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1.
J Am Geriatr Soc ; 70(3): 650-658, 2022 03.
Article in English | MEDLINE | ID: covidwho-1731188

ABSTRACT

BACKGROUND: There is incomplete information regarding evolution of antibody titers against SARS-CoV-2 after a two-dose strategy vaccination with BNT162b2 in older adults in long-term care facilities (LTCFs) with frailty, disability, or cognitive impairment. We aimed to determine IgG antibody titer loss in older adults in LTCFs. METHODS: This is a multicenter longitudinal cohort study including 127 residents (90 females and 37 males) with a mean age of 82.7 years (range 65-99) with different frailty and disability profiles in two LTCFs in Albacete, Spain. Residents received two doses of BNT162b2 as per label, and antibody levels were determined 1 and 6 months after the second dose. Age, sex, previous history of coronavirus disease 2019 (COVID-19), comorbidity (Charlson Index), performance in activities of daily living (Barthel Index), frailty (FRAIL instrument), and cognitive status were assessed. RESULTS: The mean antibody titers 1 and 6 months after the second vaccine dose were 32,145 AU/ml (SD 41,206) and 6182 AU/ml (SD 13,316), respectively. Across all participants, the median antibody titer loss measured 77.6% (interquartile range [IQR] 23.8%). Notably, the decline of titers in individuals with pre-vaccination COVID-19 infection was significantly lower than in those without a history of SARS-CoV-2 infection (72.2% vs. 85.3%; p < 0.001). The median titer decrease per follow-up day was 0.47% (IQR 0.14%) and only pre-vaccination COVID-19 was associated with lower rate of antibody decline at 6 months (hazard ratio 0.17; 95% confidence interval 0.07-0.41; p < 0.001). Frailty, disability, older age, cognitive impairment, or comorbidity were not associated with the extent of antibody loss. CONCLUSIONS: Older adults in LTCFs experience a rapid loss of antibodies over the first 6 months after the second dose of BNT162b2 vaccine. Only pre-vaccination COVID-19 is associated with a slower rate of antibody decrease. Our data support immunization with a third dose in this vulnerable, high-risk population.


Subject(s)
/immunology , COVID-19/immunology , COVID-19/prevention & control , Disabled Persons , Frail Elderly , Aged , Aged, 80 and over , Antibody Formation , Female , Humans , Longitudinal Studies , Male , Nursing Homes , SARS-CoV-2 , Spain
2.
Sci Adv ; 7(1)2021 01.
Article in English | MEDLINE | ID: covidwho-1388432

ABSTRACT

Using AI, we identified baricitinib as having antiviral and anticytokine efficacy. We now show a 71% (95% CI 0.15 to 0.58) mortality benefit in 83 patients with moderate-severe SARS-CoV-2 pneumonia with few drug-induced adverse events, including a large elderly cohort (median age, 81 years). An additional 48 cases with mild-moderate pneumonia recovered uneventfully. Using organotypic 3D cultures of primary human liver cells, we demonstrate that interferon-α2 increases ACE2 expression and SARS-CoV-2 infectivity in parenchymal cells by greater than fivefold. RNA-seq reveals gene response signatures associated with platelet activation, fully inhibited by baricitinib. Using viral load quantifications and superresolution microscopy, we found that baricitinib exerts activity rapidly through the inhibition of host proteins (numb-associated kinases), uniquely among antivirals. This reveals mechanistic actions of a Janus kinase-1/2 inhibitor targeting viral entry, replication, and the cytokine storm and is associated with beneficial outcomes including in severely ill elderly patients, data that incentivize further randomized controlled trials.


Subject(s)
Antiviral Agents/pharmacology , Azetidines/pharmacology , COVID-19/mortality , Enzyme Inhibitors/pharmacology , Janus Kinases/antagonists & inhibitors , Liver/virology , Purines/pharmacology , Pyrazoles/pharmacology , SARS-CoV-2/pathogenicity , Sulfonamides/pharmacology , Adult , Aged , Aged, 80 and over , COVID-19/drug therapy , COVID-19/metabolism , COVID-19/virology , Cytokine Release Syndrome , Cytokines/metabolism , Drug Evaluation, Preclinical , Female , Gene Expression Profiling , Humans , Interferon alpha-2/metabolism , Italy , Janus Kinases/metabolism , Liver/drug effects , Male , Middle Aged , Patient Safety , Platelet Activation , Proportional Hazards Models , RNA-Seq , Spain , Virus Internalization/drug effects
3.
Rheumatology (Oxford) ; 60(1): 399-407, 2021 01 05.
Article in English | MEDLINE | ID: covidwho-1388014

