Ramifications of pancytopenia in children in a tertiary care center in North Indian

Nikhil Gupta; Sonam Chalotra; Ravi Kumar Parihar; Preeti Sharma

doi:10.4103/joah.joah_97_22

ORIGINAL ARTICLE

Year : 2023 | Volume : 14 | Issue : 2 | Page : 95-100

Ramifications of pancytopenia in children in a tertiary care center in North Indian

Nikhil Gupta, Sonam Chalotra, Ravi Kumar Parihar, Preeti Sharma
Department of Pediatrics, SMGSH, GMC, Jammu, Jammu and Kashmir, India

Date of Submission	01-Nov-2022
Date of Decision	05-Feb-2023
Date of Acceptance	13-Feb-2023
Date of Web Publication	27-Jul-2023

Correspondence Address:
Dr. Preeti Sharma
Department of Pediatrics, SMGSH, GMC, Jammu, Jammu and Kashmir
India

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/joah.joah_97_22

Abstract

BACKGROUND: Pancytopenia generally suggests the likelihood of bone marrow failure syndromes or leukemias. However, other easily treatable entities can also cause pancytopenia. To know the underlying cause of pancytopenia is essential for definite management and prognosis.
AIM: The aim of this study is to study the prevalence, clinico-hematological profile, and etiology of pancytopenia in hospitalized children of 1 month to 18 years of age.
METHODS: Descriptive study conducted in a tertiary care center included children of age 1 month to 18 years hospitalized with pancytopenia. Sociodemographic data, presenting complaints, and detailed history were noted. Detailed clinical examination and relevant investigations were done.
RESULTS: The prevalence of pancytopenia was 2%. Majority of the patients were >10 years of age. Female: Male ratio was 1.15:1. The most common presentation was progressive pallor, followed by fever, icterus, and bleeding manifestations. The most common clinical examination finding was pallor, followed by splenomegaly, hepatomegaly, icterus, and lymphadenopathy. Macrocytic blood picture was most common, followed by microcytic, atypical cells, and normocytic picture. Mean serum ferritin (ng/ml) was 374.77 ± 1662.64. Mean serum B12 (pg/ml) was 117.72 ± 64.71. In bone marrow aspirate examination, megaloblastic erythropoiesis was most common, followed by normoblastic erythropoiesis, dual deficiency, malignant cells of lymphoid series, hypocellular marrow, and malignant cells of myeloid series. Megaloblastic anemia was the most common etiology, followed by dimorphic anemia amid acute leukemia.
CONCLUSION: The study showed that megaloblastic anemia and infections (tuberculosis, dengue fever, and enteric fever) both of which are eminently treatable, cause nearly 65% of pancytopenia cases in pediatric patients.

Keywords: Children, clinico-hematological profile, demography, etiology, pancytopenia, prevalence

How to cite this article:
Gupta N, Chalotra S, Parihar RK, Sharma P. Ramifications of pancytopenia in children in a tertiary care center in North Indian. J Appl Hematol 2023;14:95-100

How to cite this URL:
Gupta N, Chalotra S, Parihar RK, Sharma P. Ramifications of pancytopenia in children in a tertiary care center in North Indian. J Appl Hematol [serial online] 2023 [cited 2023 Oct 4];14:95-100. Available from: https://www.jahjournal.org/text.asp?2023/14/2/95/382419

