Erythrovirus-B19-Induced Pure Red Cell Aplasia Revealing Untreated HIV Infection

Introduction

Erythrovirus (formerly parvovirus) B19 (B19V) is a single-stranded DNA virus that usually causes mild, self-limited disease, such as erythema infectiosum in children, hydrops fetalis in pregnant women, or transient arthropathy in adults [1]. Its clinical significance lies in its tropism for erythroid precursors, which may lead to transient aplastic crises in patients with chronic hemolysis and to persistent pure red cell aplasia (PRCA) in immunocompromised individuals [2,3]. PRCA results from the failure to generate neutralizing antibodies against B19V capsid proteins (VP1/VP2), a defect commonly associated with immunosuppression. Persistent viremia allows ongoing infection of erythroid progenitors, which undergo apoptosis mediated by NS1 and the 11-kDa protein, along with cell cycle disruption, ultimately leading to severe chronic anemia [4].

Among people living with human immunodeficiency virus (HIV), erythrovirus infection can result in severe, recurrent anemia that often requires intravenous immunoglobulin (IVIG) therapy [5,6]. However, the disease is sufficiently rare that controlled studies have not been performed; the rationale for use of IVIG in B19V-associated PRCA is based on small retrospective studies and case reports [7]. Here, we present a case of PRCA due to primary B19V infection as the first manifestation of acquired immunodeficiency syndrome (AIDS) in an HIV-naïve patient. This presentation is exceptional because B19V is rarely the sentinel event leading to an HIV diagnosis; such cases remain scarcely documented, underscoring their clinical and scientific relevance.

Case Report

A previously healthy 23-year-old cisgender homosexual male university student presented with a 1-month history of progressive fatigue, exertional dyspnea, dizziness, and a syncopal episode. He denied bleeding, use of chronic medications, allergies, and tobacco or illicit drug use; he reported occasional alcohol intake once weekly. He had not traveled recently and reported no occupational exposure to toxic substances. At a community hospital, the patient was diagnosed with severe isolated anemia: hemoglobin level of 3.6 g/dL, hematocrit of 7%, mean corpuscular volume of 80 fL, and red cell distribution width of 14.4%. The findings were consistent with a normocytic, normochromic pattern lacking associated cytopenias. He required transfusional support at that time. Baseline and follow-up laboratory findings are summarized in Table 1. During that admission, serologic testing revealed newly diagnosed HIV infection. Baseline testing in July 2025 showed an HIV-1 RNA viral load of 811 000 copies/mL (log 5.91) and a CD4 lymphocyte count of 33 cells/μL (2.43%), with a CD4/CD8 ratio of 0.04. Combination antiretroviral therapy (ART) with tenofovir, lamivudine, and dolutegravir was initiated in late July 2025, along with folic acid supplementation and trimethoprim-sulfamethoxazole for prophylaxis against opportunistic infections. An extensive etiological investigation of anemia was not performed during the first hospitalization because the patient was admitted to a low-complexity community hospital, where the immediate priority was lifesaving transfusional support and initiation of ART after the diagnosis of advanced HIV infection. In the absence of other systemic symptoms or clinical evidence of opportunistic disease, the anemia was initially attributed to advanced HIV-related bone marrow suppression; further diagnostic evaluation was deferred until reassessment after clinical stabilization.

Approximately 15 days later, the patient was admitted to a tertiary care hospital with recurrent fatigue, exertional dyspnea, and dizziness. On admission, laboratory results revealed a hemoglobin level of 6.2 g/dL, hematocrit of 19%, red blood cell count of 2.24 million/μL, mean corpuscular volume of 84.6 fL, mean corpuscular hemoglobin of 27.7 pg, mean corpuscular hemoglobin concentration of 32.6 g/dL, and red cell distribution width of 13.8%. A peripheral blood smear showed no abnormalities. The reticulocyte count was 0.3%. The white blood cell count was 6410/μL (including 622 lymphocytes and 4731 neutrophils), and the platelet count was 325 000/μL. Iron studies showed a ferritin level of 530 ng/mL, serum iron of 227 μg/dL, total iron-binding capacity of 231 μg/dL, and transferrin saturation of 25.6%. The vitamin B12 level was 418 pg/mL, serum folate was 8.5 ng/mL, and vitamin D was 8.7 ng/mL. Haptoglobin was 153 mg/dL, and the direct Coombs test result was negative. Kidney function tests showed a creatinine level of 1.35 mg/dL and urea level of 51 mg/dL. Liver function test results were within normal limits (alkaline phosphatase 75 U/L, aspartate aminotransferase 36 U/L, alanine aminotransferase 29 U/L, gamma-glutamyl transferase 48 U/L, total bilirubin 0.3 mg/dL). The international normalized ratio was 1.2, and the activated partial thromboplastin time was 23.5 seconds.