ABSTRACT

OBJECTIVES: The Janus kinase (JAK) inhibitor baricitinib may block viral entry into pneumocytes and prevent cytokine storm in patients with SARS-CoV-2 pneumonia. We aimed to assess whether baricitinib improved pulmonary function in patients treated with high-dose corticosteroids for moderate to severe SARS-CoV-2 pneumonia. METHODS: This observational study enrolled patients with moderate to severe SARS-CoV-2 pneumonia [arterial oxygen partial pressure (PaO2)/fraction of inspired oxygen (FiO2) <200 mmHg] who received lopinavir/ritonavir and HCQ plus either corticosteroids (CS group, n = 50) or corticosteroids and baricitinib (BCT-CS group, n = 62). The primary end point was the change in oxygen saturation as measured by pulse oximetry (SpO2)/FiO2 from hospitalization to discharge. Secondary end points included the proportion of patients requiring supplemental oxygen at discharge and 1 month later. Statistics were adjusted by the inverse propensity score weighting (IPSW). RESULTS: A greater improvement in SpO2/FiO2 from hospitalization to discharge was observed in the BCT-CS vs CS group (mean differences adjusted for IPSW, 49; 95% CI: 22, 77; P < 0.001). A higher proportion of patients required supplemental oxygen both at discharge (62.0% vs 25.8%; reduction of the risk by 82%, OR adjusted for IPSW, 0.18; 95% CI: 0.08, 0.43; P < 0.001) and 1 month later (28.0% vs 12.9%, reduction of the risk by 69%, OR adjusted for IPSW, 0.31; 95% CI: 0.11, 0.86; P = 0.024) in the CS vs BCT-CS group. CONCLUSIONS: . In patients with moderate to severe SARS-CoV-2 pneumonia a combination of baricitinib with corticosteroids was associated with greater improvement in pulmonary function when compared with corticosteroids alone. TRIAL REGISTRATION: European Network of Centres for Pharmacoepidemiology and Pharmacovigilance, ENCEPP (EUPAS34966, http://www.encepp.eu/encepp/viewResource.htm? id = 34967).


Subject(s)
Azetidines/therapeutic use , COVID-19/drug therapy , Glucocorticoids/therapeutic use , Hypoxia/therapy , Janus Kinase Inhibitors/therapeutic use , Methylprednisolone/therapeutic use , Oxygen Inhalation Therapy/statistics & numerical data , Purines/therapeutic use , Pyrazoles/therapeutic use , Sulfonamides/therapeutic use , Aged , Antiviral Agents/therapeutic use , COVID-19/metabolism , COVID-19/physiopathology , Cohort Studies , Drug Combinations , Drug Therapy, Combination , Endothelium, Vascular , Enzyme Inhibitors/therapeutic use , Female , Fibrin Fibrinogen Degradation Products/metabolism , Humans , Hydroxychloroquine/therapeutic use , Immunoglobulins, Intravenous/therapeutic use , Immunologic Factors/therapeutic use , Interferon beta-1b/therapeutic use , Lopinavir/therapeutic use , Lung/blood supply , Male , Middle Aged , Oximetry , Prospective Studies , Ritonavir/therapeutic use , SARS-CoV-2 , Severity of Illness Index
4.
J Am Geriatr Soc ; 69(10): 2752-2758, 2021 10.
Article in English | MEDLINE | ID: covidwho-1301522

