Drug-related hepatitis in patients treated with standard anti-tuberculosis chemotherapy over a 30-year period.

SETTING: Drug-induced hepatitis is known to occur in a proportion of patients on treatment for active tuberculosis (TB). DESIGN: We prospectively examined the incidence of drug-induced hepatitis in 2070 patients treated for TB with the standard regimen based on 6 months of rifampicin (R, RMP) and isoniazid (H, INH), with 2 months of initial pyrazinamide (Z, PZA) and ethambutol (E, EMB), over a 30-year period from 1981 to 2010, in Blackburn, UK. RESULTS: Of the 1031 (49.8%) males and 1039 (50.2%) females studied, 451 (21.8%) were White and 1585 (76.6%) were of South Asian origin. Only 34 (1.6%) were of African or other origins. Of the total number of patients treated, 63 (3.0%) had drug-related hepatitis, 26 (5.8%) of whom were White, 37 (2.33%) Asians and 0 other. Incidence was significantly higher in Whites than Asians (OR 2.13, P = 0.008). Incidence increased with increasing age (OR 1.16, P = 0.02). The presumed causative drug was PZA 57%, RMP 32%, INH 11%, EMB 0%. There was no trend of increased hepatitis rates over time. CONCLUSION: Rates of drug-induced hepatitis where change of treatment is required are low in patients treated with standard RHZE-based therapy (3%). Caucasians and older patients were more likely to develop hepatitis than their counterparts.

The outcome of a cohort of tuberculin-positive predominantly South Asian new entrants aged 16-34 to the UK: Blackburn 1989-2001.

SETTING: Blackburn, Hyndburn and Ribble Valley Local Government areas of England and Wales, the former a high tuberculosis (TB) prevalence district. BACKGROUND: The incidence of tuberculosis in new entrants aged 16-34 with positive tuberculin skin tests but normal chest X-rays after initial entry is not definitely known, and was previously estimated from cross-sectional national surveys and derived data for the 2006 and 2011 NICE economic appraisals of new entrant TB screening. METHODS: New entrants aged 16-34 years predominantly from South Asia (India, Pakistan and Bangladesh), with tuberculin tests inappropriately positive for their BCG history were identified for the years 1989-2001 inclusive from a new entrant database. These entrants were compared with the current GP registration database to see if local residence could be confirmed and the local TB notification database to October 2008. Survival analysis was carried out using Kaplan-Meier survival curves and a Cox Regression model. RESULTS: Four hundred and seventy-nine such new entrants with normal initial chest X-rays were identified. Of these 402 (84%) registered with a General Practitioner in East Lancashire for a period of time and could be followed up by this study. The crude incidence density of active TB amongst these individuals with latent disease was 1297 per 100 000 person-years (95% CI; 991-1698 per 100 000 person-years). After 10 and 15 years of follow-up 13.5 and 16.3% of individuals, respectively, had progressed on to active disease. CONCLUSION: This patient-derived, rather than estimated, data shows a minimum risk of TB disease of 16.3% at 15 years. The 2006 NICE economic appraisal, suggested that treatment for latent TB infection (LTBI) was cost-effective when the incidence of clinical TB over 15 years surpassed 18% in these populations. The 2011 NICE economic appraisal reduced this to 12% active TB over 15 years, and showed that at 16% active TB over 15 years a single interferon gamma release assay was the most cost-effective strategy. Further cohort studies are urgently needed to confirm or revise the assumptions behind the 2011 NICE economic appraisal.

Molecular epidemiology of Mycobacterium tuberculosis in East Lancashire 2001-2009.

