Update to Chapter 194: Common Viral Respiratory Infections

There have now been >4 million cases of COVID-19 worldwide, with >275,000 deaths. The United States alone accounts for >1.3 million cases and >80,000 deaths. With >60,000 new worldwide cases each day (>20,000 new cases in the United States), frenzied research activity regarding COVID-19 continues throughout the world. Some highlights regarding the most recent findings over the past few weeks are encapsulated below.

Symptomatology and at-risk populations

• The U.S. Centers for Disease Control and Prevention (CDC) has recently added six symptoms that are associated with COVID-19: chills, rigors, myalgias, headache, sore throat, and the new loss of taste or smell. These were added to the original symptoms that included fever, cough, and shortness of breath.

• In the United States, ~80% of COVID-19-related deaths have occurred in adults ≥65 years of age, and ~ 92% of deaths occur in adults ≥55 years old.

• Other at-risk groups include those living in close quarters, such as people in nursing homes, long-term care facilities, and prisons. Pregnant women—or their offspring—do not appear to be at increased risk of severe disease.

• Children are largely asymptomatic or have mild symptoms from SARS-CoV-2 infection. The reason for this age-related discrepancy in disease severity is currently unknown, but it is different from what is seen with influenza and other respiratory diseases where the very young are often also significantly at risk for poor outcomes.

• Although children typically have not had severe disease with classic COVID-19 symptoms, reports of a multisystem inflammatory syndrome have been increasingly reported in Europe and the United States. Early reports suggest that this resembles Kawasaki disease, the etiology of which remains unknown but has long been thought to be related to infection; however, the cardiac manifestations more closely resemble myocarditis than the coronary artery dilation seen in Kawasaki disease. There have been >80 suspected cases in the United States, with at least 3 deaths. Given that testing for SARS-CoV-2 is not uniformly positive in these patients, there is no definitive link between COVID-19 and this new pediatric syndrome.

Testing

• After a flurry of diagnostic tests were granted emergency use authorization (EUA) by the U.S. Food and Drug Administration (FDA) and rapidly implemented on the front lines, it quickly became apparent that many of these tests had suboptimal or unknown characteristics. Rather than using actual clinical samples to determine characteristics of the test—a process that can take months to years to complete—companies were allowed to use “contrived” samples where lab-generated SARS-CoV-2 RNA is incorporated into a nasal mucus-like medium for testing. While this abbreviated process has enabled these tests to come to market faster and be used to diagnose patients, it was not clear how well these tests would work in the clinical setting. While this expediency is critically important in the setting of a pandemic such as this, there have not been concerted efforts to compare the performance of these different assays using real-world samples.

• This issue of rushing to implement new diagnostics was recently highlighted by a rash of new tests that detect SARS-CoV-2-related antibodies. Scientists began to realize that many of these tests had very poor test characteristics with unacceptably high false-negative rates (or at least what appeared to be false-negative rates given the lack of a true “gold standard”) and inconsistent results. In response, the FDA provided a 10-day period, which is still ongoing, for manufacturers to provide these performance data or face removal from the market. While the push to make tests available to the public is noble, at least a modicum of governmental oversight is necessary to ensure that the tests actually do what they claim before large-scale implementation. This could have been done in conjunction with having in place a robust process to continue to monitor test characteristics as implementation increases. Unfortunately, the current quagmire of tests has left clinical microbiology labs and physicians unclear how to interpret—or whether to trust—results from the various antibody tests available.

• However, using a validated system for detection of virus-specific antibodies, a recent report in Nature Medicine demonstrated that 100% of patients with COVID-19 (n = 285) developed SARS-CoV-2-specific antibodies within 19 days after symptom onset (Long et al, 2020). There was no real pattern as to whether IgM or IgG developed first, but titers of both antibody types plateaued within 6 days of seroconversion. While these studies demonstrate that the immune system is capable of recognizing SARS-CoV-2, it is not yet known whether these antibodies have any role in virus neutralization and/or may confer immunity to a possible second infection. Of note, this type of work to assess development of neutralizing antibodies is actively ongoing in many labs around the world, and this notion of protective immunity will be critical in determining the long-range outlook for the pandemic.

Treatment

• Data are beginning to emerge from various trials of remdesivir, a nucleoside analogue prodrug, although early results have been conflicting.

  • A double-blind, placebo-controlled, multicenter trial in Hubei, China, was recently published in The Lancet (Wang et al, 2020). Patients were ≥18 years old and had confirmed SARS-CoV-2 infection, ≤12 days between symptom onset and enrollment, radiographic evidence of pneumonia, and an oxygen saturation of ≤94% on room air (or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of ≤300 mmHg), and they were randomized in a 2:1 ratio to IV remdesivir (200 mg on day 1, 100 mg on days 2–10) or placebo (158 and 79 patients in the remdesivir and placebo groups, respectively). In an intention-to-treat analysis, remdesivir use was not associated with faster clinical improvement (hazard ratio [HR], 1.23; 95% confidence interval [CI], 0.87–1.75).

  • In an industry-sponsored trial involving just over 1000 patients randomized to remdesivir or placebo, early unpublished results suggest that remdesivir use was associated with a shorter duration of hospitalization (11 vs 15 days) with no statistically significant differences seen in mortality (8% vs 11.6%; p = .059). Although these results were the basis for an EUA granted by the FDA, additional details have not yet been made widely available in either a preprint or published version. It will be important to understand the inclusion and exclusion criteria, potential adverse events, and analysis methods to determine how generalizable these findings are.

  • Hopefully, the differences between these two studies will be better explained by several additional trials involving remdesivir that are still ongoing. That said, patients—in the United States at least—are beginning to receive remdesivir outside of clinical trials, although the distribution of the drug is being handled, for now, by the federal government instead of the manufacturer.

• An open-label, randomized, phase 2 trial just published in The Lancet demonstrated that patients (n = 86) receiving a combination of lopinavir-ritonavir, ribavirin, and—for those patients who presented within ≤7 days of symptom onset—interferon b-1b had a significantly shorter time to negative nasopharyngeal swab tests than patients (n = 41) receiving just lopinavir-ritonavir (7 vs 12 days; HR, 4.37; 95% CI, 1.86–10.24) (Hung et al, 2020). Moreover, combination therapy had a shorter time to complete alleviation of symptoms (4 vs 8 days; HR, 3.92; 95% CI, 1.66–9.23) and shorter median hospital stay (9.0 vs 14.5 days; HR, 2.72; 95% CI, 1.2–6.1). Subgroup analysis suggested that interferon b-1b might be a key component of the combination therapy.

Although none of these treatment regimens is yet a “home run” that conclusively demonstrates a dramatic decrease in the mortality rate, these studies are critical in demonstrating that disease resolution can be hastened with appropriate antiviral therapy. Efforts to identify better, more effective therapies are actively ongoing in academic labs, pharmaceutical companies, and clinical trials.

References