Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia

BACKGROUND Coronavirus disease 2019 (Covid-19) is associated with immune dysregulation and hyperinflammation, including elevated interleukin-6 levels. The use of tocilizu- mab, a monoclonal antibody against the interleukin-6 receptor, has resulted in better outcomes in patients with severe Covid-19 pneumonia in case reports and retrospective observational cohort studies. Data are needed from randomized, placebo-controlled trials. METHODS In this phase 3 trial, we randomly assigned patients who were hospitalized with severe Covid-19 pneumonia in a 2:1 ratio receive a single intravenous infusion of tocilizumab (at a dose of 8 mg per kilogram of body weight) or placebo. Approxi- mately one quarter of the participants received a second dose of tocilizumab or placebo 8 to 24 hours after the first dose. The primary outcome was clinical status at day 28 on an ordinal scale ranging from 1 (discharged or ready for discharge) to 7 (death) in the modified intention-to-treat population, which included all the patients who had received at least one dose of tocilizumab or placebo. RESULTS Of the 452 patients who underwent randomization, 438 (294 in the tocilizumab group and 144 in the placebo group) were included in the primary and secondary analyses. The median value for clinical status on the ordinal scale at day 28 was 1.0 (95% confidence interval [CI], 1.0 to 1.0) in the tocilizumab group and 2.0 (non-ICU hospitalization without supplemental oxygen) (95% CI, 1.0 to 4.0) in the placebo group (between-group difference, −1.0; 95% CI, −2.5 to 0; P=0.31 by the van Elteren test). In the safety population, serious adverse events occurred in 103 of 295 patients (34.9%) in the tocilizumab group and in 55 of 143 patients (38.5%) in the placebo group. Mortality at day 28 was 19.7% in the tocilizumab group and 19.4% in the placebo group (weighted difference, 0.3 percentage points (95% CI, –7.6 to 8.2; nominal P=0.94). CONCLUSIONS In this randomized trial involving hospitalized patients with severe Covid-19 pneu- monia, the use of tocilizumab did not result in significantly better clinical status or lower mortality than placebo at 28 days. (Funded by F. Hoffmann–La Roche and the Department of Health and Human Services; COVACTA ClinicalTrials.gov num- ber, NCT04320615.

A fatal case of AIDS-defining meningoencephalitis by C. Neoformans, sensitive to antifungal therapy

Cryptococcus neoformans is the most common cause of life threatening meningoencephalitis in HIV-infected patients. Diagnosis is based on tests for cryptoccocal antigen in serum and cerebrospinal fluid, and on culture of the organism. We present a case of AIDS-related cryptococcal meningoencephalitis unresponsive to antifungal combination therapy, despite of evidence of fungal susceptibility in vitro. Significant decreases in cryptococcal antigen titers in serum and cerebrospinal fluid did not correlate with progress in disease and fatal outcome

Older age does not influence CD4 cell recovery in HIV-1 infected patients receiving Highly Active Anti Retroviral Therapy

BACKGROUND: Diagnosis of HIV infection is recently occurring with increasing frequency in middle-aged and in older individuals. As HAART became available, a minimal beneficial effect on immunological outcome in older in respect of younger subjects has been reported. In fact, both the intensity and the rapidity of the immunological response appeared to be reduced in elderly subjects. On the contrary, only few reports have indicated a similar immunological outcome both in older and younger HIV-positive subjects. Interestingly, older age did not seem to significantly affect the long-term virological outcome of HAART treated subjects. METHODS: To characterise epidemiological and clinical features of older HIV+ subjects, a prospective case-control study was performed: 120 subjects ≥ 50 and 476 between 20 and 35 years were initially compared. Subsequently, to better define the impact of HAART on their viro-immunological response, 81 older were compared with 162 younger subjects. RESULTS: At baseline cases presented significantly lower TCD4+ cell number and were more frequently affected by comorbid conditions. Under HAART a statistically significant increase in TCD4+ cell number was observed in cases and controls. At multivariate analysis, there was no statistically significant difference between cases and controls regarding viro-immunological response. CONCLUSIONS: Although older subjects present a more severe HIV infection, they can achieve, under HAART, the same viro-immunological success as the younger individuals

AIDS-related primary central nervous system lymphoma: a Norwegian national survey 1989–2003

