We also highlight the simple blood test biomarker that could help more respiratory patients start off with the right label and, most importantly, the right treatment.
Is that an asthmatic wheeze or a smoker’s cough? Is it a ‘weak lung’ from a childhood disease or ‘twitchy’ lungs due to asthma?
Respiratory physician Jeff Garrett believes fixating on fitting respiratory patients into neat diagnostic boxes for asthma, chronic obstructive pulmonary disease (COPD) or bronchiectasis may not be as helpful as targeting the right treatment.
Taking a patient’s history can reveal whether the patient wheezes, coughs up phlegm, has ever smoked or gets breathless upon exercise. Testing lung function with a peak flow meter can tell you more – and a spirometry test even more again. Garrett believes that spirometry should be routinely available, but only half of those in general practice in New Zealand have access to it.
Bringing all the information together can give you a likely diagnosis and an indication of where the patient sits on the spectrum.
“But you can still end up with substantial overlap,” says Garrett, who is also clinical director of medicine at Middlemore Hospital and an asthma researcher. An example can be someone in their 60s who has experienced a lifetime of asthma and, over time, has developed fixed airways obstruction (i.e. COPD) due to ‘remodelling’of their airways.
“So which box do you put them in now – the COPD box or the asthma box?” he says.
Furthermore, about 20 per cent of people with smoking-related COPD will end up with bronchiectasis because of recurrent infections, and as many as 10–15 per cent of more severe asthmatics will develop bronchiectasis due to remodelling of their airways, resulting first in COPD, then in recurrent infections and bronchiectasis.
“So the diagnostic labels are pretty crude ways of classifying patients, though they still have their uses,” says Garrett.
Steroids fighting or feeding inflammation?
The answer, Garret believes, is to spend less time trying to fit an asthma or COPD label onto patients and more time regarding people as having an inflammatory airways disorder.
“You need to think about such patients as having an airways disorder that is associated with inflammation – reddening and swelling.”
He believes the best way to identify what is causing the inflammation – and therefore which treatment is best – is to use a biomarker.
Canadian researchers in the 1990s developed a test that revealed the different types of inflammatory cells in patients’ airways. They developed an induced sputum test, where patients are given a very salty solution (hypertonic saline) by nebuliser that causes them to cough up sputum, which is tested to evaluate whether eosinophils, neutrophils or both cells are present. (Eosinophil levels rise in response to allergens and neutrophils in response to bacterial or viral infection or as a result of exposure to an irritant.)
Subsequent researchers, including Garrett, have found that when the sputum of asthmatics, or suspected asthmatics, is tested, around 40 per cent are found to contain eosinophils, 20 per cent neutrophils, 5–10 percent have both and about 30 per cent have few, if any, inflammatory cells (because they either have well-controlled asthma or don’t have asthma at all).
Further research has confirmed that the most helpful treatment for a respiratory patient with elevated eosinophil levels is inhaled steroids at a dose required to return eosinophils back into the normal range.
“Eosinophils dislike steroids and if used correctly and if targeted to the right part of the airway will usually lead to satisfactory control,” says Garrett.
However, if neutrophils are present instead (neutrophils are associated with COPD but also found in the airways of some people labelled as asthmatic) then Garrett says inhaled or oral steroids will make absolutely no difference. “If anything, they may make the situation somewhat worse.”
Garrett says the best treatment for the neutrophils group is to identify what is irritating the airways or to treat the bug or the condition that is causing the neutrophilic inflammation.
“These people tend to require antibiotics,” says Garrett. “If you continue to give inhaled or oral steroids to these people [with neutrophilic inflammation], you actually reduce the effectiveness of the antibiotic.
“Because the bugs that are down there love steroids, they will proliferate, so the worst thing you can do is to give steroids to somebody with neutrophilic inflammation.”
This group includes the 20 per cent of people labelled with asthma who don’t have eosinophilic inflammation and most COPD patients.
Too many misprescribed steroids
Research has found that the vast majority of COPD patients don’t have eosinophil cells in their airways. In fact, it is estimated that only about 10–15 per cent of people labelled as COPD have lung inflammation due to eosinophils.
But Garrett says that current audits suggest that as many as 70 per cent of COPD labelled patients in New Zealand are currently being prescribed inhaled steroids. “For two-thirds of those people, they are not getting any benefit from steroids and potentially the steroids are doing harm.
“The harm is that recent research has shown you can increase their risk of episodes of pneumonia, particularly if you give them high doses of steroids – for example, 500mcg Flixotide a day or doses of Pulmicort greater than 800mcg a day.”
