Increased Respiratory Viral Detection and Symptom Burden Among Patients with Primary Antibody Deficiency: Results from the BIPAD Study.

BACKGROUND: Patients with primary antibody deficiency (PAD) are at increased risk of respiratory tract infections, but our understanding of their nature and consequences remains limited. OBJECTIVE: To define the symptomatic and microbial burden of upper airway infection in adults with PAD relative to age-matched controls. METHODS: Prospective 12-month observational study consisting of a daily upper and lower airway symptom score alongside fortnightly nasal swab with molecular detection of 19 pathogen targets. RESULTS: A total of 44 patients and 42 controls (including 34 household pairs) were recruited, providing more than 22,500 days of symptom scores and 1,496 nasal swabs. Swab and questionnaire compliance exceeded 70%. At enrollment, 64% of patients received prophylactic antibiotics, with a 34% prevalence of bronchiectasis. On average, patients with PAD experienced symptomatic respiratory exacerbations every 6 days compared with 6 weeks for controls, associated with significant impairment of respiratory-specific quality-of-life scores. Viral detections were associated with worsening of symptom scores from a participant's baseline. Patients with PAD had increased odds ratio (OR) for pathogen detection, particularly viral (OR, 2.73; 95% CI, 2.09-3.57), specifically human rhinovirus (OR, 3.60; 95% CI, 2.53-5.13) and parainfluenza (OR, 3.06; 95% CI, 1.25-7.50). Haemophilus influenzae and Streptococcus pneumoniae were also more frequent in PAD. Young child exposure, IgM deficiency, and presence of bronchiectasis were independent risk factors for viral detection. Prophylactic antibiotic use was associated with a lower risk of bacterial detection by PCR. CONCLUSIONS: Patients with PAD have a significant respiratory symptom burden associated with increased viral infection frequency despite immunoglobulin replacement and prophylactic antibiotic use. This highlights a clear need for future therapeutic trials in the population with PAD, and informs future study design.

Transforming growth factor-ß enhances invasion and metastasis in Ras-transfected human malignant epidermal keratinocytes.

Transforming growth factor-ß (TGF-ß) is known to act as a tumour suppressor early in carcinogenesis, but then switches to a pro-metastatic factor in some late stage cancers. However, the actions of TGF-ß are context dependent, and it is currently unclear how TGF-ß influences the progression of human squamous cell carcinoma (SCC). This study examined the effect of overexpression of TGF-ß1 or TGF-ß2 in Ras-transfected human malignant epidermal keratinocytes that represent the early stages of human SCC. In vitro, the proliferation of cells overexpressing TGF-ß1 or TGF-ß2 was inhibited by exogenous TGF-ß1; cells overexpressing TGF-ß1 also grew more slowly than controls, but the growth rate of TGF-ß2 overexpressing cells was unaltered. However, cells that overexpressed either TGF-ß1 or TGF-ß2 were markedly more invasive than controls in an organotypic model of SCC. The proliferation of the invading TGF-ß1 overexpressing cells in the organotypic assays was higher than controls. Similarly, tumours formed by the TGF-ß1 overexpressing cells following transplantation to athymic mice were larger than tumours formed by control cells and proliferated at a higher rate. Our results demonstrate that elevated expression of either TGF-ß1 or TGF-ß2 in cells that represent the early stages in the development of human SCC results in a more aggressive phenotype.

TGF-ß inhibits metastasis in late stage human squamous cell carcinoma of the skin by a mechanism that does not involve Id1.

It is now generally accepted that TGF-ß acts as a pro-metastatic factor in advanced human breast cancer. However, it is well documented, that TGF-ß is context dependent, and whether the TGF-ß pathway switches to promote metastasis during the progression of squamous cell carcinoma (SCC) is unknown. This study examined the role of TGF-ß signalling in SCC using a series of genetically related keratinocyte cell lines representing later stages of the disease, stably transduced with a dominant negative TßRII cDNA (dnTßRII). We demonstrated that clones expressing dnTßRII lost their growth inhibitory response to TGF-ßin vitro, while ligand expression remained unchanged. Following transplantation of transduced cells to athymic mice in vivo, we showed that attenuation of the TGF-ß signal resulted in a loss of differentiation and increased metastasis. In human tissue samples loss of TGF-ß signal transduction as measured by pSmad2 activity also correlated with a loss of differentiation. Id1, previously shown to be down regulated by TGF-ß, an inhibitor of differentiation and associated with metastasis, was weakly expressed in focal areas of a small number of human tumours but expression did not correlate with low levels of pSmad2. Our data demonstrate that TGF-ß does not switch to promote metastasis in late stage human SCC of the skin and that inhibition of TGF-ß signalling results in a loss of differentiation and increased metastasis in the later stages of this disease.