2017 ERS Methacholine Challenge Standards

After a couple years of waiting for the new methacholine standards to be released “any day now”, they were finally published in this month’s issue of the European Respiratory Journal. The standard is an open access article and can be downloaded by anyone.

The length of time taken to develop the standard was acknowledged and although active ATS participation was withdrawn because the original timeline was not met, for the most part the original ATS participants continued with the task group and the standard has been officially endorsed by the ATS.

The biggest difference between the 1999 standards and those from 2017 is the change from PC20 (provocative concentration causing a 20% decline in FEV) to PD20 (the provocative dose causing a 20% decline in FEV1) as the primary endpoint and this alone will make a difference in how methacholine challenges are performed and calculated.

The 1999 standard included both tidal volume and dosimeter protocols. The dosimeter protocol consisted of 5 breaths to TLC. The 2017 standards state that a dosimeter may be used but that this is primarily to make counting breaths and calculating the cumulative dose easier and that inhalations to TLC are specifically contraindicated due to “the bronchodilating or bronchoprotective effect of a maximal inspiratory manoeuvre with a breathhold at TLC”.

Other differences include:

• The 1999 standard had both absolute and relative contraindications. There are only contraindications in the 2017 standard.
• Absolute contraindications in the 1999 standards included an FEV1 < 50% of predicted (or < 1.0 L, age group unspecified) and for the 2017 standard it is an FEV1 < 60% of predicted (or 1.5 L, adults) which were relative contraindications in 1999.

