|Year : 2020 | Volume
| Issue : 4 | Page : 208-210
Disease in disguise – An unusual cause of leukocytosis in an infant – A case report and review of the literature
Meenakshi Mohan1, Dhaarani Jayaraman2, Sri Gayathri Shanmugam3, Julius Xavier Scott2
1 Department of Pediatrics, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
2 Department of Pediatrics, Division of Pediatric Hemato-Oncology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
3 Department of Pathology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
|Date of Submission||27-May-2020|
|Date of Decision||01-Aug-2020|
|Date of Acceptance||12-Sep-2020|
|Date of Web Publication||17-Nov-2020|
Dr. Dhaarani Jayaraman
Department of Pediatrics, Division of Pediatric Hemato-Oncology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Leukocytosis with cytopenias of other cell lines and organomegaly in children pose a significant diagnostic challenge. Leukemoid reaction is exaggerated leukocytosis, whereas misinterpretation of nucleated red blood cells (nRBC) leads to spurious leukocytosis. These need to be considered in given clinical context to investigate further appropriately. We describe a report of 6 months infant who was referred with suspected acute leukemia based on initial evaluation when he presented with severe pallor and hepatosplenomegaly with white blood cell >50× ×109/L. He was later found to have spurious leukocytosis with an underlying hemolytic anemia. The strikingly normal platelet count, absence of blasts in smear and low mean corpuscular volume for age gave initial clues away from leukemia. This case emphasizes the need for systematic approach to clinical features followed by meticulous analysis of every parameter of hemogram and peripheral smear to arrive at appropriate diagnosis and to avoid unnecessary investigations.
Keywords: Beta thalassemia, hemolytic anemia, leukemoid reaction, nucleated red cells, spurious leukocytosis
|How to cite this article:|
Mohan M, Jayaraman D, Shanmugam SG, Scott JX. Disease in disguise – An unusual cause of leukocytosis in an infant – A case report and review of the literature. J Appl Hematol 2020;11:208-10
|How to cite this URL:|
Mohan M, Jayaraman D, Shanmugam SG, Scott JX. Disease in disguise – An unusual cause of leukocytosis in an infant – A case report and review of the literature. J Appl Hematol [serial online] 2020 [cited 2021 Apr 11];11:208-10. Available from: https://www.jahjournal.org/text.asp?2020/11/4/208/300774
| Introduction|| |
Leukocytosis in children carries wide range of differentials with infections being most common cause. Hemoglobinopathies are associated with numerous nucleated red blood cells (nRBC) in peripheral blood giving rise to spuriously high leukocyte counts leading to clinical dilemma. Thalassemia major, the most common hemoglobinopathy usually presents after 6 months of age with severe anemia and hepatosplenomegaly. nRBC are characteristic of thalassemia major, however, white blood cell (WBC) count >50 × 109 is uncommon. We report an infant with beta-thalassemia major who presented with spurious leukocytosis.
| Case Report|| |
A 6-month-old developmentally normal boy, born of third degree consanguinity was referred for the evaluation of low-grade fever and abdominal distension for 1 week. There were no other symptoms reported. Investigations revealed elevated white blood cell (WBC-69 × 109/L) and severe anemia (Hb-3.6 g/dL), hence was suspected to have acute leukemia elsewhere.
Evaluation at our center revealed pallor, massive splenomegaly (beyond umbilicus) and hepatomegaly (span-9 cm). There was no lymphadenopathy, incessant cry, or bleeding. Investigations showed anemia (Hb-4.6 g/dL); WBC-56.9 × 109/L and platelets-311 × 109/L, with mean corpuscular volume (MCV-70.6fL). Renal function and serum electrolytes were normal. Lactate dehydrogenase (1031 IU/L) and uric acid (7.8 mg/dL) were elevated, with liver function test revealing indirect hyperbilirubinemia (total bilirubin-2.45 mg/dL; direct bilirubin-0.57 mg/dL). Reticulocyte count (3.0%) and serum ferritin level (603.5 ng/ml) were elevated. Peripheral smear (PS) showed microcytic hypochromic red cells with anisopoikilocytosis, target cells, tear drop cells, reactive lymphocytes, and nRBCs (289/100 WBCs) with corrected WBC count of 14.6 × 109/L [Figure 1]. Direct Coombs test was negative.
|Figure 1: Peripheral smear ×100 view; Leishman stained shows microcytic hypochromic anemia, anisopoikilocytosis, numerous nucleated red blood cells, and target cells|
Click here to view
In view of unconjugated hyperbilirubinemia, nRBCs in PS, normal platelet count, and no blasts despite elevated WBCs, possibility of hemolytic anemia was considered and necessary samples were drawn prior to packed red cell transfusion.
