Timely treatment of patients at risk for severe COVID-19 prevents severe outcomes

Despite widespread uptake of vaccinations, COVID-19 remains a serious health issue for high-risk patients, owing to the emergence of new variants of concern (VOCs), waning immunity, and breakthrough infections.

At a recent symposium in Singapore, esteemed experts Dr Asok Kurup, Consultant Infectious Diseases Physician at Mount Elizabeth Medical Centre, Singapore, and Dr Alex Soriano, Head of Infectious Diseases Department, Hospital Clínic of Barcelona and Assistant Professor, University of Barcelona, Spain, gave insights on the evolution of global trends since the start of the COVID-19 pandemic and discussed key challenges in managing high-risk patients with COVID-19 in the ICU. They also highlighted early treatment strategies to minimize the burden of COVID-19 on healthcare systems.

Identify individuals at risk for severe disease
The majority of Singapore’s population has been vaccinated and boosted, but there are still vulnerable groups with suboptimal response to vaccination, such as the elderly with stacked comorbidities and immunocompromised persons.

“In the new normal, surveillance for new VOCs should be maintained, as future variants may be more virulent and could infect more people,” warned Kurup. “There is an urgent need to support frontline healthcare workers to avoid exhaustion from COVID-19 combat fatigue. Vulnerable persons should be ring-fenced at home or places of care. To minimize hospital and ICU admissions, it is important to identify those at risk for severe disease early so interventions are calibrated according to the risks.”

Risk factors for severe COVID-19
Risk factors for severe COVID-19 in adults can be categorized into host factors, societal factors, and viral factors. Host factors include older age, male sex, obesity, and underlying conditions such as pulmonary disease, cardiovascular disease (CVD), immunosuppression, and chronic kidney disease. [Lancet 2020;395:497-506; Lancet 2020;395:1054-1062; JAMA Intern Med 2020;180:934-943] Stacked comorbidities increase the risk of severe COVID disease (Figure 1).

“In certain parts of the world, societal and structural factors such as poverty and racism may confer greater risk to marginalized groups. Viral factors such as inoculum size and variant also influence the risk,” Kurup added.

Managing COVID-19 in the ICU
Managing COVID-19 in the ICU presents many challenges. Critically ill adults with COVID-19 are at increased risk of thrombo-inflammatory disease. Endothelial injury and hypercoagulability play a critical role in the progression of severe COVID-19, with endothelial dysfunction being a key driver of organ failure. [N Eng J Med 2020;383:120-128; CMAJ 2020;192(40):E1156-E1161; Intensive Care Med 2021;47:86-89]

Treatment is complex. Unlike typical acute respiratory distress syndrome (ARDS), COVID-19 pneumonia has different phenotypes (H vs L type) that require individualized therapy and selection of appropriate rescue treatment. [Crit Care 2020:24:154; JAMA 2020;323:2329-2330; Eur J Anaesthesiol 2022;39:445-451]

Early treatment slows the progression of infection
The clinical spectrum of COVID-19 infection is broad, ranging from completely asymptomatic to progressive life-threatening viral pneumonia. “In the Omicron era, approximately 85–95 percent of cases are asymptomatic to mild, while 5–10 percent of cases are moderate to severe,” said Soriano.

The rapid viral replication seen with respiratory viruses drives the rapid progression towards severe infection. The increase in the viral load triggers an inflammatory response to try to control viral replication. “The window of opportunity for decreasing the viral load is generally within the first 5 days of starting viral replication,” Soriano shared. “In the majority of the vaccinated population, viral replication lasts 5–10 days, triggering an inflammatory immune response that is adequate to combat the infection. However, patients predisposed to developing severe infection (those with older age, comorbidities, and gene mutations or autoantibodies) often have dysregulated immune responses; these are associated with longer viral replication times of >10 days, resulting in greater risk of progression to pneumonia, ARDS, and thrombosis (Figure 2). [Clin Infect Dis 2021;72:1467-1474]

“In these high-risk groups, it is important to evaluate the impact of antivirals on the progression of the disease and admission to the hospital,” Soriano emphasized. “Early treatment with antivirals slows or stops the progression of the infection from mild-to-moderate to severe or from moderate-to-severe to critical COVID-19.”

Nirmatrelvir/ritonavir for mild-to-moderate COVID-19
A cohort study demonstrated the importance of timely antiviral treatment in COVID-19 patients. Three groups of hospitalized adult patients with mild-to-moderate COVID-19 who had high risk for progression to severe disease were analysed; one group was treated with nirmatrelvir/ritonavir within the first 5 days from symptom onset (treated ≤5 days), another group received nirmatrelvir/ritonavir after 5 days from symptoms onset (treated >5 days), while a third group was not treated with antivirals (nontreated). After adjusting for severity variables, the use of nirmatrelvir/ritonavir was associated with a significantly shorter time to negative RT-PCR conversion (10 days vs 17 days) in patients treated ≤5 days from symptom onset and in nontreated patients, respectively. However, no difference was observed between the “untreated” and “treated >5 days” cohorts. [Clin Infect Dis 2022;ciac600]

In the phase II/III EPIC-HR (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients) trial involving symptomatic, unvaccinated, nonhospitalized adults at high risk for progression to severe COVID-19, nirmatrelvir/ritonavir significantly reduced the risk of hospitalization for COVID-19 or death from any cause by 87.8 percent (0.77 percent vs 6.31 percent for placebo; p<0.001) in those who commenced treatment within 5 days after symptom onset. [N Engl J Med 2022;386:1397-1408]

“While results from subgroup analyses were consistent across subgroups, there was a trend showing greater benefit of nirmatrelvir/ritonavir over placebo in the subgroup of patients with older age (≥65 years vs <65 years), higher BMI (≥30 kg/m² vs 25–30 kg/m²  vs <25 kg/m² ), higher viral loads vs lower viral loads, and higher number of comorbidities at baseline (≥2 vs <2),” said Soriano.

Another study of nirmatrelvir/ritonavir during the Omicron era, using real-world data from the Israel Clalit Health Services (CHS) database and the Israeli Ministry of Health (MOH) COVID-19 database, showed that the combination therapy was associated with a significant decrease in the rate of severe COVID-19 or mortality (hazard ratio [HR], 0.54, 95 percent confidence interval [CI], 0.39-0.75). It appeared to be more effective in older, immunosuppressed patients, and those with underlying neurological or CVD (interaction p<0.05 for all). [Clin Infect Dis 2022;ciac443] Of 180,351 eligible patients, 2.6 percent received nirmatrelvir/ritonavir and 75.1 percent had adequate COVID-19 vaccination status.