Accurate Identification of Viral-associated Pathological Hematopoiesis in Infants: Insights from Two Case Studies

Accurate Identification of Viral-associated Pathological Hematopoiesis in Infants: Insights from Two Case Studies | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 21 July 2025 V1 Latest version Share on Accurate Identification of Viral-associated Pathological Hematopoiesis in Infants: Insights from Two Case Studies Authors : Haifeng Yin 0009-0000-8049-866X , Doudou Guo , Wei Wang , Wanxin Chen 0000-0002-8110-8480 , and Lei Li [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.175309042.20050207/v1 140 views 89 downloads Contents Abstract Background Conflict of Interest Author Contributions Funding Acknowledgments Data Availability Statement Supplementary Material References Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Background: Postnatal cytomegalovirus (CMV) infection in infants can lead to severe hematological abnormalities, especially severe thrombocytopenia. There are few reports on cases that fail to respond to conventional treatments such as immunoglobulin and steroids, and studies on pathological hematopoietic changes in the bone marrow are lacking. Methods: This study reports two infants with postnatal CMV infection and multilineage hematopoiesis characterized by severe thrombocytopenia. Both infants underwent bone marrow cytology to find the cause and evaluate the effect of antiviral treatment to restore normal hematopoiesis. Results: Both infants presented with multilineage hematopoiesis and severe thrombocytopenia that were unresponsive to conventional treatment. Bone marrow cytology showed multilineage dysplasia. CMV infection was confirmed by polymerase chain reaction (PCR) testing. Antiviral treatment can significantly improve clinical manifestations and pathological hematopoiesis in the bone marrow. Conclusion: These findings emphasize the importance of identifying postnatal CMV infection as a cause of hematological abnormalities in infants. Early diagnosis and intervention through bone marrow examination and antiviral treatment are crucial for restoring normal hematopoiesis and preventing severe hematological diseases, providing new insights into the mechanisms of CMV-induced blood damage. Haifeng Yin 1 , Doudou Guo 1 , Wei Wang 2 , Wanxin Chen 2 , Lei Li 1* 1 Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China 2 Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China * Correspondence: Lei Li, Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue Wuhan, 430022, Hubei, China. Tel: 13971370301; e-mail: [email protected] Keywords: cytomegalovirus, hematological system, infant, bone marrow, pathological hematopoiesis. Abstract Background: Postnatal cytomegalovirus (CMV) infection in infants can lead to severe hematological abnormalities, especially severe thrombocytopenia. There are few reports on cases that fail to respond to conventional treatments such as immunoglobulin and steroids, and studies on pathological hematopoietic changes in the bone marrow are lacking. Methods: This study reports two infants with postnatal CMV infection and multilineage hematopoiesis characterized by severe thrombocytopenia. Both infants underwent bone marrow cytology to find the cause and evaluate the effect of antiviral treatment to restore normal hematopoiesis. Results: Both infants presented with multilineage hematopoiesis and severe thrombocytopenia that were unresponsive to conventional treatment. Bone marrow cytology showed multilineage dysplasia. CMV infection was confirmed by polymerase chain reaction (PCR) testing. Antiviral treatment can significantly improve clinical manifestations and pathological hematopoiesis in the bone marrow. Conclusion: These findings emphasize the importance of identifying postnatal CMV infection as a cause of hematological abnormalities in infants. Early diagnosis and intervention through bone marrow examination and antiviral treatment are crucial for restoring normal hematopoiesis and preventing severe hematological diseases, providing new insights into the mechanisms of CMV-induced blood damage. Background Persistent cytomegalovirus (CMV) infection after birth can lead to significant long-term consequences, including lifelong neurological impairment, sensorineural hearing loss, and microcephaly, however, the understanding of the effects of postnatal CMV infection remains incomplete. While breast milk is the primary route of transmission, most infants recover without antiviral treatment, reserving ganciclovir for severe cases. 1-3 However, CMV-induced abnormal proliferation of hematopoietic cells in the bone marrow is rare and understudied. Notably, a case-control study suggests a link between congenital CMV infection and an increased risk of acute lymphoblastic leukemia, highlighting the importance of accurately identifying CMV-associated hematopoietic disorders. 