European consensus for starting and stopping enzyme replacement therapy in adult patients with Pompe disease: a 10-year experience.

BACKGROUND AND PURPOSE: Pompe disease is a rare inheritable muscle disorder for which enzyme replacement therapy (ERT) has been available since 2006. Uniform criteria for starting and stopping ERT in adult patients were developed and reported here. METHODS: Three consensus meetings were organized through the European Pompe Consortium, a network of experts from 11 European countries in the field of Pompe disease. A systematic review of the literature was undertaken to determine the effectiveness of ERT in adult patients on a range of clinical outcome measures and quality of life. A narrative synthesis is presented. RESULTS: Consensus was reached on how the diagnosis of Pompe disease should be confirmed, when treatment should be started, reasons for stopping treatment and the use of ERT during pregnancy. This was based on expert opinion and supported by the literature. One clinical trial and 43 observational studies, covering a total of 586 individual adult patients, provided evidence of a beneficial effect of ERT at group level. At individual patient level, the response to treatment varied, but factors associated with a patient's response to ERT were not described in many studies. Eleven observational studies focused on more severely affected patients, suggesting that ERT can also be beneficial in these patients. There are no studies on the effects of ERT in pre-symptomatic patients. CONCLUSIONS: This is the first European consensus recommendation for starting and stopping ERT in adult patients with Pompe disease, based on the extensive experience of experts from different countries.

Ten years of the international Pompe survey: patient reported outcomes as a reliable tool for studying treated and untreated children and adults with non-classic Pompe disease.

Pompe disease is a rare, progressive lysosomal storage disorder for which enzyme therapy (ERT) became available in 2006. Four years earlier, the IPA/Erasmus MC survey, an international longitudinal prospective survey, was established to collect information on the natural course of the disease and its burden on patients. The survey is a collaboration between Erasmus MC University Medical Center and the International Pompe Association (IPA) and comprises an annual questionnaire that was specifically designed to assess the symptoms and problems of the disease. Here we review our results of over 10 years of follow-up, and discuss the survey's contribution to the field. Tracking 408 Pompe patients between 2002 and 2013, the cumulative data reveals the broad range of clinical manifestations that interfere with patients' lives. The survey allowed us to quantify the rate of disease progression and the positive effects of ERT on patients' quality of life, fatigue, and participation in daily life. Furthermore, it showed for the first time that survival is reduced in adult Pompe disease and improved by ERT. Our results show that a patient survey can serve as a valuable and reliable tool for obtaining quantifiable information on the natural course of a rare disease and on the effects of therapy in a large cohort over a very long time. Most importantly, by working with patient reported outcomes, the survey provides the data that is truly relevant to the patient and complementary to clinical datasets.

Comparison of EQ-5D and SF-6D utilities in Pompe disease.

PURPOSE: Comparative studies between Euroqol-5D (EQ-5D) and ShortForm 6D (SF-6D) utilities have been performed for a number of diseases, but not yet for orphan diseases. Pompe disease is an orphan disease with a prevalence of <5/10,000, characterized by impaired ambulatory and pulmonary functioning. We compared the psychometric properties of EQ-5D and SF-6D in patients with this disease and assessed their convergent validity, discriminative ability and sensitivity to change. METHODS: EQ-5D utilities and SF-6D utilities were computed using the UK value set. Dimensions and utilities of the two instruments were compared by correlation coefficients and descriptive statistics. We assessed whether EQ-5D and SF-6D were able to discriminate between different levels of severity and examined sensitivity to change for patients with multiple observations. RESULTS: Correlations between theoretically related dimensions of the EQ-5D and SF-6D were highly significant and were moderate to strong (range rho = 0.409-0.564). Utility values derived from the two instruments were similar (mean EQ-5D = 0.670; mean SF-6D = 0.699) and correlated strongly (rho = 0.591). Discriminative properties were somewhat better for EQ-5D; mean changes and effect sizes were better for SF-6D. CONCLUSIONS: Overall, we conclude that both instruments appear to be equally appropriate with respect to assessing utilities in Pompe disease, but neither of them performed excellently. The descriptive system of the SF-6D describes health states for Pompe disease more accurately. EQ-5D showed better discriminative properties. The SF-6D performed better with respect to sensitivity to change.

Pain in adult patients with Pompe disease: a cross-sectional survey.

