Professor Alyn H MoriceAcademic Department of MedicineCastle Hill HospitalCastle RoadCottinghamEast YorkshireHU16 5JQ
Tel: 01482 624067Fax: 01482 624068Email: [email protected]
Cough is the commonest respiratory symptom, indeed it is probably the commonest of allsymptoms which results in a consultation. The ten yearly morbidity Statistics in GeneralPractice Survey reveal that consultation for cough and upper respiratory tract infectionoutweighs any other presenting condition by an order of magnitude. In the UK themarket for cough remedies, most of which are at best poorly effective, is ten millionpounds, whereas in the USA the cough/cold market is a staggering thousand milliondollars. This massive health care burden is poorly understood in terms of etiologicalmechanisms and is very poorly treated, even with those drugs currently available. Because of a lack of knowledge of the pharmacology of these agents many patients areunder treated.
In contrast to acute cough which is almost universally caused by a variety of viralrespiratory pathogens, chronic cough is a diagnostic challenge which causes heart sinkin most clinicians. In reality however the vast majority of chronic cough is easilyexplicable with a knowledge of the mechanisms sustaining cough. The problem iscompounded by the fact that cough may arise from the upper respiratory tract – therealm of surgeons specialising in otolaryngology or the oesophagus and stomach, areasof expertise of the gastroenterologists. Yet, patients with chronic cough are mostlyreferred to chest physicians who have little or no training in either of these other areas. Thus, from general practice the patient is referred to the ‘specialist’ but unfortunately thespecialist is poorly equipped to deal with the range of systems covered in the properinvestigation and diagnosis of the chronic cough syndrome. Specialist cough clinics arerelatively few in number and require the combined skills of specialist nursing staff,respiratory function tests not normally found within the average district general hospital,accurate and well tried oesophageal and gastric physiology departments and skilled andknowledgeable ENT and oesophageal surgeons. Without such a complexmultidisciplinary approach many patients fall through the diagnostic net and are classifiedas ‘idiopathic’. The complete and thorough investigation of a patient with chronic coughrequires a true multidisciplinary approach. When such an approach is applied aremarkably high success rate is achievable. Some American authors claim a 100%success rate! On this side of the Atlantic the rates are less spectacular. The majority ofpatients, between 80 and 90% are successfully treated with sufficient resolution ofsymptoms to allow a return to a normal life.
My own experience in setting up a cough clinic after moving to Hull has confirmed thatpatients with chronic intractable cough can be treated successfully in specialist clinics. Our own success rate is running at about 90% over the past 250 referrals. What hasbeen striking is that the quality of referrals has dramatically changed over this period oftime. Instead of being asked to see patients who have had no trials of therapy for coughwe are increasingly being asked to review patients who have undergone therapeuticchallenge with all of the correct litany of drugs. This must mean that an increasinglylarge selection of patients are being successfully treated in general practice and one ofthe major aims of this monograph is to equip clinicians in primary care with theknowledge to enable all but the most intractable cases of chronic cough to besuccessfully treated without the need for referral.
Because acute cough and chronic cough have such widely differing causes andtreatments I have made an attempt to strictly differentiate these two syndromes aroundthe arbitrary cut off point of eight weeks. Because acute cough is a distressing butbenign and self limiting condition current therapy is designed purely around suppressionof cough. Whilst some of the suggested measures may be of use in the treatment ofchronic cough, particularly in the short term, they should not be viewed as adequate
therapy for chronic cough. In contrast, chronic cough requires careful consideration ofthe diagnosis. Many hospital based authorities recommend rigorous evaluation usingmany tests, indeed, in the clinical protocol suggested by Palombini, all patientsunderwent a battery of 20, sometimes unpleasant, diagnostic tests. In contrast to thisinvestigational feeding frenzy, most patients with chronic cough can be diagnosed from acareful history followed by appropriate therapeutic challenge. My objective is to providethe reader with the necessary knowledge to enable them to correctly advise andameliorate both acute and chronic cough in the overwhelming majority of patients. Andy I have use I a lot here. Should this be we and I think you need to add a bit aboutthe kids section in this intro
Cough is a protective reflex which removes inhaled foreign bodies and excessivesecretions from the respiratory tract. Thus, the main anatomical areas stimulating thecough reflex are located in the upper airways, particular the larynx, and cough sensitivitydiminishes as the airways divide until, in the smallest airways, cough cannot be elicited. It is important to realise that cough can be precipitated at sites other than at therespiratory tract. Instrumentation of the ear may precipitate coughing as can, in sensitiveindividuals, irritation of the oesophagus. The common thread which unites of all of thesedisparate sites is that they are supplied by the vagus nerve. Stimulation of vagalafferents (there is still much debate as to the type of fibre which is stimulated) leads tostimulation of the brain stem. A distinct cough centre has never been clearly identified. Throughout this afferent part of the cough reflex neuronal traffic is subject to majormodification. In man cortical influences are very important and it is possible toconsciously suppress cough for considerable periods. Similarly the desire to cough maybe inhibited by simple measures such as drinking cold water. This may result fromstimulation of inhibitory pharyngeal receptors and a combination of pharyngeal andcortical effects may underlie the activity of cough linctus with a so called demulcentaction.
