Patient-Related Factors Key to COVID-19 Disease Severity

By Marilynn Larkin

June 02, 2020

NEW YORK (Reuters Health) - Patient-related factors, including age, lymphocytopenia and cytokine levels are associated with COVID-19 disease severity, according to researchers in China.

The findings have led medical teams there "to formulate a comprehensive evaluation model for every COVID-19 patient," Dr. Hongzhou Lu of Fudan University in Shanghai told Reuters Health by email. "High-risk patients would receive early intervention therapies, such as convalescent plasma or interleukin-6 receptor blockade."

The team also found that, up to now, "the viral genome is largely stable - i.e., a low rate of sequence variation. There is no indication that some strain of virus is more infectious or more pathogenic than other strains."

Dr. Lu and colleagues analyzed immunological parameters and viral genomes from clinical samples, and delineated factors associated with prognosis and epidemiological features. Disease severity was categorized as asymptomatic, mild, severe or critical, according to the Guidelines on the Diagnosis and Treatment of Novel Coronavirus issued by the National Health Commission.

As reported in Nature, 326 patients (median age, 52; male:female ratio, 1.10) in Shanghai between January 20 - February 25, 2020 were included in the study; 38% had at least one comorbidity, the most common of which were hypertension (76 cases), diabetes (24), coronary heart disease (13) and chronic hepatitis B (10).

Progressive lymphocytopenia was a prominent COVID-19 feature, particularly in severe and critical disease. A detailed analysis of lymphocyte subtypes revealed that CD3+ T cells were most significantly affected, with similar trends seen with CD4+ and CD8+ T cells.

Notably, the changes in T lymphocytes were statistically significant not only in critical cases but also in asymptomatic, mild and severe cases. By contrast, although a significant drop in CD19+ B cells was seen in critical cases, no apparent changes were observed in asymptomatic, mild and severe cases.

A significantly higher IL-6 level six to 10 days post-onset was found in critical group. Similarly, a significant difference was observed in the IL-8 levels from day 16 to 20 post-onset. Taken together, the data suggest "a strong link" between inflammatory cytokines and SARS-CoV2 infection pathogenesis, according to the authors.

Further, analyses by comorbidity found a significantly higher risk for disease progression if complicated by a coexisting condition.

As for viral genetics, sequencing of 121 sputum and oropharyngeal swab samples from COVID-19 patients revealed two major clades, both of which included cases diagnosed in early December 2019.

Additional analyses found that the two clades exhibited similar pathogenic effects despite their genome sequence variations, and there was no significant association between disease severity and the 13 most frequent variations.

Dr. Lu said, "Monitoring the genetic changes is crucial for understanding the epidemiology and evolution of the virus. We are continuing our efforts to sequence additional genomes from patients hospitalized at later times. We hope that our experience will help clinicians all over the world to better fight this disease."

Dr. Julie Kehdi, an infectious disease specialist at Spectrum Health in Grand Rapids, Michigan, commented in an email to Reuters Health, "The preliminary data are conclusive in that more pronounced lymphopenia at time of diagnosis, as well as higher IL-6 and IL-8 levels, correlate with increased severity of disease. Despite this, majority of patients infected will not progress to critical or even severe disease."

With that said, she noted, "With millions of infected individuals worldwide, this study population of 326 is a relatively small sample size. Furthermore, based on the ever-evolving nature of this virus, with data collection spanning only from January 20 - February 25, we are missing an important longitudinal look at genetic stability and correlation between serovars and disease, specifically with regards to infectivity, presentation, and severity."

Dr. Benjamin Segal, co-director of The Ohio State University Wexner Medical Center's Neurological Institute in Columbus, told Reuters Health by email, "One limitation of this study is that there were relatively few patients in the cohort who were either asymptomatic (1.53% of the subjects), or severely (3.68%) or critically (4.9%) ill. This could potentially have biased the molecular and immunological data gleaned from individuals at the extremes of the clinical severity spectrum."

The finding that elevations of serum levels of IL-6 and IL-8 over time correlated with disease progression in the critically ill subset, he said, "suggests that treatment of severely affected COVID-19 patients with immunomodulatory therapies, such as IL-6 or IL-8 receptor blocking agents, could be ameliorative."

Biochemist Jonathan Lai of Albert Einstein College of Medicine in New York City noted in an email to Reuters Health, "The implications of the work are highly significant for understanding both the timing/origin of the zoonotic spillover event that began the pandemic, as well as the immunological correlates of severe disease. But like all scientific results, they must be confirmed by other scientists and with additional studies."

SOURCE: Nature, online May 20, 2020.