key: cord-0775572-35ma6o0f
authors: Widdicombe, John; Kamath, Shankar
title: Acute Cough in the Elderly: Aetiology, Diagnosis and Therapy
date: 2012-08-29
journal: Drugs Aging
DOI: 10.2165/00002512-200421040-00003
sha: 0693ce44c8059f0c65a977fa97e2d86d581698c7
doc_id: 775572
cord_uid: 35ma6o0f

Although the frequency of physician consultations and the sale of over-the-counter remedies establish the high prevalence of acute cough in the elderly, epidemiological studies have tended to be imprecise. However, respiratory tract infections in nose, larynx and/or bronchi, either viral or bacterial or both, are by far the commonest cause of acute cough. These are especially frequent and hazardous in the elderly, and community living and institutionalisation may aggravate this problem. A variety of viruses and bacteria have been incriminated, with rhinovirus, influenza and respiratory syncytial viruses, and Streptococcus pneumoniae, Haemophilus influenza and Bordetella pertussis being especially important. Viral infections can readily lead to community-acquired pneumonia. Successful diagnosis should point to successful treatment, and in this respect clinical examination and patient history are paramount, supplemented by chest X-ray, viral and bacterial culture and serological testing. Depending on the results of these tests, specific antibacterial therapy may be called for, although there is dispute as to the merits of antibacterial therapy in cases of uncertain diagnosis. Prevention and prophylaxis for influenza and S. pneumoniae infections are now commendably routine in the elderly, especially those in communities. Treatment, as well as the use of antibacterials, may also be directed against the inflammatory and infective processes in the airways. Non-specific antitussive therapy is common and usually highly desirable to prevent the adverse effects of repeated coughing. There have been few advances in antitussive therapy in recent years, opioids and dextromethorphan being the most commonly used agents; they act centrally on the brainstem, but also have a large placebo effect. However they work, they are much appreciated by patients and their partners. Moreover, striking advances in our understanding of the peripheral sensory and central nervous pathways of the cough reflex in recent years should soon lead to a new and more specific choice of agents to inhibit cough.

Although the frequency of physician consultations and the sale of over-the-Abstract -counter remedies establish the high prevalence of acute cough in the elderly, epidemiological studies have tended to be imprecise. However, respiratory tract infections in nose, larynx and/or bronchi, either viral or bacterial or both, are by far the commonest cause of acute cough. These are especially frequent and hazardous in the elderly, and community living and institutionalisation may aggravate this problem. A variety of viruses and bacteria have been incriminated, with rhinovirus, influenza and respiratory syncytial viruses, and Streptococcus pneumoniae, Haemophilus influenza and Bordetella pertussis being especially important. Viral infections can readily lead to community-acquired pneumonia. Successful diagnosis should point to successful treatment, and in this respect clinical examination and patient history are paramount, supplemented by chest X-ray, viral and bacterial culture and serological testing. Depending on the results of these tests, specific antibacterial therapy may be called for, although there is dispute as to the merits of antibacterial therapy in cases of uncertain diagnosis. Prevention and prophylaxis for influenza and S. pneumoniae infections are now commendably routine in the elderly, especially those in communities. Treatment, as well as the use of antibacterials, may also be directed against the inflammatory and infective processes in the airways. Non-specific antitussive therapy is common and usually highly desirable to prevent the adverse effects of repeated coughing. There have been few advances in antitussive therapy in recent years, opioids and dextromethorphan being the most commonly used agents; they act centrally on the brainstem, but also have a large placebo effect. However they work, they are much appreciated by patients and their partners. Moreover, striking advances in our understanding of the peripheral sensory and central nervous pathways of the cough reflex in recent years should soon lead to a new and more specific choice of agents to inhibit cough.

