key: cord-1001837-ju7hawwu
authors: Al‐Saadi, Enass Abdul Kareem Dagher; Abdulnabi, Marwa Ali
title: Hematological changes associated with COVID‐19 infection
date: 2021-11-16
journal: J Clin Lab Anal
DOI: 10.1002/jcla.24064
sha: 13784c5f24111ab1c4f1bc23a3f28015803ef039
doc_id: 1001837
cord_uid: ju7hawwu

BACKGROUND: The unresolved COVID‐19 pandemic considerably impacts the health services in Iraq and worldwide. Consecutive waves of mutated virus increased virus spread and further constrained health systems. Although molecular identification of the virus by polymerase chain reaction is the only recommended method in diagnosing COVID‐19 infection, radiological, biochemical, and hematological studies are substantially important in risk stratification, patient follow‐up, and outcome prediction. AIM: This narrative review summarized the hematological changes including the blood indices, coagulative indicators, and other associated biochemical laboratory markers in different stages of COVID‐19 infection, highlighting the diagnostic and prognostic significance. METHODS: Literature search was conducted for multiple combinations of different hematological tests and manifestations with novel COVID‐19 using the following key words: “hematological,” “complete blood count,” “lymphopenia,” “blood indices,” “markers” "platelet" OR "thrombocytopenia" AND "COVID‐19," "coronavirus2019," "2019‐nCoV," OR "SARS‐CoV‐2." Articles written in the English language and conducted on human samples between December 2019 and January 2021 were included. RESULTS: Hematological changes are not reported in asymptomatic or presymptomatic COVID‐19 patients. In nonsevere cases, hematological changes are subtle, included mainly lymphocytopenia (80.4%). In severe, critically ill patients and those with cytokine storm, neutrophilia, lymphocytopenia, elevated D‐dimer, prolonged PT, and reduced fibrinogen are predictors of disease progression and adverse outcome. CONCLUSION: Monitoring hematological changes in patients with COVID‐19 can predict patients needing additional care and stratify the risk for severe course of the disease. More studies are required in Iraq to reflect the hematological changes in COVID‐19 as compared to global data.

The highly contagious novel coronavirus, also known as and SARS-COV-2, was first reported in Wuhan, China, in December 2019. 1, 2 It has spread worldwide over 110 countries affecting over 118,000 cases in a short period of less than 4 months raising a global concern. Hence, World Health Organization (WHO) declared COVID-19 a pandemic on March 11.

During 2020, two waves of COVID-19 hit Europe. 3 The first spike was in April which has been managed with general restrictions and lockdown in the absence of curative treatment and vaccine, fol- again, yet the Ministry of health has not confirmed European mutated strain in Iraq. 5 Novel COVID-19 is a single-stranded RNA from Coronaviridae family. It is an enveloped human β-coronavirus which shares 80% of human SARS-CoV-1 genetic sequence and 96.2% of bat coronavirus RaTG13. 6 Virus envelop is coated by spike (S) glycoprotein consisting of S1 and S2 subunits. S1 mediates virus entry by binding host angiotensin-converting enzyme 2 (ACE2), sialic acid, 7 and CD147. 8 Several strains of COVID-19 appeared since it was first reported.

Phylogenetic tree analysis identified various Asian strains (L, S, V, O) and European strains (G, GH, GR). 9 GR strain has exposed to several mutations in S1 subunit, of which G614 variant linked to increased virus infectivity and transmissibility rather than severity of the illness compared to the original D614 form 9,10 via promoting viral replication in human lung epithelial cells and primary human airway tissues. 11 The clinical manifestations of novel COVID-19 vary from asymptomatic to acute respiratory distress, depending on virus rout of entry, virus load, host immunity, and comorbidity human. 12 Common clinical presentation is summarized in Table 1 . Respiratory and gastrointestinal infection represent the bulk of the COVID-19-positive patient presentation, yet, asymptomatic/ presymptomatic infection is estimated to be 40% of all cases. 13 Many extrapulmonary neurological, dermatological, and cardiovascular manifestations have been frequently reported 14 concomitant with, after, or less frequently independent of respiratory infection (Table 1) . Acute respiratory distress and subsequent respiratory failure are the leading cause of death in COVID-19-positive patients. 15, 16 Although molecular identification of the virus by polymerase chain reaction (PCR) is the only recommended method in diagnosing COVID-19 infection 17,18 radiological, biochemical, biomarkers, and hematological studies are substantially important in risk stratification, patient follow-up, and outcome prediction. [19] [20] [21] Hematological tests including complete blood picture and coagulation studies in PCR-positive patients depict variable degree of changes according to the patient immune response and infection severity. 22 Many physicians consider early hematological changes as a clue for COVID-19

