Eight International London Cough Symposium 2014: Cough hypersensitivity syndrome as the basis for chronic cough

Accepted Manuscript Eight International London Cough Symposium 2014: Cough Hypersensitivity Syndrome as the basis for chronic cough Kian Fan Chung, Professor, Brendan Canning, Lorcan McGarvey PII:

S1094-5539(15)00094-2

DOI:

10.1016/j.pupt.2015.08.009

Reference:

YPUPT 1483

To appear in:

Pulmonary Pharmacology & Therapeutics

Received Date: 26 August 2015 Accepted Date: 31 August 2015

Please cite this article as: Chung KF, Canning B, McGarvey L, Eight International London Cough Symposium 2014: Cough Hypersensitivity Syndrome as the basis for chronic cough, Pulmonary Pharmacology & Therapeutics (2015), doi: 10.1016/j.pupt.2015.08.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Eight International London Cough Symposium 2014: Cough Hypersensitivity Syndrome as the basis for chronic cough

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Kian Fan Chung1, Brendan Canning2, Lorcan McGarvey3

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Experimental Studies, National Heart and Lung Institute, Imperial College London, UK; Royal Brompton NIHR Biomedical Research Unit, London, UK.

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The Johns Hopkins Asthma and Allergy Center, Baltimore, MD 21224, USA

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Department of Respiratory Medicine, Centre for Infection and Immunity, Queen's University Belfast, UK.

Correspondence: Professor K F Chung,

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Short title: Cough hypersensitivity syndrome: mechanisms and antitussives

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National Heart & Lung Institute, Imperial College London,

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Dovehouse St,

London SW3 6LY, UK

[email protected]

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ACCEPTED MANUSCRIPT Summary: At the Eighth International London Cough Conference held in London in July 2014, the focus was on the relatively novel concept of cough hypersensitivity syndrome (CHS) as forming the basis of chronic cough. This concept has been formulated following understanding of the neuronal pathways for cough and a realisation that not all chronic cough is usually

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associated with a cause. The CHS is defined by troublesome coughing triggered by low level of thermal, mechanical or chemical exposure. It also emcompasses other symptoms or sensations such as laryngeal hypersensitivity, nasal hypersensitivity and possibly also

symptoms related to gastrooesopahgeal reflux. The pathophysiologic basis of the CHS is

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now being increasingly linked to an enhancement of the afferent pathways of the cough reflex both at the peripheral and central levels. Mechanisms involved include the

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interactions of inflammatory mechanisms with cough sensors in the upper airways and with neuronal pathways of cough, associated with a central component. Tools for assessing CHS in the clinic need to be developed. New drugs may be developed to control CHS. A roadmap is suggested from the inception of the CHS concept towards the development of newer

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antitussives at the Symposium.

Key words: Chronic cough, Cough hypersensitivity syndrome, Laryngeal hypersensitivity, neural pathways, antitussives, neuroinflammation, TRPV1, TRPA1, Gabapentin,

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Amitryptiline, P2X2/3 receptors.

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ACCEPTED MANUSCRIPT Introduction

There is now a broad consensus that chronic cough should be considered not solely as a symptom but a distinct clinical entity termed cough hypersensitivity syndrome (CHS) [1]. It has been proposed that the common pathophysiological mechanism underlying cough, regardless of the aetiology, is an inflammation-induced injurious effect of the nervous

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system that leads to CHS [2]. Clinically, CHS is characterised by troublesome coughing often triggered by low levels of thermal, mechanical or chemical exposure. Patients frequently report that simple things such as changes in ambient temperature, taking a deep breath, laughing, talking on the phone for more than a few minutes, cigarette smoke, aerosol

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sprays, scents, or eating crumbly dry food are common triggers for their cough [3]. The pathophysiologic basis of the CHS is now being increasingly linked to an enhancement of the

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afferent pathways of the cough reflex both at the peripheral and central levels. What leads to this enhancement is still unclear but inflammatory mechanisms through an interaction with cough reflex pathways may be important. Considerable progress in these areas of cough research has been made over the past decade. The object of this review is to discuss recent findings which have been presented at the Eight International London Cough

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Symposium in July 2014 at Imperial College London, findings which indicate how the road towards finding new antitussives has been opened up by this novel concept of CHS.

