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. 2021 Jul 27;16(7):e0255379. doi: 10.1371/journal.pone.0255379

Hematological abnormalities and comorbidities are associated with COVID-19 severity among hospitalized patients: Experience from Bangladesh

Md Ashrafur Rahman 1, Yeasna Shanjana 2, Md Ismail Tushar 1, Tarif Mahmud 1, Ghazi Muhammad Sayedur Rahman 1, Zahid Hossain Milan 1, Tamanna Sultana 1, Ali Mohammed Lutful Hoq Chowdhury 3, Mohiuddin Ahmed Bhuiyan 4, Md Rabiul Islam 4,*, Hasan Mahmud Reza 1,*
Editor: Robert Jeenchen Chen5
PMCID: PMC8315496  PMID: 34314447

Abstract

Background

The hematological abnormalities are assumed to be involved in the disease progression of COVID-19. However, the actual associations between specific blood parameters and COVID-19 are not well understood. Here we aimed to assess the correlations between hematological parameters and the severity of COVID-19.

Methods

We included COVID-19 patients who were admitted to Evercare Hospital Ltd, Dhaka, Bangladesh, between November 10, 2020, to April 12, 2021, with a confirmed case of RT-PCR test. We recorded demographic information, clinical data, and routine hematological examination results of all COVID-19 patients. We performed statistical analyses and interpretation of data to compare severe COVID-19 patients (SCP) and non-severe COVID-19 patients (NSCP).

Results

The age and BMI of the admitted COVID-19 patients were 48.79±8.53 years and 25.82±3.75 kg/m2. This study included a total of 306 hospitalized COVID-19 patients. Among them, NSCP and SCP were 198 and 108, respectively. And we recorded 12 deaths from SCP. We observed the alterations of several hematological parameters between SCP and NSCP. Among them, we noticed the increased levels of C-reactive protein (CRP), d-dimer, and ferritin showed good indicative value to evaluate the severity of COVID-19. Also, there were positive correlations among these parameters. Moreover, we found correlations between the outcomes of COVID-19 patients with patient’s demographics and comorbid diseases.

Conclusion

Based on our results, CRP, d-dimer, and ferritin levels at admission to hospitals represent simple assessment factors for COVID-19 severity and the treatment decisions at the hospital setup. These blood parameters could serve as indicators for the prognosis and severity of COVID-19. Therefore, our study findings might help to develop a treatment protocol for COVID-19 patients at the hospital setup.

Introduction

The outbreak of the COVID-19 due to the SARS-CoV-2 was firstly epi-centered in Hubei province, Wuhan, China. The SARS-CoV-2 is a high transmissible virus that spread across the world within a short period [1, 2]. Therefore, on March 12, 2020, the world health organization (WHO) declared COVID-19 a pandemic for the world. Globally, the ongoing pandemic has created numerous challenges to the healthcare systems of many countries [3]. The risk of coronavirus infection and the development of severe COVID-19 is associated with age and comorbid diseases of patients [4]. The COVID-19 primarily targets the lungs of the patients. However, it can damage other organs in severe cases. Therefore, hematological abnormalities and their intensities are involved in the severity of COVID-19. About half of the COVID-19 patients are asymptomatic carriers and pre-symptomatic. The fever, cough, sore throat, fatigue, dyspnea, myalgia, and breathing problems are the initial symptoms of COVID-19. These symptoms may progress to acute respiratory distress syndrome (ARDS), metabolic acidosis multi-organ failure, and shock in severe COVID-19 cases. These worsen conditions of patients may lead to death [5, 6].

COVID-19 plays a critical role in the host immune response in disease pathogenesis and clinical manifestation. It triggers the antiviral immune system to produce an uncontrolled inflammatory response that may lead to cause hematological abnormalities such as lymphopenia, lymphocytes, and abnormalities in granulocyte and monocyte [7]. These hematological abnormalities can facilitate the infection by other microorganisms, septic shock, and multi-organ dysfunction. Moreover, individuals with comorbid diseases such as hypertension, obesity, diabetes, etc., are at higher risk of coronavirus infection. Most comorbidities are frequently associated with excessive body fat mass [8]. As a result, it alters various hormonal, metabolic, and inflammatory functions. Also, adipose tissue may involve in the pathogenesis of COVID-19, where obesity plays an important role [9]. Hypertension is also a risk factor for coronavirus infection. COVID-19 patients with hypertension might increase severity and mortality rates. Hypertension should consider as a clinical predictor for the severity of COVID-19 both in adults and children [10]. Also, diabetes is another comorbidity to increase the COVID-19 disease burden and mortality worldwide [11, 12]. It plays a primary role in the development of pneumonia and sepsis due to the virus infection. A study showed that diabetic patients are at higher risk of coronavirus infection. Also, they have an increased chance of COVID-19 severity and mortality [13]. However, some COVID-19 patients with comorbid diseases are recovering. Unfortunately, it might create an increased burden for them due to post-COVID complications.

We have seen increasing evidence about hematological abnormalities and comorbidities with the severity of COVID-19 and duration of hospitalization. Still, the elaborative studies regarding the relationship of hematological abnormalities with the severity and extended hospitalization of COVID-19 patients are limited in different countries. Also, the severity and mortality of coronavirus infection vary from country to country due to the local mutation of the virus in various geographical locations [14]. Thus, most studies have limitations according to geographical consideration, parameters analyzed, and prognostic value of altered elements. Moreover, Bangladesh is a densely populated country with a significant number of aged populations [15, 16]. In Bangladesh, 7.7% of the total population is over 60 years, and 53.8% of elderly adults have comorbidities such as blood disorders, hypertension, diabetes, COPD, etc. [17–21]. Also, the inadequate number of health care service providers and limited healthcare facilities making the situation more destructive [22]. Therefore, we aimed to assess the associations of hematological parameters and comorbid diseases with the severity levels of COVID-19 patients in Bangladesh.

