (CI) 4.69–37.47, p < 0.001). Moraxella catarrhalis was detected in three cases in both groups, and Staphylococcus aureus was additionally found in five cases in the pre-relaxation group (Table 2(a)). In the pre-relaxation group, methicillin-resistant Staphylococcus aureus (MRSA) was co-detected with Flu A, and Candida albicans was co-detected with PIV1. In the post-relaxation group, methicillin-sensitive Staphylococcus aureus and RSV were co-detected.

Table 2.

Sputum culture results for COPD exacerbation, asthma exacerbation and AE-IPF before and after relaxation of infection control measures.

(a) COPD exacerbation.
Variables	Pre-relaxation group (n = 16)	Post-relaxation group (n = 10)
Moraxella catarrhalis	3 [19]	3 [30]
Staphylococcus aureus (MSSA/MRSA)	5 (2/3) [31]	1 (1/0) [10]
Pseudomonas aeruginosa	1 [6]	0
Haemophilus influenzae	0	1 [10]
Haemophilus parainfluenza	1 [6]	0
Streptococcus agalactiae	1 [6]	0
Candida albicans	1 [6]	0
Not detected	4 [25]	5 [50]
(b) Asthma exacerbation.
Variables	Pre-relaxation group (n = 8)	Post-relaxation group (n = 3)
Moraxella catarrhalis	2 [25]	0
Haemophilus influenzae	2 [25]	0
Haemophilus parainfluenza	0	1 [33]
Streptococcus pneumoniae	0	1 [33]
Achromobacter xylosoxidans	1 [13]	0
Not detected	3 [38]	1 [33]
(c) AE-IPF
Variables	Pre-relaxation group (n = 5)	Post-relaxation group (n = 3)
Klebsiella variicola	1 [20]	0
Enterobacter cloacae complex	1 [20]	0
Not detected	3 [60]	3 [100]

Data are presented as counts [%].

AE-IPF, acute exacerbation of idiopathic pulmonary fibrosis; COPD, chronic obstructive pulmonary disease; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-sensitive Staphylococcus aureus.

Similarly, in asthma exacerbation, viruses were detected in 39.7% (27/68) of the patients in the pre-relaxation group and 66.7% (24/36) in the post-relaxation group, with RV/EV at 33.3% (12/36), RSV at 8.3% (3/36) and Flu A at 13.9% (5/36) showing a significantly higher rate in the latter group (p = 0.009). Univariate logistic regression analysis revealed that patients in the post-relaxation group were significantly more likely to test positive for respiratory viruses (OR 3.03, 95% CI 1.30–7.08, p = 0.010). Multiple detections in the pre-relaxation group included SARS-CoV-2 or RV/EV with RSV. As the multiplex PCR assay was qualitative, the predominant causative virus could not be determined. These cases were classified as ‘multi-detected’, as shown in Figure 2(b). In the pre-relaxation group, Moraxella catarrhalis and Haemophilus influenzae were each detected in two cases (Table 2(b)). Staphylococcus aureus was co-detected with RSV, and Acinetobacter ursingii was co-detected with Flu A. In the post-relaxation group, Streptococcus pneumoniae was co-detected with RV/EV, and Haemophilus parainfluenzae was co-detected with RV/EV.

Figure 2.

Mosaic plots of respiratory viruses detected using multiplex PCR. (a) COPD exacerbation. (b) Asthma exacerbation. (c) AE-IPF.

In patients with AE-IPF, the viral detection rates were 2.5% (1/40) in the pre-relaxation group and 5.0% (1/20) in the post-relaxation group, with no significant difference between the groups (p = 0.61). Univariate logistic regression yielded an OR of 2.02 (95% CI 0.12–34.63, p = 0.62), also indicating no significant difference (Figure 2, Supplemental Table 2). In cases of COPD exacerbations, asthma exacerbations and AEs-IPF, no bacteria were detected using multiplex PCR testing. In the pre-relaxation group, bacteria were detected in two cases; however, no co-detection of bacteria and viruses was observed. In the post-relaxation group, no bacteria were detected (Table 2(c)).

COPD exacerbations were more commonly observed in summer and winter prior to the relaxation of IPC measures but were relatively frequent in summer and autumn after the relaxation. In Japan, the seasons from March to May are generally regarded as spring, from June to August as summer, from September to November as autumn and from December to February as winter. There was little involvement of viral infections throughout the pre-relaxation period. However, immediately after the relaxation of IPC measures, an increase in exacerbations associated with multiple virus types was noted, and this trend continued until the end of 2023. Asthma exacerbations were more frequent during summer before the relaxation of IPC measures but were observed more uniformly across the seasons afterwards. Similar to COPD exacerbations, an increase and persistence of virus-associated asthma exacerbations was observed immediately after the relaxation of IPC measures. While RV/EV-associated asthma exacerbations were observed regardless of the season in the pre-relaxation and post-relaxation periods, RSV and Flu A-related exacerbations exhibited seasonal patterns in the post-relaxation period. AEs-IPF were generally observed throughout the year prior to the relaxation of IPC measures but predominantly occurred in winter following the relaxation (Figure 3, Supplemental Table 3).

