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1 대한내과학회지 : 제 91 권제 1 호 In-depthreview 만성난치성기침 가톨릭대학교의과대학내과학교실 김성경 Chronic Refractory Cough Sung Kyoung Kim Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea Chronic refractory cough is defined as a cough that persists despite guideline based treatment. It is seen in 20-46% of patients presenting to specialist cough clinics and it has a substantial impact on quality of life and healthcare utilization. Several terms have been used to describe this condition, including the recently introduced term cough hypersensitivity syndrome. Key symptoms include a dry irritated cough localized around the laryngeal region. Symptoms are not restricted to cough and can include globus, dyspnea, and dysphonia. Chronic refractory cough has factors in common with laryngeal hypersensitivity syndromes and chronic pain syndromes, and these similarities help to shed light on the pathophysiology of the condition. Its pathophysiology includes cough reflex sensitivity, central sensitization, peripheral sensitization, and paradoxical vocal fold movement. Chronic refractory cough often occurs after a viral infection. The diagnosis is made once the main disease that causes chronic cough have been excluded (or treated) and cough remains refractory to medical treatment. Treatments include speech pathology interventions using techniques adapted from the treatment of hyperfunctional voice disorders, as well as the use of centrally acting neuromodulators such as gabapentin and pregabalin. Potential new treatments in development also show promise. (Korean J Med 2016;91:18-27) Keyword: Cough 서론기침의지역사회유병률은세계적으로성인인구의약 % 를차지하며, 이중만성기침의유병률은약 10-38% 로보고되고있다 [1,2]. 만성기침의국내유병률에대한연구는드물지만, 최근지역사회노인인구를대상으로한설문조사에서는 % 로보고되었다 [3]. 대부분의만성기 침은국내기침진료지침을포함한여러진료지침에제시된가이드라인및프로토콜에따라적절한검사및치료를하면기침의원인에대한확인과치료가가능하다 [4,5]. 하지만, 일부만성기침의경우진료지침에제시된가이드라인이나프로토콜을따라검사및치료를함에도불구하고원인을파악하기어렵고치료가안되는경우가있다. 최근에는이러한경우를원인을찾는데실패한것이아니라, 하나의 Correspondence to Sung Kyoung Kim, M.D. Division of Pulmonology, Department of Internal Medicine, St. Vincent s Hospital, The Catholic University of Korea, 93 Jungbu-daero, Paldal-gu, Suwon 16247, Korea Tel: , Fax: , kimskmd@gmail.com Copyright c 2016 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 - Sung Kyoung Kim. Chronic refractory cough - 다른임상적질환으로접근을해야한다는의견들이대두되고있으며여기에대한연구들이많이보고되고있다 [6]. 이를만성난치성기침 (chronic refractory cough) 또는만성특발성기침 (chronic idiopathic cough) 이라는용어를사용하여정의하고있는데, 본고에서는이러한만성난치성기침에대해좀더자세히알아보고자한다. 