Neuronal pathways for cough and neuroinflammatory mechanisms

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New therapeutic strategies for cough are most likely to arise from a better understanding of the physiology and projections of the afferent pathways regulating cough. In animals,

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bronchopulmonary vagal afferent neurons have been characterized based on their responsiveness to chemical and mechanical stimuli, their gene expression and by their embryological and morphological characteristics [4]. These studies have accurately predicted clinical outcomes and observations in patients. Amongst the therapeutic targets in cough predicted from preclinical studies performed over the past decade include P2X3-type receptors for ATP and the ion channels TRPV1 and TRPA1 [5-7]. Studies of the vagal afferent nerve subtypes regulating cough in animals have also been predictive of results in patients. In animals, 2 types of vagal afferent nerves primarily responsible for regulating cough have been described [8]. Consistent with these observations, recent morphological study performed using

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ACCEPTED MANUSCRIPT biopsies taken from chronic cough patients identified at least 2 types of afferent terminals in the human airway mucosa [9]. Perhaps the more significant advances in our understanding of cough reflex mechanisms have come from studies focusing on the central regulation and projections of cough pathways. Preclinical and modeling studies have described the substrate of a cough neuronal network in

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the brain stem, and mid brain [10-12]. These mapping studies predicted behavioural outcomes (urge-to-cough) and their associated regulatory mechanisms including descending (inhibitory and excitatory) modulation from the cortex. Recent functional magnetic resonance imaging approaches used in patients validate to some extent the complexity of cough regulation in

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patients [13-15]. In parallel, physiological and pharmacological approaches have described several therapeutic strategies for cough suppression, notably NMDA-type glutamate receptors,

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nicotinic receptors and α2-adrenergic receptors [16-18]. Existing clinical literature support the validity of these approaches to cough suppression and recent clinical studies utilizing the NMDA receptor channel blocker memantine, and nicotine derived from electronic cigarettes provides further validation of both NMDA and nicotinic receptors respectively, as potentially-viable antitussive targets [19, 20].

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One area where progress has lagged behind in cough research has been our ability to identify and localize relevant therapeutic strategies at the peripheral terminals of bronchopulmonary vagal afferent nerves. Indeed, it is remarkable that with few exceptions the chemical and mechanical stimuli driving cough in patients is unknown. This includes the

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pathogenesis of cough in common conditions such as asthma, COPD and gastro-oesophageal reflux disease, but also in the less common chronic diseases or acute illnesses where cough is a

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prominent symptom such respiratory tract infections (pertussis, influenza, rhinovirus), idiopathic pulmonary fibrosis, and pulmonary oedema (with or without associated cardiovascular

disease),

blood

gas

abnormalities

(e.g.

from

altitude

sickness),

thromboembolism or hypoxic pulmonary vasoconstriction/ pulmonary hypertension. In many of these diseases, there are associated pathophysiological features that may modulate cough reflex sensitivity (e.g. bronchospasm, accumulated secretions, inflammatory mediators recovered in lavage or sputum) but the direct evidence that these stimuli initiate coughing is either lacking or negative. This may explain in part why bronchodilators, drugs that reduce mucus secretion (e.g. anticholinergics), drugs that suppress gastric acid secretion, or receptor selective antagonists for autacoids known to be found in the airways of patients with cough 4

ACCEPTED MANUSCRIPT (e.g. leukotriene cysLT1 receptor antagonists, peripherally restricted antihistamines) have variable and often disappointing antitussive effects in patients [21]. An enhanced ability to localize the receptors and ion channels uniquely expressed at the peripheral terminals of the vagal afferent nerves regulating cough might facilitate the identification of novel therapeutic strategies with more desirable side effect profiles than

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currently used antitussive agents. There have been several examples of successful labelling of vagal afferent nerve terminals relevant to cough in animals and in human airway biopsies, including TRPV1 and Na+-K+ ATPase [22, 23]. But the recent study by West et al. highlights the challenges in this area of research, with the authors using antibodies previously validated for

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multiple targets thought likely to be expressed by vagal afferent nerves (ASIC3, TRPV1, TRPA1, TRPV4) and yet failing to provide selective labelling in whole mount biopsies [9]. At present we

