Hermansky-Pudlak syndrome with a novel genetic variant in HPS1 and subsequent accelerated pulmonary fibrosis: significance for phenocopy diseases.

The Hermansky-Pudlak syndrome (HPS) is a collection of autosomal-recessive disorders characterised by tyrosinase-positive oculocutaneous albinism (OCA), bleeding diatheses and, in selected individuals, early-onset accelerated pulmonary fibrosis, neutropaenia and granulomatous colitis. We describe a young man who presented following a self-directed literature review prompted by severe bleeding complications following minor surgical and dental procedures in the context of OCA. HPS was clinically suspected, with subsequent genetic testing confirming biallelic mutations in the HPS1 gene. Of interest, this is the only described HPS type 1 patient with two different (compound heterozygote) splice site variants in HPS1 In addition to detailing a novel genetic result and outlining the progressive clinical course of disease in this case, we discuss the management of HPS, the prognostic value of subtype analysis and the technical difficulties relating to transplantation in the case of HPS-associated advanced pulmonary fibrosis. This case also illustrates the concept of lung phenocopy relationships and the potential for elucidating the pathogenesis of more common pulmonary disorders by studying genetic diseases that result in similar phenotypes. Furthermore, it re-emphasises the importance of the patient voice, particularly with regard to complex diagnoses and rare diseases.

The impact of smoke exposure on the clinical phenotype of alpha-1 antitrypsin deficiency in Ireland: exploiting a national registry to understand a rare disease.

Individuals with Alpha-1 antitrypsin deficiency (AATD) have mutations in the SERPINA1 gene causing genetic susceptibility to early onset lung and liver disease that may result in premature death. Environmental interactions have a significant impact in determining the disease phenotype and outcome in AATD. The aim of this study was to assess the impact of smoke exposure on the clinical phenotype of AATD in Ireland. Clinical demographics and available thoracic computerised tomography (CT) imaging were detected from 139 PiZZ individuals identified from the Irish National AATD Registry. Clinical information was collected by questionnaire. Data was analysed to assess AATD disease severity and evaluate predictors of clinical phenotype. Questionnaires were collected from 107/139 (77%) and thoracic CT evaluation was available in 72/107 (67.2%). 74% of respondents had severe Chronic Obstructive Pulmonary Disease (COPD) (GOLD stage C or D). Cigarette smoking was the greatest predictor of impairment in FEV1 and DLCO (%predicted) and the extent of emphysema correlated most significantly with DLCO. Interestingly the rate of FEV1 decline was similar in ex-smokers when compared to never-smokers. Passive smoke exposure in childhood resulted in a greater total pack-year smoking history. Radiological evidence of bronchiectasis was a common finding and associated with increasing age. The Irish National AATD Registry facilitates clinical and basic science research of this condition in Ireland. This study illustrates the detrimental effect of smoke exposure on the clinical phenotype of AATD in Ireland and the benefit of immediate smoking cessation at any stage of lung disease.

Aspergillus-associated airway disease, inflammation, and the innate immune response.

Aspergillus moulds exist ubiquitously as spores that are inhaled in large numbers daily. Whilst most are removed by anatomical barriers, disease may occur in certain circumstances. Depending on the underlying state of the human immune system, clinical consequences can ensue ranging from an excessive immune response during allergic bronchopulmonary aspergillosis to the formation of an aspergilloma in the immunocompetent state. The severest infections occur in those who are immunocompromised where invasive pulmonary aspergillosis results in high mortality rates. The diagnosis of Aspergillus-associated pulmonary disease is based on clinical, radiological, and immunological testing. An understanding of the innate and inflammatory consequences of exposure to Aspergillus species is critical in accounting for disease manifestations and preventing sequelae. The major components of the innate immune system involved in recognition and removal of the fungus include phagocytosis, antimicrobial peptide production, and recognition by pattern recognition receptors. The cytokine response is also critical facilitating cell-to-cell communication and promoting the initiation, maintenance, and resolution of the host response. In the following review, we discuss the above areas with a focus on the innate and inflammatory response to airway Aspergillus exposure and how these responses may be modulated for therapeutic benefit.

Long-term follow-up of non-calcified pulmonary nodules (<10 mm) identified during low-dose CT screening for lung cancer.

