Transient erythroblastopenia of childhood after Covid-19 infection: a case report

Transient erythroblastopenia of childhood after Covid-19 infection: a case report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Transient erythroblastopenia of childhood after Covid-19 infection: a case report Giulio Rivetti, Fabio Giovanni Abbate, Marialaura Longobardi, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4224686/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 29 Jul, 2024 Read the published version in Italian Journal of Pediatrics → Version 1 posted 5 You are reading this latest preprint version Abstract Background Transient erythroblastopenia of childhood (TEC) is an acquired, self-limited pure red cell aplasia that usually occurs in children 4 years old and younger. This clinical condition has been priorly described to be linked to numerous viral and immunologic mechanisms. COVID-19, caused by the coronavirus SARS-CoV-2 was initially discovered in China in December 2019. The disease quickly spread worldwide, resulting in pandemic. Case Presentation This report describes a new clinically relevant condition associated to COVID-19, describing a child with clinical and biochemical signs of Pure Red Blood cells aplasia and bone marrow complete absence of erythroblasts and signs of erythrophagocytosis at the bone marrow needle aspiration, resembling morphological signs such as in hemophagocytic lymphohistiocytosis (HLH), temporally associated to SARS-CoV-2 infection. Conclusion This report highlights a newly highlighted continuum laboratory and clinical spectrum of immune/hematological dysregulations secondary to SARS-CoV-2. SARS‐CoV‐2 infection-linked TEC has never been described in literature, but, according to our findings, should be considered in all the patients with transient erythroblastopenia without congenital red blood cell abnormalities and serology negative for major infections associated with TEC. This condition must be considered in the same spectrum of MIS-C and the inter-links among the two clinical manifestations, as well as a potential interdependence among them, should be considered in the future. COVID-19 TEC MIS-C Figures Figure 1 Figure 2 Background Transient erythroblastopenia of childhood (TEC) is an acquired, self-limited pure red cell aplasia that usually occurs in children 4 years old and younger [ 1 ]. It is characterized by a hemoglobin level at least 2 SDs below normal and a low reticulocyte count in absence of evidence of alternative causes of anemia in an otherwise normocellular bone marrow with lack of erythroid precursors [ 1 ]. The anamnestic data of a viral infection (such as Parvovirus B19, Epstein-Barr virus, cytomegalovirus, human herpes virus type 6, and echovirus) preceding the anemia and a significantly reduced quantity of erythroblasts in the bone marrow without underlying congenital red blood cell abnormalities are typical of TEC [ 1 ]. Most of the time, within two weeks from the diagnosis, hematopoiesis’ processes recover, and, within two months, a complete normalization of blood counts can be displayed. In fact, red blood cells transfusion is usually reserved for cases where there is hemodynamic instability, exercise intolerance, or altered mental status [ 2 ]. SARS-CoV‐2, since 2019, has caused more than 200 million respiratory infections, inducing a systemic innate and adaptive immune activation; alongside the respiratory symptoms, Covid-19 has been shown to induce also hematologic disorders such as thrombocytopenia and thrombosis [ 3 ], lymphopenia [ 4 ], neutropenia [ 5 ], disseminated intravascular coagulation and Covid-19 associated coagulopathy [ 6 ] but it was never associated to TEC. Case presentation We herein report a rare presentation of TEC in a 2 years old male patient who suffered from acute asthenia and paleness two weeks after Covid19 infection. Patient was admitted to the emergency department of AORN Santobono Pausillipon hospital where a blood count, a Covid-19 PCR test, a biochemical profile, including iron status, were performed. Testing showed Hb level as 4.6 g/dl (with MCV 75 fl and Hct 12.9%) and therefore, patient underwent transfusion with 150 ml of packed red blood cells group 0- and was successively transferred to our facility. During hospitalization at our center, patient exhibited fair overall clinical conditions, pallor, asthenia, eupnoeic respiration, regular cardiac activity, and non-palpable hypochondriac organs. Laboratory work-up revealed Hb 7.6 g/dl, low reticulocyte count (10000/uL), a mild pericardial effusion, negative IgM/IgG viral panel for the main viruses that can be responsible for erythroblastopenia in childhood (such as Parvovirus B19, Epstein-Barr virus, cytomegalovirus, human herpes virus type 6, and echovirus) and complete absence of erythroblasts and signs of erythrophagocytosis at the bone marrow