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Leukoerythroblastosis – An unsusal presentation of COVID 19 infection

Open AccessPublished:March 18, 2022DOI:https://doi.org/10.1016/j.cegh.2022.101026

      Abstract

      Objectives

      Although several peripheral blood abnormalities have been reported in COVID 19,Leukoerythroblastosis is an unusual finding. We report 33 COVID19 cases presenting with leukoerythroblastosis. We intend to describe its incidence in this novel viral infection and correlate it with the clinical outcome.

      Methods

      It is a Prospective study done at a Level 3 COVID 19 hospital of LUCKNOW, INDIA. Hematologic test records of day 1 of admission of COVID 19 cases admitted from 20th August 2020 to 30th September 2020 were reviewed. Peripheral blood smear examination was performed on test results that were flagged for abnormalities. Leukoerythroblastosis was reported when the smears showed presence of granulocyte left shift and nucleated red blood cells. Follow up smears were examined on Day 7. The findings were correlated with the clinical outcome.

      Results

      Out of 274 slides reviewed, 33 (12%) showed a leukoerythroblastic picture on day 1 of admission. Follow up smears on day 7 were available in 76% (25/33) cases. The follow up smears showed improvement in 13 cases, worsening in 9 cases and no changes in 3 cases. There were total 19 (58%) deaths. 12 patients (36%) recovered and 2 patients (6%) were shifted to other hospitals whose further follow up was not available.

      Conclusions

      Leukoerythroblastosis is an unusual presentation of COVID 19. Although rare, this peripheral blood abnormality can provide insight into the underlying pathophysiologic processes. Furthermore, it seems to be an adverse prognostic factor, so examination of follow up smears may help clinicians and intensivists to make prompt management decisions.

      Keywords

      1. Introduction

      Coronavirus disease 2019 (COVID-19) is a global pandemic disease caused by a novel coronavirus named “Severe Acute Respiratory Syndrome Corona virus-2 (SARS-CoV-2)”with surface spike protein binding to the human angiotensin-converting enzyme 2 (ACE2) receptor.
      • Bi Q.
      • Wu Y.
      • Mei S.
      • et al.
      Epidemiology and transmission of COVID-19 in 391 cases and 1286 of their close contacts in Shenzhen, China: a retrospective cohort study.
      ,
      • Clerkin K.J.
      • Fried J.A.
      • Raikhelkar J.
      • et al.
      COVID-19 and cardiovascular disease.
      SARS-CoV-2 infections ranges from asymptomatic carriers to mild respiratory symptoms and fatal acute respiratory distress syndrome. The virus causes T-cell immune dysregulation, especially in immunocompromised patients, resulting in monocyte/macrophage activation, uncontrolled cytokine release, and multiorgan dysfunction.
      • Tay M.Z.
      • Poh C.M.
      • Rénia L.
      • et al.
      The trinity of COVID-19: immunity, inflammation and intervention.
      The most common hematological findings in COVID 19 infection as reported by several studies include lymphopenia, neutrophilia, eosinopenia, thrombocytopenia and occasionally, thrombocytosis.
      • Ruan Q.
      • Yang K.
      • Wang W.
      • Jiang L.
      • Song J.
      Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China.
      • Wang F.
      • Nie J.
      • Wang H.
      • et al.
      Characteristics of peripheral lymphocyte subset alteration in COVID-19 pneumonia.
      • Sun S.
      • Cai X.
      • Wang H.
      • et al.
      Abnormalities of peripheral blood system in patients with COVID-19 in Wenzhou, China.

      Qian G.Q., Yang N.B., Ding F., et al A Retrospective, Multi-Centre Case Series, QJM; China: 2020. Epidemiologic and Clinical Characteristics of 91 Hospitalized Patients with COVID-19 in Zhejiang. ([PMC free article] [PubMed] [Google Scholar]).