Materials and methods

Study population

This observational cohort study screened 306 COVID-19 patients for hematological abnormalities and comorbid diseases from the COVID unit of Evercare Hospital, Dhaka, Bangladesh, from November 10, 2020, to April 12, 2021. The present study included hospitalized COVID-19 patients with multiple complications. Inclusion criteria were COVID-19 patients over 18 years of age with a confirmed PCR diagnosis. The severity of COVID-19 patients was assessed by: 1. patients admitted in hospital with confirmed pneumonia by lung CT, 2. patients with respiratory distress (rate > 30 breaths/min) and oxygen capacity level < 93%, and 3. patients required intensive care unit (ICU) support or mechanical ventilation [23, 24]. Exclusion criteria of this study were less than 18 years old, pregnant women and those who are taking medicine for reducing lymphocyte, leukocytes, or white blood cells count, and patients previously diagnosed with any hematological disorders.

Sample collection and analysis

Ten milliliters of blood samples were collected using an ethylenediaminetetraacetic acid-containing vacutainer tube for analysis of hematological parameters. We monitored the diet restrictions for 6 hours before taking the samples from patients. The puncture site was also adequately sanitized and cleaned before sample collection. Immediately after blood collection, the routine procedures were completed and the samples were stored at -80°C [25–28].

Several laboratory tests were performed during routine examination of admitted COVID-19 patients at the hospital. We collected data for the hematological parameters of COVID-19 patients at different severity stages. The immunoassay was performed using Beckman Coulter Access-2 and Sysmex CS-1600 to measure ferritin and d-dimer levels, respectively. Also, the same immunoturbidimetry measured the C-reactive protein (CRP) levels using Beckman Coulter, DXE 700AU. The photometric method was applied using Beckman Coulter, DXE 700AU for creatinine, liver function tests, Pro-BNP, and Sysmex XN 2000 for hemoglobin (Hb) and complete blood count (CBC). White blood cell (WBC) concentration was detected by flow cytometry method using Sysmex XN 2000. The flow detection method applied using Sysmex XN 2000 for red blood cell (RBC) and platelet count test. The ion-selective electrode method analyzed electrolyte parameters (Na+, CI-, K+, and HCO3) using Dimension EXL 200. The chemicals and reagents of analytical grade were collected from commercially available companies to perform the above tests. Also, all the standard samples were purchased from Sigma-Aldrich, Inc.

Statistical analysis

We presented the hematological parameters as the mean ± standard deviation (mean ± SD). Here we compared the changes of parameters between severe COVID-19 patients (SCP) and non-severe COVID-19 patients (NSCP) using independent sample t-tests. We assessed the correlations among different blood parameters using Pearson’s correlation test. We measured the risk factors of COVID-19 severity using univariate and multivariate analyses. We evaluated the diagnostic performance of the studied parameters using receiver operating characteristic (ROC) analysis. We performed data editing, sorting, coding, classification, and tabulation using Microsoft Excel. also, we applied IBM SPSS software (version 25.0) for all statistical analyses. We considered significant statistical variations or associations at a p-value less than 0.05.

Ethics

The Institutional Review Board (IRB) of North South University (IRB number: 2020/OR-NSU/IRB-No.0701) approved the study protocol. We performed the investigations according to the principles stated in the Declaration of Helsinki. Also, the participants and their attendants were briefed about the aim and objective of the study. Also, we obtained written consent from all the patients or their primary caregivers before participation.

Result

Demographics of study participants

The descriptive statistics for all the COVID-19 patients are summarized and presented in Table 1. Based on the severity of COVID-19 patients, we classified 198 patients as non-severe, and 108 patients were in a severe category. Of the 306 participants, 187 (61.11%) were male, and 119 (38.89%) were female. The age and BMI of our cohort were 48.79±8.53 years and 25.82±3.75 kg/m2, respectively. After treatment, 294 (96.08%) patients were tested COVID negative in the RT-PCR test, and 12 (3.92%) patients had died. Among the participants, 73.40% of patients were above 40-years of age, and 36.60% of patients were below 40 years of age. Most of the participants were between 21–60 years old. Among the COVID-19 patients, two-thirds had normal BMI, and 77.45% had any comorbidity. Common comorbidities were diabetes (54.58%), hypertension (53.27%), and bronchial asthma (22%). Besides, we also observed that 19% had a history of any other comorbid diseases.

Table 1. Characteristics and comorbid diseases of COVID-19 patients.