patients probably do not go to either a pharmacist or physician; this is because the most common causes In spite of the very high incidence of cough in the of chronic cough (cigarette smoking and atmospherpopulation, there is little information about its exact ic pollution) are not regarded as 'diseases' until prevalence, epidemiology and relation to age, other conditions such as chronic obstructive pulmonary than in paediatric conditions. In all countries where disease (COPD), chronic bronchitis or cancer defigures are available, it is the most common sympvelop. The extensive research on the pathological tom for which medical advice is sought, excluding results of cigarette smoking and pollution has been conditions related to poverty, war and starvation. [1] [2] [3] [4] largely limited to studies involving serious chronic However, probably the majority of patients with pulmonary disease, ignoring the earlier years of cough, certainly with acute cough, go to a pharmarepetitive coughing. cist rather than a physician and therefore escape

The size of the problem is reflected by the expenepidemiological surveys. This is partly because diture on OTC remedies for 'coughs-and-colds' (of acute cough is, by definition, self-limiting and most course the two are not the same, but over 90% of patients know they will get better without medical advice. Even with chronic cough, the majority of colds induce coughing). In 1999 over $US2 billion was spent in the US and over £300 million in the UK of the cough is chronic. [5, 11, 12] Other conditions that on OTC cough/cold medicines. [1, 2] It is impossible may be either acute or chronic include cough beto further analyse these figures, in terms of popula-cause of post-nasal drip (PND), [13] which may be tion subgroups or individual medications, because related to acute or chronic rhinosinusitis, or to URsuch data are not available. TI, where cough can continue for many weeks or even months after symptomatic resolution of the In 1997 in the US, of the 30 million medical primary inflammatory condition. [1, 2] Most acute consultations for cough, a third were attributed to coughs are owing to URTI, with or without acute acute tracheobronchitis. [5] [6] [7] In 1972 in the UK, the bronchitis; acute bronchitis may occur without presenting complaint in over half of the medical URTI. [5] As indicated earlier in this section, all these consultations was cough. [3, 8] In 1991-92 in the UK, conditions may lead to chronic cough. there was an average of two consultations every year per patient for acute respiratory tract infection in 1.2 'Wet' and 'Dry' Cough adults attending general practices. [3, 8] Later data generally support these very high incidences. Most

The terms 'wet' and 'dry' cough are frequently surveys have not analysed the data into young adult used. They have some limited diagnostic value. Dry and elderly subgroups, but for influenza and pneucough may point to acute laryngitis and URTI, but it monia there were 20 000 deaths per year in the US, can also occur in the chronic coughs of gastroand 90% of them were 65 years of age or older. [9] oesophageal reflux, ACE-inhibition and asthma. In discussing acute cough in the elderly, there are Wet cough usually applies to acute or, especially, three general considerations. chronic bronchitis, and conditions such as CF and bronchiectasis. At first sight wet cough should be 1.1 Acute and Chronic Cough definitive of bronchopulmonary diseases with excessive production of mucus which reaches the lar-Since this review deals with acute cough it must ynx and causes cough and expectoration. However, be defined and here there is no uniform agreement.

wet cough also occurs in PND where the secretions Some authorities refer rather imprecisely to 'acute, arise in the upper airways. self-limiting episodes' in contrast with 'chronic per-It is important to note that the terms are mostly sistent cough'. Three weeks is often taken as the qualitative and depend solely on the subjective imlimit of the acute phase and 8 weeks is usually pression of the patient. Copious amounts of mucus accepted as the time when acute cough becomes can be collected in a sputum pot, but this is an chronic. From 3 to 8 weeks is sometimes referred to inaccurate method that adds little in terms of diagas 'subacute'. A recent study showed that with an nostic value for borderline conditions. However, it is 'acute' upper respiratory tract infection (URTI) [inimportant to assess 'wetness' and 'dryness', because fecting agent not defined], cough could last from 1 this classification may eliminate some diagnoses to 10 weeks. [10] The distinction may not be imporand point to others, and therefore suggest certain tant provided the limit is defined. therapeutic antitussive approaches. Some conditions are clearly chronic and will not be discussed further in this review. They include:

cough due to COPD/chronic bronchitis, bronchopulmonary cancer, cystic fibrosis (CF), bronchiectasis, There have been extensive studies of acute cough ACE-inhibition, gastro-oesophageal reflux, asthma in children, for example in relation to infections with and habit-cough. [1, 2] COPD, asthma and CF may Bordetella pertussis (when cough may be subacute include acute episodes of cough, e.g. acute bronchit-or chronic, depending on definition), and in infants ic exacerbation of COPD, but the underlying cause with bronchiolitis and infections with respiratory syncytial virus (RSV). But in general, studies on attend respiratory or general medical clinical units. adults have not been separated into young, middle It is difficult to ascertain the exact prevalence of aged and elderly. Yet we know that the spectrum of acute cough in the general population, as there are cough-inducing pathology changes with age in many patients who do not seek professional medical adults, as do the quantitative physiological mechan-advice, but consult a pharmacist instead. Therefore, isms of the upper airways, including cough. Thus, these selective biases may overestimate the incielderly patients seem to have a weaker cough res-dence of more serious causes of cough, such as acute ponse to distilled water aerosol than younger pa-PND and bronchitis, as patients with these conditients. [14] It must also be remembered that women tions are more likely to go to units that publish have a higher sensitivity to cough-inducing aerosols papers on aetiology. than men, [15, 16] although it has not been shown if this 2.1 Acute Rhinitis and Rhinosinusitis difference changes with age. This gender-related effect may be relevant in the elderly, as there is a Cough can only be induced by inflammation or preponderance of female patients attending specialirritation of the larynx, trachea and bronchi. [25, 26] ist cough clinics, [16] as there is in community prac-Therefore, infections of the nose and pharynx cantice. [1] not per se cause cough, which will only arise if the infection extends into the larynx and lower respira-2. Epidemiology tory tract, or if nasopharyngeal secretions flow to the Acute cough is nearly always due to respiratory larynx and either stimulate it mechanically or chemtract infection (RTI), viral infections being the most ically. PND is considered an important aetiological common cause, [17] [18] [19] and typically the cough is nonfactor in chronic cough [1, 13] and presumably is the productive ('dry'). [20] With or without cough, vicause of cough in acute rhinitis and rhinosinusitis. ruses account for over 90% of acute respiratory

The viruses that commonly infect the nose and illnesses. [21] [22] [23] [24] Bacterial infections, whether superupper respiratory tract (rhinovirus, adenovirus and imposed on a viral infection or not, and including coronavirus) may also spread to the lower airconditions such as community-acquired pneumonia ways. [19, 24, [27] [28] [29] Even rhinovirus, which may prefer-(CAP), are less common. Table I lists the main viral entially infect the nose, since it grows most readily and bacterial causes of acute RTI.

in cultures at 33°C, can be found in bronchial biop-Selective populations have been used to study the sies from infected patients. [30] Since there are over epidemiology of acute cough; in the case of the 100 serotypes of rhinovirus, it is not surprising that elderly they are often institutionalised or in home it is not only the most common cause of acute care facilities, while most children and young adults rhinitis, but is also a major contributor to lower respiratory tract infection (LRTI) in the community, especially in elderly patients. [19, [27] [28] [29] In a prospective study of 533 patients aged 60-90 years with RTIs, LRTIs were defined by the presence of cough, wheezing and/or chest pain, and URTIs by their absence; 65% of patients had LRT symptoms and 98% URT symptoms. Thus, 66% of patients with 'rhinitis' also had LRTI including the symptoms of cough. [20] A pathogen was identified in 42% of patients; the commonest pathogens were rhinovirus (52%), coronavirus (26%) and influenza (mean age 79 years) showed the importance of influenza A, coronavirus and RSV in RTI, and showed The viruses that usually cause acute rhinitis (rhithat the older group had significantly more LRT novirus, adenovirus and coronavirus) presumably symptoms, including cough, than the younger (mean always reach the LRT, but in many instances do not age 36 years) group. [29] Other studies support the cause bronchitis. Moreover, rhinovirus can be deimportance of viruses associated with the common tected in bronchial biopsies of patients with URcold, rhinovirus and coronavirus, with LRTI and TI, [30] and because of the high frequency of respiracough in the elderly. [27] [28] [29] tory infections due to rhinovirus compared with other viruses, it probably contributes frequently to With regard to bacterial infections, 70% are due LRTI, especially in the elderly. [31, 32] Furthermore, to Streptococcus pneumoniae or Haemophilus inrhinovirus infection is the most common cause of fluenzae, although Moraxella catarrhalis may also acute exacerbation of asthma, [33] and a major cause be found. [13] of acute exacerbation in COPD and CF. [11, [34] [35] [36] [37] Infections with the other respiratory viruses, influenza

