Lancet Rheumatol undefined

PMC: PMC7524533

PMID: 33015645

Clinical criteria for COVID-19-associated hyperinflammatory syndrome: a cohort study

Nancy Grisel+6 authors

Supplementary Material

Supplementary appendix:

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^{Division of Infectious Diseases and Clinical Epidemiology, Intermountain Healthcare, Intermountain Medical Center, Salt Lake City, UT, USA}

^{Division of Infectious Diseases and Geographic Medicine, Stanford Medicine, Palo Alto, CA, USA}

^{Pulmonary and Critical Care Medicine, Intermountain Medical Center, Salt Lake City, UT, USA}

^{Department of Pulmonary and Critical Care Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA}

^{Division of Rheumatology, Intermountain Healthcare, Dixie Regional Medical Center, St George, UT, USA}

^{Intermountain Acute Leukemia, Blood and Marrow Transplant Program, LDS Hospital, Salt Lake City, UT, USA}

^{Division of Hospital Medicine, Intermountain Healthcare, Intermountain Medical Center, Salt Lake City, UT, USA}

^{Pharmacy Services, Antimicrobial Stewardship, Intermountain Healthcare, Salt Lake City, UT, USA}

^{Intermountain Healthcare Office of Research, Salt Lake City, UT, USA}

^{Healthcare Delivery Institute, Intermountain Healthcare, Murray, UT, USA}

^{Division of Trauma and Critical Care, Intermountain Medical Center, Murray, UT, USA}

^{Office of Patient Experience, Intermountain Healthcare, Salt Lake City, UT, USA}

^{Division of Inpatient Medicine, Department of Pediatrics, University of Utah, Salt Lake City, UT, USA}

^{Correspondence to: Dr Brandon J Webb, Division of Infectious Diseases and Clinical Epidemiology, Intermountain Healthcare, Intermountain Medical Center, Murray, UT 84157, USA}

Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

Background

A subset of patients with COVID-19 develops a hyperinflammatory syndrome that has similarities with other hyperinflammatory disorders. However, clinical criteria specifically to define COVID-19-associated hyperinflammatory syndrome (cHIS) have not been established. We aimed to develop and validate diagnostic criteria for cHIS in a cohort of inpatients with COVID-19.

Background

Methods

We searched for clinical research articles published between Jan 1, 1990, and Aug 20, 2020, on features and diagnostic criteria for secondary haemophagocytic lymphohistiocytosis, macrophage activation syndrome, macrophage activation-like syndrome of sepsis, cytokine release syndrome, and COVID-19. We compared published clinical data for COVID-19 with clinical features of other hyperinflammatory or cytokine storm syndromes. Based on a framework of conserved clinical characteristics, we developed a six-criterion additive scale for cHIS: fever, macrophage activation (hyperferritinaemia), haematological dysfunction (neutrophil to lymphocyte ratio), hepatic injury (lactate dehydrogenase or asparate aminotransferase), coagulopathy (D-dimer), and cytokinaemia (C-reactive protein, interleukin-6, or triglycerides). We then validated the association of the cHIS scale with in-hospital mortality and need for mechanical ventilation in consecutive patients in the Intermountain Prospective Observational COVID-19 (IPOC) registry who were admitted to hospital with PCR-confirmed COVID-19. We used a multistate model to estimate the temporal implications of cHIS.

Methods

Findings

We included 299 patients admitted to hospital with COVID-19 between March 13 and May 5, 2020, in analyses. Unadjusted discrimination of the maximum daily cHIS score was 0·81 (95% CI 0·74–0·88) for in-hospital mortality and 0·92 (0·88–0·96) for mechanical ventilation; these results remained significant in multivariable analysis (odds ratio 1·6 [95% CI 1·2–2·1], p=0·0020, for mortality and 4·3 [3·0–6·0], p<0·0001, for mechanical ventilation). 161 (54%) of 299 patients met two or more cHIS criteria during their hospital admission; these patients had higher risk of mortality than patients with a score of less than 2 (24 [15%] of 138 vs one [1%] of 161) and for mechanical ventilation (73 [45%] vs three [2%]). In the multistate model, using daily cHIS score as a time-dependent variable, the cHIS hazard ratio for worsening from low to moderate oxygen requirement was 1·4 (95% CI 1·2–1·6), from moderate oxygen to high-flow oxygen 2·2 (1·1–4·4), and to mechanical ventilation 4·0 (1·9–8·2).