      • Mo P.
      • Xing Y.
      • Xiao Y.
      • et al.
      Clinical characteristics of refractory COVID-19 pneumonia in Wuhan, China.
      • Zhang J.J.
      • Dong X.
      • Cao Y.Y.
      • et al.
      Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan.
      • Liu F.
      • Xu A.
      • Zhang Y.
      • et al.
      Patients of COVID-19 may benefit from sustained lopinavir-combined regimen and the increase of eosinophil may predict the outcome of COVID-19 progression.
      • Lippi G.
      • Plebani M.
      • Henry B.M.
      Thrombocytopenia is associated with severe coronavirus disease, (COVID-19) infections: a meta-analysis.
      In this study, we report unusual finding of leukoerythroblastosis on peripheral blood smear examination of patients infected with COVID 19 and correlate this finding with the clinical outcome.
      Image 1
      Image 1Review of the peripheral smears of 33 patients at 1000× magnification showing - A Nucleated Red Blood Cell along with a left shifted myeloid series with myelocyte and metamyelocyte (A); promyelocytes and metamyelocytes (B & C); Occasional Blast with prominent nucleoli and immature fine chromatin (D).

      2. Materials and methods

      It is a Prospective study done at the Emergency Laboratory of dedicated COVID 19 hospital of Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow which provides level 3 care to COVID 19 patients. This work was done after approval of institutional ethics committee and subjects were enrolled after obtaining their written informed consent. The study subjects include cases admitted between August 20, 2020 to September 30, 2020 after a positive SARS CoV2 RNA detection on nasal/nasopharyngeal swab on Reverse Transcriptase polymerase chain reaction (RTPCR) assay. The list of all patients tested positive for COVID 19 and admitted to our hospital was obtained on daily basis. Investigation records of day 1 of admission of these positive cases were reviewed for hematologic tests performed. Complete blood cell counts (CBCs) were performed on Abbott Alinity hq which provides CBC with 6 – part White blood cells (WBC) differential counts. Peripheral blood smear examination was performed on test results that were flagged for abnormalities as per slide review criteria followed in our laboratory. The blood smears were stained with Leishman stain. A total of 418 patients were admitted with COVID-19 infection during the above mentioned period of the study, out of which 274 patients had CBC abnormalities and their smears were examined. A leukoerythroblastic blood picture was reported in cases in which the smears showed presence of granulocyte left shift and nucleated red blood cells. Granulocyte left shift was defined as either
      • peripheral blood showing increased neutrophil band forms (>10% of WBC) by manual differential cell count or
      • increased number or percent of immature granulocytes detected by automated cell analyzer, which typically represents promyelocytes, myelocytes, and metamyelocytes or
      • a flag for left shift.
      Based on the document on CLINICAL MANAGEMENT PROTOCOL: COVID-19 by Ministry of Health and Family Welfare, Government of India, we categorized the patients with leukoerythroblastic blood picture into mild, moderate and severe.
      Follow up smears of these patients were examined on Day 7 after admission.

