Five-Year Study Reveals How Respiratory Pathogens Resurged After COVID-19 Restrictions Lifted

When China lifted its stringent non-pharmaceutical interventions against COVID-19 in December 2022, clinicians braced for a rebound in respiratory illness. A new five-year retrospective study now provides one of the most detailed pictures yet of what happened next. Analyzing 9,674 patients with acute respiratory infection treated between 2021 and 2025, researchers led by Ming-wen Zhao and Pei Zhao of Hebei General Hospital and Hebei Medical University tracked how the spectrum of viral and atypical bacterial pathogens shifted as pandemic-era controls ended. Their findings, published in BMC Infectious Diseases, show that pathogen circulation was sharply suppressed during the restriction period, then surged to levels well above baseline once measures were relaxed, with the bacterium Mycoplasma pneumoniae and rhinovirus emerging as the dominant causes of lower respiratory tract disease.

The study relied on a single multiplex fluorescence polymerase chain reaction panel coupled with capillary electrophoresis, applied uniformly to every patient in the cohort. This platform detects 13 targets simultaneously: 11 respiratory viruses and two atypical bacteria, Mycoplasma pneumoniae and Chlamydia. Standardizing the diagnostic method across all five years is a technical strength, because it removes a common source of bias in longitudinal surveillance studies, where changes in assay sensitivity can be mistaken for genuine shifts in pathogen epidemiology. Of the 9,674 patients, 5,289, or 54.67 percent, had lower respiratory tract infections, while 4,385, or 45.33 percent, had upper respiratory tract infections, reflecting the case mix of a hospital-based population rather than a community sample.

The contrast in detection rates between the two anatomical compartments was striking. Pathogens were identified in 2,939 of 5,289 lower respiratory tract infection cases, a positivity rate of 55.57 percent, compared with only 677 of 4,385 upper respiratory tract infection cases, or 15.44 percent. That difference of 40.13 percentage points, with a 95 percent confidence interval of 38.40 to 41.80 and a P value below 0.001, indicates that lower tract disease in this cohort was far more likely to have an identifiable infectious cause. The authors suggest this may partly reflect the deeper sampling and higher pathogen loads associated with lower tract disease, as well as the inclusion of atypical bacteria that preferentially involve the lung parenchyma and bronchial tree.

Within the lower respiratory tract infections, Mycoplasma pneumoniae was the leading pathogen, detected in 954 of 5,289 cases, or 18.04 percent. Rhinovirus followed at 618 cases, or 11.68 percent, and influenza A virus ranked third at 456 cases, or 8.62 percent. In the upper respiratory tract, by contrast, rhinovirus predominated, found in 224 of 4,385 cases, or 5.11 percent. The prominence of Mycoplasma pneumoniae is notable because this cell-wall-less bacterium, which lacks the outer membrane targeted by beta-lactam antibiotics, requires macrolides or other alternative agents and has been associated with periodic epidemics worldwide, including a pronounced wave in East Asia following the end of COVID-19 restrictions. Its rise to the top of the pathogen ranking in this Chinese cohort mirrors reports from several neighboring countries during the same period.

The temporal analysis forms the core of the study’s contribution. During 2021 and 2022, when stringent containment measures and mass vaccination were maintained across China, both the volume of acute respiratory infection consultations and the proportion of tests returning positive remained low. Positivity stood at 326 of 1,180 tests, or 27.63 percent, in 2021 and fell to 283 of 1,161 tests, or 24.38 percent, in 2022. After the relaxation of non-pharmaceutical interventions, the picture changed abruptly. In 2023, 1,486 of 4,292 tests were positive, a rate of 34.62 percent, and by 2024 the positivity rate had climbed to 1,046 of 1,913 tests, or 54.68 percent. In 2025 the rate remained elevated at 475 of 1,128 tests, or 42.11 percent.

Because the number of patients tested varied substantially from year to year, the researchers adjusted for age group in a logistic regression model to determine whether the apparent resurgence was confounded by shifts in the demographic composition of the tested population. It was not. Compared with 2021, the odds of pathogen detection were significantly higher in 2023, with an odds ratio of 2.85 and a 95 percent confidence interval of 2.09 to 3.88; in 2024, with an odds ratio of 4.19 and a confidence interval of 3.01 to 5.84; and in 2025, with an odds ratio of 2.19 and a confidence interval of 1.53 to 3.15. The persistence of this signal after adjustment strengthens the interpretation that the rebound reflects genuine changes in pathogen circulation rather than changes in who was being tested.

