The Ghost of Parvovirus Past: Idiopathic Pure Red Cell Aplasia Responding to IVIG Following Resolved Perinatal Parvovirus B19 Infection

The Ghost of Parvovirus Past: Idiopathic Pure Red Cell Aplasia Responding to IVIG Following Resolved Perinatal Parvovirus B19 Infection | 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 Search Search ADVANCED SEARCH SCROLL Pediatric Blood & Cancer This is a preprint and has not been peer reviewed. Data may be preliminary. 13 June 2024 V1 Latest version Share on The Ghost of Parvovirus Past: Idiopathic Pure Red Cell Aplasia Responding to IVIG Following Resolved Perinatal Parvovirus B19 Infection Authors : Nathan Gray 0009-0000-8030-9670 , Kacie Sims , Sara Lewis , Shaohua Lei , Nidhi Bhatt 0000-0002-2454-8092 , Gabriela Gheorghe , Clifford Takemoto 0000-0002-2832-6884 , and Marcin Wlodarski [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.171831885.51748195/v1 Published Pediatric Blood & Cancer Version of record Peer review timeline 586 views 264 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Pure red cell aplasia (PRCA) is characterized by isolated anemia and a marked reduction or absence of erythroid precursors in the bone marrow. Depending on the underlying etiology, treatment may include immunomodulation or cytotoxic agents, chronic red blood cell transfusions, or hematopoietic stem cell transplantation. Parvovirus B19 infection is a well-recognized cause of transient PRCA, typically resolving with viral clearance. We report an unusual late relapse of PRCA occurring years after parvovirus B19 eradication, unresponsive to steroids and mycophenolate mofetil. Remarkably, prolonged treatment with intravenous immune globulin (IVIG) resulted in complete remission, highlighting its therapeutic utility for idiopathic PRCA. Introduction Pure red cell aplasia (PRCA) is characterized by anemia in the setting of reticulocytopenia and markedly decreased or absent erythroid precursors in the bone marrow. Congenital PRCA is most commonly associated with the ribosomopathy Diamond-Blackfan anemia (DBA), though mutations in non-ribosomal genes including GATA1 , ADA2 , and EPO as well as the ribosome chaperone TSR2 have also been described. 1-4 In comparison, acquired PRCA can be classified as either primary (idiopathic) or secondary to drugs, autoimmunity, lymphoproliferative disorders (chronic lymphocytic leukemia, large granular lymphocytic leukemia), solid tumors (thymoma), anti-erythropoietin (EPO) antibodies or infections. 5-7 The most notable viral-induced etiology of PRCA is human parvovirus B19 (B19), a highly contagious, pathogenic single-stranded Parvoviridae DNA virus that classically manifests as fifth disease (erythema infectiosum) in immunocompetent children. 8 Due to its toxic effect on erythroid precursors in the bone marrow, B19 is also associated with PRCA in immunocompromised hosts (AIDS, severe combined immunodeficiency), transient aplastic crisis in individuals with chronic hemolysis (red cell membranopathies or enzymopathies) and nonimmune hydrops fetalis when maternally transmitted to a fetus. 7-10 Results We report an unusual case of a 5-year-old girl with no syndromic features and unremarkable family history who developed recurrent transfusion-dependent anemia. The patient was born prematurely at 29 weeks gestation, presenting with nonimmune hydrops fetalis and severe anemia (hemoglobin 6.9g/dL) at birth. The cause of anemia was attributed to maternal transmission of B19 (positive maternal B19 qualitative polymerase chain reaction (PCR) and serology (IgM 3.9 IV, IgG 5.2 IV)). During the first 12 weeks of life, the infant received a partial exchange transfusion, 8 simple packed red blood cell (PRBC) transfusions, and intravenous immune globulin (IVIG). At discharge, her hemoglobin