Introduction

Pancytopenia is defined as hemoglobin <10 g%, total white cells count <4 × 10⁹/L, absolute neutrophil count (ANC) <1500/μl, and platelet count <100,000/uL. Presenting features of pancytopenia are commonly progressive pallor, easy fatiguability, and giddiness due to anemia, recurrent infections due to leucopenia, bleeding manifestations due to thrombocytopenia, loss of weight, loss of appetite, and night sweats due to underlying primary or secondary malignancy infiltrating bone marrow.^[1] Pancytopenia can be inherited or acquired. Inherited (constitutional) pancytopenias account for approximately 30% of pediatric marrow failure syndromes. Fanconi anemia is the most common of these disorders. Others include Schwachman-Diamond syndrome, dyskeratosis congenita, and others. Causes of acquired pancytopenia are drugs including chemotherapeutic agents, antibiotics like chloramphenicol, certain anticonvulsants, chemicals like benzene, gold and ecstasy, radiations, immune disorders, certain infections, malignancies either primary or secondary, PNH, megaloblastic anemia, and collagen vascular diseases. Pancytopenia generally suggests the likelihood of bone marrow failure syndromes or leukemias. However, other easily treatable entities can also cause pancytopenia. Importantly, megaloblastic anemia and infections have also emerged as recognizable causes of varying degrees of cytopenias. Megaloblastic anemia due to B₁₂ or folic acid deficiency is now a well-recognized and established cause of cytopenias.^[2] To know the underlying cause of pancytopenia is essential for specific management and prognosis. Although several studies have been conducted about etiopathogenesis of pancytopenia in adults, there is a scarcity of data on pancytopenia in children. The aim of the present study was to study the prevalence, clinico-hematological profile, and etiology of pancytopenia in hospitalized children of 1 month to 18 years of age.

Methods

This descriptive observational study was done in the Department of Pediatrics, GMC Jammu, from November 2019 to October 2020, after taking consent from the institutional ethical committee. Children of age 1 month to 18 years who were presented with pancytopenia (Hemoglobin <10 g%, ANC <1500/mm³, and platelets <1 lakh/mm³) during the study period were included in the study.^[3],[4] Known cases of aplastic anemia and malignancies, those who were on chemotherapy or radiotherapy, and eligible patients whose parents did not give consent for participation were excluded. The data recorded were age, gender, religion, socioeconomic status (according to the modified Kuppuswamy scale), presenting complaints, history of present illness, dietary history, and past and family history. A detailed clinical examination was done. Investigations, as guided by the clinical condition, were done. Pancytopenia was reported by automated cell counter Mindray 5-part analyzer and confirmed by peripheral blood film (PBF) manually. Various investigations done were complete blood count (CBC) with indices, PBF, reticulocyte count, serum lactate dehydrogenase (LDH), liver function tests, kidney function tests, lymph node biopsy, bone marrow aspiration, and trephine biopsy. For the diagnosis of nutritional anemia, serum ferritin, and Vitamin B12 levels were done. In cases of infectious disease and autoimmune disorders like systemic lupus erythematosus (SLE), relevant investigations were done to confirm the diagnosis. Algorithm for investigative workup of pancytopenia which we follow in our center is shown in [Figure 1].

Figure 1: Algorithm for investigative workup of pancytopenia

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Statistical analysis

Descriptive statistics were used to analyze baseline data. Depending on the number of comparison groups, student t-test and ANOVA test were used to analyze normally distributed quantitative variables. The Chi-square test was used to examine qualitative variables. Fisher's exact test was employed if the expected value of any cell was <5. The data were entered into a Microsoft Excel spreadsheet, and the final analysis was performed using IBM's Statistical Package for the Social Sciences (SPSS) software, IBM manufacturer, Chicago, Illinois, USA, version 21.0. A P < 0.05 was considered statistically significant for statistical significance.