      3. Results

      Out of 274 slides reported, 33 (12%) showed a leukoerythroblastic picture on day 1. These 33 COVID-19 cases included 21 men and 12 women, with an age range of 18–87 years (Median age 49 years).
      The patients presented predominantly with shortness of breath and fever followed by cough, bodyache, tiredness, weakness and altered sensorium (Table 1).
      Table 1Clinical presentations on admission.
      Clinical presentationsShortness of breathFeverCoughBodyacheTiredness, Weakness and altered sensorium
      (n = 33)64% (n = 21)56% (n = 19)30% (n = 10)12% (n = 4)9% (n = 3)
      Based on clinical severity and assessment parameters, patients were categorized as follows. Most cases belonged to severe category (Table 2).
      Table 2Clinical severity on admission.
      Clinical severityMildModerateSevere
      (n = 33)30% (n = 10)3% (n = 1)67% (n = 22)
      CBC revealed anemia in most patients followed by neutrophilic leukocytosis and thrombocytopenia. Absolute Neutrophilia and Absolute Lymphopenia were among other common findings. Absolute monocyte count was high in 10 patients. Absolute eosinophil count was normal in all patients (Table 3).
      Table 3Hematological parameters on admission.
      CBC findingsAnemia (Hb < 12.5 g/dL)Leukocytosis (TLC >11 × 103/μL)Thrombocytopenia (Platelet Count <150 × 103/μL)Thrombocytosis (Platelet Count >400 × 103/μL)Neutrophilia (Absolute neutrophil count >7.5 × 103/μL)Lymphopenia (Absolute Lymphocyte count <1 × 103/μL)Monocytosis (Absolute Monocyte count >1 × 103/μL)
      (n = 33)(82%) (n = 27)79% (n = 26)48% (n = 16)9% (n = 3)76% (n = 25)55% (n = 18)30% (n = 10)
      Morphologic findings on peripheral smear examination of all 33 cases revealed a leukoerythroblastic blood picture. 70% (23/33) of these cases showed left shift up to metamyelocyte/myelocyte stage, 15% of cases (5/33) showed left shift up to promyelocytes, 12% (4/33) showed presence of blasts and 3% (1/33) showed left shift up to band form stage. NRBC/100 WBCs varied from 1% to 10% in these cases (See Image 1). None of these patients had a history of myeloid neoplasms and none had received chemotherapy or growth factors in the recent past.
      Most patients had comorbidities at presentation, which included hypertension in 24% (8/33) cases, type 2 Diabetes Mellitus in 21% (7/33) cases, hypothyroidism 9% (3/33) cases, pregnancy 9% (3/33) cases and chronic kidney disease 6% (2/33) cases.
      CBC and follow up smears on day 7 were available in 76% (25/33) cases. Out of these, the peripheral smear findings on day 7 showed improvement in 12 cases, worsening in 10 cases and no changes in 3 cases (Table 4).
      Table 4Correlation of follow up (Day 7) peripheral smears of mild (n=10)/moderate (n=1) and severe (n=22) groups with clinical outcome.
      Findings of follow up smears on Day 7 in mild/moderate/severe groups (n = 33)No. of patients recovered and discharged (n = 12)No. of patients expired (n = 19)Clinical outcome not known (n = 2)
      Improved (n = 12)Mild/moderate10
      Severe2
      Worsened (n = 10)Mild/moderate
      Severe19
      No change (n = 3)Mild/moderate1
      Severe2
      Not available (n = 8)Mild/moderate
      Severe62
      There were total 19 (58%) deaths. 12 patients (36%) recovered and were discharged and 2 patients (6%) were shifted to other hospitals whose clinical outcome was not known. 13 patients (39.4%) required mechanical ventilation.