• The section on technician safety is essentially identical in both the 1999 and 2017 standards, but when discussing exhalation filters the 1999 standards included a diagram of typical nebulizer-filter configurations (page 311, bottom) and the 2017 standard does not.
• Although the 1999 standards imply the use of a mouthpiece with a nebulizer this is never explicitly stated. The 2017 standard mentions the use of a face mask but states that a mouthpiece is preferred.
• In the 1999 standard patients were asked to withhold shorting-acting bronchodilators (albuterol, etc) for 8 hours prior to testing. This has been changed to 6 hours in the 2017 standard.
• In the 1999 standard patients were asked to withhold ipratropium (Atrovent) for 24 hours prior to testing. This has been changed to 12 hours in the 2017 standard.
• In the 1999 standard patients were asked to withhold long acting bronchodilators (salmeterol) for 48 hours prior to testing. This has been changed to 36 hours in the 2017 standard.
• The 2017 standard asks patients to withhold ultra-long acting beta agonists (indacterol, vilanterol, olodaterol) for 48 hours prior to testing. These medications did not exist in 1999.
• The 1999 standard asked patients to withhold cromones (nedocromil, cromolyn sodium) and leukotriene modifiers anywhere from 24 to 72 hours before testing. The 2017 standards state that it is not necessary to withhold these medications.
• The 1999 standard recommended that coffee, tea, cola drinks, chocolate be withheld the day of testing. The 2017 standard states “Normal dietary servings of caffeine and caffeine-related products (e.g. chocolate) have no effect of clinical significance…”.
• The 1999 standard stated that antihistamines (specifically hydroxazine and cetirizine) needed to be withheld 3 days ahead of testing. The 2017 standard states that “Antihistamines do not effect methacholine response.”
• The 1999 standard asked that patients “refrain from smoking for a few hours before
• testing.” The 2017 standards ask that subjects should refrain from drinking alcohol 4 hours before testing (not mentioned in the 1999 standard) and smoking 1 hour before testing.
• The 2017 standard states “Influenza vaccination, the menstrual cycle and oral contraceptives do not significantly affect airway responsiveness”. These topics were not discussed in the 1999 standard.
• Both the 1999 and 2017 standards included both 2-fold and 4-fold dilution protocols. In the 1999 standard the 2 fold dilutions were to be used with the 2-minute tidal breathing technique and the 4 fold dilutions with the dosimeter protocol. The 2017 standard indicates that the 2 fold dilution protocol is more useful in research and probably too time consuming for clinical testing.
• In the 1999 standard the 4-fold dilution protocol stopped at 0.0625 mg/ml (5 concentration steps). The 2017 4-fold dilution protocol stops at 0.015625 mg/ml (6 concentration steps).
• In the 1999 standard performing the first challenge inhalation with the diluent alone was “optional”. In the 2017 standard it is “recommended, particularly if this is the first challenge test for the patient, and to ensure there is no excessive AHR” (i.e. Airway Hyper Responsiveness).
• The 1999 standard primarily specified the use of the English Wright nebulizer for the 2-minute tidal breathing protocol and the Devilbiss 646 nebulizer for the dosimeter protocol but did note that any nebulizer with a particle mass median diameter (MMD) between 1μm and 3μm was acceptable. The 2017 standard notes that these nebulizers are no longer readily available and instead recommends that any nebulizer whose particle size distribution (although it’s unclear whether this is the same as the MMD) is ≤ 5μm can be used.
• In the 1999 standard nebulizer output was measured by changes in weight over time (page 315, bottom of column 2). The 2017 standard indicates that this approach is inaccurate because “most of the weight loss is from evaporation rather than the output of methacholine” and recommends that nebulizer output should be “measured by collection on a filter” and provided by the device manufacturer.
• The 1999 standard stated the particle size distribution for the Wright nebulizer (although interestingly not for the Devilbiss) but does not say how this was determined. The 2017 standard mentions that particle size can be measured either by “laser diffraction or inertial impaction techniques” but since this technology is out of the reach of most (if not all) PFT labs this also implies that it is the responsibility of the nebulizer manufacturer to provide this information.
• The 1999 standard suggested that the tidal breathing method should be performed for 2 minutes. The 2017 standard states that with high-output nebulizers this period can and should be shortened. In particular, it notes that for each concentration level of methacholine there is actually a specific dose target (table 4, top of page 7) and attaining this target will depend on both the nebulizer output and the subject’s cumulative inhalation time.
• In the 1999 standard, if the subject’s FEV1 decreased by ≤ 20% then albuterol was to be administered and after a 10 minute wait, spirometry was performed again. In the 2017 standard it is a 5-10 minute wait.
• The 1999 standard included the method for calculating PC20 using logarithmic interpolation (page 318). PD20 is mentioned only once and that is in the sentence “…PC20 was selected as the outcome variable because it is simple to calculate and avoids the complicated and controversial aspects of estimating a provocative dose PD20.” (last sentence, section J, page 318).
• Although the 2017 standard mentions PC20 frequently it does not indicate how PC20 should be calculated. The methods for calculating PD20 by logarithmic interpolation are included in Appendix E however the numerical values used will depend on the actual nebulizer output, length of testing, the use of dosimeter vs tidal breathing and assumptions about Ti/Ttot.
• The 1999 standard categorized the response to methacholine based on PC20 alone. The 2017 standard categorizes response primarily with the PD20 but in table 6 (page 14) includes both PC20 and PD20. In addition the 1999 standard had 4 response categories (Normal bronchial responsiveness, Borderline BHR, Mild BHR (positive test), Moderate to severe BHR). The 2017 standard has 5 categories (Normal, Borderline AHR, Mild AHR, Moderate AHR, Marked AHR).
• Interestingly, both the 1999 (figure 3, page 318) and 2017 (figure 2, page 14) standards used exactly the same graph to illustrate the pre- and post-test probability of asthma but labeled it using PC20 in the 1999 standard and PD20 in the 2017 standard.
• The 1999 standard included an FEV1 quality scoring system (page 317, section I, column 1) based on acceptability and repeatability. This is not present in the 2017 standard.
• The 1999 standard discusses the use of airway resistance and impulse oscillometry as alternatives to FEV1 but suggests that these “should be used primarily in patients who cannot perform acceptable spirometry maneuvers”. The 2017 standard raises this issue as well but states that there “is substantially less supporting research and standardisation; hence, these methods are beyond the scope of these guidelines.”

♦ ♦ ♦ ♦

Overall, the number of changes from the 1999 standard are small and for this reason it is hard to understand why the process of developing the 2017 standard took as long as it did. Even so, the update is welcome and will help clarify a number of ongoing questions and issues surrounding methacholine challenge testing.

