World TB Day: Homerton Hospital 24/03/14

It was great to see lots of trainees, as well as local GPs and other colleagues from Hackney, at World TB Day at Homerton. Interesting facts about Homerton:

• Hackney’s first hospital was founded in 1280, called the Kingsland Leper Hospital (based on Kingsland Road). It was one of ten leper hospitals set up in London.
• Ronnie and Reggie Kray were born on 25 October 1933 in Hoxton, East London, although not at the Homerton Hospital itself.
• The current Homerton Hospital opened its’ doors in July 1986. It cost £20 million and was officially opened by the Princess Royal in 1987.

Available from: http://www.giantmicrobes.com/uk/products/TB.html

TB in Hackney

Prof Bothamley began they day with a look at TB in Hackney. He gave examples of when strain typing was helpful, particularly in outbreaks and in linking index cases (national strains, stay within ethnic groups). He demonstrated how it is important to know local epidemiology, most importantly for considering likely resistance patters. In Hackney there is a significant contribution to levels of TB from India and Nigeria. Importantly, 24% of Hackney TB is from a significant conflict zones. This has implications for supporting patients effectively to complete treatment. The components of the  WHO Stop TB strategy were highlighted. Prof moved on to consider how Hackney has reduced it’s rates of TB, and how further progress might be made in the future. The patient to nurse ratio is key, and required significant political commitment (2005 onwards). Case detection has been enhanced by working with GPs and by facilitating easy access to the TB service. This has included a drive to send sputum early, new entrant screening, GP screening (at point of GP registration), direct radiology referrals, making culture for TB routine (e.g. LN) since 2006, direct histology referrals (since 2008). The use of the standardised TB treatment card facilitates audit and transparency in practice. This highlighted ways in which service design could impact quality improvement, leading to visible improvements in outcomes for patients. Prof reminded us of the risk factors for non-adherence, including: drugs, alcohol, prison, and homelessness. He highlighted that as a service improves, it identifies more people with risk factors for non adherence.  There us therefore a greater need for DOT (40% in Hackney). DOT can of course be given anywhere: in the clinic, at home, at a pharmacy, in a hostel, at school, at work, or even in an off-licence! The risks of MDR-TB were touched on, with a reminder that elsewhere in the world this is a major and growing problem.  31% in Russia. HPA data shows that most of UK MDR TB from Eastern Europe.

London TB Plan

The London TB Plan was launched in 2011/12 and aimed to reduce rates of TB in London by 50% over 10years. This was to be achieved through: early detection and diagnosis of TB including latent disease; improving the way services were commissioned to include social care/housing; and addressing variability within TB services across London. Latent TB is important as 80-85% TB cases are non UK-acquired. 3020 TB cases were notified in 2013. TB rate 36.3/100000 (decrease on 2012 42.4/100000). More stats.  It is useful to compare other examples of large cities with similar problems with TB and compare their approach and success rates. New York, Paris and Barcelona all have higher rates of TB but these are falling. Success has been achieved through a co-ordinated pan-city approach –  and significant investment. Important organisations in relation to TB in the UK:

• Public Health England/Health Protection Agency – National Collaborative TB strategy
• London TB control board
• All Party Parliamentary group on TB, highlighting political support for action on TB.
• ECDC (European Centre for Disease Prevention and Control)

The National collaborative TB strategy was launched today! It focuses on: improving access and early diagnosis; high quality diagnostics; treatment; contact tracing; vaccination; tackling drug resistance; targeting under represented populations; tackling latent disease; and effective surveillance.

Role of Outreach worker

The day continued with presentations from Sue, focused on the role of the outreach worker, and the support of patients within their own communities. Roland Ramanan presented his photographic  work centred on Gillett Square. His documentary work explores the communities and support networks that centre around this area of Hackney. Those who congregate here often have drug or alcohol dependance. He has also created a multimedia piece, featuring the words and voices of his subjects, which can be viewed on Vimeo. It was highlighted  are a large number of ‘high risk’ groups in London. ‘High risk’ can include many diverse groups with different needs, including  those who are homeless or living in squats, those who are have drug or alcohol dependancy, street sex workers, and migrants. Outreach workers support ‘hard to reach’ groups by taking services to the people who need them. Often people’s circumstances are highly complex leading to them presenting late with TB. Outreach comprises many things, including providing DOT in atypical places, providing psychosocial support, and social input. Patients may be ineligible for public funds e.g. benefits, housing especially if for whatever reason they have not complied with visa restrictions. They need support navigating access to services. A major theme to come from this talk was that housing is key! The Homeless person unit agreed a Service level agreement to house TB patients. It was nominated for an award. It is cheaper for the PCT (soon to be CCGs). It is better for patients and fairer as if they are housed they have a good chance of completing treatment and achieving a cure. Hackney TB patients and staff were featured in the documentary photograther Kristian Buus’ work. Images from the project can be viewed in his online portfolio. It gives an insight into the life on one East London TB patient, inside and outside the clinic. Looking for more art, literature and film related to TB? Look here: NYU school of medicine database.