BACKGROUND: East Lancashire has had high rates of tuberculosis for 40 years. The ethnically diverse population is predominantly of South Asian and white origin. Drug resistance data from 1960 to 1999 indirectly suggest that no significant inter-ethnic transmission has occurred. This study used mycobacterial interspersed repetitive unit variable number tandem repeat (MIRU-VNTR) fingerprinting to assess clustering within and between ethnic groups. METHODS: All isolates of Mycobacterium tuberculosis from January 2001 to July 2009 from East Lancashire postcode areas were MIRU-VNTR fingerprinted. Clusters of strains with indistinguishable profiles were also assessed epidemiologically, and their MIRU-VNTR profiles compared with the UK M tuberculosis Strain Typing Database. RESULTS: 332 strains were typed (63 white patients, and 269 non-white patients). 198 MIRU-VNTR profiles were identified, with 144 profiles occurring only once. The typing clustered 187 strains into 53 clusters indistinguishable at all 12 loci and these were further characterised using the exact tandem repeat loci A, B, and C. The 15 loci clustered 32/63 (50.8%) of white and 110/269 (40.9%) of non-white cases and all but nine clusters were of the same ethnicity. The nine inter-racial clusters were further assessed from an epidemiological and clinical perspective and fingerprinting using nine additional loci. Isolates within two of the clusters were further discriminated using the additional nine loci. However, the additional loci did not further discriminate the isolates in the other seven inter-racial clusters. CONCLUSIONS: MIRU-VNTR fingerprinting indicates that although there is evidence of a high rate of transmission within the South Asian sub-population, the data suggest that there is little inter-ethnic transmission.

Management of peripheral lymph node tuberculosis in routine practice: an unselected 10-year cohort.

BACKGROUND: The varied behaviour of tuberculous lymph nodes during TB chemotherapy can cause clinical uncertainty, resulting in prolonged courses of treatment. OBJECTIVES: To investigate whether results in routine practice in Blackburn, a high-incidence tuberculosis (TB) area in England and Wales, replicated the results of the 6-month chemotherapy trial for lymph node TB conducted by the British Thoracic Society. DESIGN: All TB cases managed at the Blackburn Chest Clinic are recorded prospectively. Patients with lymph node TB were identified over a 10-year period. RESULTS: A total of 100 patients with lymph node TB were listed in the database. Fine-needle aspiration was performed in 49 patients, while 66 underwent incisional lymph node biopsy. Culture confirmation was achieved in 60 cases. Sinus and new lymph node development was comparable between our study and the BTS trial. After cessation of treatment, 10 patients developed new/enlarged lymph nodes, but further investigations revealed that only three patients had relapsed TB. CONCLUSION: The varied behaviour of lymph node TB during and after treatment causes clinical uncertainty. Six months of chemotherapy is effective for fully susceptible TB in routine clinical practice in England. Investigation of new signs is important in differentiating patients with relapsed TB from normal varied behaviour.

Effectiveness of 3 months of rifampicin and isoniazid chemoprophylaxis for the treatment of latent tuberculosis infection in children.

UNLABELLED: BACKGROUND/SETTING: Treatment for 3 months with rifampicin (R) and isoniazid (H) (3RH) for latent tuberculosis infection (LTBI), defined as an inappropriately positive tuberculin skin test with no clinical or x-ray evidence of disease, has been used locally since 1989. The efficacy of this regimen in children in the UK has only been studied indirectly. The long-term outcome of those children treated with 3RH, in the Chest Clinic of this high tuberculosis (TB) incidence district, has been studied to derive a more direct assessment of effectiveness. METHODS: All children treated with 3RH for LTBI from 1989 to 2004 inclusive were matched with the local patient administration system (PAS), GP registration and local TB notification databases. Only those persons still registered locally on PAS, or locally GP registered were then checked for subsequent TB notification. RESULTS: A total of 334 patients were identified, of whom 252 remained locally, with 82 lost to follow-up; 3 cases of clinical TB developed in the 252 (1.19%), with 3113 years observation (mean 12.35 years) giving 0.964/1000 person years (95% CI 0.199 to 2.816). Sensitivity analyses showed a 'best case' scenario of 0.727/1000 person years (95% CI 0.15 to 2.12), and if 10% of those lost to follow-up developed clinical TB of 2.66/1000 person years (95% CI 1.33 to 4.77). CONCLUSIONS: Follow-up of those cases treated with 3RH, for a mean of 12.35 years, and over 3100 patient years observation, shows a rate of active TB of under 1/1000 patient years. This suggests that 3RH has very high efficacy when used to treat LTBI in children in the UK and compares favourably with the expected untreated TB rate.