Recent findings have made it clear that there is extreme plasticity of the afferent arm ofthe cough reflex and as a consequence, even when there is obviously a biochemicalmechanism producing the cough as in ACE inhibitor cough, cough may persist formonths after stopping treatment. In children such repetitive behaviour may underliehabitual cough. Whilst chronic cough may have very important psychological aspects wedo not believe that psychogenic cough is common. Indeed, studies have shown thatpsychological abnormalities disappear once the organic underlying cause of the chroniccough is treated.
The efferent arm of the cough reflex is a coordinated contraction of the respiratorymusculature against a closed glottis. The glottis then opens and the expelled airapproaches the speed of sound shearing off any mucus within the airways. This givesrise to the characteristic low frequency component of a wet cough. Because of a highdegree of coordination required in the respiratory musculature, particularly in the upperairways and larynx, neurological disorders such as stroke, motoneuron disease andParkinsonism may have profound effects on the efferent arm of the cough reflex.
We are beginning to understand the basic biochemical mechanisms which translatechemical or mechanical stimulus into an afferent nervous impulse. In experimentalcough the most frequently used agents for producing cough fall into two broad groups. Firstly acids, particularly complex organic acids, have been used to provoke cough sincethe 1950s. Since it seems immaterial as to which acid is used it is likely that coughreceptor is sensitive to protons. Secondly the pungent extract of peppers, capsaicin andother vanilloid compounds such as resinoferatoxin are the most potent tussive agentsknown. The putative cough receptor is an ion channel located in sensory nerves which issensitive to both acid and capsaicin . Since capsaicin is a vanilloid the receptor is calledthe vanilloid receptor or VR1. The vanilloid receptor is modulated by a range ofinflammatory mediators, particularly by lipoxygenase products similar to the leukotrienesinvolved in asthma. Through this biochemical pathway asthma other forms ofinflammation may modulate the cough reflex and it is likely that viral cough also highjacksthis receptor to produce what is the commonest symptom presenting in clinical medicine.
The vast majority of acute cough is caused by upper respiratory tract viral infection. Itmakes a perfect sense for respiratory viruses and bacteria to have evolved the ability tocause cough. Once an organism has successfully invaded the respiratory tract its mainproblem for continued survival is how to spread to the next host. Some viruses do this byproducing intense coryza and transmitting themselves from person to person by manualtransmission of infected secretion. However, the majority are required to transmitthemselves in aerosolised droplets. The ability to produce a cough is therefore a vitalpart of the pathogenic armamentarium of the respiratory tract virus. From the host’spoint of view there is little reason to suggest that the cough produced in an upperrespiratory tract infection is useful. Whilst small amount of secretions may beexpectorated they in no way contribute to the clearing of the airways in normal subjects. If one looks at a more extreme example of infective airway inflammation such ascommunity acquired pneumonia, despite sometimes extensive consolidation only a fewmls of sputum is produced, the vast majority of the purulent exudate being removed byphagocytosis via the blood stream. Thus, in normal subjects infective cough is likely tobe detrimental and there is no evidence that effective cough suppression in respiratorytract infection is harmful, indeed, it may even reduce viral transmission.
An exception to this generalisation are subjects with pre-existing lung disease. Inparticular patients with bronchitis, bronchiectasis and related conditions such as cysticfibrosis should only have treatments designed to suppress cough under specialistsupervision. Such patients can be easily identified however; they invariably have ahistory of chronic sputum production, usually of considerable volume. Such patients withchronic productive cough are at risk from extensive mucus plugging which can lead to adeterioration in the matching of ventilation and perfusion within the lung and the dangerof consequential respiratory failure. In normal subjects there is no such risks. In patientswith chronic sputum production the clinician’s most important initial response is to sendsputum for culture and sensitivity. This is because frequently ‘viral’ respiratory tractinfections lead to an exacerbation of a colonising bacteria and such organisms may benot those usually found in infections in a previously normal respiratory tract. Bacteriasuch as haemophilus influenzae, moraxella catarrhalis, pseudomonas aeruginosafrequently do not respond to first line respiratory antibiotics such as amoxicillin andtherapy should be directed by culture and sensitivities. In the rest of this chapter it will beassumed that suppression of cough is directed at patients with previously normal lungs.
