Other treatments for COVID-19 (with unknown or unproven mechanisms of action

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the acute setting of COVID-19 compared with the doses approved for use in atypical hemolytic uremic syndrome.

Acalabrutinib and ibrutinib

Acalabrutinib and ibrutinib are bruton tyrosine kinase inhibitors, used for CLL and lymphoma treatment. Ex vivo analysis revealed significantly elevated BTK activity (BTK regulates macrophage signalling and activation), as evidenced by autophosphorylation, and increased IL-6 production in blood monocytes from patients with severe COVID-19 compared with blood monocytes from healthy volunteers. In a pilot study, 19 patients with severe COVID-19 received the BTK inhibitor acalabrutinib (Roschewski 2020). Within 10-14 days, oxygenation improved “in a majority of patients”, often within 1-3 days, and inflammation markers and lymphopenia normalized quickly in most patients. At the end of acalabrutinib treatment, 8/11 (72.7%) patients in the supplemental oxygen cohort had been discharged on room air. These results suggest that targeting excessive host inflammation with a BTK inhibitor can be a therapeutic strategy. A confirmatory RCT is underway. Some reports have speculated about a protective effect of ibrutinib, another BTK inhibitor (Thibaud 2020).

ASS/Aspirin

Aspirin may help (a little bit). In a retrospective, observational cohort study of 412 adult patients admitted with COVID-19 to multiple US hospitals between March and July, 98 (24%) received aspirin within 24 hours of admission or 7 days prior to admission. Aspirin use had a crude association with less mechanical ventilation (36% vs. 48%, p = 0,03) and ICU admission (39% vs. 51%, p = 0,04), but no crude association with in-hospital mortality (26% vs. 23%, p = 0,51). After adjusting for 8 confounding variables, aspirin use was independently associated with decreased risk of mechanical ventilation (adjusted HR 0,56, 95% CI: 0,37-0,85, p = 0,007), ICU admission (adjusted HR 0,57, 95% CI: 0,38-0,85, p = 0,005), and in-hospital mortality (adjusted HR 0,53, 95% CI: 0,31-0,90, p = 0,02). According to the authors, a sufficiently powered randomized controlled trial is needed. The RECOVERY trial includes ASS as an option.

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Colchicine

Colchicine is one of the oldest known drugs which has been used for over 2000 years as a remedy for acute gout flares. Given its anti-inflammatory and anti-viral properties, it is also being tested in COVID-19 patients. In a prospective, open-label RCT from Greece, 105 hospitalized patients were randomized to either standard of care (SOC) or colchicine plus SOC (Deftereos 2020). Participants who received colchicine had statistically “significantly improved time to clinical deterioration”. However, there were no significant differences in biomarkers and the observed difference was based on a narrow margin of clinical significance; according to the authors their observations “should be considered hypothesis generating” and “be interpreted with caution”. In a retrospective cohort there was some evidence on clinical benefit (Brunetti 2020). Colchicine has been included as an early immunomodulation therapy in the RECOVERY trial.

Famotidine

Famotidine is a histamine-2 receptor antagonist that suppresses gastric acid production. It has an excellent safety profile. Initially it was thought to inhibit the 3-chymotrypsin-like protease (3CLpro), but it seems to act rather as an immune modulator, via its antagonism or inverse-agonism of histamine signaling. While results of the randomized clinical trial on the benefits of intravenous famotidine in treating COVID-19 (NCT04370262) are eagerly awaited, we can only speculate on the potential mechanisms of action of this drug (Singh 2020). • In a retrospective study on 1620 patients, 84 (5.1%) received different doses of famotidine within 24 hours of hospital admission (Freedberg 2020).

After adjusting for baseline patient characteristics, use of famotidine remained independently associated with risk for death or intubation (adjusted hazard ratio 0.42, 95% CI 0.21-0.85) and this remained unchanged after careful propensity score matching to further balance the covariables. Of note, there was no protective effect of PPIs. Plasma ferritin values during hospitalization were lower with famotidine, indicating that the drug blocks viral replication and reduces the cytokine storm. • A second propensity-matched observational study included 878 consecutive COVID-19-positive patients admitted to Hartford hospital, a tertiary care hospital in Connecticut, USA (Mather 2020). In total, 83 (9.5%) patients received famotidine. These patients were somewhat younger (63.5 vs 67.5 years) but did not differ with respect to baseline demographics or pre-existing comorbidities. Use of famotidine was associated with a de-

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creased risk of in-hospital mortality (odds ratio 0.37, 95% CI 0.16-0.86) and combined death or intubation (odds ratio 0.47, 95% CI 0.23-0.96). Patients receiving famotidine displayed lower levels of serum markers for severe disease including CRP, procalcitonin and ferritin levels. Logistic regression analysis demonstrated that famotidine was an independent predictor of both lower mortality and combined death/intubation.

Fluvoxamine

Fluvoxamine (a potent agonist of the sigma-1 receptor (σ1R)), is an antidepressant which functions pharmacologically as a selective serotonin reuptake inhibitor. In a small RCT that included 152 adult outpatients with COVID-19 and symptom onset within 7 days, clinical deterioration occurred in 0 patients treated with fluvoxamine vs 6 (8%) patients treated with placebo over 15 days (Lenze 2020). The authors acknowledge the limitations of their study: a small number of endpoint events, which makes the findings fragile. The potential advantages of fluvoxamine for outpatient treatment of COVID-19 would include its safety, widespread availability, low cost, and oral administration. Note that fluvoxamine can cause drug-drug interactions. Eagerly awaiting data from larger trials.

G-CSF

G-CSF may be helpful in some patients (Cheng 2020). In an open-label trial at 3 Chinese centers, 200 patients with lymphopenia and no comorbidities were randomized to standard of care or to 3 doses of recombinant human G-CSF (5 μg/kg, subcutaneously at days 0-2). Time to clinical improvement was similar between groups. However, the proportion of patients progressing to ARDS, sepsis, or septic shock was lower in the rhG-CSF group (2% vs 15%). Mortality was also lower (2% vs 10%).

Iloprost

Iloprost is a prostacyclin receptor agonist that promotes vasodilation of circulatory beds with minimal impact on hemodynamic parameters. It is licensed for the treatment of pulmonary arterial hypertension and is widely used for the management of peripheral vascular disease and digital vasculopathy, including digital ulcers and critical digital ischemia in systemic sclerosis. There is a case series of three morbidly obese patients with severe COVID-19 and systemic microvasculopathy who obviously benefitted from its use (Moezinia 2020).