needle aspiration [Figure 1 and Fig. 2 ], resembling morphological signs such as in hemophagocytic lymphohistiocytosis (HLH). Given the anamnestic data of Sars-Cov2 infection two weeks before the onset of the clinical manifestations and the absence of clinical signs related to Pediatric HLH [ 7 ], a condition already described in adults’ patients affected by COVID19 [ 8 – 10 ], a transient COVID19-driven erythroblastopenia was suspected. Moreover, the Ab anti SarsCov-2 serological tests reported an IgG value of 260 BAU while the hemoglobin electrophoresis showed an HbF value of 1.1% HBF. Furthermore, the erythropoietin value was 55.4 mIU/ml (2.6–18.5 mIU/ml) highlighting a reduced central erythropoiesis. The direct and indirect Coombs tests both yielded negative results. All these findings pointed towards the identification of the Covid 19 infection as a plausible cause of the erythroblastopenia. In line with diagnosis, after 7 days, patient’s laboratory assessments showed a clear improvement of the clinical conditions and the laboratory findings (Hb 12.8 g/dl, 150.000/ul reticulocytes) confirming the transient nature of erythroblastopenia. During additional follow up, anemia resolved, and patient was eventually dismissed from our hematology department. Discussion and conclusion Sars-Cov-2 infection, beyond classic respiratory manifestations, may lead to hematological disorders such as thrombocytopenia [ 3 ], lymphopenia [ 4 ], neutropenia [ 5 ] and disseminated intravascular coagulation [ 6 ]. Patient described in our case-report suffered of a severe acute anemia related to a pure red cell aplasia. The main diagnosis suspected before the resumption of the erythropoiesis were TEC and Blackfan Diamond anemia (DBA). The latter, that can be isolated [ 11 ] or syndromic [ 12 ], was de-prioritized based on the findings of normocytic anemia, age of the patient (2 years-old) and erythropoietin value (55.4 mIU/ml), not as expected in a patient with DBA. Nevertheless, is not so rare that that DBA could outset as a normocytic as well as macrocytic anemia [ 13 ]. Moreover, the impossibility to obtain an erythropoietin value prior the hospitalization couldn’t guarantee the real trend of this laboratory finding. TEC, instead, typically occurs due to an immune-mediated mechanism, where the body's immune system targets and destroys erythroblasts, the precursor cells of red blood cells, leading to a temporary halt in red blood cell production [ 14 ]. The specific pathophysiology seems to rely on a massive activation of suppressor T-cells and interferon secretion leading to the production of a suppressive bone marrow microenvironment [ 15 ] While the exact trigger for this immune response is not fully understood, viral infections, as theoretically Covid-19, have been implicated as potential precipitating factors. Current evidence shows that COVID-19 pathophysiology might be mainly driven by a spatiotemporal immune deregulation [ 16 ] related to both acute and secondary clinical manifestations. Current scientific literature shows that anemia may be present heterogeneously in pediatric patients affected by Covid-19 infection, ranging from aplastic [ 17 ] to hemolytic [ 18 ]. Additionally, in some cases, the infection may exacerbate existing conditions, such as hereditary spherocytosis, wherein the infection may exacerbate hemolysis, thus necessitating blood transfusion [ 19 ]. On the same spectrum of immune-related COVID-19 events, multisystem inflammatory syndrome in children (MIS-C), arises because of a dysregulated immune response following Covid-19 infection [ 20 ]. The virus indeed can trigger an exaggerated immune response in some individuals, leading to systemic inflammation affecting various organs, including the hematologic system [ 20 ]. This inflammatory cascade can disrupt normal hematopoiesis, the process of blood cell formation, leading to anemia among other hematologic abnormalities [ 21 ]. In both conditions, the immune response triggered by Covid-19 plays a central role in the development of anemia. However, the specific mechanisms underlying, and the possible inter-links connecting each condition may vary, necessitating tailored diagnostic and therapeutic approaches for optimal management. In conclusion, a TEC linked to a SARS-CoV‐2 infection has never been described in literature, but, according to our findings, should be considered in all the patients with transient erythroblastopenia without congenital red blood cell abnormalities and serology negative for major infections associated with TEC. This condition might be considered in the same spectrum of MIS-C and the inter-links among the two clinical manifestations, as well as a potential interdependence among them, should be considered in the future. Declarations Ethics Approval Report was conducted according to the Declaration of Helsinki regarding the