A team of scientists in Ireland recently identified certain immune markers that can predict the progression of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection to severe coronavirus disease 2019 (COVID-19). Early detection of these predictive markers can facilitate therapeutic decision-making prior to peak severity.

The study is currently available on the medRxiv* preprint server, while the article undergoes peer review.

Background  

Excessive inflammation and expansion of immature myeloid cells are the major immune hallmark of severe COVID-19. At the initial phase of COVID-19, increased production of pro-inflammatory cytokines and lung infiltration of monocytes and T lymphocytes occurs because of viral replication and host innate immune responses.

In about 20% of patients, an immune-mediated phase develops 6 – 10 days after the symptom onset. This phase is characterized by excessive inflammation, increased D-dimer level, and elevated lung infiltration. These immune changes can progressively lead to severe COVID-19 in about 5% of patients. Therapeutic interventions required to manage severe COVID-19 patients, such as mechanical ventilation, can further cause alteration in immune responses.

In the current study, the scientists have investigated clinical and immunological characteristics in COVID-19 patients to identify potential immune markers that can predict disease severity early in the course of the disease.

Study design

A total of 108 COVID-19 patients were enrolled in the study. Of them, 17 had mild COVID-19, 52 had moderate disease, and 39 had severe disease requiring mechanical ventilation.

To identify immunological and common clinical markers, blood tests were conducted 6 days after the symptom onset. For patients with severe disease, blood tests were conducted 1.5 days prior to peak oxygen requirement, which was considered to be an indicator of extreme respiratory illness.  

Important observations

The analysis of blood samples revealed that severe COVID-19 is associated with marked coagulopathy, excessive inflammation, increased neutrophil count (neutrophilia), and reduced lymphocyte count (lymphopenia). Increased levels of D-dimer and fibrinogen were also observed in the blood of severe COVID-19 patients. Although the intensity of lymphopenia increased with disease severity, it was observed across all disease severities.  

Given the marked lymphopenia in all COVID-19 patients, the scientists conducted immunophenotyping of lymphoid cells. The findings revealed an overall reduction of naïve CD4+ and CD8+ T cells and induction of activated CD4+ and CD8+ T cells and effector CD8+ T cells across all disease severities.   

Similarly, they conducted immunophenotyping of myeloid cells to further characterize the marked neutrophilia observed in severe COVID-19 patients. The findings revealed that the expressions of CD10 and CD16 on neutrophils reduced significantly with increasing disease severity. Moreover, a marked reduction in HLA-DR (Human Leukocyte Antigen – DR isotype) expression on monocytes was observed with increasing disease severity.

Compared to non-infected healthy individuals, COVID-19 patients exhibited an increased level of intermediate monocytes, which are cytokine-producing pro-inflammatory monocytes. Compared to moderately or severely affected patients, mild COVID-19 patients showed higher levels of non-classical monocytes, which are primarily associated with resolution of inflammation.

Immunological signature of severe COVID-19

The scientists identified a set of 15 immunological markers that were significantly associated with severe COVID-19. Specifically, severe COVID-19 patients exhibited increased levels of IL-6 and C-reactive protein (CRP) and reduced expressions of neutrophil marker CD10 and monocyte marker HLA-DR.

Further analysis conducted using the machine learning multivariate approach identified 12 predictive markers of severe disease. The top four markers that showed the highest predictive value were reduced HLA-DR expression on monocyte, increased IL-6 and CRP levels, and reduced CD10 expression on neutrophils. A combination of these immunological markers alone could significantly predict the progression to severe COVID-19. Other immunological markers associated with severe COVID-19 were reduced CD16 expression on neutrophils, reduced levels of intermediate and non-classical monocytes, and reduced numbers of natural killer cells.

Study significance

The study findings indicate that the severity of COVID19 can be predicted by elevated levels of pro-inflammatory mediators and expansion of immature neutrophils and monocytes (emergency myelopoiesis).

A reduced expression of CD10 is a characteristic feature of immature neutrophils, which are associated with aberrant immunostimulation by increasing T cell proliferation and survival and interferon production. Similarly, the presence of monocytes with reduced HLA-DR expression in blood has been found to be associated with poor disease outcomes.    

As mentioned by the scientists, early detection of these immunological markers could be helpful for the timely initiation of appropriate treatment.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Dr. Sanchari Sinha Dutta

Dr. Sanchari Sinha Dutta is a science communicator who believes in spreading the power of science in every corner of the world. She has a Bachelor of Science (B.Sc.) degree and a Master's of Science (M.Sc.) in biology and human physiology. Following her Master's degree, Sanchari went on to study a Ph.D. in human physiology. She has authored more than 10 original research articles, all of which have been published in world renowned international journals.