정의기침은지속기간에따라급성기침 (3주미만 ), 아급성기침 (3주이상 8주미만 ), 만성기침 (8주이상 ) 으로분류한다. 만성난치성기침의정의는아직도명확하지않지만, 8주이상의기침의만성기침환자에서제시된진료지침의가이드라인에따른충분한검사및치료에도불구하고기침의호전이없는경우로정의되고있다. 만성기침으로병원을찾는환자들의약 20-46% 에서만성난치성기침의특징을보인다고알려져있으며용어로는만성난치성기침이나만성특발성기침, 또는설명되지않는만성기침 (unexplained chronic cough) 등이사용된다. 하지만, 용어를좀더구분하자면기침의원인을확인할수없을경우에는만성특발성기침또는설명되지않는기침이라고하고, 기침의원인이될만한질환에대해적절한치료를함에도불구하고기침의호전이없는경우를만성난치성기침이라고할수있다. 하지만, 설명되지않는만성기침이나만성특발성기침의경우대부분이흡입스테로이드제제나프로톤펌프억제제등의경험적치료를함에도불구하고계속기침이지속되기때문에이들도만성난치성기침에포함시킬수있다. 기침과민증후군 (cough hypersensitivity syndrome) 만성난치성기침을이해하기위해서는먼저기침과민증후군의개념에대한이해가필요하다. 만성기침에대한최근의연구들은만성기침과신경병증질환 (neuropathic disorder) 과의유사성, 기침반사과민성, 후두과민성 ( 후두는기침수용체의밀도가가장높다 ) 을강조하고있다. 최근에는만성난치성기침환자들의대부분은여러가지다른원인들에의한한가지질환 (a single umbrella with different subtypes) 으로설명할수있다는의견이제시되고있는데, 이것이기침과민증후군의개념이다 [7]. 기침과민증후군은후두와상기도의과민성과관련이있는데, 기침과민증후군환자들의기도 (airway) 에는 Transient receptor potential V1 (TRPV1) 이나 TRPA1과같은기침수용체가상향조절 (upregulation) 되어있고이로인해무해한자극이더라도과민하게반응하여기침이유발되는, 일종의기도의감각신경이상으로설명할수있다는것이다 [8]. 만성기침의흔한원인으로알려져왔던기침형천식, 비부비동염, 위식도역류질환등도기침과민증후군의서로다른아형 (subtype) 이라는의견도있다 [9]. 또한, 만성난치성기침은기침과민증후군의한표현형인데, 비록유발인자는밝혀지지않았지만위식도역류가관련이있을것이라는의견도있다 [7]. 이러한관점에서보면, 왜단지몇몇사람들만흔한원인질환이있고다른사람들은그렇지않은지, 왜원인질환의치료에도종종호전이없는지, 왜원인질환없이기침이발생하는지등에대한설명이가능하다. 하지만기침과민증후군의개념에대한제한점도있는데, 대부분의근거가전문가의견이라는점과기침과민성을객관적으로확진할방법이없다는것이다. 유럽호흡기학회 (European respiratory society) 에서는 14 개국의 44명의전문가를대상으로기침과민증후군에대한설문조사를시행하였다 [10]. 대부분의응답자들 (89%) 은기침과민증후군이유용한개념이며기관지과민성과는구분된다는데 (82%) 동의하였다. 그러나기전에대해서는의견의불일치를보였다. 예를들면, 응답자의약 70% 에서는기침신경체계 (neural mechanism) 의상향조절이만성난치성기침의중요한특징이라는데동의를하였지만, 기도의염증이감각신경의활성화와직접적인관련이있다는응답자는약 41% 였으며, 기침반사과민성이대부분의증상을설명할수있다는데에는단지 45% 만이동의를하였다. 또한, 진단에있어서도기침과민증후군이구심성신경의과민성이특징이기는하지만, 현재로는객관적으로정량할수있는검사법이없기때문에단지임상증상만을가지고진단할수밖에없는실정이다 [9]. 후두과민성 (laryngeal hypersensitivity) 후두과민성은만성난치성기침을이해하는데도움이되는또하나의다른개념이다 [11-14]. 무해한자극에대한후두의과민성의증가로정의할수있으며기침, 호흡곤란, 발성장애, 또는성문연축등을동반한후두감각이상의증상들을유발한다. 만성난치성기침의환자들은기침외에도다양한증상을호소하지만, 대부분의환자들에서이러한증상들은후두에국한된다. 그래서감각이상을정의하는데에는후두과민증후군 (laryngeal hypersensitivity syndrome) 이라

3 - 대한내과학회지 : 제 91 권제 1 호통권제 671 호 는용어가좀더적절할수도있을것이다 [15]. 이러한후두의감각이상은기침그자체보다환자들을더불편하게할수도있다. 후두과민성설문지가후두과민성을측정하는데도움이될수있다 [16]. 이설문지는통증 / 온도, 자극증상, 기도폐쇄증상의 3가지그룹으로 1-7점의총 14개의항목으로구성되어있으며정상대조군의평균은 19.2점이며 17.1 점이하이면후두과민성을의심할수있다. 후두과민증후군의다른임상양상으로는모순성대주름운동 (paradoxical vocal fold movement, PVFM), 인두이물감 (globus pharyngeus), 근긴장발성장애 (muscle tension dysphonia) 등이있다 [17,18]. 만성난치성기침의병인기침반사과민성 (cough reflex hypersensitivity) 기침반사과민성은만성난치성기침의중추성또는말초성민감화에관여하는중요한특징이다 [8,19]. 