key: cord-0981695-7v3p97kk authors: Hayek, Maroun E.; Mansour, Michael; Ndetan, Harrison; Burkes, Quentin; Corkren, Robert; Dulli, Ammar; Hayek, Reya; Parvez, Karim; Singh, Satwinder title: Anti-Inflammatory treatment of COVID-19 pneumonia with tofacitinib alone or in combination with dexamethasone is safe and possibly superior to dexamethasone as a single agent in a predominantly African American cohort date: 2021-03-27 journal: Mayo Clin Proc Innov Qual Outcomes DOI: 10.1016/j.mayocpiqo.2021.03.007 sha: dafd40548edd940ed2430341bc815a2b1f36dcba doc_id: 981695 cord_uid: 7v3p97kk Objective To explore the survival benefit of tofacitinib in addition to dexamethasone in hospitalized patients treated for COVID-19 pneumonia. Patients and methods Single center retrospective observational study. All patients hospitalized, at Delta Regional Medical Center, regional hospital in the Mississippi Delta, with a COVID-19 diagnosis and discharged between March 1st and September 30th, 2020 are included. The primary outcome was in-hospital mortality in relation to receipt of tofacitinib alone or in addition to dexamethasone (designated as the Tofacitinib Group), vs dexamethasone alone (designated as the Dexamethasone Group). Results Of 269 eligible patients, 138 (51.3%) received tofacitinib uniformly and 131 (48.7%) patients received dexamethasone without tofacitinib. A total of 44 patients expired: 14 (31.82%) in the Tofacitinib Group and 30 (68.18%) in the Dexamethasone Group. The proportions of death among the Tofacitinib and Dexamethasone groups were respectively, 10.14% and 22.90%. This represents a 70% reduction in odds of dying among the Tofacitinib group compared to the Dexamethasone group after adjusting for age and clinical parameters captured at hospitalization (adjusted odds ratio=0.30, 95% confidence interval =0.12-0.76; p=0.01). Conclusions The in-patient treatment of COVID-19 pneumonia has rapidly evolved. The addition of dexamethasone has made a relevant improvement on survival. Other immunomodulators are yet to show an impact. Here we present the potential survival benefit of the JAK-STAT inhibitor tofacitinib on COVID-19 pneumonia. We found that adding tofacitinib based anti-inflammatory therapy to a treatment regimen including dexamethasone in COVID-19 pneumonia seems to have potential benefit of improving survival when compared to dexamethasone alone. Initial identification of COVID-19 pneumonia in this community established the imperative for a committed, science-based, uniform approach to maximize survival of our patients. A COVID-19 committee comprised of physicians, pharmacists, nursing, and administrative staff was assembled. This committee was charged with ongoing implementation and adjustments of COVID-19 pneumonia therapies based on the most current experiences of colleagues around the United States, published COVID-19 pneumonia data and guidelines coupled to ongoing monitoring of patients' well-being and outcome. This is a retrospective analysis of our experience treating COVID-19 pneumonia based on the usage of two anti-inflammatory therapies, tofacitinib and/or dexamethasone. Institutional Review Board (IRB) approval was granted by WCGIRB 1-1365705-1. Regimen development: The first autopsy series of COVID-19 deaths by Fox et al 18 documented three critical findings in lung parenchyma: viral cytopathic effect with intracellular small vesicles likely representing viral inclusions of unknown infectivity potential, florid lymphocytic inflammation, and diffuse capillary microthrombi. Coupled with the publication by Mehta et al 19 that points to control of the cytokine storm as key in dampening the rampant inflammation, these papers were instrumental in helping to formulate a treatment approach. We concluded that an upfront comprehensive regimen based on the combination of antiviral therapy, anti-inflammatory and anticoagulation therapy was needed to control the disastrous disease progression. The use of steroids in April 2020 was strongly discouraged by the World Health Organization guidelines 20 and published reviews 21 . The four Janus kinase (JAK) receptors present on, among others, the surface of immune cells, will phosphorylate and activate signal transducers and activators of transcription (STATs) which in turn will modulate gene expression responsible for the production of numerous cytokines as interleukin (IL) 2, IL-4, IL-6, IL-7, IL-9, IL-10, IL-11, IL-15, IL-21 and IL-22 22 . Tofacitinib, a nonspecific JAK-STAT inhibitor, is a potent immunomodulator approved as second line therapy for several autoimmune diseases 23 . By blocking this pathway, the production and serum levels of all these cytokines are significantly reduced. It is pertinent to note that the production of other cytokines such as IL-1, IL-17, IL-18, TGFβ and TNF is not affected by this pathway 22 . The successful treatment outcome of S. Najjar 24 (personal communication) with the usage of tofacitinib in moderate to severe COVID-19 pneumonia amongst his patients was key in the adoption of anti-inflammatory therapy upfront. Tocilizumab (an IL-6 inhibitor) and tofacitinib were examined at the time. However, with more than 50 cytokines involved in the inflammatory pathway 25 , it was believed early on, and later documented, that the cytokine mediated inflammatory response is central to the pneumonitis pathophysiology. 