To the editor:
Hereditary spherocytosis (HS) is one of the most common congenital
hemolytic anemia. Infections augment clinical and subclinical hemolysis
in patients with HS. On the other hand, severe aplastic crisis occurs in
human parvovirus B19 (B19V) infection. No other specific causes of
aplastic crisis have been recognized in HS patients. Here we report
severe anemia in a HS patient during the course of acute phase Kawasaki
disease (KD). The comparison of iron profiles and hepcidin levels in
this patient between KD and B19V infection indicated that KD-associated
severe anemia occurred as an episodic hypoplasia. This is the first
report of KD-driven aplastic crisis in HS patients.
A five-year-old HS boy was admitted to our hospital because of
high-grade fever lasting 6 days. He presented with prolonged jaundice at
birth and received a diagnosis of non-severe HS because of spherocytosis
without family history. This active boy showed 10-11.5 g/dL of
hemoglobin concentrations, mild splenomegaly and jaundice (Figure 1
upper). Laboratory data on admission were as follows; hemoglobin: 7.4
g/dL, reticulocyte: 29×109/L, indirect bilirubin: 1.6
mg/dL, ferritin: 315.5 μg/dL, serum iron: 14 μg/dL, and C-reactive
protein (CRP): 78.8 mg/L. On 9th febrile day, he received the diagnosis
with KD due to fever, conjunctival injection, lip erythema, extremity
changes, and slightly dilated coronary arteries. Intravenous
immunoglobulin (IVIG 2 g/kg) and oral aspirin (30 mg/kg/day) led to a
prompt defervescence on the next day. Coronary artery lesions regressed
within one month. Hemoglobin concentration showed a nadir of 6.6 g/dL on
day 11th of KD, and gradually improved without red cell transfusion.
Iron profiles monitored during the course of KD were compared with those
in his aplastic crisis at age 6 years (Figure 1). Serum hepcidin-25
levels were measured by using liquid chromatography/mass spectrometry
(Medical Care Proteomics Biotechnology, Ishikawa,
Japan)1. The reference range of hepcidin-25 in healthy
adult controls was 7.8±7.0 ng/mL2. The hepcidin level
reached a maximum of 28.5 ng/mL on day 9th of KD and 162 ng/mL on day
3th of febrile aplastic crisis in B19V infection. The hepcidin levels
peaked at the nadir of hemoglobin concentration and declined with
improved symptoms. Hepcidin is the key iron-regulating peptide
synthesized and released by hepatocytes3, 4. Iron
overload and interleukin (IL)-6 induce hepcidin secretion, that
suppresses iron metabolism and reduces hematopoiesis4,
5. Serum IL-6 levels are elevated in infection or non-infectious
systemic inflammation. Previous reports showed that hemoglobin levels in
KD patients were 1.9 g/dL and 1.3 g/dL lower than those in healthy
controls and febrile controls, respectively6, 7.
Considering the kinetics of reticulocyte counts and indirect bilirubin
levels along with iron profiles, prolonged inflammation of KD appeared
to trigger severe anemia in this patient. Inflammation control by IVIG
effectively reduced the hepcidin level with prompt recovery of anemia.
On the other hand, iron-burden by red cell transfusion without
inflammation control led to the delayed reduction of circulating
hepcidin in B19V-induced aplastic crisis. This first reported case of
KD-driven aplastic crisis was less severe than B19V-induced aplastic
crisis, but the pathophysiology shared hepcidin-mediated iron
metabolism.