The COVID-19 pandemic: Are our dermatological patients on immunomodulating medication at high-risk?
Dermatological immune-mediated diseases are treated with biologic and non-biologic immunomodulatory and immunosuppressive medication. Does the treatments involve an increased risk for an adverse outcome if these patients get infected by the novel coronavirus disease?
From the beginning of the COVID-19 pandemic it has been mentioned that the elderly, the weak, and immunocompromised people may be at increased risk for an adverse outcome when infected by this novel coronavirus disease.1 Authorities, medical associations and patient associations have advised these groups to be very cautious, and when possible to avoid any risk of COVID-19 infection.2 Many people belonging to these groups have chosen self-isolation and taken strict preventive actions.
It was assumed that immunocompromised patients have a higher risk of an adverse outcome with COVID-19 because they are at increased risk when affected by common viral infections with adenovirus, rhinovirus, norovirus, and influenza.1 The question arises whether immunocompromised patients also are at increased risk when infected with COVID-19 infection, and whether extensive actions to prevent infection are necessary?
Immunocompromised patients are defined as patients with a weak immune system, who typically have a lower immune capacity to fight infections and cancer. This group of immunocompromised patients is broad and includes those with an inherited immunodeficiency, people with HIV, patients with bad nutritional status, cancer patients especially those in active chemotherapy, patients taking immunomodulating and immunosuppressive medication for dermatological, rheumatological, gastrointestinal and other medical conditions, and immunosuppressed patients after solid organ and bone marrow transplantation.
Systemic inflammation and lung tissue damage
For patients getting ill with COVID-19, the host innate immune response appears to be the main driver of lung tissue damage.3 The primary immune response leads to viral clearance in the majority of patients. As this coronavirus is unknown to the human body, some patients react with a very severe secondary immune response.4 This includes production of very high levels of cytokines including interleukin 6, interleukin 1, anti TNF, and macrophages. Retrospective data have shown that this cytokine storm and systemic hyperinflammatory response is associated with adverse outcome leading to severe inflammatory-induced lung injury and other complications including pneumonitis, acute respiratory distress syndrome, respiratory failure, shock, organ failure, and death.3 It is still unclear which component of the cytokine storm causes most damage.
To reduce this cytokine storm and hyperinflammation, immunosuppressive drugs are currently tested in COVID-19 patients.5 These include treatment with low-dose corticosteroids, Interleukin-1 receptor antagonists, Interleukin-6 receptor antagonists, IFN-λ, intravenous immunoglobulin and anti-tumour necrosis factor.4-6 These treatments should be balanced in order to reduce the hyperinflammation, but the immune system should still be able to respond to the infection and bacterial infections.7
It has been speculated that due to the state of immunosuppression, immunocompromised patients may not be able to respond with hyperinflammation, and subsequently avoid severe lung tissue damage.8,9
Immunosuppressed transplanted patients
Early reports from China and Italy suggest that immunosuppressed transplanted patients, do not have a more severe course of COVID-19 infection than other people. Cases from China on COVID-19 in heart, kidney and liver transplant recipients report successful recovery.10-14 Furthermore, a Chinese study on 87 heart transplant recipients from the Hubei province report that 4 developed upper airway symptoms, but none of them was tested positive.15 However, there is also a case report with a renal transplant patient and a bone marrow transplant patient both infected with COVID-19. Maintenance immunosuppression was withdrawn in these two patients, and treatment with low-dose corticosteroids was initiated, unfortunately with fatal outcome.16
Preliminary reports from Italy described that no COVID-19 fatalities have occurred among transplanted patients.1 Though, a more recent study reported on three long-term liver transplant survivors who died due to COVID-19 out of a total of 111 long-term transplant survivors (Bhoori). Characteristic for all of them was that they received very low doses of immunosuppression as they had been transplanted long ago. Furthermore, all three were male, older than 65 years, overweight, and all had severe co-morbidity with diabetes, hypertension and hyperlipidemia.9 A case series from Italy showed that pediatric liver transplant recipients, despite being immunosuppressed, were not at increased risk of severe pulmonary disease compared with the general population.1