OBJECTIVES: To assess the long-term stability of small (<10 mm) non-calcified pulmonary nodules (NCNs) in high-risk subjects initially screened for lung cancer using low-dose chest computed tomography (LDCCT). METHODS: A total of 449 subjects initially underwent screening with serial LDCCT over a 2-year period. Participants identified as having NCNs ≥10 mm were referred for formal lung cancer workup. NCNs <10 mm diameter were followed in accordance with the study protocol. Seven years after baseline screening, subjects with previously documented NCNs <10 mm, which were unchanged in size after the 2-year follow-up period, were re-imaged using LDCCT to assess for interval nodule growth. RESULTS: Eighty-three subjects with previously documented stable NCNs <10 mm underwent LDCCT at 7 years. NCNs were unchanged in 78 subjects and had decreased in size in 4 subjects. There was interval growth of an NCN (from 6 mm to 9 mm) in one subject re-imaged at 7 years, but this nodule has remained stable in size over a further 2-year follow-up period. CONCLUSIONS: Non-calcified pulmonary nodules <10 mm in size that are unchanged in size or smaller after 2 years of follow-up with LDCCT are most likely benign.

Sonographically guided percutaneous muscle biopsy in diagnosis of neuromuscular disease: a useful alternative to open surgical biopsy.

OBJECTIVE: The purpose of this study was to evaluate the feasibility of sonographically guided percutaneous muscle biopsy in the investigation of neuromuscular disorders. METHODS: Sonographically guided percutaneous needle biopsy of skeletal muscle was performed with a 14-gauge core biopsy system in 40 patients over a 24-month period. Patients were referred from the Department of Neurology under investigation for neuromuscular disorders. Sonography was used to find suitable tissue and to avoid major vascular structures. A local anesthetic was applied below skin only. A 3- to 4-mm incision was made. Three 14-gauge samples were obtained from each patient. All samples were placed on saline-dampened gauze and sent for neuropathologic analysis. As a control, we retrospectively assessed results of the 40 most recent muscle samples acquired via open surgical biopsy. RESULTS: With the use of sonography, 32 (80%) of 40 patients had a histologic diagnosis made via percutaneous needle biopsy. This included 26 (93%) of 28 patients with acute muscular disease and 6 (50%) of 12 patients with chronic disease. In the surgical group (all acute disease), 38 (95%) of 40 patients had diagnostic tissue attained. CONCLUSIONS: Sonographically guided percutaneous 14-gauge core skeletal muscle biopsy is a useful procedure, facilitating diagnosis in acute muscular disease. It provides results comparable with those of open surgical biopsy in acute muscular disease. It may also be used in chronic muscular disease but repeated or open biopsy may be needed.

Alpha-1 antitrypsin deficiency and computed tomography findings.

OBJECTIVE: To investigate the severity of bronchiectasis and associated emphysema and the correlation with phenotype in patients with Alpha-1 antitrypsin deficiency. METHODS: The scoring system of Ooi and his colleagues for bronchiectasis was modified to include the degree of dilatation of bronchi in affected segments and degree of emphysema. This was applied to 26 high-resolution computed tomography thorax scans of the study population. All criteria were scored on a scale of 0-3. RESULTS: Nine patients (35%) were female and 17 (65%) were male. The median age was 56 years (range: 17-76 years). Twenty-one patients had a ZZ phenotype, 3 patients had an MZ phenotype, and 2 patients had an SZ phenotype. The median forced expiratory volume in 1 second/forced vital capacity ratio was 43% (range: 24%-87%). A total of 156 lobes were assessed, and 38 (24%) had evidence of bronchiectasis. The overall median total score in affected patients for the extent of bronchiectasis was 2, and all had a ZZ phenotype. Fourteen patients (54%) had a degree of dilatation score of 1 or more, all had a ZZ phenotype, and 4 (15%) had no evidence of emphysema. Bronchiectasis was seen most commonly affecting the upper lobes. CONCLUSION: The ZZ phenotype was associated with bronchiectasis most commonly affecting the upper lobes, with moderate emphysema throughout all lobes. Numbers of patients having the SZ and MZ phenotypes are too small to derive accurate conclusions, but none had evidence of bronchiectasis.

