First Documented Case of Influenza A (H3N2 Subtype) Infection in a Patient With Complete Interferon Gamma Receptor 1 Deficiency: A Call for Systemic Vaccination Strategies.

Abstract

To the Editor: Autosomal recessive (AR) complete interferon-γ receptor 1 (IFN-γR1) deficiency is a rare variant of Mendelian susceptibility to mycobacterial disease.1 Because these patients lack adequate cytokine response after IFN-γ stimulation, disseminated infection is a common clinical presentation, often caused by Calmette-Guérin bacillus or atypical mycobacteria such as Mycobacteria chelonae, Mycobacteria fortuitum, Mycobacteria mageritense, Mycobacteria peregrinum, Mycobacteria smegmatis and Mycobacteria scrofulaceum.1 High levels of circulating IFN-γ are characteristic for these patients. Although infections because of other pathogens such as Listeria monocytogenes, Salmonella spp and Toxoplasma spp have been described,1 reports regarding viral infections in patients with IFN-γR deficiency are scarce.1–3 To date, cytomegalovirus, human herpes virus 8, respiratory syncytial virus, parainfluenza virus type 3 and varicella zoster virus infections have been reported.1–3 The severity of viral infections in patients with AR complete IFN-γR1 deficiency is variable. Although one patient developed a fatal Kaposi’s sarcoma with human herpes virus 8 and 4 patients developed disseminated but nonfatal cytomegalovirus infections, most patients with varicella zoster virus infections showed an uncomplicated clinical course with only one patient having severe skin manifestations. Respiratory disease requiring prolonged mechanical ventilation caused by parainfluenza virus type 3 (at age 3 years) and respiratory syncytial virus (at age 3.5 years) infections was reported in one patient only.1–3 We describe here the first documented Influenza virus (subtype H3N2) infection in a patient with complete IFN-γR1 deficiency. A 4-year old boy with AR IFN-γR1 (c.523delT/c.652_654delGAA) managed with long-term triple antibiotics (azithromycin, ciprofloxacin and cotrimoxazole) because of a previous disseminated M. fortuitum infection, presented with low-grade fever (38.2°C), cough, nausea and vomits, while awaiting matched sibling donor hematopoietic stem cell transplantation (HSCT). Forty-eight hours earlier, his mother showed mild upper respiratory symptoms. Nasopharyngeal swabs taken from the mother and patient were positive for influenza A virus using a rapid antigen test (BD Directigen™, EZ Flu A+B). Polymerase chain reaction testing (Simplexa Flu A/B & RSV Direct) confirmed the diagnosis of influenza H3N2 subtype. Neither the patient nor the family members including the matched sibling donor had received seasonal influenza vaccination. Treatment with oseltamavir (30 mg/12 h/vo during 5 days) for the patient and prophylaxis for the donor (30 mg/24 h/vo during 5 days) was initiated; the patient became afebril within 24 hours while upper respiratory symptoms persisted for another 7 days. Repeated polymerase chain reaction testing for influenza H3N2 remained positive for 10 days after stopping antiviral treatment. During this episode, serum IFN-γ values were raised (>200 pg/ml, normal <40), and HSCT was delayed for 6 weeks with normalizing IFN-γ levels. Subsequently, a fully myeloablative, non-T lymphocyte-depleted matched sibling donor transplant was performed without mayor complications, and currently, 17 months after HSCT, he remains in excellent clinical condition with no signs of graft versus host disease and a stable donor chimerism of >95% without any specific treatment.3 This is the first documented case of a patient with AR IFN-γR1 deficiency suffering from influenza A virus infection as well as pre HSCT. Despite antibiotic treatment, complete IFN-γR1 deficiency is fatal in almost all cases within the first 20 years of life. HSCT remains the only curative treatment.1 Although data are promising for influenza vaccine effectiveness in patients with complete interleukin-12/23 receptor-β1 and partial IFN-γ R1 deficiencies, information is lacking for patients with complete IFN-γ R1 deficiencies.4 Although our patient showed only mild clinical symptoms and recovered under ambulant antiviral therapy, systematic influenza vaccination and subsequent determination of vaccine responses in affected patients, their families and potential HSCT donors should be considered in these patients as recently proposed by the Infectious Diseases Society of America, thereby preventing potentially severe complications or HSCT delay.5,6 Peter Olbrich, MD, PhD Lola Falcón-Neyra, MD Department of Paediatric Infectious Diseases and Immunopathologies Hospital Universitario Infantil Virgen del Rocio, Sevilla, Spain Instituto de Investigación Biomédica, Sevilla (IBiS), Sevilla, Spain Agueda Molinos-Quintana, MD, PhD Paediatric Hematology Unit Hospital Universitario Virgen del Rocio, Sevilla, Spain Magdalena Aguero-Sánchez, PhD Department of Infectious Diseases Microbiology and Preventive Medicine, Hospital Universitario Virgen del Rocio Sevilla, Spain Olaf Neth, MD, PhD Department of Paediatric Infectious Diseases and Immunopathologies Hospital Universitario Infantil Virgen del Rocio, Sevilla, Spain Instituto de Investigación Biomédica, Sevilla (IBiS), Sevilla, Spain