IJCRR - 14(19), October, 2022
Date of Publication: 05-Oct-2022
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Alteration of Hematological and Biochemical Parameters to Predict Severity in SARS-CoV-2 Infection
Author: Shrewastwa Mukesh Kumar, Acharya Viyatprajna, Aggrawal Kavita
Abstract:Introduction: SARS- CoV-2 global pandemic has fired the world into a notable health catastrophe, with over 187,348,181 cases and 4,044,898 deaths as of July 10 2021. Many studies have been conducted to determine the clinical, biological, and radiological characteristics of COVID-19 for better identification of infected people at an early stage and stop disease development to an advanced state. Objectives: The aim & objective of our study was to take advantage of the biochemical and hematological parameters in pre-dicting the prognosis and mortality in disease severity COVID-19 patients. Methods: This single-center retrospective, observational study was supervised to have all the admitted patients (n = 90) possessing COVID-19 Polymerase chain reaction (PCR) positive, and assessed those for prognosis and disease outcome by taking advantage of several biochemical and hematological markers. Results: Out of 90 patients, 53(58.89%) had mild to moderate disease that were included in the non-severe group; 37(41.11%) had severe to critical disease, of which 17 died and 20 survived. Advanced age, presence of comorbidities and infection were risk factors for advancement to severe disease. The existence of statistically significant abnormalities in the following parameters were strongly related with the advancement to severe disease: white blood cells (WBC, p=0.002), neutrophils (p=0.001), lymphocytes (p=0.001), C-reactive protein (CRP, P< 0.001), D-dimer (P< 0.001), Lactate dehydrogenase (LDH, p< 0.001), Ferritin (P< 0.001), creatinine (p=0.001), aspartate aminotransferase (AST, P=0.012), procalcitonin (P< 0.001) and alanine aminotransferase (ALT, P=0.001) during both admission and hospitalization. Conclusion: The inflammatory markers, biochemical parameters and hematological indices are a good guide for predicting the severity and disease outcome of coronavirus disease.
Keywords: Acute respiratory distress syndrome (ARDS), C-reactive protein(CRP), Lactate dehydrogenase(LDH), Fibrin degradation product (FDP or D-dimer), White blood cells (WBC), Alanine aminotransferase (ALT), Aspartate aminotransferase (AST)
Caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), otherwise known as the COVID-19 pandemic is the largest pandemic of the century. It is an up surging disease that is spreading promptly worldwide and alarms the bio security of all countries1,2, with the number of cases outstripping 187,348,181 and death of more than 4,044,898 people. The two most overwhelmed countries are the United States of America and India, with a death toll of 622,821 in the USA and 408,072 in India as of July 10, 2021.The infection rate was 24,035 cases per million populations.
The COVID-19 pandemic in Nepal is part of the worldwide pandemic of coronavirus disease. In Nepal, the first case was approved as Covid-19 positive test on 23 January 2020 when a 31-year-old student had returned to Kathmandu from Wuhan on 9 January.3It was also the first noted case of COVID-19 in South Asia.4 Nepal's first case of local transmission was approved on 4th April in Kailali District. The number of cases confirmed in the different regions of our country was 652,002 including 9,400 deaths in July 12, 2021.
This alarming viral transmission and mortality have prompted the publication of many studies to determine clinical, biological, radiological, and genetic predictors for the progression to severe and fatal forms of the coronavirus disease.5Acknowledgement of these predictors would make it possible to differentiate the risk and conduct the intervention studies to triage the patients.
Clinical (comorbidities, acute respiratory distress syndrome [ARDS]), Demographic (advanced age, male sex) and radiological predictors have been broadly comprehensive in many studies.5–7Biological (lymphopenia, hyperferritinemia, serum C-reactive protein [CRP] levels) predictors 5, 8 have been described but remain mainly unreported/ under-reported in western region of Nepal. A simple and potent index to evaluate the severity and decide the prognosis of new crown pneumonia is urgently needed at this stage of coronavirus disease.
Lymphocytes take part in a pivotal role in maintaining the body’s immune homeostasis and inflammatory response. The knowledge regarding the mechanisms involving in changes in these blood biochemical indexes is contemplated to give an effective approach for the treatment of COVID-19. In addition, the promotion, protection and maintenance of lymphocyte counts may promote the treatment and prevention strategy regarding development of new crown pneumonia in COVID-19 patients.