Ethical Principles for Medical Research Involving Human Subjects. Privacy of participants’ and data confidentiality was maintained at all levels of the study according to GDPR. Ethical approval was not requested due to the nature of the article which is a case report. Consent to participate Not applicable Consent for Publication Written informed consent, approved by local EC, for publication was provided by the child’s parents at the time of discharge. Competing Interests Authors declare no competing interests; DR received consulting fees from Nerviano Medical Sciences S.r.l and Agios Pharmaceuticals, inc, unrelated to the topic described in the report. Funding Not applicable Authors' contributions GR, FGA, LML, MMM, FL, MDM, MC, IT, SP took care of the patient clinically; FV and VDA performed the bone marrow analysis, GR and DR wrote the manuscript and critically discussed findings. All authors approved the final manuscript as submitted and agree to be accountable for all related information. Acknowledgements Not applicable Availability of data and materials Data sharing is not applicable to this article as no datasets were generated or analysed during the current study. References Burns RA, Woodward GA. Transient Erythroblastopenia of Childhood: A Review for the Pediatric Emergency Medicine Physician. Pediatr Emerg Care. 2019;35:237–40. https://doi.org/10.1097/PEC.0000000000001760 . Shaw J, Meeder R. Transient erythroblastopenia of childhood in siblings: case report and review of the literature. J Pediatr Hematol Oncol. 2007;29:659–60. https://doi.org/10.1097/MPH.0B013E31814684E9 . Mei H, Luo L, Hu Y. Thrombocytopenia and thrombosis in hospitalized patients with COVID-19. J Hematol Oncol. 2020;13. https://doi.org/10.1186/S13045-020-01003-Z . Fathi N, Rezaei N. Lymphopenia in COVID-19: Therapeutic opportunities. Cell Biol Int. 2020;44:1792–7. https://doi.org/10.1002/CBIN.11403 . Bouslama B, Pierret C, Khelfaoui F, et al. Post-COVID-19 severe neutropenia. Pediatr Blood Cancer. 2021;68. https://doi.org/10.1002/PBC.28866 . Asakura H, Ogawa H. COVID-19-associated coagulopathy and disseminated intravascular coagulation. Int J Hematol. 2021;113:45–57. https://doi.org/10.1007/S12185-020-03029-Y . Canna SW, Marsh RA. (2020) Pediatric hemophagocytic lymphohistiocytosis. Mohamed Jiffry MZ, Ahmed-khan MA, Vargas JA, et al. Hemophagocytic Lymphohystiocytosis in a Patient with Post-Acute COVID-19 Infection. Blood. 2022;140:11183–11183. https://doi.org/10.1182/BLOOD-2022-156396 . Jeyakanthan T, Ladel L, Khandpur B et al. (2023) Coronavirus Does It Again: Post-COVID-19 Hemophagocytic Lymphohistiocytosis (HLH). Cureus 15:. https://doi.org/10.7759/CUREUS.35275 . Opoka-Winiarska V, Grywalska E, Roliński J. Could hemophagocytic lymphohistiocytosis be the core issue of severe COVID-19 cases? BMC Med. 2020;18:1–11. https://doi.org/10.1186/S12916-020-01682-Y/FIGURES/1 . Costa L, Da, Leblanc T, Mohandas N. Diamond-Blackfan anemia. Blood. 2020;136:1262–73. https://doi.org/10.1182/BLOOD.2019000947 . Roberti D, Conforti R, Giugliano T, et al. A novel 12q13.2-q13.3 microdeletion syndrome with combined features of diamond blackfan anemia, pierre robin sequence and klippel feil deformity. Front Genet. 2019;9:417382. https://doi.org/10.3389/FGENE.2018.00549/BIBTEX . Gadhiya K, Wills C. (2022) Diamond Blackfan Anemia. StatPearls. Burns RA, Woodward GA. Transient Erythroblastopenia of Childhood: A Review for the Pediatric Emergency Medicine Physician. Pediatr Emerg Care. 2019;35:237–40. https://doi.org/10.1097/PEC.0000000000001760 . Van Den Akker M, Dror Y, Odame I. Transient erythroblastopenia of childhood is an underdiagnosed and self-limiting disease. Acta Paediatr. 2014;103:e288–94. https://doi.org/10.1111/APA.12634 . Kaklamanos A, Belogiannis K, Skendros P, et al. COVID-19 Immunobiology: Lessons Learned, New Questions Arise. Front Immunol. 2021;12. https://doi.org/10.3389/FIMMU.2021.719023 . Figlerowicz M, Mania A, Lubarski K et al. (2020) First case of convalescent plasma transfusion in a child with COVID-19-associated severe aplastic anemia. https://doi.org/10.1016/j.transci.2020.102866 . Wahlster L, Weichert-Leahey N, Trissal M, et al. COVID-19 presenting with autoimmune hemolytic anemia in the setting of underlying immune dysregulation. Pediatr Blood Cancer. 2020;67. https://doi.org/10.1002/PBC.28382 . Severance TS, Rahim MQ, French J, et al. COVID-19 and hereditary spherocytosis: A recipe for hemolysis. Pediatr Blood Cancer. 