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1.
JCI Insight ; 7(9)2022 05 09.
Article in English | MEDLINE | ID: covidwho-1765224

ABSTRACT

Transplant recipients exhibit an impaired protective immunity after SARS-CoV-2 vaccination, potentially caused by mycophenolate (MPA) immunosuppression. Recent data from patients with autoimmune disorders suggest that temporary MPA hold might greatly improve booster vaccination outcomes. We applied a fourth dose of SARS-CoV-2 vaccine to 29 kidney transplant recipients during a temporary (5 weeks) MPA/azathioprine hold, who had not mounted a humoral immune response to previous vaccinations. Seroconversion until day 32 after vaccination was observed in 76% of patients, associated with acquisition of virus-neutralizing capacity. Interestingly, 21/25 (84%) calcineurin inhibitor-treated patients responded, but only 1/4 belatacept-treated patients responded. In line with humoral responses, counts and relative frequencies of spike receptor binding domain-specific (RBD-specific) B cells were markedly increased on day 7 after vaccination, with an increase in RBD-specific CD27++CD38+ plasmablasts. Whereas overall proportions of spike-reactive CD4+ T cells remained unaltered after the fourth dose, frequencies were positively correlated with specific IgG levels. Importantly, antigen-specific proliferating Ki67+ and in vivo-activated programmed cell death 1-positive T cells significantly increased after revaccination during MPA hold, whereas cytokine production and memory differentiation remained unaffected. In summary, antimetabolite hold augmented all arms of immunity during booster vaccination. These data suggest further studies of antimetabolite hold in kidney transplant recipients.


Subject(s)
Antimetabolites , COVID-19 Vaccines , COVID-19 , Kidney Transplantation , Antibodies, Viral , Antimetabolites/therapeutic use , COVID-19/prevention & control , COVID-19 Vaccines/immunology , Humans , Immunity, Cellular , Immunity, Humoral , Immunosuppressive Agents/therapeutic use , SARS-CoV-2 , Transplant Recipients , Vaccination
2.
Intensive Care Med ; 47(11): 1258-1270, 2021 11.
Article in English | MEDLINE | ID: covidwho-1449953

ABSTRACT

PURPOSE: Trials of tocilizumab in patients with severe COVID-19 pneumonia have demonstrated mixed results, and the role of tocilizumab in combination with other treatments is uncertain. Here we evaluated whether tocilizumab plus remdesivir provides greater benefit than remdesivir alone in patients with severe COVID-19 pneumonia. METHODS: This randomized, double-blind, placebo-controlled, multicenter trial included patients hospitalized with severe COVID-19 pneumonia requiring > 6 L/min supplemental oxygen. Patients were randomly assigned (2:1 ratio) to receive tocilizumab 8 mg/kg or placebo intravenously plus ≤ 10 days of remdesivir. The primary outcome was time from randomization to hospital discharge or "ready for discharge" (defined as category 1, assessed by the investigator on a 7-category ordinal scale of clinical status) to day 28. Patients were followed for 60 days. RESULTS: Among 649 enrolled patients, 434 were randomly assigned to tocilizumab plus remdesivir and 215 to placebo plus remdesivir. 566 patients (88.2%) received corticosteroids during the trial to day 28. Median time from randomization to hospital discharge or "ready for discharge" was 14 (95% CI 12-15) days with tocilizumab plus remdesivir and 14 (95% CI 11-16) days with placebo plus remdesivir [log-rank P = 0.74; Cox proportional hazards ratio 0.97 (95% CI 0.78-1.19)]. Serious adverse events occurred in 128 (29.8%) tocilizumab plus remdesivir and 72 (33.8%) placebo plus remdesivir patients; 78 (18.2%) and 42 (19.7%) patients, respectively, died by day 28. CONCLUSIONS: Tocilizumab plus remdesivir did not shorten time to hospital discharge or "ready for discharge" to day 28 compared with placebo plus remdesivir in patients with severe COVID-19 pneumonia.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antimetabolites/therapeutic use , Antiviral Agents , COVID-19 , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Humans
3.
JAMA Oncol ; 7(11): 1686-1691, 2021 11 01.
Article in English | MEDLINE | ID: covidwho-1363628