Abdominal tuberculosis in a district general hospital: a retrospective review of 86 cases.

BACKGROUND: Abdominal tuberculosis (ATB) is a great mimic and an important cause of morbidity. Its incidence is more common in certain groups. AIM: To review the cases of ATB in Blackburn from 1985 to 2004, with emphasis on presentation, investigation, diagnosis, treatment and follow-up. METHODS: A retrospective cases note analysis from a prospectively compiled database. RESULTS: Eighty-six cases of ATB were on a prospective database of all tuberculosis (TB) cases in Blackburn for 1985-2004 inclusive. Full case papers were available for 82 and partial data for the remaining four cases. Median age was 34.8 years, with an equal sex distribution. South Asians accounted for 91% of cases. The highest proportion of patients had peritoneal TB, and a considerable number (27%) had TB at multiple sites. CONCLUSION: The diagnosis can be difficult to make because of the varied presentation, the low percentage with positive microscopy for acid-fast bacilli and the time delay of up to several weeks for a positive TB culture. The thresholds for laparoscopy and/or laparotomy for the diagnosis were therefore very low. The diagnosis could be made rapidly by these methods, and early treatment instituted. Six months short-course chemotherapy is very effective in ATB. This should be changed, if appropriate, on the basis of drug susceptibility data.

Bone and joint tuberculosis: cases in Blackburn between 1988 and 2005.

We report 79 cases of bone and joint tuberculosis between 1988 and 2005, eight of which were in the Caucasian population and 71 in the non-white population. The diagnosis was made in the majority (73.4%) by positive bacteriology and/or histology. The mean age at the time of diagnosis was higher in the Caucasian group at 51.5 years (28 to 66) than in the South Asian group at 36.85 years (12 to 93). Only one patient had previous BCG immunisation. The spine was the site most commonly affected (44.3%). Surgical stabilisation and/or decompression was performed in 23% of these cases because of cord compression on imaging or the presence of neurological signs. A six-month course of chemotherapy comprising of an initial two months of rifampicin, isoniazide, pyrazinamide and sometimes ethambutol followed by four months treatment with rifampicin and isoniazide, was successful in all cases without proven drug resistance.

A case control study in the Indian subcontinent ethnic population on the effect of return visits and the subsequent development of tuberculosis.

SETTING: A local government area in North West England with a significant population of Indian subcontinent (ISC) ethnic origin and a high incidence of tuberculosis. OBJECTIVE: To assess whether return visits to the ISC are associated with an increased risk of developing clinical tuberculosis. METHODS: Analysis of data prospectively obtained from ISC patients diagnosed with TB in 1998-2002 (cases) and age and sex matched ISC patients in two local GP practices (controls). RESULTS: There is at best weak evidence of association between case status and whether individuals have had a repeat visit to the subcontinent within 3 years of notification in this cohort; odds ratio 1.26 (95% CI (0.95, 1.76)); Fishers exact test P=0.09.

Multidrug-resistant tuberculosis (MDR-TB): epidemiology, prevention and treatment.

