Immunodeficiency 65, susceptibility to viral infections

Immunodeficiency 65 (IMD65) is a rare autosomal recessive disorder caused by a homozygous mutation in the IRF9 gene (147574; located on chromosome 14q12). Immunodeficiency is characterized by the occurrence of recurrent and severe viral infections beginning in early childhood.

Affected individuals are impaired in their ability to fight viral infections in a regular manner, leading to clinically significant conditions such as recurrent pneumonia, bronchiectasis, and septic shock.

Lymphopenia or hypogammaglobulinemia are possible. Impaired cellular type I interferon response (see interferons below).

Possible development of septic shock and poor outcomes following vaccination with live attenuated vaccines; such vaccines should not be administered to patients with known impaired interferon response.

Treatment with intravenous immunoglobulin(IVIG) is successful.

Hernandez et al (2018) reported a 5-year-old girl with severe and recurrent viral respiratory infections. At 16 months of age, bile perforation presented after measles/mumps/rubella (MMR) vaccination; continued coagulation abnormalities, elevated liver function enzymes, and suspected septic shock. At 23 months of age, severe influenza A virus (IAV) infection. Subsequently, recurrent fevers and gastrointestinal tract infections. Gum infections. Lab: A detailed immunological examination revealed normal findings, immunoglobulins normal, normal vaccine responses to most pathogens, and normal lymphocyte counts. Treatment with IVIG resulted in clinical improvement.

Gavo Garcia-Morato et al (2019) emphasized the rapid development of severe viral ec disease after vaccination with live attenuated vaccines. They reported two siblings born to consanguineous parents of Portuguese origin with severe and recurrent DNA and RNA viral infections from infancy. The 10-year-old patient had multiple infections, including multiple pneumonias, disseminated chickenpox after vaccination, H1N1 influenza, influenza B, dengue fever, Zika virus, and enterovirus encephalitis; neurologic impairment; and bronchiectasis. An older sibling had early severe viral infections, including sepsis and meningoencephalitis associated with HSV infection. She died at 14 months of age from enterohemorrhagic fever after vaccination against yellow fever virus.Laboratory studies showed hypogammaglobulinemia, undetectable antibodies to tetanus and diphtheria, and an impaired lymphoproliferative response to mitogens. Therapy: Treatment with IVIG resulted in significant clinical improvement.

1. Akira S et al (2006) Pathogen recognition and innate immunity. Cell 124: 783-801.
2. Bravo Garcia-Morato et al (2019) Impaired control of multiple viral infections in a family with complete IRF9 deficiency. J Allergy Clin Immun 144: 309-312.
3. Christofferson DE et al (2010) Necroptosis as an alternative form of programmed cell death. Curr Opin Cell Biol 22: 263-268.
4. Hernandez N et al (2018) Life-threatening influenza pneumonitis in a child with inherited IRF9 deficiency. J Exp Med 215: 2567-2585.

5. Michalska A et al (2018) A Positive Feedback Amplifier Circuit That Regulates Interferon (IFN)-Stimulated Gene Expression and Controls Type I and Type II IFN Responses. Front Immunol 9:1135.