NET Training Day: Barts Hospital 12/01/17

The first training day of the new year was hosted by Barts Health. Many thanks to Dr Tino Cappocci for organising the day, and for putting so much thought into the content and refreshment options!

Bronchiectasis: the imaging fundamentals

Dr Emma Cheasty started the day with some beautiful images of the lungs, and some classic examples of bronchiectasis.

The pathological process in bronchiectasis is a primary insult causing damage to the ciliated epithelium and mucosal glands, and impaired mucociliary clearance. The relevant anatomy when thinking about the signs on CT, is the secondary pulmonary lobule. This contains a centrilobular bronchiole and arteriole.

Imaging: historically thick slices were taken or a HRCT was done (thin slices but non-contiguous). Now we use helical CT with 1-1.5mm slices (whole parenchyma scanned). These can be reformatted in any plane, with high spatial resolution. Post processing with MIPS is also useful. On imaging bronchi may be normal/cyclindrical/varicose/saccular/cystic.

The distribution of bronchiectasis can provide a clue as to the cause:

• Recurrent aspiration: lower zones, peripheral.
• ABPA: upper and central zones (finger-in-glove appearance)
• Chronic and atypical NTM: middle and lingula
• Swyer James Syndrome: focal unilateral
• CF: upper zones, central, progressive
• PCD: middle and lingula
• Mounier-Kuhn syndrome: central
• Bronchial atresia/pulmonary sequestration: focal
• Sarcoidosis: upper and middle zones
• Pulmonary fibrosis: lower zones, peripheral (traction) “helicopter” distribution
• ARDS: middle, lingula, lower.
• Other: eg endobronchial tumour, foreign bodies, strictures: focal

In normal lungs you should not see bronchi 1cm from pleura – if they are visible then there is probable bronchiectasis. The bronchus: artery ratio should be 1:1.  Other signs include Signet ring sign and Tram-track sign. Swyer James also known as Swyer-James-MacLeod syndrome and Bret syndrome. It is a form of bronchiolitis obliterates secondary to injury to the immature lung. It is an air-trapping process and therefore looks blacker. There is a reduction in the number of arteries.

If you want to see more examples of bronchiectasis imaging have a look at Radiopaedia – a great learning resource.

Bronchiectasis cases

Dr Tino Capocci was up next, with some interesting cases from the bronchiectasis clinic.

Case 1: 11yr old refugee with a cough from age 1. Multiple courses of amoxicillin throughout childhood. He also had recurrent glue ear and learning difficulties. Sputum culture grew Haemophilus. CXR showed dextrocardia a portacath and port. Bronchiectasis was primarily in the lower zones and middle lobe.

Dx: PCD. ARMC4 mutation – an outer dynein arm defect

• Fry, Andrew M., Michelle J. Leaper, and Richard Bayliss. “The primary cilium: guardian of organ development and homeostasis.” Organogenesis 10.1 (2014): 62-68.

We had a refresher on the structure and function of the primary cilium, and the existence of both motile and non-motile cilia. We were reminded that primary ciliopathy is not PCD! As ever, ‘it’s more complicated than that’ so remember that patients may have Situs solitus, situs inversus totalis, or heteroplexy! Kartageners syndrome is defined as a triad of: situs inverses, bronchiectasis and sinusitis. Ciliary problems often lead to otitis media, sinusitis, and hypo-fertility. There are many milder phenotypes, the vast majority of which are an Autosomal Recessive inheritance pattern. Wet cough with an early onset has a strong association with PCD, and therefore this is a useful question in the history. Nasal NO is a useful investigation where this is available. However, in a milder phenotype with radial spoke mutation nasal NO is not useful as it is not abnormal. This test is also not specific.

Case 2: 24yr old male with a history of asthma and bronchiectasis referred from St Elsewhere. FEV1 0.67 (17% predicted). Upper lobe central bronchiectasis on imaging with nasal polyps, type 1 DM and low body weight. Also a history of DIOS (distal intestinal obstruction). Sputum culture grew staph aureus.

Dx: CF with ABPA.

This patient was treated with steroids and itraconazole and their FEV1 increased 6 times to 3L!  We were reminded that UK screening for CF started in 2006 (regional since 1970s) with IRT (immunoreactive trypsinogen = heelprick). It is also important to consider that US and Europe sweat test cutoffs are different, but this mainly applies to ‘equivocal’ levels. 60 is abnormal. 40 is equivocal. Nasal potential difference is a useful investigation in equivocal cases.