ABSTRACT

Importance: Novel therapies for SARS-CoV-2 infection are urgently needed. Antineoplastic compounds that target cellular machinery used by SARS-CoV-2 for entry and replication, including angiotensin-converting enzyme 2 (ACE2), may disrupt SARS-CoV-2 activity. Objectives: To determine whether patients with cancer treated with potential ACE2-lowering antineoplastic compounds exhibit lower SARS-CoV-2 infection rates. Design, Setting, and Participants: We used the Library of Integrated Network-Based Cellular Signatures database to identify antineoplastic compounds associated with decreased ACE2 gene expression across cell lines. We then evaluated a retrospective cohort of 1701 patients who were undergoing antineoplastic therapy at Memorial Sloan Kettering Cancer Center in New York, New York, during the COVID-19 pandemic to determine if treatment with an ACE2-lowering antineoplastic was associated with a decreased odds ratio (OR) of SARS-CoV-2 infection. Patients included in the analysis underwent active treatment for cancer and received a SARS-CoV-2 test between March 10 and May 28, 2020. Main Outcome and Measure: The association between potential ACE2-lowering antineoplastic treatment and a positive SARS-CoV-2 test. Results: In the cohort of 1701 patients, SARS-CoV-2 infection rates were determined for 949 (55.8%) female and 752 (44.2%) male patients (mean [SD] age, 63.1 [13.1] years) with diverse cancers receiving antineoplastic therapy. In silico analysis of gene expression signatures after drug treatment identified 91 compounds associated with downregulation of ACE2 across cell lines. Of the total cohort, 215 (12.6%) patients were treated with 8 of these compounds, including 3 mTOR/PI3K inhibitors and 2 antimetabolites. In a multivariable analysis of patients who received an ACE2-lowering antineoplastic adjusting for confounders, 15 of 215 (7.0%) patients had a positive SARS-CoV-2 test compared with 191 of 1486 (12.9%) patients who received other antineoplastic therapies (OR, 0.53; 95% CI, 0.29-0.88). Findings were confirmed in additional sensitivity analyses including cancer type, steroid use, and a propensity-matched subcohort. Gemcitabine treatment was associated with reduced SARS-CoV-2 infection (OR, 0.42; 95% CI, 0.17-0.87). Conclusions and Relevance: In this cohort study, in silico analysis of drug-associated gene expression signatures identified potential ACE2-lowering antineoplastic compounds, including mTOR/PI3K inhibitors and antimetabolites. Patients who received these compounds exhibited statistically significantly lower rates of SARS-CoV-2 infection compared with patients given other antineoplastics. Further evaluation of the biological and clinical anti-SARS-CoV-2 properties of identified antineoplastic compounds is warranted.


Subject(s)
Antineoplastic Agents/therapeutic use , COVID-19 , Neoplasms , Aged , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Antimetabolites/therapeutic use , COVID-19/epidemiology , Female , Humans , Male , Middle Aged , Neoplasms/drug therapy , Neoplasms/epidemiology , Pandemics , Phosphoinositide-3 Kinase Inhibitors , Retrospective Studies , TOR Serine-Threonine Kinases/antagonists & inhibitors
4.
J Med Virol ; 93(5): 3176-3183, 2021 05.
Article in English | MEDLINE | ID: covidwho-1196542

ABSTRACT

This trial compared the rate and time of viral clearance in subjects receiving a combination of nitazoxanide, ribavirin, and ivermectin plus Zinc versus those receiving supportive treatment. This non-randomized controlled trial included 62 patients on the triple combination treatment versus 51 age- and sex-matched patients on routine supportive treatment. all of them confirmed cases by positive reverse-transcription polymerase chain reaction of a nasopharyngeal swab. Trial results showed that the clearance rates were 0% and 58.1% on the 7th day and 13.7% and 73.1% on the 15th day in the supportive treatment and combined antiviral groups, respectively. The cumulative clearance rates on the 15th day are 13.7% and 88.7% in the supportive treatment and combined antiviral groups, respectively. This trial concluded by stating that the combined use of nitazoxanide, ribavirin, and ivermectin plus zinc supplement effectively cleared the SARS-COV2 from the nasopharynx in a shorter time than symptomatic therapy.


