Background The major complication of COVID-19 is hypoxaemic respiratory failure from capillary leak and alveolar oedema. Experimental and early clinical data suggest that the tyrosine-kinase inhibitor imatinib reverses pulmonary capillary leak. Methods This randomised, double-blind, placebo-controlled, clinical trial was done at 13 academic and non-academic teaching hospitals in the Netherlands. Hospitalised patients (aged ≥18 years) with COVID-19, as confirmed by an RT-PCR test for SARS-CoV-2, requiring supplemental oxygen to maintain a peripheral oxygen saturation of greater than 94% were eligible. Patients were excluded if they had severe pre-existing pulmonary disease, had pre-existing heart failure, had undergone active treatment of a haematological or non-haematological malignancy in the previous 12 months, had cytopenia, or were receiving concomitant treatment with medication known to strongly interact with imatinib. Patients were randomly assigned (1:1) to receive either oral imatinib, given as a loading dose of 800 mg on day 0 followed by 400 mg daily on days 1–9, or placebo. Randomisation was done with a computer-based clinical data management platform with variable block sizes (containing two, four, or six patients), stratified by study site. The primary outcome was time to discontinuation of mechanical ventilation and supplemental oxygen for more than 48 consecutive hours, while being alive during a 28-day period. Secondary outcomes included safety, mortality at 28 days, and the need for invasive mechanical ventilation. All efficacy and safety analyses were done in all randomised patients who had received at least one dose of study medication (modified intention-to-treat population). This study is registered with the EU Clinical Trials Register (EudraCT 2020–001236–10). Findings Between March 31, 2020, and Jan 4, 2021, 805 patients were screened, of whom 400 were eligible and randomly assigned to the imatinib group (n=204) or the placebo group (n=196). A total of 385 (96%) patients (median age 64 years [IQR 56–73]) received at least one dose of study medication and were included in the modified intention-to-treat population. Time to discontinuation of ventilation and supplemental oxygen for more than 48 h was not significantly different between the two groups (unadjusted hazard ratio [HR] 0·95 [95% CI 0·76–1·20]). At day 28, 15 (8%) of 197 patients had died in the imatinib group compared with 27 (14%) of 188 patients in the placebo group (unadjusted HR 0·51 [0·27–0·95]). After adjusting for baseline imbalances between the two groups (sex, obesity, diabetes, and cardiovascular disease) the HR for mortality was 0·52 (95% CI 0·26–1·05). The HR for mechanical ventilation in the imatinib group compared with the placebo group was 1·07 (0·63–1·80; p=0·81). The median duration of invasive mechanical ventilation was 7 days (IQR 3–13) in the imatinib group compared with 12 days (6–20) in the placebo group (p=0·0080). 91 (46%) of 197 pa...

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Worldwide, tuberculosis (TB) is among the top five causes of death for women aged 15-44 years [1]. In 2014, an estimated 480 000 of newly reported TB cases were multidrug-resistant (MDR) TB [1]. Pregnancy is a risk factor for reactivation of TB, but data about multidrug-resistant (MDR)-TB in pregnant women are lacking. There are few data about the efficacy and safety of second-line anti-TB drugs during pregnancy for both the mother and the unborn child [2]. One study from Peru showed a mortality rate of 13% in 38 patients and 13% of these 38 patients were lost to follow-up. Five of the pregnancies ended in spontaneous abortions, and one child was stillborn. Data for pregnant women did not differ from the general MDR-TB population in Peru [2]. To assure efficacy while minimising adverse events, therapeutic drug monitoring (TDM) has been proposed [3]. In TDM of anti-TB drugs, the accurately measured exposure to the drug [4] is evaluated in relation to the minimum inhibitory concentration (MIC) of the offending strain of Mycobacterium tuberculosis [5]. Low drug exposure is associated with an increased risk of treatment failure or with acquired resistance. High drug exposure might result in increased toxicity and adverse events [6]. Little is known about the effects of pregnancy in patients with MDR-TB with regards to the pharmacokinetics of second-line anti-TB drugs [2]. During pregnancy, pharmacokinetic parameters might change over time because of dynamic physiological changes in different stages of pregnancy, leading to inadequate treatment and poor outcome. In this case study, we aimed to describe the pharmacokinetics of moxifloxacin (Mfx) and linezolid (Lzd) during and after pregnancy in a patient with MDR-TB. A 25-year-old HIV-negative female from Somalia presented with a cough of several months' duration. She had arrived in the Netherlands 10 months earlier [7]. Her sister had been diagnosed with TB 12 years ago, and had been treated successfully. Physical examination revealed an enlarged lymph node in her neck. Culture from a fine-needle aspirate yielded M. tuberculosis. The chest radiograph showed no abnormalities; she was started on rifampin, isoniazid, pyrazinamide and ethambutol. Molecular susceptibility testing of the cultured isolate showed mutations in both the rpoB and katG genes. She was diagnosed with MDR-TB and transferred to our TB reference centre at 11 weeks' gestation. The first-line anti-TB drugs were discontinued and we decided to wait for further susceptibility results before starting with-second line anti-TB drugs to avoid giving inactive but potentially toxic drugs to the fetus. We considered it safe to withhold the treatment for some time as lymph node TB is paucibacillary and she was clinically stable without apparent disease activity apart from the nuchal lymph nodes. In vitro phenotypical susceptibility testing was performed, and the isolate appeared resistant to the first-line drugs rifampicin, isoniazid and ethambutol, but susceptible to all injectables, moxifloxacin, prothionamide, ...

