Neurological immunotherapy in the era of COVID-19 — looking for consensus in the literature

Nature Reviews Neurology - Tập 16 Số 9 - Trang 493-505 - 2020
Catharina Korsukewitz1, Stephen W. Reddel2, Amit Bar‐Or3, Heinz Wiendl1
1Department of Neurology with Institute of Translational Neurology, University of Muenster, Muenster, Germany
2Department of Neurology, Concord Hospital and The Brain and Mind Centre, University of Sydney, Sydney, Australia
3Center for Neuroinflammation and Neurotherapeutics and the Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA

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Zhu, N. et al. A novel coronavirus from patients with pneumonia in China, 2019. N. Engl. J. Med. 382, 727–733 (2020).

Zhou, P. et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270–273 (2020).

Siordia, J. A. Epidemiology and clinical features of COVID-19: a review of current literature. J. Clin. Virol. 127, 104357 (2020).

Iwasaki, A. & Yang, Y. The potential danger of suboptimal antibody responses in COVID-19. Nat. Rev. Immunol. 20, 339–341 (2020).

Herold, T. et al. Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19. J. Allergy Clin. Immunol. https://doi.org/10.1016/j.jaci.2020.05.008 (2020).

Gorse, G. J., Donovan, M. M. & Patel, G. B. Antibodies to coronaviruses are higher in older compared with younger adults and binding antibodies are more sensitive than neutralizing antibodies in identifying coronavirus-associated illnesses. J. Med. Virol. 92, 512–517 (2020).

Wang, L., Wang, F.-S. & Gershwin, M. E. Human autoimmune diseases: a comprehensive update. J. Intern. Med. 278, 369–395 (2015).

Kovarik, J. From immunosuppression to immunomodulation: current principles and future strategies. Pathobiology 80, 275–281 (2013).

Willis, M. D. & Robertson, N. P. Multiple sclerosis and the risk of infection: considerations in the threat of the novel coronavirus, COVID-19/SARS-CoV-2. J. Neurol. 267, 1567–1569 (2020).

Luna, G. et al. Infection risks among patients with multiple sclerosis treated with fingolimod, natalizumab, rituximab, and injectable therapies. JAMA Neurol. 77, 184–191 (2020).

Fu, Y., Cheng, Y. & Wu, Y. Understanding SARS-CoV-2-mediated inflammatory responses: from mechanisms to potential therapeutic tools. Virol. Sin. https://doi.org/10.1007/s12250-020-00207-4 (2020).

Jamilloux, Y. et al. Should we stimulate or suppress immune responses in COVID-19? Cytokine and anti-cytokine interventions. Autoimmun. Rev. 19, 102567 (2020).

Steinberg, K. P. et al. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N. Engl. J. Med. 354, 1671–1684 (2006).

Sormani, M. P. Italian study group on COVID-19 infection in multiple sclerosis. An Italian programme for COVID-19 infection in multiple sclerosis. Lancet Neurol. 19, 481–482 (2020).

Minotti, C., Tirelli, F., Barbieri, E., Giaquinto, C. & Donà, D. How is immunosuppressive status affecting children and adults in SARS-CoV-2 infection? A systematic review. J. Infect. 81, e61–e66 (2020).

Haberman, R. et al. Covid-19 in immune-mediated inflammatory diseases – case series from New York. N. Engl. J. Med. https://doi.org/10.1056/NEJMc2009567 (2020).

Boulkedid, R., Abdoul, H., Loustau, M., Sibony, O. & Alberti, C. Using and reporting the Delphi method for selecting healthcare quality indicators: a systematic review. PLoS One 6, e20476 (2011).

Cain, D. W. & Cidlowski, J. A. Immune regulation by glucocorticoids. Nat. Rev. Immunol. 17, 233–247 (2017).

Fan, P. T. et al. Effect of corticosteroids on the human immune response: comparison of one and three daily 1 gm intravenous pulses of methylprednisolone. J. Lab. Clin. Med. 91, 625–634 (1978).

Youssef, J., Novosad, S. A. & Winthrop, K. L. Infection risk and safety of corticosteroid use. Rheum. Dis. Clin. North. Am. 42, 157–176 (2016).

Arabi, Y. M. et al. Corticosteroid therapy for critically ill patients with Middle East respiratory syndrome. Am. J. Respir. Crit. Care Med. 197, 757–767 (2018).

