Pernicious Anemia Following ChAdOx1 nCoV-19 Vaccination in a Previously Healthy Adult: A Case Report

Pernicious Anemia Following ChAdOx1 nCoV-19 Vaccination in a Previously Healthy Adult: 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 Case Report Pernicious Anemia Following ChAdOx1 nCoV-19 Vaccination in a Previously Healthy Adult: A Case Report Mahnaz Danesh, Pari Hashemi², Sobhan Parvizi³, Sayyideh Forough Hosseini This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8874389/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 8 You are reading this latest preprint version Abstract Background: COVID-19 vaccines have demonstrated a favorable safety profile and have been critical in reducing morbidity and mortality from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although most adverse events are mild and self-limited, rare immune-mediated conditions temporally associated with vaccination have been reported. Pernicious anemia (PA) is an autoimmune disorder characterized by vitamin B₁₂ malabsorption due to antibodies against intrinsic factor (IF) and is infrequently described in this context. We report a case of symptomatic vitamin B₁₂ deficiency due to PA occurring shortly after ChAdOx1 nCoV-19 (AstraZeneca) COVID-19 vaccination. Case Presentation: A 39-year-old previously healthy woman developed progressive fatigue, light-headedness, and exertional dyspnea three weeks after receiving her second dose of the ChAdOx1 nCoV-19 (AstraZeneca) COVID-19 vaccine. Laboratory investigations revealed macrocytic anemia (hemoglobin 100 g/L; mean corpuscular volume [MCV] 111 fL), severe vitamin B₁₂ deficiency (90 pmol/L), and markedly elevated lactate dehydrogenase (LDH). Anti-intrinsic factor (IF) antibodies were positive. Upper gastrointestinal endoscopy demonstrated fundic atrophic gastritis, and bone marrow examination confirmed megaloblastic erythropoiesis. The patient was treated with intramuscular hydroxocobalamin, resulting in complete clinical and hematologic recovery during follow-up. Conclusion: This case describes Pernicious anemia (PA) presenting in close temporal association with COVID-19 vaccination in a previously healthy individual. Although causality cannot be established, the temporal relationship raises the possibility of immune activation contributing to disease onset. Early recognition and prompt vitamin B₁₂ replacement led to full recovery and may prevent irreversible neurologic complications. Pernicious Anemia (PA) Vitamin B12 Deficiency ChAdOx1 nCoV-19 Vaccine (AstraZeneca) Autoimmune Gastritis Figures Figure 1 Introduction Pernicious anemia (PA) is a classical autoimmune disorder characterized by vitamin B₁₂ deficiency resulting from impaired intestinal absorption due to antibodies directed against intrinsic factor (IF) or gastric parietal cells ( 1 , 2 ). The condition leads to ineffective erythropoiesis and may manifest with macrocytic anemia, cytopenia, and neurologic complications, including subacute combined degeneration of the spinal cord ( 3 ). PA typically develops insidiously over months to years and is traditionally regarded as a lifelong condition requiring ongoing vitamin B₁₂ replacement therapy ( 4 ). Early recognition is critical, as delayed diagnosis may result in irreversible neurologic injury ( 5 ). Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been central to mitigating the global burden of COVID-19. Several vaccine platforms have been developed, including messenger ribonucleic acid (mRNA)–based vaccines and adenoviral vector–based vaccines such as ChAdOx1 nCoV-19 (AstraZeneca), which have demonstrated favorable safety and efficacy profiles in large, randomized trials and real-world studies ( 6 – 8 ). The majority of reported adverse effects are mild and self-limited; however, rare immune-mediated complications temporally associated with vaccination have been described, including immune thrombocytopenia, Guillain–Barré syndrome, autoimmune hepatitis, and thrombosis with thrombocytopenia syndrome ( 9 – 12 ). Although uncommon, immune-mediated hematologic disorders temporally associated with vaccination have been reported. Proposed mechanisms include immune activation leading to molecular mimicry, epitope spreading, or bystander activation of autoreactive lymphocytes in susceptible individuals ( 13 , 14 ). While autoimmune hemolytic anemia and immune thrombocytopenia have been described more frequently, vitamin B₁₂ deficiency syndromes and PA occurring in close temporal association with COVID-19 vaccination remain rare, with only a limited number of cases reported in the literature to date ( 15 , 16 ). Whether such presentations represent vaccine-triggered autoimmune phenomena or the unmasking of previously subclinical autoimmune disease remains uncertain. Here, we report a rare case of newly diagnosed PA presenting within three weeks of administration of the ChAdOx1 nCoV-19 vaccine in a previously healthy adult with no identifiable gastrointestinal, dietary, or autoimmune risk factors. The clinical presentation, diagnostic findings, and subsequent course raise the possibility of a transient immune-mediated process temporally associated with vaccination and contribute to the growing literature on rare autoimmune hematologic phenomena following immunization. Case Presentation A 39-year-old Caucasian female with no significant past medical history presented with progressive fatigue, dizziness, particularly on standing, and exertional dyspnea. She denied fever, weight loss, gastrointestinal bleeding, neurological complaints, or recent infections. The patient followed an omnivorous diet, did not smoke, and consumed alcohol only occasionally. Notably, she had received the second dose of the ChAdOx1 nCoV-19 vaccine 21 days before the onset of symptoms. She was not taking any medications except for a low-dose folic acid supplement (1 mg daily) for pre-pregnancy planning. On examination, the patient appeared pale but was alert and hemodynamically stable. Vital signs demonstrated mild tachycardia (heart rate 102 beats/min) with normal blood pressure (110/70 mmHg) and afebrile temperature. Conjunctival pallor was present without scleral icterus. Cardiovascular, respiratory, abdominal, and neurological examinations were otherwise unremarkable. No lymphadenopathy or hepatosplenomegaly was identified. Initial laboratory testing revealed macrocytic anemia with associated mild leukopenia and thrombocytopenia (Table 1 ). The reticulocyte count was inappropriately low for the degree of anemia. Serum vitamin B₁₂ was markedly reduced, while folate and iron indices were within normal