19, 26, 27 It was J o u r n a l P r e -p r o o f concluded that rather than targeting one chemokine versus another (tocilizumab for IL-6 or Anakinra for IL-1), tofacitinib was a more reasonable choice due to its broad spectrum at cytokine production inhibition. Regarding the black box warning of Tofacitinib 23 in relation to malignancies, hypercoagulability, and immunosuppression, it was concluded that seven days of an FDA approved anti-inflammatory drug was unlikely to cause a malignancy risk. All patients were anticoagulated during hospital stay and at discharge; therefore, the clotting issue was of little concern. As to the infectious risk, all patients were screened for human immunodeficiency virus, viral hepatitis, and tuberculosis by QuantiFERON, and broad antibiotic coverage with azithromycin and ceftriaxone was instituted from day one. As the RECOVERY trial 2 was published in July 2020 proving a survival benefit for dexamethasone as an anti-inflammatory in COVID-19, we stopped using tofacitinib as the primary anti-inflammatory and adopted dexamethasone. Regimen implementation and evolution: The patient cohort was a single center experience comprised of patients from Delta Regional Medical Center. This is an intent to treat analysis. All patients admitted for COVID-19 related hypoxemia and discharged by September 30 th , 2020 were included, regardless of time of death. (Figure 1 ). A total of 326 patients were eligible. Nine patients with repeat admissions were counted only once (If expired, then death was counted, if not, only one admission was counted). Fifty-seven patients while COVID-19 positive had no hypoxemia and no evidence of inflammation, and therefore never treated with dexamethasone and/or tofacitinib were not included. For the 269 remaining, most patients were admitted for COVID-19 pneumonia from the emergency room. Our admitting criteria were hypoxemia on room air with oxygen saturation < 93% documented in emergency department with bilateral J o u r n a l P r e -p r o o f chest infiltrates on X ray or computed tomography (CT) scan. For patients that arrived by ambulance on oxygen, we did not record oxygen saturation on room air. Other admission criteria were prerenal azotemia from severe diarrhea or rhabdomyolysis that was occasionally present. Polymerase chain reaction (PCR) results, at times, took several days to be reported. Per treatment protocol, based on the fundamental principle of early intervention, treatment was not delayed when the evaluating physician diagnosed presumptive COVID-19 pneumonia. Sixty-five of these patients had their PCR testing done at outside institutions. All but nine were traced and proven positive. Of the nine remaining, no PCR test could be traced. All were documented positive in the admitting notes, and had bilateral typical chest CT findings with hypoxemia, elevated C Reactive Protein (CRP) and hyperferritinemia. Of these, five had follow-up positive IgG to SARS-CoV2. Of the remaining four patients, one live patient in the Tofacitinib group could not be reached, one in the dexamethasone group had expired, and two in Tofacitinib group had expired. They were included in the analysis. In addition to appropriate supportive care, all admitted patients for COVID-19 induced hypoxemia or severe inflammation as noted by CRP > 50 mg/dl or Ferritin > 500 ng/ml received uniformly, the full regimen, immediately on admission, whether patients required supplemental nasal oxygen, high flow oxygen or intubation. This decision was based on our conclusion that the need for hospital admission was, by itself, a significant severity factor, coupled with our incapacity to identify those that would deteriorate. All admitted patients had their infectious aspect of the disease managed exclusively by Dr Singh and their coagulation and inflammatory aspects by Dr. Hayek. Antiviral therapy included the combination of Hydroxychloroquine, Azithromycin and Zinc and subsequently changed to Remdesivir as it became available. As many of our patient population had a GFR < 31 ml/mn where Remdesivir usage is cautioned 28 , we opted to treat with 200 mg IV on arrival and 100 mg IV every 48 H J o u r n a l P r e -p r o o f for 3 to 4 doses. The determination was made considering Remdesivir and its active metabolite are approximately 74% renally eliminated, the available formulations contain relatively low concentrations of Sufobutylether-Bcyclodextrin as a carrier and the duration of treatment was 10 days or less. Regarding anticoagulation, patients received a therapeutic dose of Apixaban or Enoxaparin. Unless contraindicated, patients were discharged on therapeutic Apixaban for a total of 4 weeks from admission, to be followed by Aspirin at 81 mg per day for 3 to 4 months aiming at reducing delayed vascular events from both the viral infection 29 and the patient's own risk factors 30 . For anti-inflammatory therapy, we went through three separate phases. 