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are largely limited to functional studies. Perhaps techniques such as in situ imaging of Ca++ responses in peripheral nerve terminals or single cells RNA sequencing/ microarray approaches will soon facilitate and open up this currently-lagging area of cough research [24, 25]. The interactions of inflammatory mechanisms with cough sensors in the upper airways have been previously reviewed [2]. The concomitant presence of inflammation and of

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neurogenic mechanisms in the airways might suggest that inflammatory-neural mechanisms may be at work. However, very little is known about these interactions. Specific studies interacting sensory nerves and cough-initiating insults will provide much needed insight into such mechanisms. In the 2014 International Cough Symposium, a session was devoted to the

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respiratory virus induced cough as a potential model of an inflammatory-neural interactions that can lead to a cough hypersensitivity state [26], and the mechanism underlying itch was

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seen to be highly relevant to similar mechanisms operating for CHS [27]. In addition, the interactions of TRPV1 and TRPA1 have been discussed [28].

Tools for assessing cough hypersensitivity syndrome In light of the progress being made towards a better understanding of cough mechanisms and given an encouraging pipeline of novel anti-tussive treatments currently undergoing evaluation [29, 30], it is important that tools to measure cough are valid and relevant [31]. Over the last five decades, a variety of measures have been developed to assess various clinical aspects of cough such as severity, frequency, sensitivity and impact on health status. Traditionally, inhalation airway challenge using tussive chemicals such as citric acid 5

ACCEPTED MANUSCRIPT and capsaicin has been utilised for both experimental research and as a treatment endpoint in clinical trials. Typically, cough reflex sensitivity is measured in individual subjects before and after an intervention (e.g. active treatment or placebo) or clinical event (viral infection) and recorded as the concentration of tussive chemical inducing two (C2) or five (C5) coughs (6). Intra or inter-patient (group) comparisons are then made by comparing mean doubling

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concentrations of the stimulus required to achieve C2 and or C5. A limiting feature of this approach has been the overlap in C2 and C5 endpoints between healthy subjects and those with chronic cough. Recently by applying pharmacodynamic modelling to capsaicin cough responses, it has been suggested that the maximum cough response evoked (Emax) rather

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than the C2 and C5 is reported to be superior in discriminating health from disease [32]. One of the issues regarding the use of capsaicin or citric acid challenges as a measure of airway

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cough hypersensitivity is that they have not been predictive of the cough suppressive effects of various antitussives such as gabapentin and morphine that are believed to inhibit central hypersensitivity pathways [33, 34]. Perhaps, we will need to review the need for more predictive cough challenges.

To gain a deeper insight into the mechanisms responsible for CHS there is a need to

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extend challenge methodology beyond the lower airway to include chemical and physical (mechanical, electrical) stimulation of extra-pulmonary sites to include the larynx, nasal passages and oesophagus [35-38]. The notion that there may be hypersensitivity at these extrapulmonary sites is not new. Otorhinolaryngologists have long recognised a postviral

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vagal neuropathy presenting with dysphonia, vocal fatigue, cough, globus and also sometimes dysphagia[39, 40]. The hypothesis is that viral infection causes or triggers vagal dysfunction

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that is localised to the larynx. There no specific tests for laryngeal hypersensitivity syndrome but direct visualisation of the laryngeal movements under baseline conditons or under stress of exercise may be useful. A questionnaire specific for detecting laryngeal hypersensitivity syndrome has been published [41]. Similar questionnaires or tests could be developed for detecting nasal or oesophageal hypersensitivity. Furthermore, evaluation of tussive challenges should not be confined to the peripheral nervous system but include imaging of the central nervous system which is considered integral to the neural sensitization associated with chronic cough. This has been made possible by considerable advances made in utilising functional magnetic resonance imaging

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ACCEPTED MANUSCRIPT (fMRI) technology to identify precise sites of brain activation during cough and associated with the sensation of urge-to-cough [42, 43]. Other objective measures of cough include acoustic recording and to date the available devices have been primarily focused on measuring cough frequency. Both the Leicester Cough Monitor (LCM) and VitaloJAK are validated and have been used to measure cough

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frequency in acute and chronic cough and in trials of novel anti-tussive treatments [44-46]. However cough recorders do not reliably assess the impact of cough and provide no diagnostic information. It is possible detailed analysis of cough acoustics and the temporal pattern of cough may provide diagnostic clues and mechanistic insights in the future. An

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additional gap in current capability is the reliable measure of cough intensity. Advances in technology to capture composites of cough flow, electromyography and oesophageal

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(thoracic) pressure may help to meet this need.