Russell, C. D., Millar, J. E. & Baillie, J. K. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet 395, 473–475 (2020).

Alhazzani, W. et al. Surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19). Crit. Care Med. https://doi.org/10.1097/CCM.0000000000004363 (2020).

Horby, P et al. Effect of dexamethasone in hospitalized patients with COVID-19: preliminary report. Preprint at medRxiv https://doi.org/10.1101/2020.06.22.20137273 (2020).

Nguyen, A. A. et al. Immunoglobulins in the treatment of COVID-19 infection: proceed with caution! Clin. Immunol. 216, 108459 (2020).

Guidon, A. C. & Amato, A. A. COVID-19 and neuromuscular disorders. Neurology https://doi.org/10.1212/WNL.0000000000009566 (2020).

Klok, F. A. et al. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: an updated analysis. Thromb. Res. https://doi.org/10.1016/j.thromres.2020.04.041 (2020).

Palace, J. et al. Outcome prediction models in AQP4-IgG positive neuromyelitis optica spectrum disorders. Brain 142, 1310–1323 (2019).

Kleiter, I. et al. Apheresis therapies for NMOSD attacks: a retrospective study of 207 therapeutic interventions. Neurol. Neuroimmunol. Neuroinflamm 5, e504 (2018).

Carnero Contentti, E. & Correa, J. Immunosuppression during the COVID-19 pandemic in neuromyelitis optica spectrum disorders patients: a new challenge. Mult. Scler. Relat. Disord. 41, 102097 (2020).

Sanders, D. B. et al. International consensus guidance for management of myasthenia gravis: Executive summary. Neurology 87, 419–425 (2016).

Delly, F., Syed, M. J., Lisak, R. P. & Zutshi, D. Myasthenic crisis in COVID-19. J. Neurol. Sci. 414, 116888 (2020).

Anand, P. et al. COVID-19 in patients with myasthenia gravis. Muscle Nerve 19, 1 (2020).

International MG/COVID-19 Working Group. et al. Guidance for the management of myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS) during the COVID-19 pandemic. J. Neurol. Sci. 412, 116803 (2020).

Feldman, C. H. et al. Serious infections among adult Medicaid beneficiaries with systemic lupus erythematosus and lupus nephritis. Arthritis Rheumatol. 67, 1577–1585 (2015).

Wilson, J. C. et al. Serious adverse effects associated with glucocorticoid therapy in patients with giant cell arteritis (GCA): a nested case-control analysis. Semin. Arthritis Rheum. 46, 819–827 (2017).

Wilson, J. C. et al. Incidence and risk of glucocorticoid-associated adverse effects in patients with rheumatoid arthritis. Arthritis Care Res. 71, 498–511 (2019).

Rajabally, Y. A., Goedee, H. S., Attarian, S. & Hartung, H.-P. Management challenges for chronic dysimmune neuropathies during the COVID-19 pandemic. Muscle Nerve 62, 34–40 (2020).

Schmedt, N., Andersohn, F. & Garbe, E. Signals of progressive multifocal leukoencephalopathy for immunosuppressants: a disproportionality analysis of spontaneous reports within the US Adverse Event Reporting System (AERS). Pharmacoepidemiol. Drug. Saf. 21, 1216–1220 (2012).

Sebela Ireland Ltd. IMURAN (azathioprine): Product information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/016324s039lbl.pdf (2018).

Aspen. Australian Product Information: Azathioprine (Imuran) https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-06832-3 (2019).

Goodkin, D. E. Interferon beta-1b. Lancet 344, 1057–1060 (1994).

Mark, D. F., Lu, S. D., Creasey, A. A., Yamamoto, R. & Lin, L. S. Site-specific mutagenesis of the human fibroblast interferon gene. Proc. Natl Acad. Sci. USA 81, 5662–5666 (1984).

Sheahan, T. P. et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat. Commun. 11, 222 (2020).

Weinstock-Guttman, B., Nair, K. V., Glajch, J. L., Ganguly, T. C. & Kantor, D. Two decades of glatiramer acetate: from initial discovery to the current development of generics. J. Neurol. Sci. 376, 255–259 (2017).

Häusler, D. et al. Glatiramer acetate immune modulates B-cell antigen presentation in treatment of MS. Neurol. Neuroimmunol. Neuroinflamm 7, e698 (2020).

