key: cord-0832149-j32ns1o3 authors: Rezaei, Mitra; Barati, Saghar; Babamahmoodi, Abdolreza; Dastan, Farzaneh; Marjani, Majid title: The Possible Role of Bruton Tyrosine Kinase (BTK) Inhibitors in the Treatment of COVID-19: A Review date: 2021-12-15 journal: Curr Ther Res Clin Exp DOI: 10.1016/j.curtheres.2021.100658 sha: 869200e344ad332f9f1b56c78bc3df44c6884495 doc_id: 832149 cord_uid: j32ns1o3 Background The coronavirus (SARS-CoV-2) has led to a vast pandemic with an astonishing spread rate. Its treatment is unknown, its mortality is significant, and its socioeconomic complications are uncontrollable. Although there is still little known about the pathogenesis of the disease, severe cases of COVID-19 are usually associated with cytokine release syndrome and high serum levels of inflammatory cytokines, which are thought to be a major cause of mortality in these patients. Different pathways cause inflammation and the release of cytokines. One of these pathways is the Bruton Tyrosine Kinase (BTK) pathway, which is essential for the production of several anti-inflammatory cytokines. Theoretically, the inhibition of BTK signaling can reduce cytokine levels and subsequent anti-inflammatory effects. Objective This review aims to investigate the role of the BTK pathway in the pathogenesis of COVID-19 and the possible effects of its inhibition in the treatment of this disease. Methods This narrative review provides information regarding the use of BTK inhibitors in patients with COVID-19 and discusses whether clinicians should consider these medications while managing their patients based on the literature. Data was gathered using the Pubmed, Scopus, and Web of Science databases. Conclusions Some data support the use of BTK inhibitors for treating COVID-19. It is recommended that patients continue their medications in this class if they develop COVID-19 and were receiving these agents before the disease developed. The use of BTK inhibitors might enable patients to experience less severe immune responses to the SARS-CoV-2 virus. Well-designed studies are needed to evaluate the effectiveness of BTKis in the management of COVID-19. Coronaviruses are a large family of respiratory viruses that can create a wide range of illnesses, from the common cold to the Middle East respiratory syndrome (MERS) and severe acute respiratory symptoms (SARS). In late 2019, a new kind of coronavirus was named SARS-CoV-2 by the World Health Organization, and the resulting disease was called COVID-19. The condition has quickly become a pandemic and has involved almost every country in the world 1 . The pathophysiology of COVID- 19 has not yet been clearly defined. The recent evidence proposes that the excessive host immune response may play a role in the pathogenesis of the disease 2 . Severe cases of COVID-19 are usually associated with cytokines release syndrome and significant serum levels of inflammatory cytokines that are thought to be the leading cause of mortality for these patients 3 . The BTK pathway is crucial for the production of several antiinflammatory cytokines 4 , and inhibiting BTK signaling reduces cytokine levels and consequently has an anti-inflammatory effect. Impairments to BTK signal regulation in lung macrophages may be a significant pathophysiological component of SARS-CoV-2-induced lung injuries. Therefore, inhibiting the BTK pathway may reduce the excessive and harmful immune response in the severe form of COVID-19 and the respiratory complications resulting from it. Tyrosine kinase is an enzyme whose role is to transfer a phosphate group from the Adenosine Triphosphate (ATP) molecule to a protein. This enzyme acts as an "off-on" key in many cellular activities 5 . Tyrosine kinases are a subset of protein kinases whose role is to bind phosphate groups to other amino acids such as serine and threonine. The phosphate group is attached to the amino acid tyrosine in proteins, and the phosphorylation of proteins by kinases is the main stage in cell signal transduction 5 . Tyrosine kinases catalyze the phosphorylation of tyrosine residues in proteins. The phosphorylation of tyrosine residues, in turn, alters the function of proteins existing in them 6 . The phosphorylation of tyrosine residues controls a wide range of properties existing in proteins, such as enzyme activity, intracellular localization, and interactions between molecules. Moreover, tyrosine kinases are used in many signal transduction cascades in which extracellular signals are transmitted through the cell membrane to the cytoplasm and often