Role of interleukin 6 as a predictive factor for a severe course of Covid-19: retrospective data analysis of patients from a long-term care facility during Covid-19 outbreak

Coronavirus disease 2019 (Covid-19) is a disease caused by the zoonotic novel Coronavirus called SARS-CoV-2 [1]. Covid-19 quickly spread across the globe from a place of its origin in Hubei China and pandemic was declared by WHO on March 11, 2020 [2]. Most patients with Covid-19 experience mild self-limiting disease. However, up to 20% of known cases of Covid-19 are complicated by severe pneumonia which might result in acute respiratory distress syndrome (ARDS) which causes acute hypoxemic respiratory failure [1, 3]. The overall infection fatality ratio is estimated to be below 1% [4]. It should be noted that fatal outcome may occur at any age including children and young adults [5]. Also, physiologic condition, pregnancy is associated with higher risk of severe disease [6]. However, the risk of death in Covid-19 is increasing with age and a presence of comorbidities, especially cardiovascular diseases, diabetes mellitus and obesity [3]. According to data from the early China epidemic, the case-fatality ratio in the patients over 80 is up to 15% [7]. Elderly and highly comorbid residents of long-term care facilities (LTCF) are at high risk of Covid-19 associated morbidity and mortality [8‐10]. In one well-documented outbreak in LTCF in Washington, USA, more than half of the infected residents required hospitalization and more than one third died [10]. On the background of the ongoing pandemic, the spreading 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. Such intervention consists of quick identification of cases, immediate introduction of infection control measures, initial triage, and daily monitoring of patients. An effective screening tool is essential to identify the patients at risk for severe illness and death [11]. Such patients need close monitoring and early transfer to the hospital. Various biomarkers, especially inflammatory markers like C-reactive protein (CRP), ferritin, fibrinogen, D-dimer and Interleukin 6 (IL-6) are associated with Covid-19 progression [12, 13]. According to known evidence, IL-6 is superior to CRP and other markers of inflammation in predicting respiratory failure in Covid-19 [14, 15]. IL-6 appears to be the most important driver of immune dysregulation and ARDS in Covid-19 [16‐19]. The role of systematic measurement of IL-6, CRP, and other markers of inflammation at the initial assessment during Covid-19 outbreak in LTCF and its ability to predict the severe course of disease is yet to be determined.

We conducted a retrospective data analysis of laboratory-confirmed cases of COVID-19, diagnosed during the outbreak in one LTCF in Slovakia between April 11, 2020, and May 5, 2020. A confirmed case of COVID-19 was defined as a positive result on real-time reverse-transcriptase–polymerase-chain-reaction assay of nasopharyngeal swab specimens for SARS-CoV-2. In our analysis, we aimed to identify laboratory markers predicting the severe course of the disease at the initial assessment.

