Bronchiectasis: a complex condition
A 39-year-old man was admitted to hospital with a two-week history of worsening shortness of breath, decreased exercise tolerance and increased sputum production despite repeated courses of oral antibiotics (amoxicillin, co-amoxiclav and ciprofloxacin). These symptoms had been gradually increasing over two months. He had noticed some weight loss but did not know how much. (On admission he weighed 68kg.) He had experienced night sweats and fevers in the three weeks before admission.
The patient had a history of steroid-dependent sarcoidosis with bilateral pulmonary fibrosis and hypercalcaemia, bronchiectasis (see Panel 1) with intermittent pseudomonas infection, recurrent pneumothoraces and gout. He had no drug allergies and was an ex-smoker.
His regular medicines included the following:
• Azathioprine 75mg od (for steroid-sparing)
• Prednisolone 25mg od
• Allopurinol 100mg od
• Lansoprazole 30mg od
• Colistimethate sodium 2MU nebulised bd
• Fluticasone proprionate/salmeterol 250/25 inhaler two puffs bd
• Salbutamol 100mg MDI prn
Panel 1: What is bronchiectasis?
Bronchiectasis is an endpoint that results from many disease processes, including immune defects, cystic fibrosis, ciliary dysfunction, aspiration and infections (eg, tuberculosis, pneumonia and whooping cough), although it has been reported that 40 per cent of patients do not have a clearly defined event. It is characterised by dilated, thick-walled bronchi and is a persistent, usually progressive condition. Symptoms vary from intermittent episodes of expectoration and infection to daily expectoration of large volumes of purulent sputum. Other common symptoms include dyspnoea, and haemoptysis. Respiratory failure and cor pulmonale may occur.
Events such as previous pneumonia, tuberculosis and gastric aspiration may give rise to the primary insult, while defects in host defences (eg, reduced mucociliary clearance) can potentiate damage. A perpetual cycle of infection, inflammation and enzymatic tissue damage harms the airways. Treatments known to be effective in the long-term treatment of bronchiectasis act by disrupting this cycle.
The patient could speak in full sentences. His temperature was 38C, blood pressure 150/90mmHg and pulse rate 110bpm (60–100bpm). His respiratory rate was 17 (10–20 breaths/minute), with SaO2 98 per cent after 8L O2 — a high oxygen requirement to reverse hypoxaemia likely to be due to mucus plugging. Most recent spirometry results were:
• FEV1 41 per cent of predicted
• FVC 65 per cent of predicted
• FEV1/FVC 64 per cent
On auscultation, he had bilateral crackles and wheeze throughout both lungs.
Recent sputum culture results found Staphylococcus aureus and Aspergillus fumigatus. On routine surveillance two months previously sputum was acid fast bacillus (AFB) smear positive — Mycobacterium avium was cultured.
Initial laboratory results revealed elevated C-reactive protein 69mg/L (0–5mg/L). White cell count was 10.1x109 (4–11.1x109), with neutrophilia. Other parameters — including serum angiotensin-converting enzyme, which may be elevated in active sarcoidosis — were unremarkable.
Chest X-ray showed patchy consolidation in the right lower zone on a background of lower lobe bronchiectasis and established sarcoid-related fibrosis in the mid and upper zones.
Aspergillus specific IgG and IgE, and total IgE were within normal limits (elevated total IgE and IgE- and IgG-mediated immunological responses to A fumigatus are found in allergic bronchopulmonary aspergillosis, which requires treatment with steroids and antifungals).
Diagnosis and treatment
A diagnosis of infective exacerbation of bronchiectasis was made. The general management of bronchiectasis is described in Panel 2. Repeat sputum samples were sent for AFB microscopy and culture. Piperacillin-tazobactam was prescribed, prednisolone increased to 40mg daily, and salbutamol given regularly via a nebuliser. Azathioprine was withheld because dissemination of non-tuberculous mycobacteria (NTM) infections has been observed in adults with immunosuppression.
Panel 2: Management of bronchiectasis
Management of bronchiectasis should be in accordance with the British Thoracic Society guideline (for non-cystic fibrosis bronchiectasis; 2010). This categorises management approaches into the following:
Airway clearance By increasing the osmotic drive, nebulised hypertonic saline (4ml of a 3—7 per cent solution two to four times a day, depending on tolerability) may increase sputum yield and reduce sputum viscosity to aid expectoration. There may be a role for carbocysteine.
