Pure Red Cell Aplasia Caused by Parvovirus B19 in Patients with Human Immunodeficiency Virus Infection: A Series of Four Cases

Abstract

Parvovirus B19 (B19V) infection can cause pure red cell aplasia (PRCA) in patients with human immunodeficiency virus (HIV) infection. Intravenous immunoglobulin (IVIG) is a preferred treatment option. From July 2019 to March 2022, four patients with HIV infection were admitted to Guangzhou Eighth People’s Hospital with dizziness and fatigue and were diagnosed with PRCA. Blood investigations revealed severe anemia and the B19V genome. Therefore, the four patients were diagnosed with B19V-induced PRCA. All four patients received red blood cell transfusion in the setting of antiretroviral therapy, and two of the four patients received intravenous immunoglobulin (IVIG). After 3–7 months of treatment, all four patients recovered, although two did not receive IVIG. This suggests that IVIG is not always necessary for the treatment of PRCA in patients with HIV infection and that effective antiretroviral therapy and immunological reconstitution play an important role in the eradication of parvovirus.

1. Introduction

Anemia is the most common hematologic abnormality in patients with human immunodeficiency virus (HIV) infection, with an incidence of 20%–84% in different clinical settings. The causes of anemia among patients with HIV are multifactorial and include the direct effects of HIV infection, adverse effects of antiretroviral therapy (ART), opportunistic infections, tumors, malnutrition, and hemorrhage.^[1] Persistent infection with human parvovirus B19 (B19V) is an important cause of anemia in patients with HIV.

B19V, a member of the family Parvoviridae, is a nonenveloped single-stranded DNA virus, which is classified into three genotypes (genotypes 1, 2, and 3).^[2] According to genetic divergence, genotypes 1 and 3 are further divided into two subgenotypes (1a and 1b for genotype 1, and 3a and 3b for genotype 3). All three genotypes appear to have similar pathogenic and antigenic properties.^[2] In immunocompetent individuals, B19V infections are usually asymptomatic and cause self-limiting disease. In immunocompromised patients with HIV infection, persistent B19V infection can cause pure red cell aplasia (PRCA) due to inadequate neutralizing antibody production.^[3] The seroprevalence of B19V has been documented in some areas of China,^[4] but few reports are available on the clinical treatment of PRCA caused by B19V in patients with HIV infection. We retrospectively analyzed the laboratory characteristics and clinical treatment of PRCA caused by B19V infection in four patients with HIV infection admitted to Guangzhou Eighth People’s Hospital between July 2019 and March 2022 to provide recommendations for diagnosis and treatment of B19V infection in patients with HIV infection.

2. Case presentation

The age of the four patients ranged from 22 to 53 years. Their general characteristics are shown in Table 1. Three of the four patients were receiving ART.

Table 1.

Clinical characteristics and laboratory data of four HIV-infected patients at admission

Parameters	Case 1	Case 2	Case 3	Case 4
Age (y)	48	53	22	30
Sex	M	F	M	M
ART regimens	TDF + 3TC + DTG	TDF + 3TC + DTG	No ART	TDF + 3TC + EFV
ART duration	1 month	2 months	None	5 years
Complication	Syphilis	Not found	Not found	Syphilis
Hb (g/L)	15	20	35	69
RCC (×1012/L)	1.06	1.38	1.52	1.12
MCV (fL)	98	99	96	103
Ret (%)	0.20	0.22	0.28	0.21
WBC (×109/L)	5.45	4.77	3.07	4.57
LYM (×109/L)	1.91	0.62	0.68	1.68
PLT (×109/L)	459	508	315	363
CD4 (cells/μL)	68	46	24	86
HIV RNA (copies/mL)	<20	206	492000	<20
B19V DNA	+	+	+	+
B19V IgM	N/A	−	−	−
B19V IgG	N/A	−	−	−
EB DNA (copies/mL)	−	−	−	−
CMV DNA (copies/mL)	−	−	−	−

+: Positive; −: Negative; 3TC: Lamivudine; ART: Antiretroviral therapy; B19V: Parvovirus B19 virus; CD4: CD4 T-cell; CMV: Cytomegalovirus; DTG: Dolutegravir; EB: Epstein-Barr virus; EFV: Efavirenz; F: Female; Hb: Hemoglobin; HIV: Human immunodeficiency virus; LYM: Lymphocytes; M: Male; MCV: Mean cell volume; N/A: Not available; PLT: Platelets; RCC: Red cell count; Ret: Reticulocyte percentage; TDF: Tenofovir disoproxil; WBC: White blood cells.