Screening of new entrants in primary care

Prof Bothamley continued the day by presenting data from the cluster RCT in Hackney, which began screening of new entrants in primary care.

• Bothamley, G. H., et al. “Screening for tuberculosis: the port of arrival scheme compared with screening in general practice and the homeless.” Thorax 57.1 (2002): 45-49.

Primary outcomes were active cases, latent cases, and BCG vaccination rates. Since 2005  there has been a large increase in the proportion of new entrants screened and given treatment. A local enhanced service has maintained improvements suggested by RCT, highlighting how research can lead to service improvement for the benefit of a larger population/community. The value of BCG was discussed, as it is given to children in Hackney. Prof suggested that it was worthwhile on cost grounds since the cost of BCG is £1 with 1350 NNT to prevent a case, which must be balanced against the cost of TB meningitis (£23million if significantly disabled).

We look forward to the results of the TBNET study and PREDICT which will give us an idea of the appropriate cut off for treatment of latent TB (based on IGRA and TST) balancing risks vs benefits. We know that >35yrs there is a higher chance of drug induced hepatitis. This risk is substantial >45yrs. However, the true rate of reactivation is unknown. Latent treatment is offered to healthcare workers. Other patients should be helped to weigh up individual risk and benefits.

Preventing MDR TB – the 2 month appointment

Prof Onn Min Kon gave us a clinically focused review of MDR-TB. He highlighted that a TB cavity contains around  1×10^8 organisms. If INH given alone, 100 organisms are resistant on day 1. Spontaneous mutations develop as bacilli proliferate, therefore a multi-drug regime from the start. Otherwise we select for resistance. ‘Spontaneous’ MDR is rare. So what drives MDR? Low dosing, poor drug quality, poor adherence, functional monotherapy, continuation of treatment when failing, adding a single agent when failing. In the London/Europe INH resistance outbreak 7 developed MDR TB.  Intermittent treatment has a higher risk of drug resistant amplification than daily treatment. This has implications for the use of DOT. Prevalence of MDR-TB is inversely correlated with the quality of national TB programmes. TB programmes need investment as treating MDR-TB is very expensive? £50,000 per case in UK (Veronica White study) – underpricing?. Prob £200,000 now. For comparison, non-MDR TB treatment costs £6000. Key points for clinical practice:

• If failing always re-sample.
• Know your local immigration patterns and where MDR TB comes from in London? Eastern Europe. 35% INH resistant. 24% MDR. 10% INH resistance in London.
• At the 2 month review: complete a clinical review including weight, and review doses accordingly
• At 2 month review check sputum. If still positive: send again for culture and drug sensitivities; consider PCR and extension of regime (may just be dead bugs!); repeat at 3/12. There are many possible reasons for positive smear at 2/12 – global estimate 10%. NPV more valuable than PPV. If smear positive at 2/12 treatment options include: consider extending induction phase; consider DOT; check drug levels; check sensitivities (consider if not going as expected. Always check. if not growing, send more, check index case sensitivities —> make risk assessment); reassess diagnosis – cavity ?cancer.

Beware dual diagnoses – nodes from TB and cancer! Always rethink, reassess, resample. To prevent MDR-TB we must deal with INH resistance properly. How to do this remains controversial:

• NICE 2011 guidance:  RZE 2 months, RE further 10 months – total 1 year.  If know H resistant in advance 7RZSE 2RE
• CDC 2003 says 6RZE + quinolone for extensive disease.
• Other regimes. Tubercle 1988 Mar 69(1) – basis of current NICE guidance.
• Moxiflox regime alternative. 2RZEMox 2REMox 5RE

If you have not yet read the TBNet consensus statement on the management of MDR-TB, where have you been? Get it in the European Respiratory Journal.