We retrospectively analyzed the patients admitted to Nepalgunj Medical College & teaching hospital, Kolhapur who had been cured of COVID-19 and discharged from the hospital between January 1, 2020, and August 30, 2020 because all the literature published regarding COVID-19 patients are mainly concentrated on hospitalized patients, with many patients still being under hospitalization or under treatment. We propose the prediction reliability and accuracy of this study are higher because the clinical end point has been accomplished in these patients.
The main objective of our study was to report the haematological and biochemical abnormalities in Nepalese patients with COVID-19 and to determine the prediction efficacy of parameters that can help to distinguish those likely to develop severe COVID-19. We expect that the findings of this study can give helpful information for early decision-making and treatment for severe COVID-19 patients.
Study design and methods
A retrospective, observational and single-centre study was approved by institutional review committees of Nepalgunj medical college & teaching hospital, Kolhapur of ethical clearance letter number:743/077-078 and was planned to be conducted at Nepalgunj medical college & teaching hospital, Kolhapur which was started from 1 January, 2020 till 30 August 2020 and including all patients who were diagnosed as COVID-19 positive via on a reverse-transcriptase polymerase chain reaction (RT-PCR, Kit Maccura Biotechnology) assay using a nasopharyngeal swab specimen.
A total of 90 patients were recruited which were divided into two groups: 37 severe patients and 53 non-severe patients that were randomly taken without age and gender matched. Severely ill patients were defined as those admitted to the ICU with one of the following signs: respiratory rate more than 30 breaths/min, oxygen saturation less than 93% at room air, ARDS, or requirement of mechanical ventilation.9 Non-severe patients were those with mild or moderate forms of COVID-19 according to World Health Organization criteria.9 This study reports the clinical presentation, demographic characteristics, laboratory findings, and outcomes of incident cases of COVID-19 admitted to the intensive care unit (ICU) from 1 January, 2020 till 30 August 2020.The time frame was chosen to have a minimum follow-up of 15 days for all patients. The nadir and peak haematological and biochemical parameters were taken by following patients from admission to their last blood test.
Normally distributed continuous variables were expressed as means ± standard deviation [SD] whereas variables not normally distributed were expressed as medians (interquartile range [IQR]); categorical variables were presented as counts (%). The Kolmogorov-Smirnov test was used to assess the normality of distribution of continuous variables. Baseline demographic, clinical, and biological characteristics were compared among severe and non-severe patients. We used the Student’s t-test (parametric distribution) or Mann-Whitney’s U test (nonparametric distribution) for continuous variables and the chi-squared or Fisher’s exact test for categorical variables to compare differences between the two groups. Statistical analyses were performed using SPSS version 20.0 (IBM SPSS) and p-value below 0.05 was considered statistically significant for two-tailed.
Out of 90 PCR positiveCOVID-19 patients, 53 (58.89%) were admitted to general wardwhereas37 (41.11%) patients were severe due to corona diseases who required treatment in the ICU. During treatment of severe covid-19 patients in ICU, 20 survived and 17 died. Gender-wise, males had a higher preponderance for the disease.
The age and comorbidities of the patients were statistically significant associated with disease severity (P<0.05) and the age of maximum number of patients belonging to severe group was old age. Marginally greater than half of the patients (47 [52.22%]) had comorbidities, with hypertension (34 [37.78%]) being the most common, followed by diabetes (29 [32.22%]) and kidney disease (16 [17.79%]).
The most common symptoms were weakness (74 [82.22%]), followed by fever (71 [78.89%]) and headache (64[71.11%]). The further symptoms (cough, pharyngalgia, Expectoration, dyspnea, myalgia, dizziness, chills and diarrhoea) were observed in our series less frequently (Table 1)).
17 deaths (45.94%) occurred in the severe group, out of which 12 (32.43%) patients underwent invasive mechanical ventilation and 5 (13.51%) had sudden cardiorespiratory arrest under non-invasive ventilation. The causes of death were principally due to development to severe ARDS alone (4 [10.8%]) or associated with acute kidney injury (10 cases [27.02%]), septic shock (2 [5.4%]), and cirrhotic decompensation (1 [2.70%]). Other complications that the severe patients developed were thromboembolic events (4 [10.81%]), arrhythmia (7 [18.9%]) and pneumothorax (4 [10.81%]).