A and B, parainfluenza and RSV, probably always involve the LRT and quite often the nose. The Cough originates from an irritated or inflamed incidence of LRT viral infections was RSV > inflularynx. Theoretically, it seems unlikely that the deenza A > coronavirus in one study, [27] rhinovirus > coronavirus > influenza in another, [20] and coronscent of mucus into the pharynx would provide an avirus > rhinovirus in a third. [29] In a group of elderly adequate mechanical stimulus for cough, since the patients, RSV was isolated more frequently than mucus would preferentially be swallowed, while rhinovirus; [32] these two topped the list of 41 types of mucus ascending up the trachea may contact the virus isolated. In a group of 168 elderly patients vocal folds and provide the stimulus to cough. Howhospitalised with acute respiratory disease, 18% had ever, this is conjectural due to the lack of research infection with influenza A virus. [38, 39] While the and insight on mucus flow as a stimulus to cough. selection criteria of the groups may differ, and not What is certain is that URTI frequently, if not usuprovide the best representation of the general popually, leads to cough or expiratory efforts. If the lation, the viruses listed earlier in this section are cough is dry, i.e. no mucus is present, the 'urge to most likely responsible for most cases of acute broncough' may be related to the irritation of the larynchitis in the elderly, as well as in adults generally. geal sensory receptors.

As noted in section 2.1, some authors would diagnose LRTI by the presence of cough. This may About 5-10% of adult patients with acute trachebe dependent on whether the larynx is defined as obronchitis develop pneumonia with a bacterial inpart of the URT or of the LRT, but this distinction is fection deep in the lungs. [18] The most common also important in terms of mechanisms. Acute larynagents in elderly patients are Mycoplasma pneugitis can occur in the absence of tracheobronchial moniae, Chlamydia pneumoniae and B. pertussymptoms (wheeze, chest pain and mucus producsis, [18, 19] although H. influenzae, M. catarrhalis and tion). In the absence of laryngoscopy, acute laryngi-Staphylococcus aureus have also been detected. [27] tis can be identified by the sensations of irritation, One study showed that in elderly patients with acute soreness and even pain in the laryngeal region.

bronchitis, S. pneumoniae and H. influenzae were the most frequent bacterial pathogens. [40] Some se-tions associated with acute cough. Diagnosis and rological studies are consistent with these find-therapy will depend, among other factors, on the ings. [41] B. pertussis is being increasingly identified identification of these pathogens. in patients with acute bronchitis, probably due to the 3. Diagnosis and Management of now common use of the polymerase chain reac-Patients with Acute Cough tion. [42] [43] [44] This infection becomes more prevalent with increasing age, possibly because immunity In the great majority of patients, diagnosis of the may wane in previously vaccinated individuals, and cause of cough is by patient history and physical thus the infection and cough may be more common examination. In a small minority of patients, more in elderly patients. [45, 46] Since bacterial infections sophisticated tests are necessary and this may be may prolong the course of a viral tracheobronchitis, especially true in the elderly where symptoms may cough may last longer. be more detrimental, or may be masked by aging Patients with CAP usually present with sympprocesses. Signs and symptoms may be restricted to toms (including cough) of acute bronchitis. Four one or two parts of the respiratory tract, the nose, million patients in the US develop CAP each year, larynx and lungs, even though the infection probwith 50% of them being >65 years old. [47] There are ably affects all parts of the respiratory system. Diag-70 000 deaths per year in the US from CAP, with nosis of the cause of the acute cough is important not 90% of them being in the elderly group. [47, 48] The only for the patient's treatment, but also to limit the most frequent agent detected is S. pneumoniae, folspread of infection. lowed by H. influenza, Staphylococcus aureus, C.