Results

A total of 8024 patients of age 1 month to 18 years were admitted to our hospital during the study period. Pancytopenia cases were 161 making the prevalence 2%. Out of these 161, 10 patients were excluded from the study (five were known cases of malignancies and were on chemotherapy, one patient was on radiotherapy, three cases of aplastic anemia, and in one case parents did not give consent to participate). A total of 151 cases were included in the study. Majority of the patient belonged to the age group >10 years (68 [45.03%]), followed by 1–5 years age group (40 [26.49%]), whereas the minimum number were from the age group <1 year (14 [9.27%]). Out of 151 patients, 81 (53.64%) were female and 70 (46.36%) were male, with female: Male ratio of 1.15:1. Hinduism contributed to maximum number of cases (108 [71.52%]) followed by Muslim (37 [24.50%]) and Sikh (6 [3.97%]) cases. Majority of the patients belonged to the lower-middle class (75 [49.67%]), followed by upper lower (51 [33.77%]), upper middle (14 [9.27%]), and lower class (11 [7.28%]). Out of total six patients from 1 to 6-month age group, 2 (33.33%) were exclusively breastfed and rest 4 (66.67%) were on mixed and replacement feeding. In the age group above 6 months to 18 years, majority were on vegetarian diet (87 [60%]) as compared to nonvegetarian (58 [40%]). Presenting complaints and clinical examination findings of study subjects are shown in [Table 1]. In our study, 151 CBC reports were analyzed and descriptive statistics of CBC of study subjects are shown in [Table 2] and [Figure 2]. Reticulocyte count (%) in our study was found to be with range from 0.01 to 4.5 with mean of 1.53 ± 0.84. In PBF analysis of study subjects, macrocytic (50.33%) picture was the most common, followed by microcytic (35.76%), atypical cells (11.26%), and normocytic picture (5.96%). Range of serum LDH (U/liter) in our study was from 206 to 5904 with mean of 1034.48 ± 840.35. Mean serum bilirubin (mg/dl) in the present study was 0.99 ± 0.58 and mean SGOT (U/liter) and SGPT (U/liter) were 75.68 ± 33.22 and 80.77 ± 33.36, respectively. Serum ferritin (ng/ml) ranged from 2.2 to 13159 with mean of 374.77 ± 1662.64. Vitamin B12 (pg/ml) levels ranged from 5 to 261 in our study with mean of 117.72 ± 64.71 which was significantly lower in patients of pancytopenia. In bone marrow study, majority of patients had megaloblastic erythropoiesis (54.30%), followed by normoblastic erythropoiesis (35.76%), dual deficiency (11.26%), malignant cells of lymphoid series (7.95%), hypocellular marrow (5.96%), malignant cells of myeloid series (2.65%), and others (3.97%) which included LD bodies, hemophagocytic lymphohistiocytosis, pure red cell aplasia and transient erthroblastopenia of childhood. Etiology of pancytopenia of study subjects is given in [Table 3]. Serum LDH (U/Liter) levels were found to be significantly higher in those with Vitamin B12 deficiency with P < 0.0001[Table 4]. Vitamin B12 deficiency is significantly found to be associated with vegetarian diet as shown in [Table 5].

Table 1: Presenting complaints and clinical examination findings of study subjects

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Figure 2: Distribution of etiology of pancytopenia in study subjects

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Table 2: Descriptive statistics of complete blood count of study subjects

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Table 3: Etiology of pancytopenia in study subjects

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Table 4: Association of serum lactate dehydrogenase (U/l) with Vitamin B12 deficiency

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Table 5: Association of dietary history with Vitamin B12 deficiency