infection when the presenting sign and symptoms are unusual particularly when there is constrain of molecular testing. 23 On the other hand, hematological changes provide help when the symptomatic patient receives a negative molecular test, fishing for patients who require PCR test repeat. Taking into consideration the marked heterogeneity of the reference ranges of complete blood cell counts and leukocyte differential cell counts in different racial, ethnic group, 24 in this review, we summarized the hematological changes in different stage of COVID-19 infection highlighting the diagnostic and prognostic significance.

Literature search was conducted for multiple combinations of different hematological tests and manifestations with novel COVID-19 using the following key words: "hematological," "complete blood count," "lymphopenia," "blood indices," "markers" "platelet" OR "thrombocytopenia" AND "COVID-19," "coronavirus2019," "2019-nCoV" OR "SARS-CoV-2." Articles written in the English language and conducted on human samples between December 2019

and February 2021 were included. The initial search results were scanned by title and abstract for relevance, then complete texts of the related articles were reviewed. We further included directly relevant studies from reference lists of appropriate records. Non-English articles were excluded from the study.

According to NIH guidelines reviewed in October 2020, COVID-19

patients are grouped into five severity categories with slight over- Most of the hematological changes reported early in the beginning of the pandemic were based on hospital admitted patients.

Moreover, severity definition was not consistent in the literature;

some studies considered all patient not requiring intensive care unit (ICU) admission as mild cases. [26] [27] [28] Subsequent population-based clinical and laboratory studies increased our understanding of the role of hematology changes in disease prognosis and outcome. In this review, we summarized the hematological changes according to the severity of the presentation. We grouped the asymptomatic, mild, and moderate cases with Po2 >94% as none severe conditions, and patients with severe or critical condition who required assisted ventilation or ICU care as severe conditions. We also reviewed the hematological changes in special groups including children and pregnant women.

The majority of early published laboratory findings of none severe 

Hemoglobin and to less extent hematocrit are the only RBC indices reported in COVID-19 studies. Available literature showed no significant alteration in hemoglobin of those with a mild/moderate disease. 34-36

Early studies in Wuhan and Germany showed no significant differences in the platelet count of none severe compared with severe COVID-19 patients. 35, 37 A larger study included 926 none severe cases reported a mean platelet count of 172,000 (139,000-212,000), which was significantly higher than that reported in severely ill patients. 38 There was no significant changes in the levels of other blood coagulation parameters in none severe illness.

There are consistent data indicating that lymphocytopenia and neutrophilia are features of severe COVID-19 illness ( June-20 Jun-20 

