key: cord-0735138-j9xisckx authors: Kharouf, Fadi; Ishay, Yuval; Kenig, Ariel; Bitan, Menachem; Ben-Chetrit, Eldad title: Incidence and course of COVID-19 hospitalizations among patients with familial Mediterranean fever date: 2021-07-22 journal: Rheumatology (Oxford) DOI: 10.1093/rheumatology/keab577 sha: 09564ac2a5f733475c89514d6cd05b7ad17d4629 doc_id: 735138 cord_uid: j9xisckx OBJECTIVES: To evaluate the incidence of hospitalization for COVID-19 in patients with familial Mediterranean fever (FMF), as compared with the general population, and to compare the disease course between FMF inpatients, and age, sex, ethnicity, and comorbidity-matched non-FMF COVID-19 inpatients. METHODS: We used electronic medical records (EMR) to obtain data about the total number of the insured population and the number of FMF patients in the two largest health management organizations (HMOs) in Jerusalem, Clalit and Meuhedet. The total number of COVID-19 inpatients at the Hadassah Medical Center, including those with FMF, for the period between the 1 February 2020, and the 10 March 2021 was retrieved from the EMR of Hadassah. COVID-19 course was compared between the FMF inpatient group and age, sex, ethnicity, and comorbidity-matched non-FMF COVID-19 inpatients. Each FMF inpatient was matched with 2 non-FMF controls. RESULTS: We found no statistically significant difference in the odds of hospitalization for COVID-19 between FMF patients and the non-FMF population (0.46% vs 0.41%; p= 0.73). Furthermore, we found similar disease severity and therapeutic approach in FMF COVID-19 inpatients and matched non-FMF COVID-19 inpatients. CONCLUSIONS: Neither FMF, nor baseline colchicine therapy appear to affect the incidence of hospitalization for COVID-19 or the disease course, in terms of severity and therapeutic approach. pandemic proportions, affecting every facet of modern life. In most cases, COVID-19 is a mild-to-moderate illness, characterized by fever, cough, and malaise. However, in certain cases, the disease takes a more ominous course, necessitating hospitalization, respiratory support, and is potentially lethal. Whether or not patients with pre-existing autoinflammatory rheumatic diseases are at an increased risk of SARS-CoV-2 infection or of severe COVID-19 remains unknown. When SARS-CoV-2 enters the cell, the NLR Pyrin domain containing 3 (NLRP3) inflammasome is triggered via immunological mechanisms. The elevated presence of NLRP3-induced pro-inflammatory cytokines (Interleukin (IL)-1, IL-1β) in the serum of SARS-CoV-2-infected patients supports a hypothesis of innate immunity involvement in the pathogenesis and evolution of the disease 1 . Familial Mediterranean fever (FMF) is an autoinflammatory hereditary disease characterized by recurrent attacks of fever and serositis, commonly lasting 1-3 days. Its pathogenesis involves defects in the innate immune system, namely 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 enhancement of the proinflammatory effects of the Pyrin inflammasome 2 . Severe COVID-19 induces an intense inflammatory response known as 'cytokine storm' 1 , raising the question of the susceptibility and severity of SARS-CoV-2 infection in patients with a priori innate immunity disorders, such as those with FMF. Colchicine is the drug of choice for FMF treatment since 1972. It prevents acute attacks and fends off the development of amyloidosis 3 . Its anti-inflammatory mechanism is mediated by inhibition of microtubule polymerization. Microtubules play an important role in cell migration, signal transduction, and gene expression. Colchicine acts on NLRP3 and probably on the Pyrin protein, resulting in inhibition of pathways involved in cellular inflammatory signaling 4 . Since it is thought that one of the important pathogenic mechanisms of COVID-19 is through the activation of NLRP3 inflammasome, there is a rationale for considering colchicine use in this disease. Several recent reviews have discussed the role of colchicine in preventing COVID-19 complications [5] [6] [7] . However, clinical studies evaluating colchicine use Page 9 of 26 Rheumatology 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 in SARS-CoV-2-infected patients have produced conflicting results [8] [9] [10] This is a convenient sample and no power calculation was used, however statistical analyses were adjusted for the power available. Ethical approval and waiver of informed consent was sought and given by the Hadassah Medical Center Ethics Committee (0089-21-HMO). The appropriate use of statistical tests was determined by the nature of the variables and the sample size. The relation between categorial independent variables and the dichotomous outcome variable was determined using the Fisher's exact test when applied to the hospitalized patient groups, and by the chi-square test in the assessment of the odds of COVID-19 hospitalization in FMF patients. The relation between the dichotomous