to the nucleus, where gene expression may be modified. Finally, mutations can activate some tyrosine kinases, leading to an unstoppable functional state that may play a role in the onset or progression of cancer 7 . Tyrosine kinases are involved in various processes, pathways, and functions, and they are responsible for several critical events in the body. Receptor tyrosine kinases are involved in intermembrane signaling, while intracellular tyrosine kinases play a role in signal transmission to the nucleus. Tyrosine kinase activity in the nucleus includes cell cycle control and the properties of transcription factors. Thus, tyrosine kinase activity is involved in mitogenesis (the induction of mitosis in a cell). The proteins available in the cytosol and the nucleus are phosphorylated in the tyrosine residues during this process 7 . Bruton's tyrosine kinase (BTK) has a vital role in producing mature B cells because it is essential for the transmission of signals from the pre-B cell receptor, which is formed after the successful rearrangement of the heavy chain immunoglobulin 8 . It, also, has a role in the activation of mast cells via IgE receptor with high affinity 9 . Btk contains a pleckstrin-homology domain that binds trisphosphate (PIP3-3,4,5) to phosphatidylinositol. Binding Btk induces PIP3 to phosphorylate phospholipase C., which in turn hydrolyzes PIP2 (an inositol phosphatidyl) to the two-second messengers, inositol triphosphate (IP3), and diacylglycerol, which subsequently regulates the activities of the downstream proteins in B cell 9 . Nicolson et al. showed that the use of tyrosine kinase inhibitors can simultaneously reduce clotting and inflammatory responses effectively 10 . It has also been observed in influenza mouse models that BTK inhibitors (BTKis) can save mice from acute fatal lung injuries. Sick mice with respiratory failure who had not received the medication were in complete contrast to mice receiving ibrutinib according to tomography and histology findings compatible with lung injury. The control mice lost weight and died, while all ibrutinib-treated mice regained their weight and survived. The main point was that decreased infiltration of inflammatory cells; proinflammatory cytokines; and chemo-attractants such as IL-1b, IL-6 KC / CXCL1, TNF-a, and MCP-1, were observed in the lung tissues of mice treated with ibrutinib 11 . The serum samples collected from patients with chronic lymphocytic leukemia (CLL), Waldenström's macroglobulinemia (WM), and chronic graft versus host disease (GVHD) after ibrutinib monotherapy indicated significant reductions in proinflammatory cytokines and chemo-attractants, which are highly present in the lungs of SARS-CoV-2 and SARS-CoV-1 patients 12 . Therefore, the dysregulation of the BTK signal in lung macrophages may be a leading pathophysiological component of SARS-CoV-2related lung damage 13 . Thus, inhibiting the BTK pathway could reduce the excessive and inappropriate immune response associated with severe COVID-19 and prevent related respiratory complications. In a review article written by Otsuka and Senio, the authors suggest treating COVID-19 patients upon the administration of BTKis 14 . Figure 1 shows the proposed role of BTK pathway in COVID-19. Ibrutinib is available as an oral once-daily formulation and is approved to treat CLL, WM, marginal zone lymphoma, and chronic GVHD 23 . Acalabrutinib (a second-generation BTKi) was approved in October 2017 to treat recurrent mantle cell lymphoma; also, 95% improvement has been reported regarding its use for recurrent Acalabrutinib is available as a twice-daily oral formulation. Zanubrutinib is a second-generation BTK inhibitor recommended to treat mantle cell lymphoma and can be taken orally after using another BTKi family drug. It is believed that zanubrutinib has fewer toxicities than the first-generation class 27 . There is currently one clinical trial evaluating the effectiveness of zanubrutinib in COVID-19 hospitalized patients (NCT04382586) 28 . Zanubrutinib is available as an oral formulation that can be administered once or twice daily. We believe that ibrutinib may be associated with better patient adherence considering its oncedaily dosing. However, its use may be associated with more severe adverse effects. Zanubrutinib is also available as a once-daily formulation. Moreover, fewer adverse effects may be developed regarding its use, as it is a second-generation BTKi. It is recommended to wait for the results of ongoing clinical trials before making a firm choice among these