BACKGROUND: Pompe disease is a rare hereditary metabolic myopathy caused by a deficiency of acid-α-glucosidase. We investigated the presence and severity of pain and its interference with daily activities in a large group of adults with Pompe disease, who we compared with an age-matched control group. METHODS: Data were collected in a cross-sectional survey in Germany and The Netherlands. Pain was assessed using the short-form brief pain inventory (BPI). Patients also completed the Short Form-36 item (SF-36v2), the Hospital Anxiety and Depression Scale (HADS) and the Rotterdam Handicap Scale (RHS). RESULTS: Forty-five percent of the 124 adult Pompe patients reported having had pain in the previous 24h, against 27% of the 111 controls (p=0.004). The median pain severity score in Pompe patients reporting pain was 3.1 (on a scale from 0 to 10), indicating mild pain; against 2.6 amongst controls (p=0.06). The median score of pain interference with daily activities in patients who reported pain was 3.3, against 1.3 in controls (p=0.001). Relative to patients without pain, those with pain had lower RHS scores (p=0.02), lower SF-36 Physical and Mental component summary scores (p<0.001 and p=0.049), and higher levels of depression and anxiety (p=0.005 and p=0.003). CONCLUSIONS: To date, this is one of the largest studies on pain in a specific neuromuscular disorder. Nearly one in two Pompe patients had experienced pain in the previous 24h. Although pain severity and its interference with daily life were mild, pain was related to a reduced quality of life, less participation in daily life, and greater depression and anxiety. Its management should therefore be seen as part of clinical practice involving Pompe patients.

Factors associated with being lost to follow-up before completing tuberculosis treatment: analysis of surveillance data.

Completion of treatment is key to tuberculosis control. Using national surveillance data we assessed factors associated with tuberculosis patients being lost to follow-up before completing treatment ('lost'). Patients reported in England, Wales and Northern Ireland between 2001 and 2007 who were lost 12 months after beginning treatment were compared to those who completed, or were still on treatment, using univariable and multivariable logistic regression. Of 41 120 patients, men [adjusted odds ratio (aOR) 1·29; 95% confidence interval (CI) 1·23-1·35], 15- to 44-year-olds (P<0·001), and patients with pulmonary sputum smear-positive disease (aOR 1·25, 95% CI 1·12-1·45) were at higher risk of being lost. Those recently arrived in the UK were also at increased risk, particularly those of the White ethnic group (aOR 6·39, 95% CI 4·46-9·14). Finally, lost patients had a higher risk of drug resistance (aOR 1·41, 95% CI 1·17-1·69). Patients at risk of being lost require enhanced case management and novel case retention methods are needed to prevent this group contributing towards onward transmission.

Tuberculosis and HIV co-infection in healthcare workers in England and Wales, 1999-2005.

This study used linked national tuberculosis (TB) and HIV surveillance data to investigate recent trends and factors associated with HIV co-infection (TB-HIV) in healthcare workers (HCWs) with TB in England and Wales. Methods applied were the χ2 trend test and logistic regression. Overall 14% (231/1627) of HCWs with TB were co-infected with HIV, increasing from 8% in 1999 to 14% in 2005 (P<0·001). Most (78%) HCWs were non-UK born and 74% of these developed TB ⩾2 years post-entry. Being born in Sub-Saharan Africa was an independent predictor for TB-HIV, especially for female HCWs (odds ratio 66·5, 95% confidence interval 16·3-271·1), who also had a lower median CD4 count than other co-infected women (106/mm3, interquartile range 40-200, P<0·01). Voluntary HIV testing of new HCWs should be encouraged as an opportunity for early diagnosis. Post-entry, a high index of clinical suspicion for TB in those most at risk remains important.

Tuberculosis and HIV co-infection in European Union and European Economic Area countries.

In order to ensure the availability of resources for tuberculosis (TB) and HIV management and control, it is imperative that countries monitor and plan for co-infection in order to identify, treat and prevent TB-HIV co-infection, thereby reducing TB burden and increasing the years of healthy life of people living with HIV. A systematic review was undertaken to determine the burden of TB-HIV infection in the European Union (EU) and European Economic Area (EEA). Data on the burden of HIV infection in TB patients and risk factors for TB-HIV co-infection in the EU/EEA were extracted from studies that collected information in 1996 and later, regardless of the year of initiation of data collection, and a narrative synthesis presented. The proportion of HIV-co-infected TB patients varied from 0 to 15%. Western and eastern countries had higher levels and increasing trends of infection over time compared with central EU/EEA countries. Groups at higher risk of TB-HIV co-infection were males, young adults, foreign-born persons, the homeless, injecting drug users and prisoners. Further research is needed into the burden and associated risk factors of co-infection in Europe, to help plan effective control measures. Increased HIV testing of TB patients and targeted and informed strategies for control and prevention could help curb the co-infection epidemic.