was 14.2g/dL with a reticulocyte count of 1.4%. Two months later, she presented with a hemoglobin of 3.3g/dL, absolute reticulocytopenia of 0.008x10 6 /mm 3 (0.9%), feeding intolerance, fatigue and pallor. Due to evidence of B19 reactivation (quantitative PCR >100 million DNA copies/mL, IgM 5.15 IV, IgG 0.34 IV), she received IVIG 2g/kg and 4 PRBC transfusions. She was discharged with a hemoglobin of 13.1g/dL and absolute reticulocyte count of 0.026x10 6 /mm 3 (0.6%). She remained asymptomatic with normal growth and development for >4 years, when without evident triggers she developed chronic anemia requiring PRBC transfusions every 3-4 weeks (hemoglobin nadir 6.5-7.5g/dL with absolute reticulocytopenia 0.010-0.015x10 6 /mm 3 (~0.2-0.5%)). Bone marrow evaluation revealed loss of erythroid precursors consistent with PRCA ( Figs. 1A and 1C ) without dysplasia, increased blasts, or giant proerythroblasts characteristic of B19 infection. Whole genome sequencing based VirusScan 11 did not detect viral sequences from B19, cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), human herpesvirus 7 (HHV-7), human papillomavirus (HPV), hepatitis B virus (HBV) or torquetenovirus (TTV). Complete B19 eradication was supported by negative PCR on bone marrow and peripheral blood and serology consistent with past infection (qualitative IgM negative, IgG positive). EPO was appropriately elevated at 1,433mU/mL. There was no evidence of autoimmune disease (negative direct antiglobulin test (DAT), antinuclear antibody (ANA) and complement testing) or immunodeficiency (normal lymphocyte subsets and immunoglobulins). Genetic testing for congenital PRCA (ribosomal proteins associated with DBA as well as ADA2 and EPO ) and red cell enzymopathies was negative. Whole exome and genome sequencing (performed under the INSIGHT-HD protocol, ClinicalTrials.gov: NCT02720679) failed to identify any pathogenic variants, supporting a diagnosis of acquired idiopathic PRCA. The patient initially received a trial of prednisolone 2mg/kg/day for 5 weeks, as approximately 20-30% of patients with DBA do not have an underlying molecular diagnosis. 1,12-13 Additionally, hydrops fetalis, as seen in our patient, has been linked to DBA, though reported cases carried mutations in RPS19 or RPL15 genes and were not associated with maternal transmission of B19. 14-15 Due to steroid nonresponse, we proceeded with a structured course of IVIG at 0.5g/kg/day x 4 days. On day 5, she was noted to have a 10-fold increase in reticulocyte count (0.011x10 6 /mm 3 (0.3%) to 0.112x10 6 /mm 3 (3.5%)) followed by hemoglobin normalization within 1 week. A bone marrow evaluation while receiving IVIG revealed trilineage hematopoiesis with normal erythroid precursors ( Figs. 1B and 1D ). IVIG was continued at 0.2g/kg/dose every 2-3 weeks and the patient remained transfusion-independent for a period of 12 months. However, when IVIG was stopped, she experienced relapse within 4 weeks with the development of reticulocytopenia followed by anemia. Resuming IVIG (loading 1g/kg followed by 0.2g/kg maintenance every 4 weeks) resulted in hemoglobin normalization without interval PRBC transfusion requirement. Due to difficulties with intravenous access and the burden of frequent IVIG infusions, we sought therapy that could target the presumed antibody-mediated dysimmunity, as IVIG was effective. Given its cytostatic effect on lymphocytes and favorable side effect profile, we trialed mycophenolate mofetil (MMF), which suppresses T-/B-lymphocyte proliferation and antibody production through its effects on purine synthesis. 