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Role of neutrophil to lymphocyte ratio as a prognostic indicator for COVID‐19

Abstract Background Coronavirus disease 2019 (COVID‐19) is a new pandemic disease, associated with substantial morbidity and mortality. Its diagnosis requires centralized facilities and time. Aims To describe the exposure history and clinical picture of the COVID‐19 patients, to study the SARS‐CoV‐2 Virus load and some determinants that may correlate with its prognosis, and to evaluate the role of inflammatory index NLR as an early predictor of COVID‐19 prognosis. Methodology A prospective follow‐up study included laboratory‐confirmed 179 COVID‐19 cases out of 660 suspected COVID‐19 cases, at El‐Madinah El‐Monawarah General Hospital in April 2020. Confirmed cases were managed by the Saudi Protocol and followed up every 2 weeks by PCR, neutrophil to lymphocyte ratio (NLR) for 1 month. Data were collected through a validated questionnaire and by qualified infection control staff. Results The majority of the COVID‐19 cases were 67 (37.4%) aged 30 to <45 years, 157 (87.7%) males, 76.0% working outside the medical field. 38.0% were asymptomatic and 26.3% had severe symptoms, while the main presenting symptoms were fever and dry cough (49.7% and 43.6%), respectively. The case fatality was 7.8%. The male, nonmedical occupation, and low level of education had a statistically significant relationship with the baseline PCR. There was an inverse significant correlation between baseline PCR readings and the recovery duration and health status outcomes. NLR was noted to be significantly higher among old age, illiterate nonmedical occupation, case with severe symptoms, MICU admission, and worst health status outcomes, but it was paradoxically higher among nonadmitted positive cases. Conclusion Admitted COVID‐19 cases outcomes (disease severity, ICU admission, and mortality) significantly correlated to NLR and not to the baseline PCR viral load. NLR could be a beneficial prognostic and triaging parameter especially old nonmedical COVID‐19 patients.


| INTRODUCTION
Coronavirus disease 2019 (COVID-19) is a new pandemic disease, 1 associated with substantial morbidity and mortality. 2 Its clinical spectrum is very heterogeneous, and the leading cause of death is the respiratory failure from acute respiratory distress syndrome (ARDS). 3 COVID-19 transmission occurs through respiratory droplets, direct contact, 4,5 nosocomial, 1,3 and airborne in healthcare settings during aerosol-generating procedures and some community outbreaks. 6 Super spreading events can pass the infection to large numbers of contacts 7 and are associated with explosive growth early in an outbreak and sustained transmission in later stages. 8 The SARS-CoV-2 RNA virus shedding was observed in mild and severe cases. 9 The shedding duration is longer in stool samples than in respiratory and serum samples {22 days (d), vs 18 days, 16 d} 10 and in symptomatic than asymptomatic patients (25.2 days vs 22.6 days). 11 Factors associated with prolonged shedding include older age, male sex, comorbid hypertension, severe illness on admission or delayed hospital admission after symptom onset, use of corticosteroids, and invasive mechanical ventilation. 12,13 The virus load peaks within the first week of disease onset 14 and detected in high levels in nasal and throat swabs after symptom onset and be nearly similar in asymptomatic and symptomatic patients. 15,16 Baseline high viral load may increase the risk of disease progression. 17 The virus particles invade the lymphocyte cytoplasmic component and cause destructive necrosis or apoptosis. 18 Therefore, the severity of lymphocytopenia reflects the severity of infection. Neutrophil to lymphocyte ratio (NLR) is a meaningful parameter for prognosis and risk state and can help to appropriately allocate medical resources. 19 The prognostic factors that increase the risk of unfavorable outcomes include male sex, age ≥ 50 year, comorbidities (eg, hypertension, diabetes), smoking, lymphopenia, thrombocytopenia, liver or renal impairment, cardiac injury, elevated inflammatory markers (C-reactive protein, ferritin), elevated D-dimer, and elevated interleukin-6. 20 Most of these findings are a result of studies initially performed in China, and additional validation studies, especially outside of China, are required. 21 There is increasing evidence that easily obtained laboratory biomarkers, such as NLR, can have a predictive role and can be used to stratify patient risk and individualize treatment strategy in a variety of medical conditions. Such laboratory tests are being used in conditions such as acute coronary syndrome, 22 cerebral hemorrhage, 23 ischemic stroke, 24,25 and sepsis, and other infectious pathologies. 26 We aim to study the SARS-CoV-2 Virus load and explore some determinants that affect its prognosis, through the following objectives and a hospital-based study in Saudi Arabia;

| Sample size
We recruited all the admitted cases. • Sample collection through a well-strained GP and the laboratory team

| Data collection through the
• Lab sheet (record base) for results of the collected samples.

| The data collection tool
The questionnaire was designed on Arabic Google forms was used to collect data, after validated by nine experts for validating its content and its reliability and then Pilot testing was done and involved 25 participants in order to ensure clarity of the questionnaire, and results of the pilot were not included in the study. The questionnaire consisted of main parts: 1. The demographic characteristics of the studied cases.

