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The length of time taken to develop the standard was acknowledged and although active ATS participation was withdrawn because the original timeline was not met, for the most part the original ATS participants continued with the task group and the standard has been officially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.”
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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:
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
PFT Blog by Richard Johnston is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License
Hello Richard,
Thank you again for a great assessment of changes in ATS/ERS document changes! I have supported a pediatric pulmonary group at a major academic medical center for 26 years. During the first 5 years with the group I did approximately 5 methacholine challenges all ordered by the allergists on staff at the time. The requests dried up completely for the most part and I was also moved to a space with inadequate ventilation and prevented from doing them by epidemiology so I gave my Devilbiss nebulizers.to the adult PFT Lab who still does them semi frequently and mostly for allergists as well. As a result, I haven’t done one in the past 20 years.The prevailing opinion of my pediatric pulmonary group has been in line with the statement you cited that “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 in general most of the pediatric pulmonologists at my institution feel that MCT’s may be useful from a research perspective but they have no use for methacholine challenges for clinical diagnosis and treatment. As a result we only perform treadmill exercise provocations in the pediatric PFT Lab
.
We tried Aridol DPI mannitol challenges for a short period mostly because of allergy department pressure to provide pharmaceutical bronchial provocation, but as you probably know the company pulled out of the U.S. and I could not get any more kits. Additionally, the pediatric pulmonary group has also shown no interest in cold air provocation studies.
As I/we only perform exercise bronchial-provocations, do you know if any updates have been made to earlier exercise study recommendations or test standards?
Thank you,
Jim Norton
Jim –
Although the 1999 challenge standards included exercise, the update included only methacholine challenge. When discussing indirect challenges it did mention mannitol, eucapnic voluntary hyperventilation and exercise (page 3, paragraph 2 and last paragraph) but more or less excluded them from the current standard. So, no official updates and no idea if it’s even on anybody’s agenda.
Regards, Richard
Thank you Sir!
Thank you so much for this great explanation. It really helped me. I am currently trying to rewrite the new policy for our hospital and I am confused on some of the details. Are the new guidelines saying that with a breath actuated nebulizer we have them breathe the methacholine for one minute using tidal volume breathing (not deep breathing, regular breathing) then perform spirometry testing? Thank you for any direction you can provide me?
Jenny –
From the 2017 ERS methacholine standard (bottom page 9 through top, page 10):
“The prior recommendation of tidal breathing for 2 min was influenced by data showing better reproducibility with this time compared to 30 s of tidal breathing [64]. Using newer devices with higher rates of dose delivery than the English Wright nebuliser will require shorter nebulisation time or lower initial concentration or both. For example, in vitro data shows that one modern nebuliser would deliver the same amount of methacholine in 12 s as the English Wright did in 2 min, i.e. a 10-fold increase [9]. In vivo data exists for both 20 and 30 s using a breath-activated nebuliser [10, 11]. To reduce the variability of dose delivery based on the breathing pattern, the task force recommends a breathing time of at least 1 min.”
So yes, it would seem that a 1 minute tidal breathing period is being specified as an option.
I will admit to being very dissatisfied with the 2017 methacholine standards however. Many of the changes from the 1999 standards seem to be based on minimal evidence and in particular the switch to reporting PD20 rather than PC20 is based on a single pair of papers from the same authors. I’ve read the literature concerning methacholine challenges extensively and have to say that there is a lot of contradictory evidence out there. Although I consider methacholine challenges to be useful in selected cases, no matter how you perform them or how you calculate the results, they are not a precision tool.
Regards, Richard
I was disappointed that there were no directives regarding the use of other outcome measures (e.g.sGaw, IOS) to assess the response to MCT. We measure sGaw with every MCT and see plenty of patients who report identical symptoms that prompted the test coupled with significant drops in sGaw (as much as 70%) with little change in FEV1. This phenotype is believed to be due to dysanapsis. These tests are interpreted as positive for AHR. We will continue to use our dosimeter with the same sub-TLC inhalation strategy as described by Cockcroft many years ago. The deep inhalation is the villain, not the dosimeter.
Jeff –
My experience with RAW maneuvers in the plethysmograph are so-so at best, and usually see a real broad spread in values. What level of reproducibility do you look for in the pre-BD RAW/SGaw maneuvers and what amount of change do you consider to be significant? And does your box calculuate inspiratory and expiratory RAW and SGaw separately (my system doesn’t and averages the two)? If so, which do you use?
– Richard
Hi Richard,
Love the write up!
I’ll be bugging suppliers shortly for the information required to establish dosing protocols for our nebulizer that we currently employ.
I really wish they would have included a step by step procedure to determine the timing and dosing protocol for a sample nebulizer. Like you had mentioned all of the information is there, it would have just been nice to see an example since this aspect will be new to everyone.
