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      The BTK inhibitor ibrutinib may protect against pulmonary injury in COVID-19–infected patients

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          Abstract

          TO THE EDITOR: The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is used to treat indolent B-cell malignancies and chronic graft-versus-host disease (cGVHD). The potential for ibrutinib to abrogate pulmonary inflammatory cytokines, lung injury, and death was demonstrated in a highly relevant lethal flu animal model. 1 Therefore, we sought to clarify the impact of ibrutinib in COVID-19 patients. We care for 600 to 800 Waldenstrom macroglobulinemia (WM) patients each year, ∼300 of whom are on a BTK inhibitor. We identified 6 patients receiving ibrutinib for WM who were diagnosed with COVID-19; these patients consented to the use of their data. Their clinical characteristics appear in Table 1. Their median age was 66 years, and 5 were on the recommended treatment dose of 420 mg/d; the sixth patient was on a reduced dose of 140 mg/d because of arthralgias. For all patients, the median time on ibrutinib was 52 months. Their median time with COVID-19–related symptoms prior to diagnostic testing was 5 days, and the median time since diagnosis of COVID-19 was 22 days. All 6 patients experienced cough and fever as prodromal symptoms. The 5 patients on ibrutinib, 420 mg/d, did not experience dyspnea and did not require hospitalization. Their course was marked by steady improvement, and resolution or near resolution of COVID-19–related symptoms during the follow-up period. Table 1. Clinical characteristics of 6 patients with WM on ibrutinib with COVID-19 infection Demographics Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Age, y 65 61 72 67 71 58 Sex M M F F M M Time since B-cell diagnosis, mo 39 54 95 202 52 107 Received treatment prior to ibrutinib for WM No No Yes Yes No Yes Time on ibrutinib, mo 39 54 83 50 47 85 Dose of ibrutinib, mg/d 420 420 420 420 420 140-HELD-420 COVID-19 symptoms  Time with symptoms prior to COVID-19 diagnostic testing, d 5 2 6 7 10 5  Time since COVID-19 diagnostic testing, d 24 20 17 28 13 29  Cough Yes Yes Yes Yes Yes Yes  Fever Yes Yes Yes Yes Yes Yes  Dyspnea No No No No No Yes  Sore throat Yes No No No No Yes  Taste loss No No Yes No Yes No  Smell loss No No Yes No Yes No  Hospitalization No No No No No Yes  Required ICU admission Yes No No No No Yes  Required supplemental O2 No No No No No Yes  Required mechanical ventilation No No No No No Yes  Other COVID-19 symptoms No Anorexia Diarrhea Headache No No  Other medication for COVID-19 HCQ, AZ NA No NA No HCQ, AZ, TOCI Disposition  COVID-19 symptoms resolved No Yes Yes Yes Yes No  COVID-19 symptoms persist Yes No Yes Yes No Yes  COVID-19 symptoms improved Yes Yes Yes Yes Yes Yes 140-HELD-420 denotes that this patient was on 140 mg/d of ibrutinib prior to hospitalization that was held upon admission; he experienced worsening hypoxia after ibrutinib was held and required mechanical ventilation, following which he was restarted on 420 mg/d of ibrutinib and showed rapid improvement in oxygenation. AZ, azithromycin; F, female; HCQ, hydroxychloroquine; ICU, Intensive Care Unit; M, male; TOCI, tocilizumab. The patient on reduced-dose ibrutinib (Patient 6; Table 1) experienced progressive dyspnea and hypoxia prompting hospitalization. Chest computed tomography showed bilateral ground glass opacities and a pleural effusion on admission prompting a hold on ibrutinib, during which his hypoxia acutely worsened, necessitating supplemental oxygen use. Hydroxychloroquine (HCQ) and azithromycin were administered. Azithromycin was stopped after 3 days because of wide QRS complex tachyarrhythmia; HCQ was given for a total of 5 days. Hypoxia worsened and fever persisted during HCQ course. Ibrutinib was restarted at 140 mg/d, and tocilizumab, 400 mg, was coadministered on hospital day 5 with improved oxygenation, as well as decreased C-reactive protein (CRP) levels (83 mg/L to 9 mg/L). IV immunoglobulin