limits. Functional markers of vitamin B₁₂ deficiency were elevated, with increased methylmalonic acid (MMA) and homocysteine levels, supporting a diagnosis of true cellular vitamin B₁₂ deficiency. LDH was markedly elevated, while total bilirubin remained within the reference range, arguing against overt hemolysis. Serologic testing demonstrated the presence of anti-IF antibodies, with borderline positivity for anti–parietal cell antibodies, supporting an autoimmune etiology. Table 1 Laboratory and Diagnostic Findings of the Patient Test Result Reference Range Interpretation Hemoglobin 100 g/L 120–160 g/L Low MCV 111 fL 80–100 fL Macrocytic Reticulocyte Count 20 ×10⁹/L 25–75 ×10⁹/L Inappropriately low White Blood Cell Count 3.8 ×10⁹/L 4.0–11.0 ×10⁹/L Mild leukopenia Platelets 145 ×10⁹/L 150–400 ×10⁹/L Mild thrombocytopenia MMA 1.1 µmol/L 7 nmol/L Normal LDH 2500 U/L 100–250 U/L Markedly elevated Total Bilirubin 16 µmol/L 5–21 µmol/L Normal Ferritin 154 µg/L 30–300 µg/L Normal Anti-IF Antibody Positive Negative Highly specific Anti-Parietal Cell Antibody Borderline Negative Suggestive of autoimmunity Peripheral blood smear examination revealed macro-ovalocytes and hypersegmented neutrophils, consistent with megaloblastic hematopoiesis. Elevated MMA and homocysteine levels further confirmed functional vitamin B₁₂ deficiency and excluded isolated folate deficiency. Upper gastrointestinal endoscopy demonstrated pallor of the gastric mucosa with visible submucosal vasculature and reduced rugal folds, predominantly involving the fundus and body. Targeted biopsies confirmed chronic atrophic gastritis with glandular atrophy and intestinal metaplasia. Given the presence of multilineage cytopenia, a bone marrow examination was performed to rule out primary hematologic malignancy or marrow failure syndromes. The marrow was hypercellular, with marked erythroid hyperplasia and classic megaloblastic changes, including nuclear–cytoplasmic asynchrony. Based on the constellation of macrocytic anemia, severe vitamin B12 deficiency, positive anti-IF antibodies, and histopathologic evidence of autoimmune gastritis, a diagnosis of pernicious anemia was established. Given the close temporal relationship between symptom onset and recent COVID-19 vaccination, a possible association with immune activation was considered. The patient was treated with intramuscular hydroxocobalamin 1000 mcg daily for 7 days, followed by twice weekly for 2 weeks, then weekly for 1 month. Additional iron and folate supplementation was not indicated. Neurological consultation ruled out subacute combined degeneration. Following stabilization, long-term intramuscular vitamin B12 replacement was continued at maintenance dosing every two months, with scheduled clinical and laboratory follow-up every three months. By week 4, the patient reported full resolution of fatigue and dyspnea. By week 8, her hemoglobin had normalized to 132 g/L, and serum vitamin B₁₂ had increased to 485 pmol/L. At the six-month follow-up, repeat endoscopy revealed reduced inflammatory changes in the gastric mucosa, without further progression of atrophic features. Anti-IF antibodies were no longer detectable at that time; however, this finding was interpreted cautiously, given the possibility of initial false positives or natural fluctuations in antibody titers. At one-year follow-up, the patient remained asymptomatic with stable hematologic parameters and no evidence of recurrent anemia or emergence of new autoimmune phenomena. In view of the suspected immune-mediated mechanism and in the absence of long-term safety data in similar contexts, revaccination with the same adenoviral vector platform was deferred as a precautionary measure. Discussion Pernicious anemia is a well-established autoimmune disorder resulting from impaired vitamin B₁₂ absorption due to intrinsic factor or parietal cell autoantibodies. Although classically characterized by an insidious course, subacute presentations have increasingly been recognized in settings associated with immune activation. In this case, symptomatic macrocytic anemia with biochemical and histologic features consistent with pernicious anemia developed within three weeks of ChAdOx1 nCoV-19 vaccination. COVID-19 vaccines, including adenovirus-vector platforms such as ChAdOx1 nCoV-19, are designed to elicit robust innate and adaptive immune responses. While their overall safety profile is well established, rare autoimmune phenomena temporally associated with vaccination have been reported. These include Guillain–Barré syndrome, immune thrombocytopenia, autoimmune hepatitis, and transverse myelitis ( 9 – 12 ). Proposed mechanisms underlying such events include molecular mimicry between vaccine antigens and host proteins, epitope spreading following immune activation, and bystander activation of autoreactive lymphocytes in genetically predisposed individuals ( 13 , 14 ). Autoimmune hematologic manifestations following vaccination are uncommon but increasingly recognized. Isolated reports have described autoimmune hemolytic anemia, immune-mediated thrombocytopenia, and vitamin B12 deficiency syndromes emerging after COVID-19 vaccination. Soltani et al. reported two cases of pernicious anemia developing shortly after vaccination, with clinical features and temporal patterns like those observed in the present case ( 15 ). In addition, Jafarzadeh et al. highlighted autoimmune hemolytic anemia following vaccination, noting that macrocytosis and vitamin B12 deficiency may coexist in immune-mediated hematologic disorders ( 16 ). The temporal relationship observed in this patient, symptom onset approximately three weeks after vaccination, corresponds to the expected timeframe for the development of an adaptive immune response ( 13 ). The diagnosis of PA was supported by macrocytic anemia with ineffective erythropoiesis, severely reduced serum vitamin B12 levels, elevated MMA and homocysteine levels, positive anti–intrinsic factor antibodies, and histologic evidence of autoimmune gastritis involving the gastric fundus and body ( 1 – 3 ). Notably, the absence of dietary deficiency, gastrointestinal malabsorption, medication-related interference with B12 absorption, or prior autoimmune disease strengthens the plausibility of a vaccination-associated immune trigger. An important aspect of this case is the subsequent normalization of IF antibody testing and accompanied by endoscopic evidence of reduced inflammatory changes and absence of progression of atrophic features in the gastric mucosa at six-month follow-up. Classical pernicious anemia is generally regarded as a lifelong