Parameters SCP (n = 108) NSCP (n = 198) p-value
n % Mean ± SD n % Mean ± SD
Age in years 54.07±9.82 45.55±6.34 <0.01
    20–40 24 22 88 44
    41–60 38 35 66 33
    61–80 46 43 44 22
Sex <0.05
    Male 92 85 95 48
    Female 16 15 103 52
BMI (kg/m2) 27.73±4.82  24.45±3.82 <0.01
    Below 18.5 (CED) 1 1 7 4
    18.5–25 (normal) 63 58 139 70
    Above 25 (obese) 44 41 52 26
Presence of comorbid disease <0.01
    Yes 102 94 135 68
    No 6 6 63 32
Hypertension <0.01
    Yes 73 68 90 45
    No 35 32 108 55
Diabetes
    Yes 79 73 88 44
    No 29 27 110 56
Bronchial Asthma <0.05
    Yes 38 35 30 15
    No 70 65 168 85
CKD <0.01
    Yes 3 3 1 1
    No 105 97 197 99
Outcome <0.01
    COVID-19 survivors 96 89 198 100
    Death 12 11 0 0
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SCP: Severe COVID-19 patient; NSCP: Non-severe COVID-19 patient; BMI: Body mass index; CED: Chronic energy deficiency; CKD: Chronic kidney disease.

Hematological abnormalities in COVID-19 patients

We presented the hematological alterations of the cohort in Table 2. First, we compared hematological variations between SCP and NSCP. The SCP had lower RBC and Hb levels than NSCP. The NSCP showed significantly lower WBC, neutrophils, platelet, CRP, ferritin, d-dimer, creatinine, SGPT, SGOT, and bilirubin levels than SCP. However, we observed the electrolyte levels (Na+, K+, Cl-, and HCO3) were higher in NSCP than SCP. We demonstrated the changes of hematological parameters in two different disease states using box-plot graphs (Fig 1).

Table 2. Hematological parameters of the study cohort at different severity levels of COVID-19.

Parameter Reference value SCP (n = 108) Mean±SD NSCP (n = 198) Mean±SD P-value
Hb (g/dL) Male: 13.8–17.2; Female: 12.1–15.1 12.61±5.98 12.68 ±1.36 0.012
RBC (× 1012/L) Male: 4.7–6.1; Female: 4.2–5.4 4.48±0.64 4.54±0.44 <0.001
PCV (%) Male: 38.3–48.6; Female: 35.5–44.9 36.58±5.20 40.99±2.77 <0.001
MCV (fL) 80–100 81.71±6.48 87.90±3.88 <0.001
WBC (× 109/L) Male: 3.9–10.6; Female: 3.5–11 8.30±3.65 7.32±1.98 <0.001
Neutrophils (%) 40–60 72.54±11.27 64.51±9.19 <0.001
Lymphocytes (%) 20–40 21.61±11.89 30.36±5.92 <0.001
Monocytes (%) 2–8 4.13±1.95 4.48±1.36 0.005
Eosinophils (%) 1–4 1.27±1.58 2.96±1.51 <0.001
Basophils (%) <1 0.38±0.36 0.42±0.38 0.049
Platelet (× 109/L) 150–400 240.41±95.45 235.02±66.29 0.019
CRP (mg/dL) <10 6.55±7.25 0.19±0.11 <0.001
Ferritin (ng/mL) Male: 20–250; Female: 12–263 651.86±793.30 86.41±34.78 <0.001
D-Dimer (ng/mL) <250 756.73±600.08 239.00±99.25 <0.001
Creatinine (mg/dL) 0.6–1.3 1.15±0.93 0.83±0.27 <0.001
Albumin (g/dL) 3.5–5.5 3.32±0.55 4.16±0.51 0.259
SGPT (U/L) 7 to 56 58.04±45.12 36.86±12.67 <0.001
SGOT (U/L) 5 to 40 39.34±29.32 28.15±8.14 <0.001
Bilirubin (mg/dL) 0.3–1.0 0.49±0.27 0.46±0.27 0.049
Na+ (mmol/L) 135–145 136.41±5.28 139.89±2.90 <0.001
K+ (mmol/L) 3.5–5.5 3.81±0.66 4.04±0.44 <0.001
Cl- (mmol/L) 98–106 101.19±5.22 102.66±3.36 <0.001
HCO3 (mmol/L) 23–29 26.58±3.89 28.05±2.29 <0.001
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p<0.05 (Significant difference between patient and control groups at 95% confidence interval). SCP, severe COVID-19 patients; NSCP, non-severe COVID-19 patients; Hb, hemoglobin; RBC, red blood cell; PCV, packed cell volume; MCV, mean corpuscular volume; WBC, white blood cell; CRP, carbon reactive protein, SGPT, serum glutamic pyruvic transaminase; SGOT, serum glutamic oxaloacetic transaminase; Na, sodium; K, potassium; CI, chloride; HCO3, bicarbonate.

Fig 1. Changes of blood parameters in two different disease states.

Fig 1

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Independent sample t-test was applied and p < 0.05 was considered as significant at 95% confidence of interval. NSCP, non-severe COVID-19 patients; SCP, severe COVID-19 patients.

Relationships among hematological parameters

Pearson correlation coefficient were used for statistical analysis for correlating inter parameter variables. Relationships among the parameters of the cohort at different severity levels of COVID-19 are presented Table 3. Briefly, in SCP, Hb levels were positively associated with RBC (r = 0.456; p<0.001) and PCV (r = 0.593; p<0.001). RBC and PCV levels were positively correlated with each other in SCP group (r = 0.593; p<0.001). Whereas, PCV and d-dimer levels were negatively correlated with each other (r = -0.302; p<0.001). WBC and neutrophil levels were positively correlated with each other (r = 0.333; p<0.001), whereas, WBC levels were negatively correlated with lymphocyte (r = 0.400; p<0.001) and monocyte levels (r = 0.330; p<0.001). Moreover, neutrophil levels were negatively correlated with Lymphocyte (r = -0.530; p<0.001) and monocyte (r = -0.354; p<0.001) levels. And CRP and creatinine were positively connected with each other (r = 0.330; p<0.001).