The fat pad sign following elbow trauma in adults: its usefulness and reliability in suspecting occult fracture.

OBJECTIVE: An elbow joint effusion with no fracture seen on radiographs after acute trauma has become synonymous with occult fracture. This study evaluates the incidence of fracture in such cases as determined by MR imaging and the predictive value of an elbow joint effusion. METHODS: Twenty consecutive patients whose posttrauma elbow radiographs showed an effusion but no fracture and who were suitable for MR imaging were recruited. The elbow effusion size, represented by anterior and posterior fat pad displacement, was measured from the initial lateral elbow radiograph. Suitable candidates underwent MR imaging using a bone marrow sensitive sequence. The time between injury and MR imaging ranged from 0 to 12 days (mean 4 days). RESULTS: Seventy-five percent of the 20 patients who underwent MR imaging had radiographically occult fractures identified. Some (86.6%) of these fractures were located in the radial head, 6.7% were in the lateral epicondyle, and 6.7% were in the olecranon. Ninety percent had evidence of bone marrow edema. Fifteen percent had collateral ligament disruption identified on MR imaging, and 5% had a loose body. There was no change in patient management as a result of the additional imaging. The anterior fat pad displacement ranged from 5 to 15 mm (mean 9.25), and the posterior fat pad was elevated from 1 to 6 mm (mean 3.2). CONCLUSION: Our data using MR imaging suggests that fat pad elevation in the presence of recent trauma is frequently associated with a fracture. The size of the effusion, anterior/posterior fat pad elevation, or a combination of both does not correspond to the likelihood of an underlying fracture. MR imaging reveals a broad spectrum of bone and soft tissue injury beyond that recognizable on plain radiographs as demonstrated by all patients in this study.

The accuracy of references in manuscripts submitted for publication.

OBJECTIVE: To analyze the errors present in references cited in papers submitted for peer review for possible publication. METHODS: Nineteen consecutive manuscripts submitted for peer review were assessed. They contained a total of 261 references. Manuscripts were submitted to 1 of 5 major radiology journals. Journal references were compared with either the original articles or abstracts obtained through MEDLINE. Book references were checked against the original book. In total, 259 of 261 references were obtained. The remaining 2 references were both out-of-print books that were not available. Each reference was checked and errors were identified as either major or minor, depending on the gravity of the error. Errors were analyzed to see whether they could be attributed to not adhering to journal guidelines or to other reasons. RESULTS: Of a total of 259 references, 56% (n = 145) contained at least 1 error, 53% (n = 137) contained minor errors and 15% (n = 39) contained major errors. Five per cent (n = 13) of references had more than 3 errors, and 79% (n = 274) of all errors were the direct result of authors not following journal instructions. CONCLUSION: Over half of all references included in manuscripts submitted to radiology journals contain at least 1 error. The majority are avoidable, resulting from failure to follow the journal's instructions to authors.

Patient positioning after lung biopsy: influence on the incidence of pneumothorax.

OBJECTIVE: To determine if post-biopsy complication rates were influenced by patient positioning after the procedure. METHODS: A prospective evaluation of post-biopsy complications in 87 patients (55 men, 32 women; mean age 66 yr, range 20-86 yr) undergoing fine-needle aspiration biopsy of lung nodules was performed. Biopsies were performed under computed tomographic guidance in 66 patients, fluoroscopic guidance in 18 and ultrasonographic guidance in 3 patients. Patients were randomly assigned to be placed either in the lateral decubitus "biopsy-side-down" position or in the "biopsy-site-dependent" position (i.e., lying directly on the skin puncture site) after surgery. Chest imaging was performed immediately and at 4 hours after biopsy. RESULTS: Immediately after the procedure, 6 (14%) of the 42 patients in the decubitus biopsy-side-down group and 15 (33%) of the 45 patients in the site-dependent group experienced pneumothoraces (p > 0.05). No patient required tube thoracostomy. Two patients in the decubitus group and 1 in the site-dependent group experienced hemoptysis immediately after biopsy. On the 4-hour chest radiographs, there was no progression in size of the existing pneumothoraces. CONCLUSION: Positioning the patient either decubitus biopsy-side-down or lying directly on the puncture site after lung biopsy does not appear to affect complication rates.