NET Training Day: Newham Hospital 07/02/17

In February we met at Newham for a day of TB-related talks. Many thanks to Dr Nivenka Jayasekera for organising the day.

The Collaborative TB Strategy in Action 

We started the day with an overview of the collaborative TB strategy and a reminder of the TB rates in the UK, highest in London. Newham has particularly high rates. We compared TB rates in the UK vs US – when the US invested in social support/non-medical issues their rates declined (this was an especially successful strategy in New York). Rates of TB continue to increase in the UK.

You can read the collaborative TB strategy for 2015-2020 on the NHS England site. The 10 point plan comprises of:

• improving access to services and ensuring early diagnosis
• providing universal access to high quality diagnostics
• improving treatment and care services
• ensuring comprehensive contact tracing
• improving BCG vaccination uptake
• reducing drug-resistant TB
• tackling TB in under-served populations
• systematically implementing new entrant latent TB screening
• strengthening surveillance monitoring and;
• ensuring an appropriate workforce to deliver TB control

What is your Trust doing to achieve these aims, and how can you support this work?

TB nurses  

Sue Dart, nursing lead for TB in Newham, was up next, with her perspective on the role of specialist nurses in the MDT, contact tracing and treating underserved populations.

BCG
Traditionally TB nurses were involved in vaccination. There was a policy change 10yrs ago and vaccination moved out of TB services to primary care/neonatal vaccination service. All infants <1yr living in high incidence areas (e.g. Newham), or with parent/grandparent born in a country with a high incidence are offered the vaccine, in addition to those <16yrs who are contacts of pulmonary TB. Adults in high risk occupations e.g. healthcare, vets, mortuary workers are also offered BCG.

BCG does not confer 100% immunity. It has 70-80% efficacy against severe forms of TB in children e.g. TB meningitis. It is less effective against pulmonary disease. Protection wanes after 10-15yrs. There is some evidence that vaccination protects against infection as well as progression from infection to disease:

• Roy, A., et al. “Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta-analysis.” BMJ 349 (2014): g4643.

Contraindications are: immunocompromise, previous BCG, previous TB history or positive Mantoux, generalised skin infection. Indications to postpone vaccination are: live vaccine in last 4/52, and acute illness. The BCG is given intradermally, usually on the left arm at the deltoid insertion point but it can be given anywhere. Not everyone scars. There is a 1/1000000 rate of anaphylaxis. Dizziness/fainting is more common. Delay in healing is caused by faulty technique/overdose (in past), or immunodeficiency. Lymph node swelling +/- abscess formation is possible post-vaccine. Disseminated TB occurs in 3 in 1000000 doses (usually linked to immunodeficiency).

Contact tracing – why, who, how?
Contact tracing is an integral part of effective TB control and a core component of the TB nurse role. TB is of course a notifiable disease, with Public Health implications. NICE guidance changed last year. Previously all contacts were screened, regardless of site of disease. Now contacts of pulmonary or laryngeal TB, all contacts of children with active TB regardless of site, and symptomatic contacts regardless of site are screened. (Local practice may vary eg Whipps X still screen contacts of LN TB due to previous case finding experience).

Factors which increase the risk of transmission from the index case include: sputum positive disease, length of time index case has been infectious, cavitatory disease,  small room size, poor ventilation, frequent exposure, close physical proximity (sleeping in same room). Based on airline exposure/transmission it is proposed that those with 8hrs exposure a week are screened. Home visits are an important part of the TB nurse role.

Contacts at increased risk of infection are: pre-school children, immunocompromised people, homeless people, and those with substance misuse. Contact tracing involves a symptom check, Mantoux (<16yrs), IGRA (>16yrs), CXR, CRP, sputum AFBs & culture. New guidelines (NICE) suggest using Mantoux for all ages up to 65yrs. Barts Health have continued the use of the T-spot. The population requires contact tracing and screening in massive numbers. A Mantoux requires 2 visits with an experienced nurse and DNA rates are high. The IGRA easier to deliver. Cohort review is a structured process of outcome measurement over a quarter. It includes results from contact tracing. It is important to pursue household, workplace, and leisure contacts.
For pulmonary TB 5 contacts should be identified for each case.

