key: cord-0916420-frzos2kk
authors: Tatum, Danielle; Taghavi, Sharven; Houghton, August; Stover, Jacob; Toraih, Eman; Duchesne, Juan
title: Neutrophil-to-Lymphocyte Ratio and Outcomes in Louisiana Covid-19 Patients
date: 2020-06-19
journal: Shock
DOI: 10.1097/shk.0000000000001585
sha: 853032ee8f8c0573550180e121b54ac9c447b6d1
doc_id: 916420
cord_uid: frzos2kk

BACKGROUND: Due to the rapidly escalating number of cases and the low baseline of overall health in Louisiana, we sought to determine the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) in hospitalized COVID patients in 2 major metropolitan areas with the highest prevalence of cases and exceedingly high rates of obesity and other comorbid conditions. We hypothesized that elevated NLR would be a prognostic indicator of mortality. METHODS: This was a review of a prospective registry of adult (18+ years) hospitalized SARS-CoV-2 patients from to two large urban safety net hospitals in Louisiana. Blood cell counts at days 2 and 5 were used to obtain NLR. Receiver operating characteristic (ROC) curve analysis assessed predictive capacity of NLR on mortality. Kaplan-Meier (KM) survival analysis and Cox regression models examined the effect of NLR on survival. RESULTS: The study population of 125 patients was majority African American (88.6%) and female (54.8%) with a mean age and BMI of 58.7 years and 34.2. Most (96.0%) had comorbidities of which hypertension (72.0%), obesity (66.7%), and diabetes (40.0%) were the most common. Mortality was 18.4%. NLR > 4.94 on day 1 predicted intubation (P = 0.02). NLR above established cutoff values on hospital days 2 and 5 each significantly predicted mortality (P < 0.001 and P = 0.002, respectively). CONCLUSIONS: NLR is a prognostic factor for endotracheal intubation upon hospital admission and independent predictor for risk of mortality in SARS-CoV-2 patients on subsequent hospital days. Clinical research efforts should examine effects of strategies such as arginase inhibition alone and/or inhaled nitric oxide to ameliorate the effects of elevated NLR.

In late 2019, a cluster of 27 cases of pneumonia caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), now commonly referred to as COVID-19,was discovered in the Hubei Province of China.(1) The first COVID-19 case was reported in the United States (US)in late January 2020, and in March, the World Health Organization officially classified the disease outbreak to be a pandemic. (2, 3) As of April30, 2020, the United States (US) has surpassed all other countries in number of confirmed COVID-19 cases with over one million, more than ten times the reported numbers in China.(4) Several states have experienced larger, more severe outbreaks than others, with New York, New Jersey, and Louisiana being among the worst. Louisiana currently has more than 21,000 known cases, which is the 3 rd highest number of cases per capita, and the fastest growth rate of coronavirus cases in the world. (5, 6) That Louisiana has become a hotbed for COVID19 is not unexpected. In addition to the recent Mardi Gras celebrations which welcomed more than 1 million tourists to the state, Louisiana regularly ranks among the unhealthiest states in the nation. (7) In 2019, the state ranked 46 th in cardiovascular deaths, 47 th in diabetes, and 47 th in obesity. In the same year, the state ranked last in health-related behavior, which included measures such as such as smoking (ranked 43 rd ), physical inactivity (ranked 46 th ), and high school graduation (ranked 47 th ). (7) Inflammation plays a key role in the development of COVID-19 and is likely an important factor in its prognosis. The innate immune response to respiratory infection is characterized by an influx of neutrophils to the lungs, particularly the alveoli.(8) However, high levels of neutrophil infiltration may lead to collateral tissue damage, vascular stasis and cytotoxicity. (8) (9) (10) Previous studies have demonstrated that a sustained release of antiinflammatory cytokines may lead to widespread apoptosis of lymphocytes, resulting in Copyright © 2020 by the Shock Society. Unauthorized reproduction of this article is prohibited.