Cough can be measured subjectively by patient reported outcome (PRO) measures such as quality of life (QoL) questionnaires and rating scales [47-49]. Both types of tools are widely used as outcome measures in clinical research and treatment trials but importantly can also be used in routine clinical practice. The simplicity of rating scales such

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as a visual analogue scale (VAS) for ‘cough severity’ or ‘urge to cough’ have obvious advantages and minimum clinically important differences for such measures have now been established [49, 50]. There have been attempts to develop patient-reported outcomes (PROs) to capture the clinical aspects of CHS but the exact value of existing PRO

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measures and those under development in terms of guiding the clinical management of cough patients has not yet been worked out [51]. Overall, there is a need to refine existing

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tools (questionnaires, rating scales, cough challenge, cough counting, hypersensitivity measures) and develop novel methodologies for measuring the frequency and impact of cough and other meaningful end-points to improve the design and reliability of future clinical trials of novel therapeutics for CHS.

Therapeutic perspectives: need for effective antitussives for CHS New therapies such as symptom-suppressive antitussives are urgently needed for the chronic hypersensitivity syndrome. The current antitussives used in the treatment of cough, comprise the narcotic antitussives that include codeine and morphine, and the nonnarcotic antitussives such as dextrometorphan, which is a synthetic derivative of morphine 7

ACCEPTED MANUSCRIPT with lesser analgesic or sedative properties. Codeine is not very effective in the acute cough of the common cold and against cough of COPD patients. Dextrometorphan has a small effect on cough associated with colds. The value of these agents for chronic cough is far from clear. The slow-release formulation of morphine has been shown in patients with chronic intractable cough to produce a significant reduction of greater than one-third in

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recorded cough [34]. Larger studies are needed, particularly to evaluate the risks and benefits of this approach before its wider recommendation. With many parallels to chronic neuropathic pain, drugs previously used for neuropathic pain has been tried in chronic cough. Amitryptiline and gabapentin for example have been shown to have some effect in

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reducing idiopathic cough [33, 52]. The use of gabapentin in chronic cough is reviewed in this series [53]. The mechanisms of action of amitriptyline and gabapentin as treatment for

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neuropathic pain are likely related to their central anti-nociceptive actions. Gabapentin has been shown to reduce pain via an action on GABAergic neurotransmission or voltage gated ion channels in the spinal cord, midbrain, thalamus and/ or sensory and insula cortices in the brain [54, 55]. TRPV1 receptor antagonist

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TRPV1 remains a potential target as an antitussive agent in chronic cough. TRPV1 expression in epithelial nerves is increased by 3-fold in patients with chronic cough compared to control [22]. Several inflammatory stimuli can increase the expression of TRPV1. Increased cough responses to capsaicin which activates TRPV1 has been

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demonstrated in patients with idiopathic chronic cough, and in other conditions with chronic cough such as idiopathic pulmonary fibrosis, COPD and bronchiectasis. However, in

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a recent study in chronic idiopathic cough showed that SB-705498, a selective antagonist at the TRPV1 receptor [56] caused a significant reduction in capsaicin cough sensitivity, but did not have any effect on cough frequency [57]. One possibility is that this antagonist may not have been sufficiently active as a TRPV1 antagonist.

TRPA1 receptor antagonist TRPA1 is a receptor activated by many natural compounds that cause pain and inflammation such as cinnamaldelyde, acreolin and mustard oil [58]. Other activators of TRPA1 include oxidants, acids and chloride ions [59-61]. Prostaglandin and bradykinininduced cough were partially blocked by an inhibitor of TRPA1, HC-030031 [62]. Currently, 8

ACCEPTED MANUSCRIPT studies in chronic cough are being performed with TRPA1 antagonists such as GRC117536 [63, 64]. Sodium channel (Nav) channel blockers Local anaesthetics such as lidocaine delivered by aerosol or by nebuliser have been used to treat chronic cough with varying degrees of success [65]. The subtypes of Na+