Ziemssen, T. & Schrempf, W. Glatiramer acetate: mechanisms of action in multiple sclerosis. Int. Rev. Neurobiol. 79, 537–570 (2007).

Bar-Or, A. Teriflunomide (Aubagio®) for the treatment of multiple sclerosis. Exp. Neurol. 262, 57–65 (2014).

Klotz, L. et al. Teriflunomide treatment for multiple sclerosis modulates T cell mitochondrial respiration with affinity-dependent effects. Sci. Transl. Med. 11, eaao5563 (2019).

Comi, G. et al. Characterizing lymphocyte counts and infection rates with long-term teriflunomide treatment: pooled analysis of clinical trials. Mult. Scler. https://doi.org/10.1177/1352458519851981 (2019).

Bilger, A. et al. Leflunomide/teriflunomide inhibit Epstein-Barr virus (EBV)-induced lymphoproliferative disease and lytic viral replication. Oncotarget 8, 44266–44280 (2017).

Chon, W. J. et al. Use of leflunomide in renal transplant recipients with ganciclovir-resistant/refractory cytomegalovirus infection: a case series from the University of Chicago. Case Rep. Nephrol. Dial. 5, 96–105 (2015).

Henao-Martínez, A. F., Weinberg, A., Waldman, W. J. & Levi, M. E. Successful treatment of acyclovir-resistant herpes simplex virus type 2 proctitis with leflunomide in an HIV-infected man. J. Clin. Virol. 54, 276–278 (2012).

Lamarche, C. et al. BK polyomavirus and the transplanted kidney: immunopathology and therapeutic approaches. Transplantation 100, 2276–2287 (2016).

Xiong, R. et al. Novel and potent inhibitors targeting DHODH, a rate-limiting enzyme in de novo pyrimidine biosynthesis, are broad-spectrum antiviral against RNA viruses including newly emerged coronavirus SARS-CoV-2. Preprint at bioRxiv https://doi.org/10.1101/2020.03.11.983056 (2020).

Ghadiri, M. et al. Dimethyl fumarate-induced lymphopenia in MS due to differential T-cell subset apoptosis. Neurol. Neuroimmunol. Neuroinflamm 4, e340 (2017).

Li, R. et al. Dimethyl fumarate treatment mediates an anti-inflammatory shift in B cell subsets of patients with multiple sclerosis. J. Immunol. 198, 691–698 (2017).

Mehta, D. et al. Effect of dimethyl fumarate on lymphocytes in RRMS: implications for clinical practice. Neurology 92, e1724–e1738 (2019).

Rosenkranz, T., Novas, M. & Terborg, C. PML in a patient with lymphocytopenia treated with dimethyl fumarate. N. Engl. J. Med. 372, 1476–1478 (2015).

Perini, P. et al. Herpes simplex virus encephalitis temporally associated with dimethyl fumarate-induced lymphopenia in a multiple sclerosis patient. Multiple Scler. Relat. Disord. 26, 68–70 (2018).

Niino, M. et al. Natalizumab effects on immune cell responses in multiple sclerosis. Ann. Neurol. 59, 748–754 (2006).

Butzkueven, H. et al. Long-term safety and effectiveness of natalizumab treatment in clinical practice: 10 years of real-world data from the Tysabri Observational Program (TOP). J. Neurol. Neurosurg. Psychiatr. 91, 660–668 (2020).

Polman, C. H. et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med. 354, 899–910 (2006).

Foley, J. et al. The 5-year Tysabri Global Observational Program in Safety (TYGRIS) study confirms the long-term safety profile of natalizumab treatment in multiple sclerosis. Multiple Scler. Relat. Disord. 39, 101863 (2019).

Schwab, N., Schneider-Hohendorf, T., Melzer, N., Cutter, G. & Wiendl, H. Natalizumab-associated PML: challenges with incidence, resulting risk, and risk stratification. Neurology 88, 1197–1205 (2017).

Prosperini, L. et al. Post-natalizumab disease reactivation in multiple sclerosis: systematic review and meta-analysis. Ther. Adv. Neurol. Disord. https://doi.org/10.1177/1756286419837809 (2019).

Louapre, C. et al. Patients with MS treated with immunosuppressive agents: across the COVID-19 spectrum. Rev. Neurol. 176, 523–525 (2020).

Borriello, G. & Ianniello, A. COVID-19 occurring during natalizumab treatment: a case report in a patient with extended interval dosing approach. Mult. Scler. Relat. Disord. 41, 102165 (2020).