neutrophilia during hospitalization with a median peak absolute neutrophil count of 11.6 × 10 9 /L. 39 A retrospective study on 201 Wuhan patients, looked into risk factors associating with acute respiratory distress syndrome (ARDS) development and death, concluded that increased neutrophils (p < 0.001) and decreased lymphocytes (p < 0.001) were risk factors for ARDS, and increased neutrophils (p = 0.03) was associated with higher risk of death. 40, 41 Studies addressing peripheral blood film of a COVID-19 patient described a characteristic neutrophil nuclei with C-shaped, singlelobed nuclei, morphologic abnormalities in the granulocytic series and leukoerythroblastic reaction. 42, 43 Blue-green leukocyte inclusions were reported in the circulating neutrophils and/or monocytes of critically ill patients with liver impairment and lactic acidosis and proposed as a poor prognostic indicator. 44 By contrast, activated monocytes were observed in clinically improved patients. 42, 43 Flow cytometry performed on peripheral blood lymphocytes of ICU patients showed a significant reduction in the absolute T-cell count in most cases as well as CD45+, CD3+, CD4+, CD8+, CD19+, and CD16/56+ counts. However, unlike immunodeficiency virus (HIV) and cytomegalovirus, the CD4/CD8 ratio was not inverted in all groups of patients. 39, 45 Many studies have suggested neutrophil-to-lymphocyte ratio (NLR) as an independent risk factor for mortality in severely ill patients with COVID-19 with a cut-off value varied between 3.0 and 13, 46 

Meta-analysis results regarding hemoglobin level in severely ill COVID-19 patients are conflicting. A meta-analysis study including 224 severely ill COVID-19 patients reported significantly lower hemoglobin than none severe cases with a weighted mean difference (WMD) of −7.1 g/L; 95% CI, −8.3 to −5.9 g/L. 36 Other study found the difference was not significant. 48 The lowest hemoglobin level was seen in patients who reached a composite endpoint (included admission to ICU, requirement of invasive ventilation, and death). 49 The reduction in Hb may indicate disease progression, however, age and comorbidities are confounding factors in this patient group and data should be interpreted cautiously. 50 Elevated red blood cell distribution width (RDW), a component of complete blood counts that reflects RBC variation in volume and size, has been shown to be associated with elevated mortality risk for patients with COVID-19. 51

Altered coagulability is a poor prognostic indicator in severely and critically ill patients with COVID-19, The contribution of von Willebrand factor (vWF) in thromboinflammation is well established. Several mechanisms are involved.

These mechanisms starts with endothelial dysfunction. 60 In severely ill COVID-19 patient, marked increase in vWF and factor VIIIc level was observed similar to that seen in severely septic non-COVID-19

ICU patients. 52, 61, 62 With disease progression, and in the absence of anticoagulant treatment, VWF and fibrinogen levels decline with persistent high D-dimer levels and even higher P-selectin levels indicating poor prognosis. 52

Several biochemical tests are described as potential prognostic in- Elevated C-reactive protein (CRP) was reported in 81.5%, procalcitonin in 13.7%, and LDH in 58.1% of severe COVID-19 infection and they were linked to secondary bacterial infection. 38, 65 Additionally, erythrocyte sedimentation rate (ESR) was reported by several studies to be significantly elevated and was considered as a predictor of infection severity. 66, 67 ABO blood group was described in many studies to be associated with COVID-19. A study of pooled 31100 COVID-19 patients suggested that people with blood type A might be more susceptible to infect COVID-19 while blood type O might be less susceptible to infect COVID-19, yet no correlation between ABO blood group and severity or mortality of the infection. 68

Cytokine storm is a serious clinical state that occurs approximately 7-14 days in the course of COVID-19 infection; presented clinically as nonspecific constitutional symptoms such as persistent fever, weight loss, joint and muscle pain, fatigue, and headache. Cytokine storm characterized by a hyperinflammatory status as a consequence of proinflammatory cytokines 49 and chemokines overproduction, 69 resulting in pulmonary, cardio-circulatory, or combined disturbances.

Extensive local edema due to vasodilatation and membrane leakage may result in multiorgan failure and uncontrollable shock. [70] [71] [72] Nonsurvivor of COVID-19 as well as severe refractory patients ex- ACE2 on its surface. Lymphocytes apoptosis could be promoted by the plethora of cytokine in this stage, which may also lead to lymphoreticular organs dysfunction impeding lymphocyte turnover. 77, 78 Neutrophilia is another sign of cytokine storm and considered as a predictor of disease severity. 79 Neutrophils extravasate in the interstitial tissue form extracellular mesh of DNA/histones to control the infection, this exacerbate the inflammation and cause tissue damage. 80 Data regarding NK cells are contradicting. One study reported a reduction in the number of circulating NK cells in COVID-19 patients, 81 whereas others showed no difference in the number of CD16 + CD56 + in severe compared to none severe cases. 82

Anemia is reported in some of the critically ill COVID-19 patients;

however, detailed RBC indices changes in response to secondary adult hemophagocytic lymphohistiocytosis associated with this viral infection are not well characterized and require further studies.

