Predicting Severe Outcomes in COVID-19

Abstract

SARS-CoV2 infection enters via the nose and, after aspiration to the lower respiratory tract, may then rapidly involve the lungs, resulting in severe hypoxic pneumonia. In the later stage of coronavirus disease 2019 (COVID-19), there is also a cytokine-mediated hyperinflammatory response and coagulopathy, which in many respects simulates a viral-induced multiorgan autoimmune response1Lipworth B. Chan R. Lipworth S. RuiWen Kuo C. Weathering the cytokine storm in susceptible patients with severe SARS-CoV-2 infection.J Allergy Clin Immunol Pract. 2020; 8: 1798-1801Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar (Figure 1). Patients who tend to fare worse with more severe outcomes are males, elderly, smokers, black and Asian people, those with obesity, along with the presence of comorbidities such as diabetes, hypertension, chronic heart, lung and kidney disease, dementia, neoplasia, and immunosuppression.2Docherty A.B. Harrison E.M. Green C.A. Hardwick H.E. Pius R. Norman L. et al.Features of 20 133 UK patients in hospital with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study.BMJ. 2020; 369: m1985Crossref PubMed Scopus (1664) Google Scholar Along with these various risk factors, much interest has centered around trying to identify biomarkers to predict which patients admitted to hospital with severe COVID-19 are most likely to rapidly deteriorate and require intensive care with invasive ventilation. A ratio for arterial oxygen tension (PaO2) or oxygen saturation (SaO2) to the fraction of inspired oxygen (FiO2), referred to as the P/F or S/F ratio, respectively, of less than 300 is used to define the presence of respiratory failure, whereas a ratio of less than 100 is indicative of severe acute respiratory distress syndrome (ARDS). Some cases of ARDS with COVID-19 may be accompanied by the development of secondary hemophagocytic lymphohistiocytosis (Figure 1). Biomarkers of hyperinflammation in COVID-19 include C reactive protein (CRP), interleukin-6 (IL6), ferritin, D-dimers, lactate dehydrogenase (LDH), procalcitonin, lymphopenia, and thrombocytopenia.1Lipworth B. Chan R. Lipworth S. RuiWen Kuo C. Weathering the cytokine storm in susceptible patients with severe SARS-CoV-2 infection.J Allergy Clin Immunol Pract. 2020; 8: 1798-1801Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar Because IL6 induces hepatic synthesis of CRP, it would be expected that they would track together as makers of systemic inflammation.3Xu Z. Shi L. Wang Y. Zhang J. Huang L. Zhang C. et al.Pathological findings of COVID-19 associated with acute respiratory distress syndrome.Lancet Respir Med. 2020; 8: 420-422Abstract Full Text Full Text PDF PubMed Scopus (5408) Google Scholar This in turn begs the question as to whether circulating levels of IL6 and CRP are associated with worse outcomes in severe COVID-19. A retrospective cohort evaluation among 140 patients with COVID-19 reported that IL6 levels greater than 32.1 pg/mL and CRP levels greater than 41.8 mg/L were more likely to be related to severe disease, with respective hazard ratios of 2.4 (95% confidence interval [CI]: 1.06-5.3) and 4.4 (95% CI: 1.9-10.3).4Liu F. Li L. Xu M. Wu J. Luo D. Zhu Y. et al.Prognostic value of interleukin-6, C-reactive protein, and procalcitonin in patients with COVID-19.J Clin Virol. 2020; 127: 104370Crossref PubMed Scopus (554) Google Scholar Another study of 127 patients with COVID-19 found that IL6 was superior to other inflammatory markers in identifying severe disease in terms of the area under the receiver operating curve (AUC) being 0.84 with a sensitivity of 88% and specificity of 75%.5Zhu Z. Cai T. Fan L. Lou K. Hua X. Huang Z. et al.Clinical value of immune-inflammatory parameters to assess the severity of coronavirus disease 2019.Int J Infect Dis. 2020; 95: 332-339Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar Furthermore, when IL6 was combined with CRP and hypertension, the AUC improved to 0.90 with a sensitivity of 100% and specificity of 66%. However, relatively few of the patients in either of these studies had severe disease, in particular, with regard to patients requiring invasive ventilation. A more informative study from Germany in a single university-based hospital setting studied 2 separate cohorts comprising 89 patients with severe hypoxic COVID-19 pneumonia, evaluating biomarkers on admission and during the course of the illness, with 36% requiring invasive ventilation.6Herold T. Jurinovic V. Arnreich C. Lipworth B.J. Hellmuth J.C. Bergwelt-Baildon M.V. et al.Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19.J Allergy Clin Immunol. 