key: cord-1033337-yc2y3d7m
authors: Dorman, Susan E.; Uzel, Gulbu; Roesler, Joachim; Bradley, John S.; Bastian, John; Billman, Glenn; King, Susan; Filie, Armando; Schermerhorn, James; Holland, Steven M.
title: Viral infections in interferon-γ receptor deficiency()()
date: 2005-11-04
journal: J Pediatr
DOI: 10.1016/s0022-3476(99)70064-8
sha: 6d2cf166c2e8e45f362ec5979876227b22cbff95
doc_id: 1033337
cord_uid: yc2y3d7m

Interferon-γ receptor deficiency is a recently described immunodeficiency that is associated with onset of severe mycobacterial infections in childhood. We describe the occurrence of symptomatic and often severe viral infections in 4 patients with interferon-γ receptor deficiency and mycobacterial disease. The viral pathogens included herpes viruses, parainfluenza virus type 3, and respiratory syncytial virus. We conclude that patients with interferon-γ receptor deficiency and mycobacterial disease have increased susceptibility to some viral pathogens. (J Pediatr 1999;135:640-3)

States to consanguineous Pakistani parents. He was well until 8 months of age when he developed fever, hepatosplenomegaly, pneumonia, and anemia. A diagnosis of disseminated MAC infection was made. Subsequently, he was found to have complete absence of IFN-γ responsiveness caused by a homozygous mutation in the IFN-γ receptor 1 gene 6 (Table) . At age 3 years, he developed disseminated cytomegalovirus infection with pneumonia, diagnosed by positive cultures of blood and bronchoalveolar lavage fluid, as well as visualization of typical cytomegalic inclusion cells in the latter; he required mechanical ventilation and prolonged therapy with ganciclovir, administered intravenously. Two months later, he developed parainfluenza virus type 3 pneumonia, diagnosed by culture of bronchoalveolar lavage fluid, which was complicated by respiratory failure requiring mechanical ventilation. Five months later he Humans with absent or diminished response to interferon-γ caused by nonfunctional or dysfunctional IFN-γ receptors have recently been described. [1] [2] [3] [4] [5] [6] [7] [8] These patients acquire mycobacterial infections that are frequently due to low virulence species such as Mycobacterium avium complex and are often disseminated and refractory to treatment. Infections with Salmonella species and other intracellular bacteria also occur in patients with IFN-γ receptor deficiency. 1, 5, 7 However, increased susceptibility to viral infections has not been rec-V Viral infections in interferon-γ receptor deficiency Interferon-γ receptor deficiency is a recently described immunodeficiency that is associated with onset of severe mycobacterial infections in childhood. We describe the occurrence of symptomatic and often severe viral infections in 4 patients with interferon-γ receptor deficiency and mycobacterial disease. The viral pathogens included herpes viruses, parainfluenza virus type 3, and respiratory syncytial virus. We conclude that patients with interferon-γ receptor deficiency and mycobacterial disease have increased susceptibility to some viral pathogens. 

had severe respiratory syncytial virus pneumonia, diagnosed by culture of bronchoalveolar lavage fluid, for which mechanical ventilation was again required. This infection was treated with aerosolized ribavirin and intravenous RSV immune globulin (RespiGam; Medimmune, Gaithersburg, Md). On 2 subsequent occasions he developed pneumonia with respiratory failure requiring mechanical ventilation, although no specific causative agents were identified.

Patient 2 was born in the United States to parents of English and Portuguese descent who were not known to be consanguineous. He was well as an infant, but at age 2 years he developed fever, lymphadenopathy, and hepatosplenomegaly caused by disseminated M fortuitum and MAC infections. 3 He had no detectable IFN-γ responsiveness because of a homozygous mutation in IFN-γ receptor 2. At age 3 he developed oral ulcers, vesicular skin lesions, and severe retrosternal pain associated with eating, which resulted in weight loss. Herpes simplex virus was isolated from an oral lesion. Within 3 days of beginning oral acyclovir therapy (60 mg/kg/d), his appetite improved, and he was back to normal within 1 week. Acyclovir therapy was continued for 3 weeks. Approximately 5 weeks later, he had a recurrence of oral lesions similar in appearance to those of the prior episode, not associated with retrosternal pain. He was treated with acyclovir, administered orally, without further recurrence of lesions.