autoimmune condition ( 4 ); however, these findings raise the possibility that the immune response in this patient was transient rather than indicative of established chronic autoimmunity. An alternative explanation is that vaccination unmasked a previously subclinical autoimmune process, accelerating clinical presentation rather than initiating de novo disease. Distinguishing between these possibilities is not feasible in a single case but remains an important consideration. While temporal association alone does not establish causality, several features of this case are compatible with a vaccine-associated immune-mediated phenomenon. These include the absence of pre-existing gastrointestinal disease, dietary deficiency, autoimmune conditions, or medications known to impair vitamin B₁₂ absorption; the close temporal proximity between vaccination and symptom onset; the acute clinical presentation; the favorable response to therapy; and the subsequent normalization of IF antibody testing with improvement in gastric inflammatory changes on follow-up. Collectively, these observations raise the possibility that immune stimulation following vaccination may have unmasked or accelerated a previously subclinical autoimmune process. This concept aligns with the framework of autoimmune/inflammatory syndrome induced by immune stimulation (ASIA), first proposed by Shoenfeld et al., which describes rare autoimmune manifestations occurring in genetically predisposed individuals after exposure to strong immunologic triggers such as vaccines ( 17 ). Although ASIA remains a debated and evolving construct with incompletely defined diagnostic criteria ( 18 ), it offers a potential explanatory model for uncommon post-vaccination autoimmune phenomena. Further systematic investigation is required to clarify its clinical relevance and to better delineate the relationship between vaccination and transient or sustained autoimmune hematologic conditions. Conclusion This case describes a rare occurrence of PA developing in close temporal proximity to the administration of the ChAdOx1 nCoV-19 vaccine in a previously healthy individual. The combination of serologic and histologic findings, along with the temporal relationship between vaccination and symptom onset, raises the possibility of a transient immune-mediated mechanism. Prompt recognition and early initiation of vitamin B12 replacement therapy resulted in complete clinical and hematologic recovery, suggesting that timely intervention can prevent irreversible neurologic complications. Although the overall benefits of COVID-19 vaccination clearly outweigh potential risks, this case underscores the importance of clinical vigilance when evaluating patients presenting with macrocytic anemia and constitutional symptoms following vaccination or other immune stimuli. Such presentations, though rare, prompt consideration of vitamin B12 deficiency and autoimmune gastritis in the differential diagnosis, particularly when laboratory findings reveal macrocytosis, multilineage cytopenia, or elevated LDH. In these scenarios, appropriate testing, including serum B12, MMA, and homocysteine levels, may aid in timely diagnosis. Notably, this case also suggests that not all post-vaccination presentations resembling pernicious anemia represent permanent autoimmune disease. In contrast to classical idiopathic pernicious anemia, which typically requires lifelong therapy, some patients may experience partial or complete immunologic resolution, possibly indicating a transient vaccine-triggered autoimmune response. Given the extreme rarity of these events, population-wide screening following COVID-19 vaccination is not warranted. However, heightened awareness of such exceptional cases may support timely diagnosis and appropriate management. Continued pharmacovigilance and systematic reporting of similar cases are essential to deepen our understanding of rare immune-mediated phenomena and reinforce confidence in vaccination programs, which have significantly greater benefits than the risks. Abbreviations PA Pernicious Anemia COVID-19 Coronavirus Disease 2019 LDH Lactate Dehydrogenase MMA Methylmalonic Acid MCV Mean Corpuscular Volume IF Intrinsic Factor HCT Hematocrit WBC White Blood Cells RBC Red Blood Cells SARS-CoV-2 Severe Acute Respiratory Syndrome Coronavirus 2 Declarations Ethics approval and consent to participate Not applicable. Consent for publication Written informed consent was taken from the patient for the publication of the case report and accompanying images. Availability of data materials Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study. Competing interests The authors declare no competing interests. Funding Not applicable References Stabler SP (2013) Clinical practice. Vitamin B12 deficiency. N Engl J Med 368(2):149–160 Toh BH, van Driel IR, Gleeson PA (1997) Pernicious anemia. N Engl J Med 337(20):1441–1448 O'Leary F, Samman S (2010) Vitamin B12 in health and disease. Nutrients 2(3):299–316 Andres E, Serraj K (2012) Optimal management of pernicious anemia. J Blood Med 3:97–103 Healton EB, Savage DG, Brust JC, Garrett TJ, Lindenbaum J (1991) Neurologic aspects of cobalamin deficiency. Med (Baltim) 70(4):229–245 Voysey M, Clemens SAC, Madhi SA, Weckx LY, Folegatti PM, Aley PK et al (2021) Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet 397(10269):99–111 Polack Fernando P, Thomas Stephen J, Kitchin N, Absalon J, Gurtman A, Lockhart S et al (2020) Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med 383(27):2603–2615 Baden Lindsey R, El Sahly Hana M, Essink B, Kotloff K, Frey S, Novak R et al (2021) Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med 384(5):403–416 Greinacher A, Thiele T, Warkentin Theodore E, Weisser K, Kyrle Paul A, Eichinger S (2021) Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination. N Engl J Med 384(22):2092–2101 Schultz Nina H, Sørvoll Ingvild H, Michelsen Annika E, Munthe Ludvig A, Lund-Johansen F, Ahlen Maria T et al (2021) Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination. N Engl J Med 384(22):2124–2130 Shao Sc Fau -, Wang C-H, Wang Ch Fau - Chang K-C Chang Kc Fau - Hung M-J, Hung Mj Fau - Chen H-Y, Chen Hy Fau - Liao S-C, Liao SC. Guillain-​Barré Syndrome Associated with COVID-19 Vaccination. (1080–6059 (Electronic)) Bril F, Al Diffalha S, Dean M, Fettig DM Autoimmune hepatitis developing after coronavirus disease 2019 (COVID-19) vaccine: Causality or casualty? (1600 – 0641 (Electronic)) Segal Y, Shoenfeld Y Vaccine-induced autoimmunity: the role of molecular mimicry and immune crossreaction. (2042 – 0226 (Electronic)) Rose NR Negative