Richard Hubbard

Incidence and mortality of idiopathic pulmonary fibrosis and sarcoidosis in the UK

Background: Idiopathic pulmonary fibrosis (IPF) and sarcoidosis are common diagnoses in patients attending chest clinics, but little is known about the epidemiology of these diseases. We used data from a general practice database to provide information on the current incidence of IPF and sarcoidosis in the UK. Methods: Data were extracted for all patients with a diagnosis of IPF or sarcoidosis between 1991 and 2003. The whole population of the database was used to calculate disease incidence stratified by age, sex, region, and time period. Poisson regression was used to compare the incidence between populations and Cox regression was used to compare survival between populations. Results: 920 cases of IPF (mean age 71 years, 62% male) and 1019 cases of sarcoidosis (mean age 47 years, 47% male) were identified. The overall incidence rate per 100 000 person-years was 4.6 for IPF and 5.0 for sarcoidosis. The incidence of IPF increased progressively between 1991 and 2003 (p<0.00001), and was highest in Northern England and Scotland (p<0.0001). The survival of patients with IPF was stable over time. In contrast, the incidence of sarcoidosis was highest in London, West Midlands and Northern Ireland and remained stable over time. Conclusions: The incidence of IPF has more than doubled between 1990 and 2003; this is not due to the ageing of the UK population or an increased ascertainment of milder cases. The incidence of sarcoidosis has not changed during this time period. Our findings suggest that more than 4000 new cases of IPF and 3000 new cases of sarcoidosis are currently diagnosed each year in the UK.

The rising incidence of idiopathic pulmonary fibrosis in the UK

Background Previous studies have shown that the incidence of idiopathic pulmonary fibrosis (IPF) is rising in the UK and USA. Death registrations and primary care data were used to determine the current trends in IPF incidence in the UK. Because routine clinical data sets were used, the term IPF clinical syndrome (IPF-CS) is used to describe individuals in this study. Methods Age- and stratum-specific death registration rates between 1968 and 2008 were calculated and these were applied to the 2008 population to generate annual standardised expected number of deaths. Annual mortality rate ratios were calculated using Poisson regression. Computerised primary care records were used to determine incidence rates of IPF-CS between 2000 and 2008 stratified by age, sex and geographical region, and survival rates between calendar periods were compared. Results Annual death certificate recording of IPF-CS rose sixfold across the study period from 0.92 per 100 000 in the 1968–1972 calendar periods to 5.10 per 100 000 in the 2006–2008 calendar period, and were higher in men and the older age groups. The incidence of IPF-CS in primary care increased by 35% from 2000 to 2008, with an overall incidence rate of 7.44 per 100 000 person-years (95% CI 7.12 to 7.77). Incidence was higher in men, the older population and in Northwest England. Conclusions The incidence of IPF-CS in primary care and registered deaths from this cause in the UK continues to rise in the 21st century. The current findings suggest that there are >5000 new cases diagnosed each year in the UK.

Vascular Factors and Risk of Dementia: Design of the Three-City Study and Baseline Characteristics of the Study Population

Objective: To describe the baseline characteristics of the participants in the Three-City (3C) Study, a study aiming to evaluate the risk of dementia and cognitive impairment attributable to vascular factors. Methods: Between 1999 and 2001, 9,693 persons aged 65 years and over, noninstitutionalized, were recruited from the electoral rolls of three French cities, i.e. Bordeaux, Dijon and Montpellier. Health-related data were collected during face-to-face interviews using standardized questionnaires. The baseline examination included cognitive testing and diagnosis of dementia, and assessment of vascular risk factors, including blood pressure measurements, ultrasound examination of the carotid arteries, and measurement of biological parameters (glycemia, total, high-density lipoprotein and low-density lipoprotein cholesterol, triglycerides, creatinemia); 3,442 magnetic resonance imaging (MRI) examinations were performed in subjects aged 65–79. Measurements of ultrasound, blood, and MRI parameters were centralized. Two follow-up examinations (at 2 and 4 years) were planned. Results: After exclusion of the participants who had subsequently refused the medical interview, the 3C Study sample consisted of 3,649 men (39.3%) and 5,645 women, mean age 74.4 years, with a relatively high level of education and income. Forty-two percent of the participants reported to be followed up for hypertension, about one third for hypercholesterolemia, and 8% for diabetes; 65% had elevated blood pressure measures (systolic blood pressure ≧140 or diastolic blood pressure ≧90). The proportion of Mini-Mental State Examination scores below 24 was 7% and dementia was diagnosed in 2.2% of the participants. Conclusion: Distribution of baseline characteristics of the 3C Study participants suggests that this study will provide a unique opportunity to estimate the risk of dementia attributable to vascular factors.