independent variables and non-normally distributed outcome variables was examined using the Man 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 (0.46%) were hospitalized in Hadassah. No difference in odds was detected between suffering from FMF and being hospitalized in our center due to COVID-19 (p=0.73) (Figure 1 ). We then sought to characterize the disease course in FMF patients and to detect any differences between FMF patients and a matched COVID-19 inpatient cohort. Twelve FMF patients were hospitalized in the Hadassah COVID-19 wards in the relevant period; 9 patient from the cohort and 3 additional patients from other HMOs. Twenty-four non-FMF COVID-19 inpatients matched as best possible were used as a control cohort. The groups were similar in age, gender, ethnicity, and major comorbidities. All patients were hospitalized between June of 2020 and March of 2021. Most patients (26/36, 72%) were hospitalized in the 6 months between August 2020 and January 2021. The diagnosis of amyloidosis was more prevalent in the FMF group, as expected. Table 1A summarizes the baseline characteristics of the two cohorts. Both cohorts were assessed for the prevalence of fever and respiratory symptoms (including cough and shortness of breath) during the disease, length 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 3 patients in the FMF group were being concurrently treated with anti-cytokine medications, 2 with Adalimumab and 1 with Anakinra. No patients in the control group were under anti-cytokine treatment at admission. Analysis of COVID-19 disease mechanisms suggests a central role for the hyper-activation of the innate immune system in patients, with sinister outcomes 11 . Theoretically, colchicine, by targeting intersecting pathways in the SARS-CoV-2-induced inflammatory cascade, may reduce COVID-19 hospitalization and mortality 6 . Ongoing prospective clinical studies aim to evaluate efficacy of the drug in COVID-19 7 . Preliminary results of the COLCORONA study suggest that colchicine reduces the composite rate of death or hospitalization among non-hospitalized patients with COVID-19 12 . In a randomised double-blinded, placebo-controlled clinical trial, the addition of colchicine to the standard of care (SOC) in moderate-severe COVID-19 patients resulted in a reduced length of supplemental oxygen therapy and hospitalisation 8 . Furthermore, an Italian study compared 122 Colchicine has also been suggested to protect against the acquisition of SARS- 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 cohort was similar to that of the general population. Severe disease was mainly present in those with comorbidities 15 . It is worth mentioning that anakinra (IL-1 receptor antagonist), a drug commonly used in resistant FMF, was found to reduce both the need for invasive ventilation and mortality among patients with severe COVID-19 16 Our cohort was composed of a unique Arab and Jewish population and drawn from the 2 biggest HMOs in the Jerusalem area, serving over 750,000 persons. We found no statistically significant difference in the odds of hospitalization for COVID-19 between FMF patients and the non-FMF population. We also found a similar disease course between FMF COVID-19 inpatients and well-matched COVID-19 hospitalized controls. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 All of the FMF inpatients in our cohort, except for one, were adherent to colchicine therapy. This was confirmed through a combination of direct questioning and revision of the documented recent purchases from the pharmacies. It is noteworthy that almost all ( 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Our results suggest that neither a background FMF, nor baseline colchicine therapy provide protection against COVID-19 infection or hospitalization. The disease course, in terms of severity and treatment, was similar in FMF inpatients when compared to age, sex, ethnicity, and comorbidity-matched non-FMF COVID-19 inpatients. It is interesting to note that while comorbidities and chronic immunosuppression were relatively common in our cohort, a protracted, life-threatening disease course was rare. Our study has several limitations. Firstly, the number of FMF COVID-19 inpatients in our tertiary care center during the study period was low; this is due to the fact that FMF is a relatively rare disease. Secondly, the disease course was charted only for hospitalized FMF patients and may not necessarily be generalizable to outpatients. Our relatively youthful cohort may also not be 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Figures Page 22 of 26 Rheumatology 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Abbreviations: CI, confidence interval; FMF, familial Mediterranean fever; OR, odds ratio. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Familial Mediterranean Fever and COVID-19: Friends or Foes? 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