Chronic rotavirus infection in an infant with severe combined immunodeficiency: successful treatment by hematopoietic stem cell transplantation.

Kobrynski et al. [1] showed gastrointestinal complaints in children can be an early sign of primary immunodeficiency disease (PIDD). Rotavirus infection associated with PIDD can be life-threatening. Rotavirus is a leading cause of childhood gastrointestinal disease worldwide [2]. Most rotavirus disease is caused by 5 G types (G1-G4 and G9) and 3 P types (P1A[8], P1B[4], and P2A[6]) [2]. Two live oral rotavirus vaccines, RotaTeq® (5 different human-bovine reassortant rotavirus strains; Merck and Co, Whitehouse Station, NJ) and Rotarix® (1 human rotavirus strain; GlaxoSmithKline, Rixensart, Belgium) are recommended for routine immunization of US infants [2]. Disease caused by emerging worldwide rotavirus type, G9P[8] may be prevented by both vaccines although this strain is not included in either vaccine. Severe combined immunodeficiency (SCID) is characterized by lack of T cells and life-threatening infections [3]. Treatment of viral infections prior to hematopoietic stem cell transplantation (HSCT) with intravenous immunoglobulin (IVIG) and antivirals has been attempted, but persistence of viral disease has been reported [3–8]. We report a 7 month-old male infant with SCID who had persistent, nonvaccine-associated rotavirus gastroenteritis and viremia despite oral and IVIG administration. T-cell engraftment following HSCT possibly helped by oral and IVIG was necessary to eliminate rotavirus infection. The full-term, formula-fed infant received RotaTeq at 2 and 4 months of age. The patient developed chronic intermittent diarrhea at 2 months of age and was hospitalized at 7 months of age with respiratory distress, diarrhea, and failure to thrive. A peripheral white blood cell count was 16,140 cells/μl with 59% neutrophils, 17% lymphocytes (absolute lymphocyte count=2743cells/μl [normal range 3,900–9,000]), 7% monocytes, and 13% eosinophils. Bronchoscopy aspirate revealed Pneumocystis jiroveci. Stool for rotavirus was positive by electron microscopy (EM). Immunoglobulins were very low including IgG 77 mg/dL (normal range 184–974 mg/dL), IgA <6 mg/dL (normal range 9–107 mg/dL), and IgM 36 mg/dL (normal range 41–197 mg/dL). The CD3+T cells were severely low (32 cells/mm3, normal range 1919–5054 cells/mm3), CD19+B cells were elevated (2715 cells/mm3, normal range 566–2535 cells/mm3), and CD3−CD56+CD16+NK cells were low (28 cells/mm3, normal range 181–901 cells/mm3). T-cell proliferation to mitogens was markedly depressed. A hemizygous mutation (nucleotide substitution A for G at position 1451 in the polyA tail region) was present in the common gamma chain of interleukin-2 receptor consistent with X-linked SCID. Multipe doses of IVIG (Gamunex®, Talecris) were given before and after transplantation, including two doses of 300 mg/kg administered orally at 8 months of age (Fig. 1). Molecular analysis of stool and serum specimens identified a non-vaccine associated human rotavirus strain G9P[8]. The patient received a 10/10 matched unrelated donor unfractionated HSCT with pretransplant myeloablative conditioning at 9.5 months of age. Rotavirus-positive diarrhea persisted until 2 months post transplant (age 11.5 months), coincident with T-cell engraftment (Fig. 1). The patient, last tested at 14.5 months of age, had no detectable rotavirus. Figure 1 The detection of rotavirus in relation to the presence of CD3+,CD4+, and CD8+T-cell quantification before and after bone marrow transplantation. *=CD3+T cells were 100% donor origin calculated by short tandem repeat studies; ¥=Several serum samples ... Reverse transcriptase polymerase chain reaction (RT-PCR) using rotavirus gene 9 and gene 4 primer sets resulted in cDNA products from stool and serum samples. Homology of gene 9 and gene 4 amplicon sequences to GenBank database sequences confirmed the patient’s stools contained rotavirus strain G9P[8]. There was 98% nucleotide homology between the stool rotavirus gene 4 sequence, which comprised 51% of the 2328 nt ORF, and two fully-sequenced P[8] rotaviruses but no significant homology with a partial RotaTeq vaccine gene 4 sequence. There was 98% nucleotide homology between the stool rotavirus gene 9 sequence, which comprised 85% of the 978 nt ORF, and two fully-sequenced G9 rotaviruses. There was a single nucleotide change in gene 9 (residue 595 C→T, resulting in a silent mutation) between two stools obtained 74 days apart. There was no change in gene 4 sequence between stools obtained 54 days apart. Neutralizing antibodies to rotavirus G9 were present in the orally administered immunoglobulin product at a concentration of 1:1600. Neutralizing antibodies to serotypes G1(WA, 1:800; K8, 1:1600) and G3 (SA11, 1:3200) were present at similar concentrations. CD3+T cells were very low (32 cells/ml, normal range 2500–6500 cells/ml) prior to transplantation (Fig. 1). Rotavirus became undetectable by EM two months post transplantation with CD3+, CD4+, and CD8+T-cell engraftment as shown by return of lymphocytes by 65 days post transplantation (CD3+T cells=138/mm3 at 2 months post transplantation). T-cell proliferation, as assessed by response to mitogens, was <3% of normal range and became present at five months post transplantation (data not shown). Chimerism analysis showed presence of donor T cells (100%) and absence of donor B cells (0%) at two and seven months post transplantation.