2.a Phase one: April 14 until end of June 2020 We started tofacitinib 10 mg PO BID for 5 days. As we grew comfortable in its usage and noticed the need for extended therapy, we extended its usage up to 14 days. In intubated patients, when possible, a nasogastric tube was placed and tofacitinib was administered after being crushed by the pharmacy in compliance with regulatory requirement for handling this drug category. As the medical news started reporting on the RECOVERY trial results 2 many of our patients started receiving, upon arrival to the emergency room, one or two doses of dexamethasone in addition to tofacitinib. Recognizing that a new standard of care was established by RECOVERY 2 , the COVID-19 hospital committee amended the regimen to uniformly cease the usage of tofacitinib and replace it with dexamethasone at 10 mg IVP for 5 to 10 days. 2.c Phase three: September 2020 (Closure of the database). Through data monitoring, we noticed that since stopping tofacitinib our mortality nearly doubled. However, we had a sense of a faster symptomatic improvement in the Dexamethasone group. We therefore opted to revert to tofacitinib for 7 to 10 days with the addition of two dexamethasone doses of 10 mg, one on admission and one more 24 hours later. 2.d Protocol deviations: Starting August 2020, as the literature reported on Tocilizumab, this monoclonal antibody was administered occasionally in patients with 100% oxygen requirement on arrival. The primary outcome of interest in this analysis was the disposition (death or alive) of the patients at discharge. After obtaining IRB approval we retrospectively reviewed the records of 326 patients admitted for COVID-19. The analytical file for this study was synthetic derivative (de-identified, non-re-linkable copy) of the DRMC's electronic medical records database. Apart from socio-demographics (age, race, and sex), of interest were: (1) Clinical parameters that were related to COVID-19 severity such as diabetes, hypertension, and obesity. Due to critical nursing shortage and critical patient loads, other comorbidities could not be reliably identified in the electronic health record and where not manually retrieved. (2) Inflammatory severity and coagulation markers: lymphocyte count, creatinine clearance, D-dimer, ferritin, CRP, and oxygen saturation, noted at the first day they were measured. (3) ICU patients refer to those requiring mechanical ventilation only. Due to our limited resources, all other patients on any other form of oxygen supplementation were treated on the floor. (4) The exposure of interest (treatment) was a binary categorical variable: dexamethasone only (referred to as the dexamethasone group) vs. tofacitinib whether with dexamethasone or not (referred to as Tofacitinib group). J o u r n a l P r e -p r o o f Data management and analyses were performed using Statistical Analysis System, version 9.4 (SAS Institute, Cary, NC, USA) software. The Pearson's chi-square test homogeneity (or Fisher's exact test where conditions for chi-square statistics were violated), assessed at the 5% level of significance, was used to explore potential differences in baseline distributions of the socio-demographic and clinical parameters between the two treatment groups. Binary logic regression model generating odds ratios (OR) and corresponding 95% confidence intervals (CI) were used to assess the likelihood that individuals diagnosed with COVID-19 related hypoxemia undergoing treatment with tofacitinib expired compared to those treated with dexamethasone only. Age and captured clinical parameters were adjusted for using a multiple logistic regression model, generating adjusted odds ratio (AOR) and corresponding confidence intervals. The survival experience of the patients was modelled on a Kaplan-Meier survival plot, depicting the two treatment groups (Figure-2) . The analytical sample comprised 269 patients. All patients met the endpoint of death or discharged alive. Baseline characteristics between group comparisons are shown in Table 1 . A total of 138 (51.3%) patients were uniformly exposed to tofacitinib, versus 131(48.7%) to dexamethasone without tofacitinib. Among the 63 patients intubated in the ICU, 32 (50.79%) died, with statistically significant high likelihood compared to those not intubated (OR=31.20, 95%CI =7.77-35.83; p<0.001). However, there was no statistically significant difference in these mechanically ventilated patients based on the two treatment modalities (p=0.93). Exploring potential differences in baseline distributions of the variables between the two treatment groups, the data was indicative of a statistically significant difference for age, and for D-dimer being higher in the Dexamethasone group J o u r n a l P r e -p r o o f (p<0.001). However, the Tofacitinib group had more