This study analyzed prospective cohort study data on hospitalized patients with C-CAP and NC-CAP, providing insights into clinical outcomes both during hospitalization and a subsequent follow-up. Spanning five countries and 35 clinical centers over 54 months, the findings underscore the enormous severity in COVID-19 pneumonia during the early stages of the pandemic. The results portray the temporal spectrum of COVID-19 pneumonia.

treatment, trajectory, and outcomes during the peak of a global health emergency, and put them into context with NC-CAP.

The analysis revealed a four-fold higher risk for in-hospital death, an eight-fold higher risk of ICU treatment, and two-fold higher risk of hospitalization exceeding seven days in C-CAP compared to NC-CAP patients. Underlining this, C-CAP patients’ median length of invasive MV exceeded NC-CAP by eleven days. In cases of in-hospital death, C-CAP patients’ treatment duration was more than double than in NC-CAP. This highlights an exceptional burden of severe illness and elevated healthcare demand in C-CAP compared to NC-CAP, particularly among ICU-treated patients, whose risk of remaining hospitalized over seven days was six-fold higher in C-CAP. We observed variability in C-CAP outcomes across pandemic phases, with longer hospital stays in the first wave, but higher risk of in-hospital death during the second and third wave. Having reported excess LOHS during the first wave compared to second and third wave resembling our results, investigators from Bologna assigned this to changing containment policies and improved clinical management during the later stages of the pandemic [19]. Additionally, Lampl et al. discussed caution regarding hospital admission of COVID-19 cases among both patients and clinics during the later stages of the pandemic, potentially leading to delayed hospitalizations and, consequently, to shorter hospital stays either through discharge or due to in-hospital mortality as in our study [20].

COVID-19 case fatality rates and mortality throughout the pandemic were shaped by the emergence of evolving virus variants, improved treatment guidelines, the demographic composition, including age structure and comorbidities among COVID-19 cases, as well as the rising rates of immunization [21, 22]. Supporting our results, Lampl et al. reported the highest COVID-19 case fatality rate in the Regensburg area during the second COVID-19 wave, attributing this to the spreading of the disease to an older-aged population during late 2020 and 2021, where a strained health-care system disposed over limited resources and effective SARS-CoV-2 vaccines were not yet broadly available [20]. Interestingly, there were no significant differences in NC-CAP outcomes comparing the recruitment phases before and during the pandemic in our study, emphasizing the distinct impact of the pandemic evolution on C-CAP outcomes.

Antibiotic treatment in C-CAP was associated with ICU treatment, in-hospital death, and excess LOHS in our cohort. Of note, though in our cohort the use of antibiotics in C-CAP decreased from the first to the third wave patients, mortality increased. We assume that this seemingly paradoxical relationship is caused by improved guidelines for antibiotic use in COVID-19 based on the observation that only less than 10% and especially ICU patients had bacterial superinfection during the early stages of the pandemic [23].

In the multivariate analyses of factors associated with in-hospital mortality, LOHS over seven days, and ICU treatment, we observed further differences between C-CAP and NC-CAP: Notably, female sex in C-CAP was independently associated with lower risk of ICU treatment, while sex had no significant impact on the outcomes in NC-CAP. The roles of sex and gender in COVID-19 have been extensively discussed: While gender-associated disparities in lifestyle, profession, and the resulting risk of SARS-CoV-2 transmission were crucial for the higher incidence and disease severity in male gender during the early stages of the pandemic [24], sex-determined differences are a major factor influencing a patient’s immune response to SARS-CoV-2 with different mechanisms of acute deterioration [25]. In contrast to our findings, a systematic review highlighted worse outcomes for men also in NC-CAP [26]. More research is needed to distinguish biological and social determinants for unfavorable outcomes in CAP.

These findings are an important contribution to existing results from retrospective and registry analyses attempting a contextualization of C-CAP among CAP. In line with our results, Cangemi et al. found in a prospective cohort study that COVID-19 was associated with a five-fold increase in the in-hospital mortality rate compared to NC-CAP [6]. In a retrospective analysis of hospitalized patients with COVID-19 or Influenza A from a nation-wide hospital network in Germany, Kodde et al. found that COVID-19 was associated with three-fold increased odds for in-hospital death than Influenza A patients [27]. Serrano Fernandez et al. observed rates of in-hospital death and invasive MV twice as high in COVID-19 pneumonia than in bacteremic pneumococcal CAP [28].

In our study, C-CAP was associated with a lower risk of recurrent hospitalization in a 180-days follow up than NC-CAP. This finding is in line with Novelli et al. [29], suggesting that long-term morbidity in COVID-19 depends less on the initial disease severity, but more on patients’ baseline morbidity. Nevertheless, it is important to note that post-discharge morbidity in COVID-19 can manifest in the diverse features of the post-COVID-19 syndrome, characterized by long-lasting fatigue, respiratory and neurocognitive symptoms, and pulmonary function impairment [30], and does not necessarily lead to re-hospitalization. As we did not evaluate the occurrence of long-lasting symptoms, we cannot draw conclusions regarding the post-COVID-19 syndrome and comparable features in NC-CAP. To improve our understanding of morbidity after hospitalization for community-acquired pneumonia, prospective studies like the German national pandemic cohort network NAPKON, evaluating symptoms, pathophysiology, and ideally interventional measures, are desperately needed [31].

Strengths of our analysis are the prospective, multi-national dataset and the harmonized definition of the study participation criteria, yielding a highly comparable sample of both C-CAP and NC-CAP patients examined under the same study protocol for in-hospital and post-discharge outcomes. This analysis provides a comprehensive report of hospitalization and follow-up outcomes comparing both disease groups, offering a retrospective contextualization of the pandemic’s impact on the spectrum of CAP patients. The data show the diverging disease trajectories in C-CAP and NC-CAP and how both treatment and outcomes in C-CAP changed chronologically with the progression of the pandemic.

This study has limitations. The total number of eligible patients is unknown, introducing potential selection bias. E. g., patients with severe C-CAP immediately intubated upon hospital arrival may not have been included, possibly impacting the results. However, time to intubation did not differ between C-CAP and NC-CAP ICU patients, supporting the data validity. Seventeen study participants were excluded, as they were transferred to another hospital. This could introduce a referral bias, particularly as cases with complex disease trajectories, such as those needing extracorporeal membrane oxygenation therapy or extended weaning from mechanical ventilation, are more likely to be referred to specialized hospitals. Furthermore, our analysis focused on in-hospital death, ICU treatment, and LOHS as indicators for disease severity. A more detailed classification of pneumonia outcomes, e. g. varying levels of respiratory support such as high flow nasal oxygen or extra-corporal membrane oxygenation, was not feasible in our data sample. Future large-scale prospective studies need to address CAP severity degrees in more detail.