was also given on hospital days 6 through 10. On day 10 of hospitalization, the patient experienced worsening hypoxia that was accompanied by increased CRP (28 mg/L) and required mechanical ventilation. Given the lack of hypoxia in the other COVID-19–infected WM patients on full-dose ibrutinib, ibrutinib was increased to 420 mg/d on days 11 and 12. A rapid improvement in oxygenation followed, and the patient was successfully extubated late on day 12 and maintained oxygen saturations of 94% to 96% on 3 L/min supplemental oxygen by nasal cannula. The next day, supplemental oxygen was decreased to 2 L/min, with oxygen saturations of 96% to 98% and a CRP level of 10 mg/L. On day 14, oxygen saturation was 95% on room air, repeat CRP level was 6 mg/L, and he was discharged home off supplemental oxygen and on 420 mg/d of ibrutinib. Seven days later, he continues to do well, without fever, cough, or dyspnea at rest. He remains on ibrutinib, 420 mg/d, and is tolerating therapy well. Pulmonary failure is the main cause of mortality related to COVID-19 infection. 2,3 Up to 80% of patients hospitalized for COVID-19 infection require supplemental oxygenation, of whom 30% to 40% may require mechanical ventilation. 2,4,5 SARS-CoV-2 binds via the ACE2 receptor that is highly expressed on alveolar type II (ATII) cells in the lung. 6 ATII cells constitute 5% to 15% of the lung epithelium. Although ATI cells are highly adapted for gas exchange, ATII cells have a specialized role in innate immune response. 7 -9 ATII cells express Toll-like receptors (TLRs) and can trigger inflammatory cytokines and chemoattractants in response to pathogens that recruit and activate other immune cells, including macrophages and neutrophils. 7 -9 Highly relevant to coronavirus infection, expression of proinflammatory and chemoattractant cytokines interleukin-1β (IL-1β), IL-6, IP-10/CXCL10, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-α (TNF-α) was identified in ACE2+ cells from autopsy tissue of SARS-CoV-1–infected patients, which appeared to be causally related to the acute lung injury and pathogenesis observed with SARS-CoV-1. 10 A similar profile of elevated cytokine levels was reported in the plasma of SARS-CoV-1 patients during the progressive and end stage of infection, 11 which was consistent with an M1-polarized macrophage response. 12 SARS-CoV-1 shares 86% homology with SARS-CoV-2. SARS-Cov-2 patients requiring intensive care also showed elevated plasma levels of inflammatory cytokines and chemoattractants, such as IL-2, IL-6, IL-7, IL-10, granulocyte colony-stimulating factor, IP-10/CXCL-10, MCP-1/CCL2, MIP-1a/CCL3, and TNF-α. 13 The importance of inflammatory cytokines to lung injury in SARS-CoV-2–infected patients has been suggested by reports of benefit with IL-6 and IL-6 receptor–blocking antibodies, and clinical trials to examine their use have been initiated (NCT04317092, NCT04306705, NCT04315298). We and other investigators previously showed that BTK and its upstream activator HCK were involved in TLR-mediated signaling. 14 -16 BTK and HCK are triggered by MYD88, a TLR adaptor protein that signals for all TLRs, with the exception of TLR3, in response to viral and bacterial pathogens, including coronaviruses. 17 ATII cells express TLRs, as do alveolar macrophages that coordinate inflammatory responses with ATII cells. 7 -9 As components of TLR/MYD88 signaling, BTK and HCK can drive inflammatory cytokine production through ERK1/2. 18 In a transgenic mouse model, activated HCK overexpression promoted extensive pulmonary inflammation and an enhanced innate immune response, particularly in older mice. 19 Elevated levels of TNF-α were identified in the bronchoalveolar lavage fluids of these mice following lipopolysaccharide challenge. The pulmonary pathology findings from these mice show great overlap with those from patients with COVID-19 infection, which included serous and fibrin exudation with alveolar infiltration consisting mostly of macrophages and monocytes. 