We showed that NLR and PLR are able to distinguish between the patients with mild/moderate Covid-19 and patients who had a severe disease (with need of non-invasive ventilation, ICU admission or invasive ventilation or patients who died). In fact, both ratio show higher values in the population with severe disease. A NLR that is continually increasing at successive timepoints, in particular, is able to predict death.
We also computed cut-offs for males and females for the four outcomes at each timepoint. Males NLR cutoff is higher that females of at least 1 point. Sensitivity is also higher in males. At each timepoint an “easy to remember” value (e.g. 6.3 and 7.0 at admission for females and males respectively, or 5.3 and 7.3 at 48 hours for males and females respectively) could be quite good a predicting all the outcomes, with a sensitivity that increases progressively at successive timepoints (the minimum is 0.61 for females at admission for ICU admission, the maximum 0.91 for males at 7 days for invasive ventilation). The positive predictive value are low, but the negative predictive values range from 0.73 to 0.98, making our cutoffs efficacious in excluding patients at risk if their NLR is lower. The same can be said for PLR cutoffs, even though, differently from NLR, they start out similar for males and females. Moreover, at a single timepoint, PLR cutoffs for the various outcomes can be quite different (e.g. 250 vs. 293 for males at 48 hours for CPAP and death respectively), possibly making it easier to distinguish different grades of severity.
Finally, we showed that NLR in generally better than PLR at predicting severity.
A Chinese study aimed at finding NLR and PLR reference values for healthy subjects showed that both are sex and age dependent22; successive studies confirmed that this distinction is maintained in disease23, in line with our findings.
Four Chinese studies plotted NLR and PLR from admission to post-discharge and obtained trends similar to ours, with lower and stable values for non-severe patients and higher and increasing values for severe patients14-20-24-25.
Regarding the predictive value of the ratios and their cut-off, several studies plotted ROC curves for NLR and PLR, finding that they perform well in predicting severity and death, with NLR performing better than PLR in those studies that compared them12-14-15-21-25-26-27. A Turkish study on 306 patients found that at admission NLR (but not PLR) significantly predicted Covid-19 pneumonia, and they computed a cutoff of 1.7326. A similar study on 69 patients found a cutoff for severe disease of 3.3 for NLR and 180 for PLR, and another on 61 patients used 3.13 for NLR11-21. All of these studies, however, did not aim at distinguishing severe from non-severe patients, but patients with or without pneumonia, which could explain the difference between their cut-offs and ours, that are much higher. In fact, a study which tried to distinguish different grades of severity (common cases, severe non-ICU patients and severe-ICU patients) found values of NLR and PLR that increase with severity, although they did not compute any cutoffs25. A cutoff was actually computed by Ye et al, who found a NLR cutoff of 7.13 for death and 7.28 for invasive ventilation, both values that are very similar to our own24. An Indian study limited to severe patients found a cutoff of 5.1 for mortality, but it did not specify at which point during hospitalization the NLR was extracted25. Finally, Yldiz et al computed a 5.94 NLR cutoff on a derivation cohort for mortality and subsequently validated in a successive cohort27.
All these studies have the limitation of being retrospective and limited to a single centre with no more than a few hundreds of patients. Our study presents the same limitations, but dealt with more than 2000 patients, thus limiting the confounding factors and outliers. We also divided our results for males and females, which we consider a strength as it takes into consideration the physiologic differences of NLR and PLR and adds a further level of stratification. Moreover, our cutoffs do not only deal with severity and mortality but allow for a more tailored approach, dividing severe patients in who can still be treated in an ordinary ward, possibly with the implementation of CPAP, and those who need early referral to the ICU.
Another limitation is selection bias, since we selected our patients and stratified them in severity grades based on ICD9 codes, which can be inaccurate.
Finally, another confounder could be the use of anti inflammatory or myelotoxic drugs, but the this effect should be corrected by the number and the periodicity of observations. In fact, the greatest usefulness of the cutoffs lies in the admission and 48 hours timepoints, where the steroid-induced neutrophilia is not yet present.