Effect of lactoferrin treatment on symptoms and physical performance in long COVID patients: a randomised, double-blind, placebo-controlled trial.

Background: Long COVID is a heterogeneous condition with a variety of symptoms that persist at least 3 months after SARS-CoV-2 infection, often with a profound impact on quality of life. Lactoferrin is an iron-binding glycoprotein with anti-inflammatory and antiviral properties. Current hypotheses regarding long COVID aetiology include ongoing immune activation, viral persistence and auto-immune dysregulation. Therefore, we hypothesised that long COVID patients may potentially benefit from lactoferrin treatment. The aims of the present study were to investigate the effect of lactoferrin on various long COVID domains: fatigue, anxiety, depression, cognitive failure and muscle strength. Methods: We performed a randomised, double-blind, placebo-controlled trial in long COVID patients aged 18-70 years within 12 months after proven SARS-CoV-2 infection. Patients were randomised (1:1) to 6 weeks of lactoferrin (1200 mg daily) or placebo. At three hospital visits (T0, T6 and T12 weeks), patient-reported outcome measures were collected, physical performance tests were performed and blood was drawn. The difference in fatigue at T6 was the primary outcome. Results: 72 participants were randomised to lactoferrin (n=36) or placebo (n=36). We found a significant decrease in fatigue, as measured with the Fatigue Assessment Scale, between T0 and T6 in both study arms, but without significant difference between the study arms (lactoferrin: 3.9, 95% CI 2.3-5.5, p=0.007; placebo: 4.1, 95% CI 2.3-5.9, p=0.013). No significant differences were found in any of the other outcomes in favour of the lactoferrin arm at T6 or T12. Conclusion: Although both long COVID arms showed improved clinical outcomes at T6, the improvement did not continue until T12. Lactoferrin provided no benefit in terms of fatigue, other patient-reported outcome measures or physical functioning.

Imatinib in patients with severe COVID-19: a randomised, double-blind, placebo-controlled, clinical trial.

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 patients in the imatinib group and 82 (44%) of 188 patients in the placebo group had at least one grade 3 or higher adverse event. The safety evaluation revealed no imatinib-associated adverse events. INTERPRETATION: The study failed to meet its primary outcome, as imatinib did not reduce the time to discontinuation of ventilation and supplemental oxygen for more than 48 consecutive hours in patients with COVID-19 requiring supplemental oxygen. The observed effects on survival (although attenuated after adjustment for baseline imbalances) and duration of mechanical ventilation suggest that imatinib might confer clinical benefit in hospitalised patients with COVID-19, but further studies are required to validate these findings. FUNDING: Amsterdam Medical Center Foundation, Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ZonMW, and the European Union Innovative Medicines Initiative 2.

Pneumomediastinum in a patient with COVID-19 due to diffuse alveolar damage.

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.

Pulmonary haemorrhage in Weil's disease.

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.

[Variable presentation of antiglomerular basement membrane (anti-GBM) disease: rapid recognition vitally important]. / Wisselende presentatie van antiglomerulaire-basaalmembraanziekte: snelle herkenning van vitaal belang.

The classic clinical presentation of anti-GBM disease, or Goodpasture's disease, is pulmonary haemorrhage in combination with rapidly progressive glomerulonephritis. However, presenting symptoms vary considerably. To illustrate this, this article describes 3 male patients with anti-GBM disease, aged 25, 27 and 25 years respectively. The first patient presented with massive haemoptysis without glomerulonephritis, the second patient presented with a microcytic anaemia, caused by subclinical alveolar bleeding, and the third patient presented with rapidly progressive glomerulonephritis in combination with respiratory failure. All 3 patients required mechanical ventilation but did survive. Two patients progressed to end-stage renal disease (ESRD). Earlier recognition might prevent respiratory failure and ESRD. Therefore, despite heterogeneous clinical presentation, immediate recognition of anti-GBM disease is vitally important in view of the potentially lethal consequences if left untreated.