Ryerson, L. Z. et al. Risk of natalizumab-associated PML in patients with MS is reduced with extended interval dosing. Neurology 93, e1452–e1462 (2019).

Paniz-Mondolfi, A. et al. Central nervous system involvement by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). J. Med. Virol. 92, 699–702 (2020).

Asadi-Pooya, A. A. & Simani, L. Central nervous system manifestations of COVID-19: a systematic review. J. Neurol. Sci. 413, 116832 (2020).

Sigrist, C. J., Bridge, A. & Le Mercier, P. A potential role for integrins in host cell entry by SARS-CoV-2. Antivir. Res. 177, 104759 (2020).

Tresoldi, I., Sangiuolo, C. F., Manzari, V. & Modesti, A. SARS-COV-2 and infectivity: possible increase in infectivity associated to integrin motif expression. J. Med. Virol. 177, 104759 (2020).

Arvin, A. M. et al. Varicella-zoster virus infections in patients treated with fingolimod: risk assessment and consensus recommendations for management. JAMA Neurol. 72, 31–39 (2015).

Tagawa, A. et al. Hepatitis C virus (HCV) reactivation during fingolimod treatment for relapsing and remitting multiple sclerosis. Mult. Scler. Relat. Disord. 9, 155–157 (2016).

Beadnall, H. N., Gill, A. J., Riminton, S. & Barnett, M. H. Virus-related Merkel cell carcinoma complicating fingolimod treatment for multiple sclerosis. Neurology 87, 2595–2597 (2016).

Benedetti, M. D. et al. HPV-related papillary squamous cell carcinoma of the tonsil during treatment with fingolimod. Mult. Scler. Relat. Disord. 23, 24–26 (2018).

Cohen, J. A. et al. Safety and efficacy of the selective sphingosine 1-phosphate receptor modulator ozanimod in relapsing multiple sclerosis (RADIANCE): a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 15, 373–381 (2016).

Cohen, J. A. et al. Efficacy and safety of ozanimod in multiple sclerosis: dose-blinded extension of a randomized phase II study. Mult. Scler. 25, 1255–1262 (2019).

Comi, G. et al. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial. Lancet Neurol. 18, 1009–1020 (2019).

Kappos, L. et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet 391, 1263–1273 (2018).

Ghadiri, M. et al. Reconstitution of the peripheral immune repertoire following withdrawal of fingolimod. Mult. Scler. 23, 1225–1232 (2017).

Tay, M. Z., Poh, C. M., Rénia, L., MacAry, P. A. & Ng, L. F. P. The trinity of COVID-19: immunity, inflammation and intervention. Nat. Rev. Immunol. 20, 363–374 (2020).

US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04280588 (2020).

Cooper, N. & Arnold, D. M. The effect of rituximab on humoral and cell mediated immunity and infection in the treatment of autoimmune diseases. Br. J. Haematol. 149, 3–13 (2010).

Hauser, S. L. et al. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N. Engl. J. Med. 376, 221–234 (2017).

Bar-Or, A. et al. Subcutaneous ofatumumab in patients with relapsing-remitting multiple sclerosis: The MIRROR study. Neurology 90, e1805–e1814 (2018).

Ciardi, M. R. et al. Reactivation of hepatitis B virus with immune-escape mutations after ocrelizumab treatment for multiple sclerosis. Open. Forum Infect. Dis. 6, ofy356 (2019).

Lin, K.-M., Lin, J.-C., Tseng, W.-Y. & Cheng, T.-T. Rituximab-induced hepatitis C virus reactivation in rheumatoid arthritis. J. Microbiol. Immunol. Infect. 46, 65–67 (2013).

Sul, J. et al. Progressive multifocal leukoencephalopathy in a patient on ocrelizumab monotherapy. Neurology 94, 4875 (2020).

Novi, G. et al. COVID-19 in a MS patient treated with ocrelizumab: does immunosuppression have a protective role? Mult. Scler. Relat. Disord. 42, 102120 (2020).

Hughes, R., Pedotti, R. & Koendgen, H. COVID-19 in persons with multiple sclerosis treated with ocrelizumab – a pharmacovigilance case series. Mult. Scler. Relat. Disord. 42, 102192 (2020).

Amor, S., Baker, D., Khoury, S. J., Schmierer, K. & Giovanonni, G. SARS-CoV-2 and multiple sclerosis: not all immune depleting DMTs are equal or bad. Ann. Neurol. 87, 794–797 (2020).