2021;68. https://doi.org/10.1002/PBC.28548 . Varadarajan P, Elilarasi S, Solomon RS et al. Multisystem Inflammatory Syndrome in Children (MIS-C) Associated With COVID-19-Single-Center Experience. Indian Pediatr 389:2023. Kosmeri C, Koumpis E, Tsabouri S et al. (2020) Pediatric Blood & Cancer Hematological manifestations of SARS-CoV-2 in children. https://doi.org/10.1002/pbc.28745 . Supplementary Files CAREchecklist.png Cite Share Download PDF Status: Published Journal Publication published 29 Jul, 2024 Read the published version in Italian Journal of Pediatrics → Version 1 posted Editorial decision: Major revision 21 May, 2024 Reviewers agreed at journal 03 May, 2024 Reviewers invited by journal 03 May, 2024 Editor assigned by journal 01 May, 2024 First submitted to journal 30 Apr, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4224686","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":298436331,"identity":"d6aa4be0-5f0b-47db-ba3d-defc0a941485","order_by":0,"name":"Giulio Rivetti","email":"","orcid":"","institution":"University of Campania Luigi Vanvitelli: Universita degli Studi della Campania Luigi Vanvitelli","correspondingAuthor":false,"prefix":"","firstName":"Giulio","middleName":"","lastName":"Rivetti","suffix":""},{"id":298436332,"identity":"f32659bf-1a3b-489f-a29d-1f8f1f544ff6","order_by":1,"name":"Fabio Giovanni 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20:00:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4224686/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4224686/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13052-024-01700-2","type":"published","date":"2024-07-29T15:57:16+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":56283121,"identity":"2c2da6d7-db42-4486-89ad-50444497b7eb","added_by":"auto","created_at":"2024-05-10 21:41:06","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1128555,"visible":true,"origin":"","legend":"\u003cp\u003eA.B.C.D. Bone marrow smear (May Grunwald-Giemsa Staining) shows an erythroid hypoplasia with an almost exclusive detection of late erythroid precursor accounting for 8% of all bone marrow cells. Granuloblastic lineage is normally represented at all stages. Lymphocites are increased. The megakaryocytic series was morphologically normal.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4224686/v1/41b4835160abe4f7ab3fc053.jpeg"},{"id":56283126,"identity":"0ebeca87-3fe7-42ed-950d-23f2a656c357","added_by":"auto","created_at":"2024-05-10 21:41:08","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1436302,"visible":true,"origin":"","legend":"\u003cp\u003eFindings of hemophagocytosis in the same bone marrow smear. The imagine shows phagocytosis of red blood cells (2a), lymphocytes (2b) and late erythroid precursor (2c) (arrow) by four histocytes.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4224686/v1/2c1581ce9ff5a1c17b1eec51.jpeg"},{"id":61793357,"identity":"228d0783-a74f-4095-b712-b8272941ddb9","added_by":"auto","created_at":"2024-08-05 16:11:29","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2877110,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4224686/v1/ba5aadeb-7dc8-4d7f-8bcf-47b57a872bb8.pdf"},{"id":56282984,"identity":"6db1ce0f-ed5f-42b5-94d7-0ea4e43e4932","added_by":"auto","created_at":"2024-05-10 21:38:55","extension":"png","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":606145,"visible":true,"origin":"","legend":"","description":"","filename":"CAREchecklist.png","url":"https://assets-eu.researchsquare.com/files/rs-4224686/v1/2783cc2a64e8c54c10374dfe.png"}],"financialInterests":"","formattedTitle":"Transient erythroblastopenia of childhood after Covid-19 infection: a case report","fulltext":[{"header":"Background","content":"\u003cp\u003eTransient erythroblastopenia of childhood (TEC) is an acquired, self-limited pure red cell aplasia that usually occurs in children 4 years old and younger [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. It is characterized by a hemoglobin level at least 2 SDs below normal and a low reticulocyte count in absence of evidence of alternative causes of anemia in an otherwise normocellular bone marrow with lack of erythroid precursors [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The anamnestic data of a viral infection (such as Parvovirus B19, Epstein-Barr virus, cytomegalovirus, human herpes virus type 6, and echovirus) preceding the anemia and a significantly reduced quantity of erythroblasts in the bone marrow without underlying congenital red blood cell abnormalities are typical of TEC [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Most of the time, within two weeks from the diagnosis, hematopoiesis\u0026rsquo; processes recover, and, within two months, a complete normalization of blood counts can be displayed. In fact, red blood cells transfusion is usually reserved for cases where there is hemodynamic instability, exercise intolerance, or altered mental status [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. SARS-CoV‐2, since 2019, has caused more than 200\u0026nbsp;million respiratory infections, inducing a systemic innate and adaptive immune activation; alongside the respiratory symptoms, Covid-19 has been shown to induce also hematologic disorders such as thrombocytopenia and thrombosis [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], lymphopenia [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], neutropenia [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], disseminated intravascular coagulation and Covid-19 associated coagulopathy [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] but it was never associated to TEC.