Case 3: 67M never smoker with an abnormal cardiac MRI referred for further assessment. LLL sub-segmental collapse and plugging on CT. The patient had been ‘chesty’ from childhood but had no history of severe chest infections. He produced 1/2 cup sputum per day. This patient had Haemopilus on sputum and was given 2/52 ciprofloxacin.

We reviewed the evidence for the use of inhaled ICS in bronchiectasis. Indications are very limited – if IBD related bronchiectasis high dose ICS is useful. Also in ABPA and in those with a concurrent asthmatic phenotype. Otherwise ICS are no use – as shown by a Cochrane review.

We reviewed the evidence for azithromycin in Bronchiectasis which comes from the EMBRACE or BAT trials. Before starting Azithro: at least 3xAFB culture to rule out NTM. Also consider bronchoscopy. An ECG is important before starting the medication (check QTc). You would also expect to review FBC, and LFTs. Audiometry is required if there is tinnitus or hearing impairment at baseline.

This patient had localised LLL bronchiectasis, raised IgA and poor fertility. PCD was felt to be likely. He had a normal sweat test. On bronchoscopy there was chronic inflammation with a weblike stricture. PCD diagnostics are awaited.

Asthma as an immunodeficiency & an immunocompromising state

Dr Paul Pfeffer shared his passion for immunology and helped us towards a greater understanding of the pathology of asthma. He reminded us of the function of the adaptive immune system and Th1, Th2, Th17.

He highlighted the importance of infections as precipitants of asthma attacks – not only common viruses and bacteria, but also fungi.

• Iikura, Motoyasu, et al. “The importance of bacterial and viral infections associated with adult asthma exacerbations in clinical practice.” PLoS One 10.4 (2015): e0123584.
• Liao, Hua, et al. “Impact of viral infection on acute exacerbation of asthma in out-patient clinics: a prospective study.” Journal of thoracic disease 8.3 (2016): 505.
• Liew, Foo Yew, Jean-Philippe Girard, and Heth Roderick Turnquist. “Interleukin-33 in health and disease.” Nature Reviews Immunology 16.11 (2016): 676-689.
• Moss, Richard B. “Treatment options in severe fungal asthma and allergic bronchopulmonary aspergillosis.” European Respiratory Journal 43.5 (2014): 1487-1500.

Paul highlighted the fact that the response to exposure is dependant on a bias of Th1/Th2 response which leads to different outcomes. There are also antigen independant effects eg Aspergillus protease. So if IgE is blocked this does not block all effects. Bacteria such as H. influenza are highly pro-inflammatory and can lead to steroid-resistant inflammation.

• Essilfie, Ama-Tawiah, et al. “Haemophilus influenzae infection drives IL-17-mediated neutrophilic allergic airways disease.” PLoS Pathog 7.10 (2011): e1002244.

We moved on to consider asthma as an immunocompromising state. In asthma there is a bias to a Th2 response, leading to more IL-4 release and more suppression of Th1 and Th17 type responses. So patients are more vulnerable to infections.

• Contoli, M., et al. “Th2 cytokines impair innate immune responses to rhinovirus in respiratory epithelial cells.” Allergy 70.8 (2015): 910-920.

TLR3 is important in the antiviral immune response. The amount is suppressed by giving IL4 “a whole world of badness”. This leads to higher amounts of replicating rhinovirus in cells. In the flu pandemic of 2009-10 risk factors for severe illness were pregnancy and asthma. This suggests Th2 immune pathways.

• Kloepfer, Kirsten M., et al. “Increased H1N1 infection rate in children with asthma.” American journal of respiratory and critical care medicine 185.12 (2012): 1275-1279. (OR 4.0 if asthma.)
• Talbot, Thomas R., et al. “Asthma as a risk factor for invasive pneumococcal disease.” New England Journal of Medicine 352.20 (2005): 2082-2090.

Multiple studies have shown reduced immunoglobulins in asthma.

• Zhao, Hongxia, et al. “Asthma and antibodies to pneumococcal virulence proteins.” Infection 41.5 (2013): 927-934.

Paul asked is there such a thing as low Th2 asthma? And is this, in association with hypogammaglobulinaemia, a form of CVID? There is substantial overlap but we do not currently treat them as a spectrum of a similar disease. Food for thought…

A further problem is that we can overshoot with steroid treatments which then suppresses immune function and leaves patients at risk of infection related exacerbations – in this case we need to reduce steroids. This can be difficult as patients are often reluctant.

• Pfeffer, Paul E., et al. “Eosinophilia, meningitis and pulmonary nodules in a young woman.” Thorax 65.12 (2010): 1066-1066. A real life example of the vicious circle.

Eosinophils >0.27 in asthmatic more likely to have eosinophils in sputum. If >0.4 definitely in sputum. If on steroids should be suppressed i.e. 0.1.

Can treating their asthma reduce their immunocompromise?

• Doull, Iolo JM, et al. “Effect of inhaled corticosteroids on episodes of wheezing associated with viral infection in school age children: randomised double blind placebo controlled trial.” BMJ 315.7112 (1997): 858-862.
• Teach, Stephen J., et al. “Preseasonal treatment with either omalizumab or an inhaled corticosteroid boost to prevent fall asthma exacerbations.” Journal of Allergy and Clinical Immunology 136.6 (2015): 1476-1485.
• Juhn, Young J. “Risks for infection in patients with asthma (or other atopic conditions): is asthma more than a chronic airway disease?.” Journal of Allergy and Clinical Immunology 134.2 (2014): 247-257.
• Tung, Hui-Ying, et al. “Allergen-encoded signals that control allergic responses.” Current opinion in allergy and clinical immunology 16.1 (2016): 51.

Mepoluzimab is approved for patients with eosinophil levels >0.3, on appropriate treatment, with 4 exacerbations requiring oral Pred or on continuous Pred. It is given in a severe asthma service. There are lots of clinical trials ongoing, even if the patient is not appropriate for mepoluzimab, so there is a clear advantage for patients with severe asthmatics to be seen in a severe asthma clinic.

Primary immunodeficiencies and respiratory sequelae

Dr Sorena Kiani and Dr Tino Capocci took us through some more cases with useful learning points. They reinforced the fact that there are things you can do about bronchiectasis. Think – have they got CF? If yes there is a lot we can do. Plus CF has (relatively) good funding. If they have ABPA this is very treatable. Some bugs are eradicable. If none of these are present consider immunodeficiency as treatments make a difference.

Case 1: 18F student with no PMH, never smoker, on OCP. L Pleuritic chest pain, fever, 1 episode haemoptysis. Yellow sputum. Chest clear, CRP 121. Infiltrates on CXR. Rx dose Tinz then MedReg said no CTPA needed. Patient went home. CXR flagged as ?TB. Seen in TB clinic. Xray worse. HIV -ve. Low IgG and IgM. Haemophilus in sputum.
Infiltrates and mediastinal LN on CT.

Dx: CVID

Often get autoimmune phenomenon too. Can look like sarcoid. If also adenopathy may be GLILD: granulomatous and lymphocytic lung disease – looks just like sarcoid. Learning point: do immunglobulins in people you think have sarcoid.
1/20-25000 – the most common antibody deficiency. The form with autoimmune and dysregulatory phenomenon has a worse prognosis.

NB. an immunodeficiency panel includes: CD3 – all T cells. CD4 Thelper. CD8 cytotoxic. CD19 B cells. CD56 NK cells.

Case 2: 46F from Pakistan. SOB, wheeze, fevers, weight loss. History of seronegative RA. Adult onset Still’s type presentation. On Rituximab. Asthma. Treated as PE! CTPA —> tramlines, tree in bud. Bronch – Pseudomonas. H influenza. FEV1 45% predicted. Low IgM. Normal ABPA serology. 8/13 protective pneumococcal serotypes. Low CD19 (expected as on Rituximab which depletes B cells). Low IgG1. No response to vaccine challenge Prevenar 3 serotypes.

Dx: Specific antibody deficiency

With treatment lung function got better.

If <7 antipneumococcal antibodies give Pneumovax (polysaccharide). In a month recheck antibodies. If no response then Prevenar x 2. Then recheck antipneumococcal antibodies.

If assessing someone for immunodeficiency look for T-dependant and T-independant responses.

Case 3: 36F with previous CAP. Then Strep sanguines brain abscesses. Hx ovarian rhabdomyosarcoma – treated with RTX/chemo. Lots of bronchiectasis. Pseudomonas in sputum. IgM 2x upper limit normal. CF sweat chloride normal. Anti-pneumococcal panel – only 2 of panel. High IgG subsets. No response to pneumovax. Also poor response to prevenar.

Dx: E1021K mutation found (de novo). Activated PI3-K delta syndrome.

Management of Invasive Fungal Disease in Haemato-Oncology 

Dr Samir Agrawal gave us his take on the challenging area of diagnosis and treatment of fungal disease in the immunocompromised. The epidemiology of this problem is challenging as we don’t usually grow any fungus. Invasive candidiasis > invasive aspergillosis > PCP > Cryptococcossis > zygomycosis > scedosporium > fusarium > histoplasmosis > others

Galactomannon is a serum biomarker that is more or less specific for Aspergillus. Dr Agrawal stated that he almost never sees a positive result in practice.

• De Pauw, Ben, et al. “Revised definitions of invasive fungal disease from the European organization for research and treatment of cancer/invasive fungal infections cooperative group and the national institute of allergy and infectious diseases mycoses study group (EORTC/MSG) consensus group.” Clinical infectious diseases 46.12 (2008): 1813-1821.

The EORTC/MSG criteria classifies invasive fungal disease into proven/probable/possible/not classified.

Lots of empirical treatment is given as it is difficult to prove whether a haematology patient has fungal disease and there are lots of worries about invasive disease. Empirical treatment guidelines suggest: liposomal amphotericin or caspofungin, but this is not always what is given in practice.

• Agrawal, Samir, et al. “A practical critique of antifungal treatment guidelines for haemato-oncologists.” Critical reviews in microbiology 38.3 (2012): 203-216.

Dr Agrawal suggests if there is probable or proven aspergillosis to give iv voraconozoleg or liposomal amphotericin.
There are also new drugs appearing, which may be hopeful in the context of growing fears about resistance to azoles across Europe. However, there has been no change to clinical practice as yet, as so far we have not seen significant resistance clinically.

• Maertens, Johan A., et al. “Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial.” The Lancet 387.10020 (2016): 760-769.

2 negative galactomannans in serum NPV>90%. B-D-glucan is useful for Candida. It also has the problem of false positives, same as galactomannon. Candida is not such a great problem in haematology patients as they receive good prophylaxis. Some people would like to use for PCP. BAL galactomanon is used in practice. >3 in BAL fluid diagnostic of invasive aspergillosis. If >1 suggestive.

Want to know more? Why not go to the fungalupdate on Fri 3rd – Sat 4th Feb 2017 in the Great Hall, St Barts.

Imaging of fungal disease

Dr Balan, Consultant Radiologist, took us through imaging in bronchiectasis. She started by reminding us of the ways in which Aspergillus can affect the lung:

• Non-invasive: ABPA
• Invasive: eg angioinvasive
• Chronic pulmonary aspergillosis: simple aspergilloma / CCPA / CFPA / CNPA / aspergillus nodule

Categorisation is not straightforward and can overlap. Imaging in with CXR  and CT.

Example cases we reviewed included:

1. Air crescent sign – aspergilloma. Complication – haemorrhage, May need embolisation. Aspergilloma does not progress over 3/12 so interval imaging is useful.
2. CCPA – tends to be in immunocompetent patients. Usually slow cavitation over months – years.
3. CFPA – can be end stage of untreated CCPA. Usually affects at least 2 lobes of lung. Significant volume loss. Solid appearance.
4. Chronic necrotising/semi-invasive aspergillosis. Relatively immunosuppressed.

Differential diagnosis of CPA: TB, NTM, chronic cavitatory histoplasmosis.

• Jepson, S. L., et al. “Pulmonary complications in the non-HIV immunocompromised patient.” Clinical radiology 67.10 (2012): 1001-1010.

Fungal diagnostics and antifungal top-tips 

Dr Jon Lambourne, microbiologist, discussed the diagnostics of fungal disease. He conveyed his excitement about the wonders of microbiology and lab work.

The gold standard diagnostic test for invasive fungal disease is histology but this is rarely achievable. More usually we have a combination of the clinical presentation & appropriate risk factors, micro, radiology, +/- cytology/histology. No test is 100% sensitive or specific. Serum galactomannon is about 75% sensitive in haemato-oncology patients, but only 20% in solid organ patients, and almost always negative in chronic granulomatous disease. The 2008 EORTC guidelines were designed for clinical trials but is quite useful for pragmatic clinical use.