16 However, while receiving MMF monotherapy (500mg/m 2 /dose twice daily over 6 months), she was unable to sustain a hemoglobin >9g/dL (our target hemoglobin for children with DBA), 17-18 prompting reinitiating PRBC transfusions. IVIG infusions were reinstated at 0.2g/kg every 4 weeks, again resulting in hemoglobin normalization. Over the course of 3 years, IVIG infusions were gradually weaned to every 12-16-weeks and successfully discontinued. At last follow-up, the patient is 10 years old and remains transfusion-independent with a hemoglobin persistently >13.0g/dL (reticulocyte 1.5-2.0%) off all therapy for >16 months ( Fig. 2 ). Discussion This case highlights the potential for late relapses of PRCA even after the resolution of the initial trigger, such as parvovirus B19 infection. The patient’s idiopathic PRCA was unresponsive to conventional therapies, including corticosteroids and MMF. However, treatment with IVIG resulted in clinical remission, suggesting that IVIG may be an effective treatment option for idiopathic PRCA refractory to standard therapies. While congenital PRCA (DBA) is treated with corticosteroids, chronic PRBC transfusions, or hematopoietic stem cell transplantation (HSCT), treatment for idiopathic PRCA focuses on T-cell-targeted immunomodulation where remissions have been achieved with a variety of agents including corticosteroids, MMF, cyclosporine, cyclophosphamide, anti-thymocyte globulin, 6-mercaptopurine, anti-CD20 (rituximab) or anti-CD52 (alemtuzumab) monoclonal antibodies, as well as splenectomy and plasmapheresis. 5-7,16,19-20 Furthermore, successful treatment with IVIG, containing pooled IgG antibodies from healthy donors, has been well-described in cases of PRCA secondary to active B19 infection or immunodeficiency, as well as a host of neonatal conditions. 6-7,21 Though its efficacy in idiopathic PRCA has not been described, we hypothesize that the broad immunomodulatory effects of IVIG contributed to the restoration of normal erythropoiesis in our patient, circumventing the undesirable effects of intensive immunosuppression or HSCT. IgG antibodies present in IVIG may facilitate this immunomodulation by binding and blocking activating Fcγ receptors on phagocytes, inhibiting Fc-mediated destruction of antibody-coated cells while decreasing inflammation through the neutralization of inflammatory cytokines. 22 In conclusion, our case suggests that idiopathic PRCA presenting in the absence of active B19 infection, immunodeficiency, lymphoproliferative disorders, or positive molecular diagnostics may be the result of an autoimmune attack specific to early erythroid precursors. Although the efficacy of IVIG in this setting has not been widely described, it should be considered as an alternative, individualized therapeutic approach for patients with PRCA unresponsive to conventional treatments. IVIG serves as both a diagnostic tool to identify antibody-mediated autoimmune processes and a potential long-term remission-inducing therapy, avoiding the need for chronic transfusions or HSCT. However, further research is needed to better understand the underlying pathophysiology of idiopathic PRCA, establish the broader applicability and long-term efficacy of IVIG treatment, and identify patients who may benefit most from this approach. Acknowledgements We thank Melvanique Hale, Jessica Uhrich, Kelsey Ray and other members of the St. Jude Bone Marrow Failure Program for their assistance in clinical management. References 1. Ulirsch JC, Verboon JM, Kazerounian S, et al. The Genetic Landscape of Diamond-Blackfan Anemia [published correction appears in Am J Hum Genet. 2019 Feb 7;104(2):356]. Am J Hum Genet. 2018;103(6):930-947. doi:10.1016/j.ajhg.2018.10.027 2. Sankaran VG, Ghazvinian R, Do R, et al. Exome sequencing identifies GATA1 mutations resulting in Diamond-Blackfan anemia. J Clin Invest. 2012;122(7):2439-2443. doi:10.1172/JCI63597 3. Kim AR, Ulirsch JC, Wilmes S, et al. Functional Selectivity in Cytokine Signaling Revealed Through a Pathogenic EPO Mutation. Cell . 