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Discussion

Prevalence of pancytopenia in our study was found to be 2% which is comparable with other previously done studies.^{[4],[5],[6],[7]} Most of the patients belonged to the age group of more than 10 years (45.03%), followed by the age group of 1–5 years (26.49%). Similar results were shown by Vijayakrishnan et al. and Kibria et al. (2010) in their studies.^[8],[9] Contrary to our results, in some studies maximum number of cases belonged to 6 months to 5 years age group.^[2],[7],[10] Female: Male ratio in our study was 1.15:1 which was similar to that found in study done by Vijayakrishnan et al. and Dubey et al.^[8],[11] In the current study progressive pallor (84.11%) was most common presenting complaint, followed by fever (54.30%), icterus (17.88%), and bleeding manifestations (13.91%). The most common clinical examination finding was pallor (97.35%), followed by splenomegaly (23.18%), hepatomegaly (20.53%), and icterus (17.88%). Similar results were found in other studies.^{[4],[7],[12],[13],[14]} Among 151 study subjects 19 (12.58%) cases showed malignant etiology and rest were of nonmalignant etiology. Lymphoblastic series of acute leukemia were more common than myeloid series (acute lymphocytic leukemia type L1 being the most common). Similar results were found in other studies also.^{[4],[3],[7],[10]} In our study among the nonmalignant causes of pancytopenia, the most common was megaloblastic anemia. Other studies also showed similar results.^{[4],[14],[15],[16]} Ineffective erythropoiesis, leukopoiesis, and thrombopoiesis resulting due to enhanced programmed cell death in absence of Vitamin B12 or folic acid and decrease survival of precursors in peripheral blood are most commonly implicated in causing pancytopenia in megaloblastic anemia. In our study, hypersplenism was the reason for pancytopenia in six cases (3.97%). Hypersplenism due to massively enlarged spleen causes pancytopenia in these patients and underlying disease in these patients was thalassemia in three patients and extrahepatic portal venous obstruction in remaining three. Various infections as causes of pancytopenia have been variably documented. In our study, infectious causes of pancytopenia were tuberculosis (6 [3.97%]), rickettsial fever (6 [3.97%]), dengue fever (7 [4.64%]), enteric fever (4 [2.65%]), malaria (3 [1.99%]), and Leishmania (2 [1.32%]). Rickettsial fever was confirmed by rickettsial serology and Weil‒Felix test. Enteric fever was confirmed by Salmonella Typhi serology immunoglobulin M and blood cultures. Pancytopenia in rickettsial and enteric fever is caused by varied mechanisms. Bone marrow may undergo histiocytic hyperplasia along with hemophagocytosis or complete necrosis. Immune-mediated hemolysis or leukopenia, hypersplenism, and transient disseminated intravascular hemolysis are other contributory mechanisms. James et al. showed an 8.3% prevalence of pancytopenia due to enteric fever.^[17] Enteric fever contributed to 5 cases (2.7%) in a study by Singh et al. consistent with our study.^[7] In patients with tuberculosis, various hematological abnormalities including anemia, thrombocytopenia, and pancytopenia have been described in various studies. In our study, six patients with pancytopenia had tuberculosis. Besides this, malaria due to Plasmodium vivax has been implicated in causation of pancytopenia. Three patients of malaria due to P. vivax had pancytopenia in our study. Aouba reported hemophagocytic syndrome due to P. vivax infection as a cause of pancytopenia.^[18] Malaria causes anemia and thrombocytopenia due to direct invasion by parasite, immune hemolysis, disseminated intravascular coagulation hypersplenism, and hemophagocytosis. In our study, there were two patients of Leishmaniasis (kala-azar) who had pancytopenia, confirmed by bone marrow evidence of Leishmania donovani bodies (LD bodies). Pancytopenia is caused by hypersplenism, ineffective erythropoiesis, and reticuloendothelial hyperplasia. Both of these patients came from endemic areas and had a history of prolonged fever with massive splenomegaly. One of the patients responded well to liposomal amphotericin B and the other patient expired during the course of treatment. Kumar et al. reported kala-azar in 4% of pancytopenia patients. In our study, 2 (1.31%) cases of pancytopenia were due to hemophagocytic lymphohistiocytosis confirmed clinically, laboratory, and bone marrow study.^[19] Both of the patients responded well to immunosuppressant and on follow-up had improved blood counts. Other causes including celiac disease are also prevalent in our area, five patients (3.33%) were diagnosed with celiac disease. In celiac disease due to chronic exposure to gluten antigen, the duodenal mucosa gets inflamed and surface area reduced. This leads to the deficiency of micronutrient absorbed at here and overall deficient state for iron, zinc, calcium, folate, and Vitamin B12. Deficiency of these leads to pancytopenia. Fisgin et al. showed hematological manifestation in celiac disease.^[20] In our study, SLE was the reason of pancytopenia in two cases. It may be due to autoimmune destruction, hypersplenism, or bone marrow suppression. Fulminant bacterial sepsis as cause of pancytopenia is scarcely reported in the literature. Three of our patients had all three cell lines affected due to sepsis at presentation but no definite cause could be elicited and two of them were managed as Gram-negative septicemia. Garewal et al. reported Gram-negative sepsis due to bone marrow necrosis in two patients.^[21] One case each of transient erythroblastopenia of childhood and pure red cell aplasia was attributed to pancytopenia in our study. One case of chronic renal failure, reported pancytopenia, this may be due to prolonged urea and creatinine which lead to depression of bone marrow. Similar results were present in other studies.^[6],[7] In bone marrow studies, megaloblastic erythropoiesis (82 [54.30%]) was most common, followed by normoblastic erythropoiesis (54 [35.76%]), which was comparable with study from Singh et al.^[7]and Munir et al.^[16] In our study, vegetarian diet accounted for 60% of cases, and a significant association was found between vegetarian diet and deficiency of Vitamin B12 was found. Pawlak et al. (2014) also showed higher Vitamin B12 deficiency prevalence in vegans.^[22] A significant association was seen between Vitamin B12 deficiency and higher LDH levels in this study, reflecting ineffective erythropoiesis. Kumar and Mirji also found the same association.^[23]