This pattern is consistent with the concept of immunity debt, a hypothesis proposed early in the pandemic suggesting that prolonged reduction in exposure to common respiratory pathogens, combined with the aging of the cohort of infants and children who never encountered them, could produce a delayed and intensified wave of infections once transmission resumed. The study cannot directly measure population immunity, and the authors are careful to frame their findings as descriptive surveillance rather than proof of any single mechanism. Nevertheless, the sharp rise in positivity after December 2022, and the dominance of Mycoplasma pneumoniae, a pathogen known for cyclical epidemics at multi-year intervals, fit the broader pattern documented across the region after restrictions ended.

Perhaps the most clinically consequential findings concern the sickest patients. Among 79 patients who required intensive care for severe lower respiratory tract infection, at least one pathogen was detected in every single case, and bacterial or fungal co-infection was documented in 72 of them, or 91.14 percent. Even more alarming, multidrug-resistant organisms were identified in 42 of these ICU patients, or 53.16 percent. Severe disease in this cohort was characterized by advanced age and a heavy burden of secondary infection, underscoring a well-recognized but persistently difficult problem in respiratory critical care: viral injury to the respiratory epithelium creates conditions in which resistant hospital-associated and community-acquired bacteria and fungi can flourish, complicating treatment and worsening outcomes.

The high rate of co-infection in severe cases also carries implications for diagnostic and antimicrobial stewardship. Because mixed infections were more frequent in lower respiratory tract infections than in upper tract disease, the authors argue that multiplex molecular panels, which can identify several pathogens from a single specimen in a few hours, are particularly valuable in hospitalized patients, where distinguishing viral pneumonia from bacterial superinfection directly affects antibiotic decisions. The detection of multidrug-resistant organisms in more than half of the intensive care cohort adds urgency, since empiric broad-spectrum therapy in such patients must be balanced against the risk of further selecting for resistance.

The study’s limitations are those inherent to its retrospective, single-region design. The cohort comes from a hospital in Shijiazhuang, Hebei Province, and the 13-target panel does not cover all respiratory pathogens, notably excluding common bacteria such as Streptococcus pneumoniae and Haemophilus influenzae, so the true burden of bacterial co-infection in the wider population may differ. Hospital-based sampling also means the results describe patients ill enough to seek care rather than community transmission as a whole. Still, the five-year span, the uniform diagnostic method, and the age-adjusted analysis together offer a rigorous record of how one region’s respiratory pathogen landscape responded to the end of pandemic controls. The authors conclude that the suppression and resurgence they documented, together with the heavy burden of resistant co-infection in severe disease, argue for continued vigilance, sustained molecular surveillance, and optimized management of lower respiratory tract infections in the post-pandemic era.

Subject of Research: Respiratory pathogen epidemiology and co-infection patterns in acute respiratory infections during and after the COVID-19 pandemic

Article Title: Respiratory pathogen spectrum and co-infection patterns in patients with acute respiratory infection during and after the coronavirus COVID-19 pandemic: a five-year retrospective study, 2021–2025

Article References: Zhao, M.-W., Yang, J., Li, Y.-H., Qiu, P., Zhang, Y., Zhang, X.-W., Gao, S., Wang, J., & Zhao, P. (2026). Respiratory pathogen spectrum and co-infection patterns in patients with acute respiratory infection during and after the coronavirus COVID-19 pandemic: a five-year retrospective study, 2021–2025. BMC Infectious Diseases. https://doi.org/10.1186/s12879-026-14526-6

Image Credits: AI Generated

DOI: 10.1186/s12879-026-14526-6

Keywords: acute respiratory infection, Mycoplasma pneumoniae, rhinovirus, influenza A, co-infection, COVID-19, non-pharmaceutical interventions, lower respiratory tract infection, multidrug-resistant organisms, multiplex PCR, immunity debt, intensive care