It is helpful to understand the natural history of some of the more common respiratorytract pathogens since this can predict the time course and intensity of disease. Unfortunately in our present state of knowledge there is only a relatively few areas wherewe can specifically intervene in the etiology of cough. It is clear from cough challengestudies where subjects are asked to inhale increasing doses of agents such as capsaicinor citric acid that the cough reflex is heightened during the viral respiratory tract infection. This explains the precipitation of cough by non specific stimuli such as cold air andpollutants such as tobacco smoke. How viruses cause this up-regulation of the reflexremains a mystery.
Epidemiological studies have shown that the average person has a clinically observablerespiratory tract infection by virus three or four times per year. The viruses causing theseinfections include influenza, parainfluenza, rhinovirus, adenovirus, respiratory syncytial
and the respiratory corona virus. All of these viruses share a common short incubationperiod of between one and four days.
Because of its ability to undergo antigenic shift and genetic recombination influenzaoccurs in epidemics. Influenza viruses are RNA viruses of the orthomyxoviruses groupand are classified into three serotypes, A, B and C. Influenza A is the commonest andmost severe type. The viral structure is important in terms of therapy since the viralproteins required for successful binding to the host cell, haemagglutinin andneuramidase, are targets for therapy; in particular neuramidase is blocked by the anti-influenza drug Relenza. Clinically influenza has an incubation period of two days. Apresentation of a patient with fever in the presence of a known outbreak of influenza issufficient for accurate diagnosis. Typically the cough comes on within six hours of startof illness and maybe prolonged for at least two to three weeks after other symptomshave resolved. The patient failing to respond, particularly those with diseased lungs,bacterial super-infection should be considered.
The most widely used method of prophylaxis against influenza is the use of vaccination. Two types of vaccine are available, one consisting of inactivated whole virions and thesecond ‘split’ subunits. They are administered in two doses in children, one month apart,and annually to susceptible individuals.
Because of the changing nature of the influenza virus, each year a different vaccine willbe required. The actual nature of the vaccine is recommended by the World HealthOrganisation and the antigenic type thought to be the most likely to be responsible for thecoming season’s infections are grown on chick embryos. This latter method of cultureleads to them being contraindicated in those with hypersensitivity to eggs.
Because of the annual variation in the influenza virus and the necessity of the vaccinebeing a best guess, vaccination is not a universally successful strategy and protectionmay range around 75% on average. This is too little to prevent epidemics but is a usefulstrategy in individual patients. Influenza vaccine is therefore recommended only for highrisk individuals. The following groups are specifically targeted:
• chronic respiratory disease including asthma
• immunosuppression due to disease or treatment, including asplenia or asplenic
Immunisation is also recommended for all persons over 65 years and for residents ofresidential homes for the elderly and long stay facilities. In pandemic years vaccinationof medical staff is also recommended.
Amantadine hydrochloride has been shown to be effective in short term prophylaxis forinfluenza infection. It probably acts by inhibiting viral uncoating or transcription of the
viral RNA. Amantadine is not without side effects and should only be used for high riskpatients.
Parainfluenza viruses differ from influenza viruses in that they are much moreantigenically stable and have a different pattern of assembly within infected cells. Thereare four subtypes. Types one and three are particularly important causing serious lowerrespiratory tract infections, croup and tracheobronchitis in infants and young children. Inall parainfluenza viruses are thought to be responsible for a fifth of all non bacterialrespiratory tract disease in childhood.
Clinically the disease may present with abrupt croup but is more commonly gradual onsetprogressing over two to three days. The condition usually remits within two weeks. Since immunity to re-infection is only transient it is one of the commonest causes of thetypical infective cough which plagues families with small children. There is no currentmethod of control or specific therapy.
Respiratory syncytial virus (RSV) is the single most important aetiological agent in coughin infancy. RSV occurs in epidemics, usually between the autumn and early spring. Each outbreak lasts between two and three months and can involve as many as half ofall families with children. It seems that older family members introduce the virus to theyounger children, in whom most of the serious effects are seen. There is also a secondpeak of infectivity in the elderly.
The usual incubation period is one to four days and the onset is characterised by rhinitis. The disease rapidly reaches a peak and is characterised by paroxysmal cough,wheezing and frequently respiratory distress in the younger patient. Stridor may or maynot be present and in its absence the mistaken diagnosis of asthma is sometimes made. Unfortunately, immunity to RSV infection is transient so re-infection is common.
Ribavirin may be given by inhalation for the treatment of the severe bronchiolitis causedby RSV in infants.
Palivizumab is a recently introduced monoclonal antibody indicated for the prevention ofRSV infection in infants. Its use is restricted to those at severe risk.
There are over 100 serotypes of adenovirus. Perhaps eight of these serotypes areimportant in the production of a syndrome of severe acute cough. Clinically adenovirusinfection may be detected by the presence of pharyngitis and/or conjunctivitis. Indeed,the phrase pharyngoconjunctival fever has been described as the illness associated withadenoviral infection. Immunity following infection is good but since so many serotypesare associated with cough then there is plenty of opportunity for repeated infectionswithin a lifetime. There is no specific therapy.