상기도감염에의한기도의자극이기침을유발하는데, 이때기도점막에손상을주고감각신경의염증성신경병증변화를일으켜기침반사의과민성이일어나게된다 [8]. 또한, 바이러스에의한상기도감염에서는기도의 transient receptor potential (TRP) 수용체가상향조절되고 [20] 이로인해기침이반복되면서화학매개체들이분비되는염증성기전을통하여더욱기침을조장하게된다 [8]. 말초성민감화 (peripheral sensitization) 만성기침에서의말초성민감화는인후두, 식도, 비강, 기관지등미주신경에의해감각이매개되는부위에서일어난다. 히스타민이나프로스타글란딘같은염증매개물질들이구심성신경말단 (C-fiber) 을감작시키고구심성신경의흥분도를증가시켜기침의역치를감소시키는데 [21], 이는만성난치성기침에서 TPRV1 수용체의발현의증가와연관이있다 [22]. 기침반사의민감도는 TRPV1 수용체를활성화시키는 capsaicin의흡입으로측정할수있는데, 만성난치성기침에서는 capsaicin에대한기침반사과민성이현저히증가해있다 (Fig. 1) [11]. 비록만성난치성기침에서 TRPV1 수용체의역할이증명되기는하였지만, TRPV1 길항제인 SB 을이용한임상시험에서는의미있는결과를보여주지는못하였다. SB 은 capsaicin 에대한기침반사감수성은유의하게향상시켰지만, 객관적인기침횟수, 기침의강도, urge-to-cough, 기침관련삶의질등의기침에대한임상적인결과에대해서는대조군에비해유의한결과를보이지못하 였다 [23]. 이는기침반사감수성은말초성기전의억제로감소시킬수있지만, 기침자체에대한치료를위해서는중추성기전에대한치료도필요하다고할수있겠다. 중추성민감화 (central sensitization) 중추성민감화는기침을막하려고하는, 하기직전의느낌인 urge-to-cough 라고도하며중추성감각경로의흥분도의증가가특징이다 [24,25]. 중추성민감화는대표적으로신경병증통증의기전으로알려져있는데, 만성난치성기침과신경병증통증사이에는유사한공통점이있어서 [26] 만성난치성기침을신경병증기침으로도생각할수있다. 즉, 신경병증통증에서는말초의감각신경이나중추성투사경로 (central projection pathway) 의조직손상으로신경세포의활성도가변하게되고 ( 말초성또는중추성민감화 ), 이로인하여통각과민증 (hyperalgesia) 이나무해자극통증 (allodynia) 등과같은비정상적인통증이발생한다. 즉, 만성난치성기침인신경병증기침의 3가지특징들, 후두감각이상, 기침과민증 (hypertussia), 무해자극기침 (allotussia) 은신경병증통증과매우유사하다는것이다. 목의감각이상을호소하는후두감각이상은신경병증통증에서의피부의얼얼한느낌 (tingling sensation) 과같은감각이상과유사하고, 기침을유발하는자극에대한과도한기침인 hypertussia 는신경병증통증에서의자극에대해과도하게통증반응을호소하는 hyperalgesia 와유사하다. 기침을유발하는자극에아님에도불구하고기침을하는 allotussia는신경병증통증에서의만지기만해도통증을호소하는 allodynia와유사하다 (Table 1) [27]. 이에대한 Figure 1. Cough reflex sensitivity at baseline, median (interquartile range). *p < vs. healthy controls (HC). C5, capsaicin dose to elicit 5 or more coughs 30 seconds after dose administered; CC, chronic cough; PVCM, paradoxical vocal cord movement [11]

4 - 김성경. 만성난치성기침 - Table 1. Comparison of features of chronic pain and chronic refractory cough [27] Neuropathic pain Neuropathic cough Concept Definition Example Concept Definition Example Paresthesia Abnormal sensation Tingling sensation in the skin Hyperalgesia Increased response to a stimulus that is normally painful but at a reduced threshold Allodynia Pain in response to a stimulus that does not normally produce pain, such as a mechanical or thermal stimulus Increased pain response to a needle stick Pain in response to touch Laryngeal paresthesia Hypertussia Allotussia Abnormal sensation in the throat Increased cough response to a tussigenic stimulus Cough in response to a non-tussigenic stimulus Tickle or itch in throat Fumes, smoke, aspirate Thermal, vocalization, exercise 근거로는피부와기도의말초신경분포에서서로같은종류의신경섬유 (Aβ, Aδ, C-fiber) 로구성되어있다는것과통증과기침을담당하는감각신경의수용체의종류가서로같다는것이다 [26]. 