A Pediatric Rheumatologist’s Approach to Severe COVID-19 Illness
Severe life-threatening and life-taking COVID-19 illness has been devastating for many patients and families. More successful treatment is desperately needed. [1, 2] In this article a pediatric rheumatologist’s suggestions for improved treatment of severe COVID illness are summarized. This set of suggestions is best viewed as a hypothesis, regarding how treatment of severe COVID illness might be improved.
Hypothesis: A high percentage of patients with severe, life-threatening COVID-19 Illness could be successfully treated, if an aggressive, compulsive pediatric rheumatology treatment approach were implemented.
This hypothesis posits that the number of COVID deaths and the stress of COVID on ICU capacities, could be markedly reduced, if patients with severe COVID-19 illness were proactively studied for viral load (using SARS-CoV-2 PCR Ct values for guidance, as explained in a companion article) and treated in a timely and precise fashion with anti-viral therapies (when needed) and appropriately aggressive immunosuppression (when anticipatory monitoring reveals presence of hyperinflammatory, hyperimmune reactions).
The bases for this hypothesis, and details about a “pediatric rheumatology approach,” are fully explained and referenced in a longer article (LONG VERSION) entitled, Treatment of Severe COVID-19 Illness—A Pediatric Rheumatologist’s Perspective and Proposed Treatment Protocol, which may be found on the “Notes from the Social Clinic” website: https://notesfromthesocialclinic.org/treatment-of-severe-covid-19-illness/
The above hypothesis is based on an understanding that in many cases of severe COVID-19 illness (the exact percentage is not yet known) the main problem is not ongoing active viral infection, but an array of excessive, life-threatening immune reactions triggered by the virus (hyperinflammatory, hyperimmune, autoimmune reactions, often with “cytokine storm”) [3-13]—reactions that need to be suppressed in order to save life. Many severely ill patients may need only immunosuppression (because their viral infection has already come under adequate control). Others may need only anti-viral therapies (because their main problem is difficulty eradicating the virus, and they are not experiencing excessive immune reactions). Some patients may need both immunosuppression (e.g., corticosteroid and/or anti-cytokine therapy) and antiviral therapies (e.g., remdesivir, monoclonal antibodies, convalescent plasma, or interferon alpha 2b, or combinations of these). Treatment needs to be tailored to the patient’s specific situation and must be timely and precise.
The exact percentage of severely ill patients that fall into each of the above categories has not yet been determined. Preliminary data suggest that the largest category may be those who are suffering primarily (even only) from severe hyperimmune/hyperinflammatory reactions and, therefore, primarily (even only) need timely immunosuppression. [3-13]
According to this hypothesis: If patients with early, brewing severe COVID-19 illness are promptly recognized, carefully monitored, accurately interpreted, and promptly treated with appropriately aggressive immunosuppression (when indicated) or anti-viral therapies (when indicated), or both (in a timely fashion and in proportion to need), it is more likely that they can be saved, often without need to go to the ICU, often without residual long-term complications.
The life-threatening hyperimmune/hyperinflammatory reactions mentioned above are not new or unique to COVID-19 infection. For many years it has been known that life-threatening hyperinflammation and “cytokine storm” occur with many bacterial infections and with many other viral infections, including seasonal influenza infection. [13]
Over the past 40 years pediatric rheumatologists have developed extensive experience with excessive immune reactions (hyperinflammatory, hyperimmune, autoimmune, and cytokine storm reactions), including how to bring them under control. [14-32] Much of this experience has come from managing systemic onset juvenile idiopathic arthritis (formerly called juvenile rheumatoid arthritis) that has become complicated by “macrophage activation syndrome” and “cytokine storm.” The pediatric rheumatology approach to hyperinflammatory states is characterized by early, anticipatory, appropriately compulsive, serial monitoring; prompt and appropriately bold immunosuppression of hyperinflammation, carefully using corticosteroid and specific anti-cytokine therapies (e.g., anakinra); and careful, anticipatory, tailored adjustments along the way—always balancing concerns about risks versus benefits.
Pediatric rheumatologists have experienced remarkable success with this approach to treatment of hyperinflammatory/hyperimmune reactions, whether triggered by infection or occurring as a complication of rheumatic disease. [14-32] This approach can dramatically bring life-threatening cytokine storm under control, often within 1-4 days. Prior to development of this treatment approach, morbidity and mortality were high.