Airway drug therapy If airflow obstruction is reversible, a beta2 agonist or anticholinergic bronchodilator may be required. Current evidence does not support routine use of inhaled corticosteroids for bronchiectasis except for patients with asthma but there is some evidence to suggest that they are probably efficacious among some patients with severe bronchiectasis.1
Antibiotic therapy Studies indicate antibiotics can improve symptoms and hasten recovery in exacerbations. Exacerbations requiring antibiotic therapy are characterised by increased sputum volume and purulence, in addition to increased cough, wheeze, breathlessness, malaise, fever and weight loss. In general, 14 days’ treatment is recommended. Intravenous antibiotics will be prescribed if a patient is particularly unwell, has resistant organisms or has failed to respond to oral therapy.
Common organisms associated with exacerbations include Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus and Pseudomonas aeruginosa.
Although most patients will have exacerbations caused by H influenzae, risk factors for P aeruginosa should be considered in the absence of cultures. These include recent hospital stay, frequent or recent administration of antibiotics, severe disease (FEV1<30 per cent) and oral steroid use (>10mg prednisolone/day in the previous two weeks).2 Those with P aeruginosa may be treated with an oral quinolone such as ciprofloxacin, but intravenous antibiotics are often required. Ceftazidime, carbapenems or piperacillin-tazobactam are agents of choice — reference to previous sputum results where available can be useful to guide treatment. A combination of two antibiotics, including an aminoglycoside, should be considered for strains of P aeruginosa resistant to one or more antipseudomonal antibiotics.
For patients having frequent exacerbations (ie, three or more a year), or with significant morbidity, long-term oral or nebulised antibiotics may improve quality of life and slow FEV1 decline. Nebulised antibiotics offer the advantage of high concentrations delivered to the site of action, with lower potential for adverse effects.
Surgery Studies have reported lung resection as a treatment option. There is a lack of literature on lung transplants in patients with bronchiectasis but the BTS guideline recommends referring patients for evaluation for transplant if FEV1 falls below 30 per cent or if there is rapid progressive respiratory deterioration despite optimal medical management. In our hospital, eight patients have been referred in the past five years.
Complications Pharmacological treatments may be required for complications such as haemoptysis or non-tuberculous mycobacterial infections (see Panel 3). Non-invasive ventilation may be an option for those with chronic respiratory failure. Oxygen may be required.
Although an initial improvement was seen, the rapidly declining FEV1 (from ~80 per cent predicted to ~40 per cent predicted over the previous 24 months) and increasing frequency of exacerbations were cause for concern. Three out of three mycobacterial sputum cultures were smear and culture positive for M avium (Panel 3 discusses NTM infections) so the patient was prescribed rifampicin, started at 600mg od, ethambutol 1,000mg (15mg/kg) od and azithromycin 500mg od. (An eye examination was conducted before starting ethambutol because of the drug’s ocular toxicity.) The dose of prednisolone was doubled to account for increased clearance due to rifampicin. Azathioprine was formally discontinued.
Following 14 days of IV piperacillin-tazobactam, the patient returned to his normal health and his sputum production was normal. Aminophylline was added for generalised expiratory wheeze.
Panel 3: Non-tuberculous mycobacterial infections
As with other forms of lung damage, bronchiectasis increases the risk of infection by non-tuberculous mycobacteria (NTM), which have been isolated in up to 10 per cent of sputum specimens.3 The clinical significance of this is not always clear, because NTM are not always pathogenic. Colonisation can occur without change in clinical status but may lead to infection.
Assessment of mycobacterial disease can be complicated by non-mycobacterial exacerbations, which are common. Current guidelines (American Thoracic Society) for diagnosis and treatment of NTM infection require pulmonary symptoms or typical changes on chest X-ray or high resolution computed tomography, exclusion of other diagnoses or pathogens, at least two positive separate sputum cultures (or one positive bronchoscopy sample or a biopsy with histological features of NTM infection and positive culture), and an assessment of risks and benefits of treatment in the individual.
Mycobacterium avium M avium is one of the mycobacterial species collectively known as M avium complex (MAC). It is widely believed that environmental sources, such as water and soil, are reservoirs for most MAC species infecting humans.
MAC lung disease rarely occurs in immunocompetent hosts. Those with underlying lung disease, such as bronchiectasis, are more likely to develop progressive MAC lung disease.
Treatment involves multiple drugs so the risk of adverse reactions is relatively high. In addition, the optimal therapeutic regimen has yet to be established. Treatment is best directed by those with experience in mycobacterial infections.
There is disparity between current UK and US guidelines. British Thoracic Society guidelines4 (1999) recommend rifampicin and ethambutol ± isoniazid for 24 months, with macrolides reserved for HIV-positive individuals and those who fail to become culture negative or relapse on standard therapy. The more recent ATS guidelines5 recommend a combination of rifampicin, ethambutol and a macrolide (if macrolide sensitive). Therapy is continued until sputum has remained culture negative for 12 months. BTS guidelines are to be updated this year.
Macrolide-resistant MAC is a problem and involves a more complex and protracted treatment regimen, akin to treatment of multidrug resistant tuberculosis. Risk factors for macrolide-resistant MAC include macrolide monotherapy and macrolides prescribed with insufficient companion medicines. A particular concern is the injudicious use of macrolides to disrupt the infection-inflammation cycle in bronchiectasis.
The patient was discharged on the following:
• Prednisolone 40mg bd (not a usual regimen)
• Allopurinol 100mg od
• Lansoprazole 30mg od
• Colistimethate sodium 2MU nebulised bd
• Fluticasone proprionate/salmeterol 250/25 inhaler two puffs bd
• Salbutamol 100mg MDI prn
• Rifampicin 600mg od
• Ethambutol 1,000mg od
• Azithromycin 500mg od
• Aminophylline 225mg bd
• Alendronate 70mg once weekly (No calcium or vitamin D because of hypercalcaemia history. Serum calcium was within normal limits during treatment.)
In the UK, patients with M avium infection are generally treated with antibiotics for a minimum of 24 months, in accordance with British Thoracic Society (BTS) guidelines.4 The patient completed 24 months’ treatment and remained sputum smear and culture negative for more than 12 months, but rifampicin, ethambutol and azithromycin was continued because he was put on the active list for lung transplantation and untreated M avium infection is a contraindication.
This regimen can have some unpleasant adverse effects, including staining body fluids (and clothes) and hepatotoxicity. Weighing the risk of relapse (reported to be ~20 per cent) in a patient on an active transplant
list against the potential for adverse outcomes, the balance in this case tips in favour of remaining on treatment for as long as it can be tolerated.
Role of the pharmacist
The pharmacist has an important role to play in the long-term management of patients with bronchiectasis. Optimisation of drug therapy is imperative, and particularly important for those awaiting lung transplantation. In addition, the amount of input required to support adherence must be commensurate with the complexity of the treatment burden.
Although an important treatment, nebulised antibiotics are used off-label for bronchiectasis and often require shared care guidelines or equivalent to ensure continuation in primary care. Pharmacists are ideally placed to negotiate ongoing prescribing. The recent development of a comprehensive guide to drugs used in the treatment of bronchiectasis for primary care at Barts Health NHS Trust has supported community pharmacists, GPs and other primary care colleagues in the appropriate management of this condition [for a copy, email email@example.com].
There is also an important role with respect to managing the introduction of new medicines (eg, rifampicin and ethambutol) and their adverse effect profiles, along with ongoing management and monitoring.
The adverse effects of long-term high dose corticosteroids require appropriate precautions. High doses of corticosteroids can make postoperative recovery difficult after transplantation, due to decreased wound healing and increased infection risk — ideally, patients should be treated with less than 10mg daily of prednisolone or equivalent before transplantation. Pharmacists can support steroid dose reductions and management of adrenal suppression, as well as supporting prescribers in “sick day rules” advice (eg, doubling the dose of steroid for 48 hours for mild illness, or recommending intramuscular hydrocortisone if the enteral route is compromised due to vomiting).
Pharmacists must also be alert for drug interactions. Of note in this case, rifampicin and aminophylline have significant interactions. Rifampicin is a potent inducer of microsomal enzymes (particularly cytochrome P450 isoenzymes of the CYP3A subclass) which accounts for the accelerated metabolism of prednisolone and a host of other drugs. Rifampicin also induces transporter proteins such as P-glycoprotein which, for example, can decrease absorption of drugs that are ejected from intestinal cells via this efflux pump (eg, digoxin).
Aminophylline, on the other hand, is a cytochrome P450 substrate, notably metabolised by CYP1A2. Drugs that inhibit the metabolism of aminophylline or theophylline should be avoided, to prevent toxic levels of theophylline. However, where this is not possible (where concomitant use of ciprofloxacin is indicated, for example) pharmacists and prescribers should be alert for the possibility of increased theophylline levels and take appropriate precautions, such as adjusting doses and warning patients of signs of toxicity.