또한, 기능적뇌자기공명영상에서 capsaicin으로자극후 urge-to-cough를느낄때와손바닥에유해한열을가했을때활성화되는뇌영역이서로유사한것도만성난치성기침과신경병증통증사이의유사성을뒷받침하는증거가될수있다 [26]. 기침이유발되기직전의 urge-to-cough를느낄때대뇌피질의여러부위가활성화되는것은알려진기침반사의수준인뇌간 (brain stem) 을넘어서더높은수준의중추성기전 (higher brain regulation) 이만성난치성기침과관련이있음을시사한다고할수있다 [28]. 또한, 만성난치성기침에서 gabapentin [29], pregabalin [30,31], morphine [32], amitriptyline [33] 등의같은중추성신경조절물질에대한치료반응역시만성난치성기침에서중추성민감화의역할을뒷받침하는근거가될수있다 [8,29]. 만성난치성기침에서중추성민감화의기전이관여한다는결과를보여주는연구들을표 2에요약하였다. 성대주름모순운동 (PVFM) 만성난치성기침은 PVFM 과도연관이있다 [11]. PVFM 은 Table 2. Evidence of central sensitization in chronic refractory cough Abnormalities on quantitative sensory testing [18] Overlap in symptoms between chronic refractory cough and laryngeal conditions [13,34] Cortical activation during functional magnetic resonance imaging studies [28,49,50] Cross stimulus responses [18] Response to centrally acting neuromodulators [29,31,32,45] 자극후에흡기시성대주름의내전으로인해성대가열리지않고닫혀버리는비정상적인후두의운동패턴이다. 흔한증상으로는흡기시호흡곤란, 협착음, 목의답답함, 기침등이있는데, 이러한증상들역시만성난치성기침의증상들과유사하다. 즉, 증상, 유발인자, 목소리분석결과, 동반된내과적질환등이만성난치성기침과 PVFM 환자들에서서로다르지않다는점에서 PVFM 역시만성난치성기침의하나의병태생리로여겨지고있다 (Fig. 2) [18]. 만성난치성기침의임상양상만성난치성기침의임상적특징은하루종일발생하는간헐적인기침발작이다. 기침은주로후두근처에서발생하며에어컨이나발성같은정상적으로는기침을유발하지않는자극에기침을하는 allotussia와아주낮은농도의자극에도기침을하는 hypertussia가있다. 후두의불편감이나감각이상도기침을일으키는유발인자가될수있다 [34]. 기침은수개월에서수년동안지속되기도하며특히, 여성에서유병률이높다. 이는 capsaicin에대한기침반사민감도가남성에비해서여성에서더높고 [10,35] 또한여성에서대뇌피질의일차성체성감각의활성도가높은것과연관이있다 [10]. 한연구에서는기침의발생시점이폐경과관련이있다고보고하였는데, 이는에스트로겐농도의감소가기침반사의민감도를높이고, 폐경동안무증상의기도염증이증가되는것으로설명하고있다 [35]. 다른연구에서는만성난치성기침환자들의 42% 에서는기침이바이러스성상기도감염과함께시작하였고바이러스성상기도감염환자의 36-43% 에서는감염후 3개월이상기침이지속되었다고보고하였다 [19,36]. 환자들은기침과더불어후두증상도흔히호소하며만성난치성기침환자의약 40% 에서발성장애가동반된다

5 - The Korean Journal of Medicine: Vol. 91, No. 1, Figure 2. Symptom scores based on symptom frequency and severity scale in the CRC, PVFM, globus and MTD groups. All domains were higher in case groups vs controls (p < 0.05). CRC, chronic refractory cough; MTD, muscle tension dysphonia; PVFM, paradoxical vocal fold movement [18]. [14,34]. 후두과민성과기침반사과민성은건강한정상대조군에비해서증가되어있으며성문폐쇄반사 (glottic closure reflex) 라고하는후두자극에대한성문의반사적인닫힘역시만성난치성기침환자에서증가되어있다 [37]. 만성난치성기침의진단만성난치성기침은만성기침의알려진원인에대한검사및치료에도불구하고기침의호전이없을때진단할수있다 [38]. 하지만기침의심각한원인을암시하는경고증상 (alarm symptom) 이있을경우에는이에대한검사가먼저필요하다 (Table 3). 객혈, 과도한흡연, 호흡기계진찰이나흉부방사선사진의이상소견등의대표적인증상이있을경우에는폐암, 감염증, 또는심각한질환에대한검사가즉시이루어져야한다. 