Granulocytic Signature Predictive of COVID-19 Diagnosis and Severity

Nurse holds blood sample to treat Sars-CoV-2-related Kawasaki disease in children under five, conceptual image, unbranded generic drug containers and hypothetical bar codes
Researchers conducted an observational, prospective, multicentric study to assess the possible relationship between granulocytic markers and COVID-19 infection and severity.

In addition to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-associated lymphopenia, changes in frequency and activation of granulocyte subsets may be predictive of clinical worsening during coronavirus disease 2019 (COVID-19), according to study results published in the The Journal of Infectious Diseases.

A sudden deterioration 7 to 10 days after the onset of symptoms in 10% to 20% of patients is the hallmark of COVID-19 and can lead to an increased risk for acute respiratory distress syndrome, intensive care unit (ICU) admission, and death. Previous studies have explored the immune response in patients with COVID-19 and suggested that SARS-CoV-2 may induce unique patterns of immune dysregulation. However, no systemic approach of SARS-CoV-2-induced immune dysregulation at the phenotypic level has been performed to date.

In the current observational, prospective, multicenter study, researchers aimed to identify previously unreported immune markers able to categorize patients with COVID-19 from healthy control participants and to predict mild and severe disease.

In total, 26 patients with confirmed COVID-19 were included in the study (mild/moderate, 7 patients; severe, 19 patients) along with 25 healthy control participants. All participants received immunophenotyping of whole blood leukocytes via a multiparametric flow cytometry approach on hospital or ICU admission. Unsupervised analysis and mapping of leukocyte surface markers were performed to identify clinically relevant associations. The primary objective was to identify immunophenotypic patterns that were most accurately associated with COVID-19 diagnosis and severity.

There were notable demographic differences between the mild and severe COVID-19 groups. When compared with the mild group, the severe group had an elevated body mass index (29 vs 24 kg/m2; P =.005), more frequent cases of hypertension (15 [79%] vs 2 [29%]; P =.03), increased levels of C-reactive protein (150 vs 17 mg/L; P =.0003), and significantly higher severity scores, including the World Health Organization (WHO) progression score (P <.0001) and the Sepsis-related Organ Failure Assessment (SOFA) score (P =.005).

Results suggested that phenotypic markers of circulating granulocytes could be used as strong discriminators between severity stages and individuals infected and uninfected with COVID-19. Unsupervised mapping of leukocyte surface markers identified a distinct granulocytic COVID-19 signature. Compared with control participants, patients with COVID-19 showed downregulation of eosinophil and basophil CRTH2, increased counts of CD15+CD16+ neutrophils, and a decreased expression of granulocytic CD11b. Furthermore, COVID-19 severity was associated with a more profound imbalance of granulocyte subsets and functional markers of the disease. The frequency of CD15+ granulocytes and CD15+CD16+ neutrophils were significantly increased (P =.002) and eosinophil CRTH2 expression significantly decreased in the severe vs mild group.

 Compared to mild COVID-19, severe COVID-19 disease was associated with the emergence of unique markers, including significantly increased expression of PDL1 checkpoint inhibitor in basophils and eosinophils. Both WHO and SOFA scores positively correlated (R2=0.567) with innate immune checkpoints like PDL1 expression and negatively correlated with neutrophil CD11b and eosinophil CRTH2 expression.

Study limitations included variable timing of blood sampling between the mild and severe COVID-19 groups and the small population size, which may preclude definitive conclusions; however, results in this study were homogenous in each subgroup and were consistent with published literature.

Researchers concluded, “Taken together, our data show an early and deep impairment of the immune response, and question the use of drugs that could alleviate the immune response in patients [with] COVID-19, especially in the most severe forms requiring intensive care unit admission.”

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Vitte J, Diallo AB, Boumaza A, et al. A granulocytic signature identifies COVID-19 and its severity. Published online September 17, 2020. J Infect Dis. doi:10.1993/infdis/jiaa591/5907982