Whereas most cases of acute cough start with a pneumoniae, M. pneumoniae, Legionella pneuviral infection, the development of bacterial infecmoniae and respiratory viruses. [49, 50] The incidence tion is a potentially more hazardous state which may of CAP increases in elderly patients and the bacterrequire specific therapy. Hospitalisation and ventiial spectrum may change from that in younger latory support may be urgently required, with or adults.

without chemotherapy. [47, 49] It should be noted that repeated and vigourous The possible existence of comorbidities is imporcoughing may in itself have adverse effects on the tant, especially in the elderly. [47] This consideration elderly patient. These effects include incontinence applies to many neurological disorders, such as (especially in females), rib fractures and vagally Parkinson's disease and cerebrovascular diseases mediated cardiac instabilities. such as stroke. Here, not only may the disease depress the cough mechanism, but aspiration may 3.1 Viral Infections also lead to pneumonia superimposed on a defective cough reflex. Other conditions are alcoholism and

The diagnosis of viral influenza is important to mental deterioration, where cough may be weak and distinguish it from the common cold, and to anticithe chances of contracting bacterial pneumonia are pate the possible development of bacterial pneumoenhanced.

nia, leading to appropriate anti-infective treatment. [50] In summary, epidemiological studies on acute cough and its underlying causes have identified With influenza, there is sudden onset of malaise many viral and bacterial pathogens. While the de-and fever, followed by cough, headache, myalgia tailed patterns of effective causes vary, presumably and nasal and chest symptoms. Cough is the combecause of different population groups and methods monest symptom, present in 95% of patients. [51] In of study, the general pattern is clear; an identified the elderly, the signs and symptoms of influenza range of pathogens can lead to the respiratory condi-may be atypical and consist of low-grade fever, lassitude, confusion and nasal obstruction; tachy-more accurate delineation of sinus involvepnoea may be prominent especially if pneumonia ment. [13, 56] Bacteriological and serological tests may develops. [18, 48, 49] The risk factors for developing identify the infective agent and suggest appropriate complications include age >50 years, residence in a chemotherapy. nursing home or chronic care facility, and various 3.3 Acute Bronchitis chronic diseases, including pulmonary diseases, that are frequent in the elderly. [50] The distinction between viral and bacterial infec-Initially influenza may be difficult to distinguish tion in bronchitis may be difficult by clinical examfrom the common cold, but the dominance of constiination alone, yet the identification of bacterial tutional symptoms and the course of development pneumonia, if present, is crucial in terms of treatrapidly make the distinction clear. [52] The Center for ment [5] (see section 3.4). A review concluded that Disease Control and Prevention in the US has dechest x-ray (CXR) was no more helpful than clinical fined clinical criteria for influenza infection as havexamination of the chest and patient history; [57] ing a fever of at least 100°F orally and at least one of however, this may not apply to the elderly who may the following: cough, sore throat or rhinorrhoea (the have chest infections but present with mainly nonfirst criterion, fever, may not be applicable to the respiratory symptoms, such as confusion or frequent elderly). [53] Influenza can be diagnosed by viral culfalls. [58] CXR is strongly recommended if pneumoture from respiratory secretions obtained by pharynnia is suspected, [5, 18, 47] although in a minority of geal swab, sputum or nasopharyngeal aspiration, patients the CXR signs are marginal and may not although the older methods of culture may be too clearly distinguish between viral and bacterial pneuslow in relation to the time-course of the disease. monias. As with nasal investigations, the use of More rapid diagnostic tests are available [48] and sputum Gram stains and culture are not very precise, some can distinguish between influenza types A and and their value is disputed. [59] [60] [61] [62] Moreover, satisfac-B.

