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BACKGROUND: Upregulation of IL-6 has been associated with worse prognosis in COVID-19 patients. Impact on IL-6 signaling has mostly been limited to clinical outcomes in IL-6 receptor antagonist trials. METHODS: We performed a phase 2, randomised, double-blind, placebo-controlled trial (NCT04380961) of US-based hospitalised adults (<85 years) with laboratory-confirmed SARS-CoV-2 infection and severe (low levels of supplemental oxygen) or critical disease (high levels of oxygen supplementation). Patients received sirukumab 5mg/kg or placebo single dose IV on Day 1 plus standard of care. The primary endpoint was time to sustained clinical improvement up to Day 28 based on an ordinal scale. Secondary endpoints included clinical improvement, all-cause mortality, and safety. Following an interim analysis, the protocol was amended to only recruit patients with critical COVID-19. FINDINGS: From May 2020-March 2021, 209 patients were randomised; 112 had critical disease (72 sirukumab, 40 placebo) at baseline. Median time to sustained clinical improvement in critical patients was 17 and 23 days in the sirukumab and placebo groups (HR, 1â1; 95% CI, 0â66-1â88; p >0â05). At Day 28, 59â4% versus 55â0% of patients achieved clinical improvement with sirukumab versus placebo and rates of all-cause mortality were 24â6% versus 30â0%, respectively. Rates of grade ≥3 adverse events were comparable between the sirukumab and placebo groups (25â9% vs 32â9%; all patients). INTERPRETATION: In critical COVID-19 patients who received sirukumab, there was no statistically significant difference in time to sustained clinical improvement versus placebo despite objective sequestration of circulating IL-6, questioning IL-6 as a key therapeutic target in COVID-19. FUNDING: Janssen Research & Development, LLC.
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We present a case of a 72-year-old liver transplant recipient 7 years prior who presents to our hospital with general malaise, fatigue, low-grade fevers, and watery diarrhea. He was found to have Astrovirus via PCR testing in a comprehensive stool panel. The patient's home mycophenolic acid was held upon admission, while cyclosporine was continued through his hospital stay. Generally, Astroviridae infection is a rarely identified cause of enteritis and even less so in the transplant population. Although reports have been published regarding devastating cases of encephalitis in immunocompromised patients, our patient did not exhibit these symptoms and draws into question the danger of this virus in other immunosuppressed populations. This case helps to better elucidate which patient populations should be approached with caution in the setting of Astroviridae infection.
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Infecciones por Astroviridae , Astroviridae , Enteritis , Trasplante de Hígado , Trasplante de Órganos , Masculino , Humanos , Anciano , Infecciones por Astroviridae/diagnóstico , Infecciones por Astroviridae/epidemiología , Trasplante de Hígado/efectos adversos , Diarrea , Enteritis/diagnóstico , Enteritis/tratamiento farmacológicoRESUMEN
BACKGROUND: Transplanting kidneys from donors with a recent history of severe SARS-CoV-2 pneumonia is uncommon due to concerns about the risk of viral transmission and the quality of kidneys from these donors. To date, there are no conclusive data on viral transmission from extrapulmonary solid organ transplants. Given the prevalence of SARS-CoV-2 infections in potential donors, shortage of kidneys available for transplantation, and low risk of viral transmission, we developed a clinical protocol for accepting kidneys from donors with recent severe SARS-CoV-2 pneumonia who demonstrate preserved kidney function. MATERIALS AND METHODS: We collected data on early outcomes of 5 kidney transplant recipients from 4 deceased donors hospitalized for severe SARS-CoV-2 infection. RESULTS: Donor creatinine ranged from 0.51 to 0.60 mg/dL and kidney donor profile index (KDPI) from 14 to 52%. Three of the five kidneys were from donation after circulatory death. All recipients were fully vaccinated, and 4/5 received post-exposure prophylactic monoclonal antibody treatment. While 3 recipients had delayed graft function, all had excellent graft function at 3 or 4 weeks post-operatively. None of the recipients displayed signs or symptoms of SARS-CoV-2 infection post-transplant. CONCLUSION: Our findings suggest that kidney grafts from donors with a recent history of severe SARS-CoV-2 infection but with preserved kidney function can be safely used and have good early outcomes.