Seroprevalence, correlates, and characteristics of undetected coeliac disease in England

Objective: To examine the seroprevalence, correlates, and characteristics of undetected coeliac disease in a large adult population sample in Cambridge, UK. Methods: The Cambridge General Practice Health Study invited individuals from 12 general practices, aged 45–76 years, to attend for a health survey that included a bone density measurement, between 1990 and 1995. A total of 7550 participants’ serum samples were tested for antiendomysial antibody (EMA). Seroprevalence of undetected coeliac disease was based on EMA positivity. Differences between EMA positive and negative participants of various physiological correlates and reported characteristics were estimated by multivariate logistic and linear regression and adjusted for age, sex, social class, and smoking behaviour. Results: The seroprevalence of undetected coeliac disease in this general population sample aged 45–76 was 1.2% (95% confidence interval (CI) 0.9–1.4). EMA positive participants (n=87) were on average slightly lighter by 2.2 kg (p=0.08), were more likely to have reported their general health as being “good or excellent” (odds ratio (OR) 1.76 (95% CI 0.90–3.46)), and were less likely to report being a current smoker (OR for current versus never 0.36 (95% CI 0.14–0.90)) than EMA negative participants. EMA positivity was associated with an 8% reduction in mean serum cholesterol (0.5 mmol/l; p<0.01) and reductions in mean haemoglobin (0.3 g/dl; p<0.01), total protein (1.0 g/l; p<0.05), and corrected serum calcium (0.02 mmol/l; p<0.05). There was an increased risk of osteoporosis in EMA positive participants (OR 3.1 (95% CI 1.3–7.2)) and of mild anaemia (OR 4.6 (95% CI 2.5–8.2)) compared with EMA negative participants. Conclusions: Undetected coeliac disease is likely to affect approximately 1% of the population of England aged 45–76 years, a value similar to several other countries. Those affected report “better health” but they do have an increased risk of osteoporosis and mild anaemia. In contrast, they have a favourable cardiovascular risk profile that may afford protection from ischaemic heart disease and stroke.

Bullous pemphigoid and pemphigus vulgaris—incidence and mortality in the UK: population based cohort study

Objective To determine the incidence of and mortality from bullous pemphigoid and pemphigus vulgaris in the United Kingdom. Design Retrospective historical cohort study. Setting Computerised medical records from the health improvement network, a large population based UK general practice database. Participants Patients with pemphigus vulgaris and bullous pemphigoid diagnostic codes and age, sex, and practice matched controls. Main outcome measures Incidence and mortality compared with the control population by calendar period, age group, sex, geographical region, and degree of social deprivation. Results 869 people with bullous pemphigoid and 138 people with pemphigus vulgaris were identified. The median age at presentation for bullous pemphigoid was 80 (range 23-102) years, and 534 (61%) patients were female. The median age at presentation for pemphigus vulgaris was 71 (21-102) years, and 91 (66%) patients were female. Incidences of bullous pemphigoid and pemphigus vulgaris were 4.3 (95% confidence interval 4.0 to 4.6) and 0.7 (0.6 to 0.8) per 100 000 person years. The incidence of bullous pemphigoid increased over time; the average yearly increase was 17% (incidence rate ratio=1.2, 95% confidence interval 1.1 to 1.2). An average yearly increase in incidence of pemphigus vulgaris of 11% (incidence rate ratio=1.1, 1.0 to 1.2) occurred. The risk of death for patients with bullous pemphigoid was twice as great as for controls (adjusted hazard ratio=2.3, 95% confidence interval 2.0 to 2.7). For pemphigus vulgaris, the risk of death was three times greater than for controls (adjusted hazard ratio=3.3, 2.2 to 5.2). Conclusions Incidences of bullous pemphigoid and pemphigus vulgaris are increasing. The reasons for the changes in incidence are not clearly understood but have implications for identifying causative factors. Both disorders are associated with a high risk of death. Previous estimates may have underestimated the risk of death associated with these diseases.

