The COVID-19 pandemic has been one of the biggest global health crises faced in generations. Due to the unprecedented scale of ethical, organizational, and clinical challenges, medical communities around the world have been forced to work tirelessly to respond to the pandemic and important lessons have been learned in the process.
Leidi and colleagues in this issue of Internal and Emergency Medicine  confirm that COVID-19 waves are different in term of patients’ morbidity and mortality. In their paper, inpatient mortality was significantly higher (more than double) during the first wave than in the subsequent waves (24.2% vs. 11%). Yet, the strength of their work lies in the fact that this confirmation is presented in unvaccinated COVID patients admitted to hospital. Such a “clean” population may serve as a better model to explain why patients in the first wave had much poorer outcomes than those in subsequent waves.
First, severity of COVID at admission is different between waves, with patients of the first wave showing worse clinical and laboratory parameters. During the first phase of the pandemic, late presentations of cases to hospitals were frequent, because patients with mild symptoms of COVID-19 were encouraged to self-quarantine at home and advised to come to hospital only when illness was severe enough to justify access to healthcare . Moreover, hospitals became seen as a place where active cases of COVID were concentrating in large numbers, where the risk of SARS-CoV-2 transmission was high, and many feared to come into hospitals if not necessary and were often in a compromised state [3, 4]. Critical shortage of acute hospital beds at the first wave was corrected only at subsequent waves by reconversion of hospital wards in COVID units with additional hospital beds . Shortage of hospital beds is clearly represented in the paper by Leidi and colleagues by the noticeably longer period (8 vs. 6 days) between the onset of symptoms and hospital admission during the first wave compared to the second wave.
Second, better clinical outcomes in unvaccinated patients could have been the result of development of herd immunity in the population. Due to the widespread circulation of the virus among the population in the first 3 months of the pandemic, many could have acquired natural immunity against the virus [6,7,8], which mitigated the severity of clinical manifestation of COVID-19 in the subsequent waves. The need for mass vaccination programs when a high proportion of the population has already acquired natural immunity against the virus (i.e., herd immunity) requires careful evaluation.
Fourth, introduction of more effective treatment schemes for COVID-19 has certainly played a major role in improving patients’ survival between waves, in particular early use of systemic steroids and high-dose low-molecular-weight heparin (LMWH) [11, 12]. Thanks to autopsy studies, we gained a better understand of COVID pathophysiology and the key role of the massive inflammatory response (the so-called “cytokine storm”) triggered by SARS-CoV-2 . The excessive inflammatory response was also responsible of a generalized prothrombotic state potentially leading to massive pulmonary embolism with poorly responsive ventilation/perfusion (V/Q) mismatch . Accordingly, for patients with severe COVID-19, systemic corticosteroids, and high-dose LMWH are strongly recommended [15, 16]. In the study of Leidi et al., the use of systemic steroid increased threefold from 31.1% during the first phase to 92.0% at subsequent t waves. High-dose LMWH use increased fourfold from 11.9 to 43.9%.
Fifth, mortality rate during first wave was also elevated because of ineffective treatment with antibiotics, hydroxychloroquine, and antivirals , and those who made it through palliative management of respiratory failure (i.e., mechanical ventilation, high flow oxygen, etc.) did probably so because of natural selection (better immune system allowing them to survive—advanced age is a well-known predictor for risk of COVID death, and immunosenescence is likely to play a role). This is confirmed by the findings of the logistic regression analysis by Leidi et al. showing advanced age as a risk factor for poor survival only in patients of the first wave.
Advanced age and symptoms’ duration before hospitalization were the most important predictors associated with mortality during first wave in Leidi et al. Surprisingly, smoking rates of people hospitalized for COVID-19 in between waves were similar and very low at around 14%. This finding agrees with the other studies that have identified a significant lower prevalence of smoking among hospitalized COVID-19 patients than that expected based on population smoking prevalence [18, 19]. For the evidence about the effects of smoking on COVID-19, the accuracy of reporting has been questioned . The potential bias in estimation of smoking prevalence by self-reporting was recently addressed in a recent population-based study . The study used direct laboratory measures of smoking exposure (i.e., serum cotinine), to investigate the true association between SARS-CoV-2 infection susceptibility and active smoking ; the study reported a lower proportion of positive SARS-CoV-2 serology in current smokers compared with non-smokers/ex-smokers.
COVID lessons have been available for some time now and have advanced our understanding of the ethical, organizational, and clinical challenges associated with the disease. Nonetheless, it is important to move beyond lessons learned and explore new uncharted territory preparing for future health crisis that may arise again.