Refractory autoimmune hemolytic anemia with poor erythropoietic compensation in combined immunodeficiency: A case series

To the Editor,

Genetic combined immunodeficiencies (CID) are characterized by a profound susceptibility to autoimmunity, with autoimmune cytopenias representing a major cause of morbidity. ¹ , ² The management is particularly complex, as the underlying T‐cell dysfunction necessitates a delicate balance between immunosuppression and the risk of infectious complications. We report three patients with genetic CID who developed severe, refractory autoimmune hemolytic anemia (AIHA), characterized by poor erythropoietic compensation.

1. CASE 1

Patient 1 was a male with 22q11.2 deletion syndrome (22q11.2DS) and a long‐standing history of relapsing autoimmune cytopenias. ³ At 19 years of age, following a rhinovirus infection, he developed acute worsening of chronic thrombocytopenia and an atypical rapidly progressive AIHA, with a 2.5‐fold hemoglobin drop up to 5.1 g/dL in 48 h with direct antiglobulin test (DAT) positive for IgG, inappropriately normal reticulocyte counts (99 × 10⁹/L), and low bone marrow responsiveness index (BMRI 75.6).

Initial treatment with high‐dose methylprednisolone (mPDN) and intravenous immunoglobulin (IVIG) was ineffective. Consequently, given the rapid Hb decline and the delayed activity of second‐line agents, concomitant therapies targeting multiple pathways of immune‐dysregulation were initiated (Figure 1A). This approach was further justified by a previous rituximab failure at 13.5 years of age during a severe episode of immune thrombocytopenic purpura (ITP) and AIHA while on sirolimus maintenance; despite romiplostim and eltrombopag, the patient remained with a platelet count critically below 10,000/μL until a course of proteasome inhibitor bortezomib at age 14 achieved a prolonged, though transient, remission. ³ Nonetheless, the clinical course rapidly deteriorated with hypoxia, causing myocardial ischemia. Therapeutic plasma exchange (PLEX) and splenectomy were considered contraindicated because of the patient's instability. Given the multicompartmental anomalies sustaining immune dysregulation in 22q11DS (reduced Tregs, expanded activated PD‐1+ circulating T follicular helper cells and low B memory cells), ⁴ multihit treatment was escalated first to daratumumab to eradicate CD20‐/CD38+ mature, autoantibody‐producing plasma cells escaping rituximab ⁵ , ⁶ ; second, to sirolimus to suppress autoreactive T‐effector cells and promote regulatory T‐cells, ⁷ , ⁸ alongside rituximab to neutralize remaining CD20+ autoreactive B cells ⁹ ; and then to off‐label eculizumab to prevent intravascular lysis through the membrane attack complex. ¹⁰ Eventually, due to persistent, life‐threatening anemia, the spleen tyrosine kinase inhibitor fostamatinib was added to paralyze macrophage signal transduction, halting Fc‐gamma receptor‐mediated splenic extravascular phagocytosis. ¹¹ , ¹² Ten days after hospital admission, the patient developed severe coagulopathy and intraventricular hemorrhage. He died despite maximal supportive care.

FIGURE 1.

Clinical course and therapeutic interventions. The red lines in the charts illustrate the longitudinal progression of hemoglobin (Hb) levels (g/dL) over the days (x axis), while the blue lines represent the reticulocyte counts (10^9/L) for patients 1 (A), 2 (B), and 3 (C), respectively. As patient 1 had only two determinations of reticulocytes, these are represented by two diamonds. The timing of immunosuppressive treatments or rescue interventions is indicated by colored arrows, while continuous therapies are represented by colored bars. EPO, erythropoietin; IV mPDN, intravenous methylprednisolone; IVIG, intravenous immunoglobulins; PLEX, plasma exchange; RBC, red blood cells.

2. CASE 2

Patient 2, the monozygotic twin of patient 1, has 22q11.2DS with CID and a prior episode of ITP responsive to standard therapy. Shortly after his brother's death and following a documented rhinovirus infection, he developed severe AIHA.

