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Aims: To examine the impact of off-label and unlicensed (OLUL) prescribing on adverse drug reactions (ADRs) causing unplanned admissions to a paediatric hospital., Methods: Prescription data from a 12 month prospective cohort study of ADRs detected in children admitted to a paediatric hospital were scrutinized. The relative risk for off-label and unlicensed medicines being implicated in an ADR was calculated. Logistic regression analyses were carried out with exposure to off-label and unlicensed medicines and number of off-label and unlicensed medicines administered as predictor variables., Results: Off-label and unlicensed medicines were more likely to be implicated in an ADR than authorized medicines (relative risk 1.67, 95% CI 1.38, 2.02, P < 0.001). There was a 25% increase in ADR risk (95% CI 1.16, 1.35, P < 0.001) with each additional authorized medicine and 23% (95% CI 1.10, 1.36, P < 0.001) with each additional off-label or unlicensed medicine. Logistic regression analysis focusing on non-oncology patients demonstrated that the number of authorized medicines (odds ratio 1.33, 95% CI 1.23, 1.44, P < 0.001), but not the number of off-label and unlicensed medicine courses, was a predictor of ADR risk., Conclusions: In a heterogeneous population of children admitted to a secondary/tertiary hospital, off-label and unlicensed medicines are more likely to be implicated in an ADR than authorized medicines. This was largely driven by ADRs related to drugs used in oncological practice, where the usage of off-label or unlicensed medicines was associated with a higher ADR risk than in non-oncological areas., (© 2013 The British Pharmacological Society.)

Background: Off-label and unlicensed (OLUL) prescribing has been prevalent in pediatric practice. Using data from a prospective cohort study of adverse drug reactions (ADRs) among pediatric inpatients, we aimed to test the hypothesis that OLUL status is a risk factor for ADRs., Methods: A nested case?control study was conducted within a prospective cohort study. Details of all medicines administered were recorded, including information about OLUL status. The odds ratio for OLUL medicines being implicated in a probable or definite ADR was calculated. A multivariate Cox proportional hazards regression model was fitted to the data to assess the influence that OLUL medicine use had on the hazard of an ADR occurring., Results: A total of 10,699 medicine courses were administered to 1,388 patients. The odds ratio (OR) of an OLUL medicine being implicated in an ADR compared with an authorized medicine was 2.25 (95% confidence interval (CI) 1.95 to 2.59). Medicines licensed in children but given to a child below the minimum age or weight had the greatest odds of being implicated in an ADR (19% of courses in this category were implicated, OR 3.54 (95% CI 2.82 to 4.44). Each additional OLUL medicine given significantly increased the hazard of an ADR (hazard ratio (HR) 1.3 95% CI 1.2 to 1.3, P <0.001). Each additional authorized medicine given also significantly increased the hazard (HR 1.2 95% CI 1.2 to 1.3, P <0.001)., Conclusions: OLUL medicines are more likely to be implicated in an ADR than authorized medicines. The number of medicines administered is a risk factor for ADRs highlighting the need to use the lowest number of medicines, at the lowest dose for the shortest period, with continual vigilance by prescribers, in order to reduce the risk of ADRs.

Tuberculosis cases in children (aged under 15 years) in the National Surveys rose from 308 (rate: 3.3 per 100,000) in 1988 to 408 (4.2 per 100,000) in 1993 and then fell to 364 (3.6 per 100,000) in 1998. The rates in white children were 1.6, 2.0, and 1.1 per 100,000 respectively; in Indian subcontinent children, the rates were unchanged between 1988 and 1993 at around 33 per 100,000 but fell to 23 per 100,000 in 1998. In black African children, the rates were 15, 34, and 71 per 100,000 respectively. From 1988 to 1998, the proportion of cases resident in London more than doubled to 49% (rate: 11.9 per 100,000) and the proportion of cases in children born abroad increased from 13% to 27% in the country as a whole. Although the overall rate of tuberculosis in children in England and Wales has changed little between 1988 and 1998, the distribution of disease has changed in line with the change in adults. Services for the diagnosis and treatment of tuberculosis in children should be adapted to the changing pattern of disease in this group. Continuous enhanced tuberculosis surveillance will enable more detailed and timely scrutiny of trends in tuberculosis in the future.