<p>Abstract</p> <p>Background</p> <p>Primary central nervous system lymphoma (PCNSL) is a frequent complication in acquired immunodeficiency syndrome (AIDS). The objective of this survey was to investigate incidence, clinical features, radiological findings, histologic diagnosis, treatment and outcome for all patients with histologically verified AIDS-related PCNSL diagnosed in Norway in 1989–2003.</p> <p>Methods</p> <p>We identified the patients by chart review of all cases recorded as PCNSL in The Norwegian Cancer Registry (by law recording all cases of cancer in Norway) and all cases recorded as AIDS-related PCNSL in the autopsy registry at a hospital having 67% autopsy rate and treating 59% of AIDS patients in Norway, from 1989 to 2003. Histologic material and radiological images were reviewed. We used person-time techniques to calculate incidence rates of PCNSL among AIDS patients based on recordings on AIDS at the Norwegian Surveillance System for Communicable Diseases (by law recording all cases of AIDS in Norway).</p> <p>Results</p> <p>Twenty-nine patients had histologically confirmed, newly diagnosed AIDS-related PCNSL in Norway from 1989–2003. Only 2 patients had this diagnosis established while alive. AIDS patients had 5.5% lifetime risk of PCNSL. Their absolute incidence rate of PCNSL per 100 person-years was 1.7 (95%CI: 1.1–2.4) and decreased during the consecutive 5-year periods from 3.6, to 2.5, and to 0.4 (p < 0.001). Median survival from initial symptom of PCNSL was 2.3 months, but one patient was still alive 4 years after completed radiotherapy.</p> <p>Conclusion</p> <p>This is the first national survey to confirm decreasing incidence of AIDS-related PCNSL. Despite dismal survival in most patients, the possibility of long term survival should prompt more aggressive diagnostics in suspected PCNSL.</p

Prevalence and clinical management of cytomegalovirus retinitis in AIDS patients in shanghai, china

<p>Abstract</p> <p>Background</p> <p>Cytomegalovirus retinitis is a common AIDS-associated illness, leading to blindness in up to 30% of patients. This study was to investigate the prevalence and clinical management of the cytomegalovirus retinitis associated with AIDS in a large municipality of China.</p> <p>Methods</p> <p>Clinical and laboratory data from 23 cytomegalovirus retinitis patients (35 eyes) out of 303 hospitalized AIDS individuals in a single medical center were analyzed retrospectively. Two of 23 patients were diagnosed cytomegalovirus retinitis just before hospitalization without anti-CMV therapy. Ganciclovir combined with the high active anti-retroviral therapy was installed for treatment of cytomegalovirus retinitis after diagnosis was confirmed. The data were analyzed by specialists and statistics was also applied.</p> <p>Results</p> <p>The prevalence of cytomegalovirus retinitis in hospitalized AIDS patients was 7.6% in this study. The level of CD₄⁺T lymphocytes was correlated well with the occurrence of cytomegalovirus retinitis, showing 16.8% (19/113) (95% confidence interval: 10.4,25.0), 5.4% (3/56) (95% confidence interval: 1.1,14.9), and 1.4% (1/69) (95% confidence interval: 0.0,7.8) occurrence in the patients with CD₄⁺T lymphocyte counts < 50, 50~99, and 100~199 cells/μl, respectively. The mean CD₄⁺T lymphocyte counts was 31.7 ± 38.6 cells/μl in 23 AIDS patients with cytomegalovirus retinitis. Median CD₄⁺T lymphocyte count is 20 cells/μl with inter-quartile range as (5, 36). Seven patients died (11 eyes) and 16 patients (24 eyes) survived. The proportion of blindness and low vision in eyes infected with cytomegalovirus retinitis respectively was 20.8% (5/24) and 29.2% (7/24) when they were diagnosed in survivors. The ganciclovir therapy was effective in 16 patients (24 eyes). Clinical recovery of cytomegalovirus retinitis was 41.7% (10/24) and clinical improvement 58.3% (14/24). After anti-CMV treatment, the proportion of blindness or low vision was 16.7% (4/24).</p> <p>Conclusions</p> <p>The AIDS patients with CD₄⁺T lymphocyte < 50 cells/μl had increased susceptibility to cytomegalovirus associated retinitis. Cytomegalovirus retinitis is a serious disease causing blindness. The cytomegalovirus retinitis in the AIDS patients was response well to ganciclovir therapy. We should check their eyes routinely such as dilated fundus examination with an indirect ophthalmoscope in the AIDS patients with CD₄⁺T lymphocyte counts < 50 cells/μl.</p