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channels that mediate this potential antitussive effect are unclear. Three of the nine subtypes of Nav channels, Nav 1.7,1.8 and 1.9, are selectively expressed in sensory nerves in the airways [66, 67]. Nav 1.7 channel appear to be important in cough reflex induced by acid and is abundantly expressed in vagal ganglia in guinea pigs [67]. A pan-Nav channel

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inhibitor has been shown to inhibit vagal nerve induction and cough [68]. ATP receptor P2X2/3 antagonists

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ATP can activate transmission of signals along sensory nerves and this effect is modulated by P2X and P2Y receptors. P2X2 and P2X3 receptors have been found on sensory C-fibres outside the CNS and activation by ATP leads to sensitisation of vagal afferents [7]. An antagonist at the P2X3 receptor, AF219, has been shown to reduce coughing in patients with chronic refractory cough [45]. This compound was particularly

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effective in those with a high cough count, but some subjects have noticed a loss of taste, indicating the role of P2X3 receptors in taste function. Thalidomide

In a 24-week, double-blind trial of 20 patients with idiopathic pulmonary fibrosis

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suffering from chronic cough, thalidomide improved cough quality of life questionnaire scores, as well as respiratory quality of life [69]. The majority of the thalidomide-treated

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patients reported adverse events such as constipation. Controlled studies are required to evaluate the effects of thalidomide on objective cough measures and in other types of chronic cough.

Thalidomide may have immunomodulatory or anti-inflammatory

properties. Prednisolone improves cough hypersensitivity to capsaicin in patients with idiopathic pulmonary fibrosis [70].

Conclusion

The Eight International London Cough Symposium served as a platform to discuss the implications of considering chronic cough as a cough hypersensitivity syndrome, a 9

ACCEPTED MANUSCRIPT concept that appears to have gained ground within the respiratory medicine, and for which several neural-inflammatory mechanisms have been proposed. Evidence is gradually accumulating although will be challenging because of inaccessibility of tissues for exact definition of these underlying mechanisms. Nevertheless, it is important to develop reliable tools. Cough suppression is still at its developmental stage with the use

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of agents established for the treatment of neuropathic pain, and more recent drugs targeting TRPV1 and TRPA1 appear to have failed with the exception of the ATP P2X3 receptor antagonists showing promise.

A roadmap is included illustrating the steps from the inception of the CHS concept

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towards the development of newer antitussives derived from discussion at the Symposium (Figure). This road includes the mechanistic understanding of peripheral and

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central pathways of CHS, development of tools for diagnostic evaluation of patients with CHS, the development of human and animal experimental models, analysis of clinical and experimental biological samples, the phenotyping and endotyping of large well-defined cohorts of CHS, target identification and drug discovery, and appropriately-designed clinical trials in these well-defined cohorts. The road will be long but the destination will

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Acknowledgements:

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be reached.

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The Eight International Cough Symposium was supported by educational grants from Proctor & Gamble, Boehringer Ingelheim, Almirall and Bionorica.