Rhinoviruses are known as the common cold virus. In fact, they represent over 100serotypes and are the major cause of mild upper respiratory tract infection and cough inchildren and adults. Because of the myriad of serotypes of rhinoviruses immunity to theclinical disease is very poor and there is no current specific therapy.
These viruses are similar in clinical presentation to rhinoviruses and may be responsiblefor between 5 and 10 % of human coughs and colds.
When cough, which has been precipitated by viral respiratory tract infection persists forlonger than eight weeks the syndrome is termed post viral cough. This clinicallyrecognised condition is represented within the European literature but is not mentioned instudies from America. This is one of a number of examples of different appreciation of‘diseases’ in different societies.
Some patients endure repeated episodes of post viral cough and it seems that they arepredisposed to sustained increase in the cough reflex following viral inflammation. Thisheightened sensitivity can be demonstrated with inhalational cough challenge. It ispossible that the receptors responsible for transmitting cough are upregulated by theinflammation of respiratory tract infection and that the upregulation continues well afterthe virus has disappeared. Post viral cough can be resistant to treatment. Both shortacting bronchodilators and anti cholinergic agents have been tried and been found to beineffective. Inhaled steroids may work in some patients but evidence is difficult to obtainin a condition which remits spontaneously. Once again clinical trials with adequatenumbers of patients have not been performed. A pragmatic approach would be to treatpost viral cough in the same fashion as viral cough and await spontaneous resolution.
A number of interesting features of acute cough may be gleaned from the MorbidityStatistics in General Practice Survey. The data set is collected by participating practicesand represents a snapshot of consultation and diagnosis within England and Wales. Presentation with upper respiratory tract infection is by far the commonest consultation ingeneral practice and, therefore, represents an enormous workload within the NationalHealth Service. The rate of consultation varies enormously with age and sex. Perhapsunsurprisingly children, or rather their parents, consult at a very high rate: a mean of sixconsultations per annum. The rate rapidly falls in childhood and at age 15 a veryinteresting gender difference appears in consultation rates. During the reproductiveyears consultations are twice that for women than they are for men. After the age of 55consultation rates in both men and women become equal again. Whilst this could beexplicable by societal differences in that women have easier access to general practiceand consult more, this is not borne out by examination of the statistics for othersymptoms and there are intriguing clues to the fact that women may have a heightenedcough reflex compared to men. Women exposed to cough challenge with protussiveagents cough twice as much as men or conversely cough the same amount at a lower
dose. This could be explained as being an artifact of inhaling drug into a smaller lungvolume but women are also over-represented in those patients who develop ACEinhibitor cough. Again, the ratio of men to women is approximately two to one. Thus, itis possible that the increased consultation rate seen in women in the reproductive yearsis due to an intrinsically heightened cough reflex in women.
The reason for the well recognised winter exacerbation of respiratory tract infectioninduced cough is unknown. In recent years this has only been in part due to influenza. The other major viruses circulating causing the winter exacerbation are adenovirusesand respiratory syncytial virus. The seasonal nature of acute cough makes forpredictable strain on the Health Service. The few specific remedies available to us suchas influenza vaccination and the prophylactic use of drugs such as Relenza may have animpact on winter exacerbations but there is still each year an increase of ten fold in thenumber of consultations. One method of reducing patient contact may be by supplyingsimple written advice such as that detailed in Table 1.
By definition acute cough is benign and self-limiting. A case can be made therefore forwithholding treatment and indeed this is what the majority of the population does. However, some infections produce cough of such distressing intensity that treatment maybe requested or even demanded. Such treatment was recently reviewed by the Drug &Therapeutics Bulletin and it was concluded that there was no effective treatment. This isbecause there is a marked lack of clinical trial evidence in this area. Whilst thisobservation is correct I believe the conclusion to be wrong. The problem with determiningwhat is efficacious in cough arises from the extreme difficulty of performing properrandomised, double blind studies in a variable symptom such as acute cough. Coughitself is a very variable and episodic phenomenon and within a given population there isalso a marked intersubject variation in cough intensity and duration. Finally, in asymptom caused by a wide variety of different organisms of varying natural history,providing adequate power to compare treatment with the control group requires vastnumbers of patients. Thus, there is no gold standard clinical study in the literature onwhich to base treatment strategies. I believe however, absence of evidence is notevidence of absence (of therapeutic effect).
If one takes second line evidence, such as those obtained from cough challenge studiesand there is a wealth of evidence suggesting that many treatments available do have asignificant effect on the cough reflex.
As alluded to previously there have been very few well conducted studies in thetreatment of acute viral cough. Based on indirect evidence from challenge studiestreatment aimed at cough suppression can be considered at least partially evidencebased.