At onset, laboratory findings were misleading, with IgG‐positive DAT and isolated hyperbilirubinemia as the main marker of hemolysis. As for his twin, reticulocyte counts were inappropriately low (43 × 10⁹/L, BMRI 25.0), as was endogenous erythropoietin (EPO, 74.2 mU/mL). Treatment was initiated with mPDN and IVIG; sirolimus was introduced early (Figure 1B). The Hb levels were initially preserved, but over the following hours, the patient lost 5 g/dL of Hb, with a persistent downward trend (nadir 3.2 g/dL), progressing to multiorgan dysfunction requiring mechanical ventilation. A bone marrow aspiration showed marked erythroid hyperplasia with features of dyserythropoiesis, with hemophagocytic phenomena. The patient remained afebrile, with ferritin, fibrinogen, and triglyceride levels within reference ranges during the acute hemolytic phase, and anemia was the only cytopenia. The uncontrolled hemolysis prompted urgent splenectomy, followed by two sessions of therapeutic PLEX. Histological analysis revealed normal spleen size, with massive intrasplenic hemophagocytosis (Figure 2).

FIGURE 2.

Spleen histology of patient 2. (A) Hematoxylin–eosin stain showing preserved splenic parenchyma; (B) CD68 immunostaining highlighting numerous activated macrophages; (C) Macrophages showing hemophagocytic activity (arrows), with cytoplasm containing erythrocytes.

Immunosuppression was intensified with steroid pulses, rituximab, and bortezomib; erythropoiesis‐stimulating agent (ESA) was added. Although the life‐threatening phase resolved, Hb recovery was slow. Sirolimus was replaced with mycophenolate mofetil (MMF) as a steroid‐sparing strategy, based on emerging evidence of activity in refractory autoimmune cytopenias associated with 22q11.2DS. ¹³ , ¹⁴

Hemolysis resolved; transfusion independence was achieved by day 65, and Hb stabilized above 12 g/dL after 4 months, with ESA discontinuation.

3. CASE 3

Patient 3 is a boy with Wiskott‐Aldrich syndrome (WAS, gene variant c.254 T>C), initially manifesting as X‐linked thrombocytopenia. His history included recurrent otitis media and herpesvirus reactivations, never requiring hospitalization. Immunologic evaluation (Table S1) revealed isolated IgM deficiency and reduced CD8⁺ T cells, while WASp expression was markedly reduced. At 10 years of age, he was admitted for suspected abdominal abscess and treated empirically with piperacillin–tazobactam. During hospitalization, he developed severe AIHA (IgG‐positive DAT) with low reticulocytes (58 × 10⁹/L) and BMRI (29.9). Extensive infectious workup only revealed a positive rhinovirus nasal swab.

First‐line treatment with mPDN (5 mg/kg/day) and ESA was ineffective. Subsequently, therapy was escalated to high dose mPDN, IVIG, PLEX, and four doses of rituximab (Figure 1C). Due to persistent steroid dependence, sirolimus was introduced as a steroid‐sparing agent, leading to a gradual and sustained improvement of Hb levels and reticulocytosis.

4. DISCUSSION

We describe three cases of refractory warm AIHA with inappropriately low reticulocyte counts following rhinovirus infection in patients with genetic CID, which occurred in close temporal proximity. The detection of rhinovirus in all patients highlights the role of common viruses as potential triggers of serious complications in CID. Conversely, the concordant clinical presentation in two monozygotic twins underscores the contribution of the genetic background.

AIHA affects up to 23% of WAS and 8% of 22q11.2DS patients. ¹⁵ , ¹⁶ In 22q11.2DS, specific immunologic phenotypes are associated with immune cytopenia development, notably decreased naïve CD4+ T and switched memory B cells <2%. Patients 1 and 2 immunophenotypes (Table S1) are consistent with these observations. Conversely, while AIHA in WAS is typically associated with elevated IgM, ¹⁵ patient 3 atypically presented with isolated IgM deficiency.