To date, the pediatric rheumatology approach described in this article (and succinctly detailed in the Appendix of the longer, full article) has not been commonly or fully applied to treatment of adults with severe COVID illness. For example, Ct values have not been routinely used to estimate viral load; use of corticosteroid has been hesitant; anakinra has not been frequently used; and when anti-cytokine therapies have been used, they have often been used late in the disease course, rather than early.
In short, the hypothesis presented in this article is: A “pediatric rheumatology approach,” when applied to management of severe COVID-19, has great potential to save lives, prevent organ damage, reduce ICU admissions, minimize need for mechanical ventilation, shorten length of hospital and ICU stays, prevent “long hauler” COVID complications, and reduce hospital costs; and, in the process, could reduce fears, angst, moral stress, hopelessness, and a sense of powerlessness among patients, families, physicians, nurses, other health care workers, and the public. Details of this approach are provided in the long, full article mentioned earlier.
There is already considerable scientific support for this hypothesis. [3-13] Further study, of course, is needed, and urgently so. In the meantime, the public, especially patients who develop severe COVID illness, deserve to know what approaches and treatment options are available for management of severe COVID-19 illness.
Robert M Rennebohm, MD
Email: rmrennebohm@gmail.com
Website: https://notesfromthesocialclinic.org/
About the Author: https://notesfromthesocialclinic.org/about-me/
REFERENCES:
- Rennebohm RM. Has undertreatment of severe COVID illness been widespread? A pediatric rheumatologist’s perspective. Russia Biomedical Research, 2020, Vol 5, No 3, p. 3-13.
- Rennebohm RM. Analysis of the COVID-19 epidemic: an additional narrative; an alternative response. Pediatrician (St. Petersburg). 2020;11(3):23-40. https://doi.org/10.17816/PED11323-40
- Henderson LA, Canna SW, Schulert GS, et al. On the alert for cytokine storm: immunopathology in COVID-19. Arthritis Rheumatol 2020; published online April 15. DOI:10.1002/art.41285.
- Qin C, Zhou L, Hu Z, Zhang S, Yang S et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clinical Infectious Diseases: an official publication of the Infectious Diseases Society of America 2020. doi: 10.1093/ cid/ciaa248
- Wang W, He J, Lie p, Huang l, Wu S et al. The definition and risks of cytokine release syndrome-like in 11 COVID-19-infected pneumonia critically ill patients: disease characteristics and retrospective analysis. MedRxiv 2020. doi: 10.1101/2020.02.26.20026989
- Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020; 395: 1033–34.
- Channappanavar R, Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Seminars in Immunopathology 2017; 39 (5): 529-539. doi: 10.1007/s00281-017-0629-x
- Shareef KA, et al. Cytokine Blood Filtration Responses in COVID-19. Blood Purification. Published online: May 28, 2020.
- Cron RQ, Chatham WW. The rheumatologist’s role in COVID-19. J Rheumatol 2020; 47: 639–42.
- Halpert G, Shoenfeld Y. SARS-CoV-2, the autoimmune virus. Autoimmunity Reviews 19 (2020) 102695. https://doi.org/10.1016/j.autrev.2020.102695
- Shoenfeld Y. Corona (COVID-19) time musings: Our involvement in COVID-19 pathogenesis, diagnosis, treatment and vaccine planning. Autoimmunity Reviews 19 (2020) 102538. https://doi.org/10.1016/j.autrev.2020.102538
- Ruscitti P, Berardicurti O, Di Benedetto P, et, al. (2020) Severe COVID-19, Another Piece in the Puzzle of the Hyperferritinemic Syndrome. An Immunomodulatory Perspective to Alleviate the Storm. Front. Immunol. 11:1130. doi: 10.3389/fimmu.2020.01130
- Ryabkova VA, Churilov LP, Shoenfeld Y. Influenza infection, SARS, MERS and COVID-19: Cytokine storm – The common denominator and the lessons to be learned. Clinical Immunology 223 (2021) 108652 https://doi.org/10.1016/j.clim.2020.108652
- Ravelli A, et al; for the Paediatric Rheumatology International Trials Organisation, Childhood Arthritis and Rheumatology Research Alliance, Pediatric Rheumatology Collaborative Study Group, and the Histiocyte Society. 2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborative Initiative. Ann Rheum Dis. 2016 Mar;75(3):481-9. doi: 10.1136/annrheumdis-2015-208982.PMID: 26865703
- Minoia F, et al; for the Pediatric Rheumatology International Trials Organization; Childhood Arthritis and Rheumatology Research Alliance; Pediatric Rheumatology Collaborative Study Group; Histiocyte Society. Clinical features, treatment, and outcome of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a multinational, multicenter study of 362 patients. Arthritis Rheumatol. 2014 Nov;66(11):3160-9. doi: 10.1002/art.38802.PMID: 25077692
- Boom et al. Evidence-based diagnosis and treatment of macrophage activation syndrome in systemic juvenile idiopathic arthritis. Pediatric Rheumatology (2015) 13:55
- Lin CI, Yu HH, Lee JH, Wang LC, Lin YT, Yang YH, et al. Clinical analysis of macrophage activation syndrome in pediatric patients with autoimmune diseases. Clin Rheumatol. 2012; 31:1223–30.
