The primary goal in conducting this study was to analyze the clinical characteristics of young people (18–50 years) hospitalized patients with COVID-19 and the risk factors for the development of respiratory failure. To do this, we analyzed the SEMI-COVID-19 Registry in which 150 Spanish hospitals participated. The first clinically relevant finding is that 15% of COVID-19 patients admitted to hospital were under 50 years of age. The strength of our study is that it is a real-life multicenter study with a large number of patients, a total of 2327 hospitalized young patients, which is to the best of our knowledge the largest report on this subgroup of COVID-19 patients.
Second, it provides insights into the evolution and prognosis of COVID-19 in patients who are younger than those generally enrolled in clinical studies. As a result, we have been able to analyze specific risk factors in this subgroup of patients without the interference of frailty or aging-associated comorbidities and to show the importance of obesity and a few laboratory parameters for making an early evaluation of the possible development of respiratory failure, which is the main cause of SARS-CoV2-related death.
The third major conclusion is that this younger population is not exempt from serious complications, since respiratory failure, ICU admission, and in-hospital mortality were found in 14.7%, 8.2%, and 2.3% of patients, respectively. This mortality rate is similar to that described by other authors.33
The fourth major finding is that young patients with respiratory failure present more medical complications, as other studies have highlighted.16,18,24,34 There was a notable presence of acute kidney injury, venous thrombosis, and, especially, the development of MACE events. Hence, early identification of patients at potential risk of complications is essential to ensure adequate management.
The fifth conclusion is that comorbidity, obesity, alcohol abuse, and sleep apnea syndrome, as well as the presence of fever, were independent predictors of respiratory failure, which is consistent with previous publications,4,5,10,18 and lymphocytes, LDH, AST, sodium, and CRP were predictors of poor prognosis, as other studies have also pointed out.5,7,10,16,18
We decided to use respiratory failure as the main endpoint because, in the vast majority of COVID-19 patients, mortality is related to the presence of respiratory failure.35 We defined it in broader terms than invasive mechanical ventilation or ICU admission in order to obtain a more realistic view of the demands of the first wave of the pandemic in terms of healthcare pressure. This approach continues to be valid, given that the pandemic is currently global. If we focus on patients who developed respiratory failure, we observe that half the cases required ICU admission, while the other 50% was managed with non-invasive ventilatory support. Likewise, we observed that the presence of respiratory failure was more frequent in men, with a slight predominance of Hispanic ethnicity and subjects with previous comorbidities, highlighting the presence of sleep apnea syndrome and previous alcohol consumption. However, the most notable differences were observed in the predictive parameters, even at the time of hospital admission, which presented important predictive values for the development of respiratory failure (Fig. 1A and B). Analytical variables were treated as continuous variables and categorized using ROC curves (Supplementary Table 2) to facilitate their management in the risk factor analysis. Although most of the analytical variables were collected in more than 90% of the subjects, a few other relevant variables were accessible in a smaller number of patients, so making them difficult to use in potential predictive models. This was the case of TnT, CPK, ferritin, albumin, prothrombin ratio, and interleukin-6 (IL-6). To deal with this, we created the first multivariate model (Fig. 1A), which included the largest possible number of patients (n = 1457). In order to analyze other widely reported prognostic variables such as ferritin and albumin,1,9,36 we constructed a second model (Fig. 1B), which included a larger number of analytical variables, although at the expense of reducing the number of patients (the final model included 503 patients). Following this approach, the only clinical variable that remained in the model was obesity. All the analytical variables in model 1 were retained, and leukocytes, ferritin, and albumin were added as prognostic markers. This second model has an accessible analysis and offers high prognostic value (AUC of 0.85) for predicting the development of respiratory failure. In both models (1 and 2 in Fig. 1), the presence of lymphocytes ≤ 1100 cells/μL, obesity, sodium < 135 mmol/L, and C-reactive protein >8 mg/dL remain independent risk factors. In the first model (which includes a larger number of cases), we would also add albumin ≤ 3.7 mg/dL, ferritin >1200 ng/mL, and leukocytes > 6×103 cells/μL. In the second model, which includes a smaller number of patients but more analytical variables, alcohol abuse, sleep apnea syndrome, Charlson index ≥ 1, LDH > 320 U/L, fever (≥ 38°C), and AST > 35 mg/dL were also additional risk factors.
These findings highlight a case analysis at admission which include those variables that allow us to identify populations at risk for the development of respiratory failure in order to increase predictive power, which would allow for optimization of the necessary care resources.
Unfortunately, the main limitation of our study is that it is a real-life registry so that, despite the inclusion of a large number of patients, some of the potential prognostic values indicated in the univariate study of biochemistry parameters, such as IL-6, lactate, and troponin, could not be confirmed in the multivariate study. These biomarkers were obtained in 338, 926, and 294 cases, respectively.
The results of this study suggest that the risk factors for poor outcome in younger patients may be different from those in older one. To confirm this observation, a study comparing the two groups directly should be performed.37
Unfortunately, our work has other limitations. First the outcomes in March–July 2020 were different than now, with more consistent use of anticoagulation (prophylactic or therapeutic when appropriate) and corticosteroids; thus, it may be hard to extrapolate or predict how similar patients would do now.
Second, the laboratory variables are dichotomized. The relationship between laboratory variables and outcomes are unlikely to be dichotomous or even linear; thus, these relationships are overly simplified.
Third, this study has been carried out in a single country in southern Europe, but we consider that it would be very appropriate to know whether the results are extrapolable to other regions of the world with different socio-demographic characteristics to ours.
In conclusion, a significant percentage of younger patients (18–50 years old) with COVID-19 requiring hospital admission presented respiratory failure, particularly those who were obese or had SAHS. This serious complication can be identified at admission by the usual laboratory tests.