Subject(s)
COVID-19/drug therapy , Ivermectin/therapeutic use , Nitro Compounds/therapeutic use , Ribavirin/therapeutic use , SARS-CoV-2 , Thiazoles/therapeutic use , Zinc/therapeutic use , Adult , Antimetabolites/administration & dosage , Antimetabolites/therapeutic use , Antiparasitic Agents/administration & dosage , Antiparasitic Agents/therapeutic use , Female , Humans , Ivermectin/administration & dosage , Male , Nitro Compounds/administration & dosage , Ribavirin/administration & dosage , Thiazoles/administration & dosage , Trace Elements/administration & dosage , Trace Elements/therapeutic use , Zinc/administration & dosage
6.
Hematology Am Soc Hematol Educ Program ; 2020(1): 319-327, 2020 12 04.
Article in English | MEDLINE | ID: covidwho-1043090

ABSTRACT

Corticosteroids constitute a first-line therapy for adults and children suffering from nonmalignant immune-mediated hematologic diseases. However, high disease relapse rates during the tapering period or upon drug discontinuation result in long-term corticosteroid use that increases the risk of infection. This same concept applies to other immunosuppressive agents, such as antimetabolites, calcineurin inhibitors, and cyclophosphamide. Corticosteroids are associated with a length-of-treatment and dose-dependent risk for infection. Screening and antimicrobial prophylaxis against tuberculosis, hepatitis B, Strongyloides stercoralis, and Pneumocystis jirovecii pneumonia (PJP) might be indicated in patients who are scheduled to be on high-dose corticosteroids for >4 weeks (>30 mg of prednisone-equivalent dose [PEQ]) or in patients chronically treated (≥8 weeks of continuous or intermittent corticosteroid use) with moderate doses (≥15 to <30 mg PEQ). Antimetabolites (azathioprine, mycophenolate) increase the risk of progressive multifocal leukoencephalopathy (PML); however, other opportunistic infections and viral reactivation have also been reported. In case of new onset of neurological symptoms, PML needs to be considered, and an urgent neurology consultation should be obtained. Cyclophosphamide-induced myelosuppression can lead to serious infections related to neutropenia. PJP prophylaxis should be considered with combination therapy of cyclophosphamide and corticosteroids until a PEQ dose ≤ 5 mg/d is reached. Data on infectious risk when cyclosporine is used in patients with nonmalignant hematologic diseases are lacking. Discontinuation of any immunosuppressive agent during an episode of infection is recommended. In all patients, adherence to an age-based immunization schedule is appropriate.


Subject(s)
Adrenal Cortex Hormones/adverse effects , Antimetabolites/adverse effects , Cyclophosphamide/adverse effects , Cyclosporine/adverse effects , Immunosuppressive Agents/adverse effects , Infections/chemically induced , Adrenal Cortex Hormones/therapeutic use , Aged , Antimetabolites/therapeutic use , Cyclophosphamide/therapeutic use , Cyclosporine/therapeutic use , Female , Hematologic Diseases/drug therapy , Herpes Zoster/chemically induced , Herpes Zoster/prevention & control , Humans , Immunosuppressive Agents/therapeutic use , Infection Control , Pneumonia, Pneumocystis/chemically induced , Pneumonia, Pneumocystis/prevention & control , Strongyloidiasis/chemically induced , Strongyloidiasis/prevention & control
7.
Autophagy ; 16(12): 2123-2127, 2020 12.
Article in English | MEDLINE | ID: covidwho-913052

ABSTRACT

In the preceding months, the novel SARS-CoV-2 pandemic has devastated global communities. The need for safe and effective prophylactic and therapeutic treatments to combat COVID-19 - the human disease resulting from SARS-CoV-2 infection - is clear. Here, we present recent developments in the effort to combat COVID-19 and consider whether SARS-CoV-2 may potentially interact with the host autophagy pathway. Abbreviations: ACE2, angiotensin converting enzyme II; ßCoV, betacoronavirus; COVID-19, Coronavirus Disease 2019; CQ, chloroquine; DMV, double-membrane vesicle; GI, gastrointestinal; HCQ, hydroxychloroquine; IL, interleukin; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MEFs, mouse embryonic fibroblasts; MERS-CoV, Middle East respiratory syndrome coronavirus; MHV, murine hepatitis virus; PE, phosphatidylethanolamine; SARS-CoV, severe acute respiratory syndrome coronavirus; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TMPRSS2, transmembrane serine protease 2; TNF, tumor necrosis factor; WHO, World Health Organization.