Table 3. Correlations among research parameters in the cohort at different severity stages of COVID-19.

Parameter SCP (n = 108) NSCP (n = 198)
r p r p
Hb and RBC 0.456 <0.001 0.053 0.353
Hb and PCV 0.593 <0.001 -0.040 0.486
RBC and PCV 0.506 <0.001 0.025 0.665
PCV and D-dimer -0.302 <0.001 0.051 0.374
WBC and Neutrophils 0.333 <0.001 0.028 0.627
WBC and Lymphocytes -0.400 <0.001 0.074 0.196
WBC and Monocytes -0.330 <0.001 -0.016 0.778
Neutrophils and Lymphocytes -0.530 <0.001 -0.050 0.381
Neutrophils and Monocytes -0.354 <0.001 -0.030 0.601
CRP and Creatinine 0.330 <0.001 -0.031 0.588
SGPT and SGOT 0.479 <0.001 -0.112 0.051
Na+ and CI- 0.455 <0.001 -0.008 0.889
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r = Correlation co-efficient; p = Significance; Negative values specify opposite correlation. Correlation is significant at 0.05 level (two-tailed). SCP, severe COVID-19 patients; NSCP, non-severe COVID-19 patients; Hb, hemoglobin; RBC, red blood cell; PCV, packed cell volume; WBC, white blood cell; CRP, carbon reactive protein, SGPT, serum glutamic pyruvic transaminase; SGOT, serum glutamic oxaloacetic transaminase; Na, sodium; CI, chloride.

Regression analysis

We performed binary logistic regression analysis to measure risk estimation of COVID-19 severity for demographic profile and comorbid diseases (Table 4). The COVID patients aged below 40 years were 1.060 times less likely to develop severe symptoms (OR = 1.060, 95% CI 1.025–1.095, <0.05) than patients aged 40 years and above. Male patients were 3.252 times more prone develop severe COVID-19 symptoms (OR = 3.252, 95% CI 1.001–15.140, <0.05). Obese subjects showed to be 1.130 times more susceptible to get severe COVID-19 (OR = 1.130, 95% CI 1.055–1.212, p<0.001) in comparison to healthy subjects. COVID-19 patients with any comorbid diseases were at 2.881 times higher risk to turn into severe COVID-19 than patients without comorbidity (OR = 2.881, 95% CI 1.364–22.727, <0.05). COVID-19 patients with diabetes, hypertension, bronchial asthma, and CKD were 3.776, 2.409, 2.835, and 2.069 times more sensitive to develop severity than patients without these comorbid diseases (OR = 3.776, 95% CI 1.832–16.264, <0.05; OR = 2.409, 95% CI 1.693–9.090, <0.05; OR = 2.835, 95% CI 1.023–12.978, <0.05; OR = 2.069, 95% CI 1.011–10.422, p<0.001, respectively).

Table 4. Univariate and multivariate analysis of risk factors associated with COVID-19 severity.

Characteristics of patients Univariate analysis of risk factors Multivariate analysis of risk factors
SCP (n = 108) NSCP (n = 198) p-value OR 95% CI p-value
Age above 40 years 84 (78) 110 (56) <0.01 1.060 1.025–1.095 <0.05
Male sex 92 (85) 95 (48) <0.05 3.258 1.001–15.140 <0.05
Patient with obesity 44 (41) 52 (26) <0.01 1.130 1.055–1.212 <0.001
Patient with any comorbid diseases 102 (94) 135 (68) <0.01 2.881 1.364–22.727 <0.05
Patients with diabetes 79 (73) 88 (44) <0.01 3.776 1.832–16.264 <0.05
Patients with hypertension 73 (68) 90 (45) <0.01 2.409 1.693–9.090 <0.05
Patients with bronchial asthma 38 (35) 30 (15) <0.05 2.835 1.023–12.978 <0.05
Patients with CKD 3 (3) 1 (1) <0.01 2.069 1.011–10.422 <0.001
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SCP: Severe COVID-19 patient; NSCP: Non-severe COVID-19 patient; CKD: Chronic kidney disease.

Diagnostic performance evaluation of target parameters

For the analysis of significant differences of hematological parameters between SCP and NSCP, we used the receiver operating characteristic (ROC) curve analysis. Determination of the diagnostic performance is based on the area under the curve (AUC) as follows: AUC = 0.9–1.0, excellent; AUC = 0.8–0.9, good; AUC = 0.7–0.8, fair; AUC = 0.6–0.7, poor; and AUC <0.6, not useful [29, 30]. Among the parameters, CRP, d-dimer, and ferritin showed good diagnostic performances according to ROC analysis (Fig 2 and Table 5). CRP showed AUC value of 0.990 (95% CI 0.985–0.995) at a cutoff point 0.30 with 99.0% sensitivity and 79.6% specificity. Also, d-dimer showed an AUC value of 0.828 (95% CI 0.795–0.862) at a cutoff point 275.1 with 74.5% sensitivity and 64.9% specificity. Moreover, ferritin showed AUC value of 0.997 (95% CI 0.994–0.999; p<0.001) at a cutoff point 120.5 with 99.7% sensitivity and 82.0% specificity.

Fig 2. Receiver operating characteristic (ROC) curve is showing the relative diagnostic performances of creatinine, CRP, D-dimer, ferritin, neutrophils, and SGPTA.