Case scenario: 15yr old school pupil with sputum positive pulmonary TB. The case was notified to the Health Protection Team. Family screening was undertaken (1 child active TB, 2 LTBI). A school risk assessment identified 101 contacts with >8hrs timetabled contact per week. In this cohort there was 2% active TB, 24% LTBI from 1st round screening. A further 200 contacts were identified on 2nd risk assessment. In this group there was a 6% LTBI – this is probably expected rate in population so no further screening was required.

TB in underserved populations
There are several challenges for TB control: access to healthcare, delayed diagnosis, treatment length, commitment to daily medication, risk of resistance, and risk of relapse. A Key Performance Indicator (KPI) for TB services is a treatment completion rate >85%.

NICE guidance states that all patients with TB should be allocated a case manager. Their role is to to coordinate and support treatment. A risk assessment is conducted for every patient to identify possible barriers to successful treatment completion. There are programmes of both standard and enhanced case management.
It is common to have at least 1 social risk factor. There are decreased treatment completion rates if patients have 1+ social risk factors. This group have higher mortality, and greater loss to follow-up. Initiatives to support treatment completion are DOT and VOT. Incentives include meal vouchers, oyster card top-up and supported housing.

There are problems when people have no recourse to public funds. e.g. Eastern european workers, who may work cash in hand. Project Allalo House in Euston is a charity set up for Eeastern European people. The top floor accommodates TB patients who have no recourse to public funds. It has now been opened up to other nationalities. To get a patient admitted an application for CCG funding must be made. Teams are looking to see whether a similar approach could be taken to support patients in Newham. There are concerns regarding a new government policy that mandates people to provide evidence of entitlement to care. This will impact diagnostics as well as treatment and may lead to an increase in TB.

Find and Treat continues – there is just one van for the whole of London. There has been an increase in the homeless population diagnosed in Barts Health. If someone is homeless and there is a suspicion of TB they should be admitted so that an appropriate support plan for treatment can be put in place.

The LTBI project and the CATAPULT study  

Dr Matt Burman, NET SpR currently on OOPR, talked to us about LTBI and asked “is it really there? should we really care?”

Matt used a powerful metaphor to pique our interest in LTBI: if TB infection is like the water in a swimming pool, treating active TB is like catching the drops that fall over the edge. We need to drain the pool!

There is an epidemiological basis for changes in global policy that focus on treating LTBI. Data from genotyping show that in low incidence countries disease is primarily from reactivation. US data on foreign born cases 2005-2009 showed that 84% of active cases were reactivation. UK data from 1998 showed that 27.6% were from recent transmission.

• Ricks, Philip M., et al. “Estimating the burden of tuberculosis among foreign-born persons acquired prior to entering the US, 2005–2009.” PLoS One 6.11 (2011): e27405.
• Love, J., et al. “Molecular epidemiology of tuberculosis in England, 1998.” The international journal of tuberculosis and lung disease 13.2 (2009): 201-207.
• Hill, A. N., J. E. Becerra, and K. G. Castro. “Modelling tuberculosis trends in the USA.” Epidemiology and infection 140.10 (2012): 1862-1872.

The StopTB strategy – ended 2015. It focused on DOT. The Unite to end TB strategy is from 2016 onwards. The goal for low incidence countries is TB elimination (which means <1 case/million). To achieve this we need to identify risk groups and treat for LTBI. In the classic model someone with smear positive pulmonary TB infects some people who then have LTBI. It is actually more complex than that, as it is dependant on immune response.

• O’Garra, Anne, et al. “The immune response in tuberculosis.” Annual review of immunology 31 (2013): 475-527.
• Germain, Ronald N., and Pamela L. Schwartzberg. “The human condition–an immunological perspective.” Nature immunology 12.5 (2011): 369.

There is a LTBI state which is different to active TB. Subclinical disease is probably on a spectrum.

• Berry, Matthew PR, et al. “An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis.” Nature 466.7309 (2010): 973-977.

A direct measurement tool for MTB infection is not available. So, the definition is persistent immune response. There is very little evidence for key aspects of testing and treatment. Recommendations are also different for low and high incidence countries. It is challenging that there is no gold standard for LTBI diagnosis and therefore no sensitivity and specificity for the tests we have. We therefore have to use approximations of NPV and PPV.

A key question is what is the risk of progression to active TB for different population groups with LTBI? The PREDICT study in UK considers this in migrants and contacts. This is an important study. Risk is currently quoted as 1 in 10 risk of reactivation, but there is weak evidence for this figure.

• Comstock, George W., Vernat T. Livesay, and Shirley F. Woolpert. “The prognosis of a positive tuberculin reaction in childhood and adolescence.” American journal of epidemiology 99.2 (1974): 131-138.
• Trauer, James M., et al. “Risk of Active Tuberculosis in the Five Years Following Infection… 15%?.”
• Sloot, Rosa, et al. “Risk of tuberculosis after recent exposure. A 10-year follow-up study of contacts in Amsterdam.” American journal of respiratory and critical care medicine 190.9 (2014): 1044-1052.
• Choudhury, I. W., C. R. West, and L. P. Ormerod. “The outcome of a cohort of tuberculin-positive predominantly South Asian new entrants aged 16–34 to the UK: Blackburn 1989–2001.” Journal of Public Health 36.3 (2013): 390-395.

IGRAs are a test of the adaptive immune system. They answer the question have you seen MTB previously? Do you mount a response? These are not perfect tests. Some NTMs can lead to a +ve IGRA – this is a particular problem in developing countries.

• QuantiFERON is a direct test of IF gamma release to ESAT6 and CFP-10
• T-SPOT is similar but look at T cells and add antigen and see if releases IF gamma.

There is a RR 8.45 of developing active TB if positive IGRA, RR 13.55 if in low prevalence country.

Practice varies in screening of healthcare workers – in the US all healthcare workers are screened, often annually! People may be positive, but then revert to negative if test again, and may then go back to being positive. Why? We don’t know!

• Choudhury, I. W., C. R. West, and L. P. Ormerod. “The outcome of a cohort of tuberculin-positive predominantly South Asian new entrants aged 16–34 to the UK: Blackburn 1989–2001.” Journal of Public Health 36.3 (2013): 390-395.

It is essential to factor in pre-test probability and test result. Do not blindly test everyone!

For Mantoux the cut off is now 6mm. If +ve NICE guidelines 2016 suggest do an IGRA. There is no evidence to change these guidelines but many trusts just use IGRA as it’s easier.

New TB tests:

• Ruhwald, Morten, et al. “Diagnostic accuracy of the novel C-Tb skin test for LTBI, results from two phase III trials.” (2016): OA3037. The C-TB test (ESAT-6, CFP-10) was developed in Denmark. It does not require refrigeration and labs and is a skin test. It seems to have the same performance characteristics as QuantiFERON.
• Aksenova, Valentina, Nadezhda Klevno, and Tatiana Sevostyanova. “Diaskintest®-screening method in mass examination of the child population for tuberculosis in Russia.” European Respiratory Journal 44.Suppl 58 (2014): P2600. Diaskintest (DST) (ESAT, CFP) was developed in Russia. Data is less clear on performance.
• Zak, Daniel E., et al. “A blood RNA signature for tuberculosis disease risk: a prospective cohort study.” Could this be the future? In this transcriptomics study from SA whole blood RNA sequencing showed signal that accurately predicted re-activation within 6 months. Specificity 81-90%. It has been validated in other cohorts. It is not yet available as a commercial test. Trials are in progress treating the people who are ‘high risk’ with prophylaxis.
• Tornack, Julia, et al. “Human and mouse hematopoietic stem cells are a depot for dormant Mycobacterium tuberculosis.” PloS one 12.1 (2017): e0169119. Can you detect MTB DNA in blood? If this works in humans not just mouses then we would have test to prove LTBI! What a game-changer!

Current practice is to investigate (IGRA/TST), define risk category, and offer treatment. Treatment is 3RH (UK), or 6H (US).

• Stagg, Helen R., et al. “Treatment of Latent Tuberculosis InfectionA Network Meta-analysisTreatment of Latent Tuberculosis Infection.” Annals of internal medicine 161.6 (2014): 419-428. Risks/SE of treatment – hepatotoxicity AST >3x upper limit normal. 6H regime >35yrs 1.7% <35yrs 0.2%. A bit lower if use 3RH.
• Dinnes, J., et al. “A systematic review of rapid diagnostic tests for the detection of tuberculosis infection.” Health Technology Assessment. 11.3 (2007).
• Sterling, Timothy R., et al. “Three months of rifapentine and isoniazid for latent tuberculosis infection.” New England Journal of Medicine 365.23 (2011): 2155-2166.