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COVID-19 , Trasplante de Riñón , Obtención de Tejidos y Órganos , COVID-19/epidemiología , Supervivencia de Injerto , Humanos , Trasplante de Riñón/efectos adversos , Trasplante de Riñón/métodos , SARS-CoV-2 , Donantes de Tejidos , Receptores de TrasplantesRESUMEN
Rationale: GM-CSF (granulocyte-macrophage colony-stimulating factor) has emerged as a promising target against the hyperactive host immune response associated with coronavirus disease (COVID-19). Objectives: We sought to investigate the efficacy and safety of gimsilumab, an anti-GM-CSF monoclonal antibody, for the treatment of hospitalized patients with elevated inflammatory markers and hypoxemia secondary to COVID-19. Methods: We conducted a 24-week randomized, double-blind, placebo-controlled trial, BREATHE (Better Respiratory Education and Treatment Help Empower), at 21 locations in the United States. Patients were randomized 1:1 to receive two doses of intravenous gimsilumab or placebo 1 week apart. The primary endpoint was all-cause mortality rate at Day 43. Key secondary outcomes were ventilator-free survival rate, ventilator-free days, and time to hospital discharge. Enrollment was halted early for futility based on an interim analysis. Measurements and Main Results: Of the planned 270 patients, 225 were randomized and dosed; 44.9% of patients were Hispanic or Latino. The gimsilumab and placebo groups experienced an all-cause mortality rate at Day 43 of 28.3% and 23.2%, respectively (adjusted difference = 5% vs. placebo; 95% confidence interval [-6 to 17]; P = 0.377). Overall mortality rates at 24 weeks were similar across the treatment arms. The key secondary endpoints demonstrated no significant differences between groups. Despite the high background use of corticosteroids and anticoagulants, adverse events were generally balanced between treatment groups. Conclusions: Gimsilumab did not improve mortality or other key clinical outcomes in patients with COVID-19 pneumonia and evidence of systemic inflammation. The utility of anti-GM-CSF therapy for COVID-19 remains unclear. Clinical trial registered with www.clinicaltrials.gov (NCT04351243).
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Tratamiento Farmacológico de COVID-19 , Anticuerpos Monoclonales Humanizados/uso terapéutico , Método Doble Ciego , Humanos , InflamaciónRESUMEN
An unvaccinated adult male heart transplant recipient patient with recalcitrant COVID-19 due to SARS-CoV-2 delta variant with rising nasopharyngeal quantitative viral load was successfully treated with ALVR109, an off-the-shelf SARS-CoV-2-specific T cell therapy. Background immunosuppression included 0.1 mg/kg prednisone, tacrolimus, and mycophenolate mofetil 1 gm twice daily for historical antibody-mediated rejection. Prior therapies included remdesivir, corticosteroids, and tocilizumab, with requirement for high-flow nasal oxygen. Lack of clinical improvement and acutely rising nasopharyngeal viral RNA more than 3 weeks into illness prompted the request of ALVR109 through an emergency IND. The day following the first ALVR109 infusion, the patient's nasopharyngeal SARS-CoV-2 RNA declined from 7.43 to 5.02 log10 RNA copies/ml. On post-infusion day 4, the patient transitioned to low-flow oxygen. Two subsequent infusions of ALVR109 were administered 10 and 26 days after the first; nasopharyngeal SARS-CoV-2 RNA became undetectable on Day 11, and he was discharged the following day on low-flow oxygen 5 weeks after the initial diagnosis of COVID-19. The clinical and virologic improvements observed in this patient following administration of ALVR109 suggest a potential benefit that warrants further exploration in clinical trials.