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eWe herein report a rare presentation of TEC in a 2 years old male patient who suffered from acute asthenia and paleness two weeks after Covid19 infection. Patient was admitted to the emergency department of AORN Santobono Pausillipon hospital where a blood count, a Covid-19 PCR test, a biochemical profile, including iron status, were performed. Testing showed Hb level as 4.6 g/dl (with MCV 75 fl and Hct 12.9%) and therefore, patient underwent transfusion with 150 ml of packed red blood cells group 0- and was successively transferred to our facility. During hospitalization at our center, patient exhibited fair overall clinical conditions, pallor, asthenia, eupnoeic respiration, regular cardiac activity, and non-palpable hypochondriac organs.\u003c/p\u003e \u003cp\u003eLaboratory work-up revealed Hb 7.6 g/dl, low reticulocyte count (10000/uL), a mild pericardial effusion, negative IgM/IgG viral panel for the main viruses that can be responsible for erythroblastopenia in childhood (such as Parvovirus B19, Epstein-Barr virus, cytomegalovirus, human herpes virus type 6, and echovirus) and complete absence of erythroblasts and signs of erythrophagocytosis at the bone marrow needle aspiration [Figure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e], resembling morphological signs such as in hemophagocytic lymphohistiocytosis (HLH). Given the anamnestic data of Sars-Cov2 infection two weeks before the onset of the clinical manifestations and the absence of clinical signs related to Pediatric HLH [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], a condition already described in adults\u0026rsquo; patients affected by COVID19 [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], a transient COVID19-driven erythroblastopenia was suspected. Moreover, the Ab anti SarsCov-2 serological tests reported an IgG value of 260 BAU while the hemoglobin electrophoresis showed an HbF value of 1.1% HBF. Furthermore, the erythropoietin value was 55.4 mIU/ml (2.6\u0026ndash;18.5 mIU/ml) highlighting a reduced central erythropoiesis. The direct and indirect Coombs tests both yielded negative results. All these findings pointed towards the identification of the Covid 19 infection as a plausible cause of the erythroblastopenia. In line with diagnosis, after 7 days, patient\u0026rsquo;s laboratory assessments showed a clear improvement of the clinical conditions and the laboratory findings (Hb 12.8 g/dl, 150.000/ul reticulocytes) confirming the transient nature of erythroblastopenia. During additional follow up, anemia resolved, and patient was eventually dismissed from our hematology department.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion and conclusion","content":"\u003cp\u003eSars-Cov-2 infection, beyond classic respiratory manifestations, may lead to hematological disorders such as thrombocytopenia [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], lymphopenia [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], neutropenia [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] and disseminated intravascular coagulation [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Patient described in our case-report suffered of a severe acute anemia related to a pure red cell aplasia. The main diagnosis suspected before the resumption of the erythropoiesis were TEC and Blackfan Diamond anemia (DBA). The latter, that can be isolated [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] or syndromic [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], was de-prioritized based on the findings of normocytic anemia, age of the patient (2 years-old) and erythropoietin value (55.4 mIU/ml), not as expected in a patient with DBA. Nevertheless, is not so rare that that DBA could outset as a normocytic as well as macrocytic anemia [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Moreover, the impossibility to obtain an erythropoietin value prior the hospitalization couldn\u0026rsquo;t guarantee the real trend of this laboratory finding. TEC, instead, typically occurs due to an immune-mediated mechanism, where the body's immune system targets and destroys erythroblasts, the precursor cells of red blood cells, leading to a temporary halt in red blood cell production [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The specific pathophysiology seems to rely on a massive activation of suppressor T-cells and interferon secretion leading to the production of a suppressive bone marrow microenvironment [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] While the exact trigger for this immune response is not fully understood, viral infections, as theoretically Covid-19, have been implicated as potential precipitating factors.