Cheers
Hello Richard and fellow clinicians,
There is a lot to consider with administering methacholine aerosol during methacholine challenge testing (MCT). We can appreciate some factors are not well understood and there is little supportive publication to define all the issues and concerns. Any diagnostic test procedure is based on defined standards which are essential to the patient preparation, test procedure, results reported and the interpretation of that data. With any changes we have the responsibility to see our concerns addressed. If we use nebulizers which have different output characteristics we then need to verify that the results, and ultimately the patient outcome, are not affected by false positive or negative results.
We can no longer obtain the old nebulizers defined and validated under the ATS/ER 1999 standard for the tidal breathing method. There are some attempting to bring them to market, so we can remain hopeful a suitable device is available for direct substitution.
Have been using the “wright-type” nebulizer for the tidal-breathing MCT protocol for many years. It may be important to note, the “wright-type” nebulizer most recently purchasable isn’t the same device as the “English-wright” (manufactured in England, off market for many years). They have slightly different operational characteristics but both were part of the validation done leading up to the ATS/ERS 1999 standard.
The “challenge” is obtaining verification of nebulizer performance: output, particle size, evaporation, respirable fraction etc.
All modern nebulizers are manufactured for optimizing aerosol delivery, not for the controlled output (low) defined by the ATS/ERS 1999 standard (and 2001 AARC update). The output of modern nebulizers are significantly higher so adopting a device which can’t be verified to administer at the 0.13 ml/min output (at target particle size!) will result in the needed changes the 2017 MCT standard is hoping to address (shorter tidal breathing time, cumulative dose, PD20 instead of PC20).
I have not been successful in obtaining the necessary validation data from some manufacturers and am still working to obtain final confirmation from several regarding their nebulizer’s operational characteristics.
For the companies which have outlined their nebulizer output characteristics some may not have quoted the particle size across the output (output is different from the driving flow) we would like to use for testing. There are not regulations to define what and how the operational characteristics are to be identified and what specific equipment is required. We can only estimate output gravimetrically (weight – run nebulizer for 2 minutes – reweigh) which won’t verify particle size, deposition in the lungs, evaporation etc.
I am glad you mentioned the specialized equipment required to validate the operational characteristics, this is what we are currently missing and where proper validation data is required to move forward.
If we use a nebulizer with an output significantly higher aerosol delivery and we can’t accurately measure the inspired delivery (Ti/To, count breaths etc) then the new recommendations suggest that changes will be required to maintain equivalent dose delivery. The new reference ranges for interpreting response to methacholine is also significantly different.
More to come…
Best regards,
Tony
With the new 2 min continuous aerosolization vs 5 breath doses, are there increased concerned about therapist exposure to Methacholine? We are using NebuPent aerosol devices which include a filter on the exhalation limb. We do not perform these tests in a negative pressure room and at this time the recommendation is to keep the door closed during administration of the methacholine. Any input on safety issues?
Nancy –
The 2017 methacholine standard addressed technician safety pretty directly. From page 6 of the standard:
Precautions for technician/respiratory scientist safety during methacholine challenge testing
Measures should be taken to minimise technician exposure to methacholine aerosol, especially for those with asthma or a positive methacholine challenge [3]. The testing room must have adequate ventilation to provide at least two complete exchanges of air per hour. Other, optional methods to reduce methacholine exposures include using low resistance exhalation filters, a laboratory fume hood, supplemental local exhaust ventilation and/or a HEPA room air cleaner. The use of a mouthpiece so that exhaled methacholine can be directed onto a filter is preferable to the use of a face mask, where environmental contamination is inevitable (and pulmonary deposition will be less than with a mouthpiece [32]). Furthermore, if the subject comes off the nebuliser for any reason (e.g. to cough), any aerosol that continues to be produced directly enters the room. Use of a breath-actuated nebuliser will minimise environmental methacholine exposure since aerosol is produced only during inspiration. Such nebulisers produce an aerosol only once a certain inspiratory flow has been reached or, alternatively, a pulse of aerosol once inspiration is sensed. However, some environmental loss is always present unless a filter is placed on the expiratory limb [9]. Technicians/ respiratory scientists may also want to stand well away from the patient when methacholine is being nebulised, which can be a challenge if they are required to assist a coughing patient.
Not much I can add to that.
Regards, Richard
Thanks for the reference and excellent input.
I too have been wondering what the long term effects of the exposure to technicians, especially those with asthma. I am an asthmatic therapist who’s been performing these for many years (12) and have noticed a decline in my PFT’s. Is there any information on this?
