Fatal Enteroviral Encephalitis in a Patient with Common Variable Immunodeficiency Harbouring a Novel Mutation in NFKB2.

Common variable immunodeficiency is the most prevalent of the primary immunodeficiency diseases, yet its pathogenesis is largely poorly understood. Of the cases that are monogenic, many arise due to pathogenic variants in NFKB1 and NFKB2. Here, we report enteroviral encephalomyelitis as the cause of a fatal neurodegenerative condition in a patient with a novel heterozygous mutation in NFKB2 (c.2543insG, p.P850Sfs36*) that disrupts non-canonical NF-κB signaling. Investigations of primary and secondary lymphoid tissue demonstrated a complete absence of B cells and germinal centers. Despite multiple negative viral PCR testing of cerebrospinal fluid during her disease progression, post-mortem analysis of cerebral tissue revealed a chronic lymphocytic meningoencephalitis, in the presence of Cocksackie A16 virus, as the cause of death. The clinical features, and progression of disease reported here, demonstrate divergent clinical and immunological phenotypes of individuals within a single family. This is the first reported case of fatal enteroviral encephalomyelitis in a patient with NF-κB2 deficiency and mandates a low threshold for early brain biopsy and the administration of increased immunoglobulin replacement in any patient with a defect in this pathway and deterioration of neurological status.

Delayed Diagnosis and Complications of Predominantly Antibody Deficiencies in a Cohort of Australian Adults.

Background: Predominantly antibody deficiencies (PADs) are the most common type of primary immunodeficiency in adults. PADs frequently pass undetected leading to delayed diagnosis, delayed treatment, and the potential for end-organ damage including bronchiectasis. In addition, PADs are frequently accompanied by comorbid autoimmune disease, and an increased risk of malignancy. Objectives: To characterize the diagnostic and clinical features of adult PAD patients in Victoria, Australia. Methods: We identified adult patients receiving, or having previously received immunoglobulin replacement therapy for a PAD at four hospitals in metropolitan Melbourne, and retrospectively characterized their clinical and diagnostic features. Results: 179 patients from The Royal Melbourne, Alfred and Austin Hospitals, and Monash Medical Centre were included in the study with a median age of 49.7 years (range: 16-87 years), of whom 98 (54.7%) were female. The majority of patients (116; 64.8%) met diagnostic criteria for common variable immunodeficiency (CVID), and 21 (11.7%) were diagnosed with X-linked agammaglobulinemia (XLA). Unclassified hypogammaglobulinemia (HGG) was described in 22 patients (12.3%), IgG subclass deficiency (IGSCD) in 12 (6.7%), and specific antibody deficiency (SpAD) in 4 individuals (2.2%). The remaining four patients had a diagnosis of Good syndrome (thymoma with immunodeficiency). There was no significant difference between the age at diagnosis of the disorders, with the exception of XLA, with a median age at diagnosis of less than 1 year. The median age of reported symptom onset was 20 years for those with a diagnosis of CVID, with a median age at diagnosis of 35 years. CVID patients experienced significantly more non-infectious complications, such as autoimmune cytopenias and lymphoproliferative disease, than the other antibody deficiency disorders. The presence of non-infectious complications was associated with significantly reduced survival in the cohort. Conclusion: Our data are largely consistent with the experience of other centers internationally, with clear areas for improvement, including reducing diagnostic delay for patients with PADs. It is likely that these challenges will be in part overcome by continued advances in implementation of genomic sequencing for diagnosis of PADs, and with that opportunities for targeted treatment of non-infectious complications.

Improvement of Fabry Disease-Related Gastrointestinal Symptoms in a Significant Proportion of Female Patients Treated with Agalsidase Beta: Data from the Fabry Registry.

Fabry disease, an X-linked inherited lysosomal storage disorder, is caused by mutations in the gene encoding α-galactosidase, GLA. In patients with Fabry disease, glycosphingolipids accumulate in various cell types, triggering a range of cellular and tissue responses that result in a wide spectrum of organ involvement. Although variable, gastrointestinal symptoms are among the most common and significant early clinical manifestations; they tend to persist into adulthood if left untreated. To further understand the effects of sustained enzyme replacement therapy (ERT) with agalsidase beta on gastrointestinal symptoms in heterozygotes, a data analysis of female patients enrolled in the Fabry Registry was conducted. To be included, females of any age must have received agalsidase beta (average dose 1.0 mg/kg every 2 weeks) for at least 2.5 years. Measured outcomes were self-reported gastrointestinal symptoms (abdominal pain, diarrhea). Outcomes at baseline and last follow-up, and their change from baseline to last follow-up, were assessed. Relevant data were available for 168 female patients. Mean age at the start of ERT was 43 years and mean treatment duration 5.7 years. Baseline pre-treatment abdominal pain was reported by 45% of females and diarrhea by 39%. At last follow-up, 31% reported abdominal pain (p < 0.01) and 27% diarrhea (p < 0.01). The results of this Fabry Registry analysis suggest that while on sustained treatment with agalsidase beta (1.0 mg/kg every 2 weeks), both abdominal pain and diarrhea improved in many female patients with Fabry disease.

Immunoglobulin E-Mediated Hypersensitivity Reaction to Ketamine.

INTRODUCTION: Ketamine is a commonly used analgesic agent in the management of both acute and chronic pain. While dose-dependent side effects are well described, allergy to ketamine is extremely rare. CASE: A 41-year-old woman with chronic pelvic pain and previous ketamine exposure developed a widespread urticarial rash and mild perioral edema following the initiation of a ketamine infusion. The infusion was ceased and the patient was treated with oral antihistamine, with rapid resolution of symptoms. Serum tryptase levels were elevated at 2 and 6 hours after the infusion was ceased, and subsequent intradermal skin testing supported the diagnosis of type I hypersensitivity reaction to ketamine. DISCUSSION: This case represents a likely immunoglobulin E-mediated type I hypersensitivity reaction to ketamine, supported by elevated tryptase levels and positive intradermal skin testing. The interpretation of these results and likely mechanism of the hypersensitivity reaction are described. The patient and treating team were advised against subsequent use of ketamine, due to the risk of serious adverse systemic reaction with repeat exposure.

An unusual urticarial eruption: Familial cold autoinflammatory syndrome.

This is a case of a 26-year-old Caucasian woman with a lifelong history of an episodic urticaria associated with arthralgia, precipitated by exposure to cold. She had no other significant past medical history. She reported several family members with a history of very similar episodic eruptions without definitive diagnoses. An examination showed an urticarial eruption over her limbs with no other systemic findings. A baseline full blood examination, serology and autoimmune screen were normal. A skin biopsy was consistent with urticaria, with dermal oedema and a perivascular infiltrate. Following genetic testing, she was found to be heterozygous for a mutation, p.Ala439Val in the NLRP3 gene, known to cause familial cold autoinflammatory syndrome (FCAS), which typically presents with urticaria, conjunctivitis and arthralgia, as described in this patient. FCAS is one subtype of a group of conditions known as cryopyrin-associated periodic syndromes (CAPS). CAPS are rare, autosomal dominant inherited conditions with a spectrum of phenotypes, characterised by increased interleukin-1ß release with subsequent local and systemic proinflammatory and pyrogenic effects.