This antitussive agent is virtually unknown within the prescribing medical community andyet is the commonest used antitussive. Its efficacy in cough suppression has beenshown in several studies but dosing in over the counter medicines is rarely adequate. Being the dextro isomer of morphine dextromethorphan is virtually devoid of opiate sideeffects and causes little constipation, drowsiness or euphoria except at extremely high
doses. Because of its very good safety profile it is found in the majority of coughremedies. There is a dose response in terms of efficacy on the cough reflex and innormal adults 60 mg will give significant suppression of the cough reflex. We havedemonstrated that the effects of dextromethorphan are long lived and, indeed, one studyshowed significant suppression of cough 24 hours after dosing. The schedule for dosingin most cough remedies therefore is illogical and is not based on a knowledge ofpharmacokinetics. Patients should take an adequate first dose of medication ie 60 mg inthe adult and repeat dosing should be infrequent rather than the qds recommended.
Dextromethorphan has an interesting metabolism in that it is converted to the less activecompound dextrorphan in the liver by the cytochrome P4502D6. This cytochrome ispolymorphic in that approximately 1 in 10 of the caucasian population has little or noenzyme activity. These slow metabolisers will have long lived high drug levels, but giventhe safety of dextromethorphan this appears to have no deleterious effects.
Unlike dextromethorphan codeine is an agonist at the conventional opiate receptors. Treatment of cough with codeine produces the usual spectrum of side effects, which at adose required for effective antitussive activity may be unacceptable to many patients. Ina recent clinical study 60 mg of codeine was equivalent in terms of cough suppression todextromethorphan but a considerable number of our subjects suffered profoundhypotension, nausea and dysphoria. So, whilst codeine is often seen as the goldstandard in terms of antitussive therapy its side effect profile makes it unsuitable forroutine clinical practice. This tendency for side effects has been got over in manyproducts by inadequate dosing leaving the codeine portion of any remedy little more thana placebo.
Alcohol in the form of spirits has been demonstrated to effectively suppress the coughreflex. In adult patients this can be particularly successful for nocturnal coughsuppression. In my own hands a 10 year old malt whisky from Islay appears particularlyeffective.
Menthol is an effective cough suppressant working on ion channels to diminish theactivity of the afferent neurons of cough reflex. The major problem with menthol therapyis that there is no suitable delivery device. Suppression of evoked cough has beendemonstrated even with chest rubs. Oral therapy is ineffective due to the rapidmetabolism of the menthol. Sustained release of menthol from buccal absorption is themost usual strategy used in cough linctus. Some patients with chronic cough findsucking of menthol or menthol/liquorice lozenges useful. In infants menthol solutions maybe administered by application to clothing or bedding.
The three common causes of chronic cough, cough predominant asthma, oesophagealdisease and rhinitis may present without any other clues to diagnosis. However, everyeffort should be made to find a specific diagnosis in an individual patient since therapy isfrequently lifelong and therefore errors are costly. Clues to the diagnosis may beobtained in the history but this should be considered in the light of the therapeuticresponse. A common presentation to the cough clinic is "asthma" without any responseto medication. The cough remits on withdrawal of inhaled medication and institution oftreatment for the otherwise asymptomatic reflux or rhinitis.
A major difficulty with the diagnosis of asthmatic cough is the varied understanding ofwhat is meant by a diagnosis of asthma. In the minds of many clinicians asthma ischaracterised by variability in lung function, either spontaneously or induced bypharmacological agents. Indeed, such ‘reversibility’ is frequently used as entry criteriafor trial of anti-asthma therapy. In clinical practice however less than 10% of patients inasthma clinics may actually exhibit the required 15% reversibility to high doses of inhaledsalbutamol. So, whilst this criteria is good for including patients with definite asthma inclinical studies it is very poor at identifying all patients with asthma.
Another feature of asthma that is commonly used in epidemiological studies to define thesize of a problem in a population is a challenge test with an inhaled bronchoconstrictingagent. This is usually a substance such as methocholine or histamine which eitherdirectly or indirectly causes spasm of bronchial smooth muscle and thus wheezing. Asthmatic subjects wheeze and bronchoconstrict at much lower concentrations thannormal subjects. Such tests, whilst more accurately defining asthmatics, do miss aconsiderable number of subjects. Either patients with mild bronchialhyperresponsiveness due to other atopic diseases such as hay fever are included oalternatively subjects with bronchospastic asthma may on rare occasions not exhibithyperresponsiveness. Thus bronchial hyperresponsiveness, whilst being fairly closelyassociated with asthma, is not an absolute necessary requirement for the diagnosis. Inany case such tests are usually restricted to hospital practice and even then performedrelatively rarely.
Other attempts to objectively define asthma have focused around the type ofinflammation within the airways peculiar to asthma. The detection of eosinophils in thesputum or markers of inflammation for breath such as NO are taken by some as beingthe best non-invasive test to establish a diagnosis of asthma. However, examining thesputum for eosinophils is fiercely difficult and requires skilled technical support which isnot available in most hospitals.
