Fractional exhaled nitric oxide and its correlation with bioptic results in chronic cough patients

Summary

Background.
Chronic nonproductive cough in nonsmokers with negative thoracic X-ray and normal spirometry is frequently encountered problem in the out-patient departments of specialists both pneumologists and allergologists. A lot of those patients present with already ongoing treatment with inhaled steroids. This work attempted to find valid markers of inflammation in our group of patients.

Methods and results :
ICS naive nonsmokers with negative X-ray of the chest, ACE-inhibitors non-users with no signs of UACS have been examined by bronchoscopy and FENO. Combination of these two methods aimed to confirm or exclude presence of bronchial inflammation. Recommendation for treatment with ICS can be more valid based on positive results. Very small number of patients with eosinophilic type of bronchial inflammation on biopsy (3 from total no.48) was found. In the group of those 3 patients with possitive finding of eosinophilia in mucosa – regarding changes there were also high values of FENO whereas in all other „allergy negative“ patients the FENO values were low.

Conclusion:
There was low incidence of eosinophilic inflammation in our group of chronic cough patients. Bronchoscopy and FENO were in good agreement in ruling out or in confirmation of eosinophilic inflammation. FENO appears to be good discriminator for ICS treatment decision in our group of patiens.

Key words:
chronic cough patients, FENO, bronchoscopy.

Chronic nonproductive cough in nonsmokers with negative chest X-ray and normal spirometry is frequently encountered problem in the out-patient departments of specialists both pneumologists and allergologists (1,2)

Precise and early diagnostics is a mainstem of succesful treatment in this patient population. This is however usually an uneasy problem. Not always it is possible to carry on all sensible diagnostic procedures. Due to different algorithms the patient might be the subject of very intense diagnostic program including pH metry and bronchoscopy which might lead to the refusal or decrease of patient compliance. Further frequent fact which complicates the diagnostic process is the concurrence of several causes of chronic cough in one patient.(3)

Three most often seen causative states are – problems in the nasopharynx and dorsal ethmoidal sinuses (UACS)- formerly postnasal drip syndrome, gastroesophagal reflux and asthmatic equivalent or cough variant asthma.(1,4,5,28). It is vital to exclude the side effect of ACE inhibitor during medical history taking . This is not always done in the office of primary physician.(6). We can also conclude that the patient has got chronic bronchitis if there is an expectoration of the phlegm 3 months in row for 2 following years. Detailed review of the possible causes of chronic cough (the cough lasting more than 8 weeks) is out of the scope of this article.

Many patients come into the offices of specialists with polypragmatic treatment or already on the medication by inhaled steroids. Such a medication is not always sufficiently reasonable. This treatment approach is often the results of oversimplifying of the treatment accompanied by the common knowledge of minimal or zero risk resulting from such inhalation treatment. We have raised the question in our work if there are some signs of bronchial inflammation on pathologic assessment of the mucosa in the subset of randomly presented patients. Second question was if evaluation of FENO will be equally reliable as bronchoscopy in the assessment of (eosinofilic) inflammation of the bronchial airways. We considered bronchoscopy as standard procedure in this setting. We gave priority to FENO from the spectrum of existing exhaled markers due to its standardization (ATS). We have started from the premise confirmed by several studies that FENO is being a good marker of eosinophilic bronchial inflammation in steroid naïve (but not steroid treated) patients (7). There are reports as well illustrating that values of FENO in asthmatic patients correlate well with the activity of the disease. (8). FENO also correlates well with the findings in bronchial biopsies (9,10)

The use of exhaled nitric oxide for the diagnostic purposes originated in Karolinska Institute (Sweden) introduced by two independent teams. Gustafson in 1991 was the first who described and determined NO in the exhaled breath ad secondly Alving in 1993 determined practical correlation between FENO elevation and asthma severity in children population.(11,12)

It is impossible to consider the diagnosis of asthma and FENO congruent. It is however well possible to parallel asthma with eosinophilic inflammation in nine from ten patients (90% of asthma cased are accompanied by eosinophilic inflammation of the airways).

Exhaled nitric oxide is currently standardized in the areas of both sampling and measurement (13). One parameter cannot however describe all the complexity of the inflammatory reaction and it is why we have to interpret it with the knowledge of its limited diagnostic value. It is why some authors choose the denomination – prototype of non-invasive marker (14). It is impossible to overestimate the representative value of the FENO for such highly variable and heterogenic disease as asthma undoubtedly is. Proves of the FENO measurement significance are evident (15). There are many original articles describing this problems in every possible way.(14,16,17,18,19,20,21,22,23).

Originally FDA has permitted FENO measurement for the monitoring of the disease and treatment effect evaluation. Recently however there are many information supporting its use for diagnostic purposes.(24,25,26,27).

Combination of bronchoscopy with FENO measurement is not usually able to set up a clear diagnosis but it can prove or negate the inflammation in the bronchial mucosa by two independent means. By such method it is possible to express clear position towards local corticosteroid treatment.

From the everyday praxis point of view the presence of eosinophilic inflammation in the mucosa occurring in the chronic cough patients with negative X-ray of the chest and spirometric values is crucial and important factor influencing the therapeutic choice. (12,28).

Set of patients, methods

The aim of the study was to verify the presence of the signs of inflammation in the set of our patients by two independent methods (combination of invasive- bronchoscopy and noninvasive- FENO) and by that mean obtain the information about the proportion of the patients which would profit from anti-inflammatory therapy with local corticosteroids. The evalulated parameter was also agreement /disagreement of the histological/FENO examinations in the diagnosis of allergic inflammation of the airways. We took bronchoscopic finding as a golden standard from which the specificity and sensitivity of the FENO measurements were derived. Our further aim was to confirm our presumption that the amount of randomly examined patients with chronic cough with the proof of bronchial eosinophilic inflammation will be very small. This would also suggest that the proportion of the patients that would be indicated for the treatment with ICS would be low.

Inclusion criteria:

Included patients had been suffering from non-productive cough for more than 8 weeks. They were non-smokers with negative x-ray of the chest and normal spirometric values, nonusers of ACEi and no clinical signs of UACS (upper airway cough syndrome)- headache, rhinorhoea, postnasal dripping, nasal obstruction, mucosal oedema, increased tonsils and visible phlegm in the pharynx. They were also free of GER symptoms- including heartburns , singultus, regurgitation, halitosis, acidity feeling in the mouths, chronic nausea. None of the probands have been treated by per oral or inhaled corticosteroids (ICS). Patients with pre-existing pulmonary or bronchial disorder have been excluded.

Permitted medications were: symptomatic treatment by antitussic medications, expectorants, and antihistamines. No other anti-inflammatory therapy (antileukotrienes or cromones) has been approved.

Patients have not been examined by ENT specialist or pH metry until the examination by bronchoscopy + FENO unless there has been strong clinical suspicion on such a problem. In such a case however they have been excluded from the study.

Overall 56 patients (34 female and 22 men mean age 42 years) came to the office of allergologist of pulmonary specialist NNH with chronic cough lasting from 8 weeks to 7 years. They all have been subjected to basic examination (history, physical examination, X-ray of the chest and spirometry) and all of them had been examined by FENO followed by bronchoscopy including mucosal biopsy for histological examination. For the FENO assessment the analyzer NIOX MINO® (Aerocrine, Sweden) has been used measuring exhaled nitric oxide online in real time based of electrochemical detection.

Macroscopic appearance of the mucosa has influenced the choice of the place of biopsy (we have used modern diagnostic method as narrow ban imaging and autofluorescent bronchoscopy) . Relevant sample from bronchoscopic examination sufficient for pathology evaluation was obtained in 48 patients. Other patients have been excluded from the study.

Histology evaluation of eosinophilic infiltration was based on the description of eosinophilic mucosal inflammation and enlargement of basal membrane.

