# Cytomegalovirus-induced Severe Aregenerative Autoimmune Hemolytic Anemia in an Immunocompetent Patient

Chaïmaâ Zeroual, Mina Moudatir, Khadija Echchilali, Siham Nagib, Hassan Elkabli

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## To cite this version:

Chaïmaâ Zeroual, Mina Moudatir, Khadija Echchilali, Siham Nagib, Hassan Elkabli. Cytomegalovirus-induced Severe Aregenerative Autoimmune Hemolytic Anemia in an Immunocompetent Patient. Asian Journal of Research in Infectious Diseases, 2025, 16 (10), pp.42-47. 10.9734/ajrid/2025/v16i10497. hal-05315180

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# Cytomegalovirus-induced Severe Aregenerative Autoimmune Hemolytic Anemia in an Immunocompetent Patient

Chaïmaâ Zeroual a*, Mina Moudatir a, Khadija Echchilali a, Siham Nagib b and Hassan Elkabli a

## Authors' contributions

This work was carried out in collaboration among all authors. All authors read and approved the final manuscript.

## Article Information

DOI: https://doi.org/10.9734/ajrid/2025/v16i10497

### Open Peer Review History:

This journal follows the Advanced Open Peer Review policy. Identity of the Reviewers, Editor(s) and additional Reviewers, peer review comments, different versions of the manuscript, comments of the editors, etc are available here: https://pr.sdiarticle5.com/review-history/145044

## Case Report

Received: 25/07/2025

Published: 14/10/2025

## ABSTRACT

**Background:** While cytomegalovirus (CMV) infection is usually benign in immunocompetent adults, it can exceptionally trigger severe hematological autoimmunity.

**Case Presentation:** We report the case of a 41-year-old immunocompetent woman admitted with profound symptomatic anemia (Hb 1.9 g/dL). Laboratory findings showed positive direct antiglobulin test and marked aregenerative anemia. Bone marrow biopsy excluded malignant or aplastic processes. CMV serology confirmed acute primary infection, and the patient was initially treated with red blood cell transfusions associated with antiviral therapy. Corticosteroids were

<footnote>a Internal Medicine and Geriatrics Department, Faculty of Medicine and Pharmacy of Casablanca, Ibn Rochd University Hospital, Casablanca, Morocco.</footnote>

<footnote>b Department of Anatomopathology, Faculty of Medicine and Pharmacy of Casablanca, Ibn Rochd University Hospital, Casablanca, Morocco.</footnote>

<footnote>*Corresponding author: E-mail: chaimaazeroual42@gmail.com;</footnote>
added afterwards. Clinical evolution was favorable, with complete clinical and hematologic recovery.

**Conclusion:** CMV-induced anemia, although exceptional in immunocompetent adults, should be recognized as a potential diagnostic challenge in acute severe anemia. This case highlights the need for greater awareness among clinicians and for future research to establish standardized therapeutic strategies and evaluate the long-term autoimmune implications of CMV infection.

Keywords: Cytomegalovirus; anemia; immunocompetent; autoimmunity; ganciclovir.

# 1. INTRODUCTION

Severe anemia triggered by viral infections is uncommon in immunocompetent adults. While cytomegalovirus (CMV) infection is frequent and usually asymptomatic or mild in this population, it can very rarely induce lethal hematologic complications. Even more exceptional are cases in which CMV causes anemia through both mechanisms—aregenerative due to bone marrow suppression and autoimmune hemolytic due to immune-mediated red blood cell destruction (Varani and Landini, 2011; Taglietti et al., 2010). Such dual-mechanism anemia is lifethreatening and demands prompt recognition, comprehensive diagnostic workup, and timely management to prevent serious morbidity.

We report the case of a previously healthy 41-year-old woman who developed severe CMV-associated anemia with both aregenerative and hemolytic features, presenting with profound symptoms and requiring intensive intervention. This report highlights the diagnostic challenges and therapeutic considerations in managing this rare and critical manifestation of CMV infection.

# 2. CASE PRESENTATION

We report the case of a 41-year-old woman with no past medical history of cardiopathy, renal or hepatic disease, autoimmune disorders, hemoglobinopathies, nutritional deficiencies, chronic inflammatory disease, malignancy, or bleeding diathesis. She was admitted for a poorly tolerated acute anemic syndrome characterized by dyspnea on minimal exertion, palpitations, and asthenia. Clinical examination revealed a profoundly pale patient without hemorrhagic signs or tumor syndrome, including no lymphadenopathy, hepatomegaly, or splenomegaly.