4 In this study, we present two cases of infants with postnatal CMV infection leading to secondary pathological hematopoiesis. These cases emphasize the need for further investigation into the hematological effects of postnatal CMV infection and the potential benefits of early antiviral intervention, contributing to better care and management of affected infants. Case 1 A four-month-old female infant was referred to our facility due to persistent cutaneous bleeding points for five days. She was a full-term neonate with no previous hematologic disorders. Her mother reported no history of thrombocytopenia or antenatal bleeding. Initial blood tests at a local hospital revealed a platelet count of 5×10 9 /L, elevated alanine aminotransferase (115 U/L), and aspartate aminotransferase (105 U/L) levels. Despite treatment for presumed immune thrombocytopenia with intravenous immunoglobulin (IGIV) (2 mg/kg), dexamethasone (0.5 mg/kg/d for two days), and platelet transfusions (0.5 U), her platelet count only rose to 28×10 9 /L, and bleeding symptoms persisted. Anemia worsened, with hemoglobin dropping to 80 g/L. Further treatments, including methylprednisolone (5 mg/kg, twice daily with gradual dose reduction after two days), along with platelet transfusions (1 U) and red blood cell transfusion (1 U) among other therapies, did not prevent fecal occult blood positivity or a nadir platelet count of 1×10 9 /L. Physical examination showed petechiae and ecchymosis. Polymerase chain reaction (PCR) tests confirmed CMV in the patient’s urine and her mother’s breast milk, with high viral loads (initial CMV viral load in urine was graded as ”++”, and CMV-DNA was detected at a concentration of 16, 000 copies/mL in breast milk). Chromosome testing showed a normal karyotype (46, XX). Additionally, bone marrow analysis demonstrated granulocytic dysplasia characterized by reduced cytoplasmic granules (22%), imbalanced nuclear and cytoplasmic development (6%), and the presence of cytoplasmic vacuolization (3%). Occasional observations included binuclear erythrocytes (2%), immature erythrocyte nuclei sprouting (2%), erythrocytic vacuolization (2%), and petal nuclei resulting from erythroid dysplasia. Pathological hematopoiesis was evident in the megakaryocyte lineage, characterized by the presence of double-round nucleus, poly-round nucleus megakaryocytes, and lymphoid small megakaryocytes ( Figure 1 ). Antiviral therapy with ganciclovir (5 mg/kg, twice daily for five days) significantly improved platelet counts and hematopoietic abnormalities ( Figure 3A ). Urinary CMV load decreased, and subsequent oral valganciclovir was given for four weeks. Post-treatment follow-ups showed normal blood counts. The patient, previously in good health, presented with an illness of less than four months. The patient’s bone marrow changes were consistent with reactive pathological hematopoiesis due to CMV infection, which responded well to antiviral therapy. Case 2 A 50-day-old male infant with an unremarkable medical history was admitted for sustained cutaneous bleeding lasting twelve hours. He is the fourth child of his mother, whose previous pregnancies ended in complications. The mother had a normal platelet count and an uncomplicated gestation. The infant presented with stable vital signs and a soft anterior fontanelle but had scattered bleeding spots on his skin and mucosa, without hepatosplenomegaly or lymphadenopathy. A complete blood test showed a platelet count of 1×10 9 /L, white blood cell count of 4.64×10 9 /L, and a hemoglobin count of 92 g/L. Other tests, including blood coagulation, liver and kidney function, electrolytes, fecal analysis, radiographic scans, and cardiac assessments, were normal. CMV infection was confirmed with high CMV-DNA levels in urine (45,400 copies/mL) and blood (65.7 copies/mL). The mother also had high CMV-DNA levels in breast milk and tested positive for anti-CMV IgG antibodies. Smear analysis showed 8% atypical lymphocytes. Initial treatment with gamma globulin (2 mg/kg) and a 0.5 U platelet transfusion raised the platelet count to 200×10 9 /L, but it quickly dropped to 8×10 9 /L the next day, accompanied by a decrease in white blood cell count to 3.47×10 9 /L and hemoglobin level to 82 g/L. These findings suggested autoantibody-mediated platelet destruction. Furthermore, myocardial damage developed in the patient possibly due to severe thrombocytopenia and CMV infection. Anemia was corrected with a red blood cell transfusion (1 U). Bone marrow examination revealed dysplasia in two myeloid cell lines and ring sideroblasts in erythroid cells, indicating impaired bone marrow function ( Figure 2 ). Considering that the disease duration was less than four months, a diagnosis of CMV-induced reactive pathological hematopoiesis was established based on evidence of CMV infection and abnormal bone marrow cell morphology. The treatment with intravenous ganciclovir improved thrombocytopenia and resolved hemorrhaging ( Figure 3B ). A subsequent four-week course of oral valganciclovir prevented CMV reactivation. Follow-up tests confirmed normal hematological parameters, undetectable CMV-DNA in peripheral blood, and complete bone marrow recovery. Discussion The etiology of infantile thrombocytopenia can be primarily categorized into immune-mediated thrombocytopenia and non-immune thrombocytopenia. This study reports two cases of infants with severe persistent thrombocytopenia and multilineage dysplasia in bone marrow caused by CMV infection. Both infants exhibited high CMV-DNA viral loads in urine samples, with one case additionally showing positivity in blood specimens, collectively indicative of active CMV infection. Notably, high CMV-DNA loads were also detected in the breast milk of both mothers. Breastfeeding represents the most common route of postnatal CMV transmission from seropositive mothers to infants, with up to 96% of CMV-seropositive mothers experiencing viral reactivation during lactation. The transmission rate of CMV through breastfeeding in term infants ranges from 58% to 69%. 