selection, epitope mimicry and autoimmunity. (1879 – 0372 (Electronic)) Soltani H, Taghizade S, Sadeghi A, Farahat A, Owlia MB (2008) Pernicious Anemia Following COVID-19 Vaccination: A Report of Two Cases. –3009 (Print)) Jafarzadeh AA-O, Jafarzadeh S, Pardehshenas M, Nemati M, Mortazavi SMJ Development and exacerbation of autoimmune hemolytic anemia following COVID-19 vaccination: A systematic review. (1751-553X (Electronic)). Shoenfeld Y, Agmon-Levin N 'ASIA' - autoimmune/inflammatory syndrome induced by adjuvants. (1095–9157 (Electronic)) Ameratunga R, Gillis D, Gold M, Linneberg A, Elwood JM Evidence Refuting the Existence of Autoimmune/Autoinflammatory Syndrome Induced by Adjuvants (ASIA). (2213 – 2201 (Electronic)) Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 31 Mar, 2026 Reviews received at journal 25 Mar, 2026 Reviewers agreed at journal 18 Mar, 2026 Reviewers agreed at journal 18 Mar, 2026 Reviewers invited by journal 06 Mar, 2026 Editor assigned by journal 26 Feb, 2026 Submission checks completed at journal 19 Feb, 2026 First submitted to journal 13 Feb, 2026 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-8874389","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":601884570,"identity":"3d912c34-b10b-4ee4-9195-570fdfe89080","order_by":0,"name":"Mahnaz Danesh","email":"","orcid":"","institution":"Isfahan University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Mahnaz","middleName":"","lastName":"Danesh","suffix":""},{"id":601884571,"identity":"b3e21d7e-a836-47eb-bbdd-166cd9ef3696","order_by":1,"name":"Pari Hashemi²","email":"","orcid":"","institution":"Golestan University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Pari","middleName":"","lastName":"Hashemi²","suffix":""},{"id":601884572,"identity":"af1554a9-2ef9-4095-9edc-8355b6401b39","order_by":2,"name":"Sobhan Parvizi³","email":"","orcid":"","institution":"Isfahan University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Sobhan","middleName":"","lastName":"Parvizi³","suffix":""},{"id":601884573,"identity":"fce67624-6117-4560-b8cc-c7a4d523e57d","order_by":3,"name":"Sayyideh Forough Hosseini","email":"data:image/png;base64,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","orcid":"","institution":"Isfahan University of Medical Sciences","correspondingAuthor":true,"prefix":"","firstName":"Sayyideh","middleName":"Forough","lastName":"Hosseini","suffix":""}],"badges":[],"createdAt":"2026-02-13 17:24:31","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8874389/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8874389/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104413855,"identity":"84ec8aa7-9277-4635-bfa1-a6ce0a65e3de","added_by":"auto","created_at":"2026-03-11 13:05:41","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":537873,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePeripheral blood smear showing macro-ovalocytes and hypersegmented neutrophils, consistent with megaloblastic hematopoiesis in a patient with pernicious anemia\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8874389/v1/d0253caa2d75a518f354f39a.png"},{"id":104416371,"identity":"03a8b560-9e0f-412c-b683-6cd7a9020592","added_by":"auto","created_at":"2026-03-11 13:15:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1023923,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8874389/v1/74bba1b7-47a9-4de7-a927-27af195d3cb9.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Pernicious Anemia Following ChAdOx1 nCoV-19 Vaccination in a Previously Healthy Adult: A Case Report","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePernicious anemia (PA) is a classical autoimmune disorder characterized by vitamin B₁₂ deficiency resulting from impaired intestinal absorption due to antibodies directed against intrinsic factor (IF) or gastric parietal cells (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). The condition leads to ineffective erythropoiesis and may manifest with macrocytic anemia, cytopenia, and neurologic complications, including subacute combined degeneration of the spinal cord (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). PA typically develops insidiously over months to years and is traditionally regarded as a lifelong condition requiring ongoing vitamin B₁₂ replacement therapy (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Early recognition is critical, as delayed diagnosis may result in irreversible neurologic injury (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eVaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been central to mitigating the global burden of COVID-19. Several vaccine platforms have been developed, including messenger ribonucleic acid (mRNA)\u0026ndash;based vaccines and adenoviral vector\u0026ndash;based vaccines such as ChAdOx1 nCoV-19 (AstraZeneca), which have demonstrated favorable safety and efficacy profiles in large, randomized trials and real-world studies (\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). The majority of reported adverse effects are mild and self-limited; however, rare immune-mediated complications temporally associated with vaccination have been described, including immune thrombocytopenia, Guillain\u0026ndash;Barr\u0026eacute; syndrome, autoimmune hepatitis, and thrombosis with thrombocytopenia syndrome (\u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAlthough uncommon, immune-mediated hematologic disorders temporally associated with vaccination have been reported. Proposed mechanisms include immune activation leading to molecular mimicry, epitope spreading, or bystander activation of autoreactive lymphocytes in susceptible individuals (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). While autoimmune hemolytic anemia and immune thrombocytopenia have been described more frequently, vitamin B₁₂ deficiency syndromes and PA occurring in close temporal association with COVID-19 vaccination remain rare, with only a limited number of cases reported in the literature to date (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Whether such presentations represent vaccine-triggered autoimmune phenomena or the unmasking of previously subclinical autoimmune disease remains uncertain.\u003c/p\u003e \u003cp\u003eHere, we report a rare case of newly diagnosed PA presenting within three weeks of administration of the ChAdOx1 nCoV-19 vaccine in a previously healthy adult with no identifiable gastrointestinal, dietary, or autoimmune risk factors. The clinical presentation, diagnostic findings, and subsequent course raise the possibility of a transient immune-mediated process temporally associated with vaccination and contribute to the growing literature on rare autoimmune hematologic phenomena following immunization.