• Detect organism: microscopy (Giemsa stain, antibody-mediated immunofluorence assay), culture, PCR.
• Detect immune response: galactomannon, beta D glucan
• Detect serum ‘biomarkers’ of infection e.g. CRP, procalcitonin

Galactomannnon has good negative predictive value, especially in prolonged neutropenia. If have been on prophylaxis then will be reduced anyway so ? change cut offs. Serum cut off 0.5. Options for testing: diagnostic driven, screening (twice weekly levels in ‘at risk’ patients – not good data, depends on prevalence, centre-specific), monitor treatment response over wks.

• Karageorgopoulos, Drosos E., et al. “β-D-glucan assay for the diagnosis of invasive fungal infections: a meta-analysis.” Clinical Infectious Diseases 52.6 (2011): 750-770.

A meta-analysis for beta-D-glucan showed good NPV. The accuracy in HIV + ve/-ve patients is not significantly different. There is no data on beta-D-glucan in BAL. Molecular tests e.g. organism specific PCR. Also pan-fungal targets: 18S rRNA, or IRIDCA (panel).

Similarly PCP PCR has good NPV. But also problem with false positives.

Antifungals
Anti fungal classes include:

• Cell membrane: azoles, amphotericin, nystatin
• Cell wall: caspofungin
• DNA: flucytosine

There are many more antibacterial classes. There are no anti-fungal classes against protein synthesis etc.
The problem is that they are eukaryotes so more similar cellular structure. Selective toxicity limits repertoire of antifungals. It is also important to be aware of side effects. Voriconazole makes your vision purple/pink due to an effect on retinal cones! It is fully reversible. A 28 day course previously cost £3000 – but now it is off patent it is £24! 100x difference.

Therapeutic drug monitoring – thresholds are based on population data, but trying to apply to an individual. Careful. Need to do levels in azoles (except fluconazole) and amphotericin.

Infections in patients with non-HIV immunodeficiency

Prof Jerry Brown was as engaging as ever, encouraging us to identify the pathogen in a number of cases. He described the triumvirate of evil: PCP, Aspergillus, CMV – opportunists in immunocompromised patients. Although we breathe in Aspergillus spores every day we have neutrophils so we are ok. Some of our patients are not so lucky…

Causes of pneumonia in immunocompromised patients:

• Large range of bacterial pathogens: gram +ve/-ve etc
• Opportunistic fungal: Aspergillus, PCP
• Weak pathogens: CMV, Resp viruses eg RSV, flu, metapneumaviruses, parainfluenza
• Non-Infective causes: ARDS, fluid overload, drugs, non-specific pneumonia syndrome, haemorrhage, DXT.

Useful Ix: CMV in blood. Antigen and PCR. NPA for respiratory viruses. Galactomannon is not helpful in those on loads of antifungals. BAL. Biopsy.

The real question is not what is the bug, it is what is the best empirical treatment? The background clinical picture helps us to make this decision, as does the pattern of disease.

• Rapid onset —> bacterial pneumonia, aspiration. ARDS, pulmonary oedema. Haem/engraftment.
• Lack of hypoxia: Aspergillus, Nocardia
• Insidious onset: PCP, GvHD.

To get a diagnosis, histology helps a lot – so get a biopsy if you can. A reasonable option is to treat and see what happens if fungal infection is very likely from the clinical picture and imaging.

Patients with bilateral diffuse infiltrates only get referred to Resp at the point at which they are too hypoxic for a bronchoscopy! Brown’s rule.

CMV pneumonitis can look just like PCP, but may be more basal (whereas PCP mid/upper). Need levels in blood (PCR) but there can be a divorce between blood CMV and pneumonitis. Perhaps this occurs when we don’t catch the peak of CMV levels and the pneumonitis is delayed? Can be very tricky. BAL can be diagnostic in this circumstance. If there is a peribronchial organising pneumonia then VATs should be considered to aid diagnosis. Could give trial of treatment (steroids).

There are new drugs with interesting immune function effects e.g. MAPK inhibitors (imatinib) – we don’t know what diseases they lead to. There have been reports of Aspergillosis. Taxols increase the risk of PCP. With ongoing developments in immunomodulatory drugs who knows what the future holds? Prof Brown will remain busy….

Thanks again to all involved in organising the day.

See you at the next training day on 7th February at Newham. Don’t forget GIM training sessions happening before that. Check the latest news and opportunities for an up to date list of training days.