Background First studies indicate that up to 6 months after hospital discharge, coronavirus disease 2019 (COVID-19) causes severe physical, cognitive, and psychological impairments, which may affect participation and health-related quality of life (HRQoL). After hospitalization for COVID-19, a number of patients are referred to medical rehabilitation centers or skilled nursing facilities for further treatment, while others go home with or without aftercare. The aftercare paths include 1] community-based rehabilitation; 2] in- and outpatient medical rehabilitation; 3] inpatient rehabilitation in skilled nursing facilities; and 4] sheltered care (inpatient). These aftercare paths and the trajectories of recovery after COVID-19 urgently need long-term in-depth evaluation to optimize and personalize treatment. CO-FLOW aims, by following the outcomes and aftercare paths of all COVID-19 patients after hospital discharge, to systematically study over a 2-year period: 1] trajectories of physical, cognitive, and psychological recovery; 2] patient flows, healthcare utilization, patient satisfaction with aftercare, and barriers/facilitators regarding aftercare as experienced by healthcare professionals; 3] effects of physical, cognitive, and psychological outcomes on participation and HRQoL; and 4] predictors for long-term recovery, health care utilization, and patient satisfaction with aftercare. Methods CO-FLOW is a multicenter prospective cohort study in the mid-west of the Netherlands with a 2-year follow-up period. Measurements comprise non-invasive clinical tests and patient reported outcome measures from a combined rehabilitation, pulmonary, and intensive care perspective. Measurements are performed at 3, 6, 12, and 24 months after hospital discharge and, if applicable, at rehabilitation discharge. CO-FLOW aims to include at least 500 patients who survived hospitalization for COVID-19, aged ≥18 years. Discussion CO-FLOW will provide in-depth knowledge on the long-term sequelae of COVID-19 and the quality of current aftercare paths for patients who survived hospitalization. This knowledge is a prerequisite to facilitate the right care in the right place for COVID-19 and comparable future infectious diseases. Trial registration The Netherlands Trial Register (NTR), https://www.trialregister.nl. Registered: 12-06-2020, CO-FLOW trialregister no. NL8710.

Leptospirosisis a zoonosis caused by spirochaetes from the species Leptospira. The more severe form of leptospirosis, known as Weil’s disease, is characterised by the triad of jaundice, renal impairment and haemorrhages. Pulmonary involvement occurs in 20%–70% of the patients, with severity ranging from non-productive cough to respiratory failure mainly due to pulmonary haemorrhage. Recognition of Weil’s disease in patients presenting with pulmonary symptoms can be difficult. This case illustrates a classic case of pulmonary haemorrhagic involvement in Weil’s disease.

A 74-year-old man with COVID-19 was admitted and experienced progressive dyspnoea while receiving supplemental oxygen via high-flow nasal cannula (HFNC). A CT of the thorax showed a pneumomediastinum. The HFNC was temporally interrupted, since it was uncertain whether the positive end-expiratory pressure of the HFNC could be the cause of the pneumomediastinum. After restart of the HFNC, there was no increase of symptoms. We suggest that the pneumomediastinum was the result of COVID-19-related alveolar damage, and not due to the use of HFNC. This observation is relevant since HFNC is often used in the treatment of severe COVID-19 pneumonia.

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