Influenza has threatened human health for decades (Taubenberger and Morens, 2006). It is estimated that global seasonal influenza-associated respiratory deaths account for 4.0–8.8 per 100,000 individuals annually (Iuliano et al., 2018). During the influenza A (H1N1) virus pandemic in the United States in 2009, 26% of patients with H1N1 pneumonia progressed to acute respiratory distress syndrome (ARDS), and 52% of them were admitted to intensive care unit (ICU) (Jain et al., 2012). The study from Mexico and Canada during the 2013–2014 influenza season showed that the 90-day mortality of critical illness in ICUs was 34.6% (Dominguez-Cherit et al., 2016). It is important to understand the long-term outcomes in survivors.

A study from Canada that focused on the one-year outcomes in survivors of ARDS showed that carbon monoxide diffusion capacity remained low throughout the 12-month follow-up (Herridge et al., 2003). At the 5-year follow-up, pulmonary function was normal to near-normal, but none of the survivors returned to normal predicted levels of physical function (Herridge et al., 2011). Another study from Spain on survivors of ARDS with 6-month follow-up showed a poorer health-related quality of life and mild to moderate pulmonary functional abnormalities compared with the healthy population (Masclans et al., 2011). Similar results were found in survivors among H1N1 patients during the 12-month follow-up (Luyt et al., 2012). However, most studies focused on long-term outcomes in the survivors of H1N1 during the 2009 pandemic. In addition, there are still fewer systematic evaluations of the physical function, pulmonary imaging, and quality of life in such patients. There have been many cases of critical illness of severe H1N1 pneumonia and ARDS in every flu season after 2009 (Iuliano et al., 2018; Li et al., 2019).

This study aimed to characterize long-term outcomes in survivors of severe H1N1 pneumonia and ARDS during 12 months of follow-up. And try to explore the relationship between the long-term pulmonary function and exercise capacity, health-related quality of life, pulmonary imaging, with clinical situation and serological biomarkers acquired in the early stage while ICU admission.

From March 1, 2016, to December 31, 2019, a total of 345 patients with SCAP and ARDS were admitted to the respiratory ICU of Beijing Chao-Yang Hospital. In total, 92 (26.7%) of them were diagnosed with influenza A (H1N1) virus–induced SCAP, of which 70 (76.1%) patients were male, and the median age was 49 (41, 63) years. The median acute lung injury score was 3.25 (2.75, 3.74), and Acute Physiology and Chronic Health Evaluation (APACHE) II was 12 (9, 18) at the time of admission. The median PaO₂/FiO₂ was 107.5 (77.0, 137.8) mm Hg. All of the patients received mechanical ventilation during ICU therapy. Invasive mechanical ventilation (IMV) was used in 70 (76.1%) patients, including 38 (41.3%) patients who received extracorporeal membrane oxygenation (ECMO) support. The ICU mortality was 34.8%, and the median length of ICU stay was 16 (10, 27) days ( Supplementary Table S1 ). Sixty survivors underwent four follow-up examinations at 1, 3, 6, and 12 months after ICU discharge. Six patients were lost to follow-up, and one patient died for cerebrovascular disease ( Supplementary Figure S1 ).

This study systematically assessed the long-term outcomes of pulmonary function, exercise capacity, HRCT manifestations, and health-related quality of life in survivors of severe H1N1 pneumonia and ARDS who had been discharged from ICU. The improvements in pulmonary function and exercise capacity, HRCT, and health-related quality of life had different time phase and impact on each other. The decrease in D_LCO was the main abnormality in pulmonary function, which improved at 3 months after ICU discharge. Although GGO and consolidation were fully absorbed at 3 months after ICU discharge, reticulation or interlobular septal thickening was the main long-term manifestation on HRCT, which did not begin to improve significantly until the 12-month follow-up, and had a negative correlation with D_LCO. Regarding health-related quality of life, general health and mental health were without any changes during one year after ICU discharge, even though there was a positive correlation between D_LCO and general health. The severity of primary disease, tidal volume of mechanical ventilation, and levels of fibrogenic cytokines at the early stage of ICU admission affected the long-term outcomes of reticulation or interlobular septal thickening on HRCT.

