PROGNOSTIC SIGNIFICANCE OF PERIPHERAL BLOOD MARKERS IN COVID-19
9 June 2021
Inflammation is caused by infectious diseases, and growing evidence supports its significant role in the progression of various viral pneumonia, including COVID-19. Severe inflammatory responses contribute to weak adaptive immune response, thereby resulting in immune response imbalance. Therefore, circulating biomarkers that can represent inflammation and immune status are potential predictors for the prognosis of COVID-19 patients. Peripheral white blood cell (WBC) count, neutrophil (NEU)-to-lymphocyte (LYM) ratio (NLR), derived NLR ratio (d-NLR, neutrophil count divided by the result of WBC count minus neutrophil count), platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR) are indicators of the systematic inflammatory response that are widely investigated as useful predictors for the prognosis of patients with viral pneumonia.
Neutrophils constitute the majority of the leukocytes and are primarily responsible for activating the immune system by migrating from the venous system. Free oxygen radicals that can damage the nuclear material of the cell are thereby released. Viral antigens are exposed and cell-specific and humoral immunities are stimulated by an antibody-dependent cell-mediated cell. There is a growing interaction with molecules like vascular endothelial growth factor (VEGF), interleukin-6, interleukin-8, tumor necrosis factor-alpha (TNF-α), interferon-gamma, and granulocyte colony-stimulating factor. VEGF-A and VEGF-C are particularly notorious in the novel coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The immune response is massively dependent on lymphocytes. On the other hand, systemic inflammation destroys CD4+ T lymphocytes and increases suppressor CD8+ T lymphocytes, thereby leading to an increased neutrophil-to-lymphocyte ratio (NLR). Formerly, NLR was mainly used in oncological conditions, autoimmune diseases, and bacteriological infections. However, in a study conducted by Yang et al., it was found to be an independent prognostic factor in patients with coronavirus disease 2019 (COVID-19). This reinforces the belief in the relationship between hyper-inflammation and SARS-CoV-2. In another study conducted by Ciccullo et al, an NLR of greater than four was seen as a predictor of the admission of COVID-19 patients to the intensive care unit. The duration of hospital stay was prolonged, and the time lag for nucleic acid results to become negative was increased. It is a valuable tool for screening critically ill patients with confirmed SARS-CoV-2 infection, as it can contribute to the evaluative acumen of the physician.
T helper cells induce the production of cytokines such as interleukin-17 through the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling pathway, leading to increased aggregation of monocytes. SARS-CoV-2 infects circulating immune cells and increases apoptosis of lymphocytes, leading to lymphopenia. A lower ratio of circulating lymphocytes to monocytes (LMR) predicts severe and extremely severe COVID-19 as the clearance of the virus is delayed due to lymphopenia and also a decrease in CD4+ T cells. Both a rise and fall in lymphocyte levels is an extremely crucial prognostic indicator of mortality in COVID-19.
Platelets play a crucial role in homeostasis, coagulation, vascular integrity maintenance, angiogenesis, innate immunity, and inflammatory response. In a state of inflammation, interleukin-6 promotes megakaryocyte production by stimulating an increase of thrombopoietin (THPO) level. Platelet count is a sensitive reflection of the body’s infection and inflammatory state. In a study conducted by Qu et al., it was found that platelets increased first and then decreased in several of their patients during treatment. Coronavirus invades bone stromal cells, leading to hematopoietic inhibition. Also, mature megakaryocytes release platelets in the lung. Therefore, thrombocytopenia and lung damage go hand in hand. Extensive alveolar damage is also observed. Lung damage results in pulmonary endothelial injury, which in turn leads to activation, aggregation, and retention of platelets in the lung. It is followed by the formation of a thrombus, which leads to the depletion of platelets. The cytokine storm is responsible for worsening the inflammation in the patient as it causes increased secretion of Th2 cytokines that inhibit Th1 cytokines, such as interleukin-4 and interleukin-10. Tracheal intubation and deep vein catheterization are potential factors that affect platelet changes. Platelet-released platelet factor-4 can prevent agglutinin-A from inhibiting lymphocyte generation; activated platelets enhance lymphocyte adhesion to the endothelium, thereby promoting lymphocyte homing in endothelial veins and migration to inflammatory sites. It indicates both aggregation and inflammatory pathways, thereby showing the level of inflammation even during the course of treatment. This also correlated with an increase in the stay at the hospital. Therefore, the platelet-to-lymphocyte ratio (PLR) provides a reliable reflection of the extent of cytokine inflammation and can be employed for monitoring purposes in patients with COVID-19.
The mean platelet volume (MPV)-to-platelet count ratio has been recently proposed as a prognostic marker in SARS-CoV-2. In inflammation, platelet production increases due to the increased synthesis of THPO, which is mediated through cytokines. MPV reflects the proliferation of megakaryocytes and platelet production in the bone marrow. There is an increased expression of young platelets in the bloodstream, leading to increased MPV. Decreasing platelet count forces the body’s immune system to stimulate megakaryocytes to produce a large number of platelets, thereby increasing MPV. Adverse prognosis is due to the increased oxidative stress, thrombosis, and apoptosis in activated platelets. It symbolizes a higher risk of poor outcomes in COVID-19 patients.
These four ratios have been scrutinized in great detail in SARS-CoV-2 patients in other countries that have a higher financial and resource allocation for healthcare. However, in resource-limited settings or where a health facility is functioning beyond its capacity, investigations like interleukin-6, interleukin-10, and other special platelet tests cannot be routinely performed. Therefore, by employing a simple complete blood count, we can perform these tests which are proven to be very helpful in prognosis of the disease.