In univariate analysis, severe patients had statistically significant association with age (P<0.05). With increasing age, the percentage of covid-19 with severe symptoms were increased and more comorbidities, dominated by hypertension (16 [43.20%] versus 18 [34%], P<0.001), diabetes (13 [35.1%] versus 16 [30.2%], P<0.003) and kidney disease (8 [21.6%] versus 8 [15.1%], P<0.001).High levels of white blood cells (WBC), neutrophils, CRP, D-dimer, lactate dehydrogenase (LDH), ferritin, creatinine, alanine aminotransferase (ALT), procalcitoninand aspartate aminotransferase (AST), both on admission and during hospitalization, were statistically significant strongly associated with development to severe forms (Tables 2, 3 and 4) whereas decrease in count of lymphocyte number (lymphopenia) was statistically significant associated with advancement to severe forms.
In binary logistic regression step 1, higher levels of LDH were independently associated with severe covid-19 group (odds ratio (OR) per SD 0.971 [95% CI: 0.959-0.983]; P<0.01) in comparison to non-severe group and in step2, higher levels of LDH were independently associated with severe covid-19 group (odd ratio (OR) per SD 0.962 [95% CI: 0.959-0.983]; P<0.01) after adjusting procalcitonin in comparison to non-severe group.(Table 5)
The third type of coronavirus, known as SARS-CoV-2, identified in the last two decades after SARS-CoV1 and Middle East respiratory syndrome (MERS)-CoV, detected in 2003 and 2012, respectively.10, 11 8,096 people were infected by SARS-CoV-1 infection which caused the death of 774 people in 2002–2003.MERS-COV was culpable for a localized epidemic in the Middle East in 2012 which case-fatality rate was 38%.
We reported the clinicobiological profile of COVID-19 disease in the Midwestern region of Nepal having a sample of 90 patients. The demographic characteristics in our study showed that progressive age is a factor that predisposes patients to COVID-19 and develops advancement to severe disease and death which was supported by many studies.12,13,14
Zhou et al. demonstrated in their study that age greater than 50 years was strongly related to the existence of ARDS and age greater than 65 years was linked with mortality.13 But, progressive age was also noted as key independent predictor of mortality in SARS and MERS.15,16 The age associated comorbidities noted in our study population are severity and prognostic factors as showed by many studies, like Zhou et al. and Wu et al. whereas hypertension and diabetes were significantly related to the existence of ARDS in a multivariate analysis and with the existence of mortality in a univariate analysis.12,13,14 The reason for the relation between Covid-19 virus infections associated mortality and age would be impaired cellular immune function and a longer duration of inflammation in elderly people.12
In our study, gender was not statistically significant associated factor influencing the severity of COVID-19 which is not in congruence with the work of Irani authors.17 But, some study showed that male gender was as a factor influencing the increasing severity of COVID-19.18
The clinical signs manifested by our patients, as well as their frequencies and rates, were close to previousstudies.5,14 It is clear that COVID-19 disease is statistically significantly associated with morbidity, especially in patients with chronic diseases, somewhat one-fifth of them require supportive care in medical ICUs 19, which are particularly limited in most developing countries such as those in Africa. In addition, in spite of the implementation of optimal supportive interventions, the inpatient mortality rate goes on above 1.4%, come to 6.4% in the population aged over 60 years old.20, 21
The biological profiles of our study participants are similar to that has been reported in the literature, with the existence of lymphopenia in severe patients upon admission and further an aggravation of lymphopenia during their stay. Many hypotheses have been constructed to explain the molecular mechanism for pathogenesis of lymphopenia in the context of SARS-CoV-2 infection.