5 These two cases should therefore be considered as potential postnatal CMV (pCMV) infections. However, the samples collected three weeks after birth could not definitively confirm congenital CMV infection in either infant. 6 Currently, there remains no consensus regarding the understanding of pCMV infection, and clear clinical guidelines are lacking. A cross-sectional study revealed an association between CMV gH2 genotype and decreased platelet counts in infants. 7 According to a comprehensive study, symptomatic pCMV disease affected 0%–34.5% of thrombocytopenia cases (median: 3.7%). 5 Although pCMV infection typically presents as mild and self-limiting, the two reported cases involved severe thrombocytopenia refractory to conventional therapies. A retrospective analysis of immunocompetent children with CMV-associated thrombocytopenia found that 62.1% of cases occurred in infants under 6 months of age. Among six cases requiring antiviral therapy, four were infants, underscoring the importance of antiviral treatment for refractory CMV-related thrombocytopenia in this population. 8 Furthermore, case reports have highlighted CMV’s significant role in triggering severe refractory thrombocytopenia in both children and adults, emphasizing the necessity of antiviral intervention. 9, 10 In line with previous studies and these two cases, antiviral therapy in symptomatic infants demonstrates promising potential for alleviating symptoms and shortening disease duration. 11 Bone marrow cytological examination becomes imperative when conventional therapies for pediatric thrombocytopenia, including intravenous immunoglobulin or steroids, prove ineffective. Our cases demonstrate that active CMV infection can induce pathological hematopoiesis, disrupting normal hematopoiesis and leading to characteristic cytomorphological alterations in the bone marrow, highlighting both the diagnostic value of bone marrow examination and the critical role of antiviral therapy in hematopoietic recovery. Both CMV-infected patients exhibited bilineage to trilineage dyshematopoiesis, characterized by decreased cellular ratios, reduced intracytoplasmic granules, binucleation, nuclear budding, cytoplasmic vacuolization, and polychromatic erythrocytes, with megakaryocytes additionally showing binucleation with rounded morphology, lymphoid features, and micronucleation - findings consistent with WHO-defined reactive dyshematopoiesis. 12 Following ganciclovir treatment, complete trilineage morphological recovery was observed. Notably, systemic manifestations occurred, including hepatic dysfunction in Case 1 and recurrent jaundice with myocardial injury in Case 2. In accordance with 2019 International Childhood ITP Working Group recommendations, bone marrow aspiration is indicated for patients experiencing relapse after remission, showing refractoriness to initial therapy, or being considered for splenectomy, with our refractory thrombocytopenia cases confirming the clinical utility of bone marrow evaluation in such scenarios. CMV infection can induce pathological processes and hematopoietic dysfunction through multiple mechanisms. The viral proliferation causes tissue damage and may trigger multisystem diseases, particularly in immunocompromised infants. Notably, hematopoietic progenitor cells demonstrate increased susceptibility to CMV latency and reactivation through various signaling pathways involving interleukin-6-induced Src family kinase (SFK) signaling. 13-15 CMV impairs the hematopoietic system via both direct cytotoxic effects on progenitor cells and immune-mediated processes. Infection of immune cells (B cells, T cells, NK cells) leads to immune dysfunction and generation of anti-platelet/erythrocyte antibodies, consequently suppressing bone marrow hematopoiesis. 16-18 CMV disrupts the hematopoietic microenvironment by invading stromal cells, thereby affecting progenitor cell differentiation and maturation. 19 The virus may also induce Fas-mediated apoptosis, damaging erythrocytes and causing anemia. 20 Furthermore, recent studies have established an association between congenital CMV infection and increased risk of childhood acute lymphoblastic leukemia. 21 A large cohort study involving 2,782,507 children further confirmed this specific correlation between congenital CMV infection and elevated risk of hematological malignancies. 