Patient 3 had complete absence of IFN-γ receptor function because of compound heterozygous mutations in the IFN-γ receptor 1. 7 She was vaccinated with bacille Calmette-Guérin as an infant and first came to medical attention at age 4 months with fever, pneumonia, axillary lymphadenopathy, hepatomegaly, and a vesicular skin rash. At first, appearance of the rash was typical of varicella infection, but new vesicles formed for at least 10 days, and the rash took on the appearance of Kaposi's varicelliform eruption. Serologic testing revealed presence of varicella-specific IgM antibody; culture was not performed. The rash resolved with acyclovir treatment. Cultures from a lymph node biopsy specimen obtained at that time grew bacille Calmette-Guérin; biopsies of lung and liver were not performed. Subsequent infections included disseminated MAC, disseminated M kansasii, and Listeria monocytogenes meningitis.

Patient 4 was born to nonconsanguineous parents of Korean and African descent. He was well until age 6 years when he developed multifocal osteomyelitis caused by M kansasii, and since then he has had recurrent disseminated infections with numerous nontuberculous mycobacteria. Genetic analysis showed heterozygosity for a mutant IFN-γ receptor allele containing a single nucleotide insertion (817insA), which codes for a protein with dominant negative function. 8 At age 17 years he developed shortness of breath, with numerous vesicular skin, pharyngeal, and lingual lesions. Patchy infiltrates were seen on chest x-ray film, and mechanical ventilation was required for progressive respiratory failure. Electron microscopy performed on scrapings from skin lesions showed viral particles consistent with a herpes group virus, and serology confirmed a diagnosis of acute varicella. He was treated with intravenous acyclovir and gradually improved.

IFN-γ is a pleiotropic cytokine produced by activated T lymphocytes and natural killer cells. It acts via its cognate receptor to directly stimulate antimicrobial activities of monocytes/ macrophages, and it plays a major role in activation of cell-mediated immunity. IFN-γ was first recognized for its in vitro antiviral activity. 9 Its importance in the in vivo immune response has since been confirmed in mice with targeted disruptions of the IFN-γ or IFN-γ receptor genes. These knockout mice have increased susceptibility to a wide spectrum of infectious agents, including mycobacteria, 10-13 bacteria, [14] [15] [16] parasites, [17] [18] [19] [20] and viruses. After experimental inoculation, infections with the DNA viruses HSV, 21, 22 murine CMV, 23 murine gammaherpesvirus, 24 and vaccinia virus 25 are more prolonged and/or severe in these knockout mice than in normal mice. Singlestrand RNA viruses pathogenic in these mouse models include Theiler's virus, 26 lymphocytic choriomeningitis virus, 25, 27 and mouse hepatitis virus (a coronavirus). 28 Patients with nonfunctional or dysfunctional IFN-γ receptors clearly have increased susceptibility to mycobacterial infections. These infections tend to be severe and difficult to treat and have been the major recognized cause of morbidity and mortality in this patient group. Salmonella and Listeria monocytogenes infections have also been described in a subset of patients with IFN-γ receptor deficiency and mycobacterial infections. 1, 5, 7 However, increased susceptibility to viral infections in patients with IFN-γ receptor deficiency has not been previously recognized. In each of the patients in this report, viral infection was symptomatic, and infection was severe in several instances. All patients had herpes virus infections, paralleling the heightened susceptibility of IFN-γ and IFNγ receptor knockout mice to herpes viruses. [21] [22] [23] [24] Patient 1 also had severe infections with parainfluenza virus type 3 and RSV, both of which are single-stranded RNA viruses.