Hemoglobin electrophoresis done by high performance liquid chromatography method (pretransfusion) confirmed the diagnosis of beta-thalassemia major (Hb F-73.8%, Hb A-23.6% and Hb A2:2.4%). Parent's hemoglobin electrophoresis revealed both of them to be beta-thalassemia carriers. The child was started on regular transfusion to target pretransfusion >9 g/dL, folic acid, and planned for chelation after 18 months of age. Family was counseled about need for life long transfusion and chelation, long-term complications, and bone marrow transplant.
| Discussion|| |
Leukocytosis, defined as WBC >11.0 × 109/L in adults and 20 × 109/ L in children, is a common finding with wide differentials. Neutrophilia arises from infections, stressful conditions, inflammation; whereas, lymphocytosis occurs in pertussis, syphilis, viral infections, apart from leukemia or lymphoma. Lymphocytosis is more likely to be benign in young children than in adults., Whereas leukocytosis is actual increase in WBC count based on an underlying pathology, WBC response more than 50 × 109/L termed as leukemoid reaction, is often due to severe infections, hemorrhage, burns, and inflammatory conditions and is characterized by neutrophilia and shift to left pattern, unlike in leukemia.
Hematology analyzers generate a scattergram based on the presence of nucleus, size, and granularity of cells. Nonnucleated cells are classified as RBC and platelets, based on size, 70–80fl versus 7–9 fl; whereas, nucleated WBCs are further characterized by size and granularity into various types. Hence, nRBCs, platelet aggregates, cryoglobulins, or lipids are misinterpreted as WBC by analyzers causing spurious leukocytosis. nRBCs in the peripheral blood is physiological in 1st week of life; beyond which, it is associated with malignancy, marrow fibrosis, extra medullary hematopoiesis and bone marrow reaction to stress. Corrected WBC count can be calculated with formula-WBCx 100/(nRBC per 100WBC + 100).
Meticulous detailed PS examination and correlation of the abnormalities in each cell line help us to differentiate the leukemia, leukemoid reaction from spurious leukocytosis., Hemolytic workup prior to transfusion is essential as the red cell transfusion often delays diagnosis by 8–12 weeks or necessitates expensive genetic testing to confirm the diagnosis. In our patient, the absence of blasts despite high WBC, normal platelet count, and low MCV for age lead to suspicion of hemolytic anemia even prior to PS review.
Beta-thalassemia major is an autosomal recessive disorder characterized by the quantitative defect in beta-globin chain leading to ineffective erythropoiesis due to α-/β-globin imbalance and precipitation leading to hemolysis. Children generally present beyond 6 months with anemia and hepatosplenomegaly. PS shows anisopoikilocytosis, basophilic stippling, nRBCs, and target cells. Hemoglobin electrophoresis reveals high HB-F; identifying mutations of beta-globin gene will help in cases where the child has received transfusions or in prenatal diagnosis for the next pregnancy. Nucleated RBCs are definite diagnostic features in PS of children with beta-thalassemia major, often seen at diagnosis and after splenectomy. It is often corrected when the child is on adequate transfusion therapy
Spurious leukocytosis in thalassemia is caused by hypoxia by severe anemia, leading to compensatory erythropoiesis in bone marrow and extramedullary erythropoiesis in spleen and liver that releases immature RBCs into peripheral blood.
Hyperuricemia, which often occurs in leukemia, is also seen in hemolytic anemia due to high cell turnover and decreased renal function secondary to the presence of free hemoglobin from intravascular hemolysis, proximal tubular dysfunction due to oxidative stress, hemodynamic alteration, and inflammatory response secondary to the release of immune complexes.
Fagiolo et al. reported a child with autoimmune hemolytic anemia (AIHA) presenting with thrombocytosis and leukocytosis without an association with lymphoproliferative disorder and normalizing counts with steroids. Leukocytosis was proposed to be due to lymphocyte activation and cytokine production in AIHA.
| Conclusion|| |
Leukocytosis with cytopenias of other cell lines and organomegaly in children pose a significant diagnostic challenge. Elevated counts are not always suggestive of leukemia or leukemoid reaction. Systematic study of the hemogram including each cell line, indices and a detailed PS examination in the context of clinical presentation is important to plan appropriate investigations and management.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Cerny J, Rosmarin AG. Why does my patient have leukocytosis? Hematol Oncol Clin North Am 2012;26:303-19, viii.
Riley LK, Rupert J. Evaluation of patients with leukocytosis. Am Fam Physician 2015;92:1004-11.
Lamchiagdhase P, Kurosaki J, Ariyaporn I. Evaluation of nucleated red blood cells in thalassemia by the coulter LH 750 hematology analyzer. J Hematol Transfus Med 2008;19:27-34.
Kim YR, Yee M, Metha S, Chupp V, Kendall R, Scott CS. Simultaneous differentiation and quantitation of erythroblasts and white blood cells on a high throughput clinical haematology analyser. Clin Lab Haematol 1998;20:21-9.
Constantino BT, Cogionis B. Nucleated RBCs-Significance in the peripheral blood film. Lab Med 2000;4:223-9.
Nathan DG, Gunn RB. Thalassemia: The consequences of unbalanced hemoglobin synthesis. Am J Med 1966;41:815-30.
Aldudak B, Karabay Bayazit A, Noyan A, Ozel A, Anarat A, Sasmaz I,et al
. Renal functions in pediatric patients with β-thalassemia major. Pediatr Nephrol 2000;15:109-12.
Fagiolo E, Abenante L. Lymphocyte activation and cytokine production in autoimmune hemolytic anaemia (AIHA). Autoimmunity 1996;24:147-56.