Cryptococcal Neuroradiological Lesions Correlate with Severity during Cryptococcal Meningoencephalitis in HIV-Positive Patients in the HAART Era

Cryptococcal meningoencephalitis has an overall global mortality rate of 20% in AIDS patients despite antifungals. There is a need for additional means of precise assessment of disease severity. We thus studied the radiological brain images available from 62 HIV-positive patients with cryptococcocal meningoencephalitis to analyse the brain lesions associated with cryptococcosis in relationship with disease severity, and the respective diagnostic contribution of magnetic resonance (MR) versus computed tomography (CT)

Whole Genome Characterization of the Mechanisms of Daptomycin Resistance in Clinical and Laboratory Derived Isolates of Staphylococcus aureus

Background: Daptomycin remains one of our last-line anti-staphylococcal agents. This study aims to characterize the genetic evolution to daptomycin resistance in S. aureus. Methods: Whole genome sequencing was performed on a unique collection of isogenic, clinical (21 strains) and laboratory (12 strains) derived strains that had been exposed to daptomycin and developed daptomycin-nonsusceptibility. Electron microscopy (EM) and lipid membrane studies were performed on selected isolates. Results: On average, six coding region mutations were observed across the genome in the clinical daptomycin exposed strains, whereas only two mutations on average were seen in the laboratory exposed pairs. All daptomycin-nonsusceptible strains had a mutation in a phospholipid biosynthesis gene. This included mutations in the previously described mprF gene, but also in other phospholipid biosynthesis genes, including cardiolipin synthase (cls2) and CDP-diacylglycerol-glycerol-3-phosphate 3-phosphatidyltransferase (pgsA). EM and lipid membrane composition analyses on two clinical pairs showed that the daptomycin-nonsusceptible strains had a thicker cell wall and an increase in membrane lysyl-phosphatidylglycerol. Conclusion: Point mutations in genes coding for membrane phospholipids are associated with the development of reduced susceptibility to daptomycin in S. aureus. Mutations in cls2 and pgsA appear to be new genetic mechanisms affecting daptomycin susceptibility in S. aureus

Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia

BACKGROUND Coronavirus disease 2019 (Covid-19) is associated with immune dysregulation and hyperinflammation, including elevated interleukin-6 levels. The use of tocilizumab, a monoclonal antibody against the interleukin-6 receptor, has resulted in better outcomes in patients with severe Covid-19 pneumonia in case reports and retrospective observational cohort studies. Data are needed from randomized, placebo-controlled trials. METHODS In this phase 3 trial, we randomly assigned patients who were hospitalized with severe Covid-19 pneumonia in a 2:1 ratio receive a single intravenous infusion of tocilizumab (at a dose of 8 mg per kilogram of body weight) or placebo. Approximately one quarter of the participants received a second dose of tocilizumab or placebo 8 to 24 hours after the first dose. The primary outcome was clinical status at day 28 on an ordinal scale ranging from 1 (discharged or ready for discharge) to 7 (death) in the modified intention-to-treat population, which included all the patients who had received at least one dose of tocilizumab or placebo. RESULTS Of the 452 patients who underwent randomization, 438 (294 in the tocilizumab group and 144 in the placebo group) were included in the primary and secondary analyses. The median value for clinical status on the ordinal scale at day 28 was 1.0 (95% confidence interval [CI], 1.0 to 1.0) in the tocilizumab group and 2.0 (non-ICU hospitalization without supplemental oxygen) (95% CI, 1.0 to 4.0) in the placebo group (between-group difference, −1.0; 95% CI, −2.5 to 0; P=0.31 by the van Elteren test). In the safety population, serious adverse events occurred in 103 of 295 patients (34.9%) in the tocilizumab group and in 55 of 143 patients (38.5%) in the placebo group. Mortality at day 28 was 19.7% in the tocilizumab group and 19.4% in the placebo group (weighted difference, 0.3 percentage points; 95% CI, –7.6 to 8.2; nominal P=0.94). CONCLUSIONS In this randomized trial involving hospitalized patients with severe Covid-19 pneumonia, the use of tocilizumab did not result in significantly better clinical status or lower mortality than placebo at 28 days. (Funded by F. Hoffmann–La Roche and the Department of Health and Human Services; COVACTA ClinicalTrials.gov number, NCT04320615