Malignancy and mortality in people with coeliac disease: population based cohort study

Abstract Objective To quantify the risks of malignancy and mortality in people with coeliac disease compared with the general population. Design Population based cohort study. Setting General practice research database. Participants 4732 people with coeliac disease and 23 620 matched controls. Main outcome measures Hazard ratios for malignancy and mortality. Results Of the 4732 people with coeliac disease, 134 (2.8%) had at least one malignancy and 237 (5.0%) died. The overall hazard ratios were: for any malignancy 1.29 (95% confidence interval 1.06 to 1.55), for mortality 1.31 (1.13 to 1.51), for gastrointestinal cancer 1.85 (1.22 to 2.81), for breast cancer 0.35 (0.17 to 0.72), for lung cancer 0.34 (0.13 to 0.95), and for lymphoproliferative disease 4.80 (2.71 to 8.50). The increased risk was primarily in the first year after diagnosis, with the risk for only lymphoproliferative disease remaining significantly raised thereafter. After excluding events in the year after diagnosis, the hazard ratio for malignancy was 1.10 (0.87 to 1.39) and for mortality was 1.17 (0.98 to 1.38), giving absolute excess rates of 6 and 17 per 10 000 person years, respectively. Conclusions People with coeliac disease have modest increases in overall risks of malignancy and mortality. Most of this excess risk occurs in the year of follow up after diagnosis. People with coeliac disease also have a noticeably reduced risk of breast cancer. The mechanism of this merits further attention as it may provide insights into the cause of this common malignancy.

Inhaled corticosteroid use and bone-mineral density in patients with asthma

BACKGROUND Inhaled corticosteroids are absorbed into the systemic circulation, but the extent to which they have adverse effects on bone is uncertain. The question is important since 3% of the European population take an inhaled corticosteroid regularly and may do so for many years. METHODS We studied the dose-response relation between cumulative inhaled corticosteroid dose and bone-mineral density at the lumbar spine and proximal femur in 196 adults (119 women) with asthma aged 20-40 years. Patients had taken an inhaled corticosteroid regularly for at least 6 months, and had had limited exposure to systemic steroids. Cumulative dose of inhaled corticosteroid was calculated from questionnaires and computerised and written general-practice records, and its effect on bone-mineral density was estimated by multiple regression analysis. FINDINGS Median duration of inhaled corticosteroid treatment was 6 years (range 0.5-24), and median cumulative dose was 876 mg (87-4380). There was a negative association between cumulative dose of inhaled corticosteroid and bone-mineral density at the lumbar spine (L2-L4), femoral neck, Wards triangle, and trochanter, both before and after adjustment for the effects of age and sex. A doubling in dose of inhaled corticosteroid was associated with a decrease in bone-mineral density at the lumbar spine of 0.16 SD (95% CI 0.04-0.28). Similar decreases were found at the femoral neck, Wards triangle, and trochanter. Adjustment for potential confounding factors including physical activity and past oral, nasal, dermal, and parenteral corticosteroids did not weaken the associations. INTERPRETATION This study provides evidence of a negative relation between total cumulative dose of inhaled corticosteroid and bone-mineral density in patients with asthma.