만약경고증상이없다면치료가가능한흔한원인들에대한검사가필요하다. 여기에는천식 ( 병력, 폐기능검사, 기관지유발검사, 호기산화질소검사 ), 호산구성기관지염 ( 유도객담호산구, 호기산화질소검사 ), 비부비동염 ( 비강내시경 ), 위식도역류질환 ( 위식도내시경 ) 에대한검 Table 3. Red flags: alarm symptoms and findings in chronic cough [51] Hemoptysis Smoker with > 20 pack year smoking history Smoker over 45 years of age with a new cough, altered cough, or cough with voice disturbance Prominent dyspnea, especially at rest or at night Substantial sputum production: more than one tablespoon a day Hoarseness Systemic symptoms: fever, weight loss Complicated gastroesophageal reflux disease (GERD) symptoms associated with weight loss, anemia, overt gastrointestinal bleeding (hematemesis or melena), severe symptoms, dysphagia, odynophagia, or failure of empiric treatment for GERD Recurrent pneumonia Abnormal clinical respiratory examination Abnormal chest radiograph 사들이포함된다. 이때에도놓치지말아야할심각한질환에대해서는항상염두에두고객관적인검사를포함한자세한병력청취와신체검진이적절이이루어져야한다 (Table 4)

6 - Sung Kyoung Kim. Chronic refractory cough - Table 4. Remediable conditions and conditions not to be missed in patients with chronic cough [51] Remediable conditions Asthma Gastroesophageal reflux disease Obstructive sleep apnea Angiotensin converting enzyme inhibitor use Eosinophilic bronchitis Rhinosinusitis Serious cough related conditions Cancer of the larynx, bronchus, or lung Parenchymal lung disease: chronic obstructive pulmonary disease, interstitial pulmonary fibrosis, bronchiectasis, sarcoidosis, pneumothorax Cardiovascular disease: left ventricular failure, pulmonary embolism, aortic aneurysm Infection: tuberculosis, lung abscess, pertussis 만성난치성기침은충분한내과적검사및치료에도불구하고기침이지속되는경우로정의되는배제진단으로진단이이루어진다. 이러한환자들의검사에있어서는만성기침의접근에근거한지침이필수적이다 [39,40]. 이러한지침에근거하여충분한검사및치료가이루어졌음에도불구하고기침이지속되는경우만성난치성기침으로진단할수있다. 만성난치성기침의치료 만성난치성기침의치료는비약물치료와약물치료두가지로나눌수있다. 비약물치료로는언어병리치료 (speech pathology management) 가있고약물치료에는중추신경계에작용하는약물인신경조절제 (neuromodulator) 가있다. 언어병리치료 (speech pathology management) 언어병리치료의첫번째는만성난치성기침의특징을파악하는것이다. 기침의특성은어떠한지, urge-to-cough나 PVFM은없는지, 목소리변화는없는지등을파악하는데, 이는잘수련된언어병리학자 (speech pathologist) 에의해이루어져야한다. Urge-to-cough에대해서는어떻게유발되는지즉, 특정한냄새나운동, 또는말하거나호흡하거나, 먹거나마실때유발되는지등의유발인자를찾는것이중요하다. 그래서기침이발생하기전, 이러한 urge-to-cough를느낄때이것을완화시켜서기침을억제하는테크닉을코치하는것이다. 목소리특성의확인도필요한데, 목소리의톤의높고낮음이나, 큰소리를내거나, 오랫동안말할때기침이유발되는건아 Table 5. Speech pathology management for chronic refractory cough [27] Education Cough can be triggered by irritation Cough is not always necessary Cough has limited physiological benefit in this condition Cough is under autonomic and voluntary control Symptom control techniques Cough suppression swallow Cough control breathing Paradoxical vocal fold movement release breathing Release of laryngeal constriction Reducing laryngeal irritation Behavioral management of reflux Reduce phonotraumatic behaviors Hydration Minimize exposure to irritating substances Psychoeducational counselling Treatment is hard work Setting realistic goals 닌지파악한다. 또한, PVFM 등의유무확인을위한후두평가도필요하다. 이렇게얻어진정보로언어병리치료프로그램을만든다. 언어병리치료는크게 4가지부분으로나눌수있다. 환자의기침의특성에대해교육을하고, 기침증상을조절하는테크닉을알려주고, 후두의자극을감소시키는법을알려주고, 심리교육상담을하는것이다 (Table 5) [27]. 언어병리치료의목표는기침을유발하는감각을확인하는법을교육하여기침의수의적인조절능력을향상시키고, 기침을다른신체반응, 예를들면호흡이나연하운동으로대신하게하고, 후두를자극시킬수있는행동을변화시키는것이다. 만성난치성기침에서이러한언어병리치료의효과는몇몇연구들을통해서도그효과가입증되었다 [12,41-44]. 신경조절제 (neuromodulator) 중추성신경조절제 (gabapentin, pregabalin, morphine, amitriptyline, baclofen) 는만성난치성기침의병인과관련이있는신경민감화 (neural sensitization) 에작용한다 [45]. Morphine, gabapentin, amitriptyline, pregablain 은무작위대조시험에서기침관련삶의질과레스터기침설문점수 (Leicester cough questionnaire score) 를대조군보다유의하게향상시켰다 (Table 6) [29,31-33]. Baclofen은무작위대조시험은아니지만비무작위비교연구에서대조군보다기침반사감수성을유의하게

7 - 대한내과학회지 : 제 91 권제 1 호통권제 671 호 Table 6. Effects of neuromodulator drugs on cough quality of life Study Tool used Drug Change in score from baseline (points) Amitriptyline Jeyakumar, et al. [33] CQLQ Guaifenesin-codeine 2.92 Morphine 3.2 Morice, et al. [32] LCQ a Placebo 1.2 Gabapentin 2.5 Ryan, et al. [29] LCQ a Placebo 1.1 Pregabalin b 6.6 Vertigan, et al. [31] LCQ a Placebo b 3.3 CQLQ, cough quality of life questionnaire; LCQ, Leicester cough questionnaire. a Minimally important dose is 2. b Treatment given simultaneously with speech pathology treatment. 감소시켰으며 [46], 역류성기침에서도유의한효과를보여주었다 [47]. 만성난치성기침의신경조절제치료에대한한체계적문헌고찰을보면무작위대조시험이 2개밖에없고연구들이모두이질적이기는하지만, 대부분의기침관련평가지표들에서임상적으로유의한효과가있음을보고하였다 [38]. 하지만, 이러한언어병리치료와신경조절제도제한점들이있다. 언어병리치료는기침을감소시키기는하지만, 완전히제거하지는못하고신경조절제는어지러움, 입마름, 졸리움, 인지력장애등의부작용이있다. 또한, 약제를중단하였을경우다시재발한다는단점이있다. 그래서최근에언어병리치료와신경조절제의병합치료에대한연구가진행이되었고그결과가발표가되었다. 비약물치료와신경조절제의병합치료최근만성난치성기침에서언어병리치료와신경조절제인 pregabalin의병합치료에대한연구가진행되었다 [31]. 40 명의환자를무작위배정하여한군은언어병리치료와 pregabalin 300 mg을병합하여치료하였고, 다른한군은언어병리치료와위약을병합하여두군을서로비교하였다. 기침에대한객관적인평가지표들, 레스터기침설문점수와기침 (visual analogue scale, VAS) 점수는단독치료군보다병합치료군에서더좋은효과를보였다. 중요한것은이전의 gabapentin 연구와는 [29] 달리치료종료후에도기침의억제효과가유지되었다는점이다. 기침반사민감도에서는두군모두에서좋은효과를보였지만, 특히병합치료군에서치료전과후의차이가더컸고이러한효과역시치료종료후에도계속유지되었다. 결론적으로만성난치성기침에서약물 치료와신경조절제의병합치료는서로다른경로에작용하여좀더완전한기침의해소를가져올수있었다. 