Dermatological patients on immunomodulating treatment
Dermatological immune-mediated diseases, including psoriasis, atopic dermatitis, and hidradenitis suppurativa, are treated with biologic and non-biologic immunomodulatory and immunosuppressive medication. Whether patients on immunomodulating treatment for dermatological, gastrointestinal and rheumatological diseases are at increased risk for adverse outcomes when infected by COVID-19 is currently unclear.17 Some have referred to the registration studies for psoriasis in which a slightly increased risk for infections was seen in patients treated with biologicals compared to placebo, but not for all drugs and no difference in respiratory infections was seen between biological agents for psoriasis and placebo.17,18 Based on these pivotal studies, dermatological patients are advised to continue their immunomodulating treatment to avoid worsening of their skin disease, though whether or not to continue treatment should be discussed with individual patients.17,18 It has been pointed out that evidence is lacking to stop treatment with biologicals as a preventive measure.17,19 Of course, careful consideration whether the skin disease justifies immunosuppressive treatment should always be taken into account, especially when starting new patients on immunomodulating drugs.20
Most dermatological societies advice to discontinue treatment with biological agents when patients are diagnosed with COVID-19.17 A report from Italy describes continuing biological treatment in asymptomatic patients or with mild symptoms without fever and without contact to COVID-19 patients.21 Treatment was discontinued in patients with moderate or severe respiratory symptoms (fever, cough and/or difficulty breathing) and without COVID-19 contacts. In this group treatment was restarted when complete remission of symptoms was reached and after at least 72 hours without fever. Treatment was discontinued in patients with mild respiratory problems and contact to COVID-19 confirmed cases until the patient has laboratory-confirmed negative test for COVID-19. In patients with moderate to severe respiratory symptoms and contact to COVID-19 patients or clinical/radiological COVID-19, treatment was interrupted and patients were admitted to a COVID hospital.21 More data is urgently needed to identify specific patients at high-risk (age, comorbidities, etc.) and the international league of dermatological societies has launched an app titled ‘PSOprotect’ to register how psoriasis patients taking immunomodulating medication are affected by COVID-19 infections.22 Furthermore, an online registry for patients with atopic dermatitis on immunomodulating medication, the SECURE-AD registry has been launched.23 Similar registries exist for rheumatological (Rheum-covid)24 and gastrointestinal patients (Covidibd).25 The NICE institute in the UK is currently preparing guidelines for dermatological patients on immunomodulating medication.
A Chinese study from three hospitals in Wuhan reported on 28 cancer patients infected with COVID-19.26 The most common type of cancer in this group was lung cancer (25%). Serious adverse events in these patients were very common, and mortality was high (29%). Especially patients who had received active therapy within the last 14 days were at high risk for serious adverse events.26
It is still generally unknown how immunosuppressed patients react when infected by COVID-19.8 A report from Spain describe a kidney transplant recipient who initially presented with atypical symptoms (diarrhea, fatique and fever) without respiratory symptoms.27 It might be possible that immunosuppressed patients will be presenting other symptoms than the general population.8
More research is necessary to characterize the full spectrum of clinical illness, transmission efficiency, and the duration of viral shedding for immunocompromised patients with COVID-19. Based on knowledge from other respiratory viral infections, including influenza, it is suggested that persons with COVID-19 may shed infectious virus for an extended time period after recovery.
At present, it is not possible to draw firm conclusions on whether immunosuppressed patients have a higher risk of adverse outcome when infected by COVID-19. Available reports suggest an increased risk for cancer patients in active therapy.26 Studies in immunosuppressed transplanted patients suggest that major risk factors for adverse outcome are age and comorbidity like hypertension and diabetes rather than immunosuppression.9 Whether immunosuppression helps to prevent a cytokine storm in immunosuppressed patients remains to be elucidated. Currently, there is no clear evidence to interrupt immunomodulating medication in our dermatological patients, but more epidemiological data is necessary to assess their risk of adverse outcomes with COVID-19.