Cyndi –
There are no formal studies of this, only anecdotal reports. There is a section of the ERS/ATS standards on methacholine that deals with reducing staff exposure and I hope that you and your lab are following these recommendations.
Regards, Richard
We use an dosimeter and our patients take 5 breaths from each dose. From the article it appears we can still use it as long as we use a nebulizer with particle size less than 5 um and not have the patient breath to TLC. Can anyone recommend a nebulizer that has this size output?
There is no mention of withholding beta-adrenergic blocking agents, is this still a concern?
Terry –
Apparently not and I’m not sure why there was a concern in the first place. Many contraindications have come into existence due to anecdotal information or supposed causal relationships that aren’t supported by any real evidence.
Regards, Richard
This new 2017 Methacholine guideline brings way more questions than it answers? With out a recommendation on which the nebulizer to use? and measurements of output they have? How could we ever compare a methacholine from different centers? –Or how do we compare studies after we change to the new protocol from a methacholine done from the 1999 protocols. If we don’t know what Nebulizer to use and/or how much output they have –how do we if the Methacholine is positive or negative? I totally understand the new guideline of not breathing to TLC during the Dosimeter methods. Dr. Cockcroff has done some very compelling studies pointing to the bronchial dilating affects of deep breaths. This makes sense. On the other hand, if different centers are using different nebulizers and different tidal breathing times? What does 1 minute or more, mean?? How are we ever going to standardize the test? Some centers use the wall air for their nebs. The regulator pressure affects the nebulizer output and particulate size and hence how much med is delivered? Is there anyone out there int he PFT Blog that has access to nebulizer output and could make a recommendation?
Ed –
At the moment I can’t help you with nebulizer outputs but I’ll share if I ever get that information.
I too have problems with the 2017 methacholine standards and in particular I disagree with the shift to PD20 as a method to normalize results between different nebulizers, institutions and dose protocols. Not that PC20 is perfect by any means, but in my opinion I think it reflects the underlying physiology better. The methacholine challenge test has always been a mess but despite that it still more or less works. There are always going to be individuals that obviously react; those that don’t obviously react; and those that are in a gray area no matter how you go about it.
Regards, Richard
Hello Ed,
I too hope for such questions to be addressed as we should not ignore the issues with MCT. We conduct all other PFT testing according to tight acceptability and repeatability standards, similar considerations need to be applied to MCT in order to represent consistency between devices and protocols.
The 2017 standard has certainly suggested several changes which need more in vitro and in vivo study and I welcome these to be addressed in future publications.
The MCT has always been an issue, as Richard stated. I hope that work to standardize our approach to testing and address any long standing questions will be completed and published. The 2017 standard publication is an update, it adds to the 1999 standard so we don’t ignore everything that was published in the earlier version.
Comparison of airways hyperresponsiveness between devices and protocols is not consistent so this could lead to misclassification of reactivity. This is published in several articles and referred to in the 2017 standard. Airway reactivity needs to be quantified accurately and we are to consider the aerosolized drug mass (delivered dose) administered per concentration stage. We need more data on specific nebulizers to verify they are appropriate for use with the MCT.
“1 minute or more” is intended to minimize variability in reactivity from shorter breathing intervals, previous publications demonstrated significant differences in the number of breaths with 20 and 30 second intervals. The recommendation is to avoid tidal breathing intervals of less than 1 full minute.
The 2017 technical standard update outlines their findings on what they consider to be the actual delivered dose (in mcg) of methacholine from the wright. This is the baseline comparison to use for alternative nebulizers and only one modern device is described in the 2017 update tested under similar conditions.
Since all modern nebulizers operate with greater efficiency (particle size, less evaporative loss) and at a greater rate (more drug mass delivered at respirable fraction) there will need to alterations in the delivered concentrations of methacholine. Manufacturer data does not provide methacholine drug mass data by assay as was outlined in the update. Independent testing is needed to document the drug delivery by assay with testing methods described in the standard update.
I am in the midst of comparison testing to document reactivity between our old and new devices, hope to have a working protocol validated soon which demonstrated dose equivalency.
If anyone has any comparison data to share or has other recommended devices I am very interested to hear from you.
Sincerely
Tony
Richard–
Thanks for the in depth discussion.
What happens if the PD20>400ug and you have a 20% or > drop in the FEV1? How should those results be interpreted??
Harlan R. Weinberg, MD
Dr. Weinberg –
Since this likely occurred at the very highest methacholine dose possible (16 mg/ml) I think this puts it in a gray area. The problem is that at these higher dosages there is some crossover from patients with normal airways so at best I think you can say is that it is suspicious for mild airway reactivity. I will say however, that most of the physicians I work with will go ahead and treat the patient as if they have reactive airways disease even when results are in the gray area.
Regards, Richard