      4. Discussion

      Coronavirus disease 2019 (COVID-19) is caused by a novel coronavirus.
      • Bi Q.
      • Wu Y.
      • Mei S.
      • et al.
      Epidemiology and transmission of COVID-19 in 391 cases and 1286 of their close contacts in Shenzhen, China: a retrospective cohort study.
      It is a global pandemic disease caused by the “Severe Acute Respiratory Syndrome Corona virus-2 (SARS-CoV-2)” with surface spike protein binding to the human angiotensin-converting enzyme 2 (ACE2) receptor, which is expressed in the lung (type 2 alveolar cells), heart, intestinal epithelium, vascular endothelium, and kidneys causing multi-organ dysfunction. The median incubation period is 4–5 days and 97.5% of patients will have symptoms within 11.5 days.
      • Clerkin K.J.
      • Fried J.A.
      • Raikhelkar J.
      • et al.
      COVID-19 and cardiovascular disease.
      COVID-19 is highly transmissible among humans. Most of the symptomatic patients have mild flu-like features but a significant subset develops bronchopneumonia, which clinically is the acute respiratory distress syndrome (ARDS) leading to significant morbidity and mortality.
      • Yuki K.
      • Fujiogi M.
      • Koutsogiannaki S.
      COVID-19 pathophysiology: a review.
      The fatality rates of COVID-19 are highest amongst older patients with concomitant comorbidities and/or patients who are immunosuppressed.
      • Ackermann M.
      • Verleden S.E.
      • Kuehnel M.
      • et al.
      Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19.
      In our cohort of 33 cases, most common clinical symptoms were shortness of breath and fever followed by cough, bodyache, tiredness, weakness and altered sensorium. This was in accordance with the studies of Rodriguez-Morales A.J et al., Sun P et al. and Hu Y et al. who reported fever, cough, fatigue and dyspnea as the most common clinical symptoms in COVID-19 patients.
      • Rodriguez-Morales A.J.
      • Cardona-Ospina J.A.
      • Gutierrez-Ocampo E.
      • Villamizar-Pena R.
      • Holguin-Rivera Y.
      • Escalera-Antezana J.P.
      Clinical, laboratory and imaging features of COVID-19: a systematic review and meta-analysis.
      • Sun P.
      • Qie S.
      • Liu Z.
      • Ren J.
      • Li K.
      • Xi J.
      Clinical characteristics of hospitalized patients with SARS-CoV-2 infection: a single arm meta-analysis.
      • Hu Y.
      • Sun J.
      • Dai Z.
      • Deng H.
      • Li X.
      • Huang Q.
      Prevalence and severity of corona virus disease 2019 (COVID-19): a systematic review and meta-analysis.
      Li shi et al. in their meta-analysis observed that dyspnea, rather than fever, is recommended as an indicator of poor outcome in COVID-19 patients.
      • Shi Li
      • Wang a Ying
      • Wang a Yadong
      • Duan b Guangcai
      • Yang Haiyan
      Dyspnea rather than fever is a risk factor for predicting mortality in patients with COVID-19.
      Laboratory abnormalities, particularly hematological changes, allow checking the status of SARS-CoV-2 infection, since the hematopoietic system and hemostasis suffer significant impacts during the evolution of COVID-19.
      • Debuc B.
      • Smadja D.M.
      Is COVID-19 a new hematologic disease?.
      The most common hematological findings in COVID 19 infection are lymphocytopenia,
      • Ruan Q.
      • Yang K.
      • Wang W.
      • Jiang L.
      • Song J.
      Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China.
      • Wang F.
      • Nie J.
      • Wang H.
      • et al.
      Characteristics of peripheral lymphocyte subset alteration in COVID-19 pneumonia.
      • Sun S.
      • Cai X.
      • Wang H.
      • et al.
      Abnormalities of peripheral blood system in patients with COVID-19 in Wenzhou, China.
      neutrophilia,

      Qian G.Q., Yang N.B., Ding F., et al A Retrospective, Multi-Centre Case Series, QJM; China: 2020. Epidemiologic and Clinical Characteristics of 91 Hospitalized Patients with COVID-19 in Zhejiang. ([PMC free article] [PubMed] [Google Scholar]).