Figure 3.

Distribution of detected viruses stratified by months during the pre-relaxation (from 1 October 2020 to 12 March 2023) and post-relaxation (from 13 March 2023 to 12 March 2024) periods. (a) COPD exacerbation. (b) Asthma exacerbation. (c) AE-IPF.

Discussion

To the best of our knowledge, this is the first study to demonstrate the association between the relaxation of IPC measures in Japan and the acute exacerbation of respiratory diseases associated with respiratory viruses. Relaxation of IPC measures significantly increased the proportion of virus-related exacerbations in patients with COPD and asthma, whereas no significant association was observed for AE-IPF.

The detection rate of viruses in COPD exacerbation cases in the post-relaxation group may have returned to pre-COVID-19 pandemic levels. A pre-pandemic review reported that the proportion of virus-related COPD exacerbations ranged from 22% to 57%, with strong associations identified for rhinovirus (3.1%–26.6%), respiratory syncytial virus (0.7%–40.5%) and influenza virus (2.0%–22.4%), as determined by PCR-based detection methods.²¹ These results are consistent with our findings, demonstrating a virus-associated COPD exacerbation rate of 52.5% (21/40) in the post-relaxation group, with RV/EV at 10% (4/40), RSV at 12.5% (5/40) and Flu at 10% (4/40).

Similarly, the detection rate of viruses in asthma exacerbations in the post-relaxation group may reflect the pre-pandemic levels. A pre-pandemic meta-analysis indicated that 47.17% (95% CI: 37.88%–56.56%) of adult asthma exacerbations were virus-related, compared to 66.7% in our study.²⁴ This meta-analysis reported the detection rates of RV at 17.34% (95% CI: 10.21%–25.79%), RSV at 2.16% (95% CI: 0.07%–4.19%) and influenza at 8.07% (95% CI: 5.19%–11.44%), whereas our study found the detection rates of RV at 36.1% (13/36), RSV at 8.3% (3/36) and influenza at 13.9% (5/36), exceeding the meta-analysis results.²⁴ This observation may suggest that reduced antigen exposure during strict IPC measure implementation could have contributed to an increased susceptibility to virus-induced asthma exacerbations following the relaxation of these measures.^2,4

Among patients with AE-IPF, RV/EV was detected in one patient in the pre-relaxation group and SARS-CoV-2 in one patient in the post-relaxation group, with no significant difference between the groups. Although previous reports have suggested that subclinical or occult viral infections potentially play a partial pathogenic role in AEs-IPF, in clinical practice, the involvement of viral infections in AE-IPF remains limited compared to exacerbations in COPD and asthma.^25–28 A single-centre retrospective study conducted in Japan during the pre-relaxation period reported an RV/EV detection rate of 7.1% (2/28), which is comparable to the 2.5% (1/40) reported in our study.²⁹ Pre-pandemic studies detected respiratory viruses, including human herpes viruses, in 18.5% (5/27) of patients with AE-IPF, whereas the detection rate for non-human herpes viruses was 2.7% (1/27), similar to our findings.²³ Although this study did not consider the impact of human herpes viruses, it suggests that respiratory virus-related AE-IPF may not be significantly affected by IPC measures.

Changes in the distribution of bacterial pathogens during implementation of IPC measures have been observed in patients with COPD exacerbations. Kim et al. reported that the incidence of community-acquired pathogens decreased during implementation of IPC measures, whereas the prevalence of organisms capable of chronic colonisation increased from that of the period prior to the implementation of IPC measures.³⁰ Their study concluded that IPC measures might have suppressed the transmission of community-acquired bacterial pathogens. Similarly, in our cohort, infections caused by MRSA and Pseudomonas aeruginosa were observed in 4 of 16 COPD exacerbation cases during implementation of IPC measures, whereas community-acquired pathogens such as Streptococcus pneumoniae and Haemophilus influenzae were not detected. However, this trend was not clearly observed in patients with asthma exacerbation.

Among patients with COPD exacerbation, no significant differences in CRP or WBC levels were observed between the two groups. These finding align with those of previous studies showing that inflammatory markers, such as CRP, WBC and procalcitonin, are not reliable for differentiating between the causative pathogens in COPD exacerbations.^31,32 In contrast, among patients with asthma exacerbation, CRP levels were significantly higher in the post-relaxation group, which may reflect the increased prevalence of virus-associated exacerbations in this group.