In this volume a practical approach to the diagnosis of asthma is taken. That is, if thereis an appropriate response to anti-asthma treatment then whatever the result of thevarious tests it is still asthma or rather one of the asthma syndromes.
In classic asthma there is evidence of variable airflow obstruction. Such evidence iseasy to obtain in ordinary clinical practice by asking patients to fill out a home diaryrecord card with peak flow monitoring, readings being made morning and evening. Anobservation period of peak flow measurements before starting therapy in isolated chroniccough (ie when wheezing and shortness of breath are absent) is important to establishwhether there is indeed evidence for classic asthma. Diurnal variation revealed as a sortof pattern on the peak flow chart is characteristic of classic asthma. Morning dipping firstdescribed by Sir John Floyer 400 years ago is a cardinal feature. However, such obviousdiagnostic clues are rare in patients with isolated asthmatic cough. A much morefrequent pattern is variability in peak flow of a small degree (less than 10%) withoutparticular pattern. On starting anti-asthma medication variability decreases and oftenthere is a gradual rise in peak flow compared with pre-treatment baseline. Final peakflow pattern is one without variability. Because of the difficulty in definition of "asthmaticcough" the term cough preponderant asthma has become established and the asthmaticsyndromes without bronchoconstriction are discussed below.
In 1986 Irwin described six patients with cough who responded to anti-asthma treatmentbut who did not have bronchoconstriction. When tested for bronchialhyperresponsiveness these patients exhibited typical asthmatic responses. Thus, hedefined what he called cough variant asthma as cough responding to anti-asthmatreatment in the presence of bronchial hyperresponsiveness but without bronchospasm. This entity is commonly seen in the cough clinic. Because there is a lack of significantbronchoconstriction many referring clinicians are put off the diagnosis of asthma. Cluesthat this is the correct diagnosis may be found in the history. There is often a history ofatopy and either childhood eczema or hay fever. This may be present in either thepatient or a first degree relative. Frequently the cough is productive of small quantities ofcoloured sputum. The green colour is due to the eosinophils. Unfortunately, a history ofspecific trigger factors is often not helpful. Patients with a variety of other coughmechanisms also cough to inhalation of fumes, perfume, tobacco smoke etc.
Key to the diagnosis of cough prepoderant asthma is the response to therapy. Corticosteroids are the cornerstone of this therapeutic trial. Inhaled corticosteroidsusually provide at least some clinical response. As always there is enormous problemswith drug delivery of inhaled medication. I recommend the use of dry powder inhalers,particularly those not containing any excipient, since these are less likely to cause coughduring inhalation. In the absence of response as defined by the diary record card and/orpeak flow either the diagnosis is incorrect or the patient may be relatively resistant toinhaled medication. In the absence of any other obvious diagnosis then it is permissibleto undertake a therapeutic trial of oral prednisolone 20 mg a day for two weeks. Thepatient should be fully informed that this is a therapeutic trial as an experiment to seewhether there is any reduction in cough. There is a small but significant minority ofpatients with cough preponderant asthma who only respond to parenteral treatment withsteroids. If such a response does occur then attempts to wean oral steroids usingsecond line agents such as leukotriene antagonist, long acting beta agonist or anti IgEtherapy (which should be available shortly) are appropriate.
Despite adequate doses, up to 800 mcg, of inhaled steroids many patients remainsymptomatic. There is little or no evidence that pushing the dose of inhaled steroidsabove moderate doses has any effect. Indeed, the potential for local side effects withinthe larynx and pharynx, particularly thrush and myopathy, increase rapidly with
increasing doses. Second line agents should be construed as add in therapy. Here theapproach differs from classical asthma where it is quite clear that the majority of patientswill respond to one of the long acting beta agonist in addition to moderate doses ofinhaled steroids. Since cough preponderant asthma is not characterised bybronchoconstriction a long acting beta agonist may not be the second line agent ofchoice. Two small studies show that leukotriene antagonists are effective in thiscircumstance and may be a more logical treatment here since lipoxygenase productshave recently been demonstrated to directly stimulate the putative cough receptor.
The term eosinophilic bronchitis is reserved for patients who again respond to anti-asthma medication but do not exhibit either bronchoconstriction or bronchialhyperresponsiveness. As the term implies sputum examination reveals eosinophils. Whether eosinophilic bronchitis represents a separate disease or is part of a spectrum ofasthma is hotly debated and obviously depends on which definition of asthma is used. Patients with eosinophilic bronchitis may be relatively resistant to anti-asthma therapy,only responding to high doses of parenteral steroids or more severe immunosuppression. Attempting to control the disease is important since a proportion of these patients do onto develop fixed airflow obstruction or bronchiectasis.