lymphopenia. (11) (12) (13) Specific to the current pandemic, high levels of circulating neutrophils have been demonstrated in COVID-19 patients, and a recently published meta-analysis of 660 total patients reported lymphopenia in over 40% of COVID-19 cases. (14, 15) This imbalance of neutrophils to lymphocytes can be indicative of severe inflammatory progression, which could lead to the development ofsome of the significant complications so far observed in COVID-19 such as sepsis, multisystem organ dysfunction syndrome (MODS), and acute respiratory distress syndrome (ARDS). (14) Furthermore, levels of inflammatory mediators such as interleukin (IL)-6, C-reactive protein, and tumor necrosis factor alpha (TNFα) have been shown to be elevated in cases of obesity and obesity-related diseases. (16) The neutrophil-to-lymphocyte ratio (NLR) has been identified as a marker of systemic inflammation and prognostic factor for mortality in several patient populations. (8, (17) (18) (19) Due to the rapidly escalating number of cases and the low baseline of overall health in Louisiana, we sought to determine the prognostic value of the NLR in a population of COVID patients in the 2 major metropolitan areas with the highest prevalence of cases. These metropolitan areas are demographically similar, including similar poverty rates of 17%, and contain nearly half of the 4.6 million residents in the state. These areas are served by two, large safety net hospitals -both the only trauma centers in the region, which provided the patient population for the present study. We hypothesized that elevated NLR would be a prognostic indicator of mortality in a COVID-19 patient population.

This study was conducted following approval fromour Institutional Review Board. This was a review of a prospectively collected registry of adult (18+ years), hospitalized COVID-19 positive patients. Demographic and clinical data elements collected included: age, gender, Copyright © 2020 by the Shock Society. Unauthorized reproduction of this article is prohibited. comorbidities, daily lab values, initial vital signs upon presentation to the emergency department (ED), length of stay (LOS), intensive care unit LOS (ICU LOS), days utilizing mechanical ventilation, complete blood cell count and differential,and in-hospital mortality.Differentiated blood cell counts from hospital days 2 and 5 were used to calculate the neutrophil:lymphocyte ratio (NLR). Specifically, absolute neutrophil count was divided by absolute lymphocyte count toobtain the NLR for each hospital day examined. Patients were excluded if they were below 18 years of age or if they were still hospitalized and did not have recorded outcome data. Primary outcome of interest was in-hospital mortality. Secondary outcomes of interest were risk of intubation, length of stay, and mechanical ventilation days.

Continuous variables were described as medians and interquartile ranges (IQR25 -IQR75), and categorical variables were described as frequencies and percentages. Differences in categorical values between groups were compared using Fisher's exact test or Chi Square analysis, while the Mann-Whitney U test was used to examine between group differences in continuous variables. Obesity was defined as body mass index (BMI) ≥ 30.0. Clinical diagnosis of complications were made using standard definitions such as Berlin criteria for ARDS and the Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease (RIFLE) score for renal failure.

Receiver operating characteristic (ROC) curve analysis was used to assess the predictive capacity of NLR on mortality. These results were reported as area under the curve (AUC) and 95% confidence intervals (CI). ROC curve analysis at hospital days 2 and 5 were used to establish NLR cut-off values by optimizing the Youden index.(20) Kaplan-Meier survival analysis was used to determine if these cut off values were predictive of in-hospital mortality.

Copyright © 2020 by the Shock Society. Unauthorized reproduction of this article is prohibited.

Subjects who expired were censored at day of death. The log rank test was used to examine differences between survivors and expired subjects for each hospital day examined. Cox regression analysis was used to examine NLR at hospital days 2 and 5 as independent predictors of mortality, and its results were reported as Hazard Ratio (HR) and 95% CI. Significance was defined at the P< 0.05 level.

A total of 188 patients were included in our institutionalCOVID-19 registry from two urban, safety net hospitals in southern Louisiana at the time of this analysis. (Figure 1 ) Of these, 125 had been discharged and recorded outcome data.The population was majority female (54.8%) with a mean (SD) age of 58.7 (14.8) years. (Table I There were no differences in mean age, mean body mass index (BMI), sex, race, smoking history, mean total comorbidities, or prevalence of any comorbidity between the alive and expired cohorts. Of the procedures performed in the ED that were examined, intubation and central line placement were both strongly associated with mortality (P < 0.001 for both). Mean hospital length of stay (LOS) was not different between survivors and decedents (P = 0.127).