Recommendations

It is imperative to intervene early in childhood to prevent and/or early diagnosis and management of pancytopenia patients. For this, interventions to promote a healthy lifestyle need to be taken in multiple settings (individual, school, family, parents, and community).

Exclusive breastfeeding for the first 6 months of birth followed by adequate complementary feeding with breastfeeding continued for minimum 2 years
Parental and family education regarding the routine assessment of growth and development and provision of healthy nutritious diet including iron, folic acid, and Vitamin B12 supplements
Regular and periodic health checkups in school and community are to be reinforced.
Immunization as per schedule
Strict implementation of National Health Programs and Vector Borne Disease Control Programmes and personal hygiene
Vegetarian diet should be supplemented with Vitamin B12 supplements to reduce the risk of megaloblastic anemia and its consequences.

Limitations

Infections present at the particular time of season requiring hospital admissions might have contributed to more number of cases leading to a bias in the study
This is a single-centric study. As the prevalence and etiological profile may vary with geographic location, these results cannot be generalized.

Conclusion

Pancytopenia is not a rare hematological problem in children. Timely recognition of entities causing pancytopenia undoubtedly has an impact on the outcome. The study showed that megaloblastic anemia and infections (tuberculosis, dengue fever, and enteric fever) both of which are eminently treatable, cause nearly 65% of pancytopenia cases in pediatric patients. This is contrary to the widespread perception of acute leukemia and aplastic anemia as the most common etiological factors, with their associated poor prognostic implications. It is important to be aware of these conditions as a frequent cause of pancytopenia so that prompt and appropriate investigative and therapeutic measures can be instituted.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Imbert M, Scoazec JY, Mary JY, Jouzult H, Rochant H, Sultan C. Adult patients presenting with pancytopenia: A reappraisal of underlying pathology and diagnostic procedures in 213 cases. Hematol Pathol 1989;3:159-67.
2.	Chandra J, Jain V, Narayan S, Sharma S, Singh V, Kapoor AK, et al. Folate and cobalamin deficiency in megaloblastic anemia in children. Indian Pediatr 2002;39:453-7.
3.	Zeb Jan A, Zahid B, Ahmad S, Gul Z. Pancytopenia in children: A 6-year spectrum of patients admitted to pediatric department of Rehman medical institute, Peshawar. Pak J Med Sci 2013;29:1153-7.
4.	Bhatnagar SK, Chandra J, Narayan S, Sharma S, Singh V, Dutta AK. Pancytopenia in children: Etiological profile. J Trop Pediatr 2005;51:236-9.
5.	Memon S, Shaikh S, Nizamani MA. Etiological spectrum of pancytopenia based on bone marrow examination in children. J Coll Physicians Surg Pak 2008;18:163-7.