tory samples are sometimes difficult to obtain in the RSV infection is more serious in the elderly [38, 54] elderly and, in one study, in only 42% of patients and in some studies it has been found to be more could an aetiological agent be identified. [63] Serologprevalent than influenza infection. [27, 32] Diagnostic ical tests, particularly for influenza and B. pertussis, tests, such as antigen detection and culture, tend to may be more informative [5, [58] [59] [60] and help in choosbe slow and rather insensitive. [38, 55] Clinical examining the appropriate therapy. ation in the elderly may suggest RSV rather than influenza infection: fever is low grade, there may be

Bacterial infections account for the majority of combination with wheezing and clinical deterioracases of pneumonia. [18, 47] The classical signs of tion. [55] pneumonia may be insignificant or absent in the elderly: only 40% may have fever, [47, 64] and other

symptoms may be insignificant due to mental confu-Here the diagnosis is clear from the patient his-sion. Physical findings, such as lobar consolidation, tory, symptoms and clinical examination, and the may also be absent. [65] On the other hand, tachymain question is whether a superimposed bacterial pnoea may be conspicuous. [66] With viral pneumoinfection requires specific treatment. Simple radi-nia, the typical symptoms of influenza deteriorate ographs may be unhelpful, since abnormalities in with the development of more severe cough and the sinuses may not be detectable. [13] Computerised fever, and the appearance of dyspnoea and cyanosis; axial tomography scans, when practical, allow for a the CXR may show bilateral signs, but without consolidation. The development of bacterial pneu-is reduced by 80%, a feature especially important in monia may be signalled by a recurrence and exacer-communities of the elderly. [52] bation of symptoms, their prolongation beyond 7-10 Chemoprophylaxis with antiviral agents is about days, and the appearance of areas of consolidation 80% effective in preventing influenza infection; on the CXR. Based on a large study, patients with they are effective against influenza A and, perhaps CAP were classified into five grades to predict the to a lesser extent, influenza B. [48, 70, 73] Sialidase inlikelihood of survival. Patients with the lowest hibitors may be 70-90% effective in preventing scores had a mortality rate of less then 1%, whereas influenza, [48, 74] including the elderly. [48] those with the highest scores had a rate of 8-31%. [67] In the case of pneumonia, especially CAP, vacci-This approach could be an adjunct to assessment of nation against S. pneumoniae is recommended for the need for ventilatory support.

patients aged ≥65 years. [47, [75] [76] [77] Although it is often given only once in a lifetime, it probably does not 4. Specific Treatment of provide immunity for all the known varieties of the Cough-Causing Conditions organism, and there may be a case for revaccination. [75] [76] [77] As implied above, it is particularly valua-Because approved names for drugs, and also their ble in communities of the elderly. availability, vary widely between countries and 4.2 Antiviral Agents those of OTC remedies even more, drugs will only be referred to generically in this section and very As indicated in section 4.1, antiviral agents are selectively in section 5.

only effective against influenza A and B viruses, and when given within 48 hours of the onset of illness,

reduce the severity and duration of the disease. Because of renal impairment in the elderly, the drug Annual immunisation against influenza is dosage may have to be limited since the agents and standard practice for patients over the age of 60 or their metabolites are excreted in the kidneys. [70, 74] 65 years; inactivated viruses are used because of the Sialidase inhibitors given within 48 hours of the increased risk in the elderly of incapacitation and first symptoms are also effective in reducing the further complications, including infection. [53, 68] duration and severity of symptoms. [47, 48, 70, 78, 79] Vaccinations are administered in October or November, in anticipation of an increased risk of infec-