However, ICU LOS and days utilizing mechanical ventilation were each significantly longer in the expired patient subgroup (P < 0.001 for both). The overall complication rate was 47.1%; ARDS was the most commonly incurred complication and was recorded in 26.4% of the patient Copyright © 2020 by the Shock Society. Unauthorized reproduction of this article is prohibited.

population. Renal failure was documented in 19.2% of patients, while sepsis was noted in 15.2%.

A ROC curve of the NLR at day 1 was created to determine if baseline NLR was predictive of intubation. (Figure 2 Table 2 details the cohort characteristics, admission vitals, and outcomes of the cohort with a baseline NLR above the cutoff value of 4.94 to those equal to or less than the cutoff.

There were no differences observed in age, BMI, or ED vitals. Those above the established cutoff had significantly higher mean number of comorbid conditions than those below the cutoff (2.2 vs 2.6; P =0.013, respectively). A baseline NLR above the cutoff value was significantly associated with intubation at admission (P = 0.020). The elevated NLR cohort also had significantly longer mean ICU stays (2.6 days vs 1.1; P = 0.015) and more days utilizing mechanical ventilation (2.2 vs 0.9; P = 0.019) than did the cohort below the cutoff value. Renal failure occurred significantly more often in the higher NLR cohort (33.3% vs 8.1%, P = 0.001).

Frequency of sepsis neared, but did not reach significance, and no differences were observed for the other complications examined.

In the ROC curve analysis for hospital day 2, the AUC for predicting in-hospital mortality by NLR was 0.713 (95% CI (0.564 -0.862), P = 0.004)Sensitivity and specificity were 52.4% and 96.7%, respectively. For the NLR of hospital day 5, the AUC was 0.775 (95% CI each ROC curve by maximizing Youden's index revealed optimal NLR cutoff values of 9.96 for hospital day 2 and 11.40for hospital day 5.

Kaplan-Meier survival curves were created using the established NLR cutoff points for hospital days 2 and 5. (Figures 3A, B) The differences in survival for COVID patients above the stated NLR cutoff value compared to those below the cutoff examined were highly statistically significant for each day examined (P< 0.001 for both). Cox regression analysis revealedNLR on day 2to be an independent predictor of in-hospital mortality (HR 1.07, 95% CI 1.029 -1.108 -4.202, P< 0.001). Similarly, on hospital day 5, NLR was found to be a strong prognostic factor for increased mortality (HR = 1.06, 95% CI 1.022 -1.107, P = 0.002).

The novel coronavirus, SARS-CoV-2, is a highly contagious and significantly fatal disease. At the time of this writing, there were more than 1.8 million known cases worldwide with a case fatality rate of 6.2%.(4) This fatality rate increases for cases severe enough to require hospitalization. Louisiana has one of the highest number of cases per capita numbering more than 20,000 total, of which approximately 10% (n = 2084) are hospitalized. was also more common in women (39.5%) than men (34.1%), which may help to explain the larger proportion of women than men in our present study. A previous report analyzed the National Health and Nutrition Examination Survey (NHANES) to investigate differences of NLR values in the general population and across race.(32) Interestingly, it was reported that non-Hispanic black and Hispanic subjects had significantly lower mean NLR values. Subjects with comorbidities such as diabetes, obesity, and cardiovascular disease had significantly higher NLR than those not burdened with comorbidities. (32) The same study also found that black/African 153 Values are frequencies reported as n (%) unless otherwise denoted. NLR -neutrophil to lymphocyte ratio; SD -standard deviation; BMI -body mass index; ED -emergency department; C -Celsius; IV -intravenous; HR -heart rate; SBP -systolic blood pressure; RRrespiratory rate; LOS -length of stay; ICU -intensive care unit; ARDS -acute respiratory distress syndrome; MODS -multisystem organ dysfunction syndrome

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We would like to acknowledge and thank the following for their hard work and Without their efforts, this work could not have been achieved.Copyright © 2020 by the Shock Society. Unauthorized reproduction of this article is prohibited.

Tatum, Taghavi, Houghton, Toraih, Stover, Duchesne