Background: A national survey of tuberculosis was conducted in England and Wales in 1998 to obtain detailed information on the occurrence of the disease and recent trends. This survey also piloted the methodology for enhanced tuberculosis surveillance in England and Wales and investigated the prevalence of HIV infection in adults with tuberculosis., Methods: Clinical and demographic data for all cases diagnosed during 1998 were obtained, together with microbiological data where available. Annual incidence rates in the population were estimated by age, sex, ethnic group, and geographical region using denominators from the 1998 Labour Force Survey. Incidence rates in different subgroups of the population were compared with the rates observed in previous surveys. The tuberculosis survey database for 1998 was matched against the Communicable Disease Surveillance Centre HIV/AIDS database to estimate the prevalence of HIV co-infection in adult patients with tuberculosis., Results: A total of 5658 patients with tuberculosis were included in the survey in England and Wales (94% of all formally notified cases during the same period), giving an annual rate of 10.93 per 100 000 population (95% CI 10.87 to 10.99). This represented an increase of 11% in the number of cases since the survey in 1993 and 21% since 1988. In many regions case numbers have remained little changed since 1988, but in London an increase of 71% was observed. The number of children with tuberculosis has decreased by 10% since 1993. Annual rates of tuberculosis per 100 000 population have continued to decline among the white population (4.38) and those from the Indian subcontinent, although the rate for the latter has remained high at 121 per 100 000. Annual rates per 100 000 have increased in all other ethnic groups, especially among those of black African (210) and Chinese (77.3) origin. Over 50% of all patients were born outside the UK. Recent entrants to the UK had higher rates of the disease than those who had been in the country for more than 5 years or who had been born in the UK. An estimated 3.3% of all adults with tuberculosis were co-infected with HIV., Conclusions: The epidemiology of tuberculosis continues to change in England and Wales and the annual number of cases is rising. More than one third of cases now occur in young adults and rates are particularly high in those recently arrived from high prevalence areas of the world. The geographical distribution is uneven with urban centres having the highest rates. The increase in the number of cases in London is particularly large. Tuberculosis in patients co-infected with HIV makes a small but important contribution to the overall increase, particularly in London. To be most effective and to make the most efficient use of resources, tuberculosis prevention and control measures must be based on accurate and timely information on the occurrence of disease. A new system of continuous enhanced tuberculosis surveillance was introduced in 1999, based on the methodology developed in this national survey.

Objective: To compare the cost of using intravenous epoprostenol with that of inhaled nitric oxide (NO) for treating episodes of pulmonary hypertension in children with congenital heart disease., Design: An analysis of the cost of epoprostenol and NO use over the previous 18 months was performed. Three 6-month periods were identified, two in which epoprostenol was used and the third in which inhaled NO was introduced for the treatment of pulmonary hypertension., Setting: A 10-bed pediatric cardiac intensive care unit, Royal Liverpool Children's Hospital, Alder Hey, Liverpool, England., Subjects: Children with congenital heart disease and persistently elevated pulmonary artery pressure following cardiac surgery., Main Outcome Measures: The total duration of use of epoprostenol and inhaled NO was documented. The costs per hour for epoprostenol and inhaled NO were calculated and the annual cost of each agent was estimated., Results: In the two 6-month periods prior to the introduction of inhaled NO, epoprostenol was used on 14 occasions (5 in the first period, 3 in the second). In the last 6-month period, nine children required pulmonary vasodilator therapy on 14 occasions. All nine children were treated successfully with inhaled NO; none were given or needed epoprostenol, as NO always was effective in providing pulmonary vasodilatation. For resistant pulmonary hypertension, increasing the concentration of NO would have been the next therapeutic option. The cost for the two 6-month periods using epoprostenol was $19,483.48 for the drug and $283.25 for equipment costs (total cost $19,766.73). There was no expenditure on epoprostenol in the final 6-month period. The cost of NO was $465. However, the total expenditure, including the delivery and monitoring system, was $4,722.85., Conclusions: Using inhaled NO in our pediatric cardiac intensive care unit abolished the use of epoprostenol during the reported monitoring period. The cost savings were significant, amounting to 12% of the annual drug budget for the unit. The cost of setting up the inhaled NO delivery system is recouped rapidly. The ease of delivery and measurement of inhaled NO also may have contributed to its increased clinical use.

