Infections Complicating Congenital Immunodeficiency Syndromes

Christenson, John C.; Hill, Harry R.

doi:10.1007/0-306-47527-8_14

Cited by 4 publications

(1 citation statement)

References 210 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Human cytomegalovirus (HCMV) is a major pathogen in immunocompromised individuals, especially in transplant recipients, patients with AIDS, and children with congenital immunodeficiency disorders (1,10). With the availability of effective antiviral drugs, prolonged prophylactic and therapeutic regimens are increasingly employed.…”

mentioning

confidence: 99%

Emergence of Multiple Human Cytomegalovirus Ganciclovir-Resistant Mutants with Deletions and Substitutions within the UL97 Gene in a Patient with Severe Combined Immunodeficiency

Wolf

Yaniv

Ashkenazi

et al. 2001

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Infection with multiple ganciclovir-resistant human cytomegalovirus mutants, containing different substitutions and deletions in the UL97 gene, was found in a patient with severe combined immunodeficiency (SCID) within 3 weeks of ganciclovir therapy. A novel 11-codon deletion at positions 590 to 600 was identified. These unique findings may be related to the nature of the immunodeficiency in the SCID patient.Human cytomegalovirus (HCMV) is a major pathogen in immunocompromised individuals, especially in transplant recipients, patients with AIDS, and children with congenital immunodeficiency disorders (1, 10). With the availability of effective antiviral drugs, prolonged prophylactic and therapeutic regimens are increasingly employed. Ganciclovir, a nucleoside homologue, is the most widely used anti-HCMV drug (11). However, prolonged ganciclovir therapy can lead to the development of ganciclovir-resistant strains. HCMV ganciclovir resistance results mainly from impaired phosphorylation of the drug, caused by mutations in the HCMV UL97 phosphotransferase (2,3,7,8,21).Until recently, ganciclovir-resistant strains have been recovered mainly from AIDS patients who received the drug for more than 3 months. With the widespread use of ganciclovir prophylaxis among transplant recipients, ganciclovir resistance is increasingly reported in the transplant setting, especially among solid-organ transplant recipients who have had prolonged exposure to ganciclovir (4,14,18). Recently, we described the early emergence of ganciclovir-resistant virus in children with primary combined immunodeficiency (22). Here, we report the unusual isolation of multiple drug-resistant variants, containing point mutations and different deletions of the UL97 gene, from one of these patients after 3 weeks of ganciclovir therapy.The patient (patient 4) was a 5-month-old girl with B Ϫ severe combined immunodeficiency (SCID) who received haploidentical T-cell-depleted bone marrow transplantation. She was HCMV seropositive before transplantation and received a bone marrow graft from a seronegative donor. She had been treated with acyclovir for 3 weeks before secondary HCMV infection with HCMV pneumonitis developed. Intravenous ganciclovir therapy (5 mg/kg of body weight twice daily) was initiated; however, the patient's condition deteriorated, and a leukocyte culture 3 weeks after initiation of therapy was positive for HCMV.Viral isolate propagation, plaque purification, and antiviral susceptibility assays of the isolate and the plaque-purified viruses were done as previously described (21). The laboratoryadapted ganciclovir-sensitive HCMV strain AD169 was included as a sensitive control with each assay. HCMV strains were considered sensitive to ganciclovir if their 50% effective doses (ED 50 ) were Յ6 M. The leukocyte isolate, the corresponding plasma specimen, and the plaque-purified viruses were subjected to direct PCR sequencing of the UL97 gene (21, 22), using primers encompassing nucleotides 1207 to 1979. The PCRs were performed under stringent c...

show abstract

mentioning

confidence: 99%