A study from Greece evaluated 44 patients with H1N1 infection every three months, until 6 months after discharge. There was an improvement in pulmonary function tests at the second measurement, but there were no changes between the second and third measurements (Zarogoulidis et al., 2011). Huang’s team in Taiwan followed up on nine survivors of ARDS due to severe H1N1 pneumonitis at 1, 3, and 6 months after hospital discharge. Pulmonary function and 6MWT results increased from 1 to 3 months after hospital discharge, but there was no further improvement from 3 to 6 months after discharge (Hsieh et al., 2018). Similar results were also found for ARDS of other etiologies. A 3-month follow-up study in survivors of ARDS secondary to coronavirus disease 2019 (COVID-19) showed that 82% of these patients had an impaired D_LCO (Gonzalez et al., 2021). Similar to the previous literature, the present study showed that gas transfer impairment was the main manifestation of the abnormal pulmonary function, and in most survivors, it recovered to normal range at 3 months after ICU discharge. However, there were still 25% of patients in whom there was no improvement during 12 months.

Bilateral, peripheral GGO, and/or bilateral areas of consolidation are the predominant HRCT findings in the acute phase of H1N1-induced pneumonia (Marchiori et al., 2010). Short-term serial HRCT evaluation of patients with H1N1 infection showed that GGO and/or consolidation on initial CT scans tended to resolve fibrosis, which then resolved completely or displayed substantially reduced residual disease (Li et al., 2012). Another study showed that the most common HRCT finding in the convalescent stage in patients with H1N1 pneumonia was fibrosis (Feng et al., 2015). Nevertheless, few studies have focused on the long-term radiographic outcomes in survivors of H1N1 infection.

The present study revealed the dynamic HRCT evolution in survivors of H1N1-induced pneumonia and ARDS during 12 months after ICU discharge. GGO and consolidation were the main manifestations on HRCT at the early stage after ICU discharge, similar to that at the acute phase of H1N1 pneumonia. Especially, consolidation was mostly absorbed at the 3-month visit. However, reticulation or interlobular septal thickening did not begin to improve significantly until the 12-month follow-up. It means that reticulation or interlobular septal thickening is the main long-term HRCT finding in H1N1-induced pneumonia and ARDS. A similar result was found in the study of COVID-19 survivors (Gonzalez et al., 2021; Pan et al., 2022). We also discovered that the severity of reticulation or interlobular septal thickening correlated with diffusion capacity in such patients.

A study from Australia showed that health-related quality of life of survivors of severe H1N1 influenza was comparable to that of healthy population one year after ICU discharge (Skinner et al., 2015). However, researchers from Spain proposed a significant but temporary impact on health-related quality of life in the majority of patients with H1N1 infection (Hollmann et al., 2013). According to a review from Bein’s team, surviving ARDS is associated with a long-term substantial reduction in health-related quality of life (Bein et al., 2018). Neufeld’s team also reported that two-thirds of ARDS survivors had clinically significant fatigue symptoms in the first year of follow-up (Neufeld et al., 2020). In this study, we found that general health, vitality, mental health, and role–emotion in survivors of H1N1-induced pneumonia and ARDS did not change during 12 months after ICU discharge, which might be affected partially by impaired pulmonary function, and the experience in ICU might impact long-term mental health. Therefore, for the improvement in health-related quality of life, both psychological and physical recovery should be focused on.