During cytokine storm, immune response to infection results in overproduction of proinflammatory cytokines which activate coagulation pathway. At later stage, the tightly controlled, thrombin regulating mechanisms are impaired. Reduced anticoagulant concentrations due to reduced production and increasing consumption results in microthrombosis, disseminated intravascular coagulation, and multiorgan failure. Raised D-dimer concentrations being a poor prognostic feature and disseminated intravascular coagulation are common in nonsurvivors. 83 A single-center study in china followed the dynamic platelet-tolymphocyte ratio (PLR) changes during the period of hospitalization, they suggested a possible correlation between high PLR and cytokine storm associating with prolonged hospitalization days. 84

The cytokine profile in COVID-19-associated cytokine storm is similar to secondary hemophagocytic lymphohistiocytosis, which is commonly triggered by sepsis and viral infections. In such conditions, elevated ferritin, triglycerides, uric acid, LDH, lactate, and acute kidney injury are observed along with elevated CRP, procalcitonin, D-dimer, troponin, and alanine aminotransferase. 85 

COVID-19 incidence in children is lower than that seen in adults.

Recent reports from the USA Centers for Disease Control and Prevention (CDC) indicates that children younger than 19 years constituted 5% of the all cases. The course of the disease seems to be milder than adults; nonetheless, severe cases have been recorded in 3-5% and mortality 0.3%.

Four systematic reviews and meta-analyses concluded that the majority of children with COVID-19 had a normal leukocyte count.

Lymphopenia was reported in relatively few number of cases (15%)

and was not associated with severe course. [86] [87] [88] By contrast, pooled data from 486 hospitalized children reported lymphocytosis in 22%

and leukopenia in 21%. Higher incidence of lymphocytosis up to 61% was seen in neonates, yet severe cases in these neonates were relatively higher 7%. 89, 90 Studies rarely reported changes in hemoglobin or RBC indices and coagulative system, the available literatures showed no significant change in the Hb level in children with COVID-19 whether asymptomatic, mild, severe, or critical. [90] [91] [92] [93] The infrequent reporting of thrombotic events in children may indicate its rarity in the clinical practice.

Other laboratory findings reported in children were elevated inflammatory markers including ferritin (26% ), procalcitonin (25% [21] [22] [23] [24] [25] [26] [27] [28] [29] ), and CRP (19% [16] [17] [18] [19] [20] [21] [22] ). 94

The incidence and clinical manifestations of COVID-19 in pregnant women have been reported to be similar to general population with approximately 80% having mild course of the disease or asymptomatic and good perinatal outcomes. 38 Sever cases of COVID-19 in pregnant women were reported in 15% and critical in 5%, the majority of which were associated with risk factor such as comorbidity and obesity. 76 The mortality of pregnant women with COVID-19 was relatively low (0.43%) and close to the overall maternal mortality rate worldwide (1 in 180). 95 with 173 severely to critically ill pregnant patients from the first trimester to the third trimester suggested that elevated D-dimer (82%), elevated neutrophil count (81%), elevated C-reactive protein (69%), and decreased lymphocyte count (59%) were the most frequent abnormalities. 99 In a pilot study that included 21 pregnant women in the second and third trimester with COVID-19 and 48 without, a higher aPTT level, platelet count and lower fibrinogen, D-dimer levels, and antithrombin time were observed in patient COVID-19

positive pregnant women as compared to COVID-19 negative.

However, there was no difference observed in CRP and FVIII lev- 

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