Risk of deep vein thrombosis and pulmonary embolism after acute infection in a community setting

BACKGROUND Acute infection increases the risk of arterial cardiovascular events, but effects on venous thromboembolic disease are less well established. Our aim was to investigate whether acute infections transiently increase the risk of venous thromboembolism. METHODS We used the self-controlled case-series method to study the risk of first deep vein thrombosis (DVT) (n=7278) and first pulmonary embolism (PE) (n=3755) after acute respiratory and urinary tract infections. Data were obtained from records from general practices who had registered patients with the UKs Health Improvement Network database between 1987 and 2004. FINDINGS The risks of DVT and PE were significantly raised, and were highest in the first two weeks, after urinary tract infection. The incidence ratio for DVT was 2.10 (95% CI 1.56-2.82), and that for PE 2.11 (1.38-3.23). The risk gradually fell over the subsequent months, returning to the baseline value after 1 year. The risk of DVT was also higher after respiratory tract infection, but possible diagnostic misclassification precluded a reliable estimate of the risk of PE after respiratory infection. INTERPRETATION Acute infections are associated with a transient increased risk of venous thromboembolic events in a community setting. Our results confirm that infection should be added to the list of precipitants for venous thromboembolism, and suggest a causal relation.

Increased Risk of Myocardial Infarction and Stroke Following Exacerbation of COPD

OBJECTIVE Patients with COPD are at risk for cardiovascular events. This is attributed to increased systemic inflammation. The course of COPD is punctuated by exacerbations, which further increase systemic inflammation, but the risk of vascular events in the postexacerbation period has never been defined. METHODS We analyzed data from 25,857 patients with COPD entered in The Health Improvement Network database over a 2-year period. Exacerbations were defined using a health-care use definition of prescription of oral corticosteroids > 20 mg/d and/or selected oral antibiotics. The risk of myocardial infarction (MI) and stroke in the postexacerbation period was calculated relative to the patients baseline risk using the self-controlled case series approach. RESULTS We identified 524 MIs in 426 patients and 633 ischemic strokes in 482 patients. The incidence rates of MI and stroke were 1.1 and 1.4 per 100 patient-years, respectively. There was a 2.27-fold (95% CI, 1.1-4.7; P = .03) increased risk of MI 1 to 5 days after exacerbation (defined by prescription of both steroids and antibiotics). This relative risk diminished progressively with time and was not significantly different from the baseline MI risk at any other postexacerbation time interval. One in 2,513 exacerbations was associated with MI within 1 to 5 days. There was a 1.26-fold (95% CI, 1.0-1.6; P = .05) increased risk of stroke 1 to 49 days after exacerbation. CONCLUSION The results suggest that exacerbations of COPD increase the risk of MI and stroke. This may have implications for therapy in both stable and exacerbated COPD.

OCCUPATIONAL EXPOSURE TO METAL OR WOOD DUST AND AETIOLOGY OF CRYPTOGENIC FIBROSING ALVEOLITIS

BACKGROUND We have previously suggested that cryptogenic fibrosing alveolitis (CFA) may be caused by occupational exposures, particularly to metal or wood dust. We have specifically investigated this hypothesis in a case-control study of patients with CFA. METHODS We obtained lifetime occupational histories by postal questionnaire from 218 patients with CFA and 569 controls matched for age, sex, and community, living in the Trent region of the UK. Information was subsequently verified by telephone interview in 165 cases and 408 controls. Serum IgE, rheumatoid factor, and antinuclear antibodies and skin sensitivity to common allergens were measured in cases and in one matched control for each. FINDINGS The relative risk of CFA, after adjustment for smoking, was significantly increased in relation to questionnaire-reported exposure to metal dust (odds ratio 1.68 [95% CI 1.07-2.65], p = 0.024) or to wood dust (1.71 [1.01-2.92], p = 0.048). Similar results were obtained with the telephone interview data. Significant exposure-response effects were found for both metal-dust and wood-dust exposure. CFA was also associated with the presence of rheumatoid factor or antinuclear antibodies, but not with positive allergen skin tests or raised IgE concentrations. There was no evidence of interaction between the effects of rheumatoid factor, antinuclear antibodies, positive skin allergen tests, or IgE concentrations and exposure to metal or wood dust. The combined aetiological fraction attributable to exposure to metal or wood dust was of the order of 20%. INTERPRETATION Occupational exposures to metal or wood dust are independent risk factors for CFA. Avoidance or limitation of these exposures may provide an opportunity to prevent the disease.