6.	Rathod GB, Alwani M, Patel H, Jain A. Clinico-hematological analysis of pancytopenia in pediatric patients of tertiary care hospital. IAIM 2015;2:15-9.
7.	Singh G, Agrawal DK, Agrawal R, Prakash Suthar P. Etiological profile of childhood pancytopenia with special references to non malignant presentation. Int J Med Res Prof 2016;2:204-8.
8.	Vijayakrishnan G, Thambi R, Sankar S. A 2 year study of clinico-hematological profile of bicytopenia and pancytopenia in paediatric patients attending a tertiary hospital in South India. IJPO 2020;7:207-11.
9.	Kibria S, Islam M, Chowdhury A, Ali M, Haque M, Mustanzid S, et al. Prevalence of hematological disorder: A bone marrow study of 177 cases in a private hospital at Faridpur. Faridpur Med Coll J 2010;5:11-3.
10.	Gupta V, Tripathi S, Tilak V, Bhatia BD. A study of clinico-haematological profiles of pancytopenia in children. Trop Doct 2008;38:241-3.
11.	Dubey S, Patel S, Arya AK, Singh RP. Clinico-etiological spectrum of pancytopenia in hospitalized children. Int J Contemp Pediatr 2016;3:169-72.
12.	Chand R, Singh N. Clinic-etiological profile of pancytopenia in children: A tertiary care center based study of Kumaun region, India. Int J Contemp Pediatr 2018;5:2173.
13.	Gomber S, Kela K, Dhingra N. Clinico-hematological profile of megaloblastic anemia. Indian Pediatr 1998;35:55-8.
14.	Sharif M, Masood N, Haq ZU, Dodhy A, Asghar M. Etiological spectrum of pancytopenia/Bicytopenia in children 2 months to 12 years of age. J Rawalpindi Med Coll (JRMC) 2014;18:61-5.
15.	Mishra D, Kohli A, Yadav RB, Nayak D. Megaloblastic anemia: A common cause of pancytopenia in children. Indian J Pathol Microbiol 2007;50:447-8. [PUBMED]
16.	Munir A, Shah SF, Ata T, Asim N, Sajid M, Farooq M. Prevalence of non malignant haematological disorders in patients with pancytopenia/bicytopenia: A bone marrow study of 148 cases in DHQ KDA hospital and LMH hospital, Kohat. PJMHS 2014;8:438-40.
17.	James J, Dutta TK, Jayanthi S. Correlation of clinical and hematologic profiles with bone marrow responses in typhoid fever. Am J Trop Med Hyg 1997;57:313-6.
18.	Aouba A, Noguera ME, Clauvel JP, Quint L. Hemophagocytic syndrome associated with Plasmodium Vivax infection. Br J Haematol 2000;108:832-3.
19.	Kumar V, Agarwal P, Marwah S, Nigam AS, Tiwari A. Spectrum of clinicohematological profile and its correlation with average parasite density in visceral leishmaniasis. Cytojournal 2018;15:19. [PUBMED] [Full text]
20.	Fisgin T, Yarali N, Duru F, Usta B, Kara A. Hematologic manifestation of childhood celiac disease. Acta Haematol 2004;111:211-4.
21.	Garewal G, Marwaha N, Marwaha RK, Das KC. Bone marrow necrosis and pancytopenia associated with gram negative septicemia. Indian Pediatr 1991;28:79-81.
22.	Pawlak R, Lester SE, Babatunde T. The prevalence of cobalamin deficiency among vegetarians assessed by serum vitamin B12: A review of literature. Eur J Clin Nutr 2014;68:541-8.
23.	Kumar V, Mirji G. Evaluation of serum LDH levels in the diagnosis and in monitoring the response to the treatment in children with megaloblastic anaemia. Int J Pediatr Res 2019;6:217-20.