The pattern of tuberculosis in Indian, Pakistani and Bangladeshi patients in Blackburn (1978-1987) was compared with that for England and Wales (MRC Survey), with particular reference to the proportion with parenchymal lung disease, by a generalized linear model allowing for age, ethnic group and time since first entry. In Blackburn, the proportion with lung disease was higher in Pakistani/Bangladeshi (46%) compared with 28% in Indians, although in both groups this increased with age. In the MRC Survey, the proportions with lung disease were similar (Pakistani/Bangladeshi 36.5%, Indians 34%) but there was an increase in lung disease with age and year since first entry in the Indian ethnic group only. The reasons for the differences, and their implications are discussed.

Of the 4172 patients in a survey of all cases of tuberculosis notified in a six-month period in England and Wales in 1978-79, 198 had a bone or joint lesion; 79 were white and 108 were of Indian subcontinent (Indian, Pakistani or Bangladeshi) ethnic origin. The estimated annual notification rates for orthopaedic tuberculosis were 29 per 100 000 for the Indian subcontinent group and 0.34 per 100 000 in the white group, a ratio of 85 to 1. Rates increased with age in both groups. The spine was the most common site, and was affected in 30% of the white patients and 43% of the Indian subcontinent patients; the distribution of other sites was similar in both groups. Positive culture from a bone or joint lesion was obtained in 99 (50%) of the 198 patients (58% of white patients and 47% of the Indian subcontinent patients). Bacteriological or histological confirmation of tuberculosis either from a bone or joint lesion or from another site was obtained in 68% of the patients. Mycobacterium tuberculosis was isolated from the orthopaedic lesions in 79 of the 82 patients with identification test results and M. bovis in the 3 remaining patients. Of the 61 patients with M. tuberculosis and with no history of previous chemotherapy, 5 had resistant strains compared with 1 of the 18 patients who had previously received chemotherapy. All 6 patients with resistant strains were of Indian subcontinent ethnic origin.

Between special surveys in 1971 and 1978/79 the estimated annual tuberculosis notification rate for males in England fell from 30.5 per 100 000 to 22.6 per 100 000 (a decline of 3.8% per year). For females the rate fell from 18.4 per 100 000 to 15.8 per 100 000 (1.9% per year). In each survey the lowest rates were those for the white ethnic group born in the United Kingdom. The highest rates, some more than 50 times as great, occurred in immigrants from the Indian sub-continent (Indian or Pakistani/Bangladeshi). The rates for immigrants from the West Indies were 3 to 4 times as great as than those for the white group. The most rapid reductions in rate between the surveys, of about 10% per year, occurred in West Indian immigrants of both sexes and in Pakistani/Bangladeshi male immigrants. The rate for Pakistani/Bangladeshi females fell by 6.5% per year. For whites born in the U.K. the annual rate of decline was 5.1% in each sex. There was very little change for Indian immigrants of either sex. Between the surveys, continued immigration of groups from the Indian subcontinent with high notification rates considerably slowed the decline in notification rate for the whole population. The steep downward trend in notification rate for the white ethnic group may be expected to continue, but changes in the other ethnic groups are more difficult to assess because they are influenced by so many uncertain factors. In addition, the trends in the non-white ethnic groups born in the United Kingdom cannot yet be ascertained, but will become of increasing importance.

Mortality from asthma in England and Wales has remained unchanged for at least 20 years, even in the age group 15-44. Yet in those 20 years "modern" drugs have been introduced for the treatment of asthma, such as beta 2 agonist bronchodilators and corticosteroids. Why do patients still die? Detailed review of the circumstances of 90 deaths from asthma showed that a few were inevitable but that in the remainder four main sets of circumstances in the fatal attack contributed to the death. These were, firstly, the patient's failure to recognise the severity of the asthma; secondly, very rapid progress in the severity of the attack; thirdly, misjudgment in the management of the attack; and, fourthly, delay from many causes. Patients admitted to hospital with severe acute asthma usually survive. Those at risk of a life threatening attack should be identified and taught to monitor the severity and progress of their asthma objectively. Their direct admission to hospital should be facilitated.

Published asthma death rates have risen during recent years. This may be due to a number of possible factors and it is important to assess whether or not the increase is genuine. Evidence from the BTA confidential enquiry into asthma deaths together with the results of bridge coding by the Office of Population Censuses and Surveys suggest that published death rates in the 15-44 year age group are reasonably accurate and comparisons before and after recent changes in the International Classification of Diseases are valid. The death rate in females in this age group has almost halved since the pre-epidemic levels of the 1960s, whereas the rate for males is little changed. This should alert all those involved in the management of severe acute asthma to the seriousness of the problem that remains.

