Primary Immunodeficiency during COVID-19: Can Colchicine Play a Role in This Overlooked Population?

Abstract

On July 30 the COVID-19 pandemic expanded to over 17 million cases and over 660 thousand deaths worldwide (Dong et al., 2020). High-risk populations include people older than 65 years, with comorbidities such as hypertension, diabetes, chronic pulmonary disease, and immunocompromised patients (Sokolowska et al., 2020). Primary immunodeficient patients have been identified as a high-risk population for infectious diseases including viral infections (Sokolowska et al., 2020) and severe COVID-19 (Wang et al., 2020). However, the SARS-CoV-2 infection and the course of the disease in these patients is not well known (Gao et al., 2020;Shaker et al., 2020). The impact of tailored healthcare on these patients for COVID-19 has not been stablished (Waltuch et al., 2020; Zhong et al., 2020). Although immunoglobulin replacement protects them against various types of infections, its role against COVID-19 is not guaranteed (Waltuch et al., 2020) because of the lack of SARS-CoV-2 specific antibodies (Sanders et al., 2020). Furthermore, it remains unclear if immunomodulation could play a role in immunodeficient patients (Waltuch et al., 2020;Zhong et al., 2020) or in multisystem inflammatory syndrome in children (MIS-C) (Waltuch et al., 2020;Yáñez et al., 2020b).

The COVID-19 pandemic burden has called for urgent therapeutic solutions in treating infected patients (Sanders et al., 2020). However, its poorly understood pathophysiological process remains a therapeutic challenge, especially in high risk populations as primary immunodeficiency patients (Sanders et al., 2020). Various specific and unspecific targets for SARS-CoV-2 are currently been evaluated in various preclinical and clinical studies. Some of the relevant targets include anti IL-6R antibodies, IL-1 R antagonists, JAK-STAT inhibitors, CD147 antibodies, convalescent plasma, eculizumab targeting complement C5, immunomodulators and anti-inflammatory drugs (Sanders et al., 2020). However, the inclusion of primary immunodeficiency patients is not part of the drug development paradigm. Colchicine is a drug used in various auto-inflammatory disorders such as Familiar Mediterranean Fever and Bechet disease (Maggiore and Manenti, 2020) that have a close correlation with primary immunodeficiency (Savic et al., 2020). The mechanism of action of colchicine is based on counteracting the assembly of the NLRP3 inflammasome and mitigating the interleukin activation (Deftereos et al., 2020) and potentially preventing the cytokine storm (Montealegre-Gómez et al., 2020) via presumably the viroporin E (Castaño-Rodriguez et al., 2018). Four (4) randomized clinical trials are in progress to assess colchicine efficacy in COVID-19 patients administered alone or in combination with Lopinavir/Ritonavir (Deftereos et al., 2020). However, these Phase 2 and Phase 3 clinical trials do not include primary immunodeficiency patients.

Brazil is currently the second country in the world with the highest number of confirmed COVID-19 with over 2 million cases (Dong et al., 2020). Even though there is no clear data of the total burden of primary immunodeficient patients in Brazil, it is estimated that 160,000 cases can be accounted for (Carneiro-Sampaio et al., 2013). Challenges in clinical diagnosis and auxiliary methods for primary immunodeficiencies have historically been a problem, but also in the treatment of these patients in both the public and private sectors specially in Latin America (Costa-Carvalho et al., 2017). The latter has become more evident during the COVID-19 pandemic where special care protocols for patients with immunodeficiencies are needed. However, clinics currently are focused in performing PCR tests, blood testing for antibodies, CT-scans, and consultation visits of COVID-19 confirmed or suspected cases. Thus, an immunocompromised patient would not be able to go to a regular clinic nowadays because the risk would be too high (Shaker et al., 2020).

Because of the deep concern in these patients, in our clinic in Brazil we have implemented telemedicine to monitor and continue their treatment. However, in-office consultations are still necessary to attend certain cases and because of this we have implemented strict in-office protocols. Our healthcare workers involved in the care of patients with immunodeficiencies must follow rules of behavior and social responsibility to avoid the spread of the virus. Furthermore, our healthcare workers undergo constant training to answer all their COVID-19 related concerns and provide psychological support when needed in order to avoid anxiety, distress and intention to change jobs (Yáñez et al., 2020a). We are also in the approval stage of a Phase 3 clinical trial in Brazil to evaluate effect of colchicine in COVID-19 patients (n=200). We are also in discussion with the Brazilian authorities to start a clinical trial that includes primary immunodeficient and COVID-19 concomitant patients in order to better understand the course of the disease in this population and assess potential immunomodulating treatments. The COVID-19 pandemic is a deep concern for the primary immunodeficient patients, we urge to re-evaluate their inclusion in COVID-19 clinical trials, and to pay closer attention to their proper care, treatment and monitoring in clinics. This is the right time to not overlook this neglected high-risk population in order to offer them opportune, secure and quality care.

Note: Funding: None to declare

Declaration of Interest: None to declare

Keywords: COVID-19, SARS-CoV-2, colchicine, primary immunodeficiency, Brazil