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COVID-19 , Trasplante de Corazón , Adulto , Tratamiento Basado en Trasplante de Células y Tejidos , Humanos , Masculino , ARN Viral/genética , SARS-CoV-2RESUMEN
Liver transplantation rates have been negatively affected by the pandemic caused by coronavirus disease 2019 (COVID-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Current practice in the liver transplant community is to avoid utilizing SARS-CoV-2-positive donors for liver transplantation unless there is a compelling reason such as recipient illness severity. In this case, we report the use of a donor who had a positive exposure to and symptom history for COVID-19 and tested positive for SARS-CoV-2 on admission for a liver transplant recipient with primary sclerosing cholangitis and a Model of End-Stage Liver Disease score of 23 with no known COVID-19 exposures. We focus on the decision to accept this particular organ, as well as the discussion with the recipient about the unknowns of disease transmission and risk associated with this donor. The current case argues that transplant programs should begin to consider low-risk donors with positive SARS-CoV-2 testing for recipients who have the potential to benefit from liver transplantation, which may not only be those with the most severe illness.
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Uterus transplantation is a repeatedly proven treatment for women with absolute uterine-factor infertility, which is the congenital or acquired absence of the uterus, who desire to carry, and ultimately deliver, a child. No stranger to the field of transplant or obstetrics is cytomegalovirus. Cytomegalovirus is both a frequent complication after transplant, presenting as an opportunistic infection, and a common congenital disease in the newborn child from pregnancy. To date, there have been no reported cases of pregnancy following uterus transplantation from cytomegalovirus-positive donors into cytomegalovirus-negative recipients. We present a case report describing our experience of a cytomegalovirus-negative recipient, transplanted with a uterus from a cytomegalovirus-positive living donor, and subsequently diagnosed with active cytomegalovirus infection despite prophylactic treatment. She was treated for infection prior to embryo transfer and carried a healthy child to term. This case suggests transplanting a cytomegalovirus-positive uterus into a negative donor is possible to do safely.
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Infecciones por Citomegalovirus , Trasplantes , Citomegalovirus , Infecciones por Citomegalovirus/tratamiento farmacológico , Femenino , Humanos , Recién Nacido , Donadores Vivos , Embarazo , Útero/cirugía , Útero/trasplanteAsunto(s)
COVID-19 , Albúmina Sérica , Proteínas de Fase Aguda , Humanos , Estudios Retrospectivos , SARS-CoV-2RESUMEN
The global severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic leading to coronavirus disease 2019 (COVID-19) is straining hospitals. Judicious resource allocation is paramount but difficult due to the unpredictable disease course. Once hospitalized, discerning which patients may progress to critical disease would be valuable for resource planning. Medical records were reviewed for consecutive hospitalized patients with COVID-19 in a large healthcare system in Texas. The main outcome was progression to critical disease within 10 days from admission. Albumin trends from admission to 7 days were analyzed using mixed-effects models, and progression to critical disease was modeled by multivariable logistic regression of laboratory results. Risk models were evaluated in an independent group. Of 153 non-critical patients, 28 (18%) progressed to critical disease. The rate of decrease in mean baseline-corrected (Δ) albumin was -0.08 g/dL/day (95% CI -0.11 to -0.04; p<0.001) or four times faster, in those who progressed compared with those who did not progress. A model of Δ albumin combined with lymphocyte percentage predicting progression to critical disease was validated in 60 separate patients (sensitivity, 0.70; specificity, 0.74). ALLY (delta albumin and lymphocyte percentage) is a simple tool to identify patients with COVID-19 at higher risk of disease progression when: (1) a 0.9 g/dL or greater albumin drop from baseline within 5 days of admission or (2) baseline lymphocyte of ≤10% is observed. The ALLY tool identified >70% of hospitalized cases that progressed to critical COVID-19 disease. We recommend prospectively tracking albumin. This is a globally applicable tool for all healthcare systems.
