Our retrospective data analysis suggests that IL-6 is a robust predictive factor of the development of hypoxemia requiring oxygen therapy and hospitalization. The concentration of IL-6 > 24 pg/mL at the initial assessment is showing the best combination of sensitivity and specificity.
Clinical significance and implications
The prognosis of Covid-19 in the general population is favorable with an estimated infection fatality ratio below 1% . However, in the elderly population, the prognosis is far worse. The risk of death in Covid-19 is increasing with advanced age and the presence of cardiovascular underlying conditions . According to data from the early epidemic in Wuhan, China, the crude case-fatality in the patients over 80 is up to 15% . The residents of LTCF are one of the most vulnerable populations of the Covid-19 pandemic [6, 7, 8]. The transmission of Covid-19 in LTCF might significantly burden the local health care system and markedly contributes to mortality. Timely and effective intervention is essential to reduce morbidity and mortality during the Covid-19 outbreak in the LTCF. According to the proposed guideline of response to the outbreak of Covid-19 in LTCF by Kim et al., the first phase of response should include broad testing a quick identification of cases and their clinical assessment focused on identifying patients needing immediate transfer to the hospital. In the next phase, monitoring of patients should be implemented in order to quickly identify the patients in need of hospital care . Identification of patients at high risk of deterioration during the initial assessment may significantly improve the monitoring process in order to effectively allocate the resources to high-risk patients. Especially in the case of large outbreaks and limited human resources, the focus on high-risk patients might contribute to mortality reduction and improve the overall outcome of the intervention.
In our study, all patients that developed hypoxemia requiring oxygen therapy during the follow up had the baseline concentration of IL-6 over 24 pg/mL. As a screening tool, it provides excellent sensitivity with a fairly acceptable specificity over 88%. In the screening for high-risk patients in the elderly comorbid population of LTCF residents, it might identify the patients with a high risk of hypoxemia with relatively low risk of false positivity and on the other hand identify the patients with low risk for hypoxemia with great negative predictive value. This might help in the decision making for admission during the initial triage.
For the purposes of our study, we defined that the residents that developed hypoxemia requiring oxygen therapy are the cases that needed close monitoring and early transfer to the hospital. The rationale is that patients who developed hypoxemia requiring oxygen therapy are those that might benefit from the early pharmacological intervention in order to reduce mortality. According to the body of evidence on remdesivir, it improves the outcome in the patients needing conventional oxygen therapy, however, its effectiveness in the treatment of patients with more advanced disease requiring ventilatory support remains controversial [12, 13]. Another treatment that proved to be beneficial in patients requiring conventional oxygen therapy is a 10-day course of 6 mg of dexamethasone per day. In a preprint report from RECOVERY trial, it reduces the mortality by one fifth in patients requiring low flow oxygen . Thus, the patients with early disease but in the high risk of development of severe hypoxemia requiring oxygen therapy are those patients who will profit the most from close observation and rapid initiation of remdesivir and dexamethasone treatment if they develop hypoxemia requiring conventional oxygen therapy.
IL-6 and development of severe Covid-19
There is a substantial body of evidence linking the IL-6 concentration to the severity of disease and unfavorable outcome of Covid-19 [11, 15, 16]. IL-6 is produced by stromal cells and virtually all immune system cells in the lungs and its secretion is stimulated by proinflammatory cytokines. Overexpression of IL-6 is believed to have a crucial role in the incitement and propagation of the so-called cytokine storm leading to lung injury and ARDS . A study by Giamarellos-Bourboulis et al. suggests that patients with severe respiratory failure in Covid-19 suffer from distinct types of immune dysregulation which are mediated by IL-6 upregulation. This dysregulation is characterized by high production of proinflammatory cytokines by monocytes and macrophages and CD4 lymphocyte depletion that contributes to the progression of inflammation of lung parenchyma . An important trait of IL-6 upregulation in Covid-19 is that it precedes the development of acute lung injury that implicates its usability as an early marker of severe disease [16 ].
Other markers of severe disease
In our study, patients who developed hypoxemia had significantly higher serum concentrations of AST, ALT, CRP, serum glucose, creatinine, procalcitonin, and fibrinogen. These biochemical variables were identified as markers of severe disease by previous studies . Medians of other well-established markers of serious disease, D-dimer and ferritin were higher in patients who developed hypoxemia, however, the differences were not statistically significant.
Prognosis of LTCF residents suffering from Covid-19
According to an epidemiologic study by McMichael et al., during the outbreak in one LTCF in Washington, USA, 54.5% of residents required hospitalization and required hospital admission and 33.7% of infected residents died . In our study, we identified 59 residents with positive swabs for SARS-CoV-2. Of these patients. 32 patients (54%) were admitted to hospital which is similar ber to the study by McMichael et al. In our study, 13 patients (22%) died. That is less than in the study by McMichael et al., however, this difference of proportion might be attributed to potentially different age and comorbidity status of residents.
The limitations of our study are the relatively low sample size and retrospective design. Larger prospective studies are needed to obtain more robust data and to evaluate if the examination of IL-6 during the initial assessment leads to better prognosis of LTCF residents and improves the management of the Covid-19 outbreaks in the LTCFs.
Because of the retrospective design of the study, there might be a concern of bias in the sensitivity of the diagnosis of hypoxemia between groups of hospitalized and outpatient residents. The hospitalized patients were naturally more closely monitored and therefore might be more likely to be diagnosed with hypoxemia. However, we regard this potential bias as insignificant because the outpatient residents were daily monitored for the symptoms and signs of respiratory failure, and patients suffering from dyspnea and patients with tachypnea and/or SpO2 below 90% were transferred to hospital. In normoxic patients, the bias of pulse oximetry comparing to SaO2 is regarding to be very low. It reliably identifies the patients with SaO2 below 90% and is a reliable screening tool for hypoxemia with very high negative predictive value [19, 20].