As already noted the biggest change is the use of PD20 instead of PC20. I have some reservations about this, partly because even though the scientific evidence in favor of this is reasonably clear it has actually been studied relatively few times (interestingly the decision to use PD20 appears to be based on a single research study [Drotar DE et al] and just as much on the fact that it makes it easier to compare results from different nebulizers and inhalation protocols).

In addition, the effect that body (and lung) size has on PD20 does not appear to have ever been studied. It would seem to me that even though the calculated PD20 for a 160 cm, 55 kg female and a 185 cm 100 kg male might well be the same, the larger individual has more airway surface area and the amount of methacholine per square centimeter (or however you want to measure it) is less than it is for the smaller individual.

I was also disappointed in the appendices (D and E) concerning the calculation of PD20 and would have preferred to see a more comprehensive algorithm taking a hypothetical nebulizer’s output and showing the steps necessary to calculate the inhaled dose and PD20. It may not be rocket science but being more explicit would have been helpful particularly given that the emphasis on PD20 is new.

In addition, the need to calculate the inhaled dose means that we somehow have to measure inspiratory time and respiratory rate during methacholine challenges. There is no easy way to measure inspiratory time and for this reason most everybody will default to a Ti/Tot of 0.40, since that is what the 2017 standard mentions.

The authors note that PD20 is dominated by the last delivered dose and that in fact a PD20 calculated using only the final dose is as accurate as using the dose accumulated from all prior concentration levels. The 2017 standard approach towards calculating PD20 is actually a logarithmic interpolation using only the last two doses (ignoring all previous concentration levels) which probably doesn’t affect results overall but does call into question exactly what the PD20 is.

Finally, despite measuring nebulizer particle size and output, and estimating the total delivered dose, we have to be honest with ourselves and realize that we have no idea how much methacholine is actually deposited on the airways, nor do we know which airways it is being deposited on. This means there will always be some uncertainty about interpreting results regardless of whether we are using PC20 or PD20.

I do however I applaud the movement away from the Wright and Devilbiss nebulizers. When brand new the output characteristics of these nubulizer were reasonably well known, but they are both re-useable devices and after several cleanings who can say what their output really is?

I also applaud the demise of the 5-breath dosimeter protocol. It, and in particular the calculation of a PD20 using the nebulous dose units (i.e. cumulative concentration x breaths), always seemed like pseudo-science to me.

Less clear to me however, is how easy it’s going to be to find the output characteristics for disposable nebulizers. As important as it may be I’ve never seen the particle size distribution of a nebulizer included in any sales literature. Hopefully this information is on file somewhere and now that it is a requirement in the 2017 standards it may be more forthcoming.

Anybody who performs methacholine challenges needs to read the new standards and to revise their procedures accordingly. At the same time though, we should take a moment and reflect on what it is we’re really trying to measure with a methacholine challenge. A number of years ago the medical director I had at that time said that internists and general practitioners ordered methacholine challenge tests to rule-in asthma and that pulmonary doctors ordered them to rule asthma out.

This difference in attitudes can be seen to some extent in the two standards. In 1999 the standard stated that “the most common clinical indication for MCT is to evaluate the likelihood of asthma in patients in whom the diagnosis is suggested by current symptoms but is not obvious.”. The last paragraph of the 2017 standard however states that “In summary, the major value of direct airway responsiveness challenge is to exclude a diagnosis of current asthma. Positive challenges are consistent with but not entirely diagnostic of asthma and must be interpreted in conjunction with the presence of other features of asthma or other respiratory diseases.”

So, update your procedures but keep in mind the limitations of the test and that knowing why you’re performing it shapes the answers it gives.

References:

Coates AL, Wanger J, Cockcroft DW et al. ERS technical standard on bronchial challenge testing: general considerations and performance of methacholine challenge tests. Eur Respir J 2017; 49: 1601526

Drotar DE, Davis BE, Cockcroft DW. Dose versus concentration of methacoline. Ann Allergy 1999; 83: 229-230.

Guidelines for methacholine and exercise challenge testing – 1999. Am J Respir Crit Care Med 2000; 161: 309-329