Dysregulated inflammation in severe COVID-19

The continuing COVID-19 pandemic has so far caused 9.58 million cases and more than 488,000 deaths within just six months. The spectrum of disease is broad, from completely asymptomatic cases to critical illness ending in death. Now, a new paper by researchers from Yale University and published on the preprint server medRxiv* in June 2020 identifies an imbalance in immunological response that is linked to poor outcomes and early biomarkers that may help predict the course of the disease.

The last three major coronavirus outbreaks, namely, SARS, MERS, and now COVID-19, have been characterized by severe inflammation and a paucity of lymphocytes. Early immunological analyses have shown that inflammatory monocytes and neutrophils are elevated, while lymphocytes show a steep fall. Again, an increase in the inflammatory cytokines IL-1β, IL-6, and TNF-α is linked to poorer outcomes. Yet, not much is known about how the immune response changes throughout the infection and how this is linked to the clinical symptoms.

There are three types of immune responses directed against three types of pathogens, namely, type I, type II, and type III. Type I is dominated by T cell responses, mediated by interferon-gamma (IFN-γ), and is a response to intracellular pathogens, including viruses. Type I depends on effector cells: cytotoxic T cells, ILC1, and T helper cells (Th cells).

Type II immunity is directed against helminthic parasites via effector molecules like IL-4, IL-5, IL-13 and IgE, which team up with epithelial cells, mast cells, and eosinophils, and basophils to clear the parasites from the body.

Type III immunity is directed against fungi and extracellular bacteria, to clear them with the help of neutrophils. This response is mediated by the cytokines IL-17 and IL-22.

The current study is aimed at identifying the immune phenotypes that are associated with different disease symptoms. The researchers examined the immune profiles of 113 COVID-19 patients in terms of viral RNA load by RT-PCR, cytokine levels, and white cell profiles using peripheral blood mononuclear cells (PBMCs).

The 253 samples were collected over a period of 3-51 days from the earliest symptom and compared to samples from 108 controls. The patients were classified as moderate and severe, depending on whether they needed intensive care and oxygen. In general, severe illness was associated with a higher body mass index (BMI), and very low or very high BMI was linked with a higher risk of death.

The researchers found that T cell counts and frequencies were markedly reduced, both CD4 and CD8 cells. Monocytes were increased, with reduced HLA-DR expression, as well as low-density neutrophils and eosinophils. T cell hyperactivation was also observed.

With respect to cytokines, often considered to be excessively increased in severely ill patients during these three outbreaks, the researchers observed what they call “a core COVID-19 signature”, in both moderate and severe disease. This includes several cytokines, namely, IL-1α, IL-1β, IL-17A, IL-12 p70, and IFN-α. In severe illness, another group of cytokines was elevated as well, namely, TPO, IL-33, IL-16, IL-21, IL-23, IFN-λ, eotaxin, and eotaxin 3.

In severe illness, moreover, many cytokines were common to those seen in cytokine release syndrome, a syndrome associated with the unregulated and excessive release of cytokines. These include IL-1α, IL-1β, IL-6, IL-10, IL-18, and TNF-α. These findings show that severe COVID-19 is a condition in which a broad spectrum of inflammatory changes occur, spanning all three types of cytokines and also indicating the activation of both innate and adaptive immunity.

Changes in Immune Profile Over the Course of COVID-19

The researchers then examined the changes occurring in the immune response over time in these patients. They found that the immune profile differed markedly between severe and moderate COVID-19 only after day 10 of infection. Inflammatory markers such as those in the core signature above were found to decrease in moderate disease, but to remain elevated and to rise in severe disease. In severe disease, certain cytokines associate with each other, namely, TPO and IFN-α with IFN-λ, IL-9, IL-18, IL-21, IL-23, and IL-33.

IFN-α and IFN-λ levels increased in severe and ICU patients, respectively, from the first week onwards, but fell in moderate illness. Other cytokines found in inflammasomes like IL-1β and IL-18 are also raised in severe illness, as also IL-1Ra from the tenth day onwards.

The researchers found that monocytes were increased in severe illness, along with IL-12 and IFN-γ, which is secreted by ILC1, NK, and Th1 cells. Since the CD4 and CD8 cells in both moderate and severe disease do not show measurable differences in the secreted IFN-γ. Still, this cytokine is increased in severely ill patients. It is probably secreted from non-T cells and from T cells that are not in circulation.

Type II cytokines also increased steadily over time in severe COVID-19, especially IL-4, IL-5, and IL-13. Besides the increase in IL-6, which is typically linked to CRS, type III immune markers are also increased.

Nasopharyngeal Viral Load Correlated with Cytokine Levels

The researchers found that the viral load in nasopharyngeal swabs correlate with the plasma levels of interferons and cytokines in both severe and moderate disease.

Early Cytokine Profile Predicts Disease Course

The researchers saw that certain cytokine responses early in the course of the disease showed a correlation with severe COVID-19. They included three clusters of cytokines indicating three types of disease progression, forming 4 patterns or signatures.

The first cluster indicated moderate disease, with low levels of inflammatory markers, and either comparable or increased levels of signature A, which comprises growth factors that induce tissue repair. The other two clusters had markedly raised inflammatory markers, with higher rates of clotting defects and mortality, more in cluster 3 than in cluster 2.

Type 2 signatures are found to rise in severe illness continuously. Similarly, viral load was correlated with IFN-α, IFN-γ, and TNF-α, which could mean that this is the driver of interferons release while also indicating the ineffectiveness of interferons against the virus. Instead, interferon-mediated hyperinflammation causes widespread organ dysfunction and even death.

When the researchers sorted the early cytokine levels in order of their predictive value, they found that inflammatory markers had a robust correlation with disease outcomes. When IFN-α was elevated before the 12th day from symptom onset, the duration of hospitalization and the risk of death was higher, similarly to IFN-λ, IL-1Ra, and monocyte-associated chemokines, and those linked to the recruitment and survival of T cells.

The study concludes: “Early immunological interventions that target inflammatory markers predictive of worse disease outcomes are preferred to blocking late-appearing cytokines.” This should lead to more targeted treatment of COVID-19 to improve the outcomes and reduce mortality.

*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.

Journal reference:
Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.

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