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COVID-19/sangre , COVID-19/complicaciones , Linfopenia/etiología , Modelos Biológicos , Albúmina Sérica Humana/deficiencia , Adulto , Anciano , COVID-19/epidemiología , Enfermedad Crítica , Progresión de la Enfermedad , Femenino , Humanos , Linfopenia/sangre , Masculino , Persona de Mediana Edad , Pandemias , Factores de Riesgo , SARS-CoV-2 , Índice de Severidad de la Enfermedad , Texas/epidemiología , Factores de TiempoRESUMEN
This is a retrospective analysis of patients with osteomyelitis who received telavancin at some time during their treatment course. The primary outcome was the percent of patients cured or improved at the end of telavancin therapy (EOTT). The secondary outcome was the percent of patients cured or improved three months after discontinuation of telavancin therapy. There were 32 cases of osteomyelitis with methicillin-resistant Staphylococcus aureus identified in 17 (56.7%), methicillin-sensitive Staphylococcus aureus 2(6.6%), coagulase negative staphylococci 6 (20.0%) and other pathogens, 5 (16.7%). At EOTT, 87.5% of patients had their osteomyelitis cured and 94.6% had the infection cured at three months after telavancin was completed. The most common adverse events associated with telavancin were gastrointestinal in nature (nausea (25.8%), vomiting (9.7%) and diarrhea (3.2%)) followed by metallic taste (6.5%). A favorable outcome was achieved for many patients receiving the antimicrobial regimen that included telavancin for the treatment of osteomyelitis.
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Aminoglicósidos/uso terapéutico , Antibacterianos/uso terapéutico , Lipoglucopéptidos/uso terapéutico , Osteomielitis/tratamiento farmacológico , Adulto , Anciano , Aminoglicósidos/administración & dosificación , Aminoglicósidos/efectos adversos , Antibacterianos/administración & dosificación , Antibacterianos/efectos adversos , Bacterias/efectos de los fármacos , Femenino , Estudios de Seguimiento , Humanos , Lipoglucopéptidos/administración & dosificación , Lipoglucopéptidos/efectos adversos , Masculino , Persona de Mediana Edad , Osteomielitis/microbiología , Estudios Retrospectivos , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/efectos de los fármacos , Resultado del Tratamiento , Estados UnidosRESUMEN
OBJECTIVES: HIV-infected persons with chronic herpesvirus infections may experience paradoxical worsening after initiation of antiretroviral therapy (ART), but the impact of longer term ART is unclear. We evaluated the relationships between genital herpes simplex virus (HSV) shedding and ART initiation and time on therapy in HIV and HSV-2-infected persons. DESIGN: Prospective observational study. METHODS: Rates of HSV shedding in 45 HIV and HSV-2-infected persons on or off ART were prospectively followed over up to three, noncontiguous, 60-day periods, during which participants performed daily genital swabs for HSV detection by real-time HSV DNA PCR and reported symptoms. Initiation or discontinuation of ART was at the discretion of participants' healthcare providers. RESULTS: In all, 6425 daily genital swabs were obtained from 45 persons (38 men and seven women) during 105 swabbing sessions. During the three sessions, 67, 74, and 92% of persons were on ART. HSV was detected on 26.5% of days in men and 22.3% of days in women. The overall rates of genital HSV shedding were 19.4% of days in persons not on ART, 30.2% in persons within 90 days of ART initiation, and 23.3% in persons on ART for longer than 90 days. After initiation of ART, HSV shedding decreased by 2% per month, or 23% per year (RR 0.98/month on ART; Pâ=â0.0003 in adjusted analysis). This finding was consistent after including consideration of HIV viral load and CD4 cell count. CONCLUSIONS: HSV shedding increased significantly shortly after ART initiation, but decreased with time on prolonged ART.
