key: cord-1025228-qp4cbv3i
authors: Meini, Simone
title: Overcoming the therapeutic nihilism of out-of-hospital management of COVID-19 patients
date: 2020-12-16
journal: Am J Epidemiol
DOI: 10.1093/aje/kwaa274
sha: c5d660fcba6dd636918bc839a8448c3ae2940c79
doc_id: 1025228
cord_uid: qp4cbv3i

nan

I read with great interest the Risch's paper [1] on the urgent need to discuss COVID-19 outpatient treatment. Many strategies have been tested since the pandemic began, but all that has emerged regarding non-hospitalized patients is a sort of therapeutic nihilism.

As I write (November 17, 2020), in Italy (60,244,639 inhabitants) there are 33,074 persons hospitalized for COVID-19, 3,612 requiring intensive-care, and many more (697,124) are in home isolation: our health-care system is on the verge of a new unsustainable burden. Most infected people are asymptomatic, but many will worsen and require hospitalization. It is therefore crucial to interrupt as early as possible disease progression. Outpatients do not receive regular laboratory monitoring, so the global disease impact on them remains unknown: any consideration on appropriate treatments must take into account this missing data.

I agree that hydroxychloroquine plus azithromycin (or doxycycline) could still be considered a suitable home-option, deserving further studies. Hydroxychloroquine 200mg twice-daily could optimize the efficacy/safety balance, doxycycline could be its ideal partner, inexpensive, safe and displaying antiviral, anti-inflammatory and lung-protective effects [2] .

Other options for outpatients must be considered.

Antivirals are crucial when viral replication prevails over host response, but intravenous remdesivir is suitable only for hospitalized patients [3, 4] . Oral lopinavir/ritonavir should be reconsidered [5] :

loss of interest in this option began following Cao's trial [6] Overall mortality was 22.1%: the severity of patients enrolled could have contributed to the poor efficacy observed. Cao et al. [7] concluded that lopinavir/ritonavir may still be a potential treatment, recommending that clinicians review all trial's data. Gastrointestinal adverse events represent a concern [5,6], but Baldelli et al. [8] showed that COVID-19 patients co-treated with hydroxychloroquine have lopinavir/ritonavir trough concentrations three-fold higher compared with HIV-patients, due to SARS-CoV-2-induced liver damage or to interaction with hydroxychloroquine. Further investigation is warranted for a reduced dose, for early hometreatment.

Heparins counteract SARS-CoV-2 cell-entry and modulate immunothrombosis and cytokine storm [9, 10] . The beneficial anti-thrombotic effects of enoxaparin 4000IU once-daily extend to a wide range of acutely ill medical patients (including acute respiratory failure and infectious disease), with

adverse effects comparable to placebo [11] . Low-molecular-weight-heparins in prophylactic doses, for a short time, could be a safe option for early home-treatment, especially for patients at higher risk of venous thromboembolism. Trials are ongoing (NCT04400799).

Finally, a dysregulated host response is crucial in causing organ failure: patients with clinical/laboratory evidence of inflammatory hyperactivation could benefit from anti-inflammatory interventions. Corticosteroids are associated with lower 28-day all-cause mortality in critical patients [12] , and are recommended for all hospitalized patients with severe disease 

Early Outpatient Treatment of Symptomatic, High-Risk COVID-19 Patients That Should Be Ramped Up Immediately as Key to the Pandemic Crisis

Doxycycline as a potential partner of COVID-19 therapies

ACTT-1 Study Group Members. Remdesivir for the Treatment of Covid-19 -Final Report

Repurposed antiviral drugs for COVID-19-interim WHO SOLIDARITY trial results. WHO Solidarity trial consortium

Role of Lopinavir/Ritonavir in the Treatment of Covid-19: A Review of Current Evidence, Guideline Recommendations, and Perspectives

A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19

A Trial of Lopinavir-Ritonavir in Covid-19

Lopinavir/ritonavir in COVID-19 patients: maybe yes, but at what dose?

Understanding the Pathophysiology of COVID-19: Could the Contact System Be the Key?

Use of Enoxaparin to Counteract COVID-19 Infection and Reduce Thromboembolic Venous Complications: A Review of the Current Evidence

A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group

Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis