NET Respiratory Royal Free Training Day: 14/05/15

In May we met at the Royal Free Hospital in Hampstead for a day of alpha-1-antitrypsin (A1AT), VQ-SPECT, safe sedation in Bronchoscopy, invasive fungal disease and business cases. Many thanks for James Goldring for organising a great day.

Before the main sessions, we began the day with an introduction from Dr John Hurst, and an update on the London A1ATD service. It is specialist, and cross-speciality with Respiratory physicians and Hepatologists running joint clinics on a monthly basis at URCC (UCL Royal Free COPD Centre). The clinic went live in 2013 and has now completed 22 clinics, with 75 referrals. There are great research opportunities in COPD and A1ATD and also opportunities to attend clinic. Contact j.hurst@ucl.ac.uk for more information.

A1AT: a history

We were lucky enough to hear from a big name in research, and the new Vice-Provost of UCL Medical school, Prof David Lomas. He transferred from Cambridge to UCL 2 years ago, and has merged his skills and expertise with the team already in the A1ATD service at Royal Free. He gave us an inspirational talk on the history of A1ATD and the serpinopathies.

The first case of A1ATD was described in 1963. The disease is mostly due to inheritance of the Z allele, which is prevalent in NW Europe.

• Blanco, I., E. Fernandez, and E. F. Bustillo. “Alpha‐1‐antitrypsin PI phenotypes S and Z in Europe: an analysis of the published surveys.” Clinical genetics 60, no. 1 (2001): 31-41.

Apparently it is possible to track the migration of Z allele, and in parallel track the Vikings’ movement (and rape and pillage!). A single base pair change 342Glu to Lys is the genetic defect, present in 1:1700 people of N European Caucasion descent. Only 10-15% of normal levels are found in the homozygote, with 80% of the protein retained in the liver. Liver histology shows cirrhosis. PAS positive inclusions are seen on staining. Z allele A1AT is retained in the ER, not in random amorphous aggregates, but in discrete polymers.

• Lomas, David A., et al. “The mechanism of Z α1-antitrypsin accumulation in the liver.” (1992): 605-607.
• Lomas, D.A., Finch, J.T., Seyama, K., Nukiwa, T. & Carrell, R.W. alpha1-antitrypsin Siiyama (Ser53right arrowPhe); further evidence for intracellular loop-sheet polymerisation. J. Biol. Chem. 268, 15333−15335 (1993).
• Miranda, Elena, et al. “A novel monoclonal antibody to characterize pathogenic polymers in liver disease associated with α1‐antitrypsin deficiency.” Hepatology 52.3 (2010): 1078-1088.
• Ekeowa, Ugo I., et al. “Defining the mechanism of polymerization in the serpinopathies.” Proceedings of the National Academy of Sciences 107.40 (2010): 17146-17151.

The pathway of polymerisation is disputed. Prof Lomas believes that the AT molecule with a Z mutation forms an intermediate M* which then forms dimer. Polymerisation then occurs through dimerisation.

Z is the most common variant but others exist: Silyama, Mmalton, King’s, S, I. These different variants polymerise at different rates, and this is related to the severity of disease. This demonstrates genotpye- phenotype correlation.
A1AT polymers promote neutrophil migration and activation, and are co-located in the alveoli. Cigarette smoke induces polymerisation in vivo. These experiments have led to a new paradigm for lung disease assoc with A1AT. It is not only the plasma deficiency which is relevant, but also an inflammatory mechanism.

• Alam, Sam, et al. “Oxidation of Z α1-antitrypsin by cigarette smoke induces polymerization: a novel mechanism of early-onset emphysema.” American journal of respiratory cell and molecular biology 45.2 (2011): 261-269.
• Lomas, David A., and Ravi Mahadeva. “alpha~ 1-Antitrypsin polymerization and the serpinopathies: pathobiology and prospects for therapy.” Journal of Clinical Investigation 110.11 (2002): 1585-1590.

We moved on to consider A1AT in the wider context of serpin polymerisation and disease and discovered that A1ATD is not the only serpinopathy – anti thrombin = thrombosis, C1-inhibitor = angio-oedema, A1-antichymotrypsin = emphysema, neuroserpin = dementia.

• Carrell, Robin W., and David A. Lomas. “Alpha1-antitrypsin deficiency—a model for conformational diseases.” New England Journal of Medicine 346.1 (2002): 45-53.

Of course these processes are more complex. We produce 1g of AT a day, therefore retention in the liver leads to liver disease. Other proteins have a much lower production rate, and therefore there is a concentration effect which is associated with liver disease. If someone has the Z allele they will produce polymers. But significant liver disease is dependant on an additional hit – e.g. alcohol, haemochromotosis, additional familial/genetic factors. such genes are likely involved in clearance/repair/response.

Studies of families affected by serpinopathies have led to further insights.

• Davis, Richard L., et al. “Familial dementia caused by polymerization of mutant neuroserpin.” Nature 401.6751 (1999): 376-379.

In a family with S49P neuroserpin PAS positive inclusion bodies were found in the brain. Polymers were then confirmed. This is the same mechanism of diease as A1ATD but with a different protein, and a different organ affected. This was a newly described disease, which Prof Lomas and team named FENIB (familial encephalopathy with neuroserpin inclusion bodies). Other mutations have now been described. In a further demonstration of genotpye-phenotype correlation it has been demonstrated that more polymers = earlier onset of disease.

Prof went on to explain why good crystal structure is so important to research on proteins. With the crystal structure well defined the team was able to see the cavity in the protein structure much better. Therefore there was a theoretical possibility of designing small molecules to insert into this cavity to prevent the protein from opening and dimerising. 1.2 million possibilities were screened and 68 selected for further screening. Small molecules are the key to a cure (according to Prof Lomas).

• Mallya, Meera, et al. “Small molecules block the polymerization of Z α1-antitrypsin and increase the clearance of intracellular aggregates.” Journal of medicinal chemistry 50.22 (2007): 5357-5363.

On a different note, stem cells are thought to be a possible route to treatment. Prof’s PhD student set about trying to reprogram skin cells into stem cells and then into hepatocytes. He managed to produce hepatocyte-like cells which produced AT and polymers, and got a Nature paper!

• Rashid, S. Tamir, et al. “Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells.” The Journal of clinical investigation 120.9 (2010): 3127.
• Yusa, K., Rashid, S. T., Strick-Marchand, H., Varela, I., Liu, P. Q., Paschon, D. E., … & Vallier, L. (2011). Targeted gene correction of [agr] 1-antitrypsin deficiency in induced pluripotent stem cells. Nature, 478(7369), 391-394.

He then tried to correct the point mutation in the Z allele in A1AT. When the genome was reviewed, he had managed to only introduce 27 point mutations as part of the reprogramming process. He then took this further to mouse engraftment. Hepatocyte-like cells were seen 6 wks post engraftment. This kind of research offers new strategies to prevent and treat disease. Fingers crossed for a cure developed and trialled at the Royal Free!

Prof Lomas ended by telling us that “There is no better life than being a clinical academic” and encouraged us all to do research.

A1AT diagnostics: a biochemistry perspective

We had an unusual perspective from the basement of the hospital; that place where samples disappear, and answers come out. At the Royal Free Hospital laboratory 3000 biochemistry specimens are processed a day. There is a 10% increase year on year. They now have a heavy reliance on automation as the only way to manage this. Louis Dron (clinical biochemist) provided an insight into the work of the lab, with A1AT as an example. The lab can measure A1AT levels. However, we were reminded that reference ranges are problematic. Local reference ranges are important so look at your local data. At the Royal Free the cut off is <1.1g/L. Sensitivity is 100% PPV 6.5% specificity 26.5%. This may seem a poor specificity but it means that there is a higher change of detecting heterozygotes too. An important clinical point was that A1AT is a positive acute phase reactant, therefore you should check CRP too and consider rechecking if suspicious. OCP and pregnancy can increase concentration too. Bornhorst et al Chest 2013; 143 (4) 1000-1008

• Bornhorst, Joshua A., et al. “α1-Antitrypsin phenotypes and associated serum protein concentrations in a large clinical population.” CHEST Journal 143.4 (2013): 1000-1008.

In a moment that provoked an existential crisis in some audience members, we considered the fact that all lab results are uncertain. This is a combination of pre-analytical variation, biological variation, imprecision from analysers (e.g. temperature of the lab), inaccuracy and bias (e.g. calibration). The result we are given by the lab is a quantitative point within a statistical range. Thankfully A1AT has quite a tight range.

We considered biochemical phenotyping, which is different to clinical phenotyping. Serum phenotyping by isoelectric focusing performed by a reliable laboratory is good but is qualitative. Phenotyptes are associated with distinct pattern of bands on protein electrophoresis.
We were reminded that “real life is sometimes complicated in the lab” as factors such as hyperbilirubinaemia mean that it is not always possible to do phenotyping. Therefore in severe liver disease genotyping may be warranted.

Some of the challenges of laboratory life were highlighted using some recent cases. A patient had zero A1AT detected, which is unusual. They were thought to be PiZZ or null Z. It is important to realise that homozygotes are indistinguishable from null on biochemical phenotyping. Also, any protein losing state will also lower levels (e.g. nephrotic syndrome). This is hard to separate from null and such patients need further testing. When phenotyping does not give a clear diagnosis, genotyping may be required. It should only be done when it will affect patient management, and is more than a merely academic interest question. many in the audience were unaware that not all ‘genotyping’ is created equal. Some labs do qualitative PCR, which suffers similar limitations to phenotyping. For certainty, full gene sequencing is needed. The relevance of genotyping was illustrated with a case. A patient with PiZ/QO Bellingham has a much lower risk of liver disease than PiZZ, which was good news for the patient when this was confirmed. However, this patient still has a risk of Respiratory disease as levels of A1AT are very low. Such information aids management and appropriate counselling of patients regarding behaviour change (especially regarding smoking). It costs a lot from a lab perspective so is reserved for cases where it will be useful. £460 compared to £25 for phenotyping – not that expensive in context.

A1AT deficiency: clinical practice meets research to personalise care

Dr Bibek Gooptu (Clinical Senior Lecturer in Resp Medicine, KCL and London A1AT service) began with the classic A1ATD chest x-ray, showing bibasal emphysema, and went on to describe the lung and liver effects of A1AT deficiency.

Gooptu, B., Dickens, J. A., & Lomas, D. A. (2014). The molecular and cellular pathology of α 1-antitrypsin deficiency. Trends in molecular medicine, 20(2), 116-127.

The UK has a relatively high incidence of A1ATD. It is less common as you travel East. The carrier frequency is significant, up to 1/27 in peak areas, and 1/50 in UK. 1/5 are heterozygous for S allele in the Iberian peninsula. This allele is not significant itself but important if co-locates with Z allele.

Management of A1ATD:

• Lifestyle advice/risk modification – smoking cessation, alcohol reduction
• Screening for liver disease – USS currently (other modalities under investigation)
• Genetic counselling
• Medical – bronchodilators, inhaled steroids, mucolytics, pulm rehab.
• Surgical – LVRS, lung/liver transplant.
• ? enzyme replacement therapy. This is licenced in the US, but there is no robust data of any clinically significant benefit from replacement. There is anecdotal evidence in individual cases. We are unable to give in the UK except in very occasional cases, requirement application for individual funding.

Dr Gooptu emphasised the value of combining academic and clinical work. In true bedside to bench style, clinical cases referred to the A1AT service have led to new variants being described through genetic analysis and crystal structure.

There are alternative models of polymerisation proposed in which the problem with the A1AT protein occurs at the folding stage. This is different to the ‘Lomas model’ in which there is normal folding but then formation of an intermediate which polymerises. We considered how these theories could be tested using crystallography and NMR. NMR held the understanding of structural dynamics. Interestingly different mutants have differential effects on folding, function and polymerisation. This is not a simple relationship, but does provide potentially novel targets for therapies.

• Nyon, M. P., & Gooptu, B. (2014). Therapeutic targeting of misfolding and conformational change in α1-antitrypsin deficiency. Future medicinal chemistry,6(9), 1047-1065.

A possible target is RNA interference, which takes out the mRNA before protein is made. This ablates all AT production, and would therefore be beneficial in PiZZ, but not other mutation alleles, as it addresses the toxic gain-of-function mechanisms but not loss of function. Pre-clinical studies have shown major benefit in animal models. The London A1ATD service is in talks to set up as a centre for Phase 1 first in man trials. Exciting times…

A1ATD – assessing the liver

In a move below the diaphragm, Dr Douglas Thorburn emphasised some key points regarding LFTs. We were reminded that they assess injury, not function, and that the degree of elevation does not correlate with disease severity. They are also not liver specific, which is important to keep in mind when interpreting abnormal results. The pattern is helpful (GGT, ALP = cholestatic, ALT,AST = hepatitis).

Investigating abnormal LFTS:

• Hx – any symptoms. Risk factors. other medical hx. Drugs.
• Examination – There are limitations to clinical assessment. Symptoms and signs are not sensitive in identifying advanced liver disease.
• Ix with bloods liver screen and USS (assessing architecture and severity).

BALLET study J Hepatology 2011. 1118 Birmingham patients in primary care. Most common reason for abnormal LFTs was the metabolic phenotype – NAFLD.

Progression of liver disease in adults with A1ATD due to chronic liver injury (misfiled A1AT, accumulation in ER, ER stress), plus co-factors (EtOH, hep viruses, obesity), leads to cirrhosis, which can then progress to fibrosis and therefore advanced complications. The prevalence of cirrhosis at postmortem is 37%, but lower in a self-reported registry.

• Eriksson, Sten, Joyce Carlson, and Ramon Velez. “Risk of cirrhosis and primary liver cancer in alpha1-antitrypsin deficiency.” New England journal of medicine314.12 (1986): 736-739.

When such patients develop decompensated liver disease they should be considered for transplant. 75/15,805 patients awaiting liver transplantation in USA have a diagnosis of A1ATD so it is a rare indication for liver transplant. Reassuringly post-transplant survival is comparable with other indications. 86% 1 yr survival, 80% 5yr survival.

We were given some guidance on when to screen. If a patient has abnormal LFTs >6/12 then a full screen should be conducted. Then a biopsy should be considered, in order to utilise scoring systems for fibrosis. Such scores are validated, and provide diagnostic information on the main driver for damage. The problem with biopsies is that they are invasive, have risks associated, and are impractical for a large population, in addition to being costly. Therefore biopsies are reserved for those who are high risk for advanced fibrosis, on the basis of non-invasive assessment. The intermediate risk group are more tricky.

Screening:

• Scoring systems based on indirect serum markers: FIB-4 recommended.
• Panels of direct serum markers are available, but are more costly e.g. £70 for Fibrotest.
• Imaging has been used to measure fibrosis, as a surrogate for histology from biopsy eg Fibroscan (transient elastography), ARFI (Acoustic Radiation Force Impulse). They are validated mainly for NAFLD and Hep C. It is unknown whether they perform the same in A1ATD.

In the Cambridge PiZZ cohort 17% had advanced fibrosis, often unexpectedly. Markers that were suggestive included USS appearances, platelet count <170, and spleen enlargement.

PET and SPECT-VQ lung imaging

Dr Sugama Chicklore updated us on imaging modalities. She began by explaining the difference between VQ and SPECT-VQ. In the past (and in the present in some DGHs) most centres did planar VQ scan. This uses a stationary camera, and a single angle and generates a 2D image. In the last 3-4 yrs most units have shifted over to use SPECT-VQ. In this case the camera rotates, and acquires multiple images from multiple angles, and then reconstructs a 3D view. EANM guidelines state that SPECT-VQ is first choice.

For the ventilation phase krypton (which is superior, but requires a high volume of patients to justify) or technetium-DTPA are used. Technetium-MAA is the perfusion agent. A SPECT-VQ takes 20min to acquire, and requires the full co-operation of the patient to be able to breathe in. There are much fewer indeterminate/non-diagnostic scans with SPECT-VQ compared to VQ. Sensitivity and specificity is 97% and 91% compared to 76% and 85% with planar imaging. A side effect of the new scan modality is that we are picking up more, smaller PEs. Are we now over diagnosing PEs? Which ones need treatment?

• Reinartz, Patrick, et al. “Tomographic imaging in the diagnosis of pulmonary embolism: a comparison between V/Q lung scintigraphy in SPECT technique and multislice spiral CT.” Journal of Nuclear Medicine 45.9 (2004): 1501-1508.
• Gutte, Henrik, et al. “Comparison of V/Q SPECT and planar V/Q lung scintigraphy in diagnosing acute pulmonary embolism.” Nuclear medicine communications 31.1 (2010): 82-86.

In some studies there is a higher proportion of non-diagnostic scans in CTPA. The benefit of SPECT-VQ is that the same contraindications (i.e. renal disease) do not apply. It is also much better for chronic PE/recurrent PE as VQ -SPECT has much better sensitivity in this context. Some centres (e.g. Tommy’s) combine VQ-SPECT with low dose CT – is this the best of both? VQ-SPECT Radiation doses is 4% radiation dose to female breast compared to CTPA. It is advised this should be the investigation of choice in pregnancy. There is not much difference in dose to the foetus, but as gestation increases VQ-SPECT gives a relatively lower dose. 27% of CTPA are non-diagnostic in pregnancy due to increased circulating volume, which is a problem.

VQ-SPECT of course also has limitations: it is an investigation available in hours only; it requires a longer imaging time; and provides no anatomical information; the patient must wear a tight mask; and there is an associated cost. False positives occur when mass is the cause of decreased flow (rather than PE). SPECT/CT is offered at St Thomas’. This correlates anatomy and perfusion defects. and adds less than 1msv to the VQ. If only this was available everywhere…

• Roach, Paul J., et al. “SPECT/CT in V/Q Scanning.” Seminars in nuclear medicine. Vol. 40. No. 6. WB Saunders, 2010.

VQ-SPECT is best used in patients who have a normal CXR and are younger (up to 60), or when CTPA contraindicated.
If a patient has had a previous PE, and you are worried about a new event you should use the same imaging or was used originally. Although Dr Chicklore felt that VQ-SPECT would be best, she acknowledged that it is hard to compare across image modalities.

In PET-CT radionuclides used in PET decay by B decay i.e. emissions of a positron. A positron combines with an electron and annihilates – it emits gamma rays (photons) which are detected. This is detected by a PET scanner – if they reach opposite crystals at same times this is a coincident and is therefore recorded. When acquiring the image a CT is acquired, then a PET. It extends from the base of the skull to mid-thigh. FDG is the tracer (radiolabelled-glucose). It is not a good modality for imaging the brain as this always has high uptake. CT is taken in a breath hold. PET takes longer – and therefore it can’t be done in a breath hold. Breathing artefact is therefore more of a problem. There may be inaccurate localisation of lesions in the region of the diaphragm. It is possible to use software to do respiratory gating to correct for this. The most common agent is FDG F18 with a half life of 110min. SUV values are a measurement of uptake within a region of interest normalised on the basis of a distribution value. Remember, context is everything!

FDG uptake can occur in non-malignant tissue: sarcoid, vasculitis, infection, TB, brown fat uptake. It is important to remember that there are several factors which affect FDG uptake – blood glucose level (starve for 6hrs, or 4hrs for DM – scan up to 10mmol), steroids (make sure you mention this on request, or stop if possible), delay between injection and scanning, delay between chemo-RTX and scanning, (need to know exact dates),

There are several uses of FDG-PET: diagnosis and lesion characterisation, staging, localisation of primary, assessment in suspected relapse (especially lung cancer), guiding biopsies and radiotherapy planning. For staging CT/MRI best for T stage, FDG PET best for N stage, and FDG also good for M staging – unsuspected mets and up to 7mm pick up. PET-CT is a game changer for N staging in particular – it makes a big difference to treatment choices. 100% sensitivity for adrenal mets for FDG PET. For bone mets FDG PET is best for lytic lesions. But if sclerotic lesion, bone scintigraphy is best. NICE guidelines state that all potentially operative patients should have a PET CT.

Safe sedation for Bronchoscopy

Dr Ricardo Jose gave a welcome session on safe sedation in Bronchoscopy for the non-anaesthetist. We tested our prior knowledge in an MCQ, and he then started by by highlighting existing guidelines on safe sedation by the AoMRC and the ACCP. He drew interesting comparisons between the UK and USA, where there is much greater use of propofol and remifentanyl, by physicians who are trained in sedation specifically. He felt that the BTS guidelines in 2013 were very good but were lacking as they did not review the evidence on propofol use.

Much of the drive for increased regulation around sedation stems from work done in endoscopy. When the AoMRC reviewed OGD and colonoscopy SUIs they found that 1/3 deaths within 30days were related to sedation:

• inadequate assessment and/or monitoring
• excessive doses of sedation
• drug combinations
• reliance on flumazenil
• minimal training and lack of supervision of trainees

Under-sedation is as unwarranted as over sedation so you must get it right. And there are many good reasons to improve your own sedation practice. Sedation can improve procedural tolerance and patient satisfaction. However, it is not always necessary. As ever, patient selection is important. Jose reminded is that good topical anaesthesia and patient reassurance may be sufficient. This is particularly important to remember, as sedation may be contraindicated, limiting options available.

Objectives of sedation:

• relief from pain and other noxious stimuli
• relief of anxiety, partial amnesia
• adequate sedation with minimal risk
• prompt and safe return to activities of daily living

Sedation is a spectrum. Moderate sedation = purposeful response to verbal command either alone or accompanied by light tactile stimulation is maintained.

Keys to safe sedation:

• be prepared in case things go wrong
• titration of sedative medication
• monitoring of level of sedation
• monitoring physiological response to sedation and the procedure

Pre-assessment should include airway risk assessment:

• Mallampati score (know how easy it would be to bag a patient if necessary)
• Short neck eg obesity
• Large tongue
• Reduced neck mobility
• Mouth opening <3finger breadth

In addition, if FEV1 <1.5L higher risk of desaturations. A safety checklist (like WHO surgical safety checklist) is recommended – see BTS guidelines. Is your Bronchoscopy unit using this checklist?

We revised the guidance that should be given to patients regarding fasting pre-procedure. Standard guidance is that  for 4-6hr pre-procedure the patient must have no solids or milk, and can have clear fluids up to 2hr pre-procedure. However, in obesity, pregnancy, GORD, DM, CKD it should be 8hr pre-procedure as these patients are more likely to have delayed gastric emptying

In elderly/frail/renal/hepatic impairment give 50% initial bolus dose. Always titrate the dose. Use the Ramsay sedation score 1-6, aiming for 3 to assess level of sedation
Alternative: RASS (Richmond Agitation Sedation Score)

 

 

 

 

 

 

 

 

Monitoring is essential. Mandatory parameters are pulse O2, pulse rate, and BP. Other useful features are capnography, and bispectral index monitoring (used by anaesthetists, but physicians generally have limited experience. Useful if using propofol).

Topical anaesthesia

Topical anaesthesia is essential.  It makes the procedure more tolerable and reduces the dose of sedation (reducing risks). Lidocaine is the drug of choice. Make sure you know your strengths and doses:

• xylocaine 10% to throat = 10mg/spray
• 2% lidocaine gel to nasal topical
• 1% for spray as you go (in head to head studies no advantage to 2% or 4%)
• lignocaine to airways peak serum conc 20-30min, up to 15.4mg/kg is BTS recommendation of max safe dose (based on single observational study = 1078mg for average middle aged healthy man). However, toxicity recorded at 9.6mg/kg (= 672mg). Perioral tingling, then dizziness, then CV instability. Anaesthetists use 6-7mg/kg as max safe dose (= 490mg). Manufacturers advise no more than 200mg in total.
• NB Lidocaine is contraindicated in porphyria and allergic reactions.

Benzodiazepines:

• Diazepam and lorazepam are not recommended as they have a longer half life. Midazolam is first choice.
• Midazolam: 1-5min onset of action. Peak effect 5-10min.
• Recommendation: 0.05mg/kg = 2-2.5mg initial dose. 0.5-1mg in the elderly.
• Take account of interactions – CYP3A4 inhibitors (antifungals, protease inhibitors, macrolides), CYP3A4 inducers (rifampicin, phenytoin, NNRTI)
• Reversal agent – flumazenil. 0.2mg repeated every 1min up to 1mg. Short half life so likely to wear off and need repeated doses.

Opiates:

• Morphine, hydrocodone are longer acting, with slower onset, therefore fentanyl or alfentanyl are recommended. Good for both analgesia and anti-tussive effects.
• Give fentanyl first as this attenuates the sympathetic response to intubation. Give dose over 20-50secs. CI in patients on MAO inhibitors. Caution in macrolides.
• Fentanyl: onset of action 3-5min, peak effect 5-10min.
• Recommendation: 50mcg initial dose for healthy adult, 25mcg in elderly. Then 25mcg every 3-5min.
• Reveral agent – naloxone. Dose 100-200mcg/2 minutes. Short half life of an hour – so repeated doses and monitoring are needed.

A combination of an opiate and benzodiazepine (in appropriate doses) is not associated with increased respiratory depression, but is associcated with better tolerance of the procedure.

Dreher, Michael, et al. “Sedation during flexible bronchoscopy in patients with pre-existing respiratory failure: midazolam versus midazolam plus alfentanil.”Respiration 79.4 (2010): 307-314.

Outside the UK drugs such as ketamine and propofol also used. There are also emerging sedatives: remimidazolam, dexmedetomidine
Propofol has many advantages as a sedation agent. The problem is that it has a narrow therapeutic window, and no reversal agent. It is used in some centres in US (and UK) with specifically trained physicians, or with anaesthetists in attendance. At UCL it is used for complex, eg radial EBUS, with an anaesthetist in attendance.

Discharge criteria post-bronchoscopy:

• baseline consciousness regained . It is advisable to use a post-sedation recovery score – Aldrete score pre/post/discharge. Dicharge criteria would be if baseline score regained, or -1 but normal vital signs
• vital signs normal limits for patient
• responsible adult to take them home if had sedation

Give verbal and written discharge instructions. This includes advice not to drive or operate heavy machinery for 24hours, and not to drink alcohol for 24hrs.

Recommended reading:

• José, Ricardo J., Shahzad Shaefi, and Neal Navani. “Sedation for flexible bronchoscopy: current and emerging evidence.” European Respiratory Review22.128 (2013): 106-116.
• José, Ricardo J., Shahzad Shaefi, and Neal Navani. “Anesthesia for bronchoscopy.” Current Opinion in Anesthesiology 27.4 (2014): 453-457.

Congratulations to everyone who passed the final MCQs. Don’t forget to upload your certificate to your ePortfolio and link with the relevant curriculum items.

Invasive fungal lung disease

Prof Jerry Brown got us interested in all things fungal including: filamentous fungi; pneumocystis; yeasts; and endemic mycoses such as histoplasma. He reminded us that there are a wide range of fungal lung diseases, from colonisation, to mycetomas, to hypersensitivity, and invasive infection. Invasive lung infections can be due to metastatic spread to the lungs or direct invasion. It can be asymptomatic, slow, or rapidly progressive. Prof demonstrated the diversity of fungi with some cases.

Case 1 – 55M autograft 6 months ago for NHL. Increasing SOB, cough. No signs on auscultation. CRP 70. No neutropenia.

Diagnosis: PCP. T cell defect in autograft. Septrin is not given routinely for autografts. PCP generally has an insidious onset with a low level of inflammation. Typically there is apical ground glass infiltration with peripheral sparing. The organism is pneumocystic jerovecii. Classically patients have exercise-induced desaturation and a fall in transfer factor.

Case 2 – 66M 3/52 cough and fever. Inflammatory markers not raised. RML consolidation on CXR not improving on co-amox and clarithromycin. On CT apical ground glass cysts with peripheral sparing. This was HIV +ve – undiagnosed. CD4 count <10. BAL positive for PCP. The lesson is that all patients with community acquired pneumonia need a HIV test.

Patients with a T cell defect are at risk of PCP (unicellular fungal organisms.) e.g. HIV, post-HSCT, cyclosporin/tacrolimus, lymphoma, high dose steroids 30mg Pred 3/52, newer chemo agents eg taxols. Confirmation may be through induced sputum or BAL for cytology with or without immunofluorescence. BUT this is frequently negative in non-HIV immunocompromised patients. PCR is now available but may reflect colonisation not disease. If cannot prove then need to show good response to treatment. Differential diagnosis is: drug toxicity, fluid overload, CMV/viral pneumonitis.

PCP is very interesting and can present in non-classic ways: a PCPoma, and ‘under the radar’ PCP – diffuse increased attenuation with no peripheral sparing – this is subtle, and hard to pick up. A ‘normal’ reported CT does not exclude PCP. Very unusually there may be unilateral pneumotoceles. Treatment: 1st line: 3/52 high dose septrin + corticosteroids if hypoxic PaO2<8kPa (40mg BD 5/7 then OD 5/7 then 20mg). 2nd line: clindamycin and primaquine. Prophylaxis is necessary if an immunosuppressive state persists – give co-trimoxazole.  10% die even if the right diagnosis and right treatment are given. Pneumothoraces are bad news.

Case 3 – 25F with aplastic anaemia (and therefore neutropenia for weeks). Fever and cough, with no lung signs on examination. L apex abnormal on CXR. Dense nodule, with ground glass halo. Diagnosis: invasive Aspergillosis.

If have damaged epithelium, impaired macrophage function and neutropenia high risk for invasive fungal disease.

• Patterson, Thomas F., et al. “Invasive Aspergillosis Disease Spectrum, Treatment Practices, and Outcomes.” Medicine 79.4 (2000): 250-260.

Diagnosis: BAL has poor sensitivity (50%). Galactomannon antigen ELISA in serum, CSF and/or BAL is useful. It may be positive before clinical or radiological evidence of IPA. Beware of false positives e.g. on Tazocin. IgG is not useful in acute disease. Biopsy is diagnostic and is most often CT-guided. Grocott’s/PAS staining reveal branching hyphae. Limitations to getting a biopsy may be low platelets and abnormal clotting. Culture +ve <50% – therefore confirming species is difficult, but most are sensitive to amphotericin. CT specific signs: cavitation, halo sign (early sign, first wk), air crescent sign (around mycetoma, later sign, 3/52)

When talking about invasive aspergillus think in terms of proven vs probable vs possible. Risk factors are key – neutropenia >10/7, 21 days steroids are high risk. Haemoptysis in aspergilloma is very worrying. Patients may die from major haemoptysis.

Case 4 – 30M on high dose steroids longterm for asthma. Found to have a thickened stenotic tracheal wall. This was a case of invasive Aspergilllus tracheobronchitis.
PC: cough, cough, cough. Often CT is not that helpful. Bronchoscopy is diagnostic. Appearances at Bronch are characterisitic. BAL and biopsy show hyphae.

Chronic forms of pulmonary aspergillosis.:

• Invasive/destructive
  • Chronic necrotising pulmonary aspergillosis (CNPA)
  • Chronic cavitatory pulmonary aspergillosis (CCPA)
  • Chronic fibrosing pulmonary aspergillosis (CFPA)
• Non-invasive
  • Mycetoma

Case 5 – 69M with recurrent empyema. He had undergone decortication, drainage, and a Claggett window. CT showed a mycetoma within the Clagett window cavity, a fungal ball with no invasive infection. The learning point was that a Claggett window can occur in any cavity open to the air. However you don’t necessarily need to worry about mycetoma. The risk is massive haemoptysis – then worry! Mycetomas do not become invasive, unless people become immunocompromised – then there is a risk.

Case 6 – 54F EtOH, DM, months of malaise, cough, eight loss. Repeatedly AFB -ve. Bi-apical cavities, with L small fluid level.

• Thin walled cavity = not cancer or bacterial.
• Poorly defined walls = active process, not old TB.
• Dry/minimal fluid = probably not bacterial.
• Active TB/NTM with cavitation should be AFB +ve.

Therefore diagnosis was chronic cavitatory pulmonary aspergillosis. IgE 785, Asp IgG positive. CCPA is relatively newly described.

• Denning, David W., et al. “Chronic cavitary and fibrosing pulmonary and pleural aspergillosis: case series, proposed nomenclature change, and review.” Clinical infectious diseases 37.Supplement 3 (2003): S265-S280.

Suspect when there are expanding lung cavities, often multiple with no underlying immune defect. Usually this follows an indolent course. Helpfully patients are always Asp antibodies +ve. Biopsy (difficult to get) may see hyphae at edge of wall. Sensitivity of culture is poor. CXR worsens over time. Can get pleural thickening associated. Occ assoc with CFPA. Give itraconozaole – disease regresses, fungus falls in on itself to form a mycetoma.

Case 7 – 33F  with a thymoma underwent surgery and chemotherapy in 2006. RTX for recurrence in 2007. Then presented with cough and increased CXR changes. Given steroids for ? RTX pneumonitis.

Having been given steroids the cavity increased in size “like petrol on a fire”. The lesson is that you must be absolutely sure Aspergillus is not the diagnosis before giving steroids.  Sputum +ve for Aspergillus. Asp serology -ve. Treated with 3/52 ambisome then longterm voriconazole.

Case 8 – 28F with a diagnostic label of ‘asthma’. Found to have a large RUL thick walled cavity. Thought to be TB (not typical). Given steroids for ‘asthma’ and cavity got much bigger. This was in fact CCPA. It can be considered as ABPA with intrapulmonary mycetoma. Asp serology +ve. Small mass on CXR. Ball of Aspergillus in the lung, not a cavity. PET +ve. Non-progressive. Diff diagnosis includes cancer. But does not make patient unwell.

• Acute disease – treat with antifungals until develop stable quiescence.
• Chronic disease – antifungals for months/yrs – usually oral azoles.
• Consider surgery if single lesion and good lung function.
• Monitoring is tricky – CXR changes very slowly, no blood tests to help, symptoms difficult. Refer to lung infection expert. Consider involving National Aspergillosis Centre in Manchester.

If you are interested in research, particularly in bronchiectasis and/or S pneumoniae, then talk to Jerry  jeremy.brown@ucl.ac.uk.

Producing a Business Case

Dr James Goldring advised us all to look beyond the training programme to the Consultant interview! He reflected that we spend training trying to be the same (ie passing ARCP by fulfilling externally imposed requirements), and then at Consultant applications we need to show what we have to offer that is unique. One way to do that is to have a hand in QIP or a new service. If you do this at the hospital in which you hope to get a Consultant job, it also helps you to meet some of the people who may be involved in your appointment.
A business case does not have to be for a major change. As a registrar you rotate around different trusts, and can see how things don’t work – and then change a frustrating situation.

Examples:

• new USS machine at UCLH
• designing novel clinic – e.g. pulmonary nodule telephone clinic follow-up
• new EBUS service

You need a business case if you are devising a change in practice that may have a significant impact on a resource or patient activity. It involves a systematic analysis of the proposed new service to ensure it is in the best clinical interests of patients and financial interests of Trust. Every Trust will have a template for writing a business case, so get hold of one and get started.

One way into a project is to keep an eye out for the current in vogue respiratory thing e.g. pleural lead, EBUS service, difficult asthma lead….what is currently influenced by national strategy and commissioning. Think about future-proofing – gold standard or better! Do some horizon-scanning. Consider how you are going to set up a quality service from day 1 as some may be looking out for you to fail. Think about your network and understand local politics. Think about how you will acquire skills, and how others in your team will acquire training. Dissect out current pathway for patient. Think about things like coding as you need to ensure your Trust is not disadvantaged. Think broadly about health and satiety, infection control, local protocols, committees, reporting systems, audit, peer review. Measure outcomes from day 1. It may be helpful to think about the strategic context in which you are working. What is the Trust’s 5 year strategy?

The example used was a new EBUS service.

Step 1: plan the new service – what is the current service, analyse problems, research an alternative, consider giving a presentation to respiratory lead/operations manager/finance manager, particularly as they will inform you about SWOT of your proposals (need for change? viable), and might save you wasting time needed to write a business plan

Step 2: get your local business case template. Needs to be concise, clear, persuasive of a need and how you are going to fill that need. Try to prove economic case, or quality case, or both.

Step 3: take it to the board.

Good luck!