The emphasis on asthma management in the past three decades has resolved around reducing airway inflammation; and the more recent, and likely future advancements, are largely targeted therapy of cells or cytokine activity blockade, thus reducing cellular activity [6]. Figure 1 is a simplified conceptualization of asthma pathophysiology. The intrinsically present AHR becomes inundated with a cellular constituency, largely eosinophilic, ultimately resulting in a chronic inflammatory state.

Figure 1.Triad elements of active asthma

Working top down, controlling inflammation with reduction of cellular presence and/or cell products (i.e. cytokines) has the potential to subtly influencing AHR; however, unless the intrinsic asthma state (condition) remits and never returns the native AHR persists.

The evidence that asthma symptoms recur when anti-inflammatory medications are stopped or reduced is well accepted. Asthma has to be gone or it’s not gone! Current 2019 GINA (Global Initiative for Asthma) recommends inhaled corticosteroids for all persistent adult and adolescent asthma; while adding a biological modifier as an option for more severe forms [7,8]. Obviously, controlling inflammation and reducing cellularity is critical for asthma symptom control.

In essence the presence of a long-acting bronchodilator as a co-component of an inhaled corticosteroid (ICS) has the benefit of a sympathomimetic opposition of intrinsic parasympathomimetic (AHR) tendencies; but in clinical practice it’s non-uncommon to find additional bronchodilation after short-acting bronchodilators, further delineating an active, albeit controlled asthmatic status. In essence, AHR is a “non-touchable” component of our proposed triad. Are there options?

Returning to the original truisms: methacholine responsiveness, an indirect measure of AHR, can be abrogated using an anti-cholinergic agent. In recent publications, long-acting anti-cholinergic agents (LAMA) are suggested as add-on therapy in severe pediatric asthma [9], and have long been additive therapy in severe adult asthma [10]. The use of LAMA in asthma, pediatric or adult, appears to be a therapeutic modality to abrogate the long standing soldier in the asthma triad (Figure 1), namely, the intrinsic AHR of all asthmatics. Whether it’s earlier use in mild to moderate patients might shift AHR tendencies, or act in concert with ICS with or without LABA to assist with disarming all three components of the active asthma state, is a fertile field for investigation.

Adding to the eventual potential of LAMA in a wide range of asthmatics are current agents that combine ICS, LAMA and LABA in different combinations; but which currently are out of the asthma therapeutic armamentarium [11]. The emphasis on asthma control has shifted to a focus on inflammatory and cellularity components of asthma, while minimal progress has been made in blocking or reducing AHR. Given no potential cures for asthma on the horizon, attacking as many of the individual components of active asthma should remain viable.

Discussion

Yield of TBNA, forcep biopsy and other conventional diagnostic techniques in submucosal lesions

Out of 200 cases with submucosal abnormalities 99 cases were diagnosed by combination of all bronchoscopic procedures including TBNA, forcep biopsy, bronchial brush cytology and bronchial wash. Total yield of all fiberoptic bronchoscopy guided procedures in submucosal lesions is 49.50%. Roth et al. [14] reported diagnostic yield in submucosal lesions 34.4% in their study.

TBNA has low yield i.e. 40.05% as compared to forcep biopsy i.e. 49.50% in diagnosis in submucosal lesions. Additional diagnostic yield of other CDTs like BB and BW has nil effect on yield difference over forcep biopsy (P>0.11). Karahalli E et al. [15] and Lundgren et al. [16] reported that TBNA had lower diagnostic yield than forcep biopsy in submucosal lesions. Roth et al. [14] concluded no additional yield of bronchial brush and small volume lavage over TBNA and forcep biopsy in submucosal lesions. Though yield of TBNA is low, it has 81.81% sensitivity in diagnosing disease in submucosal lesions in our study. Khoe et al. [17] reported 83% sensitivity of TBNA in their study.

In our study, it is observed that TBNA plus CDTs has no added advantage over CDTs alone and Forcep Biopsy has individually comparable yield with all CDTs like BB and BW. Caglayan et al. [12] reported TBNA combined with CDTs has no additional yield over CDT in submucosal lesions.

Yield of TBNA, Forcep biopsy and other conventional diagnostic techniques in Peribronchial Lesions (bulge)

In peribronchial lesions, TBNA has significant diagnostic yield i.e 68.66% individually as compared to forcep biopsy 27.33% and CDT 41.33%. Additional CDTs like bronchial brush cytology and bronchial wash has additive yield to forcep biopsy from 27.33% to 41.33% in peribronchial lesions (P<0.00001). Ladina Joos et al (18) reported yield of TBNA was 43.6% in their study. Harrow EM et al. [19] reported success rate of TBNA up to 80% for peribronchial disease.

Additional CDTs like bronchial brush cytology and bronchial wash has additive yield to forcep biopsy from 27.33% to 41.33% in peribronchial Lesions (P<0.0001). Dasgupta et al. [6], Govert et al. [20] found combination of higher yield of TBNA over CDT and have increased yield CDT over forcep biopsy alone in their studies. Caglayan et al. [12] in peribronchial disease reported diagnostic rate was 52% by CDT, 87% by TBNA plus CDT and superiority of combination over CDT was significant (p<0.001).

TBNA was the only diagnostic technique in 31 out of 101 cases of peribronchial lesions in our study. Sole yield of TBNA in our study is 30.69% (31/101) which is significantly higher than any Individual CDTs. Caglayan et al. [12] reported 34.3% yield of TBNA as a sole in their study in peribronchial lesions.