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA 39-year-old Caucasian female with no significant past medical history presented with progressive fatigue, dizziness, particularly on standing, and exertional dyspnea. She denied fever, weight loss, gastrointestinal bleeding, neurological complaints, or recent infections. The patient followed an omnivorous diet, did not smoke, and consumed alcohol only occasionally. Notably, she had received the second dose of the ChAdOx1 nCoV-19 vaccine 21 days before the onset of symptoms. She was not taking any medications except for a low-dose folic acid supplement (1 mg daily) for pre-pregnancy planning.\u003c/p\u003e \u003cp\u003eOn examination, the patient appeared pale but was alert and hemodynamically stable. Vital signs demonstrated mild tachycardia (heart rate 102 beats/min) with normal blood pressure (110/70 mmHg) and afebrile temperature. Conjunctival pallor was present without scleral icterus. Cardiovascular, respiratory, abdominal, and neurological examinations were otherwise unremarkable. No lymphadenopathy or hepatosplenomegaly was identified.\u003c/p\u003e \u003cp\u003eInitial laboratory testing revealed macrocytic anemia with associated mild leukopenia and thrombocytopenia (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The reticulocyte count was inappropriately low for the degree of anemia. Serum vitamin B₁₂ was markedly reduced, while folate and iron indices were within normal limits. Functional markers of vitamin B₁₂ deficiency were elevated, with increased methylmalonic acid (MMA) and homocysteine levels, supporting a diagnosis of true cellular vitamin B₁₂ deficiency. LDH was markedly elevated, while total bilirubin remained within the reference range, arguing against overt hemolysis. Serologic testing demonstrated the presence of anti-IF antibodies, with borderline positivity for anti\u0026ndash;parietal cell antibodies, supporting an autoimmune etiology.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eLaboratory and Diagnostic Findings of the Patient\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTest\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eResult\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eReference Range\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eInterpretation\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemoglobin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e100 g/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e120\u0026ndash;160 g/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMCV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e111 fL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e80\u0026ndash;100 fL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMacrocytic\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReticulocyte Count\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 \u0026times;10⁹/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25\u0026ndash;75 \u0026times;10⁹/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eInappropriately low\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWhite Blood Cell Count\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.8 \u0026times;10⁹/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.0\u0026ndash;11.0 \u0026times;10⁹/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMild leukopenia\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatelets\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e145 \u0026times;10⁹/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e150\u0026ndash;400 \u0026times;10⁹/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMild thrombocytopenia\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMMA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.1 \u0026micro;mol/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.40 \u0026micro;mol/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eElevated\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVitamin B12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e90 pmol/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e138\u0026ndash;652 pmol/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSeverely deficient\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHomocysteine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34 \u0026micro;mol/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u0026ndash;15 \u0026micro;mol/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eElevated\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFolate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 nmol/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;7 nmol/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLDH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2500 U/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e100\u0026ndash;250 U/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMarkedly elevated\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal Bilirubin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 \u0026micro;mol/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5\u0026ndash;21 \u0026micro;mol/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFerritin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e154 \u0026micro;g/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30\u0026ndash;300 \u0026micro;g/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNormal\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnti-IF Antibody\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHighly specific\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnti-Parietal Cell Antibody\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBorderline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSuggestive of autoimmunity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003ePeripheral blood smear examination revealed macro-ovalocytes and hypersegmented neutrophils, consistent with megaloblastic hematopoiesis. Elevated MMA and homocysteine levels further confirmed functional vitamin B₁₂ deficiency and excluded isolated folate deficiency.\u003c/p\u003e \u003cp\u003eUpper gastrointestinal endoscopy demonstrated pallor of the gastric mucosa with visible submucosal vasculature and reduced rugal folds, predominantly involving the fundus and body. Targeted biopsies confirmed chronic atrophic gastritis with glandular atrophy and intestinal metaplasia.