Subject(s)
Autophagy/physiology , COVID-19/immunology , SARS-CoV-2/immunology , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/therapeutic use , Animals , Antibodies, Monoclonal/therapeutic use , Antimetabolites/therapeutic use , Antiviral Agents/therapeutic use , Betacoronavirus/physiology , COVID-19/epidemiology , COVID-19/pathology , COVID-19/therapy , Dexamethasone/therapeutic use , Disease Outbreaks , Drug Development/trends , Humans , Mice , Pandemics , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology , Signal Transduction/physiology , Virus Internalization
8.
Front Endocrinol (Lausanne) ; 11: 554, 2020.
Article in English | MEDLINE | ID: covidwho-804167

ABSTRACT

Introduction: Italy, since the end of February 2020, is experiencing the corona virus disease 2019 (COVID-19) pandemic that may present as an acute respiratory infection. We report on COVID-19 pneumonia in the context of a complex case of Cushing's disease (CD). Case Report: A 67-year-old man with CD, who was admitted to our hospital, presented with signs and symptoms of adrenal insufficiency with persistent hypotension and glycemia toward the lower limits. We progressively withdrew almost all treatments for diabetes and CD (pasireotide and metyrapone), and i.v. hydrocortisone was necessary. A tendency to hyperkalemia was probably associated to enoxaparin. We summarized the many possible interactions between medications of Cushing's syndrome (CS) and COVID-19. Conclusion: Adrenal insufficiency might be a clinical challenge that needs a prompt treatment also in CS patients during COVID-19 infection. We should consider the possibility to titrate or temporary halt medical therapies of CS in the context of COVID-19 infection. Unexpected hyperkalemia in CS patients under treatment with heparin might be the signal of aldosterone suppression.


Subject(s)
Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Cushing Syndrome/drug therapy , Hydrocortisone/therapeutic use , Metyrapone/therapeutic use , Pneumonia, Viral/drug therapy , Aged , Anti-Inflammatory Agents/therapeutic use , Antimetabolites/therapeutic use , Betacoronavirus/isolation & purification , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/virology , Cushing Syndrome/complications , Cushing Syndrome/virology , Disease Management , Humans , Male , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/virology , SARS-CoV-2
9.
Virus Res ; 288: 198137, 2020 10 15.
Article in English | MEDLINE | ID: covidwho-720734

ABSTRACT

Several randomized controlled trials (RCTs) were conducted to investigate the effect of remdesivir for patients with COVID-19, but their results were conflicting. Thus, we conducted a network meta-analysis comparing the rate of clinical improvement among patients with COVID-19 who received 5-day course of remdesivir versus 10-day course of remdesivir versus standard care. Our network meta-analysis of 4 randomized controlled trials demonstrated that the rate of clinical improvement was significantly higher in the 5-day remdesivir group and 10-day remdesivir group compared to standard care group (OR [95% confidence interval [CI]] =1.89 [1.40-2.56], P <0.001, OR [95% CI] =1.38 [1.15-1.66], P <0.001, respectively). In addition, the rate of clinical improvement was significantly higher in the 5-day remdesivir group compared to the 10-day remdesivir group (OR [95% confidence interval [CI]] =1.37 [1.01-1.85], P =0.041). Our analysis demonstrated that the use of remdesivir for patients with COVID-19 was associated with the significantly higher clinical improvement rate compared with standard care alone.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antimetabolites/therapeutic use , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Adenosine Monophosphate/therapeutic use , Alanine/therapeutic use , Betacoronavirus/growth & development , Betacoronavirus/metabolism , COVID-19 , Coronavirus Infections/diagnosis , Coronavirus Infections/mortality , Coronavirus Infections/virology , Disease Progression , Drug Administration Schedule , Humans , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/mortality , Pneumonia, Viral/virology , Randomized Controlled Trials as Topic , SARS-CoV-2 , Severity of Illness Index , Survival Analysis , Treatment Outcome
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