Background In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov ( NCT04381936 ). Findings Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding UK Research and Innovation (Medical Research Council) and National Institute of Health Research.

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BackgroundThe addition of Rituximab (R) to standard chemotherapy (C) has been reported to improve the end of treatment outcome in patients affected by CD-20 positive malignant lymphomas (CD20+ ML). Nevertheless, given the profound and prolonged immunosuppression produced by R there are concerns that severe infections may arise. A systematic review and meta-analysis were performed to determine whether or not the addition of R to C may increase the risk of severe infections in adults undergoing induction therapy for CD20+ ML.MethodsOnly randomised controlled trials comparing R-C to C standard alone in adult patients with CD20+ ML were included. Meta-analysis was performed on overall incidence of severe infection, risk of dying as the consequence of infection, risk of febrile neutropenia, risk of severe leucopenia, risk of severe granulocytopenia and overall response assuming a fixed effect model. Heterogeneity was investigated, if present and I2 >20%, according to several predefined baseline characteristics of the study populations.ResultsSeveral relevant results have emerged. First, the addition of R to standard C does not increase the overall risk of severe infections (RR = 1.00; 95% CI 0.87 to 1.14) nor does it increase the risk of dying as a consequence of infection (RR = 1.60; 95% CI 0.68 to 3.75). Second, we confirmed that the addition of R to standard C increases the proportion of overall response (RR = 1.12; 95% CI 1.09 to 1.15), but it also increases the risk of severe leucopenia (RR = 1.24; 95% CI 1.12 to 1.37) and granulocytopenia (RR = 1.07; 95% CI 1.02 to 1.12).ConclusionsR-C is superior to standard C in terms of overall response and it does not increase the overall incidence of severe infection. However, data on special groups of patients (for example, HIV positive subjects and HBV carriers) are lacking. In our opinion more studies are needed to explore the potential effect of R on silent and chronic viral infections.

The prevalence of Salmonella enterica serotype Paratyphi A infection is increasing, and multidrug resistance is a well-recognized problem. Resistance to fluoroquinolones is common and leads to more frequent use of newer agents like azithromycin. We report the first case of azithromycin resistance and treatment failure in a patient with S. Paratyphi A infection. CASE REPORTA 48-year-old male doctor presented to the accident and emergency department with a 2-week history of rigors, fever, and lethargy following a 10-day vacation in Islamabad, Pakistan. He had not been vaccinated against typhoid or taken antimalarial chemoprophylaxis. He developed diarrhea 2 days prior to the end of his stay in Pakistan and took oral metronidazole at 400 mg three times daily for 5 days. The diarrhea resolved, but his temperature continued to spike to 39°C over the following 2 weeks. He had a prior medical history of hypercholesterolemia and gout and had had an appendectomy as a young student. His regular medications consisted of allopurinol at 200 mg once daily and simvastatin at 20 mg once daily. Clinical examination on presentation was unremarkable other than a temperature of 38.5°C.Initial laboratory investigations revealed a raised alanine transaminase (ALT) level of 93 IU/liter (normal value, 10 to 50 IU/liter), a bilirubin level of 20 mol/liter (normal value, 3 to 17 mol/liter), and a C-reactive protein (CRP) level of 70 mg/liter (normal value, Ͻ5 mg/liter). Full blood count, serum electrolytes, and creatinine were within normal limits. Chest and abdominal radiographs showed no abnormalities. A malaria blood film and antigen test were negative.In view of the possibility of enteric fever, he was started on oral ciprofloxacin at 500 mg twice daily according to the hospital antibiotic policy. He was reluctant to be admitted to the hospital and was discharged with a follow-up appointment in the infectious diseases outpatient clinic. Blood cultures taken on admission yielded Salmonella enterica serotype Paratyphi A, which was reported as sensitive to ciprofloxacin on disc testing.The patient presented again following 7 days of treatment with persistent fever and rigors. He remained reluctant to be admitted, and so antimicrobial therapy was changed to oral azithromycin.His symptoms worsened over the next 3 days, and he was admitted to the hospital. He complained of increasing frequency of rigors and fevers, occurring every 4 h and lasting for 2 h, and a dry cough. He had been fully adherent to the antimicrobial therapy prescribed. On examination he had a temperature of 38°C and the spleen was palpable 1 cm below the costal margin. In view of the poor response to treatment, antimicrobial therapy was changed to intravenous ceftriaxone at 2 g once daily.Laboratory investigations revealed a raised CRP level of 65 mg/liter (normal value, Ͻ5 mg/liter), an ALT level of 358 IU/liter (normal value, 10 to 50 IU/liter), an alkaline phosphatase level of 256 IU/liter (normal value, 30 to 200 IU/liter), and a negative malaria film. A repeat ches...

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