The NEJM trial was weekly rifapentine and isoniazid vs 9 months of daily isoniazid. The weakness of this trial was that patients were under DOT in the weekly arm, but not in the daily arm. This did not reach primary outcome for decrease in rates, but there was a significant increase in treatment completion which is important. This regime is not available in the UK yet. The HALT-LTBI trial is an RCT comparing 3HP vs 3RH. It recently completed recruitment in the UK.

Major developments in the UK include:

• Pre-entry screening for migrants for active TB in country of origin
• Post-arrival LTBI in primary care

Pre-entry screening has been effective in identifying active TB. It is suggested that it also dissuades people from coming to the UK (according to TB in England (2016) report from PHE). Some other European countries screen migrants but tests used and actions taken are variable. UK policy is to screen recent migrants 16-35yrs from country with incidence >150/100000. No money put aside for screening children.

Newham sees a lot of TB. In 2015 8% of all TB was managed by Barts Health! Newham is the epicentre of that. Incidence >100/100000. 86% cases are among non-UK born patients. The vast majority are due to reactivation of latent disease. Therefore Newham took a different approach to screening than other places and decided to do this before WHO or National TB strategy was published. Funding from NHS England was secured to set up an extended primary care service. GPs do the IGRA test – along with LFT, CRP, HIV, Hep B/C, FBC and CXR. If the GP is happy that there is no active TB but there is evidence of LTBI then the pharmacist takes on the role of managing LTBI treatment. Anyone with complicating factors or any signs of active TB are referred to TB clinic.

• Pareek, Manish, et al. “Screening of immigrants in the UK for imported latent tuberculosis: a multicentre cohort study and cost-effectiveness analysis.” The Lancet infectious diseases 11.6 (2011): 435-444.
• Alsdurf, Hannah, et al. “The cascade of care in diagnosis and treatment of latent tuberculosis infection: a systematic review and meta-analysis.” The Lancet Infectious Diseases 16.11 (2016): 1269-1278.

Evidence for cost effectiveness of screening comes from Pareek et al. As Alsdurf et al showed, people drop off at every point in care. Overall there is a 50% treatment completion rate, 14% in migrants. We need new models and evidence for them.

Matt presented lots of interesting data from Newham. In 2015-16 88.4% of all LTBI screening done in the UK was done in Newham! There is variation in IGRA results by country of birth within Newham. Overall rates of IGRA positivity are about 20%.

Matt presented details of the CATAPULT study, a cluster RCT looking at the delivering of TB care to migrants. It compares the Newham model of care vs national model of care. The primary outcome is treatment completion. It is aiming to recruit 780 – 1000 patients in the next 2yrs. The study has been funded by Barts charity. Patients’ care is still funded by the CCG. 12 GP practices continue using the Newham model. 12 GP practices send everyone to secondary care. Is seeks to determine which is the most effective model and is there a difference in patient satisfaction? This is likely to be applicable to other urban populations, including those outside the UK. Also the model of care may be applicable to non-TB care. We look forward to the results!

 

 

Developing a LN TB pathway 

Dr Nivenka Jayasekera gave us an insight into the development of a LN-TB pathway, which is in development in Newham. There is increasing extra-pulmonary TB in London, such that pTB is now <50%. It is unclear why this trend has occurred. Possibilities include different ethnicities of migrants, and reactivation occurring later.

It is important to develop pathways together with other specialities to get the diagnostics right. Extra-pulmonary TB is more difficult to diagnose than pTB. There is a large array of symptoms, atypical symptoms, a large differential, and poor sensitivities for AFB. An additional challenge is the reduced clinical experience of other organ systems, for the TB physician. Patients may not present to the Respiratory service and there may be a reluctance of non-TB clinicians to perform invasive diagnostic tests for TB. AFB are too often not sent. Several appointments are often required with inherent delays in diagnosis.

Some cases illustrated the challenges of getting the diagnosis of extra-pulmonary TB right in a timely manner.

Case 1: 40M white, never-smoker born in UK. No history of TB exposure. Persistent cough. Mediastinal LN. Referred on 2ww pathway. Necrotic LN on CT. EBUS – pus aspirated. Started on RHZE and referred to TB clinic. Actually had metastatic SqCC. Referred to Oncology. Died a few months later.