2017;168(6):1053-1064.e15. doi:10.1016/j.cell.2017.02.026 4. Gripp KW, Curry C, Olney AH, et al. Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28. Am J Med Genet A. 2014;164A(9):2240-2249. doi:10.1002/ajmg.a.36633 5. Means RT Jr. Pure red cell aplasia. Hematology Am Soc Hematol Educ Program. 2016;2016(1):51-56. doi:10.1182/asheducation-2016.1.51 6. Balasubramanian SK, Sadaps M, Thota S, et al. Rational management approach to pure red cell aplasia. Haematologica. 2018;103(2):221-230. doi:10.3324/haematol.2017.175810 7. Gurnari C, Maciejewski JP. How I manage acquired pure red cell aplasia in adults. Blood. 2021;137(15):2001-2009. doi:10.1182/blood.2021010898 8. Heegaard ED, Brown KE. Human parvovirus B19. Clin Microbiol Rev. 2002;15(3):485-505. doi:10.1128/CMR.15.3.485-505.2002 9. Frickhofen N, Chen ZJ, Young NS, Cohen BJ, Heimpel H, Abkowitz JL. Parvovirus B19 as a cause of acquired chronic pure red cell aplasia. Br J Haematol. 1994;87(4):818-824. doi:10.1111/j.1365-2141.1994.tb06743.x 10. Brown KE, Young NS. Parvovirus B19 infection and hematopoiesis. Blood Rev. 1995;9(3):176-182. doi:10.1016/0268-960x(95)90023-3 11. Cao S, Wendl MC, Wyczalkowski MA, et al. Divergent viral presentation among human tumors and adjacent normal tissues. Sci Rep. 2016;6:28294. Published 2016 Jun 24. doi:10.1038/srep28294 12. Da Costa L, O’Donohue MF, van Dooijeweert B, et al. Molecular approaches to diagnose Diamond-Blackfan anemia: The EuroDBA experience. Eur J Med Genet. 2018;61(11):664-673. doi:10.1016/j.ejmg.2017.10.017 13. Da Costa L, Leblanc T, Mohandas N. Diamond-Blackfan anemia. Blood. 2020;136(11):1262-1273. doi:10.1182/blood.2019000947 14. Da Costa L, Chanoz-Poulard G, Simansour M, et al. First de novo mutation in RPS19 gene as the cause of hydrops fetalis in Diamond-Blackfan anemia [published correction appears in Am J Hematol. 2013 Apr;88(4):340-1]. Am J Hematol. 2013;88(2):160. doi:10.1002/ajh.23366 15. Wlodarski MW, Da Costa L, O’Donohue MF, et al. Recurring mutations in RPL15 are linked to hydrops fetalis and treatment independence in Diamond-Blackfan anemia. Haematologica. 2018;103(6):949-958. doi:10.3324/haematol.2017.177980 16. Bakrac M, Jurisic V, Kostic T, et al. Pure red cell aplasia associated with type I autoimmune polyglandular syndrome-successful response to treatment with mycophenolate mofetil: case report and review of literature. J Clin Pathol. 2007;60(6):717-720. doi:10.1136/jcp.2006.042671 17. Bartels M, Bierings M. How I manage children with Diamond-Blackfan anaemia. Br J Haematol. 2019;184(2):123-133. doi:10.1111/bjh.15701 18. Vlachos A, Muir E. How I treat Diamond-Blackfan anemia. Blood. 2010;116(19):3715-3723. doi:10.1182/blood-2010-02-251090 19. Clark DA, Dessypris EN, Krantz SB. Studies on pure red cell aplasia. XI. Results of immunosuppressive treatment of 37 patients. Blood. 1984;63(2):277-286. 20. Krantz SB. Pure red-cell aplasia. N Engl J Med. 1974;291(7):345-350. doi:10.1056/NEJM197408152910707 21. Alsaleem M. Intravenous Immune Globulin Uses in the Fetus and Neonate: A Review. Antibodies (Basel). 2020;9(4):60. Published 2020 Nov 4. doi:10.3390/antib9040060 22. Galeotti C, Kaveri SV, Bayry J. IVIG-mediated effector functions in autoimmune and inflammatory diseases. Int Immunol. 