Multidrug-resistant tuberculosis (MDR-TB) is an increasing global problem, with most cases arising from a mixture of physician error and patient non-compliance during treatment of susceptible TB. The extent and burden of MDR-TB varies significantly from country to country and region to region. As with TB itself, the overwhelming burden of MDR-TB is in high-burden resource-poor countries. The diagnosis depends on confirming the drug susceptibility pattern of isolated organisms, which is often only possible in resource-rich settings. There should be a strong suspicion of drug resistance, including MDR-TB, in persons with a history of prior treatment or in treatment failure cases. Treatment in developed countries is expensive and involves an individualized regimen based on drug susceptibility data and use of reserve drugs. In resource-poor settings a WHO retreatment regimen may be used, but increasingly the move is to a directly observed treatment based 'DOTS-plus' regimen in a supported national TB programme. However, even where such treatment is given, the outcome for patients is significantly worse than that for fully susceptible TB and has a much higher cost.

Effect of Mycobacterium vaccae (SRL172) immunotherapy on radiographic healing in tuberculosis.

OBJECTIVE: Controlled trials have failed to show an effect of Mycobacterium vaccae immunotherapy on treatment outcome and mortality in patients with tuberculosis (TB); however, several studies have suggested improvement in radiographic clearing and resolution of cavitary disease. METHODS: To assess the effect of M. vaccae immunotherapy on radiographic healing in pulmonary TB, chest X-rays from three randomized placebo-controlled trials of M. vaccae given as a single injection during the first 2 weeks of treatment were interpreted by a single, masked assessor using a standard scheme. Endpoints were the overall degree of radiographic improvement or deterioration and changes in cavitary disease at the end of antituberculosis treatment and follow-up. RESULTS: Of 1018 patients (478 HIV-infected; 540 HIV-uninfected) with an end of treatment or end of follow-up X-ray analyzed, 496 received M. vaccae and 522 received placebo. There was no difference in radiographic improvement or deterioration or cavitary disease at the end of treatment or follow-up comparing the M. vaccae and placebo groups. Results were similar comparing HIV-infected and HIV-uninfected patients. CONCLUSION: Adjunctive immunotherapy of drug-susceptible pulmonary TB with M. vaccae during the first 2 weeks of treatment did not improve radiographic responses to treatment or resolution of cavitary disease.

Outcome for adult contacts of smear-positive pulmonary tuberculosis in the absence of X-ray follow-up: 2000-03.

The effects of the policy change in X-ray follow-up of adult tuberculin-positive close contacts of sputum microscopy positive pulmonary tuberculosis made by the Joint Tuberculosis Committee of the British Thoracic Society in 2000 were monitored prospectively from late 2000 until the end of 2003. No cases in contacts that could have been detected by interval X-rays at three and 12 months were found. The data, on 291 cases, support the abandonment of X-ray follow-up in favour of an 'inform and advise' strategy after an initial normal chest X-ray in this category of tuberculosis contact.

A decade of change: tuberculosis in England and Wales 1988-98.

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.

The management of pulmonary and lymph node tuberculosis notified in England and Wales in 1998.

The management of 1,337 cases of pulmonary tuberculosis and 422 cases of lymph node tuberculosis reported to the 1998 national notification survey was compared with the recommended standards of treatment. Most patients (84%) were under the care of thoracic physicians. Culture confirmation was obtained in 67.5% of pulmonary cases and 52% of lymph node cases. Drug resistance was reported in 7%, ranging from 3.3% in white patients to 7.9-8.2% in other ethnic groups. Only a minority of non-white ethnic patients received the recommended four-drug initial phase of therapy. Non-standard durations of initial and/or continuation therapy were used in 35% of cases on recommended drug combinations. Thirty-nine (2.9%) pulmonary cases were diagnosed only at post-mortem and a further 96 died before the end of the survey period, 55 (4.3%) due to tuberculosis. The outcome for pulmonary disease, with 80% cured or completing treatment, compare favourably with European outcome data. Although overall outcome data were satisfactory, more patients should have received a four-drug initial phase, with more combination tablet use and better compliance monitoring. Outcome monitoring will henceforth be based mainly on the continuous enhanced surveillance system introduced since 1999.

Outcome of the treatment of culture negative tuberculosis (respiratory and non-respiratory): Blackburn 1996-2000.