Case 2: 46F Bangladesh. Cervical LN found on examination. Incidental axillary LN on CT. Seen in TB clinic. Referred to breast team for biopsy. Histology was CLL. Referral to Haem on 2WW. 2 months between start of investigation and appointment with Haematology. Even though TB pathway was quick, it is not as quick as 2ww pathway. Investigations are done quicker and before patient seen in clinic on 2ww pathway. This patient was seen by 3 different teams.

Case 3: Breathless, smoker, obese. BHL on CXR in 2013. Followed up with xrays/CTs. sACE normal. Smokers’ cough. Would previously have been given clinical diagnosis of sarcoidosis but we are increasingly doing EBUS on these patients. In 2015 histology showed non-necrotising granuloma. TB culture was negative. Discharged from clinic. Then a week later cultured fully sensitive TB – was started on treatment. Very little in way of symptoms. Imaging stable over years. This shows how important it is to send all samples for TB culture and ensure the results are reviewed.

What are the solutions to these problems in the diagnostic pathway?

• Radiology direct referral for LN – email to TB service/cancer office/named consultant
• LN pathway – try to get 2ww scans for ?TB as well as ?cancer pre-clinic appointment. Need access to excision biopsy (no ENT surgeons). Need to make sure samples sent for AFB from all sites. May need interventional Radiology. Reluctance to do laparotomies. How to improve this?
• LN MDT? TB physicians also become lumps and bumps doctors?

It is essential that all patients get the same pathway whatever their ethnicity. Challenges ahead, and opportunities to make a difference.

 

Cases from the MDT  

Dr Konstantinos Giaslakiotis (histopathologist), Sasikala Ainkaran (Radiologist), and Nivenka Jayasekera (Respiratory Physician) presented cases from the MDT. It was refreshing to see presentations of pathways that had not gone well, with a focus on learning from these and reflecting on our own services and how they could be improved.

Case 1: 32F from Pakistan presenting to ED with 7/12 hx cough. LUZ nodule L hilar enlargement. Referred to TB clinic. Sputum -ve. CT showed necrotic LN (subcarinal and aortopulmonary window), L hilar mass, more peripheral cavity, atelectasis. Underwent EBUS. Started on empirical anti-TB treatment. Had appointment at 2/52 but results were not available and were not chased up. Seen at 2/12 for step down to continuation phase – EBUS results only then reviewed. Histology St7 and 11: metastatic adenocarcinoma. TTF1 +ve. ALK +ve (targeted treatment eligible).

Learning points: give all patients including those with suspected TB a 2/52 appointment and a 2/12 appointment to ensure histology and late culture +ve are not missed. Make sure information on histology request is relevant. “Unexpected finding” pathways are important, but are hindered by problems with results getting sent from 1 trust to another, and even within trusts. NHS IT is rubbish….

Case 2: 63M from Sri Lanka. Incidental RUL changes and mediastinal LN found on cardiac MR. CT abnormal —> 2ww pathway. Underwent EBUS. Seen in 2ww clinic. CT: enlarged LN 7, 2, 4, 11R. Not necrotic. Bronchiectatic changes, linear fibrotic changes RUL. Cystic bronchiectasis RML. Old TB changes ? reactivation. Histology EBUS: blood worms seen at low power. Higher power showed epithelioid histiocytes, no obvious giant cells or necrosis. Non-necrotising granulomatous inflammation. Stains for AFB and fungi -ve. ?infection ?sarcoidosis. Patient was asymptomatic. Diagnosis was made: sarcoidosis. Patient was discharged. Faxed result of positive TB culture was sent. But it was not actioned. Then later faxed sensitivities. Actioned. Started on TB treatment.

Learning points: Would virtual clinics help these problems? Current limitation is payment – significantly less than physical treatment 5x less! We need to change patterns of work and get appropriately compensated to ensure best care for patients.