22 These findings collectively underscore the necessity for further exploration of CMV-induced hematological injury mechanisms. The two cases presented in this report illustrate CMV-associated thrombocytopenia and multilineage hematopoietic dysplasia, demonstrating the significant hematological consequences of CMV infection in pediatric patients while concurrently establishing the substantial therapeutic benefits of antiviral intervention. Building upon existing literature and our clinical observations, we propose a diagnostic protocol incorporating CMV screening and bone marrow cytomorphological analysis for pediatric cases presenting with severe refractory thrombocytopenia unresponsive to conventional first-line therapies. This comprehensive diagnostic approach serves to: (i) accurately characterize hematopoietic pathology, (ii) enhance clinical understanding of disease pathogenesis, (iii) facilitate identification of potential risk factors, and (iv) inform the development of targeted preventive measures. PCR Polymerase chain reaction IGIV Intravenous immunoglobulin pCMV postnatal CMV SFK Src family kinase Ethics The release of images and this case review were approved by the parents. Conflict of Interest The authors declare no conflict of interest. Author Contributions We confirm that the manuscript is original. LL put forward the idea and supervised this project. DG was responsible for writing manuscript and drawing charts. WW and WC contributed towards reviewing and editing. The authors read and approved the final manuscript. Funding Not applicable. Acknowledgments We appreciate Cleveland resident in internal medicine Yuhao Zeng’s insightful remarks on our article. Data Availability Statement The datasets used in this study are available from the corresponding author on reasonable request. Figure legends FIGURE 1. Bone marrow cytology examination of case 1: A, B, C, and D exhibited aberrant morphology in three lineages prior to ganciclovir treatment (December 27 th , 2019). (A) Immature mononuclear and binucleated megakaryocytes. (B) Megakaryocyte with granular double rounded nucleus and lobulated nucleus. (C) Decreased cytoplasmic granules in bone marrow cells. (D) Vacuolization of nucleated erythroid cells and megaloblastic changes. E and F demonstrated normal granulocyte morphology following ganciclovir treatment, with no other abnormal cells observed within either lineage (January 2 nd , 2020). Wright-Giemsa staining was used for all panels; magnification: 100×10 times. FIGURE 2. Bone marrow cytology of Case 2: A and B exhibited abnormal morphology of both lineages and a complete absence of megakaryocytes prior to ganciclovir treatment (August 26 th , 2022). (A) Reduction in granulocyte cytoplasmic granules was observed. (B) Nucleated red blood cell displayed over ten densely stained iron particles surrounding the nucleus. C and D demonstrated trilineage morphology returned to normal following ganciclovir treatment (September 6 th , 2022). (C) Morphologically normal granulocytes and erythrocytes were observed. (D) Megakaryocytes displayed normal morphology. Wright-Giemsa staining was used for panels A, C, and D; panel B utilized iron staining; magnification: 100×10 times. FIGURE 3. Clinical course and changes in peripheral blood cell count of two patients. (A) for case 1 and (B) for case 2. The timeline includes key treatment events, with the purple arrow indicating treatment administered in the local hospital. Figure 1 Figure 2 Figure 3 Supplementary Material File (figure 1.tif) Download 4.97 MB File (figure 2.tif) Download 3.92 MB File (figure 3.tif) Download 1.68 MB References 1. 1. Ross SA, Kimberlin D. Clinical outcome and the role of antivirals in congenital cytomegalovirus infection. Antiviral Res 2021; 191 : 105083.2. Osterholm EA, Schleiss MR. Impact of breast milk-acquired cytomegalovirus infection in premature infants: Pathogenesis, prevention, and clinical consequences? Rev Med Virol 2020; 30 : 1-11.3. 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Keywords hematology infections platelet disorders Authors Affiliations Haifeng Yin 0009-0000-8049-866X Huazhong University of Science and Technology Tongji Medical College Union Hospital View all articles by this author Doudou Guo Huazhong University of Science and Technology Tongji Medical College Union Hospital View all articles by this author Wei Wang Huazhong University of Science and Technology Tongji Medical College Union Hospital View all articles by this author Wanxin Chen 0000-0002-8110-8480 Huazhong University of Science and Technology Tongji Medical College Union Hospital View all articles by this author Lei Li [email protected] Huazhong University of Science and Technology Tongji Medical College Union Hospital View all articles by this author Metrics & Citations Metrics Article Usage 140 views 89 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Haifeng Yin, Doudou Guo, Wei Wang, et al. Accurate Identification of Viral-associated Pathological Hematopoiesis in Infants: Insights from Two Case Studies. Authorea . 21 July 2025. DOI: https://doi.org/10.22541/au.175309042.20050207/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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