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Antirretrovirales/uso terapéutico , Terapia Antirretroviral Altamente Activa/métodos , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Herpes Genital/virología , Herpesvirus Humano 2/aislamiento & purificación , Esparcimiento de Virus , Adulto , ADN Viral/análisis , Femenino , Estudios de Seguimiento , Genitales/virología , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Reacción en Cadena en Tiempo Real de la Polimerasa , Factores de Tiempo , Carga Viral , Adulto JovenAsunto(s)
Antivirales/uso terapéutico , Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/etiología , Ganciclovir/uso terapéutico , Hepatitis/tratamiento farmacológico , Hepatitis/etiología , Trasplante de Riñón/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
We describe a patient with history of dextro-transposition of the great vessels, ventricular septal defect, and pulmonary valve replacement who presented with fatigue, prolonged fever, and leg edema. He was found to have kidney injury, pancytopenia, and liver congestion. Echocardiogram revealed thickened leaflets with prolapsing vegetation on the pulmonary valve. Given the negative blood cultures, high Bartonella henselae immunogobulin G titer (≥1:1024) and positive immunoglobulin M titer (≥1:20), he was diagnosed with Bartonella endocarditis complicated with glomerulonephritis.
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Characteristics of cirrhosis-associated cryptococcosis first diagnosed after death are not fully known. In a multicenter study, data generated as standard of care was systematically collected in 113 consecutive patients with cirrhosis and cryptococcosis followed for 80 patient-years. The diagnosis of cryptococcosis was first established after death in 15.9% (18/113) of the patients. Compared to cases diagnosed while alive, these patients had higher MELD score (33 vs. 22, P = .029) and higher rate of cryptococcemia (75.0% vs. 41.9%, P = .027). Cases diagnosed after death, in comparison to those diagnosed during life were more likely to present with shock (OR 3.42, 95% CI 1.18-9.90, P = .023), require mechanical ventilation at admission (OR 8.5, 95% CI 2.74-26.38, P = .001), less likely to undergo testing for serum cryptococcal antigen (OR 0.07, 95% CI 0.02-0.21, P < .001) and have positive antigen when the test was performed (OR 0.07, 95% CI 0.01-0.60, P = .016). In a subset of cirrhotic patients with advanced liver disease cryptococcosis was first recognized after death. These patients had the characteristics of presenting with fulminant fungemia, were less likely to have positive serum cryptococcal antigen and posed a diagnostic challenge for care providers.
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Criptococosis/patología , Fungemia/patología , Cirrosis Hepática/complicaciones , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Índice de Severidad de la EnfermedadRESUMEN
Cavernous sinus thrombosis is a rare, potentially fatal cause of cerebral venous thrombosis. Infectious causes typically arise from the mid face, orbit, or sinonasal region. We present a case of bilateral cavernous sinus and superior ophthalmic thrombosis secondary to an extreme case of facial cellulitis.
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We report a case of a 42-year-old man who presented with progressive weakness and blindness over the course of several months and met criteria for seronegative neuromyelitis optica. This presentation was in the setting of immunosuppression following cardiac transplant. No infectious causes were found within the neuroaxis, and he ultimately died with complete blindness, quadriplegia, and respiratory failure attributed to panmyelitis and brain stem inflammation despite aggressive therapies.
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We describe an 81-year-old man receiving azacitidine monotherapy for myelodysplastic syndrome who was improving from Listeria monocytogenes bacteremia after receiving antibiotic therapy during an earlier hospital admission. Shortly after discharge he developed new-onset seizure activity, with brain imaging on subsequent admissions demonstrating a posterior right frontal lobe mass. Specimen cultures after resection of the mass revealed this to be a cerebral abscess related to L. monocytogenes. Brain abscesses related to this organism are rare.
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Myroides species are a rare source of human infection. Though not part of the human microbiota, Myroides species are commonly found in the environment. Myroides infections are typically attributed to contact with contaminated water; the most common presentation is in immunocompromised patients. We present a patient with a diabetic foot ulcer who subsequently developed Myroides odoratimimus bacteremia and bone abscess.