\u003c/p\u003e \u003cp\u003eGiven the presence of multilineage cytopenia, a bone marrow examination was performed to rule out primary hematologic malignancy or marrow failure syndromes. The marrow was hypercellular, with marked erythroid hyperplasia and classic megaloblastic changes, including nuclear\u0026ndash;cytoplasmic asynchrony.\u003c/p\u003e \u003cp\u003eBased on the constellation of macrocytic anemia, severe vitamin B12 deficiency, positive anti-IF antibodies, and histopathologic evidence of autoimmune gastritis, a diagnosis of pernicious anemia was established. Given the close temporal relationship between symptom onset and recent COVID-19 vaccination, a possible association with immune activation was considered.\u003c/p\u003e \u003cp\u003eThe patient was treated with intramuscular hydroxocobalamin 1000 mcg daily for 7 days, followed by twice weekly for 2 weeks, then weekly for 1 month. Additional iron and folate supplementation was not indicated. Neurological consultation ruled out subacute combined degeneration. Following stabilization, long-term intramuscular vitamin B12 replacement was continued at maintenance dosing every two months, with scheduled clinical and laboratory follow-up every three months.\u003c/p\u003e \u003cp\u003eBy week 4, the patient reported full resolution of fatigue and dyspnea. By week 8, her hemoglobin had normalized to 132 g/L, and serum vitamin B₁₂ had increased to 485 pmol/L. At the six-month follow-up, repeat endoscopy revealed reduced inflammatory changes in the gastric mucosa, without further progression of atrophic features. Anti-IF antibodies were no longer detectable at that time; however, this finding was interpreted cautiously, given the possibility of initial false positives or natural fluctuations in antibody titers.\u003c/p\u003e \u003cp\u003eAt one-year follow-up, the patient remained asymptomatic with stable hematologic parameters and no evidence of recurrent anemia or emergence of new autoimmune phenomena. In view of the suspected immune-mediated mechanism and in the absence of long-term safety data in similar contexts, revaccination with the same adenoviral vector platform was deferred as a precautionary measure.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003ePernicious anemia is a well-established autoimmune disorder resulting from impaired vitamin B₁₂ absorption due to intrinsic factor or parietal cell autoantibodies. Although classically characterized by an insidious course, subacute presentations have increasingly been recognized in settings associated with immune activation. In this case, symptomatic macrocytic anemia with biochemical and histologic features consistent with pernicious anemia developed within three weeks of ChAdOx1 nCoV-19 vaccination.\u003c/p\u003e \u003cp\u003eCOVID-19 vaccines, including adenovirus-vector platforms such as ChAdOx1 nCoV-19, are designed to elicit robust innate and adaptive immune responses. While their overall safety profile is well established, rare autoimmune phenomena temporally associated with vaccination have been reported. These include Guillain\u0026ndash;Barr\u0026eacute; syndrome, immune thrombocytopenia, autoimmune hepatitis, and transverse myelitis (\u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Proposed mechanisms underlying such events include molecular mimicry between vaccine antigens and host proteins, epitope spreading following immune activation, and bystander activation of autoreactive lymphocytes in genetically predisposed individuals (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAutoimmune hematologic manifestations following vaccination are uncommon but increasingly recognized. Isolated reports have described autoimmune hemolytic anemia, immune-mediated thrombocytopenia, and vitamin B12 deficiency syndromes emerging after COVID-19 vaccination. Soltani et al. reported two cases of pernicious anemia developing shortly after vaccination, with clinical features and temporal patterns like those observed in the present case (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). In addition, Jafarzadeh et al. highlighted autoimmune hemolytic anemia following vaccination, noting that macrocytosis and vitamin B12 deficiency may coexist in immune-mediated hematologic disorders (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe temporal relationship observed in this patient, symptom onset approximately three weeks after vaccination, corresponds to the expected timeframe for the development of an adaptive immune response (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). The diagnosis of PA was supported by macrocytic anemia with ineffective erythropoiesis, severely reduced serum vitamin B12 levels, elevated MMA and homocysteine levels, positive anti\u0026ndash;intrinsic factor antibodies, and histologic evidence of autoimmune gastritis involving the gastric fundus and body (\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Notably, the absence of dietary deficiency, gastrointestinal malabsorption, medication-related interference with B12 absorption, or prior autoimmune disease strengthens the plausibility of a vaccination-associated immune trigger.\u003c/p\u003e \u003cp\u003eAn important aspect of this case is the subsequent normalization of IF antibody testing and accompanied by endoscopic evidence of reduced inflammatory changes and absence of progression of atrophic features in the gastric mucosa at six-month follow-up. Classical pernicious anemia is generally regarded as a lifelong autoimmune condition (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e); however, these findings raise the possibility that the immune response in this patient was transient rather than indicative of established chronic autoimmunity. An alternative explanation is that vaccination unmasked a previously subclinical autoimmune process, accelerating clinical presentation rather than initiating de novo disease. Distinguishing between these possibilities is not feasible in a single case but remains an important consideration.