Safavi, F., Nourbakhsh, B. & Azimi, A. R. B-cell depleting therapies may affect susceptibility to acute respiratory illness among patients with multiple sclerosis during the early COVID-19 epidemic in Iran. Mult. Scler. Relat. Disord. 43, 102195 (2020).

Quinti, I. et al. A possible role for B cells in COVID-19? Lesson from patients with agammaglobulinemia. J. Allergy Clin. Immunol. https://doi.org/10.1016/j.jaci.2020.04.013 (2020).

Bearden, C. M. et al. Rituximab inhibits the in vivo primary and secondary antibody response to a neoantigen, bacteriophage phiX174. Am. J. Transplant. 5, 50–57 (2005).

Novi, G. et al. Ocrelizumab does not impair B- and T-cell responses to primary VZV infection in a patient with MS. Neurol. Neuroimmunol. Neuroinflamm. 7, e695 (2020).

Stokmeier, D. et al. Effect of ocrelizumab on vaccine responses in patients with multiple sclerosis [abstract]. Neurology 90 (Suppl. 15), S36.002 (2018).

Wiendl, H. & Kieseier, B. Reprogramming the immune repertoire with alemtuzumab in MS. Nat. Rev. Neurol. 9, 125–126 (2013).

Lünemann, J. D., Ruck, T., Muraro, P. A., Bar-Or, A. & Wiendl, H. Immune reconstitution therapies: concepts for durable remission in multiple sclerosis. Nat. Rev. Neurol. 16, 56–62 (2020).

Möhn, N. et al. Alemtuzumab therapy changes immunoglobulin levels in peripheral blood and CSF. Neurol. Neuroimmunol. Neuroinflamm. 7, e654 (2020).

Wray, S. et al. Infection risk with alemtuzumab decreases over time: pooled analysis of 6-year data from the CAMMS223, CARE-MS I, and CARE-MS II studies and the CAMMS03409 extension study. Mult. Scler. 25, 1605–1617 (2019).

Wiendl, H. et al. Lymphocyte pharmacodynamics are not associated with autoimmunity or efficacy after alemtuzumab. Neurol. Neuroimmunol. Neuroinflamm. 7, e635 (2020).

Coles, A. J. et al. Alemtuzumab CARE-MS II 5-year follow-up: efficacy and safety findings. Neurology 89, 1117–1126 (2017).

Giovannoni, G. Cladribine to treat relapsing forms of multiple sclerosis. Neurotherapeutics 14, 874–887 (2017).

Wiendl, H. Cladribine – an old newcomer for pulsed immune reconstitution in MS. Nat. Rev. Neurol. 13, 573–574 (2017).

Baker, D. et al. Both cladribine and alemtuzumab may effect MS via B-cell depletion. Neurol. Neuroimmunol. Neuroinflamm. 4, e360 (2017).

Ceronie, B. et al. Cladribine treatment of multiple sclerosis is associated with depletion of memory B cells. J. Neurol. 265, 1199–1209 (2018).

Havrdova, E. et al. Alemtuzumab CARE-MS I 5-year follow-up: durable efficacy in the absence of continuous MS therapy. Neurology 89, 1107–1116 (2017).

Willis, M. D. & Robertson, N. P. Alemtuzumab for the treatment of multiple sclerosis. Ther. Clin. Risk Manag. 11, 525–534 (2015).

Thomas, K., Eisele, J., Rodriguez-Leal, F. A., Hainke, U. & Ziemssen, T. Acute effects of alemtuzumab infusion in patients with active relapsing-remitting MS. Neurol. Neuroimmunol. Neuroinflamm. 3, e228 (2016).

Jacobs, B. M. et al. Cladribine: mechanisms and mysteries in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 89, 1266–1271 (2018).

Burt, R. K. et al. Effect of nonmyeloablative hematopoietic stem cell transplantation vs continued disease-modifying therapy on disease progression in patients with relapsing-remitting multiple sclerosis: a randomized clinical trial. JAMA 321, 165–174 (2019).

Muraro, P. A. et al. Autologous haematopoietic stem cell transplantation for treatment of multiple sclerosis. Nat. Rev. Neurol. 13, 391–405 (2017).

Zhou, F. et al. SARS-CoV-2 shedding and infectivity – authors’ reply. Lancet 395, 1340 (2020).