- Ravelli A, Magni-Manzoni S, Pistorio A, Besana C, Foti T, Ruperto N, et al. Preliminary diagnostic guidelines for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. J Pediatr. 2005; 146:598–604.
- Sawhney S, Woo P, Murray KJ. Macrophage activation syndrome: a potentially fatal complication of rheumatic disorders. Arch Dis Child. 2001; 85:421–6.
- Minoia F, Davi S, Horne A, Demirkaya E, Bovis F, Li C, et al. Clinical features, treatment, and outcome of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a multinational, multicenter study of 362 patients. Arthritis Rheumatol. 2014; 66:3160–9.
- Ravelli A, Minoia F, Davi S, Horne A, Bovis F, Pistorio A, Arico M, Avcin T, Behrens EM, de BF et al.: Development and initial validation of classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. Arthritis Rheumatol. 2015. doi: 10.1002/art.39332. [Epub ahead of print]
- Crayne CB, et al. The Immunology of Macrophage Activation Syndrome. Front Immunol. 2019 Feb 1; 10:119. doi: 10.3389/fimmu.2019.00119. eCollection 2019.PMID: 30774631
- Ravelli A, et al. Macrophage Activation Syndrome. Hematol Oncol Clin North Am. 2015 Oct;29(5):927-41. doi: 10.1016/j.hoc.2015.06.010. Epub 2015 Aug 25. PMID: 26461152 Review.
- Cron RQ, et al. Clinical features and correct diagnosis of macrophage activation syndrome. Expert Rev Clin Immunol. 2015;11(9):1043-53. doi: 10.1586/1744666X.2015.1058159. Epub 2015 Jun 16. PMID: 26082353 Review.
- Yasin S, Schulert GS. Systemic juvenile idiopathic arthritis and macrophage activation syndrome: update on pathogenesis and treatment. Curr Opin Rheumatol. 2018 Sep;30(5):514-520.
- Quartier P, et al. A multicentre, randomised, double-blind, placebo-controlled trial with the interleukin-1 receptor antagonist anakinra in patients with systemic-onset juvenile idiopathic arthritis. Ann Rheum Dis. 2011; 70:747–754. [PubMed: 21173013]
- Ruperto N, et al. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012; 367:2396–2406. [PubMed: 23252526]
- De Benedetti F, et al. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012; 367:2385–2395. [PubMed: 23252525]
- Miettunen PM, et al. Successful treatment of severe paediatric rheumatic disease-associated macrophage activation syndrome with interleukin-1 inhibition following conventional immunosuppressive therapy: case series with 12 patients. Rheumatology (Oxford). 2011.
- Durand M, Troyanov Y, Laflamme P, Gregoire G. Macrophage activation syndrome treated with anakinra. J Rheumatol. 2010; 37:879–880. [PubMed: 20360206]
- Bruck N, Suttorp M, Kabus M, Heubner G, Gahr M, Pessler F. Rapid and sustained remission of systemic juvenile idiopathic arthritis-associated macrophage activation syndrome through treatment with anakinra and corticosteroids. J Clin Rheumatol. 2011; 17:23–27. [PubMed: 21169853]
- Schulert GS, et al. Effect of Biologic Therapy on Clinical and Laboratory Features of Macrophage Activation Syndrome Associated with Systemic Juvenile Idiopathic Arthritis. Arthritis Care Res (Hoboken). 2018 Mar;70(3):409-419. doi: 10.1002/acr.23277. Epub 2018 Jan 30. PMID: 2849932950:417– 419. [PubMed: 20693540]
0 Comments