Case 3: 28M Bangladesh. Loose stools post appendicectomy. CT – abnormal. Had hemoicolectomy. Terminal ileal Crohns. LN enlarged. Still has symptoms. Now wondering ?TB. CT: thickened caecum, dilated terminal ileum, thickened wall. Caecum lying high – fibrosis. Fat stranding. Histology: caecum – non-necrotising granuloma. Inflammation in colon. Resection of colon: deep fissuring ulceration, granulation tissue, inflammation of mucosa/submucosa. No obvious granulomas in the wall. Fibrotic surrounding tissue, vascular congestion. Lymphoid aggregates arranged along muscular propria. Local lymph nodes numerous granulomata, non-necrotising. Not sent for microbiology!! Infection? Crohns? Had colonoscopy and ileal biopsies for AFBs. Did not send resection for microbiology.

Learning points: Differential from histology can be very difficult. Microbiology/AFBs from all samples is essential in high incidence areas (like Newham).  This man may end up having TB treatment anyway. Will need this anyway if ever needs immunosuppression/biologics. NB A patient can have biologics once started on treatment – usually wait 1-2/12 into treatment and ensure not MDR-TB.

Case 4: 33F from Pakistan. Diagnosis of crohns ileitis and colitis in 2006. Empirical TB treatment too for TB ileitis in 2006 ? completed treatment. Patient not sure. Documentation not optimal but suggested that had completed TB treatment. In 2013 developed cough, abnormal CXR. CT: RUL nodule + smaller surrounding nodules. No calcification. ? non calcified granulomas. Follow-up CT: nodule smaller (post abx after BAL result). Lungs otherwise normal. Later abdominal CT: caecum normal, terminal ileum markedly thickened, ‘creeping fat sign’ in mesentery, ray of vascular prominence ‘Holmes sign’. Pseudodiverticulum formation. All signs of Crohns. Few reactive LN. BAL: strep pneumonia. Had antibiotics. AFB -ve. 2015 assessed in TB clinic prior to starting infliximab. Started infliximab. CT following this showed multiple nodules bilaterally. Fully sensitive miliary TB was confirmed. CSF was also abnormal. Had 12 months treatment. All biopsies from ileum/colon inflammatory but no obvious granulomas. GI symptoms did improve on infliximab.

Learning points: Even when you do all the tests it is sometimes still difficult to diagnose. Co-diagnosis is important to look out for.

At this point in the day people were keen for lunch and started eating the biscuits, and their own arms. But it was not time to eat yet…

TB diagnostics  

Dr Robert Serafano Wani (ID physician) talked to us about TB diagnostics.

He reminded is of the MTB complex: bovis, africanum, microti, canetti, caprae, pinnipedii, orygis.
The mycobacterial cell wall gives the acid-fast staining. MTB is a gram positive aerobic bacillus.

TB remains the 2nd biggest killer disease from a single infectious agent. 9 million people were infected worldwide in 2013. 37% of the 9.6 million new cases globally are undiagnosed/not reported. This is the major route of ongoing TB transmission. Early diagnosis and systematic screening are needed.

Microbiological diagnosis: microscopy (requires many more bacteria/ml, options are ZN stain, fluorescent stains such as auramine – 10%+ more sensitive), culture (requires only 10 bacteria/ml, required for drug susceptibility. LJ slopes, agar based or liquid culture. Liquid is fastest), molecular methods (NAAT, PCR), antigen detection.

Molecular testing – requires only 1-10 organisms/ml. Rapid detection of organism in less than 48hrs.

• NAAT eg Lipoarabinomannan (LAM) component of cell wall. Detection of MTB biomarkers in urine. Sensitivity 56%
• GeneExpert MTB/RIF – cartridge based molecular assay. Simultaneous rifampicin resistance detected. Newer ones will look for isoniazid resistance too. PCR targets the 81 base pair region of rpo gene – 95% of mutations are here. Cannot distinguish live vs dead bacilli. Expensive for low income settings.
• 16s PCR

Drug sensitivity testing: phenotypic, genotypic

• Phenotypic: culturing MTB in presence of anti-TB agents to detect growth/inhibition of growth
• Genotypic: target specific molecular mutations

There are differences in specificity and sensitivity of tests dependant on different body sites