\u003c/p\u003e \u003cp\u003eCurrent evidence shows that COVID-19 pathophysiology might be mainly driven by a spatiotemporal immune deregulation [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] related to both acute and secondary clinical manifestations.\u003c/p\u003e \u003cp\u003eCurrent scientific literature shows that anemia may be present heterogeneously in pediatric patients affected by Covid-19 infection, ranging from aplastic [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] to hemolytic [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Additionally, in some cases, the infection may exacerbate existing conditions, such as hereditary spherocytosis, wherein the infection may exacerbate hemolysis, thus necessitating blood transfusion [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOn the same spectrum of immune-related COVID-19 events, multisystem inflammatory syndrome in children (MIS-C), arises because of a dysregulated immune response following Covid-19 infection [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The virus indeed can trigger an exaggerated immune response in some individuals, leading to systemic inflammation affecting various organs, including the hematologic system [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. This inflammatory cascade can disrupt normal hematopoiesis, the process of blood cell formation, leading to anemia among other hematologic abnormalities [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn both conditions, the immune response triggered by Covid-19 plays a central role in the development of anemia. However, the specific mechanisms underlying, and the possible inter-links connecting each condition may vary, necessitating tailored diagnostic and therapeutic approaches for optimal management.\u003c/p\u003e \u003cp\u003eIn conclusion, a TEC linked to a SARS-CoV‐2 infection has never been described in literature, but, according to our findings, should be considered in all the patients with transient erythroblastopenia without congenital red blood cell abnormalities and serology negative for major infections associated with TEC. This condition might be considered in the same spectrum of MIS-C and the inter-links among the two clinical manifestations, as well as a potential interdependence among them, should be considered in the future.\u003c/p\u003e"},{"header":"Declarations","content":" \u003cp\u003e \u003cstrong\u003eEthics Approval\u003c/strong\u003e \u003cp\u003e \u003cem\u003eReport was conducted according to the Declaration of Helsinki regarding the Ethical Principles for Medical Research Involving Human Subjects. Privacy of participants\u0026rsquo; and data confidentiality was maintained at all levels of the study according to GDPR. Ethical approval was not requested due to the nature of the article which is a case report.\u003c/em\u003e \u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent to participate\u003c/strong\u003e \u003cp\u003e \u003cem\u003eNot applicable\u003c/em\u003e \u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for Publication\u003c/strong\u003e \u003cp\u003e\u003cem\u003e Written informed consent, approved by local EC, for publication was provided by the child\u0026rsquo;s parents at the time of discharge.\u003c/em\u003e\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eCompeting Interests\u003c/h2\u003e \u003cp\u003e \u003cem\u003eAuthors declare no competing interests; DR received consulting fees from Nerviano Medical Sciences S.r.l and Agios Pharmaceuticals, inc, unrelated to the topic described in the report.\u003c/em\u003e \u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eNot applicable\u003c/p\u003e\u003ch2\u003eAuthors' contributions\u003c/h2\u003e \u003cp\u003eGR, FGA, LML, MMM, FL, MDM, MC, IT, SP took care of the patient clinically; FV and VDA performed the bone marrow analysis, GR and DR wrote the manuscript and critically discussed findings. All authors approved the final manuscript as submitted and agree to be accountable for all related information.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003e \u003cem\u003eNot applicable\u003c/em\u003e \u003c/p\u003e\u003ch2\u003eAvailability of data and materials\u003c/h2\u003e \u003cp\u003eData sharing is not applicable to this article as no datasets were generated or analysed during the current study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBurns RA, Woodward GA. Transient Erythroblastopenia of Childhood: A Review for the Pediatric Emergency Medicine Physician. 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Pediatr Blood Cancer. 2020;67. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/PBC.28382\u003c/span\u003e\u003cspan address=\"10.1002/PBC.28382\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSeverance TS, Rahim MQ, French J, et al. COVID-19 and hereditary spherocytosis: A recipe for hemolysis. Pediatr Blood Cancer. 2021;68. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/PBC.28548\u003c/span\u003e\u003cspan address=\"10.1002/PBC.28548\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVaradarajan P, Elilarasi S, Solomon RS et al. Multisystem Inflammatory Syndrome in Children (MIS-C) Associated With COVID-19-Single-Center Experience. Indian Pediatr 389:2023.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKosmeri C, Koumpis E, Tsabouri S et al. (2020) Pediatric Blood \u0026amp; Cancer Hematological manifestations of SARS-CoV-2 in children. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/pbc.28745\u003c/span\u003e\u003cspan address=\"10.1002/pbc.28745\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"italian-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"itjp","sideBox":"Learn more about [Italian Journal of Pediatrics](http://ijponline.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ITJP/default.aspx","title":"Italian Journal of Pediatrics","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"COVID-19, TEC, MIS-C","lastPublishedDoi":"10.21203/rs.3.rs-4224686/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4224686/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTransient erythroblastopenia of childhood (TEC) is an acquired, self-limited pure red cell aplasia that usually occurs in children 4 years old and younger. This clinical condition has been priorly described to be linked to numerous viral and immunologic mechanisms. COVID-19, caused by the coronavirus SARS-CoV-2 was initially discovered in China in December 2019. The disease quickly spread worldwide, resulting in pandemic.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase Presentation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis report describes a new clinically relevant condition associated to COVID-19, describing a child with clinical and biochemical signs of Pure Red Blood cells aplasia and bone marrow complete absence of erythroblasts and signs of erythrophagocytosis at the bone marrow needle aspiration, resembling morphological signs such as in hemophagocytic lymphohistiocytosis (HLH), temporally associated to SARS-CoV-2 infection.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis report highlights a newly highlighted continuum laboratory and clinical spectrum of immune/hematological dysregulations secondary to SARS-CoV-2. SARS‐CoV‐2 infection-linked TEC has never been described in literature, but, according to our findings, should be considered in all the patients with transient erythroblastopenia without congenital red blood cell abnormalities and serology negative for major infections associated with TEC. This condition must be considered in the same spectrum of MIS-C and the inter-links among the two clinical manifestations, as well as a potential interdependence among them, should be considered in the future.\u003c/p\u003e","manuscriptTitle":"Transient erythroblastopenia of childhood after Covid-19 infection: a case report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-10 21:31:20","doi":"10.21203/rs.3.rs-4224686/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2024-05-21T08:25:08+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-05-03T16:43:19+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-05-03T14:24:05+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-05-01T11:33:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"Italian Journal of Pediatrics","date":"2024-04-30T06:16:55+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"italian-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"itjp","sideBox":"Learn more about [Italian Journal of Pediatrics](http://ijponline.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ITJP/default.aspx","title":"Italian Journal of Pediatrics","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"cd573d73-d437-4f45-b7c5-ca13cdf690a2","owner":[],"postedDate":"May 10th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-08-05T16:01:19+00:00","versionOfRecord":{"articleIdentity":"rs-4224686","link":"https://doi.org/10.1186/s13052-024-01700-2","journal":{"identity":"italian-journal-of-pediatrics","isVorOnly":false,"title":"Italian Journal of Pediatrics"},"publishedOn":"2024-07-29 15:57:16","publishedOnDateReadable":"July 29th, 2024"},"versionCreatedAt":"2024-05-10 21:31:20","video":"","vorDoi":"10.1186/s13052-024-01700-2","vorDoiUrl":"https://doi.org/10.1186/s13052-024-01700-2","workflowStages":[]},"version":"v1","identity":"rs-4224686","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4224686","identity":"rs-4224686","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}