| The study variables
• Respiratory failure (RF) is a syndrome in which the respiratory system fails in one or both of its gas exchange functions: carbon dioxide elimination and oxygenation, classified as either hypercapnia or hypoxemic 28 • Respiratory distress (RD) is a sudden onset respiratory failure in adults that follows lung endothelium injury lung (as in sepsis or pneumonia) with the accumulation of protein-rich fluid and alveoli collapse leading to difficult, rapid breathing, and very low levels of oxygen in the blood 28 • Discharging protocol to discontinue isolation precaution, two respiratory negative samples 24 hours apart are required for all patients

| Statistical analysis
The collected data were coded and analyzed by using SPSS (version 22) at the level of significance (P-value ≤ .05). For quantitative data, summarization means, SD, median, and range were used, while Kruskall-Wallis U-test and analysis of variance (ANOVA) f-test were used for their analysis. To test the association between categorical variables, Pearson's correlation coefficient (r) was used to test the association between two continuous variables.

| Ethical issues
The questionnaire contains no sensitive or private questions. Ethi-

| Patient and public involvement
The data were collected after informed consent from the participants' records, and direct examination, and their identity was anonymous.  (Table 1) There were a statistically significant (P < .05) relationship between the type of comorbidities and the median of lymphocyte, median of NLR, and the recovery duration (d). The highest recovery duration was significantly higher among COVID-19 cases with companied comorbidities (31.5 ± 7.4). The median of NLR was significantly higher among infected patients who had DM and HTN 5.7 (6.6 ± 4.7), them among diabetic patients 3.8 (5.6 ± 5.7) compared to other groups ( Table 4).

| DISCUSSION
It is very important to grade the severity of COVID-19 infection for treatment, especially in outbreak or epidemic, because the medical resources are relatively scarce, optimize the allocation of rescue resources, and prevent the occurrence of overtreatment or under treatment. 30 In this study, we report here a prospective study on 179 patients with laboratory-confirmed COVID-19 infection.
Work was the main source of catching the history of exposure, and Doaa et al. 31 reported nearly similar main clinical symptoms because both samples had nearly similar demographic characteristics.
The viral load was found to be significantly higher (P = .00*) in patients who worked outside the medical field than those working in the medical field or not working; this can be explained by the protective measures and the higher awareness of the medical personnel.
In addition, it was significantly lower in highly educated than others; this may spotlight the importance of awareness campaign. It was higher in non-Saudi patients; this may be due to different immune responses and vaccination programs. In addition, it was higher in males than females; this can be explained by higher exposure rates in males than females in Saudi Arabia.
Fifteen percentage of patients were diabetic as it is a risk factor for severe disease, 32 hospitalization, and mortality, 33 due to the impaired in the immune response. 34 Nearly, similar findings (22%, 16.2%, and 12%) were reported in many studies (30.31, 29)  There were a statistical significant (P < .05) relationship between the type of comorbidities and the median of lymphocyte, median of NLR, and the recovery duration (d). The NLR was significantly higher among COVID-19 infected patients who had DM and HTN 5.7 (6.6 ± 4.7), them among diabetic patients 3.8 (5.6 ± 5.7) compared to other groups (Table 4). DM has a significant relation with the morbidity and mortality of the affected person that increase the burden on health care system. 37 Severe symptoms including O2 saturation < 93%, Respiratory distress (RR >30b/min), or Respiratory failure occurred in about 50% of our patients. The interval between the appearance of symptoms and the diagnosis by PCR was less than 1 week in about 80%, and less than 3 days in 45%, which is consistent with other studies. [38][39][40] Hospitalization was needed in about one-third of our patients, with ICU admission in only eight patients (4.5%) while hotel isolation in 128 patients (71.5%) ( Table 5).
In the present study, a negative correlation was found between viral load (first PCR) with duration until recovery and severity of the disease ( Medical Center, took nasopharyngeal swabs, and measured SARS-CoV-2 viral load using RT-PCR assays (Table 7). 43 We found no correlation between the baseline PCR with Lymphocyte percent, Neutrophil, second PCR, NLR, or age. A strong positive correlation between NLR and neutrophil count with disease severity, ICU admission, and mortality was found, this is in agreement with Jingyuan Liu who found that NLR is a good predictor for COVID-19 critical illness in the early stage of the disease. 44 Also, in agreement with Yang et al and Xisheng who stated that high NLR cab is considered as an independent bad prognostic biomarker. 45,46 Although all this we found that NLR was lower in patients admitted to the hospital when compared to patients who received home treatment.

| CONCLUSION
The admitted COVID-19 cases outcomes (disease severity, ICU admission, and mortality) correlated well to the NLR and not to the baseline PCR viral load. NLR could be a beneficial prognostic and triaging parameter for the admitted cases especially old non-medical patients.

| Limitations
It is difficult to assess other host risk factors for disease severity and mortality with multivariable-adjusted methods.

| Recommendation
Further detailed research studies are still required to verify and refine our findings to help develop a practical and effective tool for predicting disease outcomes in COVID-19 patients.

ACKNOWLEDGMENT
I would like to express special thanks to Dr.Sameh Elgendy, Consultant of Internal Medicine, Zagazig University, Egypt, for his expert advice throughout this research. I would also like to thank all the recruited cases in this study.

FUNDING
None declared.

CONFLICT OF INTEREST
The authors reported no potential conflict of interest.

TRANSPARENCY STATEMENT
I affirm that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.