      ,
      • Mo P.
      • Xing Y.
      • Xiao Y.
      • et al.
      Clinical characteristics of refractory COVID-19 pneumonia in Wuhan, China.
      eosinopenia,
      • Sun S.
      • Cai X.
      • Wang H.
      • et al.
      Abnormalities of peripheral blood system in patients with COVID-19 in Wenzhou, China.
      ,
      • Zhang J.J.
      • Dong X.
      • Cao Y.Y.
      • et al.
      Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan.
      ,
      • Liu F.
      • Xu A.
      • Zhang Y.
      • et al.
      Patients of COVID-19 may benefit from sustained lopinavir-combined regimen and the increase of eosinophil may predict the outcome of COVID-19 progression.
      thrombocytopenia
      • Sun S.
      • Cai X.
      • Wang H.
      • et al.
      Abnormalities of peripheral blood system in patients with COVID-19 in Wenzhou, China.
      and, less frequently, thrombocytosis.
      • Lippi G.
      • Plebani M.
      • Henry B.M.
      Thrombocytopenia is associated with severe coronavirus disease, (COVID-19) infections: a meta-analysis.
      The presence of reactive lymphocytes has been reported only occasionally.
      • Fan B.E.
      • Chong V.C.L.
      • Chan S.S.W.
      • et al.
      Hematologic parameters in patients with COVID-19 infection.
      The leukocyte count may be normal, reduced
      • Sun S.
      • Cai X.
      • Wang H.
      • et al.
      Abnormalities of peripheral blood system in patients with COVID-19 in Wenzhou, China.
      ,
      • Huang C.
      • Wang Y.
      • Li X.
      • et al.
      Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.
      or increased.
      • Wang Dawei
      • Hu Bo
      • Chang Hu
      • et al.
      Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in wuhan, China.
      According to a study, leukocytosis, lymphopenia and thrombocytopenia are associated with significant disease severity and even increased fatality in COVID-19 cases.
      • Henry B.M.
      • de Oliveira M.H.S.
      • Benoit S.
      • Plebani M.
      • Lippi G.
      Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis.
      In our study, most common hematological abnormality was anemia followed by neutrophilic leukocytosis, lymphocytopenia and thrombocytopenia. 3 cases had thrombocytosis. Absolute monocytosis was present in 10 cases. Absolute eosinophil count was normal in all patients. The CBC findings prompted peripheral blood smear evaluation in these patients.
      On peripheral smear examination, morphologic abnormalities in the granulocytic series, namely Acquired Pelger Huet Anomaly and left shift, are significantly more common in COVID-19 cases.
      • Nazarullah Alia
      • Liang Christine
      • Villarreal Andrew
      • Higgins Russell A.
      • Mais Daniel D.
      However, leukoerythroblastosis is an uncommon finding in these patients.
      Leukoerythroblastosis, is the presence of immature cells of the myeloid series and nucleated red cells in the circulating blood, with or without anemia and is not seen exclusively in malignancies. Although it is typically associated with marrow infiltrative processes, it may also represent marrow response to stressors like hypoxia, peripheral destruction/sequestration, or sepsis.
      • Burkett L.L.
      • Cox M.L.
      • Fields M.L.
      Leukoerythroblastosis in the adult.
      However, it can rarely be seen in viral infections such as parvovirus.
      • Anand A.
      • Gray E.S.
      • Brown T.
      • Clewley J.P.
      • Cohen B.J.
      Human parvovirus infection in pregnancy and hydrops fetalis.
      ,
      • Ozdemir N.
      • Akı H.
      • Hakyemez H.T.
      • Cokugras F.Ç.
      • Apak H.
      Parvovirus B19 infection mimicking juvenile myelomonocytic leukemia.
      Isolated leukoerythroblastosis resembling leukemia may also be seen in severe infections.
      • Canbolat Ayhan A.
      • Timur C.
      • Ayhan Y.
      • Kes G.
      Leukoerythroblastosis mimicking leukemia: a case report.
      Leukoerythroblastic reaction is always an abnormal finding.
      To the best of our knowledge, there are two case reports and one study till date that describe this finding in COVID 19 infection. One in a COVID-19 adult with respiratory failure
      • Mitra A.
      • Dwyre D.M.
      • Schivo M.
      • et al.
      Leukoerythroblastic reaction in a patient with COVID-19 infection.
      and other in a 7-year-old child with SARS-CoV-2–associated multisystem inflammatory syndrome.
      • Lee Won Sok
      • Margolskee Elizabeth
      Leukoerythroblastosis and plasmacytoid lymphocytes in a child with SARS-CoV-2–associated multisystem inflammatory syndrome: clinical Trials & Observations.
      In their studies, N Kaur et al. described this finding in 3 cases while Nazarullah et al. noted leukoerythroblastosis in one case.
      • Nazarullah Alia
      • Liang Christine
      • Villarreal Andrew
      • Higgins Russell A.
      • Mais Daniel D.
      Our findings of peripheral blood smears on day 1 of admission were consistent with a leukoerythroblastic picture in 33 cases (12%). Smears showed NRBC/100 WBCs ranging from 1% to 10%, anisocytosis, and rare dacrocytes. Left shifted myeloid cells, including band forms, metamyelocytes/myelocytes, promyelocytes and occasional blasts with or without neutrophilia was noted. Lymphopenia was confirmed in many cases. Platelets were reduced in most cases.