Type III procollagen is recognized as a marker of ARDS-associated lung fibroproliferation (Forel et al., 2015). KL-6 is a marker of alveolar inflammation in ARDS (Nathani et al., 2008), which is also related to long-term outcomes (Kondo et al., 2011). In the present study, KL-6 was related to reticulation or interlobular septal thickening at the 1-month and 3-month visits, but not at the 12-month follow-up. In contrast, type IV collagen, type III procollagen, hyaluronic acid, and laminin showed correlations with reticulation or interlobular septal thickening at 6 months and 12 months after ICU discharge. We considered that the lung injury and excessive lung fibroproliferation at the early stage during ICU admission might be related to long-term pulmonary fibrosis in patients with H1N1-induced ARDS. It also influences the recovery of pulmonary function and quality of life.

Lung injury and excessive lung fibroproliferation at the early stage during ICU admission might not only be related to the severity of the primary disease (Burnham et al., 2014) but also to mechanical ventilation. Many studies have tried to explore the mechanism of ventilation-induced acute lung injury and fibroproliferation in patients with ARDS, which caused poor outcomes, and high tidal volume was identified as one of the important risk factors (Foda et al., 2001; Li et al., 2008; Cabrera-Benitez et al., 2014). Lung-protective mechanical ventilation with lower tidal volumes has been widely used and could decrease the mortality of patients with ARDS (Acute Respiratory Distress Syndrome N et al., 2000). In the present study, all of the patients received standard lung-protective mechanical ventilation; nevertheless, the relationship between the tidal volume and the long-term outcome was still observed, especially influencing the pulmonary function and fibrosis manifestation on HRCT at the 12-month visit. Therefore, strictly executing the mechanical ventilation strategy with lower tidal volumes might help patients with ARDS in achieving better short-term or long-term outcomes. There is still controversy regarding the effectiveness of corticosteroids applied to reduce ventilation-induced lung fibrosis in severe H1N1 infection–induced ARDS (Burnham et al., 2014; Cabrera-Benitez et al., 2014; Moreno et al., 2018). Thus, effective pharmacological therapies to prevent the development of ventilator-induced and ARDS-related lung fibrosis should be the research priority in the future.

There are still some limitations to this study. First, this was a single-center cohort study, which may have induced the unavoidable selection bias. Second, the sample size was relatively small, which might have resulted in less statistical power. Third, this study focused on patients with H1N1 pneumonia–induced ARDS; therefore, extrapolation of the results to other etiologies of pneumonia and ARDS should be done with caution. Fourth, post-ICU life capability, workability, and delirium which was recognized as aspects related to long-term prognosis after ICU discharge was not collected in the present study. This study only describes the long-term prognosis from the perspectives of imaging, health-related quality of life, and pulmonary function. Lastly, inflammatory cytokines and fibrogenic cytokines were not measured in the bronchoalveolar lavage fluid, so we could only partly explain the injury degree of alveolar epithelial cells through the results from serum.

The improvements in pulmonary function and exercise capacity, imaging, and health-related quality of life in survivors of critical H1N1-induced pneumonia and ARDS had different time phase and impact on each other during 12 months of follow-up after ICU discharge. Long-term pulmonary fibrosis outcome, which would influence the pulmonary function and quality of life, could be observed via HRCT longitudinal evaluation. It might be not only related to the severity of the primary disease but also to mechanical ventilation. These topics still need to be explored in multicenter studies, covering various etiologies and using larger sample sizes. Moreover, the mechanism also needs to be further investigated.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by the Ethics Committee of Beijing Chao-Yang Hospital. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

XT: Conceptualization, Data curation, Investigation, Writing – original draft. X-LX: Conceptualization, Data curation, Investigation, Writing – review & editing. NW: Investigation, Writing – review & editing. YZ: Investigation, Writing – review & editing. RW: Formal analysis, Investigation, Writing – review & editing. X-YL: Investigation, Writing – review & editing. YL: Investigation, Writing – review & editing. LW: Investigation, Writing – review & editing. H-CL: Investigation, Writing – review & editing. YG: Investigation, Writing – review & editing. C-YZ: Investigation, Writing – review & editing. QY: Investigation, Writing – review & editing. Z-HT: Funding acquisition, Writing – review & editing. BS: Conceptualization, Funding acquisition, Writing – review & editing.