• Smear: 5-10,000 bacilli needed to be smear +ve. 50-80% first sputum sample, 10-14% from 2nd sample, 5-8% from 3rd sample. Multiple samples up to 90%. Culture of MTB in sputum: sens and spec 80/98%.
• NAAT/PCR on sputum: 95% sens 98% specific if smear +ve. Lower of smear -ve but still pretty good.
  In one series of those that were smear -ve 25% were culture +ve. From BAL 38% smear positive. Even if sputum and BAL smear -ve, 35% culture +ve.
• Pleural fluid/tissue: pleural fluid cultures <40% positive. Smears almost always -ve. PCR 40% sens 90% specific.
• Tissue AFB staining and culture of 3 pleural biopsy specimens combined with micro >90% cases can establish dx. PCR 40-80%.
• LN FNA – high yield in setting of HIV with high prevalence of TB (culture +ve 70-90%). Excision biopsy better yield than FNA.
• CSF: in a series of 132 adults – bacteriological dx achieved in 82%. AFB smear 58%, culture 71%. Large volume CSF (10-15ml) improves detection. Expert MTB/RIF assay in CSF 81% sens and 98% spec compared with culture.
  • Thwaites, Guy E., Tran Thi Hong Chau, and Jeremy J. Farrar. “Improving the bacteriological diagnosis of tuberculous meningitis.” Journal of clinical microbiology 42.1 (2004): 378-379.
• TB pericarditis. Pericardial fluid cultures +ve in 56% cases in study of 162 patients with TB pericarditis. Smear in only 3. PCR +ve in 30%.
  • Reuter, H., et al. “Diagnosing tuberculous pericarditis.” Journal of the Association of Physicians 99.12 (2006): 827-839.Culture of pericardial tissue provides some additional diagnostic yield. PCR more sensitive than in fluid.
• GU TB – dysuria, sterile pyuria, haematirua. 3-6 urine samples for AFB (early morning urine). AFB means not diagnostic. Single EMU 11-80% culture +ve. PCR 87-100% sens 93-98% specific.
• Skeletal – AFB smear <36%. Culture up to 48%. PCR 73% sens, 100% spec.
  • Colmenero, Juan D., et al. “Establishing the diagnosis of tuberculous vertebral osteomyelitis.” European Spine Journal 22.4 (2013): 579-586.

Despite all this, 15-20% of patients on TB treatment have no bacteriological confirmation. Varies by Trust, some significantly worse than this…

At last we had lunch! What a packed morning!

NTM update   

Dr Heinke Kunst updated us on all things NTM-related.

New BTS and ATS guidelines are awaited, so in the meantime we work with the evidence available.

• Eu Respire J 2013;42:1604-13 J van Ingen et al. The geographic diversity on NTM isolated from pulmonary samples: an NTM-NET collaborative study.

MAC is most common, followed by M. abscessus, then M. Kansasii. Most of MAC is in the USA – ATS guidelines usually followed for this reason. The difficulties of treating NTM were illustrated through some cases.

Case 1: 74F weight loss, productive cough, lethargy. Intolerant of rifampicin, isoniazid, ethambutol. Intermittent treatment for MAC for 8 months, stopped all drugs due to nausea. Multiple isolates of MAC on sputum, some abscessus. Raised inflammatory markers. Aspergillus serology -ve. CT: fibrocavitatory bronchiectasis. IF-gamma receptor defect. Immunology review – not candidate of IF-gamma therapy.
Organism sensitive to clarithromycin. Commenced on iv amikacin for 2/12. Ethambutol, Moxifloxacin, Clarithromycin introduced slowly, 1 drug at a time.
C diff diarrhoea. Moxifloxacin stopped. Rifampicin reintroduced. Visual impairment – ethambutol stopped. Nebulised amikacin given. Significant clinical improvement, particularly in fatigue. Previously housebound – went out! Significant improvement in QoL. No further isolates of MAC. Clarithromycin/Rifampicin + nebulised Amikacin continued.

Case 2: 70M multiple isolates MAC in sputum. Started on Rifinah and ethambutol. Intolerant of Rifinah – nausea, vomiting, abnormal LFTs. History of sarcoidosis (multiple courses steroids), brain tumour? Organism resistant to clarithromycin. Started on Rifampicin, Ethambutol, Moxifloxacin. Improvement. Right temporal brain lesion excised – mycobacterial spindle cell pseudotumour. ZN positive. PCR for MAC positive. Melted away. No recurrence. Culture -ve at 5yrs.