Serological investigations revealed negative findings concerning hepatitis B surface antigen, hepatitis C antibody, venereal disease research laboratory test for syphilis, anti-hepatitis B surface antibody, Chagas disease, and human T-lymphotropic virus. Toxoplasma gondii IgG and cytomegalovirus IgG were reactive, consistent with past exposure. Testing for visceral leishmaniasis using a rapid immunochromatographic assay to detect anti-rK39 antibodies showed negative results. Additional screening for arboviruses, including anti-dengue virus NS1, also showed negative findings. Bone marrow aspiration and biopsy revealed a hypocellular marrow with substantially reduced erythroid lineage (Figure 1), as well as numerous hemosiderophages (iron-laden macrophages), reflecting iron accumulation due to ineffective erythropoiesis (Figure 2). Histopathological evaluation of the bone marrow biopsy did not identify giant pronormoblasts with viral inclusions, cytoplasmic blebs, or “lantern cells”; these morphological features were not evident in the examined biopsy fragments [8]. Immunophenotyping detected 2.2% immature cells (CD34+, weak CD45+), distributed among hematopoietic stem/progenitor cells (12.8%), neutrophilic lineage (7.9%), B-lymphoid lineage (72.6%), and erythroid lineage (6.7%). Aberrant CD7 expression was observed in cells committed to the erythroid lineage, consistent with impaired erythropoiesis and supporting the diagnosis of PRCA due to B19V infection. Given the context of isolated anemia without evidence of hemolysis, nutritional deficiency, or bone marrow infiltration, infection with B19V was suspected. Polymerase chain reaction testing for B19V, performed in late August 2025 (approximately 1 month after ART initiation), showed positive results; serology confirmed acute infection based on detection of anti-B19V IgM.

The patient was treated with a single dose of human IVIG (1.5 g/kg). ART-related hematologic toxicity was excluded because symptom onset preceded initiation of therapy. During 8 days of inpatient monitoring, no further decline in hemoglobin was observed, and his symptoms progressively improved. Upon discharge with a hemoglobin level of 7.0 g/dL, he was maintained on ART, folic acid, and prophylactic trimethoprim-sulfamethoxazole; clinical stability and resolution of recurrent anemia were noted. He attended outpatient follow-up 1 month after immunoglobulin infusion for hematimetric monitoring, which showed a hemoglobin level of 10.8 g/dL and hematocrit of 33%, consistent with an initial hematologic response. At 3 months of follow-up, hemoglobin had increased to 13.5 g/dL and hematocrit had risen to 41.5%; there was no evidence of relapse during this period. Figure 3 depicts the temporal trend in hemoglobin levels, highlighting the substantial increase after immunoglobulin infusion and subsequent stabilization during follow-up.

Discussion

PRCA is an uncommon bone marrow syndrome characterized by severe anemia, reticulocytopenia, and pronounced erythroid hypoplasia [1]. Multiple causes have been reported, including autoimmune disease, thymoma, hematologic malignancies, and viral infections; however, B19V is an infrequent etiology [9]. Although PRCA is rarely the presenting manifestation of HIV infection, sporadic case reports have documented its role as an initial diagnostic clue in the setting of advanced, previously unrecognized immunosuppression [9–12]. The rarity of this association makes the present case particularly relevant, given that PRCA was not only the consequence of B19V infection but also the first clinical clue to a previously undiagnosed HIV infection. Whereas most published reports describe B19V as a complication in patients with established immunosuppression, the recognition of PRCA in our patient directly led to the identification of advanced HIV disease.

B19V has a well-established tropism for erythroid precursors, where it induces lysis of infected progenitor cells and inhibits erythropoiesis [13]. In immunocompetent hosts, infection is often subclinical or manifests as a self-limited exanthem in childhood. In contrast, among immunocompromised individuals, particularly those with untreated or advanced HIV infection, chronic B19V infection can result in severe, recurrent, and refractory anemia [14]. The pathogenic mechanism is largely explained by the inability to generate neutralizing IgM antibodies and by impaired cellular immune responses, leading to persistent viral replication and the destruction of red cell precursors. Additional dysfunction of macrophages and CD4+ T-helper cells contributes to defective antigen presentation and insufficient clearance of infected cells [3]. Consequently, patients may develop profound anemia as the only clinical manifestation of infection, often without fever, rash, or other systemic features, resulting in underdiagnosis. In some cases, anemia has been misattributed to ART cytotoxicity, a possibility excluded in our patient because the hematologic abnormalities preceded ART initiation [15].

Anemia is the most frequent hematologic abnormality in HIV-infected individuals, with prevalence estimates ranging from 60% to 80%, depending on the stage of disease [5,16]. The presence of anemia has prognostic implications and is associated with faster progression to AIDS and increased mortality [17]. The diverse etiologies include nutritional deficiencies, opportunistic infections involving the bone marrow, drug-induced myelotoxicity, and chronic inflammation. This broad differential often delays recognition of less common causes such as B19V. In our patient, extensive laboratory evaluation excluded nutritional deficiencies, hemolysis, and drug toxicity, whereas bone marrow biopsy provided critical evidence of selective erythroid aplasia, guiding molecular testing and confirmation of B19V infection.