In approximately one quarter of patients with chronic cough the cause isgastroesophageal disease. Whilst many patients suffers symptoms of heart burn andacid reflux chronic cough can be the only presenting symptom of reflux oesophagitis. Patients can be identified by clinical history. An exacerbation of cough by certain foodscan be characteristic, chocolate, hot spicy foods, and dry foods such as biscuits are mostfrequently mentioned. Some patients find that the cough occurs before food is actuallyplaced in the mouth. Other important clues to the diagnosis are exacerbation onrecumbency or bending. Worsening of symptoms on holiday or business trips alsooccurs. One useful strategy to identify causal relationships is to ask the patient to keep adiary. This can be done in association with peak flow recordings in order to differentiatebetween reflux-associated cough and asthma. Most peak flow diary record cardsprovided by the pharmaceutical industry are more than adequate to record cough as well. However, the majority of them do not try and score symptoms in any detail and weroutinely ask the patients to look back over the previous 24 hours and score their coughon a 0 –9 scale. It is sometimes helpful to ask the patient’s partner to also note coughfrequency since some patients have a very poor appreciation of the degree ofsymptomatology.
Having identified a patient as having cough possibly due to gastroesophageal diseasethe next step is a therapeutic trial of antireflux therapy. There are two importantconsiderations in the treatment of cough due to reflux. Firstly, therapy should be at ahigh dose and secondly that therapy should be prolonged – probably at least two months– before the trial is said to be unsuccessful. The reason for the delay in therapeuticresponse in some patients is unknown but probably relates to the mechanism wherebyoesophageal disease causes cough.
Until recently it was thought that cough associated with reflux was exclusively due toaspiration of stomach contents. Whilst this is maybe an important mechanism in certainconditions in such as motor neurone disease, in otherwise normal subjects this ‘up andover’ hypothesis does not explain the production of cough in all patients. In an elegantstudy from Australia, Ing et al, demonstrated that in patients with reflux cough instillation
of small amounts of acid in the lower oesophagus reproduced symptoms. Indeed, whilstmany of these patients were very sensitive to acid, some also coughed to saline solution. It appears in these patients with reflux cough that there has been an increased sensitivityof cough receptors located within the oesophagus and this resetting of the reflex mayexplain the need for prolonged therapy before resolution of the symptoms occurs.
We recently studied a number of patients with chronic cough that was thought to be dueto gastroesophageal disease. We found that a number of patients who did not havereflux as defined by the criteria for heartburn did however have marked abnormalities onoesophageal manometry. The commonest abnormality was weak lower oesophagealsphincter but gross dysmotility was also observed. We believe in addition to classic acidreflux in the oesophagus and larynx other abnormalities such as ‘volume reflux’ causedby stomach contents of neutral pH refluxing into the oesophagus and oesophagealspasm may also cause chronic cough. Thus prokinetic therapy with metoclopramide anddomperidone may be usefully added to proton pump inhibitor therapy. Response tothese prokinetic agents is however relatively infrequent and in selected case it may benecessary to prescribe cisapride on a named patient basis.
If a patient with suspected oesophageal cough has a partial response to therapy but isunsatisfied with the thought of long term drug treatment or the cough is still disruptivethen an option is operative treatment. A Nissen fundoplication performed bylaparoscopic techniques is relatively atraumatic and whilst the procedure does havesome side effects, the inability to rapidly bolt food and some weight loss, these areusually accepted by patients. Some patients selected for surgery find a dramaticimprovement in quality of life.
Rhinitis and the post nasal drip syndrome
The reported incidence of rhinitis and post nasal drip vary enormously between differentcough clinics. This is probably for two reasons. Firstly, the difficulty in defining andtherefore quantifying post nasal drip syndrome and, secondly, in a difference in thepatient reporting and understanding of symptom complex. An interesting example of thisis a large telephone survey conducted by Proctor and Gamble in which subjects wereasked whether they had a cold in the last six months. If the answer was positive theywere then questioned as to what symptoms they had during the illness. Over one third ofNorth Americans questioned said that post nasal drip was a prominent feature. This wasconsiderably less in Europe and South America. This may go some way to explain thedifference in prevalence seen in the various cough clinic studies.
Whether the syndrome is called post nasal drip or rhinitis there is little doubt that upperairway inflammation causes cough in a significant number of patients. It seems likelythat the upper airway inflammation reflects inflammation in the area of the larynx whichleads to exacerbation of cough rather than there being any physical ‘dripping’ onto thelarynx which is presumably the main source of stimulation of the cough reflex.
Patients with upper airway nasal symptoms should be given a therapeutic trial ofintranasal steroid and/or antihistamines. It is North American practice to givecombination therapy. However, in Europe it is more common to prescribe individualagents in a stepwise fashion. The choice of antihistamine is interesting. Whilst there islittle clinical trial evidence available the older agents appear to have greater efficacy thansome of the more modern non sedating antihistamines. One possible explanation for thisobservation is that many of the modern highly specific H1 antagonists have beendesigned and shown to block only the H1 receptor. Recent research has shown thatthere are at least four histamine receptors with the H3 receptor playing a possible
important role in allergic inflammation. The agents such as Cetirizine may be moreefficacious because of their broader spectrum of activity.