Findings

Interpretation

We proposed and validated criteria for hyperinflammation in COVID-19. This hyperinflammatory state, cHIS, is commonly associated with progression to mechanical ventilation and death. External validation is needed. The cHIS scale might be helpful in defining target populations for trials and immunomodulatory therapies.

Interpretation

Funding

Intermountain Research and Medical Foundation.

Funding

Intermountain Research and Medical Foundation.

Research in context

Features of hyperinflammatory syndromes and COVID-19

ARDS=acute respiratory distress syndrome. ND=no data available.

Proposed cHIS criteria

Clinical and laboratory characteristics of patients with COVID-19, stratified by peak cHIS score during the hospital stay

Data are median (IQR) or n (%) unless otherwise stated. cHIS=COVID-19-associated hyperinflammatory syndrome.

Proportions of patients by highest single-day cHIS score achieved during their admission

cHIS=COVID-19-associated hyperinflammatory syndrome.

Association with outcomes by individual cHIS components

AUROC=area under the receiver operating characteristic curve. cHIS=COVID-19-associated hyperinflammatory syndrome.

Intermountain Research and Medical Foundation provided institutional support for this study. BJW, IDP, PJ, DH, AS, NS, WB, EH, DM, RS, and SMB are members of the COVID-19 Therapeutics Committee at Intermountain Healthcare.

Contributors

BJW, IDP, PJ, DH, BH, AS, NS, WB, EH, DM, RS, and SMB contributed to the study concept. BJW, IDP, SMB, and GS were involved in the study design. BJW, IDP, PJ, WB, DH, BH, and SMB contributed to the literature review. BJW, NG, and GS collected data. BJW, GS, and SMB did the statistical analysis. BJW, IDP, PJ, DH, BH, AS, NS, WB, EH, DM, ES, RS, and SMB were involved in interpretation of results. All authors were involved in manuscript preparation and critical review of the manuscript.

Contributors

Declaration of interests

IDP reports salary support through a grant from the US National Institutes of Health (NIH). RS reports effort supported by US federal grants through the Agency for Healthcare Research and Quality, NIH, and the Patient-Centered Outcomes Research Institute, as well as institutional support (Intermountain Healthcare) in his equity as founding member of the I-PASS Patient Safety Institute. RS also reports monetary awards, honorariums, and travel reimbursement from multiple academic and professional organisations for talks about paediatric hospitalist research networks and quality of care. SMB reports salary support from the NIH, US Centers for Disease Control, and the US Department of Defense; he also reports receiving support for chairing a data and safety monitoring board for a respiratory failure trial sponsored by Hamilton, effort paid to Intermountain for steering committee work for Faron Pharmaceuticals and Sedana Pharmaceuticals for ARDS work, support from Janssen for Influenza research, and royalties for books on religion and ethics from Oxford University Press/Brigham Young University. BH reports personal fees from Kite Pharma outside the submitted work. BJW reports partial salary support from a US federal grant from the Agency for Healthcare Research and Quality. At the time of submission, Intermountain Healthcare has participated in COVID-19 trials sponsored by: AbbVie, Genentech, Gilead, Regeneron, Roche, and the NIH ACTIV and PETAL clinical trials networks; several authors (BJW, IDP, DH, BH, and SMB) were site investigators on these trials but received no direct or indirect remuneration for their effort. All other authors declare no competing interests.

Declaration of interests

Footnotes

^{Ferritin concentration might be elevated in end-stage renal disease on haemodialysis.}

^{Original validation used a 10 pg/mL threshold; post-hoc analysis suggested that 15 pg/mL has better discrimination for poor outcomes.}

^{Triglycerides might be elevated due to concomitant propofol administration.}

^{Not high-sensitivity CRP.}

^{CRP was not included in the original validation; post-hoc analysis confirmed use as a third surrogate for cytokinaemia.}

Footnotes

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