European society of clinical microbiology and infectious diseases guidelines for coronavirus disease 2019: an update on treatment of patients with mild/moderate disease

Abstract

Scope: Despite the large availability of vaccines, coronavirus disease 2019 (COVID-19), induced by severe acute respiratory syndrome coronavirus 2, continues to be a major threat for health-care providers and fragile people. A number of options are now available for outpatients with mild-to-moderate COVID-19 at the risk of disease progression for the prevention of deaths or hospitalization.

Methods: A European Society of Clinical Microbiology and Infectious Diseases COVID-19 guidelines task force was established by the European Society of Clinical Microbiology and Infectious Diseases Executive Committee. A small group was established, half appointed by the chair and the remaining selected based on an open call. Each panel met virtually once a week. For all decisions, a simple majority vote was used. A long list of clinical questions using the population, intervention, comparison, outcome format was developed at the beginning of the process. For each population, intervention, comparison, outcome, two panel members performed a literature search, with a third panelist involved in case of inconsistent results. Voting was based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

Recommendations: In this update, we focus on anti-viral agents, monoclonal antibodies (mAbs) and other treatment options proposed for patients with mild or moderate COVID-19 who are at the risk of hospitalization or death. Although the use of anti-virals is recommended, especially nirmatrelvir/ritonavir and remdesivir or, alternatively, molnupirarvir, the administration of mAbs against the spike protein strictly depends on circulating variants or the ability to test timely for variants and sub-variants. At the time of writing (April-June 2022), the only active mAb was tixagevimab/cilgavimab given the predominance of the Omicron BA.2, BA.3, BA.4 and BA.5 sub-lineages in Europe. However, considering that the epidemiological scenario is extremely dynamic, constant monitoring of variants of concern is mandatory.

Keywords: COVID-19; Cilgavimab; ESCMID; Molnupiravir; Nirmatrelvir/ritonavir; Outpatients; Remdesivir; Sotrovimab; Tixagevimab.

Fig. 1

European Society of Clinical Microbiology and Infectious Diseases coronavirus disease 2019 treatment guidelines. Summary of recommendations for outpatients with mild or moderate coronavirus disease 2019 at the risk of disease progression. COVID-19, coronavirus disease 2019; eGFR, estimated glomerular filtration rate; mAb, monoclonal antibody; RBD, receptor-binding domain; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. ^∗The risk factors for disease progression are as follows: ≥60 years of age; body mass index >25 kg/m2; cigarette smoking; immuno-suppressive disease (including human immuno-deficiency virus infection with a CD4 cell count of <200 mm3) or prolonged iatrogenic immunosuppression; chronic lung, cardiovascular, kidney, or sickle cell disease; hypertension; diabetes; cancer; neurodevelopmental disorders or other medically complex conditions or medical-related technological dependence. ∗∗ The risk factors for vaccine failure are as follows: (a) incomplete vaccination history; (b) moderate or severe primary immuno-deficiency; (c) advanced or untreated human immuno-deficiency virus infection; (d) receipt of chimeric antigen receptor-T cell therapy or haematopoietic cell transplant within the previous 2 years; (e) active treatment for a solid tumour or haematological malignancy; (f) use of immuno-suppressive therapy after a solid-organ transplant; (g) active treatment with other immuno-suppressive or immuno-modulatory drugs, such as high-dose corticosteroids (≥20 mg/d of prednisone or equivalent) and tumour necrosis factor inhibitors [13,58].

Fig. 2

Proposed algorithm of treatment for outpatients with mild or moderate coronaviris disease 2019, the onset of symptoms in the previous 5 days, and risk factors for disease progression. COVID-19, coronavirus disease 2019; NMV/r, nirmatrelvir/ritonavir; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. ^∗The risk factors for disease progression are as follows: ≥60 years of age; body mass index >25 kg/m²; cigarette smoking; immuno-suppressive disease (including human immuno-deficiency virus infection with a CD4 cell count of <200 mm³) or prolonged iatrogenic immunosuppression; chronic lung, cardiovascular, kidney, or sickle cell disease; hypertension; diabetes; cancer; neurodevelopmental disorders or other medically complex conditions or medical-related technological dependence. ^∗∗Review potential drug interactions between nirmatrelvir/ritonavir and the patient's current medications. The suggested resources are as follows: • University of Liverpool. COVID-19 Drug Interactions (https://www.covid19-druginteractions.org/checker) • National Institutes of Health. Drug-Drug Interactions Between Ritonavir-Boosted Nirmatrelvir (Paxlovid) and Concomitant Medications (https://www.covid19treatmentguidelines.nih.gov/therapies/antiviral-therapy/ritonavir-boosted-nirmatrelvir--paxlovid-/paxlovid-drug-drug-interactions/#:∼:text=Ritonavir%2C%20a%20strong%20cytochrome%20P450,concentrations%20of%20certain%20concomitant%20medications) • Infectious Diseases Society of America. Management of Drug Interactions With Nirmatrelvir/Ritonavir (Paxlovid®): Resource for Clinicians (https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/management-of-drug-interactions-with-nirmatrelvirritonavir-paxlovid/) Careful risk-benefit evaluation in pregnant women and in patients undergoing haemodialysis ^∗∗∗Consider the following issues before prescribing monoclonal antibodies: (a) availability of drugs, (b) availability of infusion centres, (c) feasibility to perform timely screening for baseline antibodies, (d) alternatively constant monitoring of the circulation of variants of concern in order to select the appropriate treatment or (e) exclude patients in whom the administration of monoclonal antibodies may be ineffective.

Fig. 3

Proposed algorithm of treatment for outpatients with mild or moderate coronavirus disease 2019, the onset of symptoms between 6 and 7 days before and risk factors for disease progression. COVID-19, coronavirus disease 2019; mAb, monoclonal antibody; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. ^∗The risk factors for disease progression are as follows: ≥60 years of age; body mass index >25 kg/m²; cigarette smoking; immuno-suppressive disease (including human immuno-deficiency virus infection with a CD4 cell count of <200 mm³) or prolonged iatrogenic immunosuppression; chronic lung, cardiovascular, kidney, or sickle cell disease; hypertension; diabetes; cancer; neurodevelopmental disorders or other medically complex conditions or medical-related technological dependence. ^∗∗Consider the following issues before prescribing monoclonal antibodies: (a) availability of drugs, (b) availability of infusion centres, (c) feasibility to perform timely screening for baseline antibodies, (d) alternatively constant monitoring of the circulation of variants of concern in order to select the appropriate treatment, (e) to exclude patients in whom the administration of monoclonal antibodies may be ineffective.