ABSTRACT

BACKGROUND: Older adults are at the highest risk of severe disease and death due to COVID-19. Randomized data have shown that baricitinib improves outcomes in these patients, but focused stratified analyses of geriatric cohorts are lacking. Our objective was to analyze the efficacy of baricitinib in older adults with COVID-19 moderate-to-severe pneumonia. METHODS: This is a propensity score [PS]-matched retrospective cohort study. Patients from the COVID-AGE and Alba-Score cohorts, hospitalized for moderate-to-severe COVID-19 pneumonia, were categorized in two age brackets of age <70 years old (86 with baricitinib and 86 PS-matched controls) or ≥70 years old (78 on baricitinib and 78 PS-matched controls). Thirty-day mortality rates were analyzed with Kaplan-Meier and Cox proportional hazard models. RESULTS: Mean age was 79.1 for those ≥70 years and 58.9 for those <70. Exactly 29.6% were female. Treatment with baricitinib resulted in a significant reduction in death from any cause by 48% in patients aged 70 or older, an 18.5% reduction in 30-day absolute mortality risk (n/N: 16/78 [20.5%] baricitinib, 30/78 [38.5%] in PS-matched controls, p < 0.001) and a lower 30-day adjusted fatality rate (HR 0.21; 95% CI 0.09-0.47; p < 0.001). Beneficial effects on mortality were also observed in the age group <70 (8.1% reduction in 30-day absolute mortality risk; HR 0.14; 95% CI 0.03-0.64; p = 0.011). CONCLUSIONS: Baricitinib is associated with an absolute mortality risk reduction of 18.5% in adults older than 70 years hospitalized with COVID-19 pneumonia.


Subject(s)
Azetidines , COVID-19 , Pneumonia, Viral , Purines , Pyrazoles , Sulfonamides , Age Factors , Aged , Aged, 80 and over , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Azetidines/administration & dosage , Azetidines/adverse effects , COVID-19/drug therapy , COVID-19/mortality , COVID-19/physiopathology , Female , Hospital Mortality , Humans , Janus Kinase Inhibitors/administration & dosage , Janus Kinase Inhibitors/adverse effects , Male , Mortality , Outcome and Process Assessment, Health Care , Pneumonia, Viral/diagnosis , Pneumonia, Viral/drug therapy , Purines/administration & dosage , Purines/adverse effects , Pyrazoles/administration & dosage , Pyrazoles/adverse effects , SARS-CoV-2/isolation & purification , Severity of Illness Index , Spain/epidemiology , Sulfonamides/administration & dosage , Sulfonamides/adverse effects
5.
J Am Geriatr Soc ; 69(6): 1441-1447, 2021 06.
Article in English | MEDLINE | ID: covidwho-1153546

ABSTRACT

BACKGROUND/OBJECTIVES: The safety and immunogenicity of the BNT162b2 coronavirus disease 2019 (COVID-19) vaccine in older adults with different frailty and disability profiles have not been well determined. Our objective was to analyze immunogenicity of the BNT162b2 mRNA COVID-19 vaccine in older adults across frailty and disability profiles. DESIGN: Multicenter longitudinal cohort study. SETTING AND PARTICIPANTS: A total of 134 residents aged ≥65 years with different frailty and disability profiles in five long-term care facilities (LTCFs) in Albacete, Spain. INTERVENTION AND MEASUREMENTS: Residents were administered two vaccine doses as per the label, and antibody levels were determined 21.9 days (SD 9.3) after both the first and second dose. Functional variables were assessed using activities of daily living (Barthel Index), and frailty status was determined with the FRAIL instrument. Cognitive status and comorbidity were also evaluated. RESULTS: Mean age was 82.9 years (range 65-99), and 71.6% were female. The mean antibody titers in residents with and without previous COVID-19 infection were 49,878 AU/ml and 15,274 AU/ml, respectively (mean difference 34,604; 95% confidence interval [CI]: 27,699-41,509). No severe adverse reactions were observed, after either vaccine dose. Those with prevaccination COVID-19 had an increased antibody level after the vaccine (B = 31,337; 95% CI: 22,725-39,950; p < 0.001). Frailty, disability, older age, sex, cognitive impairment, or comorbidities were not associated with different antibody titers. CONCLUSIONS: The BNT162b2 mRNA COVID-19 vaccine in older adults is safe and produces immunogenicity, independently of the frailty and disability profiles. Older adults in LTCFs should receive a COVID-19 vaccine.


Subject(s)
Antibody Formation , COVID-19 Vaccines/immunology , COVID-19 Vaccines/therapeutic use , COVID-19/prevention & control , Disabled Persons , Frail Elderly , Activities of Daily Living , Aged , Aged, 80 and over , COVID-19 Serological Testing , Comorbidity , Female , Health Status Indicators , Humans , Longitudinal Studies , Male , Nursing Homes , SARS-CoV-2 , Spain
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