Fig 2

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The cut-off points were detected for creatinine, CRP, d-dimer, ferritin, neutrophils, and SGPT as 0.30 mg/dL, 275.10 mg/dL, 120.5 ng/mL, 68.0ng/mL, and 40.5U/L, respectively.

Table 5. Receiver operating characteristic analysis of promising markers for severity of COVID-19.

Parameters Area under the curve Asymptotic Significance Asymptotic 95% Confidence Interval Cutoff value Sensitivity Specificity
Lower Bound Upper Bound
Creatinine 0.653 <0.001 0.610 0.697 0.85 64.4% 54.4%
CRP 0.990 <0.001 0.984 0.995 0.30 99.0% 79.6%
D-dimer 0.828 <0.001 0.795 0.862 275.1 74.5% 64.9%
Ferritin 0.997 <0.001 0.994 0.999 120.5 99.7% 82.0%
Neutrophils 0.688 <0.001 0.645 0.731 68.0 62.1% 59.2%
SGPT 0.620 <0.001 0.575 0.665 40.5 52.0% 61.9%
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p<0.05 (Significant difference between the groups at 95% confidence interval).

CRP, carbon reactive protein, SGPT, serum glutamic pyruvic transaminase.

Discussion

We conducted this observational cohort study to assess the connection of hematological abnormalities with the severity of hospitalized COVID-19 patients with complications. Amidst the increasing rate of COVID-19 transmission [31], it is vital to generate comprehensive information regarding the COVID-19 severity to measure the mortality risks. Hematological parameters and comorbid disease can help to measure COVID-19 severity [32]. Therefore, we can assess patient’s severity and mortality risks by easily monitoring those potential indicators. In our findings, we analyzed some hematological parameters in different severity stages of hospitalized COVID-19 patients. Among the parameters, we found a decreased level of Hb, RBC, packed cell volume (PCV), mean corpuscular volume (MCV), lymphocytes, eosinophils, and increased level of WBC, neutrophils in SCP than NSCP. Also, we observed increased CRP, ferritin, d-dimers, SGOT, and SGPT levels and decreased Na+, K+, CI-, and HCO3 levels in SCP than NSCP. However, the values of most parameters were within normal ranges. Therefore, these parameters might have statistical significance but not clinical significance. According to our knowledge, this is the first-ever study in Bangladesh to find an association of hematological abnormalities in COVID-19 patients with diagnostic performance analysis. Also, we validated the present study findings using ROC analysis which was absent in most earlier studies. Inconsistent with our findings, speculated evidence indicates that hematological abnormalities are very prevalent in SCP and increases the requirement of hospital stay and ICU support otherwise accelerate lethality. Different hematologic parameter level irregularities are associated with the risk of COVID-19 severity [33–35]. Terpos et al. reviewed hematological parameters in COVID patients and observed some abnormalities in SCP than NSCP [36]. Also, some other studies supported the present findings describing the evidence of the correlation between elevated CRP and ferritin levels in SCP [37–39].

After the SARS-CoV-2 entrance into the blood, it primarily affects the angiotensin-converting enzyme (ACE2), a receptor of the SARS-CoV-2 expressed in various organs like the liver, heart, gastrointestinal tract. After 7–14 days of infection, the CT scan report shows changes in the worsening situation. At this stage, lymphocyte count decreases, and inflammatory cytokine increases that deteriorate the condition of patients [40]. Lymphopenia is common in critically ill patients that correlate with the severity of COVID-19 [35, 37, 41]. Moreover, along with the increased leukocytes, reduced basophils, monocytes, lymphocytes, eosinophils, and platelets are frequently observed in SCP [42, 43]. According to studies, neutrophilia occurs in COVID-19 patients who required ICU support. Therefore, the neutrophil-to-lymphocyte ratio can serve as an indicator for the severity of COVID-19 patients [34, 44]. Several studies observed the incidence of thrombocytopenia due to decreased platelet count in a significant portion of patients who needed to admit to the hospital [35, 37]. Lippi et al. accumulated four different studies where it has been showing that the Hb level of COVID patients is in descending tendency and a contributor for worse advancement [45]. A meta-analysis of 21 studies on 3,377 patients reported the significant association of abnormal hematological parameters among SCP [46]. So, the hematological abnormalities have a close association with the severity of COVID-19, prolongation of hospitalization, and the requirement of ICU supports.

Based on the above discussion, we noticed that several previous studies recognized the hematological abnormalities in SCP. But we cannot use these changes for the assessment of COVID severity due to their absence of predictive performance [34–39]. Initial alterations of any blood parameters may not serve as a diagnostic predictor until these changes not validated for sensitivity and specificity. In the present study, we observed a lot of parameters altered in blood levels. But only CRP and ferritin showed good predicting performances for COVID-19 severity based on the diagnostic performance evaluation by ROC analysis. These three parameters demonstrated good sensitivity and specificity. Therefore, we recommend these three factors together can serve as differentiation factors for SCP and NSCP.

