Respiratory infectious burden in a cohort of antibody deficiency patients treated with immunoglobulin replacement therapy: The impact of lung pathology and gastroesophageal reflux disease.

Background: Antibody deficiencies result from reduced immunoglobulin levels and function, increasing susceptibility to, primarily, bacterial infection. Primary antibody deficiencies comprise intrinsic defects in B-cell physiology, often due to inherited errors. Hematological malignancies or B-cell suppressive therapy are major causes of secondary antibody deficiency. Although immunoglobulin replacement therapy (IGRT) reduces infectious burden in antibody deficiency patients, respiratory tract infections remain a significant health burden. We hypothesize that lung pathology and gastroesophageal reflux disease (GORD) increase the risk of pneumonia in antibody deficiency patients, as in the general population. Objective: For our cohort of patients with primary antibody deficiency and secondary antibody deficiency, we reviewed their respiratory infectious burden and the impact of lung pathologies and GORD. Methods: The medical records of 231 patients on IGRT at a tertiary referral center, from October 26, 2014, to February 19, 2021, were reviewed to determine microbial isolates from sputum samples and prevalence of common lung pathologies and GORD. Results: Haemophilus and Pseudomonas species represent a large infectious burden, being identified in 30.2% and 21.4% of sputum samples demonstrating growth, respectively; filamentous fungal and mycobacterial infections were rare. Diagnosed lung pathology increased the proportion of patients with Pseudomonas, Klebsiella, Stenotrophomonas, and Candida species isolated in their sputum, and diagnosed GORD increased the proportion with Enterobacter and Candida species isolated. Conclusions: Bacterial respiratory infectious burden remains in primary antibody deficiency and secondary antibody deficiency despite IGRT. Lung pathologies encourage growth of species less susceptible to IGRT, so specialist respiratory medicine input and additional treatments such as inhaled antibiotics are indicated to optimize respiratory outcomes.

A National Survey of Hereditary Angioedema and Acquired C1 Inhibitor Deficiency in the United Kingdom.

BACKGROUND: Detailed demographic data on people with hereditary angioedema (HAE) and acquired C1 inhibitor deficiency in the United Kingdom are relatively limited. Better demographic data would be beneficial in planning service provision, identifying areas of improvement, and improving care. OBJECTIVE: To obtain more accurate data on the demographics of HAE and acquired C1 inhibitor deficiency in the United Kingdom, including treatment modalities and services available to patients. METHODS: A survey was distributed to all centers in the United Kingdom that look after patients with HAE and acquired C1 inhibitor deficiency to collect these data. RESULTS: The survey identified 1152 patients with HAE-1/2 (58% female and 92% type 1), 22 patients with HAE with normal C1 inhibitor, and 91 patients with acquired C1 inhibitor deficiency. Data were provided by 37 centers across the United Kingdom. This gives a minimum prevalence of 1:59,000 for HAE-1/2 and 1:734,000 for acquired C1 inhibitor deficiency in the United Kingdom. A total of 45% of patients with HAE were on long-term prophylaxis (LTP) with the most used medication being danazol (55% of all patients on LTP). Eighty-two percent of patients with HAE had a home supply of acute treatment with C1 inhibitor or icatibant. A total of 45% of patients had a supply of icatibant and 56% had a supply of C1 inhibitor at home. CONCLUSIONS: Data obtained from the survey provide useful information about the demographics and treatment modalities used in HAE and acquired C1 inhibitor deficiency in the United Kingdom. These data are useful for planning service provision and improving services for these patients.

Rituximab Associated Hypogammaglobulinemia in Autoimmune Disease.

Objective: To evaluate the characteristics of patients with autoimmune disease with hypogammaglobulinemia following rituximab (RTX) and describe their long-term outcomes, including those who commenced immunoglobulin replacement therapy. Methods: Patients received RTX for autoimmune disease between 2003 and 2012 with immunoglobulin G (IgG) <7g/L were included in this retrospective series. Hypogammaglobulinemia was classified by nadir IgG subgroups of 5 to <7g/L (mild), 3 to <5g/L (moderate) and <3g/L (severe). Characteristics of patients were compared across subgroups and examined for factors associated with greater likelihood of long term hypogammaglobulinemia or immunoglobulin replacement. Results: 142 patients were included; 101 (71%) had anti-neutrophil cytoplasm antibody (ANCA) associated vasculitis (AAV), 18 (13%) systemic lupus erythematosus (SLE) and 23 (16%) other conditions. Mean follow-up was 97.2 months from first RTX. Hypogammaglobulinemia continued to be identified during long-term follow-up. Median time to IgG <5g/L was 22.5 months. Greater likelihood of moderate hypogammaglobulinemia (IgG <5g/L) and/or use of immunoglobulin replacement therapy at 60 months was observed in patients with prior cyclophosphamide exposure (odds ratio (OR) 3.60 [95% confidence interval (CI) 1.03 - 12.53], glucocorticoid use at 12 months [OR 7.48 (95% CI 1.28 - 43.55], lower nadir IgG within 12 months of RTX commencement [OR 0.68 (95% CI 0.51 - 0.90)] and female sex [OR 8.57 (95% CI 2.07 - 35.43)]. Immunoglobulin replacement was commenced in 29/142 (20%) and associated with reduction in infection rates, but not severe infection rates. Conclusion: Hypogammaglobulinemia continues to occur in long-term follow-up post-RTX. In patients with recurrent infections, immunoglobulin replacement reduced rates of non-severe infections.

Evidence that a STAT3 Mutation Causing Hyper IgE Syndrome Leads to Repression of Transcriptional Activity.