Results

Histologic evaluation: there were 91 biopsies taken from the overall 56 patients. In 48 patients (72 biopsies) materials were sufficient for the histologic evaluation . All these patients have also undergone the examination by FENO. There have been no other parameters evaluated than eosinophilic infiltration and thickness of the basal membrane as a marker of remodelation (cutoff 8 um). Concourse of both findings has been taken as indicator of eosinophilic inflammation.

Positive finding is such way has been found in tree patients (6,8%). In none of the samples there has been eosinophilic infiltration without enlargement of the basal membrane and vice versa. In our group of patients bronchoscopic biopsy hence has been considered as golden standard for diagnosis of eosinophilic inflammation towards which there have been calculations of sensitivity specificity PPV and NPV of FENO in the exhaled air. FENO: positive findings (cutoff 25 ppb) in 4 patients from 48 evaluated (8,3%).

Discussion

The dilemma of the chronic cough is a significant one. To our best knowledge no study has correlated histology finding from bronchial biopsies with FENO levels in the group of patients with chronic cough. It has been however proven (9) that the FENO levels correlates with mucosal eosinophilic inflammation in endobronchial biopsies.

Different chapter can also be so called postinfectious (postviral) cough which can be often therapeutically difficult. (29)

In the situation of negative histology finding in the patients with chronic nonproductive cough in the association with the signs of recent respiratory viral disease the inhalation of necrodomil sodium can sometimes show surprising therapeutic effect.(30). Positive effect of this treatment is probably connected with calming down of the exposed nerve endings in the mucosal surface.

Serological methods are rather unreliable for the diagnosis of Chlamydia and Mycoplasma disease. We only prove the antibodies not the agent itself and hence its interpretation might be quite difficult. There is also some degree of sensoric hyperreactivity after viral respiratory tract infections.

The utility of bronchoscopic examination in the diagnosis of chronic cough is without doubts in the presence of the chest X-ray pathology. Data from the literature varies significantly. Optical examination of the bronchial tree itself gives surprising alternative diagnosis in only about 4% of patients with chronic nonproductive irritative cough. Some authors advocate the use of bronchoscopy in this settings (31) some see its diagnostic contribution as minimal (32). No study to our knowledge has compared histological findings with the FENO values it the chronic cough patients yet. It has however proven (9) that value of FENO correlates well with mucosal eosinophilic inflammation in endobronchial biopsies.

We have also to consider possible difference of chronic nonproductive cough in adult and pediatric patients (33).

We are well aware that there can be also another type of inflammation than eosinophilic in asthma, especially neutrophilic. We have not found neutrophilic infiltration in any of our biopsy samples and there is also no place of inhalation corticosteroids in the treatment of neutrophil based asthma.

Conclusion:

Only very small number of nonsmoking patients coming to specialized office with chronic nonproductive cough and normal spirometric values have got eosinophilic infiltration of the mucosa with enlargement of the basal membrane from the bronchobiopsy (6,8%). Consequently the anticipation that such patients would profit from the chronic local steroid therapy does not seem to be correct. From this perspective the patient should me more often examined to exclude UACS and GER at the expense of ad hoc steroid treatment. Positive correlation of bronchobiopsy and FENO (cutoff 25 ppb) for the diagnosis of eosinophilic inflammation with the high suspicion of asthma is highly significant. FENO in our set of patients has got formally high predictive value for the diagnosis of eosinophilic asthma(PPV 75%, NPV 100%). We are however well aware that it is difficult to draw firm conclusions from such a small set of probands.

Abbr:

• ATS American Thoracic Society
• ACE inhibitors inhibitors of the angiotensin converting enzyme
• FENO fractionated expired nitric oxide
• GER gastroesophageal reflux
• PNDS post nasal drip
• PPV positive predictive value
• UACS upper airway cough syndrom
• NNH Nemocnice Na Homolce
• NPV negative predictive value
• IKS inhalation corticosteroids
• ppb parts per billion
• PPV positive predictive value
• TP true positivity
• FP false positivity
• SD standard deviation
• TN true negativity