Moreover, coagulation frequently occurs among SCP [38, 47]. Coagulation is associated with a higher level of d‐dimer and prothrombin time prolongation. These are frequently encountered in severe stages of COVID-19 and are also considered a prime reason for death [34, 47]. Many past studies have presumed the elevated d-dimer levels responsible for altered coagulation in COVID-19 patients [35, 48–50]. Thus d-dimer, a fibrin degradation product, is a possible predictive factor for COVID-19 severity. In the early stage of the COVID-19 pandemic, a study found elevated d-dimer levels in 260 COVID-19 patients out of 560 in China [35]. Also, scientific evidence revealed that patients who died in COVID-19 had a higher level of d-dimer [51]. Besides, significant increased d-dimer levels were in ICU patients or patients with critical conditions in different studies [34, 42]. However, the increased level of d-dimer found in hospitalized COVID patients had a significant predictive performance for the COVID severity in our country. Changes in the immune system and lung damage are some of the prime abnormalities in COVID-19 patients. It is well established that cytokine storm causes to increase several inflammatory biomarker’s levels in SCP [52, 53]. Another cohort study showed that the augmented risks of developing ARDS in SCP were associated with elevated ferritin, CRP, and other biomarkers levels [54]. Ferritin is a protein that stores iron. The increased serum ferritin levels reflect the iron level. Another study revealed that patients who died in COVID-19 had higher ferritin levels and had to stay in hospital for a longer time [55]. Therefore, elevated serum ferritin induces cytokine storms and severity of COVID-19 patients [56, 57]. Thus, ferritin levels can serve as a factor for monitoring COVID-19 severity [46]. A study reported high levels of CRP in SCP. The higher levels of CRP may cause cytokine storms and affect liver function. Therefore, hepatic abnormalities worse the situation of SCP [58]. Ferritin is an independent risk factor for the severity of COVID-19. However, there is a positive relationship between ferritin and CRP in COVID fatality [59]. CRP is a marker of severe infections and inflammatory responses [60, 61]. Many past studies reported the association between CRP levels and lung lesions in the severe stage of hospitalized COVID-19 patients [62, 63].

Additionally, COVID-19 is a systemic infection responsible for several clinical appearances [64]. In the present study, we observed that age, sex, obesity, and comorbid diseases were significantly associated with the risks for developing severity among COVID-19 patients. Several retrospective studies also demonstrated increased mortality and morbidity rates in older adults with underlying comorbidities. Myocardia injuries are also a consequence of hematological abnormalities. The recent data supports abnormal levels of leukocyte, lymphocyte, platelet counts were predominant in patients with COVID-19 who had myocardia injuries [65]. One study found that associated comorbidities and recent history of chemotherapy can potentiate viral load. Therefore, the death rate was 35% for those COVID-19 patients [66]. Another study conducted in the USA showed that most COVID-19 patients with comorbid diseases were treated in the ICU by mechanical ventilation [67]. A French study found that COVID-19 patients with abnormal BMI had 7-fold higher chances to get admitted into the hospitals for ICU support than non-obese patients [68].

Moreover, several studies showed no significant associations of CRP with the incidence of diabetes [69, 70]. Other studies reported a high-CRP association only with diabetes-induced complications, like nephropathy and cardiovascular risk. Ethnic group differences were evident in detecting the association of CRP levels with hypertension [71]. No correlation was found between CRP and hypertension levels in Bangladeshi [72], and Chinese participants, except Hispanic participants [73]. A study showed that an increased CRP level would not result in a higher CKD risk [74]. Evidence reported an association of CRP levels with the severity of asthma and COPD. We found a general increase of CRP in all SCP with or without comorbid diseases compared to NSCP, suggesting that CRP is a crucial factor in determining the severity of COVID patients [75, 76]. Patients with diabetes had generally higher d-dimer levels. A study showed increased plasma d -dimer levels in patients with impaired fasting glucose [77], which is because of developing a hypercoagulable state [78]. Increased level of d-dimer was reported in patients with hypertension [79], CKD [80], and COPD [81]. Increased level of ferritin predicts the severity of COVID-19 diseases. A high level of ferritin is independently associated with the prevalence of diabetes [82], hypertension [83], CKD [84], COPD, and worse asthma symptoms because of a strong correlation with systemic inflammation. The present found an increase of ferritin levels in SCP regardless of comorbid diseases. The increased ferritin levels may worsen COVID-19 symptoms by contributing to the cytokine storm.

Potential limitations of the study

The present study has few drawbacks. The study included COVID-19 patients from Dhaka city only. Also, the subsequent follow-up information was not available with this study. We collected the clinical outcome data from only 52.7% of admitted COVID-19 patients from the respective hospital during study time. The exact mechanism of hematological alterations in COVID-19 patients is not well-explained yet. Therefore, we recommend further studies regarding the hematological abnormalities in COVID-19 to identify the actual causes.

Conclusion

Physicians continuously monitor several blood parameters to measure the severity and mortality risks of COVID-19 patients. Among the altered hematological parameters, elevated CRP and ferritin levels might use as predictable markers to assess the COVID-19 severity and mortality risks. Also, these parameters might help to evaluate the treatment plan and decision at the hospital setup. Therefore, we recommend these parameters as factors for early detection of COVID-19 severity that facilitates the treatment decisions. This topic needs to be explored further for quick initiation of treatments for SCP and optimization of COVID-19 treatment at hospital care.

Acknowledgments

We thank all the participants and their primary care givers for their cooperation to this study. Also, we thank the physicians and administrative staffs of the COVID unit of Evercare Hospital Ltd, Dhaka, Bangladesh, for their support to this study.

Data Availability

All relevant data are within the manuscript.

Funding Statement

The author(s) received no specific funding for this work.

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Hematological abnormalities and comorbidities are associated COVID-19 related deaths among hospitalized patients: Experience from Bangladesh

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Comments to the Author

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Reviewer #1: No

Reviewer #2: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: 1. I think patient stratification is the primary concern in the current study. The SCP and NSCP are the outcomes. When the authors stratified patients according to their outcomes, their lab parameters must be different.