Pharmacists can also support use of reserve courses of antibiotics at home in selected individuals with self-management plans, and ensure patients receive pneumococcal and influenza vaccinations.
Case comment: Anna Murphy, consultant respiratory pharmacist
Bronchiectasis is an important respiratory disease often overlooked in CPD — respiratory medicine is not just asthma and chronic obstructive pulmonary disease! A 1950s study suggested a prevalence of 100 per 100,000 but this was before modern diagnostic techniques such as high-resolution computed tomography (HRCT), which indicate that up to 30 per cent of patients diagnosed with bronchitis or COPD by GPs show evidence of pathological changes seen in bronchiectasis. So in a GP practice of 2,500 patients it is expected that one or two patients will be diagnosed with bronchiectasis.
This case report describes bronchiectasis in a patient with an underlying diagnosis of sarcoidosis and non-tuberculous mycobacterial (NTM) infection, and who requires a lung transplant. However, not all cases of bronchiectasis are as complex as this. The prevalence of NTM infections in bronchiectasis is unknown. Patients in my hospital are screened once a year for NTM infection.
This case illustrates a number of important medicines management points. One thing to consider in managing bronchiectasis is that, compared with disorders such as asthma, evidence for the safety and efficacy of treatments is scarce. The goals of therapy are to improve symptoms, reduce complications, control exacerbations and reduce morbidity and mortality. Antibiotics have been the mainstay of treatment for more than 40 years. It is an important role for pharmacists to ensure that patients are prescribed the appropriate antibiotic therapy. Patients may also need support to self-administer their antibiotics (especially nebulised or intravenous) at home.
The rationale of anti-inflammatory therapy (eg, inhaled corticosteroids) is to modify the inflammatory response caused by micro-organisms associated with bronchiectasis, reducing tissue damage. Although evidence suggests some benefit from the use of these medicines, findings are not universally definitive.
In this case azithromycin is being prescribed to manage the NTM, but there is an increasing trend of azithromycin being prescribed for prophylaxis in patients with bronchiectasis. Azithromycin has known anti-inflammatory as well as antimicrobial properties. In non-CF patients, 250mg three times a week has been shown, in a small study, to decrease exacerbations and improve lung function, exacerbation frequency and sputum test results. However a significant number of patients (11 per cent) discontinued medication because of abdominal side effects and rash.6 The benefits of macrolides in non-CF bronchiectasis await confirmation in larger trials.
Drugs to assist sputum clearance are currently under investigation. In non-randomised studies, mannitol improved airway clearance and quality of life in patients with non-cystic fibrosis bronchiectasis. A large randomised controlled trial has just been completed.
Finally, do not forget that pharmacists can encourage bronchiectasis patients to stop smoking (if applicable), improve their nutritional status and to exercise. They should also ensure that patients can demonstrate a good technique with any handheld inhaler device.
- Tsang KW, Bilton D. Clinical challenges in managing bronchiectasis. Respirology 2009;14;637–50.
- Woodhead M, Blasi F, Ewig S, Garau J, Huchon G, Ieven M, Ortqvist A, Schaberg T, Torres A, ven der Heijden G, Read R, Verheij TJM. Guidelines for the management of adult lower respiratory tract infections. Clinical Microbiology and Infection 2011;(17)s6:1–24.
- Pasteur MC, Bilton D and Hill AT, on behalf of the British Thoracic Society Bronchiectasis (non-CF) Guideline Group. British Thoracic Society guideline for non-CF bronchiectasis. Thorax 2010;(65):1– 58.
- Subcommittee of the Joint Tuberculosis Committee of the British Thoracic Society. Management of opportunist mycobacterial infections: Joint Tuberculosis Committee Guidelines 1999?. Thorax 2000;(55)3:210–8.
- Griffith DE, Aksamit T, Brown-Elliott BA et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. American Journal of Respiratory and Critical Care Medicine 2007;175:367–416.
- Anwar GA, Bourke SC, Afolabi G et al. Effects of long-term low-dose azithromycin in patients with non-CF bronchiectasis. Respiritory Medicine 2008;102:1494–6.
About the authors
Keith Thompson, MRPHarmS, is a specialist pharmacist — cystic fibrosis and respiratory medicine, Hasanin Khachi, MRPHarmS, is a highly specialist pharmacist — specialist medicine, and Danie Watson is a consultant respiratory physician.
Citation: The Pharmaceutical Journal URI: 11104445
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