2020; 146: 128-136Abstract Full Text Full Text PDF PubMed Scopus (539) Google Scholar In the combined cohort, a cutoff value of IL6 of 49 pg/mL on admission had an AUC of 0.89, whereas a cutoff of 65 pg/mL for maximal levels had an AUC of 0.93, in regard to predicting the need for invasive ventilation. The corresponding cutoff and AUC values for CRP were 32 mg/L and 0.83 on admission and 97 mg/L and 0.85 for maximal levels. The cutoffs for maximal IL6 and CRP levels in the evaluation cohort of 40 patients both correctly classified 80% of patients in the validation cohort of 49 patients regarding their risk of respiratory failure, whereas the corresponding values at presentation were 71% and 76%. Moreover, in the combined cohort, patients reached the cutoff for IL6 greater than 65 pg/mL and CRP greater than 97 mg/L at a median of 23.2 and 15.7 hours before intubation. In this issue of the journal, Vultaggio et al from Italy have taken the biomarker analysis a step further in a cohort of 208 patients with severe COVID-19 in a single university-based hospital setting, with clinical deterioration occurring in 63 cases, of whom 39 were intubated and 16 died.7Vultaggio A. Vivarelli E. Virgili G. Lucenteforte E. Bartoloni A. Nozzoli C. et al.Prompt predicting of early clinical deterioration of moderate-to-severe COVID-19 patients: usefulness of a combined score using IL-6 in a preliminary study.J Allergy Clin Immunol Pract. 2020; 8: 2575-2581Abstract Full Text Full Text PDF Scopus (34) Google Scholar Notably, 45 patients worsened within 3 days of admission. The highest AUC values for predicting 3-day worsening were observed for the S/F ratio (0.81) followed by IL6 (0.78), CRP and LDH (both 0.76), and ferritin (0.70). Combining IL6, CRP, and S/F ratio in a composite score resulted in an improved AUC value of 0.88. Moreover, the composite score also exhibited good performance for predicting deterioration over 21 days or death, with AUC values of 0.83 and 0.82, respectively. The authors duly acknowledged the limitations of the study due to the relatively small sample size as well as the need for further validation of the composite score outside of a university-based hospital setting. Taken together, these findings may have some important potential implications in the management of patients with severe COVID-19. First, raised IL6 or CRP on initial presentation or rising levels during the course of the illness in conjunction with falling S/F or P/F ratio clearly indicates a need to escalate treatment. One such therapeutic intervention might be the use of systemic corticosteroids, which nonselectively suppress proinflammatory cytokines. The preliminary results from the United Kingdom RECOVERY trial in severe COVID-19 showed that, compared with 4321 patients receiving usual care, treatment with dexamethasone 6 mg for 10 days in 2014 patients was associated with a 35% relative reduction in deaths after 28 days in ventilated patients and a 20% relative reduction in patients requiring oxygenation alone.8Horby P. Lim W.S. Emberson J. Mafham M. Bell J. Linsell L. et al.Effect of dexamethasone in hospitalized patients with COVID-19: preliminary report [published online ahead of print June 22, 2020].https://doi.org/10.1101/2020.06.22.20137273Google Scholar For patients being ventilated or oxygenated, this translated into treating 8 or 25 cases, respectively, with dexamethasone in order to prevent 1 death. It will be pertinent to know if reductions in mortality with dexamethasone were more pronounced in patients who had raised levels of CRP or IL6 or a reduced P/F ratio, either alone or in combination. We propose that a tailored biomarker approach toward endotype-guided pharmacotherapy might in turn result in improved outcomes in patients with severe COVID-19. For example, one strategy in such patients might be to escalate therapy in terms of selectively inhibiting proinflammatory cytokines. In this regard, we await to see the full results from randomized controlled trials with anti-IL6 agents, as preliminary phase 2 data with sarilumab versus placebo reported marked reductions in CRP, which appeared to be disconnected from improvements in clinical outcomes in severe COVID-19.9RegeneronRegeneron and Sanofi provide update on U.S. phase 2/3 adaptive-designed trial of Kevzara (sarilumab) in hospitalized COVID-19 patients.https://investor.regeneron.com/news-releases/news-release-details/regeneron-and-sanofi-provide-update-us-phase-23-adaptiveDate accessed: June 18, 2020Google Scholar Moreover in the subsequent phase 3 trial no benefit was seen with sarilumab in patients requiring mechanical ventilation at baseline. Another approach involved selectively inhibiting IL1β with the IL1 antagonist anakinra, which in a small cohort study reduced the need for invasive ventilation and death in patients with severe COVID-19.10Huet T. Beaussier H. Voisin O. Jouveshomme S. Dauriat G. Lazareth I. et al.Anakinra for severe forms of COVID-19: a cohort study.Lancet Rheumatol. 2020; 2: E393-E400Abstract Full Text Full Text PDF PubMed Scopus (408) Google Scholar Perhaps, as is the case with dexamethasone, one might expect to see the biggest improvements with selective cytokine blockers in those patients with more critical disease where hyperinflammation and coagulopathy are most prominent. B. Lipworth had the idea and is responsible for the overall content as guarantor. B. Lipworth, R. Chan, and C. R. Kuo performed the literature search and contributed to the writing of the article. B. Lipworth attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. Prompt Predicting of Early Clinical Deterioration of Moderate-to-Severe COVID-19 Patients: Usefulness of a Combined Score Using IL-6 in a Preliminary StudyThe Journal of Allergy and Clinical Immunology: In PracticeVol. 8Issue 8PreviewThe early identification of patients at risk of clinical deterioration is of interest considering the timeline of COVID-19 after the onset of symptoms. Full-Text PDF