Case 3: 62F known bronchiectasis. No AFB sent on sputum samples. Haemoptysis. Azithromycin for 3yrs for recurrent exacerbations (never had pseudomonas isolated). Had bronchoscopy – BAL smear +ve MAC. Macrolide resistance. Stopped azithromycin. Previous retinal detachment. Not keen for clofazimine or nebulised amikacin. Occasional cough, no other symptoms. CT – nodular changes but not too bad. Normal PFTs. No further isolates for last 18/12 despite no treatment.

Case 4: 66M small cell lymphocytic lymphoma. Immunosuppressed. Disease progression . Rituximab given as part of study. Admitted with  ‘cavitating pneumonia’. BAL: M. kansasii. Also 2 x smear +ve. Ventilated on ITU. Cavity and pneumothorax on imaging. Treated with rifampicin, ethambutol, clarithromycin. Improved, and left ICU. Later developed T2RF and died.

Case 5: 72M cough, mild weight loss, smoker. Diagnosis of pTB since AFB isolated from sputum. CT: upper lobe cavities. M kansasii isolated. Azithromycin/ethambutol/rifampicin given. Significant improvement after 2/12.

Case 6: 43F severe fatigue, dyspnoea on exertion. Failing therapy for MAC. Remained culture positive despite standard therapy. iv amikacin, clofazimime, azithromycin, ethambutol. Significnat clinical improvement. Switched to nebulised amikacin after 3/12. Palpitations – long QTc. Reduced dose of azithromycin. Monitoring of real function, visual acuity and audiometry. Doing well.

Guidlines: An official ATS/IDSA statement 2007 —> look at the diagnostic criteria.
Alvarez-Uria G Current opinion Pulm Med 2010 Feb. Lung disease caused by NTM mycobacteria.
Diagnosis and treatment of NTM mycobacterial lung disease. Review.

Patients all now screened for immunological defects. Young patients v important. Refer to immunologist. HIV, complement, lymphocyte subsets.

Skin and soft tissue NTM: fortuitum, chelonae, xenopi.

Lady Windermere Syndrome? ineffective mucociliary clearance?

colonisation vs casual isolates vs infection

Respiration 2016;91:386-402. Pulmonary disease caused by NTM. Wassilew et al.

Challenges: Drug sensitivity testing is controversial – in vitro vs in vivo. For MAC should test for macrolide sensitivity and amikacin. There is a lack of standardised endpoints for treatment outcomes. Culture conversion, radiological improvement, clinical improvement…. Fatigue is often a useful symptom to track.
M kansasii parallels clinical course of MTB. Cavitatory disease upper lobes. Treatment is with rifampicin 10mg/kg/day, ethambutol 15mg/kg/day, isoniazid 5mg/kg/day OR macrolide (azithromycin) increasingly used. Treat for at least 12 months when sputum cultures -ve. Can be difficult to know when to stop – relapse? If rifampicin resistance probably need 4 drugs and to extend treatment.

MAC is treated with clarithro OR azithro, rifampicin, ethambutol. If fibrocavitatory disease consider iv/nebulised amikacin. Treat until culture negative on therapy for 1 year. If failing standard treatment add moxifloxacin. Inhaled amikacin has limited evidence. Clofazimine is a possible alternative to rifampicin or in refractory MAC disease. Trial awaited.

• Jeong, Byeong-Ho, et al. “Intermittent antibiotic therapy for nodular bronchiectatic Mycobacterium avium complex lung disease.” American journal of respiratory and critical care medicine 191.1 (2015): 96-103. BTS guidelines are changing to recommend this. This 3x a week regime is better tolerated and outcomes are similar.

M.abscessus is seen more in CF. Multi-lobar patchy reticulonodular changes or mixed interstitial alveolar pattern. Less cavitation. Treatment includes an induction phase of at least 2 ivs including amikacin and others, plus 3 oral drugs including an oral macrolide if sensitive. Then step down to oral regime.

M. xenopi is more common in France. Sputum conversion occurs rapidly but relapse rates are high. Consider surgical resection. RCT ongoing – moxifloxacin containing regimen.

Other drugs used in TB regimes include linezolid and bedaquiline —> these are used in MDR-TB regimes.

Thanks again to all involved in organising the day.

See you at the next training day. Don’t forget GIM training sessions happening before that. Check the latest news and opportunities for an up to date list of training days.