      Except for myeloid neoplasms, left shift of granulocytes is interpreted as a sign of bacterial infection. Neutrophil activation in bacterial infections is thought to trigger mobilization of marrow reserves, resulting in granulocytic left shift.
      • Honda T.
      • Uehara T.
      • Matsumoto G.
      • et al.
      Neutrophil left shift and white blood cell count as markers of bacterial infection.
      In SARS-CoV-2 cases, disease induced cytokine release causing neutrophil migration similar to bacterial infection is a possible cause for leukoerythroblastosis. Direct myelotoxicity caused by the virus or increased marrow production due to increased peripheral cell turnover may be the other causes. On admission, none of our patients had any evidence suggestive of septicemia or an underlying myeloid neoplasm or malignancy causing a myelophthisic process and none had received chemotherapy or growth factors in the recent past. Two patients, however, developed sepsis later during the hospital stay. In view of absence of an underlying cause, leukoerythroblastosis in our cases thus, may represent marrow stress and response to the COVID 19 viral infection.
      • Anand A.
      • Gray E.S.
      • Brown T.
      • Clewley J.P.
      • Cohen B.J.
      Human parvovirus infection in pregnancy and hydrops fetalis.
      • Ozdemir N.
      • Akı H.
      • Hakyemez H.T.
      • Cokugras F.Ç.
      • Apak H.
      Parvovirus B19 infection mimicking juvenile myelomonocytic leukemia.
      • Canbolat Ayhan A.
      • Timur C.
      • Ayhan Y.
      • Kes G.
      Leukoerythroblastosis mimicking leukemia: a case report.
      Most patients in our study, had comorbidities at presentation, which included hypertension, Type 2 Diabetes Mellitus, hypothyroidism, pregnancy, chronic kidney disease.
      Follow up smears on day 7 were available in 25 (76%) cases (Table 4). In 12 cases, the peripheral smear findings showed improvement. Out of these, 10 cases (mild category) were discharged after recovery, while 2 patients expired (severe category). 10 cases (severe category) showed worsening of smear findings on day 7 as compared to day 1. Of these, 9 patients expired and 1 was discharged after recovery. Among the 3 cases who had no changes in follow up smears, 1 patient (moderate category) was discharged and other 2 expired (severe category). The follow up smears of 8 patients (24%) (severe category) were not available for review as 6 of these patients expired and 2 were discharged on request before the completion of day 7 after admission.
      There were total 19 deaths (58%). Most of these patients showed worsening of smear findings on day 7 and all belonged to severe category. This observation strongly suggested that leukorythroblastosis confers a poor prognosis. 12 patients (36%) (10 mild, 1 moderate and 1 severe) recovered and were discharged. Following clinical improvement in these patients, leukoerythroblastosis and other blood findings on follow up blood smears improved. Clinical outcome of 2 patients (6%) was not known.
      Although, all these patients had leukoerythroblastosis on admission, examination of follow up smears showed changes in most of the patients, which revealed the ongoing disease process and subsequent prognosis in them. Therefore, review of follow up smears in patients with leukoerythroblastosis irrespective of flagging for abnormalities on automated cell counter was important in correlating the findings with the clinical outcome of these patients.
      We acknowledge the limitations of our study, especially the number of follow up peripheral smears that were available for review. Larger series of cases with more number of peripheral smears for review during and after treatment will be of great interest, to study the possibly transient nature of leukoerythroblastosis and its correlation with disease activity.

      5. Conclusion

      Leukoerythroblastosis is an unfamiliar finding in patients with COVID 19 infection. Although, it cannot be definitely concluded that this finding is secondary to COVID 19 infection, worsening of smear findings in severe and deceased patients and improvement of smear findings in mild and recovered patients is highly suggestive that SARS-CoV-2 infection is the likely cause of leukoerythroblastosis in the absence of other known causes. This Peripheral blood abnormality can thus, provide insight into the underlying pathophysiologic processes and help broaden awareness of the spectrum of COVID 19 infection. Furthermore, it seems to be an adverse prognostic factor, so examination of peripheral smears is an important work up for prognostication along with already established sets of investigation as it may help clinicians and intensivists to make prompt management decisions. However, as per our understanding of COVID 19 infection the implications of this finding are yet to be unveiled.

      Funding

      Nil.

      Declaration of competing interest

      None declared.

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