Our clinical experience differs from that reported previously by others. Sixteen French children with idiopathic disseminated bacille Calmette-Guérin infection, identified in a national retrospective survey, were reported to have had normal clinical courses and frequency of infections with common childhood pathogens, including varicella. 29 However, genetic and immunologic defects in those patients were not known and are likely to be heterogeneous, making comparison with the patients in this report difficult. In a small group of patients with IFN-γ receptor deficiency, Jouanguy et al 30 Although disseminated infection with non tuberculous mycobacteria is the most common clinical presentation of IFN-γ receptor deficiency in the patients described to date, our experience suggests that the frequency and severity of viral infections may also be increased in patients with this primary immunodeficiency. IFN-γ receptor deficiency should be included in the differential diagnosis in children with severe viral infections. In patients known to have IFN-γ receptor deficiency, viral pathogens should be considered in appropriate clinical settings. 

A mutation in the interferon-γ-receptor gene and susceptibility to mycobacterial infection

Interferon γ receptor deficiency in an infant with fatal bacille Calmette-Guérin infection

Mutation in the signal-transducing chain of the interferon-γ receptor and susceptibility to mycobacterial infection

Fatal disseminated Mycobacterium smegmatis infection in a child with inherited interferon γ receptor deficiency

Partial interferon-γ receptor 1 deficiency in a child with tuberculoid bacillus Calmette-Guérin infection and a sibling with clinical tuberculosis

Abnormal regulation of interferon-γ, interleukin-12, and tumor necrosis factor-α in human interferon-γ receptor 1 deficiency

Listeria monocytogenes and recurrent mycobacterial infections in a child with complete interferon-γ-receptor (IFNγR1) deficiency-mutational analysis and evaluation of therapeutic options

A human IFNGR1 small deletion hotspot associated with dominant susceptibility to mycobacterial infection

Interferon-like virus-inhibitor induced in human leukocytes by phytohemagglutinin

Disseminated tuberculosis in interferon γ gene-disrupted mice

An essential role for interferon γ in resistance to Mycobacterium tuberculosis infection

Mice that lack the interferon-γ receptor have profoundly altered responses to infection with bacillus Calmette-Guerin and subsequent challenge with lipopolysaccharide

Multiple defects of immune cell function in mice with disrupted interferon-gamma genes

Effector mechanisms responsible for γ interferon-mediated host resistance to Legionella pneumophila lung infection: the role of endogenous nitric oxide differs in susceptible and resistant murine hosts

Specific immunity to Listeria monocytogenes in the absence of IFNγ

Impact of interferon-γ receptor deficiency on experimental Staphylococcus aureus septicemia and arthritis

Role of gamma interferon in the host immune and inflammatory responses to Pneumocystis carinii infection

In the absence of endogenous IFN γ, mice develop unimpaired IL-12 responses to Toxoplasma gondii while failing to control acute infection

CD4+ effector cells default to the TH2 pathway in IFNγ-deficient mice infected with Leishmania major

Mice from a genetically resistant background lacking the interferon γ receptor are susceptible to infection with Leishmania major but mount a polarized T helper cell type CD4+ T cell response

Characterization of herpes simplex virus type 1 infection and herpetic stromal keratitis development in IFN-gamma knockout mice

Role of interferon γ in immunity to herpes simplex virus

Role of interferongamma in murine cytomegalovirus infection

Pathological changes in the spleens of gamma interferon receptordeficient mice infected with murine gammaherpesvirus: a role for CD8 T cells

Immune response in mice that lack the interferon-gamma receptor

Theiler's virus infection of 129Sv mice that lack the interferon α/β or interferon γ receptors

Functional role of type I and type II interferons in antiviral defense

Exacerbated viral hepatitis in IFN-gamma receptor-deficient mice is not suppressed by IL-12

Idiopathic disseminated bacillus Calmette-Guerin infection: a French national retrospective study

Infections in IFN γR1-deficient children