That this systemically active drug for hypertension should cause, as a side effect, chronicdry cough was such a surprising finding was that it was not found in any of the large postmarketing surveillance studies following the launch of captopril and enalapril. In factACE inhibitor cough occurs in approximately 15% of patients started on therapy and itsonset is very variable. Severe intractable cough can come on after as little as four dosesand conversely the cough may not present as a side effect until a number of years ofapparently innocuous therapy has passed. Shortly after the discovery of ACE inhibitorcough a number of studies, including our own (see figure) demonstrated that the cough isdue to a resetting of the cough reflex. Given that we now know that women have anintrinsically heightened cough reflex it is not surprising that women out number men inACE inhibitor cough by two to one.
Clinical characteristics of ACE inhibitor cough
The history in ACE inhibitor cough is quite characteristic. The patient feels that there is atickle at the back of the throat which leads to paroxysms of coughing. These may beextreme enough to lead to vomiting. Between episodes the patient is asymptomatic andACE inhibitor cough is not associated with the other known class related side effects ofACE inhibitors such as angio oedema or dysgusia. In addition there is no associationwith asthma predisposition and if the patient’s main complaint also includes shortness ofbreath then other causes such as worsening heart failure should be sought.
The majority of patients with ACE inhibitor cough are fairly easily diagnosed by cessationof therapy. Unfortunately, a group of patients continue to cough for prolonged periodsafter stopping ACE inhibitors. Referral to the cough clinic frequently is accompanied byremarks in the referral letter that the cough could not be due to ACE inhibitors sincethese have been stopped for a period of time and the cough remained. The patient hasusually then been put back onto ACE inhibitors. The correct diagnostic test should becessation of therapy or substitution with an angiotensin II receptor blocker for a period ofat least four months. Not infrequently in patients with a prolonged ACE inhibitor coughthere is a second underlying reason for cough such as gastroesophageal reflux. TheACE inhibitor causes exacerbation of cough on this background making it difficult for thepatient to differentiate the underlying cough from the superadded effects of the ACEinhibitor. A harmless way to prove this is to undertake a re-challenge with ACE inhibitorand the patient, because of their previous experience, usually recognise the onset of this‘different’ cough.
Table ? – Advice for patients with cough of recent onset
• Most short term cough is due to a virus and so antibiotics do not help
• Coughs and sneezes do spread diseases. Try not to infect others
• Effective treatment is available over the counter at the pharmacy. Ask for a cough
linctus containing the drug dextromethorphan. At least 60 mg of this drug is requiredfor effective relief in adults
• In adults a moderate amount of alcohol will help to suppress the cough, particularly at
• In both children and adults menthol, again available from the pharmacy, will help
• Simple cough/cold does not require treatment from your doctor. The most effective
medicines are available at the pharmacy. Consult your doctor if you have additionalunusual symptoms such as persistent chest pain or coughing up of blood, or if youcough goes on for longer than six weeks
Substitute ATII blocker ifrequired and review aftertwo months
∆ Gastroesophageal diseaseAlternative treatment
Table ? – The most frequent causes of chronic cough presenting to cough clinics withnormal chest Xray
4. ACE inhibitor cough5. Post viral cough
Table ? – The most common causes of cough presenting to cough clinic with abnormalchest Xray
• Allergic broncho pulmonary aspergillosis
3. Lung cancer4. Non infective pneumonias
• Cryptogenic organising pneumonitis (COP)
• Bronchiolitis obliterans organising pneumonia (BOOP)
Table ? – Basic investigations in the diagnosis of chronic cough
• Reversibility Inhalation of salbutomol (peak flow or FEV1)
• Home peak flow monitoring (one month)
• Sputum culture and sensitivity (when applicable)
Address: Budaorsi street 141. , H-1118 Budapest, HungaryMobile: +36-30-442-20-91Tel/Fax: + 36-1-788-33-17E-mail: [email protected] - for general [email protected] - for inquiries and orders CAS Number Methyl 3-(4-(aminomethyl)phenyl)propionate(3E)-4-(4-hydroxy-3-methoxyphenyl)but-3-en-2-one(R)-(-)-2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazine(2S,3R)-3-Phenyl-2-pyrrolidinecarboxylic acid
file:///C:/Users/pascal/Documents/perso/an2009/fede09/site/BUL42.htm Bulletin d'Information de Pharmacovigilance N° 42 - Septembre 2009 RAPPEL "Tout professionnel de santé ayant constaté un effet indésirable grave (soit mettant en jeu la vie du patient ou entraînant le décès, soit entraînant ou prolongeant une hospitalisation, soit entraînant une incapacité ou des séqu