Lymphopenia as a marker for disease severity in COVID-19 patients:A metaanalysis

Praveen Devanandan, Ranadheer Chowdary Puvvada, Vijey Aanandhi Muthukumar

1School of Pharmaceutical Sciences, Vels Institute of Science Technology and Advanced Studies, Chennai, India

2Department of Pharmaceutical Chemistry and Analysis, School of Pharmaceutical Sciences, Vels Institute of Science Technology and Advanced

Studies, Chennai, India

COVID-19 has become the global focus since December 2019[1].Patients usually experience cough, fever and flu-like symptoms.Most patients also experience dyspnoea.Elevated procalcitonin,lymphopenia are observed in COVID-19 patients.Recently, a case series analysis has predicted that lymphopenia may be a very good prognostic marker for disease progression in COVID-19[2].

An extensive literature search is carried out in PubMed, Scopus and Google Scholar using the medical subject heading terminology(MeSH)-‘novel coronavirus', ‘ncov-2019', ‘Wuhan', ‘COVID-19' and ‘SARS-CoV-2'.We included papers that reported the epidemiological aspects of COVID-19 such as retrospective studies,observational reports published between 1st January 2020 and 20th March 2020.Papers published in English that reported the biochemical data of these patients were included.Publications with emphasis on severity of the patients were included.Studies that did not report the absolute lymphocyte count, letters to the editor,reviews and opinions were excluded.A meta-analysis was then carried out with the selected studies and individual as well as pooled odds ratio was calculated to determine the statistical importance of lymphopenia on the severity of COVID-19 patients.

Overall 22 articles were identified using our selection criteria, out of which 16 were excluded after reviewing their abstract for full text reading.Six articles provided data of absolute lymphocyte count for all patients as well as for severely ill patients[3-8].The summarised findings are reported in Table 1.Two of the articles did not provide data on number of patients who had lymphopenia.Hence 4 manuscripts were finally selected, their individual odds ratio as well as pooled odds ratio was calculated with 95% confidence interval[3,6-8].The summarised findings are reported in Table 2 as well as Figure 1.From the calculated data, baseline absolute lymphocyte count has a significant impact on the disease severity.A case report reported that patient had a fall in the absolute lymphocyte count even after the initiation of the therapy[9].The calculated odds ratio suggested a four-fold increase in chance of disease severity (either for ICU care or death) in COVID-19 patients who had a low lymphocyte count at the baseline.In these selected studies, 90.58% (250/276) of the severely ill patients had lymphopenia.This may be a very essential factor in predicting the outcome of the treatment and the course of hospitalization of COVID-19 patients.

The common aetiology of lymphopenia is auto-immune disorders(such as rheumatoid arthritis, myasthenia gravis), carcinomas,infectious diseases like AIDS, tuberculosis and inherited conditions like ataxia-telangiectasia, and Wiskott-Aldrich syndrome.Chemotherapeutic agents may also cause lymphopenia.In the selected studies, totally 13 patients had carcinoma of various nature[3,6,8]2 patients reported immunodeficiency[8]and 2 patients reported secondary pulmonary tuberculosis[7].Among these only 3 cancer patients and 2 pulmonary tuberculosis patients reported for severe COVID-19 outcome[7,8].Even if the data of these patients are not considered, the resulting odds ratio is 3.67 (95% CI 2.39 to 5.63).

Lymphopenia is commonly observed in severe acute respiratory syndrome (SARS) as well as Middle East respiratory syndrome(MERS) although the cause of lymphopenia in these diseases isunknown.Studies reported that SARS CoV virus may lead to T cell depletion by directly infecting T cells; however, there are contraindicated studies which emphasized on the role of cytokine induced cell death as well as bone marrow hematopoietic progenitor cells suppression.It was observed from a study that delayed clearance of SARS coronavirus from the lung tissue was associated with reduced pulmonary recruitment of lymphocytes is seen in mice[10].Additional studies are essentially needed to confirm whether lymphopenia could be a predictable marker for projecting the disease severity.

Table 1.Absolute lymphocyte count in COVID-19 patients.

Table 2.Meta-analysis of the available data.

Figure 1.Forest plot of the available data:Odds ratio of the 4 selected studies along with cumulative odds ratio.

It could be observed that the absolute lymphocyte count is comparatively lesser in the severely ill patients as well as nonsurvivors.We sorted out 4 studies that reported on number of patients who had lymphopenia among all patients as well as severe cases[3,6-8].

The combined odds ratio calculated based on weight of each study is indicating extremely significant (P＜0.001) outcome.The test for heterogeneity I2=73%.An odds ratio above 1 is considered significant for the predicted outcome.The overall calculated odds ratio is 3.98 which indicates almost 4 times higher chance for the predicted outome (Disease Severity in COVID-19 patients).

In conclusion, there is a 4-fold higher risk of disease severity either ICU care or death in patients who have a low lymphocyte count at the baseline.Low lymphocyte count may affect drug selection.Hence, lymphopenia maybe a very essential factor in predicting the outcome of the treatment and the course of hospitalization of COVID-19 patients.

Conflict of interest statement

We declare that we have no conflict of interest.

Authors' contributions

P.D.developed the hypothesis, P.D., R.C.P conducted literature search.P.D, R.C.P., M.V.A carried out analytical calculations and writing of the manuscript.M.V.A is the superviser.