COPD exacerbations may have been influenced by RSV infection following the relaxation of IPC measures. In Japan, RSV infections have peaked during the summer since 2021.^5,7 In our study, no RSV was detected in COPD exacerbations before the relaxation of IPC measures, indicating minimal influence from the surrounding infection rates. However, post-relaxation RSV detection in COPD exacerbations increased during the summer, which was consistent with the surrounding epidemic trends. Given these results, the importance of RSV vaccination is expected to increase in the post-COVID-19 era.³³

Respiratory viruses that target respiratory epithelial cells are often causative pathogens of airway disease exacerbations. Frequently detected viruses, such as RV/EV, RSV and Flu A/B, infect epithelial cells in both the upper and lower respiratory tract, utilising receptors such as intercellular adhesion molecule-1, CX3C chemokine receptor 1, heparan sulphate proteoglycans and sialic acid residues.^34–36 Such viral infections induce the production of various cytokines and chemokines, cause injury to epithelial cells or disruption of tight junctions, and ultimately result in airway disease exacerbations.²¹ In contrast, SARS-CoV-2 infects the respiratory epithelium or type II alveolar epithelial cells via the angiotensin-converting enzyme 2 receptor. Its direct cytopathic effect on airway epithelial cells is considered to be relatively limited, although the infection can trigger strong immune responses contributing to tissue damage.³⁶

This study had several limitations. First, this was a single-centre retrospective study, and the results may not be generalisable. Post hoc power analysis for the chi-squared test showed sufficient power for COPD exacerbations (1.00), but low power for asthma exacerbations (0.74) and AE-IPF (0.08), indicating a potential risk of type II error in this subgroup. Second, the downgrading of the COVID-19 legal status may have altered patients’ behaviour. Patients with mild symptoms who visited before the relaxation of the IPC measures might have avoided or selected other hospitals, reducing the number of patients at our tertiary care facility. Third, multiplex PCR testing using the BioFire Respiratory Panel 2.1 was introduced at our facility in October 2020. We did not routinely detect viruses using any methods other than multiplex PCR prior to October 2020, which prevented us from measuring virus-related respiratory disease exacerbations before the COVID-19 pandemic and during the initial months of the pandemic (from March 2020 to September 2020). Fourth, this study did not allow the tracking of vaccination rates for each virus or the use of prophylactic antiviral medications throughout the study period. Exacerbation factors other than viral infections, such as the presence of allergen exposure, severity of comorbid diseases, medication adherence and long COVID-19 syndrome,³⁷ were also difficult to assess retrospectively. These factors could be potential confounders. Finally, high-quality sputum specimens were available for only a limited number of cases for pathogen evaluation. Sputum cultures were frequently attempted in patients with COPD exacerbations and AE-IPF; however, in cases of severe respiratory failure or poor expectoration, sputum samples were often unavailable or had to be obtained via suction, potentially compromising specimen quality and consistency.

In conclusion, these findings provide valuable insights into the impact of IPC measures on virus-associated exacerbations of airway diseases. Following the relaxation of IPC measures, virus-associated exacerbations in COPD and asthma increased to their pre-COVID-19 levels, whereas such changes were not observed in AE-IPF. These findings suggest that IPC measures against COVID-19 not only suppress virus-related respiratory disease exacerbations but also indicate that the impact of viral infections on exacerbations differs between airway diseases and interstitial lung diseases. Clinicians should emphasise on the implementation of IPC measures to reduce virus-induced exacerbations in patients with airway diseases.

Supplemental Material

sj-docx-1-tai-10.1177_20499361251379981 – Supplemental material for Changes in virus-related exacerbations of chronic respiratory diseases before and after the relaxation of COVID-19 infection control measures: a single-centre retrospective study in Japan

Supplemental material, sj-docx-1-tai-10.1177_20499361251379981 for Changes in virus-related exacerbations of chronic respiratory diseases before and after the relaxation of COVID-19 infection control measures: a single-centre retrospective study in Japan by Tsuyoshi Sasada, Ryota Kishi, Chigusa Shirakawa, Ryosuke Hirabayashi, Yuki Sato, Kazuma Nagata, Atsushi Nakagawa, Keisuke Tomii, Koichi Ariyoshi and Ryo Tachikawa in Therapeutic Advances in Infectious Disease

Footnotes

Acknowledgements

The authors would like to thank all the patients who participated in this study and all the medical staff for their assistance. We would like to thank Editage for the English language editing. This study did not receive any funding.

Declarations

ORCID iD

Tsuyoshi Sasada

Supplemental material

Supplemental material for this article is available online.

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