\u003c/p\u003e \u003cp\u003eWhile temporal association alone does not establish causality, several features of this case are compatible with a vaccine-associated immune-mediated phenomenon. These include the absence of pre-existing gastrointestinal disease, dietary deficiency, autoimmune conditions, or medications known to impair vitamin B₁₂ absorption; the close temporal proximity between vaccination and symptom onset; the acute clinical presentation; the favorable response to therapy; and the subsequent normalization of IF antibody testing with improvement in gastric inflammatory changes on follow-up. Collectively, these observations raise the possibility that immune stimulation following vaccination may have unmasked or accelerated a previously subclinical autoimmune process. This concept aligns with the framework of autoimmune/inflammatory syndrome induced by immune stimulation (ASIA), first proposed by Shoenfeld et al., which describes rare autoimmune manifestations occurring in genetically predisposed individuals after exposure to strong immunologic triggers such as vaccines (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Although ASIA remains a debated and evolving construct with incompletely defined diagnostic criteria (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e), it offers a potential explanatory model for uncommon post-vaccination autoimmune phenomena. Further systematic investigation is required to clarify its clinical relevance and to better delineate the relationship between vaccination and transient or sustained autoimmune hematologic conditions.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis case describes a rare occurrence of PA developing in close temporal proximity to the administration of the ChAdOx1 nCoV-19 vaccine in a previously healthy individual. The combination of serologic and histologic findings, along with the temporal relationship between vaccination and symptom onset, raises the possibility of a transient immune-mediated mechanism. Prompt recognition and early initiation of vitamin B12 replacement therapy resulted in complete clinical and hematologic recovery, suggesting that timely intervention can prevent irreversible neurologic complications.\u003c/p\u003e \u003cp\u003eAlthough the overall benefits of COVID-19 vaccination clearly outweigh potential risks, this case underscores the importance of clinical vigilance when evaluating patients presenting with macrocytic anemia and constitutional symptoms following vaccination or other immune stimuli. Such presentations, though rare, prompt consideration of vitamin B12 deficiency and autoimmune gastritis in the differential diagnosis, particularly when laboratory findings reveal macrocytosis, multilineage cytopenia, or elevated LDH. In these scenarios, appropriate testing, including serum B12, MMA, and homocysteine levels, may aid in timely diagnosis.\u003c/p\u003e \u003cp\u003eNotably, this case also suggests that not all post-vaccination presentations resembling pernicious anemia represent permanent autoimmune disease. In contrast to classical idiopathic pernicious anemia, which typically requires lifelong therapy, some patients may experience partial or complete immunologic resolution, possibly indicating a transient vaccine-triggered autoimmune response.\u003c/p\u003e \u003cp\u003eGiven the extreme rarity of these events, population-wide screening following COVID-19 vaccination is not warranted. However, heightened awareness of such exceptional cases may support timely diagnosis and appropriate management. Continued pharmacovigilance and systematic reporting of similar cases are essential to deepen our understanding of rare immune-mediated phenomena and reinforce confidence in vaccination programs, which have significantly greater benefits than the risks.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePernicious Anemia\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCOVID-19\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCoronavirus Disease 2019\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLDH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eLactate Dehydrogenase\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMMA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMethylmalonic Acid\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMCV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMean Corpuscular Volume\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eIntrinsic Factor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHCT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHematocrit\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eWBC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eWhite Blood Cells\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRBC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRed Blood Cells\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSARS-CoV-2\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSevere Acute Respiratory Syndrome Coronavirus 2\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was taken from the patient for the publication of the case report and accompanying images.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAvailability of data materials\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData sharing is not applicable to this article as no datasets were generated or analyzed during the current study.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable \u0026nbsp;\u003c/p\u003e\n\n"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eStabler SP (2013) Clinical practice. Vitamin B12 deficiency. N Engl J Med 368(2):149\u0026ndash;160\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eToh BH, van Driel IR, Gleeson PA (1997) Pernicious anemia. N Engl J Med 337(20):1441\u0026ndash;1448\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eO'Leary F, Samman S (2010) Vitamin B12 in health and disease. Nutrients 2(3):299\u0026ndash;316\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAndres E, Serraj K (2012) Optimal management of pernicious anemia. J Blood Med 3:97\u0026ndash;103\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHealton EB, Savage DG, Brust JC, Garrett TJ, Lindenbaum J (1991) Neurologic aspects of cobalamin deficiency. Med (Baltim) 70(4):229\u0026ndash;245\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVoysey M, Clemens SAC, Madhi SA, Weckx LY, Folegatti PM, Aley PK et al (2021) Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet 397(10269):99\u0026ndash;111\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePolack Fernando P, Thomas Stephen J, Kitchin N, Absalon J, Gurtman A, Lockhart S et al (2020) Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med 383(27):2603\u0026ndash;2615\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBaden Lindsey R, El Sahly Hana M, Essink B, Kotloff K, Frey S, Novak R et al (2021) Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med 384(5):403\u0026ndash;416\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGreinacher A, Thiele T, Warkentin Theodore E, Weisser K, Kyrle Paul A, Eichinger S (2021) Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination. N Engl J Med 384(22):2092\u0026ndash;2101\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchultz Nina H, S\u0026oslash;rvoll Ingvild H, Michelsen Annika