OBJECTIVE: To determine the outcome of treating patients without culture confirmation of tuberculosis, with a regimen of two months of isoniazid, rifampicin, pyrazinamide and ethambutol followed by four months of isoniazid and rifampicin (2HRZE/4HR) in a setting with a rate of isoniazid resistance of 7.5% in culture confirmed cases. SETTING: Tuberculosis patients treated in the Blackburn, Hyndburn and Ribble Valley districts of the UK between 1996 and 2000 inclusive. METHODS: Patients from a detailed prospective clinical and epidemiological data base for all tuberculosis patients were studied for the years 1996-2000. RESULTS: One hundred and fourteen cases, all but two of Indian subcontinent ethnic origin, without culture confirmation had received 2HRZE/4HR. Twenty had pulmonary, 55 other respiratory and 39 non-respiratory tuberculosis. There was no bacteriologically confirmed relapse, 1 case was retreated as a clinical relapse. CONCLUSION: The treatment of tuberculosis cases without culture confirmation with a regimen of 2HRZE/4HR gives highly acceptable results. The clinical relapse rate was 0.85% (1/114), and the cure rate 99.15%.

Tuberculosis treatment outcome monitoring: Blackburn 1988-2000.

SETTING: All cases of tuberculosis in a high prevalence district (population 269,000) of England. OBJECTIVE: To analyse the tuberculosis programme outcome for confirmed pulmonary tuberculosis, and all other categories of cases for 1988-2000 inclusive. DESIGN: The outcome of all cases treated during the period 1988-2000 inclusive was assessed by agreed European outcome criteria, retrospectively for 1988-1998 and prospectively for 1999-2000. RESULTS: A total of 729 tuberculosis cases were notified, with 209 definite (culture-positive) pulmonary cases. Of the 205 definite pulmonary cases treated in life, 182 received self-administered treatment (SAT) and 23 directly observed treatment (DOT), with an 88% cure/completion rate and a 12% death rate. The relapse rate for SAT was 1/182 (0.5%) and 1/23 for DOT (4.3%). The cure/completion rate for all patients together was 94.3%, with a relapse rate of 0.8%. CONCLUSION: In this resource-rich setting, treatment largely by SAT, but carefully monitored, gives a very high cure/completion rate. Universal rather than selective DOT would make little additional impact on patient outcome. These outcomes are not likely to be reproducible, however, with SAT in a resource-poor setting.

Serial surveys of the tuberculosis nursing and support provision in the high incidence districts of England and Wales.

Postal surveys were carried out in 1998 and 2001 in the 43 high incidence TB districts of England and Wales (defined as an incidence of 15/100,000 per annum or greater). The provision of TB nursing and support staff was then compared with that recommended by the Joint Tuberculosis Committee for the numbers of TB notifications in 1997 and 2000 in the same areas. Forty-two districts replied in 1998, and all 43 replied in 2001. In 1998 only six out of the 22 high incidence areas outside Greater London met the minimum criteria for both nursing and clerical provision; none in Greater London did so. In 2001 only five out of 22 high incidence areas outside and one out of 21 inside Greater London met both criteria. The provision of nursing and clerical support for tuberculosis falls below minimum criteria in a substantial majority of high incidence areas and is not improving. Unless addressed, continuing under-provision of resources could itself contribute to a further rise in cases of tuberculosis.

Assessment of the impact of BCG vaccination on tuberculosis incidence in south Asian adult immigrants.

Although BCG vaccination is recommended for tuberculin negative adult immigrants, there has hitherto been no evidence of its efficacy in this group. This epidemiological study compares the incidence of tuberculosis in a cohort of South Asian adult immigrants vaccinated on entry to the UK with its incidence in cohorts of immigrants of the same age and origin estimated from the five-yearly national surveys. Results suggest that BCG vaccine may have reduced the incidence of tuberculosis by up to 87.6% (95% confidence interval 55.2% to 98.5%) and support the current recommendation to vaccinate this high-risk group.