20 Ibrutinib is a highly potent covalent inhibitor of BTK (biochemical 50% inhibitory concentration [IC50], 0.5 nM). Ibrutinib is also a potent reversible inhibitor of HCK (IC50, 49 nM). The IC50 levels for BTK and HCK are within the pharmacologically attainable dosimetry of orally administered ibrutinib. 16 Serially collected blood samples from patients with chronic lymphocytic leukemia (CLL), WM, and cGVHD on ibrutinib monotherapy showed marked reductions in proinflammatory and chemoattractant cytokines that greatly overlapped with those reported to be elevated in the plasma of SARS-CoV-1 and SARS-CoV-2 patients, as well as in ACE2+ cells from lung tissue of SARS-CoV-1 patients (Table 2). 10,11,13,21 -23 In the ILLUMINATE randomized study, CLL subjects treated with ibrutinib immediately prior to infusion with obinutuzumab also showed significantly decreased levels of inflammatory cytokines associated with infusion-related reactions (a cytokine release syndrome). 24 These findings are consistent with a shift from an M1- to an M2-polarized macrophage response following ibrutinib and are supported by preclinical and clinical studies showing dependence of macrophage lineage commitment on BTK function. 25 Table 2. Summary of proinflammatory and chemoattractant cytokine patterns in patients infected with SARS-CoV-1 and SARS-CoV-2 and following ibrutinib treatment in patients with CLL, WM, or and cGVHD He et al 10 Jiang et al 11 Huang et al 13 Niemann et al 21 Greil et al 24 Vos et al 22 Miklos et al 23 Patient population CoV-1* CoV-1* CoV-2* CLL on ibrutinib† CLL on ibrutinib† WM on ibrutinib† cGVHD on ibrutinib† Tissue ACE2+ cells Plasma Plasma Plasma Plasma Plasma Plasma GM-CSF ↑ ↓ IL-1β ↑ IL-2 ↑ ↓ (IL2RA) IL-6 ↑ ↑ ↓ ↓ ↓ IL-7 ↑ IL-8 ↑ ↓ ↓ ↓ ↓ IL-10 ↑ ↓ ↓ Variable IP-10/CXCL10 ↑ ↑ ↓ ↓ ↓ MCP-1/CCL2 ↑ ↑ ↑ ↓ ↓ ↓ MIP-1A/CCL3 ↑ ↓ ↓ MIP-1B/CCL4 ↑ ↓ ↓ ↓ TNF-α ↑ ↓ ↓ ↓ ↓ ↑, denotes elevated in patients with SARS-CoV-1 or SARS-CoV-2; ↓, denotes levels decreased or inhibited in patients with the indicated condition with ibrutinib treatment; GM-CSF, granulocyte-macrophage colony-stimulating factor. * Patients infected with SARS-CoV-1 or SARS-CoV-2. † Patients with CLL, WM, or cGVHD. The potential for ibrutinib to abrogate lung injury and death was also demonstrated in an experimental model wherein mice challenged with a lethal intranasal inoculum of a mouse-adapted strain of H1N1 influenza virus were protected against lung injury. Control mice developed respiratory failure, along with histological and computed tomography findings consistent with lung injury, in sharp contrast to the mice that received ibrutinib. 1 Control mice also lost weight and died, whereas those treated with ibrutinib recovered their weight after a brief loss, and all survived. 1 Notably, mice treated with ibrutinib also showed decreased inflammatory cell infiltration, as well as proinflammatory cytokines in lung tissues, that included proinflammatory and chemoattractant cytokines, such as IL-1β, IL-6, KC/CXCL1, TNF-α, and MCP-1, in SARS-Cov-1 and SARS-CoV-2 patients. 1 The findings provide rationale that an exaggerated cytokine release syndrome triggered in ATII cells and resident macrophages by SARS-CoV-2 may underlie pulmonary injury associated with COVID-19. Therefore, ibrutinib, and possibly other BTK inhibitors, may provide protection against lung injury and even improve pulmonary function in hypoxic patients with COVID-19, as we observed in this series of WM patients on ibrutinib. These findings should be considered hypothesis generating and preliminary in nature. Patients on ibrutinib, and possibly other BTK inhibitors, may well benefit with continuation of their therapy, despite the diagnosis of COVID-19. It will be important to validate these findings in other patient populations who are taking BTK inhibitors, including CLL patients. Clinical trials examining the benefit of BTK inhibitors are being initiated by us and other investigators in COVID-19 patients in pulmonary distress, and the outcome of these prospective randomized studies will be needed to confirm these preliminary observations.