2. Table 2 shows the comparisons of hematological parameters between the SCP and NSCP groups. We can see many items with statistical significance (ex. Hb, RBC, WBC, Platelet, liver functions…..). However, the values of these parameters were all within normal ranges, suggesting these parameters might have statistical significance but not clinical significance.

3. In table 3, the authors analyzed the correlation among laboratory parameters and different disease severity. Even the p values were < 0.05 in some analyses, the correlation coefficient value was low, indicating the limited clinical applications.

4. On line 200, page 13, the authors analyzed the risk factors associated with COVID-19 “outcome.” I would suggest not using the word “outcome” but “severity.”

5. In Table 4, I would suggest the authors identify the risk factors by univariate analysis first and put substantial elements found by univariate analysis into multivariate analysis.

6. In Table 5, the sensitivity and specificity of creatinine, D-dimer, neutrophil counts, and GPT were low, suggesting these parameters are NOT promising markers for COVID-19 severity.

Reviewer #2: Major comments:

1. I suggest it is better to compare the parameters between SCP and NSCP in Table 1.

2. Since you compare SCP and NSCP but not survivors and COVID-19-derived death (3.92% in this study), title “associated COVID-19 related deaths” is not appropriate.

3. Please show normal range of the parameter in Table 2. For example, WBCs ranged 3.9~10.6 for male and 3.5~11 for female are normal.

4. Please only show significant correlation r>0.3 and <-0.3 in Table3 (r=-0.3~0.3: poor correlation; r: 0.3~0.6 and -0.3~-0.6: media correlation; r=0.6~0.9 and -0.6~-0.9: high correlation; r=1 and -1: complete correlation. The comparison between individual parameter can be shown as supplemental data.

5. Please show statistical value in Figure 1.

6. Did increase of CRP, d-dimer, ferritin associate with any comorbidity disease.

**********

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Reviewer #2: No

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PLoS One. 2021 Jul 27;16(7):e0255379. doi: 10.1371/journal.pone.0255379.r002

Author response to Decision Letter 0

7 Jul 2021

Dear Editors and Reviewers,

Thank you for your letter and the reviewers' comments on our manuscript entitled "Hematological abnormalities and comorbidities are associated COVID-19 related deaths among hospitalized patients: Experience from Bangladesh" (Manuscript ID PONE-D-21-19091). All the comments were valuable and helpful to the revision and improvement of the manuscript. We have carefully studied the comments and made corrections, which we hope will merit your approval. We marked the revised portions using track changes. Our point-by-point answers to the reviewers’ comments appear at the end of this letter.

We earnestly appreciate the Editors'/Reviewers' work. We hope that after this revision, the paper will be deemed fit for publication. We would be glad to respond to any further questions and comments that you may have.

Once again, thank you very much for your comments and suggestions.

Best regards,

Md. Rabiul Islam, PhD

Assistant Professor, Department of Pharmacy, University of Asia Pacific, 74/A Green Road, Farmgate, Dhaka-1215, Bangladesh. Email: robi.ayaan@gmail.com; Cell: +8801916031831

Point by point authors’ responses to the reviewers

Manuscript ID PONE-D-21-19091

Title: Hematological abnormalities and comorbidities are associated COVID-19 related deaths among hospitalized patients: Experience from Bangladesh

Reviewer #1

Comment 1: I think patient stratification is the primary concern in the current study. The SCP and NSCP are the outcomes. When the authors stratified patients according to their outcomes, their lab parameters must be different.

Author responses

Thank you for your review and valuable comments on this manuscript.

In the present study, the severity of covid-19 patients was assessed by 1. patients admitted in hospital with confirmed pneumonia by lung CT, 2. patients with respiratory distress (rate > 30 breaths/min) and oxygen capacity level < 93%, and 3. patients required intensive care unit (ICU) support or mechanical ventilation. It would be better if we could perform patient stratification asses their severity. We are sorry for not systematically performing the risk stratification of covid patients for categorizing them into SCP and NSCP based on their health status and other factors. Therefore, we mentioned this as a limitation of the present study in the revised manuscript.

Comment 2: Table 2 shows the comparisons of hematological parameters between the SCP and NSCP groups. We can see many items with statistical significance (ex. Hb, RBC, WBC, Platelet, liver functions….). However, the values of these parameters were all within normal ranges, suggesting these parameters might have statistical significance but not clinical significance.

Author responses

Thank you for your valuable observation. All the parameters were within normal ranges in NSCP but ferritin and d-dimer were out of range in SCP. Following your comment, we have mentioned this observation in our revised (in highlighted manuscript: page 17, line 259-261).

Comment 3: In table 3, the authors analyzed the correlation among laboratory parameters and different disease severity. Even the p values were < 0.05 in some analyses, the correlation coefficient value was low, indicating the limited clinical applications.

Author responses

Thank you for your valuable observation. Following your observation, we have now removed all poor correlations (r<0.3 and r>-0.3) from Table 3 in the revised manuscript even the p values were < 0.05. Now revised Table 3 is showing significant correlation among the parameters (in highlighted manuscript: page 12).

Comment 4: On line 200, page 13, the authors analyzed the risk factors associated with COVID-19 “outcome.” I would suggest not using the word “outcome” but “severity.”

Author responses

Thank you for your suggestion. We have revised this line. Also, we have replaced “outcome” in other places with similar meaning (in highlighted manuscript: page 14, line 210, Title in Table 4, page 14).