agents for treating COVID-19. The use of first-generation BTKis (ibrutinib) is associated with bleeding disorders, infections, atrial fibrillation, and diarrhea. Contrarily, second-generation BTKis are associated with less toxic side effects than ibrutinib 23 . The second-generation BTKis (acalabrutinib and zanubrutinib) were designed to increase efficacy and reduce adverse events. It is noteworthy that the use of BTKis requires careful consideration of their effects on the host's immune system. A high rate of serious infectious complications has been identified following their use in some prospective clinical trials in cancer patients. In one study, infectious complications occurred in 56% of patients who received ibrutinib alone and 52% of those who received a combination treatment including ibrutinib. Approximately one in five patients developed pneumonia, which was the leading cause of death due to infection. Many cases of pneumonia occurred due to opportunistic factors 29 . However, these adverse effects are primarily reported in cancer patients. Considering the short-term course of treatment of these agents in COVID-19, the significance of these adverse effects is not especially prominent. Table 1 summarizes the mentioned BTKis' characteristics and the ongoing clinical trials evaluating their effects in COVID-19 patients. As the number of COVID-19 patients being treated with BTKis increases, the prospective continuation or discontinuation BTKis should be considered in these patients. During the outbreak of COVID-19, the risk of increased secondary infections and impaired humoral immunity due to decreased B-cell activity regarding using these agents might favor discontinuing BTKis. However, the potential benefits of reducing the severe inflammatory reaction due to SARS-CoV-2 by weakening macrophage tendency to M1 status seem to outweigh the potential risk of humoral immunodeficiency. Despite the increased risk of secondary infections, it is recommended that BTKis are continued in patients with COVID-19 and cancer 30 . Another point to consider is that BTKis are not evaluated as monotherapy of COVID-19 management regardless of the patients' comorbidities. Hence, they should not be used in this regard. In a study conducted by the CLL Association, there was a conflict among CLL experts regarding the administration of BTKis: 40% of the experts agreed with the continuation of BTKis, while the other 60% believed that they should be discontinued in COVID-19 patients or continued only in specific clinical scenarios. The potential protective anti-inflammatory effects of the BTK inhibitors against the theoretical risk of suppressing the humoral immune system have to be considered to ensure the right decision is made 31 . In a study conducted on eight patients with CLL and COVID-19 at the same time, it was shown that despite these patients' immune disorders, the administration of BTKis led most of them to be discharged from the hospital and reduced the need for their admission to the intensive care unit (ICU) 16 . Also, in a study conducted by Chong et al. on patients with concomitant cancer and SARS-CoV-2 infection, it was suggested that despite the increased infection rate in these patients, continuing treatment with tyrosine kinase inhibitors should be considered 15 . In another meeting held to decide the best treatment for patients with WM during the COVID-19 pandemic, it was recommended that treatments with tyrosine kinase inhibitors should be continued even if the patient is utilizing other forms of therapy and had COVID-19 31 . BTK plays an essential role in the activation of B-cells and without its activation, these cells would not be able to play an appropriate role in immune reactions. BTK also plays a role in macrophage function as well. In COVID-19 disease, the over-activation of immune cells causes the overproduction of cytokines, resulting in cytokine storms. This phenomenon increases the severity of the disease and can lead to acute respiratory distress syndrome (ARDS). The use of BTKis can help patients experience less severe responses to the SARS-CoV-2 virus and overcome the disease by inhibiting this process. Well-designed studies, especially multicentered double-blind clinical trials, are needed to evaluate the effectiveness of BTKis in the management of COVID-19. Currently, we have to wait for the results of ongoing clinical trials before making any firm treatment decisions. None. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. 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