Complete blood count (CBC) showed profound anemia (Hb 1.9 g/dL), normochromic, normocytic, and markedly aregenerative

(reticulocytes 5,670/mm³), with normal leukocytes and platelets. Peripheral blood smear demonstrated anisocytosis, polychromatophilia, and hypochromia. Neither schistocytes nor spherocytes were observed. Direct antiglobulin test (IgG Coombs) was strongly positive compatible with warm antibody AIHA. Hemolysis workup revealed collapsed haptoglobin, elevated indirect bilirubin, and high LDH (1250 IU/L). Autoimmune screening showed ANA 1:640 speckled and positive anti-SSA Ro60, without clinical or laboratory signs of systemic lupus or Sjögren's disease. Testing for anti-native DNA and anti-Sm antibodies was negative.

The labial biopsy was performed showing chronic sialadenitis grade 1 of Chisholm and Masson with a focus score of 0. In parallel, bone marrow biopsy demonstrated granulocytic hyperplasia without malignancy or aplasia (Fig. 1).

<figure><img src="image_4.png" /><figcaption>Fig. 1. Histology of bone marrow with hematoxylin-eosin staining viewed under a microscope at ×400 magnification showing granulocytic hyperplasia</figcaption></figure>

CMV serology confirmed acute primary infection (initially strongly positive IgM, negative IgG, later seroconversion to IgG positive at day 20). CMV polymerase chain reaction (PCR) was negative. Other viral studies (EBV, HIV1/2, parvovirus B19 IgM and IgG, hepatitis B and C viruses) were negative too. Additional tests including chest,
abdomen and pelvis computed tomography (CT) scan, serum protein electrophoresis, ferritin, folate, and vitamin B12 were unremarkable.

<table><caption>**Table 1. Hemoglobin levels measured over time**</caption><thead><tr><td>Date</td><td>Hemoglobin (g/dL)</td></tr></thead><tbody><tr><td>01/04/2025</td><td>1.9</td></tr><tr><td>12/04/2025</td><td>2.7</td></tr><tr><td>23/04/2025</td><td>4.8</td></tr><tr><td>01/05/2025</td><td>4.2</td></tr><tr><td>13/05/2025</td><td>6.7</td></tr><tr><td>28/05/2025</td><td>7.4</td></tr><tr><td>18/06/2025</td><td>8.0</td></tr><tr><td>03/07/2025</td><td>11.6</td></tr><tr><td>14/07/2025</td><td>12.1</td></tr><tr><td>22/07/2025</td><td>12.3</td></tr></tbody></table>

Management combined initially red cell transfusions, intravenous ganciclovir 5mg/kg/12h (400mg/12h) during 21 days followed by oral valganciclovir 900mg/d. In the third week, fuldose oral corticosteroids was started with progressive tapering. Clinical course was favorable, with resolution of anemic symptoms and progressive recovery of hemoglobin from 1.9 g/dL to 12.3 g/dL (Table 1).

### 3. DISCUSSION

Cytomegalovirus (CMV), a ubiquitous member of the Herpesviridae family, exhibits seroprevalence rates exceeding 60-90% among adults globally (Griffiths and Reeves, 2021). In immunocompetent individuals, primary CMV infection is typically asymptomatic or presents as a mild mononucleosis-like syndrome. However, in rare instances, CMV can precipitate severe complications such as pneumonitis, hepatitis, colitis, or hematologic disorders (Staras et al., 2006). Among hematologic manifestations, cytopenias are well-described in immunocompromised patients but remain exceptional in otherwise healthy adults.

The pathophysiology of AIHA and aregenerative anemia occurring simultaneously in the setting of CMV infection remains enigmatic.

Cases showing simultaneous bone marrow suppression and hemolysis are exceptional.

Several hypotheses have emerged, suggesting that the virus may exploit multiple pathways to disrupt hematologic homeostasis (Table 2).

The coexistence of a positive direct antiglobulin test and a low reticulocyte count in affected patients reveals a dual pathogenic mechanism: peripheral hemolysis driven by autoantibodies and central suppression of erythropoiesis due to marrow involvement. This duality renders CMV-associated anemia exceptionally rare and potentially life-threatening.

Normally in AIHA, the bone marrow responds by increasing red blood cell production, resulting in a regenerative anemia. However, sometimes the marrow fails to sufficiently increase red blood cell output, causing a non-regenerative anemia despite a normal erythroblast population in the marrow.

This paradox occurs because red blood cell precursors in the marrow may be destroyed prematurely within the marrow itself (intramedullary hemolysis) or their maturation may be impaired by inflammation or immune activation. Consequently, although erythroblasts are present in normal numbers, they do not mature properly into reticulocytes or are destroyed before entering circulation.

At the same time, there is often an increase in granulocyte production reflecting the immune system's stimulation.

Therefore in our patient, the low reticulocyte count and resulting non-regenerative anemia are explained by ineffective erythropoiesis and intramedullary destruction of red cell precursors, despite the presence of a seemingly normal erythroid lineage in the bone marrow. This imbalance reflects a dysregulated marrow response during AIHA.

