Hypothesis: Low Vitamin A and D Levels Worsen Clinical Outcomes When Children with Sickle Cell Disease Encounter Parvovirus B19

Abstract

Human parvovirus B19 causes life-threatening anemia due to transient red cell aplasia (TRCA) in individuals with sickle cell disease (SCD). Children with SCD experiencing profound anemia during TRCA often require red blood cell transfusions and hospitalization. The prevalence of vitamin deficiencies in SCD is high and deficiencies are associated with respiratory and pain symptoms, but the effects of vitamins on acute infection with parvovirus B19 remain unclear. We performed a clinical study in which 20 SCD patients hospitalized with parvovirus B19 infections (Day 0) were monitored over a 120-day time course to query relationships between vitamins A and D and clinical outcomes. There were significant negative correlations between Day 0 vitamin levels and disease consequences (e.g., red blood cell transfusion requirements, inflammatory cytokines). There were significant positive correlations (i) between Day 0 vitamins and peak virus-specific antibodies in nasal wash, and (ii) between Day 0 virus-specific serum plus nasal wash antibodies and absolute reticulocyte counts. There was a significant negative correlation between Day 0 virus-specific serum antibodies and virus loads. To explain the results, we propose circular and complex mechanisms. Low baseline vitamin levels may weaken virus-specific immune responses to permit virus amplification and reticulocyte loss; consequent damage may further reduce vitamin levels and virus-specific immunity. While the complex benefits of vitamins are not fully understood, we propose that maintenance of replete vitamin A and D levels in children with SCD will serve as prophylaxis against parvovirus B19-induced TRCA complications.

Keywords: parvovirus B19; sickle cell anemia; vitamins A and D.

Figure 1

Indices of TRCA Severity and Vitamin Levels Over Time. The X-axis indicates time relative to the day of hospitalization (Day 0, d.0). (A–C) Hematological trends of 20 pediatric patients with SCD hospitalized due to acute parvovirus B19 infection and found to have TRCA and followed over 120 days. Over the course of 120 days, hemoglobin and reticulocyte counts steadily increased while LDH decreased. (D) Parvovirus B19 levels were measured by PCR over 120 days. Almost all patients had undetectable virus levels by Day 120. (E) Most patients were vitamin A deficient (retinol < 20 μg/dL) on Day 0. (F) Vitamin D (25[OH]D) levels were measured using a Roche Elecsys Vitamin D assay. A dotted line indicates cut-offs for deficiencies. For both vitamin A and vitamin D, levels improved after the acute illness, though many patients remained vitamin A or vitamin D deficient at Day 120. (G–H) Virus-specific IgG titers in serum and NW samples were followed using a virus-specific ELISA with VLP-coated plates over 120 days.

Figure 2

Vitamin levels correlate negatively with TRCA severity. (A–F) TRCA severity parameters correlations with Day 0 vitamin A (A,C,E) and vitamin D (B,D,F) levels. Associations were analyzed with GraphPad Prism using Spearman’s rank correlation coefficient. We scored significance as p < 0.05. Vitamin A was significantly positively correlated with hemoglobin concentration (A), and negatively correlated with transfusion volumes (C), and LDH (E). One retinol measurement was not available. Vitamin D levels significantly, negatively correlated with required PRBC transfusion volumes (D). PRBC = packed red blood cells.

Figure 3

Kinetics of cytokine/chemokine levels. The kinetics of a subset of serum cytokine/chemokine levels are shown. ND = not detected.

Figure 4

Hypothesis: circular influences among vitamins, the virus-specific immune response, virus amplification, and disease outcome. A hypothesis is illustrated to explain cause-effect relationships as follows: Low vitamin levels (step 1) cause poor virus-specific immune responses (step 2). Poor immunity allows virus amplification and reduced ARC (step 3). Downstream disease consequences, include tissue damage and requirements for transfusions (step 4). Cytokine/chemokine patterns change (step 5) and vitamin levels are further reduced (step 1). Factors are cross-regulatory, and influences are bidirectional (black arrows).