The burden of TB-HIV in the EU: how much do we know? A survey of surveillance practices and results.

Information on the burden of tuberculosis (TB)-HIV co-infection is critical for the planning and evaluation of TB-HIV control and treatment strategies. This study assessed current practices in countries of the European Union (EU) and European Economic Area (EEA) for monitoring HIV co-infection in TB surveillance systems, countries' current co-infection burden and associated clinical practice. An online survey was distributed to all national TB surveillance nominated European Centre for Disease Prevention and Control contact points in the EU/EEA. We received 25 responses from 30 countries (83% response rate). Patients' HIV status was collected in 18 out of the 25 TB surveillance systems, usually via clinician reporting (16 out of 18 surveillance systems). Although most countries recommended routine testing of TB patients for HIV, the proportion actually tested varied from 5% to 90%. The burden of HIV co-infection was found to be elevated in countries with higher levels of HIV testing and higher prevalence of HIV. We suggest that TB-HIV co-infection be monitored in all EU/EEA countries to facilitate the planning and evaluation of TB-HIV control strategies. Strengthening collaboration between TB and HIV clinicians and surveillance departments, and consideration of patient confidentiality restraints would be advantageous. The level of HIV testing in TB patients is low despite national recommendations and testing should be further promoted and monitored.

Predictors of failure to complete tuberculosis treatment in London, 2003-2006.

SETTING: London, 2003-2006. OBJECTIVES: To investigate tuberculosis (TB) treatment completion failure in London and associated risk factors during 2003-2006. DESIGN: Cross-sectional analysis of treatment outcome and other explanatory variables in a cohort of TB patients reported to the London TB Register from 2003 to 2006. METHODS: An innovative definition of TB treatment outcome more suitable for low-incidence industrialised countries, such as the United Kingdom, was adopted. A multivariable logistic approach was used to assess predictors of unsuccessful outcome. RESULTS: A total of 12,929 TB cases were notified from 2003 to 2006, of which 12% (n = 1536) failed to complete TB treatment. The proportion of cases failing to complete treatment showed a significant decrease from 2003 to 2006 (13% in 2003 vs. 10% in 2006). Males, the elderly, hospitalised patients, short- and long-term immigrants, Whites and the least deprived were more likely to fail to complete treatment. CONCLUSIONS: The proportion of TB treatment success in London exceeded the World Health Organization recommended threshold of 85%. Some specific categories of patients that are more likely to fail to complete treatment should be targeted by health services to enhance their engagement and adherence to the treatment regimen.

Health status of UK patients with active tuberculosis.

OBJECTIVE: To assess the impact of tuberculosis (TB) and its treatment on patients' health status. METHODS: Questionnaires were administered prospectively to patients at three clinics in London at diagnosis and 2 months into therapy. We assessed generic health-related quality of life (Short Form 36 [SF-36] and EQ-5D) and psychological burden (State-Trait Anxiety Short-Form, Center for Epidemiologic Studies Depression Scale, worry items). RESULTS: Of the 61 participants (response rate 94%), 89% were non-UK born, 67% had pulmonary TB and 38% were aged 30-45 years. At diagnosis, scores for all eight SF-36 dimensions were significantly worse than UK general population norm scores. At follow-up, scores had improved significantly (P < 0.01), except for physical functioning and general health perception, but remained below the UK norm, except for vitality and mental health. Respondents' mean anxiety and depression scores were high at diagnosis (48 and 22, respectively), and anxiety scores remained high at follow-up. Worries most frequently reported concerned patients' own health (92%) and that of their family (82%). CONCLUSIONS: TB patients suffer from significantly diminished health-related quality of life at diagnosis. Although treatment significantly improved patients' health status within 2 months, scores for many domains remain below UK norm scores. This emphasises the importance of a holistic approach to care and should inform the evaluation of future interventions.