COPD has been diagnosed in at least 200,000 New Zealanders (though it is thought there are another 300,000 who are undiagnosed). That is potentially a lot of money being invested in prescribing steroid inhalers that may be causing more harm than good. Garrett has estimated that up to $14 million a year is wasted on prescribing inhaled or oral steroids to patients who gain no benefit from them. This includes the 20 per cent or so of people labelled as having asthma, but who actually have small airways damage or bronchiectasis.
Simple blood test may be helpful
The gold standard for detecting whether there is airways inflammation, and whether steroids are the answer, remains the induced sputum test.
But Garrett says the test is largely limited to research laboratories (it is available privately in Auckland) and has not become standard clinical practice worldwide as it is time-consuming and reasonably costly. Consequently, researchers have sought an easier but less accurate test. A lot of time and effort was spent developing an expired nitric oxide test (simple breath test), which is reasonably good at identifying patients with eosinophilic inflammation, but not those with neutrophilic inflammation. The expired nitric oxide test is also artificially influenced by other factors, including smoking, and whether patients are on inhaled steroids at the time.
Research undertaken at Middlemore Hospital (and since validated by four other groups internationally) has revealed that the best surrogate for the induced sputum test – for predicting eosinophils in the airways – is a straightforward blood test using a white blood cell count differential.
Garrett’s team found that an eosinophil count of greater than 0.35 indicates an 80 per cent likelihood that eosinophils are present in the airways. So if a patient presents with bronchitis and blood test results show an eosinophil count of, say, 0.45, then a GP or NP could reasonably confidently prescribe inhaled or oral steroids.
Conversely, a Belgian group has found that if the eosinophil count is less than 0.25 there is a 76 per cent likelihood that neutrophils are present instead. In this situation steroids are unlikely to help and other treatment options like antibiotics and bronchodilators (non-steroidal inhalers that open the airways) should be considered.
Garrett says the simple blood test should be used by GPs and NPs whenever a respiratory patient presents with an attack of bronchitis. An English group used a simple cut off of 0.3 eosinophil levels to decide whether to use oral steroids for exacerbations of bronchitis in patients with COPD. They found if a patient with an eosinophil level of less than 0.3 was given Prednisone then the outcome was inferior to when antibiotics alone were used.
So rather than the knee-jerk reaction of sending a patient away with antibiotics and a course of the oral steroid Prednisone – that may hinder rather than help recovery – the health practitioner can use a straightforward blood count to target which patients will or won’t benefit from the addition of steroids.
Garrett says he sees plenty of patients admitted to Middlemore with bronchitis attacks who have been misprescribed oral steroids when they have low serum eosinophil counts.
“I go on my ward rounds stopping steroids left, right and centre for COPD patients with low eosinophil counts and have never seen anyone deteriorate as a consequence.”
Better diagnosis and management is key
The blood test can also be used by GPs and NPs when a patient first presents with asthma-like symptoms to better determine whether they have asthma or not.
“If you just take a patient history, measure their lung function and consider the blood test biomarker you will get it [asthma diagnosis]more right, more often,” says Garrett.
“Certainly if you are experienced at using blood tests then you get it right in between 80–90 per cent of cases when tested against the gold standard of an induced sputum test. We tested our respiratory physicians’ and nurse specialists’ ability to predict the inflammatory cell present and they were similar in their accuracy. It was mainly the mixed inflammatory subtypes, not surprisingly, where clinicians have the greatest difficulty.
“At the moment a lot of doctors are doing it by the flip of a coin – with about 50–60 per cent accuracy in predicting which inflammatory cell is present in the airways.”
Garrett adds that while on the one hand New Zealand is overprescribing unnecessary steroids for COPD patients, on the other hand it is underutilising inhaled steroids for some asthma patients. “We are not maximising their effect to control the inflammation.”
He says it doesn’t make sense to keep giving people bronchodilators (short-acting or long-acting symptom relievers) if you haven’t first done your best to control the inflammation. And, in the case of asthma patients, that means controlling the eosinophil inflammation by using inhaled steroids at the appropriate dose and frequency.
As it is Garrett says many people regard their steroid inhaler as a ‘preventer’ rather than ‘controller’ and if their asthma worsens, and they get an asthma attack, they reach for their ‘reliever’ inhaler thinking the ‘preventer’ has failed. Whereas, he argues, if their blood eosinophil count has increased above 0.35 they should be escalating their inhaled steroid dose.
He recommends that patients with suboptimal control of asthma (i.e. those who despite using 500mcg of Flixotide or 800mcg of Pulmicort remain symptomatic and with impaired lung function) should have a blood count. If the eosinophil count is high (i.e. greater than 0.35 x 109/L) then they should either double their inhaled steroid dose or switch to the most efficacious inhaler QVAR MDI. (Garrett says QVAR deposits 60 per cent of medication to the airways and to all the airways, as opposed to the other inhalers, which deposit only 15–20 per cent to the airways and only to the first few generations.