In our study Sensitivity of TBNA in diagnosing lung malignancy is 96.19% while that of CDTs 59.04%.TBNA has very high sensitivity as compared to CDTs, and is statistically significant in Peribronchial Lesions. (P<0.01) Khoo et al. [17] reported sensitivity of TBNA 89% and Shure and Fedullo et al. [13] reported sensitivity of CDTs 71% in their study.

Yield of TBNA, Forcep biopsy and other conventional diagnostic techniques in Submucosal and peribronchial Lesions (combined analysis)

Unlike exophytic endobronchial mass lesion, the diagnostic yield of CDT is low in submucosal and peribronchial diseases, where the mucosa was generally intact. TBNA enables penetration into the submucosa and access to the tumor through the bronchus wall in peribronchial disease, and usually diagnosis is available solely by TBNA [6,12,14,15,18,21-24]. Average Yield of all Fiberoptic Bronchoscopy guided procedures in Submucosal-Peribronchial Lesions in our study is 200 cases out of 350 cases i.e. 57.14%. Roth et al. reported 54.2% yield in submucosal-peribronchial group in their study. Gellart AR et al. reported yield of 55% in their study [25].

Sensitivity of forcep biopsy in diagnosing lung malignancy in submucosal-peribronchial lesions is 63.63% i.e. (140/200) and that of TBNA is 91.00% (182/210) in diagnosing lung malignancy in submucosal-peribronchial lesions. TBNA is Valuable technique and significant difference between the yield when compared with forcep biopsy (P<0.001). Kaçar N et al. [21] reported 69.04% and 94.40% sensitivity of forcep biopsy and TBNA respectively in submucosal-peribronchial lesions which was highly significant as observed in our study (P<0.008). Caglayan et al. [12] reported sensitivity of TBNA 87% and of forcep biopsy 52% which is also highly significant (p<0.001).

Other important observations during study

Results of TBNA in Submucosal lesions, fairly comparable with Forcep biopsy; still overall diagnostic yield is not up to mark?

In present study we documented, total yield of all fiberoptic bronchoscopy guided procedures in submucosal lesions is 49.50%. TBNA has low yield i.e. 40.05% as compared to forcep biopsy i.e. 49.50% in diagnosis in submucosal lesions. Additional diagnostic yield of other CDTs like BB and BW has nil effect on yield difference over forcep biopsy (P>0.11).

Possible explanation for mentioned fact as per our observation in this study is that, submucosal lesions have various bronchoscopic abnormalities like erythema, vascular flares and enhanced rugal pattern, loss of normal bronchial markings, or thickening of mucosa and narrowing of bronchus which can be equally documented in infectious, inflammatory and malignant process. Negative yield was confirmed by all possible diagnostic modalities as pathology documented in these type of lesions may be because of true infective, inflammatory process rather than malignant pathology.

Without TBNA during routine bronchoscopy in Peribronchial lesions overall yield is decreased, & need for repeat procedures are increased

When TBNA cytology was showing malignant cells with no histological type and forcep biopsy report was inconclusive or non-diagnostic. In such cases we performed repeat bronchoscopy procedure for further additional samplings. Repeat bronchoscopy can be prevented by ROSE (rapid on site evaluation) technique, which aids immediate diagnosis and helps in guiding adequacy of samples during bronchoscopy. We have rapid on site evaluation cytology facility which was helped us in decreasing repeat procedure. We require average 9 passes of TBNA in these difficult cases, and routinely we preferred 6 TBNA passes to get adequate yield and final confirmatory diagnosis. Diacon A et al. [26] reported ROSE detected diagnostic material at first site sampled in 50% of all procedures, 64% of bronchoscopy procedures were terminated early because of early diagnosis and in 35% cases only sampling methods other than TBNA is required.

TBNA procedure related adverse events documented in present study

Thirteen patients in our study was developed hypoxemia during procedures and was corrected by oxygen supplementation and finally we completed the procedure with supplementation of oxygen. We usually provide oxygen supplementation as a protocol whenever oxygen saturation falls below 90% and terminate the procedure if it is not correctable with oxygen supplementation. Bollinger CT et al. [4] documented hypoxemia during bronchoscopy procedure and recommended monitoring oxygen saturation with pulse oximetry during procedure.

Other complications like minor bleeding and significant bleeding was documented in 26 & 9 cases respectively of total 350 in our study, and manifested as post bronchoscopy hemoptysis. We were used instillation of cold saline and topical adrenaline bronchoscopically to manage bleeding. Pneumothorax which is a minor and rare complication of TBNA is observed in 0.014% (5/350) cases. Mortality rate in our study during bronchoscopic procedures was zero percent. Bollinger CT et al. [4], Jin F et al. [27] ACCP Guidelines on Interventional Pulmonology 2003 [28] reported mortality rate of 0.01% and complication rate 0.7% in their study. Other potentially life threatening complications like respiratory depression, airway obstruction, arrhythmias and infections were also not observed in our study.

Author Disclosure Statement

No personal or financial support or commercial association or conflict is relevant to this submission

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Received: October 10, 2019;
Accepted: November 13, 2019;
Published: November 18, 2019.

To cite this article : Hopp RJ. A Perspective on Airway Hyperresponsiveness in Asthma. European Journal of Respiratory Medicine. 2019: 1:1

© Hopp RJ. 2019.