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Preliminary predictive criteria for COVID-19 cytokine storm
  1. Roberto Caricchio1,
  2. Marcello Gallucci2,
  3. Chandra Dass3,
  4. Xinyan Zhang1,
  5. Stefania Gallucci4,
  6. David Fleece5,
  7. Michael Bromberg6,
  8. Gerard J Criner7
  9. Temple University COVID-19 Research Group
    1. 1 Medicine/Rheumatology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA
    2. 2 Department of Psychology, University of Milano-Bicocca, Milan, Italy
    3. 3 Radiology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA
    4. 4 Microbiology and Immunology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA
    5. 5 Pediatrics, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA
    6. 6 Medicine/Hematology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA
    7. 7 Thoracic Medicine and Surgery, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA
    1. Correspondence to Professor Roberto Caricchio, Medicine/Rheumatology, Temple University School of Medicine, Philadelphia, PA 19140, USA; roc{at}


    Objectives To develop predictive criteria for COVID-19-associated cytokine storm (CS), a severe hyperimmune response that results in organ damage in some patients infected with COVID-19. We hypothesised that criteria for inflammation and cell death would predict this type of CS.

    Methods We analysed 513 hospitalised patients who were positive for COVID-19 reverse transcriptase PCR and for ground-glass opacity by chest high-resolution CT. To achieve an early diagnosis, we analysed the laboratory results of the first 7 days of hospitalisation. We implemented logistic regression and principal component analysis to determine the predictive criteria. We used a ‘genetic algorithm’ to derive the cut-offs for each laboratory result. We validated the criteria with a second cohort of 258 patients.

    Results We found that the criteria for macrophage activation syndrome, haemophagocytic lymphohistiocytosis and the HScore did not identify the COVID-19 cytokine storm (COVID-CS). We developed new predictive criteria, with sensitivity and specificity of 0.85 and 0.80, respectively, comprising three clusters of laboratory results that involve (1) inflammation, (2) cell death and tissue damage, and (3) prerenal electrolyte imbalance. The criteria identified patients with longer hospitalisation and increased mortality. These results highlight the relevance of hyperinflammation and tissue damage in the COVID-CS.

    Conclusions We propose new early predictive criteria to identify the CS occurring in patients with COVID-19. The criteria can be readily used in clinical practice to determine the need for an early therapeutic regimen, block the hyperimmune response and possibly decrease mortality.

    • inflammation
    • cytokines
    • antirheumatic agents
    • immune system diseases

    This article is made freely available for use in accordance with BMJ’s website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.

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    • Handling editor Josef S Smolen

