This observational retrospective investigation was the first to report the cut-off values of the NLR, LMR, PLR and MPR indices in COVID-19 patients segregated by sex, since most of the patients who died from COVID-19 were men. The performance of these biomarkers, which provide insight into COVID-19 progression as well as predictions of its severity, presented significant sex-based differences. In agreement with prior reports [23, 24], the percentage of mortality in our sample was of 3.1%. The analysis of the validity of these indicators as prognostic tools of COVID-19 severity was the first conducted in Ecuador. It revealed the influence of sex in these COVID-19 severity biomarkers.
Severe subjects had a higher NLR compared to Non-Severe patients, similar to the results obtained by others[25–27], and above the mean (3.27, 95% CI: 1.99–4.55) reported in a meta-analysis.The sensitivity (66%) and specificity (48%) were however fair for this indicator and below the levels reported for these parameters elsewhere[29, 30]. Despite this, neutrophilia is the hallmark of severe COVID-19. whereas lymph cell percentage is inversely related to its progression, so a subject with NLR levels above 5.03 in our sample was very likely to be admitted to the intensive care unit[4, 5]. Indeed, there is evidence that high NLR levels are positively correlated with mortality by COVID-19[32–33]. A higher NLR value was still indicated in our sample to differentiate those subjects at risk of dying from COVID-19, especially if there were men (69% sensitivity).
The MLR biomarker was selected because of its prognostic value for Middle East Respiratory Syndrome Coronavirus (MERS-CoV) infection. A cut-off of 0.33 for MLR could discriminate severe COVID-19 patients from those non-severe with approximately of 50% of sensitivity and specificity values sin agreement with previous studies, yet with a higher cut-off. Compared to the work of Peng and colleagues, our AUC for MLR was lower. Surprisingly, the sensitivity of MLR to discriminate severe COVID-19 subjects rose to 77% in men, yet with a specificity of 23% (61% in women). The PLR parameter reveals changes in platelet and lymphocyte counts because of acute inflammatory and pro-thrombotic conditions. PLR levels associated with severe COVID-19 were within the range, since they were either higher[1, 25, 37] or lower  than the reference. PLR was higher in men, with a sensitivity of 71% (only 37% in women) and a specificity of 41%, (76% in women), which was suggestive of a different cytokine storm in COVID-19 patients pending on the sex.
The MPR parameter has recently received attention as a prognostic marker in COVID-19 pneumonia. MPV reflects the proliferation of megakaryocytes and platelet production in the bone marrow. COVID-19 patients often have mild thrombocytopenia and appear to have increased platelet consumption, together with a corresponding increase in platelet production. Although men showed a lower MPR level compared to women and it would then be thought a relationship with a higher risk of dying from COVID-19, the AUC-ROC did not detect any sex differences in predicting severity. Accordingly, the relationship between MPR and COVID-19 severity remains hazy and more research is needed to define the MLR cut-off point, sensitivity and specificity.
The AUC-ROC analysis revealed a fair performance of the combined hematology biomarkers in predicting COVID-19, which enhanced when the sample was split by sex. There is no doubt that patients with serious COVID-19 have dysregulated resistance reaction that permits viremia, thus ensuing hyper-inflammation and cytokine storm. Neutrophilia is the expression of the cytokine reaction and a hyper-immunity in this disease. Sex-driven differences in COVID-19 immune response are not fully understood. T cell activation at the early phase of SARS-CoV-2 infection is robust in older female COVID-19 patients, while it declines with age and has worse COVID-19 outcomes only in male COVID-19 patients. Women have a more robust ability to control infectious agents. Also, sex-biased expression of ACE2, coupled with the regulation of TMPRSS2 by androgens, increases SARS-CoV-2 susceptibility in men compared with women.To the best of our knowledge, this is the first report of the sex-dependent differences of biomarkers of a systemic inflammatory response such as NLR, MLR and PLR.
"Perspectives and Significance"
Severe and non-surviving patients had a higher NLR and MLR, and a lower MPR. The sensitivity of NLR, MLR and PLR to predict severity was better in men (69%-77%), while their specificity enhanced in women compared to men (70%-76% vs. 23%-48%). High NLR, MLR, PLR and low MPR levels were predictors of COVID-19 severity with different performance in men and women. Sex-dependent differences in immune responses related to COVID-19 disease would explain why current worldwide statistics show more men than women dying of SARS-CoV-2 infection.
This study was a retrospective and single-center observational analysis.