Adverse Responses to TB Treatment

Dr Jess Potter, TB Research Registrar and BTS TB SAG member gave us an overview of ADRs. ADRs are important as they threaten adherence, impact drug selection, interrupt therapy (increasing cost, increasing resistance, prolonging duration), increase morbidity and mortality, and prolong hospital stays. As a reminder, the standard TB regime is RHZE. Moxifloxacin is increasingly being used, particularly for resistance. Prolonged QT is of concern with moxifloxacin use so don’t forget to check the ECG. A general principle is that of type A vs type B reactions. Type A: dose adjust, Type B: stop the drug. Common ADRs:

• Nausea and vomiting, diarrhoea. Any – commonly RH.
• Itching, skin rashes incl photosensitivity, flushing – H and Z.
• R – thrombocytopenia
• Hepatotoxicity – RHZ
• Peripheral neuropathy, arthralgia – H
• Colour blindness – E

Management of ADRs:

• Pre-treatment evaluation – risk factors for side effects include increasing age, pre-existing allergies, malnutrition, co-infection, pregnancy, previous TB treatment, liver/renal disease, polypharmacy, ethnicity.
• Therefore screen by LFTs, Hep B and C, U+E, HIV test. Drug history including opiates and OCP.
• Treatment interruption – balance ADR with risk of treatment failure or resistance. Different options for interruption and reintroduction. Consider incremental dosing.

Useful resources:

• www.tbdrugmonographs.co.uk – an aid to monitoring patients for ADRs in MDR-TB. Fingers crossed for an app in the future.
• BTS TB FAQs
• BTS MDR-TB forum – a great service which provides expert advice to anyone managing a case of MDR or XDR-TB
• Eur Resp Monograph 58: Tuberculosis

Radiology of TB

Homerton Chest Radiologist Dr Burke took us through the radiological appearances of TB. He first reminded us that chest xray is a great test. It equates to only 4 days of background radiation so is low exposure. He ran us through the appearances of primary and post-primary TB and reminded us of the differential diagnosis for cavitation. Key features of extrapulmonary TB were highlighted. The infamous tree-in-bud appearance was reviewed and we were reminded that it is characteristic of but not pathognomonic of TB. Urging us to remember the ‘review areas’ of a chest xray he showed us a case in which it was possible to identify spinal TB. Look for the pedicles when reviewing the spine – lost pedicles suggests destruction, and with the right history this may mean spinal TB. Of course TB has protean radiological as well as clinical manifestations  and can be challenging. Common mimics include: cancer, lymphoma, and sarcoid.

TB and HIV: PR and IRIS

Image taken from worldmapper: TB cases worldwide

HIV and TB co-infection is a big deal worldwide so TB doctors should be especially  interested in HIV and its’ treatment. In the USA HAART is started at diagnosis of HIV, whereas in the UK this decision tends to be made when the CD4 drops. There is a nadir in CD4 count at initial infection which recovers, only to decline later. There may be a change in treatment strategy in future. Some would advocate for treating with HAART at a higher level of CD4 ie 350, or at any level as in the USA. There is a potential population benefit as patients are more infectious initially.

• CD4 >500 little risk
• 200-500 candidiasis, kaposi
• <200 PCP, fungal
• <100 more severe extra pulmonary e.g. CNS and disseminated
• TB is of course an AIDS-defining illness

So when should you start treatment with HAART in a patient newly diagnosed with HIV and TB? Not everyone agrees but trials suggests 2 weeks, since earlier treatment is better, but there is more TB IRIS with earlier HAART.

• Optimal treatment of codisease due to HIV and TB (J Inf Diseases, 2011)
• CDC grand rounds: the TB HIV syndemic (2012)
• Antiretroviral treatment for prevention of TB in adults with HIV: a systematic review and meta-analysis (PLOS Medicine, 2012)
• Various articles from group at LSHTMon TB and HIV co-infection and treatment 
• SAPIT trial (IRIS after initiation of HAART in patients with TB – sequential vs parallel treatment)
• CAMELIA (earlier vs later initiation of HAART)
• STRIDE

The phenomena of IRIS relates to the immunopathogenesis TB. Overall IRIS is 8-25% in trials. BHIVA guidelines are helpful so why not read them on your next tube journey? Unfortunately we cannot predict IRIS  – yet. Fingers crossed for research in this direction in the future.

Differentiation of TB and sarcoidosis by transcriptional profiling of immune responses in mediastinal LN

Dr Gillian Tomlinson, clinical lecturer at UCL, introduced us to transcriptional profiling of immune responses, and gave us hope for improved diagnostic techniques for sarcoid and TB in the future. The group has previously used this technique to study the component processes of the response to the TST and Gillian is now applying this to EBUS samples.