While Epstein-Barr virus and HIV remain classical viral triggers of AIHA, CMV-induced AIHA is a strikingly uncommon phenomenon. CMV infection in immunocompetent adults is generally self-limiting; nonetheless, accumulating reports underscore its occasional capacity to provoke severe hematologic derangements (Table 3).

Our patient's presentation mirrors these cases: sudden-onset, life-threatening anemia, direct antiglobulin test positivity, absence of other cytopenias, and serologic confirmation of acute primary CMV infection. Bone marrow examination excluded malignant or aplastic processes, reinforcing the causal relationship.
<table><caption>**Table 2. Proposed mechanisms of CMV-induced anemia in immunocompetent adults**</caption><thead><tr><td>Mechanism</td><td>Proposed pathophysiology</td><td>References</td></tr></thead><tbody><tr><td>Polyclonal B-cell activation</td><td>CMV triggers widespread immune activation, leading to production of autoantibodies targeting erythrocytes</td><td>(Berentsen and Tjønnfjord, 2012; Barcellini et al., 2020)</td></tr><tr><td>Direct bone marrow infection</td><td>CMV infects hematopoietic progenitor and stromal cells, impairing erythropoiesis and explaining the aregenerative pattern</td><td>(Griffiths and Reeves, 2021; Cho et al., 2019)</td></tr></tbody></table>

<table><caption>**Table 3. Immunocompetent adults cases about CMV-induced AIHA**</caption><thead><tr><td>Author (Year)</td><td>Patient profile</td><td>Key findings</td></tr></thead><tbody><tr><td>Gavazzi et al., 1999</td><td>Previously healthy adult</td><td>Pronounced hemolytic anemia during primary CMV infection</td></tr><tr><td>Rafailidis et al., 2008</td><td>Immunocompetent adults</td><td>Severe CMV infection in healthy adults may include significant hematologic involvement</td></tr><tr><td>Ferrão et al., 2022</td><td>Immunocompetent adult</td><td>CMV-associated hemolytic anemia highlighting need for inclusion in differential diagnosis of acute hemolysis</td></tr></tbody></table>

The treatment of CMV-associated AIHA in immunocompetent adults remains nonstandardized due to its rarity and lack of controlled studies. Management is typically guided by severity and clinical judgment.

Supportive care with red cell transfusions remains lifesaving in profound anemia.

Understanding the type of antibody is crucial for management and predicting treatment response.

In our patient, warm AIHA, mediated by IgG antibodies active at 37°C, is typically corticosteroid-sensitive, and patients often respond well to standard steroid therapy. In contrast, cold AIHA, mediated by IgM antibodies active at lower temperatures, is generally corticosteroid-resistant, requiring supportive measures such as avoiding cold exposure, transfusions, or targeted therapy like rituximab (Varani and Landini, 2011; Zanella and Barcellini, 2014; Barcellini, 2015).

Antivirals such as ganciclovir or valganciclovir are usually reserved for immunocompromised patients or severe organ disease. However, several case reports suggest that in severe AIHA, antiviral therapy may accelerate recovery by suppressing viral replication and reducing immune stimulation (Gupta and Shorman, 2025; Hodson et al., 2013).

In our case, the combination of transfusions, antiviral therapy, and corticosteroids resulted in complete hematologic recovery, highlighting the

value of a multimodal approach when anemia is life-threatening.

Early recognition is crucial, as delayed diagnosis carries a risk of fatal anemia or multiorgan failure (Gupta and Shorman, 2025; Asranna and Kumar, 2016).

Interestingly, our patient also exhibited positive ANA and anti-SSA antibodies, suggesting that CMV may not only act as a transient trigger for AIHA but could also serve as a precipitating factor for future systemic autoimmunity. Viral infections are increasingly recognized as environmental catalysts for autoimmune disease (Smatti et al., 2019; Fattizzo and Barcellini, 2022). Long-term follow-up is therefore essential to monitor for the potential emergence of systemic lupus or Sjögren's disease.

## 4. CONCLUSION

This case illustrates the rarity of severe aregenerative AIHA triggered by CMV infection in immunocompetent adults. Clinicians should keep CMV in mind when faced with acute anemia. Future efforts should focus on collecting multicenter case data to better define the role of antiviral therapy and to clarify the long-term risk of CMV as a trigger for systemic autoimmune diseases.

## CONSENT

Written informed consent was obtained from the patient for publication of this case report.
## ETHICAL APPROVAL

All procedures performed in this study are in accordance with the ethical standards of the institutional and/or national research committee.

## DISCLAIMER (ARTIFICIAL INTELLIGENCE)

Author(s) hereby declare that NO generative AI technologies such as Large Language Models (ChatGPT, COPILOT, etc) and text-to-image generators have been used during writing or editing of this manuscript.

## COMPETING INTERESTS

Authors have declared that no competing interests exist.

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