diabetic (p=0.047) and obese individuals (p=0.01). There were 62% reduced odds of dying among those treated with added tofacitinib compared to those treated without tofacitinib (OR=0.38, 95%CI =0.19-0.76; p=0.01). Controlling the effects of age and the captured clinical parameters (preexisting conditions, laboratory markers and whether or not patients were mechanically ventilated) in relation to treatment modalities on outcome of dying, the result was ordered preserved and statistically significant, indicating 70% reduced odds of dying among the Tofacitinib group compared to the dexamethasone group. AOR=0.30 95%CI =0.12-0.76; p=0.01. Table 2 Toxicity: Table 3 : We used positive blood cultures as an objective criterion to document infections. Positive blood cultures were low and similar in both groups. As stated, all our patients received broad spectrum bacterial coverage from day one to protect from the immunosuppressive effect of tofacitinib. The use of full dose anticoagulant was associated with a higher than the expected 2.5% bleeding rate reported in the non-COVID-19 population 31 . We noted no difficulties in bleeding cessation when anticoagulation was stopped in bleeding patients and no relation to mortality. All screening for Human Immunodeficiency Virus and viral hepatitis were negative. One patient was positive for TB QuantiFERON. His results were available 3 weeks after discharge (remained asymptomatic, treated per standard of care by MS board of health). Hyperglycemia in our population was a common problem in the dexamethasone group often requiring insulin coverage. Tofacitinib does offer the added advantage of metabolic neutrality. At the hypoxemic state, autoimmune inflammation in COVID-19 pneumonia is a key mechanism of deterioration 30 . Viral induced autoimmunity is a well described phenomenon whether with Epstein-Barr virus associated Systemic Lupus J o u r n a l P r e -p r o o f Erythematosus, hepatitis C virus-autoimmune hepatitis (HCV-AIH) and others 33 . Similar aberrant immune response is key for inflammatory COVID-19 pneumonitis to develop as shown by Lucas in his longitudinal analyses of immunological response to COVID-19 34 . The publication by McGonagle et al 35 supports the practice of intervening as early as possible for achieving good outcome. His work confirms a direct relation between COVID-19 disease severity and rising cytokine levels. These studies suggest a hyperinflammatory response that can rapidly progress and may increase the risk of death. Intervention aimed at modulating the inflammatory immune response by reducing toxic cytokine levels improves outcomes in the treatment of COVID-19 pneumonia. This approach is well established since the publication of RECOVERY 2 that lead to the usage of dexamethasone in admitted patients. Unlike dexamethasone, no mortality benefit has been demonstrated in treatments that target one cytokine 36, 37 hypothesized to be a central driver in inflammation. Contrary to monoclonal antibodies, tofacitinib possesses, just like dexamethasone, a broad anti-inflammatory effect, yet target a different inflammatory pathway than dexamethasone 36. The outcomes data in the Tofacitinib group lends credence to the concept that broadly reducing cytokine levels, whether with tofacitinib alone or in combination with dexamethasone is associated with a greater mortality benefit. Moreover, this analysis points to the safety of this approach as to the lack of vascular thrombosis or an increase in infectious complications. In addition, tofacitinib has the advantage of metabolic neutrality. Lack of hyperglycemia and inducing a catabolic state are significant benefits in an obese, critically ill, population. The patient cohort included in this analysis has multiple demographic and comorbidity factors that have been associated with worse outcomes from COVID-19 related illness. The effect of the socio-economic background for hospital COVID-19 related mortality variation was clarified by Wadhera et al 39 showing an inpatient COVID-19 mortality twice as high in the New York City boroughs with a higher proportion of minorities and poverty when compared to more affluent ones (Bronx versus Manhattan). African Americans are known to be at highest 6,7 risk of death from COVID-19. Other well-established risks of worse outcomes are age 6-8 , obesity 9-10 and Stage 4 & 5 chronic kidney disease. 11, 12 Admission oxygen saturation, degree of inflammation (CRP and Ferritin) and hypercoagulability (Ddimers) are also established markers of severity of illness. 