1. D’Antiga L. Dondossola D, Antonelli B, Mangioni D, Alagna L, Reggiani P, Bandera A, Rossi, G. Coronaviruses and immunosuppressed patients. The facts during the third epidemic. Liver Transplant 2020 Mar 20 . doi: 10.1002/lt.25756. 2. Andrea G, et al. Coronavirus disease and transplantation: a view from the inside. Am J Transplant 2020; https://doi.org/10.1111/ajt.15853 3. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ; HLH Across Speciality Collaboration, UK. Lancet. 2020 Mar 28;395(10229):1033-1034. doi: 10.1016/S0140-6736(20)30628-0. 4. Ye Q, Wang B, Mao J. Cytokine Storm in COVID-19 and Treatment. J Infect 2020 Apr 10 . pii: S0163-4453(20)30165-1. doi: 10.1016/j.jinf.2020.03.037. 5. Sarzi-Puttini P, Giorgi V, Sirotti S, Marotto D, Ardizzone S, Rizzardini G, Antinori S, Galli M. COVID-19, cytokines and immunosuppression: what can we learn from severe acute respiratory syndrome? Clin Exp Rheumatol. 2020 Mar-Apr;38(2):337-342. 6. Feldmann M, Maini RN, Woody JN, Holgate ST, Winter G, Rowland M, Richards D, Hussell T. Trials of anti-tumour necrosis factor therapy for COVID-19 are urgently needed. Lancet. 2020 Apr 9 . pii: S0140-6736(20)30858-8. doi: 10.1016/S0140-6736(20)30858-8. 7. Ritchie AI, Singanayagam A. Immunosuppression for hyperinflammation in COVID-19: a double-edged sword? 2020 Mar 24 . pii: S0140-6736(20)30691-7. doi: 10.1016/S0140-6736(20)30691-7. 8. Antonio R, Silvia M, Immunosuppression drug-related and clinical manifestation of Coronavirus disease 2019: a therapeutical hypothesis. Am J Transplant. 2020 Apr 3 . doi: 10.1111/ajt.15905. 9. Bhoori S, Rossi RE, Citterio D, Mazzaferro V. COVID-19 in long-term liver transplant patients: preliminary experience from an Italian transplant centre in Lombardy. Lancet Gastroenterol Hepatol. 2020 Apr 9 . pii: S2468-1253(20)30116-3. doi: 10.1016/S2468-1253(20)30116-3. 10. Li F, Cai J, Dong NJT, Jo H. First cases of COVID-19 in heart transplantation from China. Transplantation 2020 11. Bin L, Yangzhong W, Yuanyuan Z, Huibo S, Fanjun Z, Zhishui C. Successful Treatment of Severe COVID-19 Pneumonia in a Liver Transplant Recipient. Am J Transplant. 2020 Apr 3 . doi: 10.1111/ajt.15901. 12. Chen S, Yin Q, Shi H, Du D, Chang S, Ni L, Qiu H, Chen Z, Chang J, Chang W. A familial cluster, including a kidney transplant recipient, of coronavirus disease 2019 (COVID-19) in Wuhan, China. Am J Transplant 2020; doi: 10.1111/ajt.15903. 13. Qin J, Wang H, Qin X, Zhang P, Zhu L, Cai J, Yuan Y, . Perioperative presentation of COVID-19 disease in a liver transplant. Hepatology 2020. doi: 10.1002/hep.31257 14. Ju CR, Lian QY. Recommended prophylactic and management strategies for severe acute respiratory syndrome coronavirus 2 infection in transplant recipients. Chron Dis Translat Med. 2020 15. 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A call for action. Dermatol Ther. 2020 Mar 11:e13298. doi: 10.1111/dth.13298. 21. Di Lernia V, Biologics for psoriasis during COVID-19 outbreak, J Am Acad Derm 2020, doi: https://doi.org/10.1016/j.jaad.2020.04.004. 22. PSOprotect: Psoriasis patient registry for outcomes, therapy and epidemiology of Covid-19 infection. Available at https://psoprotect.org/ 23. SECURE-AD: Atopic Dermatitis Registry for outcomes, therapy and epidemiology of Covid-19 infection. Available at covidderm.org 24. Rheum-covid: Rheumatology case registry for outcomes, therapy and epidemiology of Covid-19 infection. Available at https://rheum-covid.org/ 25. COVIDIBD: Inflammatory bowel disease case registry for outcomes, therapy and epidemiology of Covid-19 infection. Available at covidibd.org/ 26. Zhang L, Zhu F, Xie L, Wang C, Wang J, Chen R, Jia P, Guan HQ, Peng L, Chen Y, Peng P, Zhang P, Chu Q, Shen Q, Wang Y, Xu SY, Zhao JP, Zhou M. Clinical characteristics of COVID-19-infected cancer patients: A retrospective case study in three hospitals within Wuhan, China. Ann Oncol. 2020 Mar 26 . pii: S0923-7534(20)36383-3. doi: 10.1016/j.annonc.2020.03.296. 27. Guillen E, Pineiro GJ, Revuelta I, Rodriquez D, Bodro M, Moreno A, Campistol JM, Diekmann F, Case report of COVID–19 in a kidney transplant recipient: Does immunosuppression alter the clinical presentation? Am J Transplant 2 doi: 10.1111/ajt.15874