All patients demonstrated refractoriness to standard therapy with corticosteroids and IVIG. Inappropriately low reticulocyte counts have been previously identified as a marker of severity in wider AIHA cohorts, often correlating with Hb levels below 6 g/dL. ¹⁷ In Patient 2, marked bone marrow dyserythropoiesis suggests that autoantibodies may target both mature erythrocytes and erythroid precursors, causing ineffective erythropoiesis potentially exacerbated by an infection‐related immune activation. In this context, though the mechanism remains partially obscured, ESA can mitigate such inhibition and improve outcomes, especially if endogenous levels are inadequate. ¹⁸ , ¹⁹ Therefore, we recommend that immunologists monitor reticulocyte kinetics and quantify BMRI; despite limited emergency access to EPO assays, endogenous EPO should be dosed whenever possible, and ESA added whenever bone marrow compensation fails. ¹⁹

Currently, no standardized treatment guidelines exist for AIHA complicating CIDs. ⁹ Considering the underlying T‐cell dysfunction and steroid refractoriness, sirolimus was introduced in all patients as a steroid‐sparing. Although PLEX and splenectomy are not routinely recommended in the management of AIHA and require careful risk–benefit evaluation in patients with IEIs, ⁹ these interventions may represent rescue strategies to gain time in fulminant/refractory cases. ¹ Given the clinical severity and the unfortunate outcome of patient 1, several lines of immunosuppressive therapy plus ESA were successfully combined in patient 2 and 3. In Patient 2, the close temporal sequence of splenectomy, PLEX, rituximab, bortezomib, ESA, and MMF precludes attribution of the response to any single intervention. Splenectomy may have been particularly relevant to the acute control of hemolysis, and MMF may have contributed to long‐term maintenance of response.

These cases confirm that AIHA is a severe complication of CID, potentially triggered by common viral infections. Early reticulocytopenia and low endogenous EPO may identify high‐risk patients, requiring prompt immunomodulatory escalation beyond standard therapy, plus ESA. Rescue strategies should remain strictly reserved for highly selected cases.

AUTHOR CONTRIBUTIONS

Elena Facchini: Investigation; supervision; writing – review and editing. Elena Sabattini: Investigation; formal analysis; writing – review and editing; supervision. Letizia Baldini: Conceptualization; data curation; investigation; writing – original draft; writing – review and editing; methodology; visualization. Mattia Moratti: Conceptualization; methodology; data curation; investigation; visualization; writing – original draft; writing – review and editing. Clara Bertuzzi: Investigation; formal analysis; writing – review and editing; writing – original draft. Maura Fois: Investigation; supervision; writing – review and editing. Fraia Melchionda: Investigation; supervision; writing – review and editing. Alessandro Ruggi: Conceptualization; methodology; data curation; investigation; visualization; writing – original draft; writing – review and editing. Francesco Licciardi: Supervision; writing – review and editing; investigation. Maria Elena Cantarini: Investigation; writing – review and editing; supervision. Veronica Barat: Investigation; supervision; writing – review and editing. Bruno Fattizzo: Investigation; supervision; writing – review and editing. Riccardo Masetti: Investigation; supervision; writing – review and editing. Giovanni Del Borrello: Investigation; supervision; writing – review and editing. Francesca Conti: Conceptualization; investigation; supervision; project administration; writing – review and editing.

FUNDING INFORMATION

The authors have nothing to report.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

ETHICS STATEMENT

This clinical letter was written in accordance with the Declaration of Helsinki. Informed consent was obtained from the patients, and data were handled according to the protocol approved by the Ethics Committee of the IRCCS University Hospital of Bologna (Project ID: 424/2023/Oss/AOUBO).

CONSENT

Informed consent to publication was obtained from the caregiver of the patients.

Supporting information

Table S1. Immunological asset and infectious workup for erythroid suppression. T and B cell subsets from Garcia‐Prat M. et al. Cytometry B Clin Cytom. 2019, except for CD3 + CD4‐CD8‐TCRαβ+ †† from Schatorjé E J H. et al. Scand J Immunol. 2012; Serum Immunoglobulin concentrations from Garcia‐Prat M. et al. J Clin Lab Anal. 2018. IRT, Immunoglobulin replacement therapy. ‡ % total lymphocytes; § % total CD4+ cells; ¶ % total CD8+ cells; †† % TCRαβ+CD3 + . Cells; ‡‡ % total CD19+ cells; §§ SI conversion factor: To convert IgG/IgA/IgM to g/L, multiply values by 10².

Baldini L, Moratti M, Ruggi A, et al. Refractory autoimmune hemolytic anemia with poor erythropoietic compensation in combined immunodeficiency: A case series. Pediatr Allergy Immunol. 2026;37:e70465. doi: 10.1111/pai.70465

DATA AVAILABILITY STATEMENT

The data that supports the findings of this study are available in the Supporting Information of this article.