The clinical course prior to diagnosis is remarkably similar across cases. Repeated blood transfusions over weeks to months have been a common feature in nearly all reports, reflecting delayed recognition of B19V as the underlying etiology of anemia [18,19]. The importance of considering B19V in this context is reinforced by the literature. Wylde et al described a 69-year-old man in Indonesia whose initial HIV presentation was B19V-associated PRCA; remission was achieved by administration of IVIG and ART [9]. Similarly, Griffin et al reported severe B19-induced erythroid hypoplasia as the first clinical manifestation of HIV in an 8-year-old child in the United States; IVIG therapy led to remission [12]. Watanabe et al described a 54-year-old HIV-positive man with advanced disease who later developed severe transfusion-dependent anemia due to B19V infection, confirmed by IgM serology and polymerase chain reaction testing [20]. Collectively, these reports emphasize that B19V can present either as the sentinel manifestation of undiagnosed HIV or as a complication of advanced infection.

When immunologic statuses are compared across reported cases, a consistent pattern of profound CD4+ T-cell depletion emerges. Most patients exhibited CD4+ counts below 100 cells/μL at presentation, regardless of age group or geographic setting [18,21]. Koduri published a review of 26 HIV-infected patients with B19V-associated PRCA, revealing that most patients had advanced immunosuppression, with a median CD4+ count of 42/μL; in all but 4 cases, the count was below 80/μL [5]. These findings underscore the link between profound immunodeficiency and susceptibility to persistent B19V infection. Importantly, nearly all patients responded to IVIG, but relapses were frequent in those with CD4+ counts below 100/μL, and maintenance therapy was sometimes required. In contrast, patients with CD4+ counts above 300/μL often achieved sustained remission after a single course of IVIG [22,23]. Our patient’s CD4+ count of 33/μL is consistent with the literature; however, he responded favorably to a single IVIG infusion, possibly reflecting the combined effect of passive neutralizing antibodies and early initiation of ART, which may have facilitated immune reconstitution. Pooled analyses indicate that approximately one-third of immunocompromised patients with B19V-associated PRCA experience relapse after initial IVIG therapy, and HIV infection is more frequent among those who fail to maintain hemoglobin correction at 12 months [7].

The use of IVIG for B19V-associated PRCA was first described by Kurtzman et al in 1988 concerning a patient with chronic infection who required repeated infusions to maintain hemoglobin levels [24]. Since then, IVIG has become the cornerstone of therapy in immunocompromised patients, including those with HIV, primary antibody deficiencies, and a need for post-transplant management [6]. Although spontaneous resolution can occur after ART restores immune function, IVIG remains critical for acutely symptomatic patients, providing immediate viral neutralization and clinical stabilization [25,26]. More recent case reports suggest that early or concurrent ART initiation can enhance the durability of responses to IVIG [18,21]. In our patient, a single IVIG dose was associated with an initial hematologic response and the absence of relapse during short-term follow-up. Although the administered IVIG dose (1.5 g/kg) was below the commonly suggested cumulative threshold of 2 g/kg, the patient demonstrated a favorable clinical response, and published evidence concerning the optimal dosing strategy remains heterogeneous. However, given the limited duration of observation and the patient’s profound immunosuppression, this finding should be interpreted as an initial therapeutic response rather than definitive sustained remission.

Beyond the clinical course, bone marrow findings in the present case offer additional insights into pathogenesis. The pronounced reduction in erythroid precursors was consistent with the virus’s tropism, supporting a diagnosis of PRCA. However, the immunophenotypic demonstration of aberrant CD7 expression in erythroid-committed cells was particularly unusual. CD7 is typically a marker of T cells and some myeloid lineages; its expression in erythroid precursors has rarely been reported. This finding may reflect virus-driven dysregulation of hematopoietic differentiation or an immune-mediated compensatory phenomenon [3,27]. Such observations highlight the potential for B19V to cause clinically significant anemia while altering the immunophenotypic architecture of the bone marrow.

Conclusions

Anemia is common in advanced HIV infection; however, its etiology is multifactorial and often requires thorough evaluation. B19V should be considered in the differential diagnosis of severe hypoproliferative anemia, particularly in profoundly immunosuppressed individuals. This case underscores the importance of recognizing B19V-associated PRCA as a possible first manifestation of HIV, the role of IVIG in achieving rapid stabilization, and the value of bone marrow studies in identifying atypical immunophenotypic features. Although the optimal IVIG regimen has not been clearly established, evidence suggests that low or intermediate doses may be ineffective, whereas cumulative doses of at least 2 g/kg per course are associated with higher response rates. Given the substantial relapse rate observed within the initial months after treatment, repeated IVIG courses are frequently required [7]. Early identification of PRCA, particularly when unexplained or refractory, may serve as a critical diagnostic clue to previously unrecognized HIV infection, allowing timely intervention to reduce anemia recurrence and improve overall clinical outcomes [28].