E, Munthe Ludvig A, Lund-Johansen F, Ahlen Maria T et al (2021) Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination. N Engl J Med 384(22):2124\u0026ndash;2130\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShao Sc Fau -, Wang C-H, Wang Ch Fau - Chang K-C Chang Kc Fau - Hung M-J, Hung Mj Fau - Chen H-Y, Chen Hy Fau - Liao S-C, Liao SC. Guillain-​Barr\u0026eacute; Syndrome Associated with COVID-19 Vaccination. (1080\u0026ndash;6059 (Electronic))\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBril F, Al Diffalha S, Dean M, Fettig DM Autoimmune hepatitis developing after coronavirus disease 2019 (COVID-19) vaccine: Causality or casualty? (1600\u0026thinsp;\u0026ndash;\u0026thinsp;0641 (Electronic))\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSegal Y, Shoenfeld Y Vaccine-induced autoimmunity: the role of molecular mimicry and immune crossreaction. (2042\u0026thinsp;\u0026ndash;\u0026thinsp;0226 (Electronic))\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRose NR Negative selection, epitope mimicry and autoimmunity. (1879\u0026thinsp;\u0026ndash;\u0026thinsp;0372 (Electronic))\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSoltani H, Taghizade S, Sadeghi A, Farahat A, Owlia MB (2008) Pernicious Anemia Following COVID-19 Vaccination: A Report of Two Cases. \u0026ndash;3009 (Print))\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJafarzadeh AA-O, Jafarzadeh S, Pardehshenas M, Nemati M, Mortazavi SMJ Development and exacerbation of autoimmune hemolytic anemia following COVID-19 vaccination: A systematic review. (1751-553X (Electronic)).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShoenfeld Y, Agmon-Levin N 'ASIA' - autoimmune/inflammatory syndrome induced by adjuvants. (1095\u0026ndash;9157 (Electronic))\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAmeratunga R, Gillis D, Gold M, Linneberg A, Elwood JM Evidence Refuting the Existence of Autoimmune/Autoinflammatory Syndrome Induced by Adjuvants (ASIA). (2213\u0026thinsp;\u0026ndash;\u0026thinsp;2201 (Electronic))\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":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"the-egyptian-journal-of-internal-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [The Egyptian Journal of Internal Medicine](https://ejim.springeropen.com/)","snPcode":"43162","submissionUrl":"https://submission.springernature.com/new-submission/43162/3","title":"The Egyptian Journal of Internal Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Open","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Pernicious Anemia (PA), Vitamin B12 Deficiency, ChAdOx1 nCoV-19 Vaccine (AstraZeneca), Autoimmune Gastritis","lastPublishedDoi":"10.21203/rs.3.rs-8874389/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8874389/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground:\u003c/h2\u003e \u003cp\u003eCOVID-19 vaccines have demonstrated a favorable safety profile and have been critical in reducing morbidity and mortality from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although most adverse events are mild and self-limited, rare immune-mediated conditions temporally associated with vaccination have been reported. Pernicious anemia (PA) is an autoimmune disorder characterized by vitamin B₁₂ malabsorption due to antibodies against intrinsic factor (IF) and is infrequently described in this context. We report a case of symptomatic vitamin B₁₂ deficiency due to PA occurring shortly after ChAdOx1 nCoV-19 (AstraZeneca) COVID-19 vaccination.\u003c/p\u003e\u003ch2\u003eCase Presentation:\u003c/h2\u003e \u003cp\u003eA 39-year-old previously healthy woman developed progressive fatigue, light-headedness, and exertional dyspnea three weeks after receiving her second dose of the ChAdOx1 nCoV-19 (AstraZeneca) COVID-19 vaccine. Laboratory investigations revealed macrocytic anemia (hemoglobin 100 g/L; mean corpuscular volume [MCV] 111 fL), severe vitamin B₁₂ deficiency (90 pmol/L), and markedly elevated lactate dehydrogenase (LDH). Anti-intrinsic factor (IF) antibodies were positive. Upper gastrointestinal endoscopy demonstrated fundic atrophic gastritis, and bone marrow examination confirmed megaloblastic erythropoiesis. The patient was treated with intramuscular hydroxocobalamin, resulting in complete clinical and hematologic recovery during follow-up.\u003c/p\u003e\u003ch2\u003eConclusion:\u003c/h2\u003e \u003cp\u003eThis case describes Pernicious anemia (PA) presenting in close temporal association with COVID-19 vaccination in a previously healthy individual. Although causality cannot be established, the temporal relationship raises the possibility of immune activation contributing to disease onset. Early recognition and prompt vitamin B₁₂ replacement led to full recovery and may prevent irreversible neurologic complications.\u003c/p\u003e","manuscriptTitle":"Pernicious Anemia Following ChAdOx1 nCoV-19 Vaccination in a Previously Healthy Adult: A Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-11 12:04:26","doi":"10.21203/rs.3.rs-8874389/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-03-31T18:01:13+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-25T20:35:28+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"327774917781192663786278356639479387863","date":"2026-03-18T10:42:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"291233503302077559780687980773717115118","date":"2026-03-18T10:24:28+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-06T12:26:47+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-26T05:38:07+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-19T06:56:02+00:00","index":"","fulltext":""},{"type":"submitted","content":"The Egyptian Journal of Internal Medicine","date":"2026-02-13T17:19:27+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"the-egyptian-journal-of-internal-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [The Egyptian Journal of Internal Medicine](https://ejim.springeropen.com/)","snPcode":"43162","submissionUrl":"https://submission.springernature.com/new-submission/43162/3","title":"The Egyptian Journal of Internal Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Open","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fe05e7c3-9237-45e0-b28a-fed789fc9d29","owner":[],"postedDate":"March 11th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-03-11T12:04:27+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-11 12:04:26","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8874389","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8874389","identity":"rs-8874389","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}