Steroid inhaler adherence remains a major issue for asthma patients with Garrett’s research indicating that 80 per cent of people hospitalised with asthma attacks are poorly compliant and that around 50 per cent of asthmatics within the outpatient clinic are poorly compliant.
He says nursing has a key role in helping people improve adherence through the use of education and, potentially, through the support of devices such as Nexus6’s Smartinhaler (a wi-fi-based system developed in Auckland that has been shown to improve adherence by 50 per cent).
A further 25 per cent of people have poor inflammation control as a result of poor inhaler technique, which he says can be remedied by instruction from a nurse, use of a spacing device or transfer to QVAR, which overcomes a lot of the effects of a poor technique.
Diagnosing a respiratory condition – even with the help of blood test biomarkers – is still not an exact science.
But Garrett says adding the biomarker to the lung function data and the information gathered from a full patient history data helps in more accurately placing the patient on the diagnostic continuum. This allows more accurate assessment of what is causing inflammation in the airways and better targeting of treatment.
“If we use the tools available to us better and target treatment more effectively we would have 90 per cent of asthmatic patients optimally controlled (as opposed to the 50 per cent estimated from telephone surveys) and at a lower cost,” believes Garrett. “And we would have a greater proportion of COPD patients on appropriate long-acting bronchodilators and far fewer on inhaled steroids.”
That may mean no steroids for some, more steroids for others and better-targeted treatment for all. And maybe more people able to breathe a big sigh of relief.
Key points when assessing and managing patients with airway disorders
- What is the underlying diagnosis in this patient – COPD or asthma? (History/spirometry.)
- What is the key cause of their airways inflammation? (Blood count or FeNO or induced sputum if available.)
- If asthmatic, what impact does their asthma have on the patient? What are their current symptoms? What is their control level? (The Asthma Control Test www.asthmacontrol.co.nz is a validated and effective tool for assessing asthma control.)
- Are they on the right medication? (I.e. will steroids help or hinder them?)
- If on inhaled steroids, are they on the right medication, the right dose and the correct frequency?
- Are they using the right inhaler technique?
- Do they have the right inhaler for their needs?
- Are they compliant with the use of their inhalers? (Checking can be done electronically using TestSafe to see how many inhaled steroids have been dispensed in previous year.)
- Are they suitable candidates for a pulmonary rehabilitation programme (offered by a multidisciplinary team including dieticians, physiotherapists, nurses and psychologists)?
Eosinophils are the inflammatory white cells that rise in response to allergens or after certain viral infections. They are found in higher levels in sputum or blood when airways inflammation is due to an allergic response or after some viral infections.
BIOMARKER: A blood test that shows eosinophil levels greater than 0.35 indicates an 80 per cent chance that airways inflammation is eosinophilic and steroids are the treatment of choice.
Neutrophils are the most common inflammatory white blood cell and their main role is in fighting against bacterial or fungal infection, so neutrophil levels are elevated when inflamed lungs are fighting a bacterial infection. (Irritants and pollutants like tobacco smoke can also trigger neutrophilic inflammation, however, and are more strongly associated with COPD or with patients who have damaged their small airways.
BIOMARKER: If a blood test shows an eosinophil count of less than 0.25 then there is a 76 per cent likelihood that neutrophils are causing the inflammation, therefore inhaled or oral steroids should be avoided. The best treatment is to remove the cause of the irritation (i.e.stop smoking) and/or use antibiotics to combat the bacteria the neutrophils are fighting.
Chronic obstructive pulmonary disease* (COPD) is a term used to describe lung damage that makes breathing difficult, with tobacco smoking being the main cause in 70–80 per cent of cases. The two main types are emphysema and chronic bronchitis. COPD is the fourth most common cause of death in New Zealand after cancer, heart disease and stroke. It accounts for about 200,000 GP visits a year and more than 453,000 prescribed medications.
In New Zealand about one in four children and one in nine adults who have a cough or wheeze are diagnosed as having asthma*. (Garrett believes that childhood asthma is overdiagnosed and may be around half that rate). Asthma happens when airways become oversensitive and react to certain triggers by tightening up (bronchospasm), swelling (inflammation) and producing more mucus.
About 70–80 per cent of asthma in New Zealand is associated with allergies.
Bronchiectasis* is a condition caused by damaged airways, usually occurring in childhood and often leading to colonisation by pathogenic bacteria causing low grade inflammation, mucous production and repeated infections.