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          Most cited references 21

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          Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

          Summary Background A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. Methods All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by WHO and the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. Findings By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0–58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0–13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. Interpretation The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. Funding Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.
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            Characterization of cytokine/chemokine profiles of severe acute respiratory syndrome.

             S. Zhong,  PENG DENG,  Q Qin (2005)
            There is currently no optimal treatment or effective drug for severe acute respiratory syndrome (SARS), because the immunopathologic mechanism is poorly understood. To explore the immune mechanism underlying the pathogenesis of SARS, we studied the expression profile of cytokines/chemokines in the blood and the immunopathology of the lung and lymphoid tissues. Fourteen cytokines/chemokines in the blood of 23 patients with SARS were dynamically screened, using a bead-based multiassay system. Reverse transcription-polymerase chain reaction was performed to amplify mRNA. Histopathology of the lung and lymphoid tissues at autopsy was examined, using methods of immunohistochemistry and double immunofluorescence staining. Interferon-inducible protein-10 (IP-10) was markedly elevated in the blood during the early stage of SARS, and remained at a high level until convalescence. Moreover, IP-10 was highly expressed in both lung and lymphoid tissues, where monocyte-macrophage infiltration and depletion of lymphocytes were observed. The levels of interleukin-6, interleukin-8, and monocyte chemoattractant protein-1 were concomitantly increased in the blood of the patients with superinfection, and the mRNAs for these cytokines were also increased in lung tissues. Induction of IP-10 is a critical event in the initiation of immune-mediated acute lung injury and lymphocyte apoptosis during the development of SARS. Superinfection after the immune injury is the main cause of death. The prompt elevation of interleukin-6, interleukin-8, and monocyte chemoattractant protein-1 is a sign of superinfection, indicating a high risk of death.
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              A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenström macroglobulinemia.

              Myeloid differentiation factor 88 (MYD88) L265P somatic mutation is highly prevalent in Waldenström macroglobulinemia (WM) and supports malignant growth through nuclear factor κB (NF-κB). The signaling cascade(s) by which MYD88 L265P promotes NF-κB activation in WM remain unclear. By lentiviral knockdown or use of a MYD88 inhibitor, decreased phosphorylation of the NF-κB gatekeeper IκBα and survival occurred in MYD88 L265P-expressing WM cells. Conversely, WM cells engineered to overexpress MYD88 L265P showed enhanced survival. Coimmunoprecipitation studies identified Bruton tyrosine kinase (BTK) complexed to MYD88 in L265P-expressing WM cells, with preferential binding of MYD88 to phosphorylated BTK (pBTK). Increased pBTK was also observed in WM cells transduced to overexpress L265P vs wild-type MYD88. Importantly, MYD88 binding to BTK was abrogated following treatment of MYD88 L265P-expressing cells with a BTK kinase inhibitor. Inhibition of BTK or interleukin-1 receptor-associated kinase 1 and 4 (IRAK-1 and -4) kinase activity induced apoptosis of WM cells, and their combination resulted in more robust inhibition of NF-κB signaling and synergistic WM cell killing. The results establish BTK as a downstream target of MYD88 L265P signaling, and provide a framework for the study of BTK inhibitors alone, and in combination with IRAK inhibitors for the treatment of WM.
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                Author and article information

                Journal
                Blood
                Blood
                bloodjournal
                blood
                Blood
                Blood
                American Society of Hematology (Washington, DC )
                0006-4971
                1528-0020
                21 May 2020
                17 April 2020
                21 May 2020
                : 135
                : 21
                : 1912-1915
                Affiliations
                [1 ]Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston, MA;
                [2 ]Department of Medicine, Harvard Medical School, Boston, MA;
                [3 ]Lymphoproliferative Disorders Program, Novant Health, Charlotte, NC; and
                [4 ]Massachusetts General Hospital, Boston, MA
                Article
                2020/BLD2020006288
                10.1182/blood.2020006288
                7243149
                32302379
                © 2020 by The American Society of Hematology
                Page count
                Pages: 4
                Product
                Funding
                Funded by: National Institutes of Health;
                Categories
                8
                29
                34
                Letter to Blood
                Custom metadata
                free

                Hematology

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