During the intervention in the LTCF, 78 subjects were screened for COVID-19 and 59 patients (47 women, 12 men) had positive pharyngeal swabs for SARS-CoV-2 RNA by RT-PCR and were diagnosed with Covid-19. Fifty-three patients (90%) had blood sampling during the initial screening phase. In 6 patients, blood sampling was not performed because of technical difficulties. These patients were excluded from the study. In 53 patients (11 men, 42 women) in which blood sampling was performed, the clinical variables and the results of biochemical and blood count analysis were available for evaluation and were included in the study. Seven patients (1 man, 6 women) were diagnosed with severe disease in initial triage and were immediately transferred to a hospital within the first 2 days of intervention. Remaining 45 patients (10 men, 36 women) remained under observation in LTCF and were screened for severe disease and triaged on a daily basis by the intervention team. Overall, 32 patients (6 men, 26 women) were admitted. Among these patients, 19 (2 men, 17 women) had hypoxemia required oxygen therapy, 16 patients (2 men, 14 women) were admitted to ICU, and 13 patients (2 men, 12 women) died. In 11 patients (1 man, 10 women) initially suffering from hypoxemia requiring oxygen therapy, the disease progressed, and they required intubation and mechanical ventilation. All these patients died because of severe ARDS. One male, initially suffering from hypoxemia requiring oxygen therapy died because of severe gastrointestinal bleeding from gastric adenocarcinoma. One female, initially suffering from hypoxemia requiring oxygen therapy suddenly died after short period of clinical improvement. An autopsy revealed pulmonary embolism. In hospitalized patients, various severe complications were observed. Six patients developed deep vein thrombosis, 6 developed congestive heart failure, 3 patients developed new atrial fibrillation and 5 developed acute renal failure. Baseline characteristics of patients are provided in Table 1. Major clinical findings of all enrolled patients are provided in supplementary table. The baseline serum concentrations of IL-6, CRP, procalcitonin, urea, creatinine, fibrinogen, AST, ALT, fasting glucose, total bilirubin and neutrophil count were significantly higher, and lymphocyte and eosinophil count was significantly lower in patients who developed hypoxemia. All patients included in our study seroconverted and developed IgG antibodies within 1 month of diagnosis. The median of baseline serum concentrations of D-dimer and ferritin and a median total count of leukocytes were not significantly different among groups of patients with and without hypoxemia requiring oxygen therapy. Patients who developed hypoxemia requiring oxygen therapy were also significantly more comorbid according to the higher median Charlson Comorbidity Index (Table 1). In the ROC analysis, IL-6 was identified as more robust marker of hypoxemia development than CRP, procalcitonin, CRP, fibrinogen, ALT, AST and total bilirubin and lymphocyte, neutrophil and eosinophil blood count. However, all of these variables were associated with hypoxemia (Table 2). The cut-off of 24 pg/mL for IL-6 showed the best combination of sensitivity and specificity. In the group of all screened LTCF residents, baseline IL-6 concentration > 24 pg/mL predicted the development of hypoxemia with a sensitivity of 88% and specificity of 89%. Positive predictive value (PPV) was 83%, and negative predictive value was (NPV) of 93%. After excluding the 7 patients diagnosed with severe Covid-19 and transferred to the hospital after the initial assessment, baseline IL-6 concentration over 24 pg/mL predicted the development of hypoxemia during the daily monitoring in the LTCF with the sensitivity of 100%, specificity 89, PPV of 77%, and NPV 100% (Table 3). Baseline CRP concentration with cut-off of 24 mg/L showed sensitivity and specificity inferior to IL-6 (Table 4). In multivariate analysis, baseline IL-6 concentration > 24 pg/mL was positively associated with the risk of hypoxemia development during follow up in LTCF residents after adjustment for CRP, age, gender, and glomerular filtration rate (Table 5).

Our retrospective data analysis evaluated the potential role of biomarkers of inflammation, IL-6, CRP, procalcitonin, D-dimer and fibrinogen in the prediction of severe disease and need for oxygen therapy in residents of LTCF during Covid-19 outbreak. It suggests that IL-6 is a most robust predictor of hypoxemia requiring oxygen therapy. The concentration of IL-6 > 24 pg/mL at the initial assessment is showing the best combination of sensitivity and specificity in predicting the hypoxemia requiring oxygen therapy.

There is a substantial body of evidence linking the IL-6 concentration to the severity of disease and unfavorable outcome of Covid-19 [13, 14, 16‐18, 20‐23]. However, to our knowledge, this study is the first study which evaluated the ability of IL-6 to predict the need for supplementary oxygen administration as a surrogate marker of severe Covid-19 requiring hospital admission in the population of high risk elderly patients. It also suggests clinical implications for intervention procedures for Covid-19 outbreak in LTCF. Han et al. examined the predictive value of various cytokines and concluded that IL-6 is the best predictor of severe Covid-19 [14]. A metanalysis of 9 studies concluded that increased IL-6 is highly associated with severe disease. In this study, patients with severe Covid-19 had mean IL-6 58 pg/mL compared to 17 pg/mL in mild disease [22]. A study by Herold et al. found that IL-6 > 80 pg/mL the predicts respiratory failure and need for mechanical ventilation in Covid-19. Like in our study, IL-6 was superior to CRP in ROC analysis. Chen et al. found cut-off 80 pg/mL of IL-6 differentiates the survivors from the non-survivors [23]. We suggest that we found much lower optimal cut-off value (24 pg/mL compared to 80 pg/mL) because we choose less severe endpoint (need for supplementary oxygen). Overall, we can conclude that our study is in concordance with previous studies and adds new aspects to the known body of evidence.

Baseline IL-6 concentrations over 24 pg/mL in LTCF residents suffering from Covid-19 predicts the development of hypoxemia requiring oxygen therapy with excellent sensitivity and good specificity. Patients with the IL-6 above 24 pg/m at initial assessment seems to be at high risk of development of respiratory failure and might benefit from early hospitalization and close follow-up. Further studies are needed to evaluate the real benefits of systematic examination of IL-6 during the initial assessment and its use as predictive factor of severe disease.