Gudbjartsson, D. F. et al. Spread of SARS-CoV-2 in the Icelandic population. N. Engl. J. Med. 382, 2302–2315 (2020).

Yang, J.-R. et al. Persistent viral RNA positivity during recovery period of a patient with SARS-CoV-2 infection. J. Med. Virol. https://doi.org/10.1002/jmv.25940 (2020).

Prescott, J. et al. Pathogenicity and viral shedding of MERS-CoV in immunocompromised rhesus macaques. Front. Immunol. 9, 205 (2018).

de Lima, C. R. A. et al. Prolonged respiratory viral shedding in transplant patients. Transpl. Infect. Dis. 16, 165–169 (2014).

Nowak, M. D., Sordillo, E. M., Gitman, M. R. & Paniz Mondolfi, A. E. Co-infection in SARS-CoV-2 infected patients: where are influenza virus and rhinovirus/enterovirus? J. Med. Virol. https://doi.org/10.1002/jmv.25953 (2020).

Rawson, T. M. et al. Bacterial and fungal co-infection in individuals with coronavirus: a rapid review to support COVID-19 antimicrobial prescribing. Clin. Infect. Dis. https://doi.org/10.1093/cid/ciaa530 (2020).

Olberg, H. K. et al. Antibody response to seasonal influenza vaccination in patients with multiple sclerosis receiving immunomodulatory therapy. Eur. J. Neurol. 25, 527–534 (2018).

Metze, C. et al. Immunogenicity and predictors of response to a single dose trivalent seasonal influenza vaccine in multiple sclerosis patients receiving disease-modifying therapies. CNS Neurosci. Ther. 25, 245–254 (2019).

Klotz, L. et al. Risks and risk management in modern multiple sclerosis immunotherapeutic treatment. Ther. Adv. Neurol. Disord. 12, 1756286419836571 (2019).

Koyama, S., Ishii, K. J., Coban, C. & Akira, S. Innate immune response to viral infection. Cytokine 43, 336–341 (2008).

Cao, X. COVID-19: immunopathology and its implications for therapy. Nat. Rev. Immunol. 20, 269–270 (2020).

Mehta, P. et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 395, 1033–1034 (2020).

Berger, J. R., Brandstadter, R. & Bar-Or, A. COVID-19 and MS disease-modifying therapies. Neurol. Neuroimmunol. Neuroinflamm. 7, e761 (2020).

Zhang, B. et al. Immune phenotyping based on neutrophil-to-lymphocyte ratio and IgG predicts disease severity and outcome for patients with COVID-19. Preprint at medrxiv.org https://doi.org/10.1101/2020.03.12.20035048 (2020).

Sarzi-Puttini, P. et al. COVID-19, cytokines and immunosuppression: what can we learn from severe acute respiratory syndrome? Clin. Exp. Rheumatol. 38, 337–342 (2020).

Napolitano, M., Fabbrocini, G. & Patruno, C. Potential role of Janus kinase inhibitors in COVID-19. J. Am. Acad. Dermatol. 83, e65 (2020).

Risitano, A. M. et al. Complement as a target in COVID-19? Nat. Rev. Immunol. 20, 343–344 (2020).

Mastaglio, S. et al. The first case of COVID-19 treated with the complement C3 inhibitor AMY-101. Clin. Immunol. 215, 108450 (2020).

Diurno, F. et al. Eculizumab treatment in patients with COVID-19: preliminary results from real life ASL Napoli 2 Nord experience. Eur. Rev. Med. Pharmacol. Sci. 24, 4040–4047 (2020).

Seminari, E. et al. SARS Cov2 infection in a renal transplanted patient: a case report. Am. J. Transplant. https://doi.org/10.1111/ajt.15902 (2020).

Norsa, L. et al. Uneventful course in IBD patients during severe acute respiratory syndrome coronovirus 2 outbreak in northern Italy. Gastroenterology https://doi.org/10.1053/j.gastro.2020.03.062 (2020).

Romanelli, A. & Mascolo, S. Immunosuppression drug-related and clinical manifestation of coronavirus disease 2019: a therapeutical hypothesis. Am. J. Transplant. https://doi.org/10.1111/ajt.15905 (2020).

Guan, W.-J. et al. Clinical characteristics of coronavirus disease 2019 in China. N. Engl. J. Med. 382, 1708–1720 (2020).