Increase in extrapulmonary tuberculosis in England and Wales 1999-2006.

BACKGROUND: Extrapulmonary tuberculosis appears to be increasing in England and Wales. The trends in extrapulmonary tuberculosis and factors associated with these trends were examined. METHODS: National tuberculosis surveillance data from 1999-2006 for England and Wales were used, including demographic, clinical and laboratory information. Trends in the proportion of tuberculosis cases with extrapulmonary disease were investigated using the chi(2) trend test and associated factors using logistic regression. RESULTS: Among all the cases of tuberculosis, the proportion with extrapulmonary disease increased from 48% in 1999 (2717 cases) to 53% in 2006 (4205 cases, p<0.001). Regression analysis showed that the rise in extrapulmonary disease was associated with an increase in the proportion of non-UK born cases (odds ratio 2.7, 95% CI 2.6 to 2.8). A more than threefold increase was observed in the proportion of all tuberculosis cases with miliary tuberculosis from 0.7% of all cases (38 cases) to 2.2% (180 cases, p<0.001). This rise was not associated with changes in place of birth or in any of the other risk factors identified. CONCLUSIONS: The proportion of cases with extrapulmonary disease has increased over the study period. To a large extent this is due to an increasing proportion of non-UK born cases. Reasons for the rise in miliary tuberculosis require further investigation. Clinicians should have a higher index of clinical suspicion of extrapulmonary tuberculosis in non-UK born cases.

The influence of socio-economic deprivation on tuberculosis treatment delays in England, 2000-2005.

This study investigates the association between socio-economic deprivation and tuberculosis (TB) treatment delays in England, 2000-2005. Patients reported to the Enhanced TB Surveillance system were assigned a deprivation score based on residential postcode, and categorized into deprivation quartiles. Data were analysed using Cox regression. The median interval from symptom onset to treatment initiation was 67 days (inter-quartile range 30-131). The effect of deprivation on this interval was modified by ethnic group and place of birth/time since entry into the United Kingdom. Longer intervals were experienced by the most deprived black Africans, Indians/Pakistanis/Bangladeshis and recent entrants to the United Kingdom, compared to the least deprived. In contrast, among white and UK-born patients, longer intervals were experienced by the least deprived. In conclusion, the effect of deprivation on TB treatment delays varies in different population groups. Efforts are needed to reduce delays including improving awareness of TB and increasing the index of clinical suspicion.

The association between HIV and antituberculosis drug resistance.

In the UK, HIV is considered to be a risk factor for antituberculosis drug resistance. Evidence of the association is, however, inconclusive and there are few population-level data. The present study investigated the association in England and Wales during the period 1999-2005. National tuberculosis surveillance data for adults were matched to HIV/AIDS reports. Unmatched cases were assumed to be HIV-negative. Separate analyses were conducted on new tuberculosis cases and those with a previous diagnosis. Logistic regression was used for univariable and multivariable analyses. There were 1,657 previously diagnosed cases (80 HIV-positive) and 18,130 new cases (1,156 HIV-positive). Isoniazid resistance was found in 8.1% of previously diagnosed cases and 6.6% of new cases, and multidrug resistance in 2.8% and 0.7%, respectively. There was no evidence of an association between HIV and antituberculosis drug resistance among previously diagnosed cases. Among new cases, there was no overall association between HIV and isoniazid or multidrug resistance after adjusting for confounding factors. White HIV-positive patients were more likely to have multidrug resistance, but numbers were small. In contrast to some previous studies, this large, up-to-date study provides little evidence that HIV co-infected tuberculosis patients in England and Wales are at increased risk of firstline antituberculosis drug resistance.

Monitoring tuberculosis treatment outcome: analysis of national surveillance data from a clinical perspective.