In two national surveys of tuberculosis notifications in England conducted in 1978/79 and 1983 the estimated annual notification rates for the Indian subcontinent (Indian, Pakistani, and Bangladeshi) ethnic groups were considerably higher than the rate for the white ethnic group. The mean annual decline in rates between the surveys appeared to be greater for the Indian and the Pakistani and Bangladeshi ethnic groups, 15% and 16% respectively, than for the white ethnic group (7%). Data from two small sample population surveys, the National Dwelling and Housing Survey in 1978 and the Labour Force Survey in 1983, were used to calculate the rates. However, comparison of the estimates for the population of Indian subcontinent ethnic origin in England from these surveys revealed discrepancies between them. Additional information from the Labour Force Survey on the year of first entry to the United Kingdom (UK) permitted the calculation of new estimates for the 1978 population, and based on these estimates the annual notification rates for 1978/79 were 287 per 100,000 for the Indian and 286 per 100,000 for the Pakistani and Bangladeshi ethnic groups. The rates for 1983 were 178 and 169 respectively, and the mean annual decline between the surveys was 11% for the Indian and 12% for the Pakistani and Bangladeshi ethnic groups. There were important changes in the characteristics of the population of Indian subcontinent ethnic origin in England between 1978 and 1983, and therefore the rates for both surveys have been standardised by the method of direct standardisation to a common reference population. Standardizing for year of entry to the UK, place of birth (UK or abroad), age, and sex reduced the mean annual decline in the notification rate to 4% for the Indian and 9% for the Pakistani and Bangladeshi ethnic groups. The much greater reduction in the rate of decline in the Indian ethnic group is due to the substantial decline between the surveys in the proportion of recent immigrants, the group with the highest annual notification rate, in that population. Future trends will continue to be influenced by immigration patterns, but it will also be important to monitor the rates among the increasing proportion of the population born in the UK or resident in England for more than five years.

In a survey of the chemotherapy prescribed for 1312 adult patients of white or Indian subcontinent ethnic origin with pulmonary tuberculosis only, notified in the 6 months from October 1978 to March 1979, it was found that 163 (12%) patients died before they had completed chemotherapy. Of the 163 patients who died 96% were of white ethnic origin; 15% of the 1022 white patients died compared with 2% of the 290 Indian subcontinent patients. According to the death certificate, approximately half the white patients died from tuberculosis, and in a further 31% tuberculosis was a contributory factor. Death from tuberculosis most frequently occurred in the older age groups, accounting in part for the different findings in these two ethnic groups, because of the excess of older white patients. In a step-wise multivariate discriminant analysis death from tuberculosis was found to be significantly associated in the white patients with the radiographic extent of disease before treatment, and with age, extent of cavitation and a positive sputum smear result, but not sex. Most of the deaths from tuberculosis occurred early, 38% before the end of the first week of chemotherapy and 69% by the end of 4 weeks. There was a further group of 51 adult patients with pulmonary tuberculosis notified in the same 6-month period in whom the diagnosis was not made until after death, 25 of them dying from tuberculosis. It is concluded that there is still a substantial risk of death from tuberculosis in patients with extensive disease in the older age groups.

Since the early 1960s notification rates for tuberculosis in England and Wales for the whole population have been influenced by high rates in certain ethnic groups. Using data based on country of birth from the British (Thoracic and) Tuberculosis Association surveys of 1965 and 1971, and based on ethnic origin from the Medical Research Council surveys in 1978/79 and 1983, rates for the white ethnic group have been estimated at those four times, and compared with the published rates for the whole population in 1953, when only a very small proportion was of non-white ethnic origin. Between 1953 and 1983 the notification rate for the white ethnic group fell from 122.2 to 11.3 per 100,000 for males, an annual decline of 7.7%, the corresponding rates for females being 90.1 and 5.8, an annual decline of 8.8%. The greatest annual declines occurred between 1953 and 1965, 9.4% for males and 11.2% for females. The annual declines in the most recent period, 1978/79 to 1983, were 6.9% for males and 7.3% for females. In both sexes the decline was greatest in the 15-24 year age group and least in the oldest age group, and this has led to a change in the age pattern of annual notification rates. The highest rates in both sexes occurred in young adults in 1953 but in the oldest age groups in 1983. There is however no evidence of any cohort experiencing an increase in notification rate with increasing age.