All four patients were admitted to our hospital because of dizziness and fatigue, but did not have fever, bleeding, or any other symptoms. Computed tomography found no evidence of hepatomegaly, splenomegaly, or lymphadenopathy. Blood investigations revealed severe anemia (hemoglobin, 15–69 g/L; red blood cell count, 1.06 × 10¹²/L–1.52 × 10¹²/L) (Table 1). Nested polymerase chain reaction targeting the NS1/VP1u gene of B19V and phylogenetic analysis were performed as previously described.^[5] Polymerase chain reaction results showed that all four patients were infected by B19V, and the patient not receiving ART had advanced AIDS (HIV viral load 492,000 copies/mL and CD4 T-cell count 24 cells/μL) (Table 1). Phylogenetic analysis showed that all the B19V detected in the all four patients belonged to genotype 1a (Figure 1). A bone marrow biopsy was performed in case 1. The biopsy showed a decrease in erythroid progenitor cells and active granulocyte hyperplasia. All four patients were diagnosed with PRCA caused by persistent B19V infection.

Figure 1.

Phylogenetic analysis of the nucleotide sequences of the NS1/VP1u gene. The tree was generated by the neighbor-joining method using MEGA6 Software, which was drawn to scale, with branch lengths measured in the number of substitutions per site. Only branches supported by a bootstrap value above 50% are displayed. The strains detected in this study are highlighted with a solid circle. The GenBank accession number is shown at the tips. The analysis involved 11 nucleotide sequences, including B19V isolates of genotype 1a (B19-Au) and genotype 1b isolates (Vn147), genotype 2 (LaLi and A6), genotype 3a (V9), and genotype 3b (D91.1, BN58.3) with the B19V sequences obtained in the current study.

Three of the four patients (cases 1, 2, and 3) continued or commenced ART, including tenofovir disoproxil (TDF), lamivudine (3TC), and dolutegravir (DTG), and received red blood cell transfusion and/or intravenous immunoglobulin (IVIG; 400 mg/kg/d over 5 days) (Table 2). After treatment, they gradually recovered from anemia within 3.5 months (Table 2). In more than 6 months of follow-up, two patients (cases 2 and 3) showed a significant improvement in their quality of life, without dizziness, fatigue, or other symptoms. Laboratory examination showed that their Hb maintained greater than 120 g/L with undetectable B19V-DNA, and their CD4 T-cell counts remained greater than 200 cells/μL.

Table 2.

Treatment and outcome of four HIV-infected patients

Parameters	Case 1	Case 2	Case 3	Case 4
ART regimens	TDF + 3TC + DTG	TDF + 3TC + DTG	TDF + 3TC + DTG	TDF + 3TC + EFV/DTG
IVIG course (times)	1	0	0	2
RBCT (unit)	13	5	2	6
Hb (g/L)	143	110	109	166
B19V DNA	−	−	−	−
B19V IgM	N/A	−	−	−
B19V IgG	N/A	+	+	+
CD4 (cells/μL)	162	233	142	145
HIV RNA (copies/mL)	<20	<20	<20	<20
Recover period (mo)	3.5	3.0	3.0	7.0

−: Negative; +: Positive; 3TC: Lamivudine; ART: Antiretroviral therapy; B19V: Parvovirus B19 virus; CD4: CD4 T-cell; DTG: Dolutegravir; EFV: Efavirenz; Hb: Hemoglobin; HIV: Human immunodeficiency virus; IVIG: Intravenous immunoglobulin; N/A: Not available; RBCT: Red blood cell transfusion; TDF: Tenofovir disoproxil.

Case 4 initially received 4 U of packed red blood cells and one course of IVIG (400 mg/(kg·d) over 5 days). Four months later, there was no obvious improvement in the patient’s hemoglobin level (80 g/L), and his CD4 T-cell count decreased from 86 to 30 cells/μL. Subsequently, the ART regimen of TDF + 3TC + efavirenz (EFV) was switched to TDF + 3TC + DTG, and the patient was transfused with an additional 2 U of packed red blood cells and one course of IVIG (400 mg/(kg·d) over 5 days). Three months after this treatment, he was no longer anemic (hemoglobin, 166 g/L) and he had good immune reconstitution (CD4 T-cell count, 145 cells/μL) (Table 2). During a further 7 months of follow-up, he maintained a hemoglobin level greater than 164 g/L and a CD4 T-cell count of 163–278 cells/μL.