A Chinese study described the characteristics of the haemogram and lymphocyte subpopulations in 166 non-severe patients’ and286 severe patients. Severe patients had a significantly raised neutrophil/lymphocyte ratio and upraised markers of inflammation (CRP, ferritin, interleukin-6, interleukin-8, and interleukin-10). In addition, there was disparity in the lymphocyte immune response in severe patients, who possessed higher CD4 lymphopenia, higher CD4-naïve cells and CD4 suppressor T cells, and less CD4 memory cells and regulatory T cells, in comparison to non-severe patients.22 Rodriguez et al. have proposed that COVID-19 virus have effect on lymphocytes, principally T cells, perhaps diminishing CD4 and CD8 cells.18 The viral particles proliferate via the respiratory mucosa, first by utilizing the ACE2 receptor at membrane of ciliated bronchial epithelial cells and then infecting other cells. This phenomenon causes a cytokine storm in the body and provokes a series of immune responses, which induce changes in peripheral WBCs and immune cells such as lymphocytes.23 This concept has been determined by Henry et al. in their meta-analysis: the number of lymphocytes, principally CD4 lymphocytes, may provide as a biological predictor of severity and mortality; in the case of COVID-19, they also described the hypothesis that survival can be based on the ability to build up lymphocytes that are killed by the virus.24 The same authors also described statistically significant rise in ferritin and CRP levels in patients with suspected severe COVID-19 which are in line with our study.
The rise in CRP levels in blood reflects the extent of the systemic inflammatory syndrome observed in severe forms of the disease, which is followed with a huge release of inflammatory cytokines creating a "cytokine storm" culpable for acute tissue damage with the onset of severe ARDS and subsequent multi-systemic failure.24 The statistically significant rise of LDH levels in blood found in our study which is consistent with the findings of Liu who correlated LDH, lymphocyte, neutrophil, and CRP abnormalities with severe COVID pneumonia.14,25 The raised ferritin levels in blood are likely due to secondary phagocytic lymphohistiocytosis and severe cytokine release syndrome.26, 27 In our study, raised D-dimer level in blood was also significantly associated to severity group of COVID-19 patients and was the cause of coagulopathy with thromboembolic complications in 4.44% of our patients. Anaemia and thrombocytopenia were not statistically significant in my study.
Myocardial damage, as mentioned biologically by elevated troponin and creatine phosphokinase levels in blood suggestive of viral myocarditis, which has been reported by others, was not reported in our study of severe patients’ group.28,29 However, the stay was affected by the significantly distinct difference of the median nadir of WBC, lymphocytes, and Neutrophils, as well as the median peak of neutrophil, WBC, CRP, ferritin, procalcitonin, LDH, D-dimer, ALT, AST, creatinine, and urea levels. This determines the manifestation of complications of the severe form of COVID-19 including the following: bacterial super infection, severe ARDS secondary to the cytokine storm, thromboembolic disease, and organ dysfunction (which is believed to be multifactorial [comorbidities, the cytokine storm of COVID-19, the rejuvenation environment]), leading to death. This is in affirmation with other authors. 5–31
In binary logistic regression step 1, 1unit increased in levels of LDH was independently associated with increased severity by 0.971 times in severe covid-19 group (P<0.01) in comparison to non-severe group and in step 2, 1 unit increased in levels of LDH was independently associated with increased severity by 0.962 times in severe covid-19 group P<0.01) after adjusting procalcitonin in comparison to non-severe group
Our study reinforces these data by describing the experience in our least developed country, which commenced confinement measures at an early stage of the crisis, hence influence the progress of this pathology. We expect that the findings of this study can give helpful information for early decision-making and treatment for severe COVID-19 patients
The limitations of our study were as follows: the single-centre retrospective study design, which increases the chance of selection bias and impacts the generalizability of data; the absence of evaluation of immunological parameters (CD4, CD8, interleukin-6, interleukin-8, interleukin-10) studied by the other studies which could help us to properly analyse the inflammatory characteristics of our patients; the small sample size; and missing data from some pauci-symptomatic patients and patients who died at a given time. This limits the in-depth statistical analysis needed to stratify the maximum risks associated with the pathology.
Majority of the studies being done on Chinese population, there may be a bias due to ethnicity, epigenetic and environmental factors. By observing the changes in biochemical and haematological parameters, repeat CT scans and invasive procedures can be obviated in hospitalized patients to monitor prognosis.
We acknowledge the support of the Department of Biochemistry and Medicine, Nepalgunj Medical College, Kohalpur, Nepal in this study.
Conflict of interest: None
Author contribution: Shrewastwa MK - Study planning, execution, statistical analyses and article writing; Acharya V- Article writing, review and overall supervision; Agrawal Kavita -Article review.
Source of Funding: Self-funded
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