BACKGROUND: In 1998, the World Health Organization (WHO) and the International Union Against Tuberculosis and Lung Disease (IUATLD) published recommendations standardising the evaluation of tuberculosis treatment outcome in Europe. These guidelines fail to account for clinically appropriate alterations in the management of patients. OBJECTIVES: To evaluate tuberculosis treatment outcome in England, Wales and Northern Ireland by redefining the outcome criteria and investigate factors associated with unsuccessful treatment outcome 12 months after notification. METHODS: This was a prospective analysis of a cohort of patients diagnosed in England, Wales and Northern Ireland and reported to the Enhanced Tuberculosis Surveillance system in 2001 and 2002. Proportions of success and failure were calculated based on a new set of criteria following discussion with clinicians treating tuberculosis cases. Logistic regression was used to study risk factors for unsuccessful treatment outcome. RESULTS: 13 048 cases were notified in the study period. Of the 2676 that were identified as new sputum smear positive pulmonary cases, 2209 (82.5%) had treatment outcome data reported. Using the WHO/IUATLD criteria, 76.8% were classified as successful. In contrast, applying the new criteria, the success rate was 87.5%. This rate exceeds the 85% success target set by the WHO. Risk factors for unsuccessful treatment outcome included male sex (OR 1.27; 95% CI 1.08 to 1.49), being elderly (p trend < 0.001), having pulmonary tuberculosis (OR 1.28; 95% CI 1.08 to 1.53) and having resistance to any antituberculosis drug (OR 1.90; 95% CI 1.44 to 2.52). CONCLUSION: The proportion of tuberculosis cases with a successful treatment outcome exceeded the target of 85% success rate based on the modified outcome categories. Although the tuberculosis treatment outcome criteria set by WHO/IUATLD appear to be clear, they mix measures of process and outcome. Further refinement may be necessary in low incidence high income countries, especially those with a high mortality among the elderly.

The burden of upper gastrointestinal endoscopy in patients with Barrett's esophagus.

BACKGROUND AND STUDY AIMS: Patients with Barrett's esophagus are recommended to undergo regular surveillance with upper gastrointestinal endoscopy, an invasive procedure that may cause anxiety, pain, and discomfort. We assessed to what extent patients perceived this procedure as burdensome. PATIENTS AND METHODS: A total of 192 patients with Barrett's esophagus were asked to fill out questionnaires at 1 week and immediately before endoscopy, and at 1 week and 1 month afterwards. Four variables were assessed: (i) pain and discomfort experienced during endoscopy; (ii) symptoms; (iii) psychological burden, i. e., anxiety, depression and distress levels (Hospital Anxiety and Depression scale, Impact of Event Scale); and (iv) perceived risk of developing adenocarcinoma. RESULTS: At least one questionnaire was returned by 180 patients (94 %), 151 completed all four (79 %). Of all patients, only 14 % experienced the endoscopy as painful. However, 59 % reported it to be burdensome. Apart from an increase in throat ache (47 % after endoscopy versus 12 % before), the procedure did not cause physical symptoms. Patients' anxiety, depression, and distress levels were significantly increased in the week before endoscopy compared with the week after. Patients perceiving their risk of developing adenocarcinoma as high reported higher levels of psychological distress and that the procedure was a greater burden. CONCLUSIONS: Upper gastrointestinal endoscopy is burdensome for many patients with Barrett's esophagus and causes moderate distress. Perception of a high risk of adenocarcinoma may increase distress and the burden experienced from the procedure. The benefits of endoscopic surveillance for patients with Barrett's esophagus should be weighed against its drawbacks, including the short-term burden for patients.

Levels of disability in major depression: findings from the Netherlands Mental Health Survey and Incidence Study (NEMESIS).

BACKGROUND: Information on the distribution of disability associated with major depression (MD) across different groups of patients is of interest to health policy and planning. We examined the associations of severity and type (a single or recurrent episode) of MD with disability in a Dutch general population sample. METHODS: We used data from the first wave (1996) of the Netherlands Mental Health Survey and Incidence Study (NEMESIS). MD 'severity' and 'type' were diagnosed with the help of the Composite International Diagnostic Interview according to DSM-III-R criteria. SF-36 scores, days ill in bed and days absent from work were taken as indicators of disability. The differences in these variables were studied by means of variance and regression analysis. RESULTS: Recurrent MD was found not to be associated with more disability than single episode MD. Higher 'severity' classes were associated with more disability. However, the degree of disability between 'moderate' and 'severe' MD differed only very slightly. The difference in disability between non-depressed and mildly depressed individuals had a larger effect than between each successive pair of 'severity' classes. CONCLUSIONS: Three groups of MD can be distinguished based on the associated degree of disability: 'mild', 'moderate to severe' and 'severe with psychotic features'. In the future, these groups can be used to describe the distribution of disability in the depressed population. The marked difference between 'mild' MD and no MD suggests that 'mild' cases should be considered relevant.