새롭게개발중인치료약제최근에는만성난치성기침에대한새로운약제들이연구되고있는데, 주로기도의말초기침수용체에대한길항제가이에속한다. TRPV-1 길항제는무작위대조시험에서기침반사민감도가 TRPV-1 길항제치료군에서치료전후로유의하게좋은효과를보였다. 하지만, 기침의객관적인지표인시간당기침횟수나기침 VAS 점수, 레스터기침설문점수등에서는두군간에유의한차이를보이지못하였다. 즉, TRPV-1 길항제는기침반사민감도는개선시켰으나기침에대한임상적인효과는보여주지못하였다 [23]. 퓨린성 (P2X3) 수용체는기도의구심성미주신경에존재하며감각뉴런의과민성을일으킨다. 만성난치성기침환자를대상으로퓨린성수용체길항제 (AF-219) 의효과를연구한무작위대조시험에서는기침의증상에대한여러가지지표들이대조군에비해 AF-219 치료군에서유의하게좋은효과를보여주었다 [48]. 기침반사민감도에대한 AF-219 의효과에대해서는현재임상연구가진행중이다 년미국흉부의사협회가이드라인최근에미국흉부의사협회에서만성난치성기침에대한가이드라인과전문가위원단의견 (expert opinion) 을발표하였다 [45]. 여기에서는만성난치성기침을충분한검사및치료에도불구하고 8주이상지속되는경우로정의하였다. 가

8 - 김성경. 만성난치성기침 - Figure 3. A proposed algorithm detailing a management approach to the patient with difficult-to-treat cough [39]. 이드라인으로는그림과같이제시하고있으며 (Fig. 3), 만성난치성기침이라고판단이되면언어병리치료를하거나 gabapentin의경험적치료를하거나기침전문가한테의뢰를하거나임상시험에포함시킬것을권고하고있다. 이외에도아래와같은 6개의권고사항을발표하였다. 1. 만성난치성기침은검사나치료에도불구하고 8주이상의설명되지않는기침으로정의한다. 2. 만성난치성기침환자는가이드라인이나프로토콜에근거한진단을받아야하며, 여기에는기관지과민성과호산구성기관지염에대한객관적인검사또는코르티코스테로이드경험적치료등이포함된다. 3. 원인불명의만성난치성기침환자는다양한방식의언 어병리치료가권장된다. 4. 만성난치성기침환자에서기관지과민성이나유도객담호산구검사, 호기산화질소검사에대한결과가음성일경우에는흡입용코르티코스테로이드가처방되어서는안된다. 5. 만성난치성기침환자에서 gabapentin 치료를시도해볼수있는데, 치료전부작용이나위험- 이익프로파일을충분히설명해야하고, 치료후 6개월시점에서는이러한위험- 이익프로파일의재평가후약물치료의지속여부를결정해야한다. 6. 만성난치성기침환자에서산성위식도역류질환에대한정밀검사가음성일경우, 프로톤펌프억제제의사용

9 - The Korean Journal of Medicine: Vol. 91, No. 1, 을권고하지않는다. 하지만, 이상의권고사항에대한권고등급은전부전문가의견이거나 2B 또는 2C의매우약한권고등급이므로실제임상에적용할때에는이러한점을잘고려해야하겠다. 결 만성난치성기침은진료지침이나프로토콜에따른충분한검사및치료에도불구하고명확한원인을찾지못하고기침이 8주이상지속되는경우를의미한다. 병태생리에는기침반사과민성, 말초성및중추성민감화, PVFM 등이관여하는것으로알려져있으며기침과민증후군또는후두과민성의개념으로이해되고있다. 치료로는언어병리치료와신경조절제의약물치료, 또한이둘의병합치료도사용될수있다. 지난 10여년동안만성난치성기침의이론적이해와평가및치료등에대한점진적인발전이있었으며이제는하나의임상적인실체 (clinical entity) 로인식되고있다. 하지만, 진단기준이나병태생리가아직도밝혀지지않은부분이많고치료에있어서도구체적인적응증이나반응평가등객관적인기준이애매하므로향후추가의연구가더진행되어야하겠다. 중심단어 : 기침 론 REFERENCES 1. Chung KF, Pavord ID. Prevalence, pathogenesis, and causes of chronic cough. Lancet 2008;371: Song WJ, Chang YS, Faruqi S, et al. The global epidemiology of chronic cough in adults: a systematic review and meta-analysis. Eur Respir J 2015;45: Song WJ, Morice AH, Kim MH, et al. Cough in the elderly population: relationships with multiple comorbidity. PLoS One 2013;8:e Rhee CK, Jung JY, Lee SW, et al. The Korean cough guideline: recommendation and summary statement. Tuberc Respir Dis (Seoul) 2016;79: Irwin RS, French CT, Lewis SZ, et al. Overview of the management of cough: CHEST guideline and expert panel report. Chest 2014;146: McGarvey LP. Idiopathic chronic cough: a real disease or a failure of diagnosis? Cough 2005;1:9. 