40, 41 All of these severity criteria were quite elevated in our presented population and may have translated into a higher mortality than the published 18% in our state. In fact, our dexamethasone only cohort mortality was 20%. The decision to provide systemic dose anticoagulation upfront based on the New Orleans autopsy findings is consistent with other reports suggesting the efficacy of this approach 4 . The higher than expected bleeding rate did not change outcomes in this patient population. Caution in tofacitinib timing is warranted. The RECOVERY trial did show an increase in mortality when dexamethasone was given early to nonoxygen requiring patients. A similar deleterious impact may be present if tofacitinib is used early without antiviral coverage. As a retrospective analysis of hospitalized patients for COVID-19 pneumonia our analysis has a few challenges especially in relation to quality. Although it focused on exploring the potential benefit of tofacitinib in hospitalized patients for COVID-19 pneumonia, it is important to note that a few patients received tocilizumab as noted. These few patients were not segregated in this analysis and may have affected the outcome. Another deficiency is a lack of rigorous documentation of comorbidities and SOFA scores. During these times, like many other hospitals, we were facing a critical shortage of nursing and medical staff with an overwhelming patient load. Consequently, documentation suffered enough to prevent a reliable analysis of factors as COPD and immunosuppression. Future investigation that clearly delineate patients into those who receive these treatment regimens separately and in combination in a prospective factorial analysis may further elucidate the benefit of tofacitinib as a treatment modality for COVID-19 pneumonia. The experience reported here builds on the works of previous studies of COVID-19 patients pointing to a generalized severe inflammation with no one cytokine identifiable as a key driver. Rather than targeted against one cytokine, broad antiinflammatory therapy is needed to stem the florid immune response associated with COVID-19 illness. Patient response to dexamethasone and now tofacitinib both supports this theory. It is quite pertinent to mention that the RECOVERY trial group just published that tocilizumab therapy provided a significant survival benefit only when combined to dexamethasone 43 and not as a single agent. After considering this cohort's unique demographics, the severity index, the uniformity in care, and low clinical toxicity, we found the substantial survival benefit experienced by the Tofacitinib group to be a credible confirmation of this treatment. We conclude that a treatment protocol that includes anticoagulant therapy, antiviral therapy, and anti-inflammatory with tofacitinib, whether or not combined with a short course of dexamethasone, offers a solid model to move forward with further clinical research. In v a s iv e M e c h a n ic a l V e n t ila t io n . O b e s it y . 2 0 2 0 ;2 8 ( 7 ) :1 1 9 5 -1 1 9 9 . CKD is a key risk factor for COVID-19 mortality OpenSAFELY: factors associated with COVID-19-related hospital death in the linked electronic health records of 17 million adult NHS patients A first glance at COVID-19 hospitalizations in Mississippi: Demographics, Comorbidities, and Outcome of Care Mississippi state department of health. Washington county health profile Pulmonary and Cardiac Pathology in Covid-19: The First Autopsy Series from New Orleans COVID-19: consider cytokine storm syndromes and immunosuppression. The Lancet Clinical management of COVID-19 Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19) The mechanism of action of tofacitinib -an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis Tofacitinib efficacy personal communication by phone, S Nejjar to M hayek The Many Roles of Chemokines and Chemokine Receptors in Inflammation Cytokine release syndrome in severe COVID-19 CoV-2: a storm is raging Risk of Myocardial Infarction and Stroke after Acute Infection or Vaccination Recommendation: Aspirin Use to Prevent Cardiovascular Disease and Colorectal Cancer: Preventive Medication: United States Preventive Services Taskforce. Recommendation: Aspirin Use to Prevent Cardiovascular Disease and Colorectal Cancer: Preventive Medication | United States Preventive Services Taskforce Bleeding rates of Veterans taking apixaban or rivaroxaban for atrial fibrillation or venous thromboembolism COVID-19 illness in native and immunosuppressed states: A clinical-therapeutic staging proposal Cell damage and autoimmunity: a critical appraisal Longitudinal analyses reveal immunological misfiring in severe COVID-19 Autoimmun Rev Efficacy of Tocilizumab in Patients Hospitalized with Covid-19 Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study Variation in COVID-19 Hospitalizations and Deaths Across New York City Boroughs Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort study Clinical Characteristics and Morbidity Associated with Coronavirus Disease 2019 in a Series of Patients in Metropolitan Detroit Detectable 2019-nCoV viral RNA in blood is a strong indicator for the further clinical severity Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): preliminary results of a randomised, controlled, open-label The authors extend their recognition to Sessine Najjar MD critical contribution in leading with successful usage of tofacitinib and to Carol Cashion Doolittle, CFNP and Will Evans, PhD, MCHES, CWP for their editorial assistance.