Comment 5: In Table 4, I would suggest the authors identify the risk factors by univariate analysis first and put substantial elements found by univariate analysis into multivariate analysis.

Author responses

Thank you so much for your nice suggestions. We have now performed univariate analysis and shown risk factors from both univariate and multivariate analyses in Table 4 in the revised manuscript (in highlighted manuscript: Table 4, page 14).

Comment 6: In Table 5, the sensitivity and specificity of creatinine, D-dimer, neutrophil counts, and GPT were low, suggesting these parameters are NOT promising markers for COVID-19 severity.

Author responses

Thank you so much for your valuable suggestions in this regard. Based on our findings, previously we suggested elevated CRP, ferritin, and d-dimer as promising markers for COVID-19 severity. Following your observation, we have made necessary corrections according to sensitivity and specificity values. In the revised manuscript, we suggested elevated CRP and ferritin levels as promising markers for COVID-19 severity (in highlighted manuscript: page 19, lines 293; page 22, line 363).

Reviewer #2

Comment 1: I suggest it is better to compare the parameters between SCP and NSCP in Table 1.

Author responses

Thank you so much for your valuable suggestions in the point. We have now revised Table 1 comparing parameters between SCP and NSCP (in highlighted manuscript: page 8).

Comment 2: Since you compare SCP and NSCP but not survivors and COVID-19-derived death (3.92% in this study), title “associated COVID-19 related deaths” is not appropriate.

Author responses

Thank you so much for your excellent points regarding the title of the present study. Following your observation, we have now revised the title as below-

Hematological abnormalities and comorbidities are associated with COVID-19 severity among hospitalized patients: Experience from Bangladesh

Comment 3: Please show normal range of the parameter in Table 2. For example, WBCs ranged 3.9~10.6 for male and 3.5~11 for female are normal.

Author responses

Thank you for your observation. We have now shown normal range of the parameter in Table 2 in revised Table 2 (in highlighted manuscript: page 10).

Comment 4: Please only show significant correlation r>0.3 and <-0.3 in Table3 (r=-0.3~0.3: poor correlation; r: 0.3~0.6 and -0.3~-0.6: media correlation; r=0.6~0.9 and -0.6~-0.9: high correlation; r=1 and -1: complete correlation. The comparison between individual parameter can be shown as supplemental data.

Author responses

Thank you for your valuable observation. Following your observation, we have now removed all poor correlations (r<0.3 and r>-0.3) from Table 3 in the revised manuscript even the p values were < 0.05. Now revised Table 3 is showing significant correlation among the parameters. We believe the comparison between individual parameter which are not significant would add any value for this article. Therefore, we discarded them from the revised Table 3 (in highlighted manuscript: page 12). Also, we made necessary corrections according to revised table 3 in the text (in highlighted manuscript: page 11, lines 188-197).

Comment 5: Please show statistical value in Figure 1.

Author responses

Thank you so much for this insightful suggestion. We have now added all the p-values in Figure 1.

Comment 6: Did increase of CRP, d-dimer, ferritin associate with any comorbidity disease?

Author responses

Thank you for your observation. We have now added information regarding the association of increased CRP, d-dimer, ferritin levels with comorbidity diseases that were found in COVID-19 patients. The revision is as follows- (in highlighted manuscript: page 21, lines 336-353)

Moreover, several studies showed no significant associations of CRP with the incidence of diabetes [69-70]. Other studies reported a high-CRP association only with diabetes-induced complications, like nephropathy and cardiovascular risk. Ethnic group differences were evident in detecting the association of CRP levels with hypertension [71]. No correlation was found between CRP and hypertension levels in Bangladeshi [72], and Chinese participants, except Hispanic participants [73]. A study showed that an increased CRP level would not result in a higher CKD risk [74]. Evidence reported an association of CRP levels with the severity of asthma and COPD. We found a general increase of CRP in all SCP with or without comorbid diseases compared to NSCP, suggesting that CRP is a crucial factor in determining the severity of COVID patients [75, 76]. Patients with diabetes had generally higher d-dimer levels. A study showed increased plasma d -dimer levels in patients with impaired fasting glucose [77], which is because of developing a hypercoagulable state [78]. Increased level of d-dimer was reported in patients with hypertension [79], CKD [80], and COPD [81]. Increased level of ferritin predicts the severity of COVID-19 diseases. A high level of ferritin is independently associated with the prevalence of diabetes [82], hypertension [83], CKD [84], COPD, and worse asthma symptoms because of a strong correlation with systemic inflammation. The present found an increase of ferritin levels in SCP regardless of comorbid diseases. The increased ferritin levels may worsen COVID-19 symptoms by contributing to the cytokine storm.

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Decision Letter 1

Robert Jeenchen Chen

15 Jul 2021

Hematological abnormalities and comorbidities are associated with COVID-19 severity among hospitalized patients: Experience from Bangladesh

PONE-D-21-19091R1

Dear Dr. Islam,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Robert Jeenchen Chen, MD, MPH

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors have addressed all my comments adequately. The limitations of this study have been further mentioned as well. I think the paper is acceptable in the current version. Great work!

Reviewer #2: (No Response)

**********

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If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Chieh-Lin Jerry Teng

Reviewer #2: No

Acceptance letter

Robert Jeenchen Chen

19 Jul 2021

PONE-D-21-19091R1

Hematological abnormalities and comorbidities are associated with COVID-19 severity among hospitalized patients: Experience from Bangladesh

Dear Dr. Islam:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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