7. Morice AH. The cough hypersensitivity syndrome: a novel paradigm for understanding cough. Lung 2010;188 Suppl 1:S87-S Chung KF. Approach to chronic cough: the neuropathic basis for cough hypersensitivity syndrome. J Thorac Dis 2014;6:S699-S Morice AH, Millqvist E, Belvisi MG, et al. Expert opinion on the cough hypersensitivity syndrome in respiratory medicine. Eur Respir J 2014;44: Morice AH, Jakes AD, Faruqi S, et al. A worldwide survey of chronic cough: a manifestation of enhanced somatosensory response. Eur Respir J 2014;44: Ryan NM, Gibson PG. Characterization of laryngeal dysfunction in chronic persistent cough. Laryngoscope 2009;119: Vertigan AE, Theodoros DG, Gibson PG, Winkworth AL. Efficacy of speech pathology management for chronic cough: a randomised placebo controlled trial of treatment efficacy. Thorax 2006;61: Vertigan AE, Theodoros DG, Gibson PG, Winkworth AL. Voice and upper airway symptoms in people with chronic cough and paradoxical vocal fold movement. J Voice 2007;21: Vertigan AE, Theodoros DG, Winkworth AL, Gibson PG. Perceptual voice characteristics in chronic cough and paradoxical vocal fold movement. Folia Phoniatr Logop 2007;59: Hull JH, Menon A. Laryngeal hypersensitivity in chronic cough. Pulm Pharmacol Ther 2015;35: Vertigan AE, Bone SL, Gibson PG. Development and validation of the Newcastle laryngeal hypersensitivity questionnaire. Cough 2014;10: Morrison M, Rammage L, Emami AJ. The irritable larynx syndrome. J Voice 1999;13: Vertigan AE, Bone SL, Gibson PG. Laryngeal sensory dysfunction in laryngeal hypersensitivity syndrome. Respirology 2013;18: Haque RA, Usmani OS, Barnes PJ. Chronic idiopathic cough: a discrete clinical entity? Chest 2005;127: Abdullah H, Heaney LG, Cosby SL, McGarvey LP. Rhinovirus upregulates transient receptor potential channels in a human neuronal cell line: implications for respiratory virus-induced cough reflex sensitivity. Thorax 2014;69: Canning BJ, Chang AB, Bolser DC, et al. Anatomy and neurophysiology of cough: CHEST guideline and expert panel report. Chest 2014;146: Groneberg DA, Niimi A, Dinh QT, et al. Increased expression of transient receptor potential vanilloid-1 in airway nerves of chronic cough. Am J Respir Crit Care Med 2004;170: Khalid S, Murdoch R, Newlands A, et al. Transient receptor potential vanilloid 1 (TRPV1) antagonism in patients with

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