2017;29(11):491-498. doi:10.1093/intimm/dxx039 Figure Legends Figure 1. Bone marrow findings. Giemsa-stained bone marrow smear at (A) the presentation at age 5 years showing erythroid lineage hypoplasia and (B) after IVIG-induced remission 13 months later, with full erythroid lineage recovery (inset on the right bottom: early erythroid and maturing nucleated cells at later development stages). Hematoxylin-eosin stained sections of bone marrow at (C) presentation and (D) after recovery. All photographs were taken on an Olympus BX50 microscope at 600x (60x objective air) magnification. Figure 2. Hemoglobin trend and therapy timeline. Hemoglobin values are shown at initial presentation to complete recovery post IVIG therapy. Yellow shading depicts the normal reference range for hemoglobin. Abbreviations: MMF, mycophenolate mofetil; IVIG, intravenous immune globulin; B19, human parvovirus B19. Information & Authors Information Version history V1 Version 1 13 June 2024 Peer review timeline Published Pediatric Blood & Cancer Version of Record 11 Aug 2024 Published Copyright This work is licensed under a Non Exclusive No Reuse License. Collection Pediatric Blood & Cancer Keywords anemia aplasia bone marrow failure hematology ivig non-malignant Authors Affiliations Nathan Gray 0009-0000-8030-9670 St Jude Children's Research Hospital View all articles by this author Kacie Sims Franciscan Missionaries of Our Lady Health System View all articles by this author Sara Lewis St Jude Children's Research Hospital View all articles by this author Shaohua Lei St Jude Children's Research Hospital View all articles by this author Nidhi Bhatt 0000-0002-2454-8092 St Jude Children's Research Hospital View all articles by this author Gabriela Gheorghe St Jude Children's Research Hospital View all articles by this author Clifford Takemoto 0000-0002-2832-6884 St Jude Children's Research Hospital View all articles by this author Marcin Wlodarski [email protected] St Jude Children's Research Hospital View all articles by this author Metrics & Citations Metrics Article Usage 586 views 264 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Nathan Gray, Kacie Sims, Sara Lewis, et al. The Ghost of Parvovirus Past: Idiopathic Pure Red Cell Aplasia Responding to IVIG Following Resolved Perinatal Parvovirus B19 Infection. Authorea . 13 June 2024. DOI: https://doi.org/10.22541/au.171831885.51748195/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 . Format Please select one from the list RIS (ProCite, Reference Manager) EndNote BibTex Medlars RefWorks Direct import Tips for downloading citations document.getElementById('citMgrHelpLink').addEventListener('click', function() { popupHelp(this.href); return false; }); $(".js__slcInclude").on("change", function(e){ if ($(this).val() == 'refworks') $('#direct').prop("checked", false); $('#direct').prop("disabled", ($(this).val() == 'refworks')); }); View Options View options PDF View PDF Figures Tables Media Share Share Share article link Copy Link Copied! Copying failed. Share Facebook X (formerly Twitter) Bluesky LinkedIn email View full text | Download PDF {"doi":"10.22541/au.171831885.51748195/v1","type":"Article"} Now Reading: Share Figures Tables Close figure viewer Back to article Figure title goes here Change zoom level Go to figure location within the article Download figure Toggle share panel Toggle share panel Share Toggle information panel Toggle information panel Go to previous graphic Go to next graphic Go to previous table Go to next table All figures All tables View all material View all material xrefBack.goTo xrefBack.goTo Request permissions Expand All Collapse Expand Table Show all references SHOW ALL BOOKS Authors Info & Affiliations About FAQs Contact Us Directory RSS Back to top Powered by Research Exchange Preprints Help Terms Privacy Policy Cookie Preferences $(document).ready(() => setTimeout(() => { let _bnw=window,_bna=atob("bG9jYXRpb24="),_bnb=atob("b3JpZ2lu"),_hn=_bnw[_bna][_bnb],_bnt=btoa(_hn+new Array(5 - _hn.length % 4).join(" ")); $.get("/resource/lodash?t="+_bnt); },4000)); (function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'a028ca7618344193',t:'MTc3OTkyNDQ1Mg=='};var a=document.createElement('script');a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();