    • Collaborators Temple University COVID-19 Research Group: Aaron Mishkin; Abbas Abbas; Abhijit S Pathak; Abhinav Rastogi; Adam Diamond; Aditi Satti; Adria Simon; Ahmed Soliman; Alan Braveman; Albert J Mamary; Aloknath Pandya; Amy Goldberg; Amy Kambo; Andrew Gangemi; Anjali Vaidya; Ann Davison; Anuj Basil; Arthur Lau; Arundathi Jayatilleke; Bakhos, Charles T; Bill Cornwell; Brent Lawrence; Brianna Sanguily; Brittany Corso; Carla Grabianowski; Carly Sedlock; Catherine Myers; Charles Bakhos; Chenna Kesava; Reddy Mandapati; Cherie Erkmen; Chethan Gangireddy; Chih-ru Lin; Christopher T Burks; Claire Raab; Crabbe, Deborah; Crystal Chen; Daniel Edmundowicz; Daniel Sacher; Daniel Salerno; Daniele Simon; David Ambrose; David Ciccolella; Debra Gillman; Dolores Fehrle; Dominic Morano; Donnalynn Bassler; Edmund Cronin; Eduardo Dominguez; Ekam Randhawa; Ekamjeet Randhawa; Eman Hamad; Eneida Male; Erin Narewski; Francis Cordova; Frederic Jaffe; Frederich Kueppers; Fusun Dikengil; Galli, Jonathan; Gangemi, Andrew; Garfield, Jamie; Gayle Jones; Gennaro Calendo; Gerard Criner; Gilbert D’Alonzo; Ginny Marmolejos; Gordon, Matthew; Gregory Millio; Gupta, Rohit; Gustavo Fernandez; Hannah Simborio; Harwood Scott; Heidi Shore-Brown; Hernan Alvarado; Ho-Man Yeung; Ibraheem Yousef; Ifeoma Oriaku; Iris Jung-won Lee; Isaac Whitman; James Brown; Jamie L. Garfield; Janpreet Mokha; Jason Gallagher; Jeffrey Stewart; Jenna Murray; Jessica Tang; Jeyssa Gonzalez; Jichuan Wu; Jiji Thomas; Jim Murrett; Joanna Beros; John M. Travaline; Jolly Varghese; Jordan Senchak; Joseph Lambert; Joseph Ramzy; Joshua Cooper;Jun Song; Junad Chowdhury; Justin Levinson; Kaitlin Kennedy; Karim B Ahmed; Karim Loukmane; Karthik Shenoy; Kathleen Brennan; Keith Johnson; Kevin Carney; Kevin Lu; Kraftin Schreyer; Kristin Criner; Kumaran, Maruti; Lauren Miller; Laurie Jameson; Laurie Johnson; Laurie Kilpatrick; Lawrence Brent; Lii-Yoong Criner; Lily Zhang; Lindsay K Mcgann; Llera A Samuels; Marc Diamond; Margaret Kerper; Maria Vega Sanchez; Mariola Marcinkienwicz; Maritza Pedlar; Mark Aksoy; Mark Weir; Marla R. Wolfson; Marla Wolfson; Marron, Robert; Martin Keane; Massa Zantah; Mathew Zheng; Matthew Delfiner; Matthew Gordon; Maulin Patel; Megan Healy; Melinda Darnell; Melissa Navaro; Meredith A. Brisco-Bacik; Michael Bromberg; Michael Gannon; Michael Jacobs; Mira Mandal; Nanzhou Gou; Narewski, Erin; Nathaniel Marchetti; Nathaniel Xander; Navjot Kaur; Neil Nadpara; Nicole Desai; Nicole Mills; Norihisa Shigemura; Ohoud Rehbini; Oisin O’Corragain; Omar Sheriff; Oneida Arosarena; Osheen Abramian; Paige Stanley; Parag Desai; Parth Rali; Patrick Mulhal; lPravin Patil; Priju Varghese; Puja Dubal; Puja Patel; Rachael Blair; Rajagopalan Rengan; Rami Alashram; Randol Hooper; Rebecca A Armbruster; Regina Sheriden; Robert Marron; Rogers Thomas; Rohit Gupta; Rohit Soans; Roman Petrov; Roman Prosniak; Romulo Fajardo; Ruchi Bhutani; Ryan Townsend; Sabrina Islam; Samantha Pettigrew; Samantha Wallace; Sameep Sehgal; Samuel Krachman; Santosh Dhungana; Sarah Hoang; Sean Duffy; Seema Ran; iShapiro William; Sheila Weaver; Shelu Benny; Sheril George; Shuang Sun; Shubhra Srivastava-Malhotra; Stephanie Brictson; Stephanie Spivack; Stephanie Tittaferrante; Stephanie Yerkes; Stephen Priest; Steve Codella; Steven G Kelsen; Steven Houser; Steven Verga; Sudhir Bolla; Sudhir Kotnala; Sunil Karhadkar; Sylvia Johnson; Tahseen Shariff; Tammy Jacobs; Thomas Hooper; Tom Rogers; Tony S. Reed; Tse-Shuen Ku; Uma Sajjan; Victor Kim; Whitney Cabey; Wissam Chatila; Wuyan Li; Zach Dorey-Stein; Zachariah Dorey-Stein; Zachary D Repanshek.

    • Contributors RC, MC and SG designed, analysed and interpreted the data and drafted the manuscript. RC, CD, DF and XZ acquired and analysed the data. MB, DF and GJC revised the manuscript critically for important intellectual content. RC, MC, SG, RC, CD, XZ. MB, DF and GJC approved the final version of the manuscript.

    • Funding This work was supported by the NIH grant R56 AR072115-01 (to RC), Lupus Research Alliance (RC).

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.

    • Patient consent for publication Not required.

    • Ethics approval This study was approved by Temple University local institutional review board (IRB) and informed consent was waived based on retrospective evaluation of deidentified data (IRB protocol number 27120).

    • Provenance and peer review Not commissioned; externally peer reviewed.

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