• Tomlinson, Gillian S., et al. “Transcriptional profiling of innate and adaptive human immune responses to mycobacteria in the tuberculin skin test.”European journal of immunology 41.11 (2011): 3253-3260

Neal Navani and colleagues at UCL have established the utility of EBUS, not only for staging of NSCLC, but also for TB and sarcoidosis. However, only 47% of EBUS samples were TB culture positive in the UCLH cohort (where TB found to be final diagnosis). Gillian suggested the hypothesis that transcriptional profiling could be used to differentiate sarcoid vs TB. Work in this area is ongoing.

Further reading:

• Differentiation of tuberculosis and sarcoidosis by transcriptional profiling of immune responses in mediastinal lymph node samples (Thorax 2013)

EBUS-TBNA for TB

Dr James Murray and Dr Alice (visiting fellow from Milan) asked the question “what is value of EBUS TBNA in TB?” and attempted to answer it by presenting data from the Homerton cohort. Look out for a paper in the future…

Key points were:

• 363 procedures were reviewed, with LN material or definite tumour cells in 94%
• 57 cases of TB were confirmed by EBUS TBNA, with 63 patients with TB as a final diagnosis in total
• In the 57 TB diagnoses this was either by pathology grade and additional info (e.g. IGRA), or by culture
• There was a higher positive culture rate than in previous series, suggesting that with appropriate patient selection, EBUS-TBNA is even more useful for TB than previously suggested

We’d be happy to see your patients with enlarged mediastinal nodes at Homerton for EBUS.

New drugs for TB

The first ever published RCT was the 1948 MRC-funded trial of streptomycin for TB. In the 20 years to 1968 a whole range of antibiotics were discovered and TB became almost nonexistent. There was then a resurgence with HIV. The break up of health systems in countries such as the USSR further impacted on the prevalence of this disease. Although new drugs are needed, health systems and national programmes must be optimised to ensure that new treatments can be used effectively.

There are new drugs in the pipeline for TB:

• TMC-207 or bedaquiline is a first in class diarylquinolone which inhibits ATP synthase and is active against MDR-TB. This has great potential for therapeutic use, but unfortunately there are problems with diarylquinolones. They have long half lives (5.5months), prolong QT, and can’t be used with rifampicin
• delamanid is a nitro-dihdro-imidazooxazole in Phase III trials – results awaited
• There is interest in new combinations of drugs, due to synergistic effects: eg using clavulanate to induce sensitivity to B-lactams
• This collection of papers includes a paper from De Lorenzo in 2013 on the use of meropenem-clavulunate added to linezolid-containing regimes for MDR and XDR-TB.
• Trials aimed at shortening the duration of TB treatment (which would improve adherence and rates of treatment completion) include:  OFLOTUB, REMox, and RIFAQUIN

TB research

Dr Adrian Martineau gave us a personal view of a career in TB research. He began by pointing out that TB occurs in lots of fun places in the world e.g….Newham! He discussed his career trajectory and the unexpected turns it had taken. In particular a research idea he had early on took many years to come to fruition, but he maintained interest and developed his techniques and connections, allowing him to eventually get a Lancet publication.

Influence of vitamin D deficiency and vitamin D receptor polymorphisms on TB among Gujurati Asians in west London: a control study (D Wilkinson et al Lancet 2000)

Tips on (TB) research:

• Rise early, work late, strike oil!
• There is an element of luck in all research and research careers
• Read good journals – what are high impact journals looking for? What are the hot questions?
• Get published early to increase your chance of getting funding/fellowship
• Find a good supervisor – someone that suits you. There are different phenotypes of researcher and supervisor!
• Have a major hand in the development of your own project
• Establish the right clinical:research balance – what is this for you?
• If your study can’t be big make it detailed
• Own the statistical analysis of your data
• Make space to write up
• Hone your research question – make it simple/targeted

We rounded off the day with a presentation from Dr Will Rickets on the role of the BTS and other OOPE options. He highlighted opportunities for trainees to get involved in the work of the BTS, for example by joining a SAG as a trainee rep. Will enjoyed his time on the committee and helped develop a number of educational resources. Jess will now continue in this role.

Will and LJ briefly described the roles available in education as OOPEs, and the advantages of completing a qualification such as a Diploma or MA. Such roles are varied and diverse. Any interested trainees who wish to know more should get in touch (see pages on Teaching and Training for further information and contact details).