The study was conducted in accordance with the Declaration of Helsinki and was approved by the institutional review board of Guangzhou Eighth People’s Hospital, Guangzhou Medical University (Ke201816107) on December 17, 2021.

3. Discussion

B19V invades human erythroid progenitor cells of the bone marrow by targeting the primary cell surface receptor (P antigen) on the cell surface and can cause various diseases. B19V infection causes fifth disease (erythema infectiosum) in immunologically competent individuals, a transient aplastic crisis in patients with chronic hemolysis, and PRCA in immunocompromised hosts (especially in patients with HIV infection and organ transplant recipients). The seroprevalence of B19 is correlated with age, ranging from 2% in children younger than 5 years to 80% in the adult population.^[2] The reported prevalence of B19V immunoglobulin G (IgG) antibodies ranges from 21.9% to 41.8% in the greater metropolitan area of Hangzhou, East China.^[6] Another study reported that the prevalence of B19V-DNA in HIV-positive individuals was 4.5% in Sichuan, Southwest China.^[4] However, there are few reports on the clinical treatment of B19V-induced PRCA in severely immunocompromised patients in China. In this study, we retrospectively analyzed the case histories of four patients with HIV infection and B19V-induced PRCA in Guangzhou, China. The results suggest that effective ART and good immune reconstitution are central to improving the prognosis.

Globally, B19V is a common pathogen, but the geographical distribution of the three genotypes differs. Genotype 1 is the most prevalent genotype worldwide. Genotype 2 is less common than genotype 1 and is found sporadically in North America and Europe. Genotype 3 is occurs predominantly in Ghana and is found sporadically in Europe, Brazil, India, South Africa, and the United States.^[2,4] Three B19V subgenotypes (1a, 1b, and 3b) have been detected in China, and subgenotype 1a is the most prevalent.^[4,6] Phylogenetic analysis confirmed that all four patients were infected with B19V subgenotype 1a. This suggests that subgenotype 1a may be the dominant strain in Guangzhou. However, this needs to be confirmed by a systematic epidemiological study.

Cellular immunodeficiency is the primary cause of persistent B19V infection in patients with HIV infection. These individuals are unable to eliminate B19V after infection because of failure to produce stable B19V-specific neutralizing antibody. Our data showed that all three patients tested for B19V antibodies were B19V IgG- and IgM-negative, despite testing positive for B19V DNA. This result is consistent with previous studies showing that the positivity rate for B19V DNA is higher than that for IgG and IgM.^[7] This is due to HIV-induced depletion of CD4-T lymphocytes, which are required for B cell–mediated antibody production.

As IVIG contains a large amount of B19V-specific neutralizing antibody, it is an effective treatment for B19V-associated chronic anemia and PRCA.^[8] However, several case reports have indicated that relapse can occur when IVIG treatment is interrupted.^[2] Vaz et al. ^[9] reported that B19V-mediated PRCA could be successfully treated with ART alone, without the need for IVIG. Consistent with these observations, two of our patients (cases 2 and 3) remained in remission for more than 6 months after treatment with red blood cell transfusion and ART, without IVIG. In contrast, case 4 received one course of IVIG but initially experienced no remission of anemia, which may have been due to inadequate CD4 T-lymphocyte recovery. A recent retrospective clinical study suggested that DTG-based ART regimens may be more conducive to CD4 recovery than EFV-based regimens.^[10] To improve the effect of immune reconstitution, EFV (a reverse transcriptase inhibitor) was replaced with DTG (an integrase inhibitor) in the ART regimen. After this adjustment, the patient’s CD4 T-lymphocyte count increased to 145 cells/μL within 3 months and remained greater than 164 cells/μL during 7 months of follow-up. These cases highlight the importance of effective ART and good immune reconstitution in managing VB19-mediated PRCA in patients with HIV infection.

Funding

This work was supported by Guangzhou Basic Research Program on People’s Livelihood Science and Technology (202002020005), National Natural Science Foundation of China (82072265), Technology Planning Project of Guangdong Province (2021B1212040017), and Sun Yat-sen University Founded Program (2022_76220_B21127).

Author Contributions

Linghua Li, Jun Qian, and Linna Liu conceived and coordinated the study. Feilong Xu, Yulong Wang, and Linjin Fan designed, performed, and analyzed the experiments and wrote the manuscript. Yaozu He and Xiejie Chen revised the manuscript. Pengfei Ye performed data collection and data analysis. All authors reviewed the results and approved the final version of the manuscript.

Conflicts of Interest

None.

Data Available Statement

The data sets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.