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French, C.L., et al., Impact of chronic cough on quality of life. Arch.Intern.Med., 1998. 158(15): p. 1657-1661. Birring, S.S. and A. Spinou, How best to measure cough clinically. Curr Opin Pharmacol, 2015. 22: p. 37-40. Hilton, E., et al., Clinical features of the urge-to-cough in patients with chronic cough. Respir Med, 2015. 109(6): p. 701-7. Chung, K.F., Chronic 'cough hypersensitivity syndrome': a more precise label for chronic cough. Pulm Pharmacol Ther, 2011. 24(3): p. 267-71. Jeyakumar, A., T.M. Brickman, and M. Haben, Effectiveness of amitriptyline versus cough suppressants in the treatment of chronic cough resulting from postviral vagal neuropathy. Laryngoscope, 2006. 116(12): p. 2108-2112. Gibson, P., Gabapentin in chronic cough. Pulmonary Pharmacology Therapeutics, 2015. Abdi, S., D.H. Lee, and J.M. Chung, The anti-allodynic effects of amitriptyline, gabapentin, and lidocaine in a rat model of neuropathic pain. Anesth Analg, 1998. 87(6): p. 1360-6. Governo, R.J., et al., Gabapentin evoked changes in functional activity in nociceptive regions in the brain of the anaesthetized rat: an fMRI study. Br J Pharmacol, 2008. 153(7): p. 155867. Rami, H.K., et al., Discovery of SB-705498: a potent, selective and orally bioavailable TRPV1 antagonist suitable for clinical development. Bioorg Med Chem Lett, 2006. 16(12): p. 328791. Khalid, S., et al., Transient receptor potential vanilloid 1 (TRPV1) antagonism in patients with refractory chronic cough: a double-blind randomized controlled trial. J Allergy Clin Immunol, 2014. 134(1): p. 56-62. Bautista, D.M., M. Pellegrino, and M. Tsunozaki, TRPA1: A gatekeeper for inflammation. Annu Rev Physiol, 2013. 75: p. 181-200. Trevisani, M., et al., 4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1. Proc Natl Acad Sci U S A, 2007. 104(33): p. 13519-24. Taylor-Clark, T.E. and B.J. Undem, Ozone activates airway nerves via the selective stimulation of TRPA1 ion channels. J Physiol, 2010. 588(Pt 3): p. 423-33. Taylor-Clark, T.E. and B.J. Undem, Sensing pulmonary oxidative stress by lung vagal afferents. Respir Physiol Neurobiol, 2011. 178(3): p. 406-13. Grace, M., et al., Transient receptor potential channels mediate the tussive response to prostaglandin E2 and bradykinin. Thorax, 2012. 67(10): p. 891-900. Geppetti, P., et al., Cough: The Emerging Role of the TRPA1 Channel. Lung, 2010. 188 Suppl 1: p. S63-8. Spina, D. and C.P. Page, Regulating cough through modulation of sensory nerve function in the airways. Pulm Pharmacol Ther, 2013. 26(5): p. 486-90. Chong, C.F., et al., Comparison of lidocaine and bronchodilator inhalation treatments for cough suppression in patients with chronic obstructive pulmonary disease. Emerg Med J, 2005. 22(6): p. 429-32. Undem, B.J. and M.J. Carr, Targeting primary afferent nerves for novel antitussive therapy. Chest, 2010. 137(1): p. 177-84. Kwong, K., et al., Voltage-gated sodium channels in nociceptive versus non-nociceptive nodose vagal sensory neurons innervating guinea pig lungs. J Physiol, 2008. 586(5): p. 132136. Kwong K, W.E., Hunsberger GE, Osborn RR, Ghatta S, Ingleby L, Carr MJ, Kerns JK, and Rumsey W Pharmacological characterisation of GSK 2339345, a novel voltage gated sodium channel blocker for the treatment of symptomatic cough. Am J Respir Crit Care Med, 2013. 187: p. A4936.

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ACCEPTED MANUSCRIPT

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Horton, M.R., et al., Thalidomide for the treatment of cough in idiopathic pulmonary fibrosis: a randomized trial. Ann Intern Med, 2012. 157(6): p. 398-406. Hope-Gill, B.D., et al., A study of the cough reflex in idiopathic pulmonary fibrosis. Am.J Respir.Crit Care Med., 2003. 168(8): p. 995-1002.

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ACCEPTED MANUSCRIPT Legend to Figure 1: Roadmap indicating the steps and pathways from the inception of the Chronic Cough

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Hypersensitivity Syndrome towards the development of newer antitussives.

15

APPROACH ACCEPTED MANUSCRIPT SOLUTIONS

Refine existing and develop & validate new tools (challenge, imaging, PROs & rating scales, cough monitoring

TE D

Mechanistic understanding of peripheral and central pathways of CHS

Experimental Human and animal in vivo and ex vivo models of CHS Deep unbiased analysis of clinical and experimental biological samples

Clinician, scientist & industry engagement

Establish Research Consortia

SUCCESS

National and international databases of well characterised patient cohorts

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Agreed clinical endpoints to measure frequency, intensity and impact of CHS

OBJECTIVE

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Consensus statement on definition and recommendations for diagnostic evaluation

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Agreed clinical definition and approach to diagnostic evaluation across pulmonary /non pulmonary disease

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Cough Hypersensitivty Syndrome (CHS)

UNMET NEEDS

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THE PROBLEM

Valid and regulatory approved clinical endpoints

Target identification and drug discovery

Large well designed clinical trials of novel therapy

Safe and effective therapy for CHS