We present the case of a 19-year-old female with a mild form of Autosomal Dominant Hyper IgE syndrome (HIES) associated with a loss-of-function mutation in STAT3. Within the first years of life she developed multiple, Staphylococcus aureus associated abscesses in the neck and face requiring frequent incision and drainage. Respiratory tract infections were not a feature of the clinical phenotype and a high resolution thoracic CT scan was unremarkable. Retained dentition was noted but fungal nail disease and recurrent thrush were absent. The total IgE was 970 IU/L, Lymphocyte counts and immunoglobulin levels were normal (IgG borderline 18.5 gr/L). There was suboptimal response to test immunisation with Pneumovax II vaccine. Th17 cell phenotyping revealed low levels of IL-17 expressing cells (0.3% of total CD4 T Cells numbers). Genetic analysis identified a missense mutation, N567D, in a conserved region of the linker domain of STAT3. Functional studies in HEK293 cells reveal that this mutation potently inhibits STAT3 activity when compared to the wildtype protein. This is consistent with other reported mutations in STAT3 associated with HIES. However, surprisingly, the magnitude of inhibition was similar to another STAT3 mutation (V637M) which causes a much more severe form of the disease.

A novel de novo activating mutation in STAT3 identified in a patient with common variable immunodeficiency (CVID).

Common variable immunodeficiency (CVID) is characterised by repeated infection associated with primary acquired hypogammaglobulinemia. CVID frequently has a complex aetiology but, in certain cases, it has a monogenic cause. Recently, variants within the gene encoding the transcription factor STAT3 were implicated in monogenic CVID. Here, we describe a patient presenting with symptoms synonymous with CVID, who displayed reduced levels of IgG and IgA, repeated viral infections and multiple additional co-morbidities. Whole-exome sequencing revealed a de novo novel missense mutation in the coiled-coil domain of STAT3 (c.870A>T; p.K290N). Accordingly, the K290N variant of STAT3 was generated, and a STAT3 responsive dual-luciferase reporter assay revealed that the variant strongly enhances STAT3 transcriptional activity both under basal and stimulated (with IL-6) conditions. Overall, these data complement earlier studies in which CVID-associated STAT3 mutations are predicted to enhance transcriptional activity, suggesting that such patients may respond favourably to IL-6 receptor antagonists (e.g. tocilizumab).

Optimizing hereditary angioedema management through tailored treatment approaches.

Hereditary angioedema (HAE) is a rare but serious and potentially life threatening autosomal dominant condition caused by low or dysfunctional C1 esterase inhibitor (C1-INH) or uncontrolled contact pathway activation. Symptoms are characterized by spontaneous, recurrent attacks of subcutaneous or submucosal swellings typically involving the face, tongue, larynx, extremities, genitalia or bowel. The prevalence of HAE is estimated to be 1:50,000 without known racial differences. It causes psychological stress as well as significant socioeconomic burden. Early treatment and prevention of attacks are associated with better patient outcome and lower socioeconomic burden. New treatments and a better evidence base for management are emerging which, together with a move from hospital-centered to patient-centered care, will enable individualized, tailored treatment approaches.

Use of recombinant C1 inhibitor in patients with resistant or frequent attacks of hereditary or acquired angioedema.

BACKGROUND: Conestat alfa (Ruconest, rhC1INH) is the first recombinant human C1 inhibitor protein (C1INH) for the treatment of acute attacks of hereditary angioedema (HAE). OBJECTIVE: To assess clinical experience of the first 11 adult patients who received rhC1INH in clinical practice in the UK. METHODS: Eleven patients (nine HAE type 1, one HAE type 2 and one acquired angioedema with C1 inhibitor deficiency) received between one and six, mostly self-administered, doses of rhC1INH for acute HAE attacks. They were asked to record their time to first response and complete resolution following the treatment. This cohort included our most severely affected and difficult to treat patients. RESULTS: In most cases, time to first improvement following rhC1INH and complete resolution was recorded as comparable to their typical response to pdC1INH, although 4/11 patients reported that the time to first improvement was much quicker than their average pdC1INH response. Five of the 11 patients continued with rhC1INH as their preferred rescue treatment. Of those who chose not to continue the treatment, four reported a recurrence or early return of symptoms with rhC1INH. CONCLUSION: In our experience, rhC1INH is a beneficial treatment for patients with preference for a C1INH that is not plasma derived and it is suitable for home treatment. In some cases it demonstrates cost saving, especially for heavier patients who require higher doses. In some patients rhC1INH may result in faster resolution of symptoms. It may be associated with an early return of symptoms in patients with exceptionally frequent attacks.

Anaphylaxis to Patent Blue V: a case series.

Blue dyes such as Patent Blue V (PBV) have been used in medical procedures for decades, and in the United Kingdom they are routinely utilised in sentinel lymph node biopsy (SLNB) for staging the axilla in early breast cancer. However, it has long been recognised that such dyes are associated with anaphylaxis. It has recently been estimated in a prospective study that allergy to PBV occurs with a frequency of 0.9%. Since repeated SLNB (and therefore further exposure to PBV) is increasingly being advocated for the small proportion of patients who develop a local (in-breast) recurrence, and because anaphylaxis can be life-threatening, it is important that those individuals that are allergic to PBV are recognised on their first medical exposure. The measurement of serum mast-cell tryptase (MCT) and skin prick test (SPT) are used in the investigation of suspected anaphylaxis because positive results are supportive of type-1 mediated hypersensitivity. Here we report the clinical features, MCT results and SPT results that pertain to a series of four patients referred to our drug allergy clinic with suspected anaphylaxis following SLNB. We recommend that all patients that show clinical evidence of allergy following exposure to PBV are referred to a specialist drug allergy service for further evaluation to investigate the cause.