tion in January to March, in the northern hemisphere. The subtypes of virus anticipated vary from There has been considerable controversy with year to year, as therefore do the vaccines. Strains of regards to the use or overuse of antibacterials in both influenza A and B are targeted. The safety of respiratory infections. It is generally agreed that, if a the vaccine is established in asthmatics, [69] however, bacterial infection is unlikely, antibacterial therapy its efficacy is limited. In the old and the incapacitat-is not required and should not be used, but if a ed, about 50% of those vaccinated still develop bacterial infection is established antibacterial therinfluenza as the immune response may be inade-apy remains valuable. [18, 49, 50] There is a notable area quate. [51] [52] [53] 70] However, the morbidity and mortality of uncertainty, at least in the elderly, with regard to of those contracting the disease are considerably the presence or absence of bacterial infection, and reduced. [71] One study showed that mortality was generally it may be wise to err on the side of caution reduced by 80% and hospitalisation and pneumonia and to use antibacterials. The degree of morbidity by over 50%. [54] Nasal vaccines are effective espe-may be the decisive factor. In practice, antibacterials cially in children. [72] Furthermore, population spread are usually given in the US if there is purulent nasal discharge, green phlegm, use of tobacco or tonsillar 5. Symptomatic (Non-Specific) exudates. [80] Whether or not a bacterial infection had Treatment of Acute Cough been established, the use of antibacterials led to a

In general, physicians are hesitant to treat cough small improvement in cough and sputum producin acute respiratory conditions. This is partly betion, and better general improvement at followcause the cough normally lasts a few days, is probup. [81, 82] The duration of the illness does not seem to ably at its peak when consultation takes place and is be affected. [83] [84] [85] Another extensive study showed believed to improve, especially if there is effective no such improvement. [85] Guidelines for the deterspecific treatment. There may also be some doubt mination of treatment with antibacterials have been surrounding the effectiveness of antitussive agents published. [86, 87] administered at usual dosages and fears about their If bacterial infection is definitely established, the adverse effects. This is especially relevant in elderly use of antibacterials is highly desirable, especially in patients. Most studies on antitussive drugs have the elderly, [88] [89] [90] as recommended by the American been on children or non-elderly adults, but there is Thoracic Society for CAP. [90] A large number of no reason to believe that the results in general do not studies support this view. [18, 91, 92] also apply to the elderly. Antibacterials are recommended for rhinosinusi-Obviously, specific treatment is better because it tis with bacterial infection of the upper respiratory aims to cure the condition, hence alleviate the symptract. [13, 57, 93, 94] The most frequent bacterial invaders toms. Symptomatic treatment may be required, in that require appropriate antibacterial therapy are S.

addition or in place of specific treatment, if the pneumoniae and H. influenza. [13] cough is sufficiently severe or if the cough is idiopathic.

The main indications for antitussive therapy are if the cough prevents sleep or if the inflammation Bronchodilators, such as β-adrenoceptor agocausing cough (or the cough itself) is painful, as in nists, shorten the duration of cough in patients with acute laryngitis or in the chest pain of acute bronchibronchial hyperresponsiveness or wheezing, but are tis. These are the reasons most patients consult their not effective in the absence of airflow limitation. [5, 95] physician or go to the pharmacy for a cough/cold Corticosteroids have been tested to shorten the duraremedy. An additional reason is social, for example, tion of cough, but apparently without effect. [5] if the cough annoys or distresses members of the Protussive therapies, such as humidified air and family at home, or fellow workers. drugs such as guaifenesin, are widely included in Cough in itself is seldom harmful, unless it is OTC remedies; there is little evidence that they are prolonged and excessive, as with whooping cough effective against cough. [96] in the young, or it is debilitating because of the poor Other agents used to treat cough because of nasal general condition of the patient. The latter applies in infections include antihistamines, oral or topical va-the elderly; it is in these patients that the adverse soconstrictors, atropinic agents and corticoster-effects of the antitussive agents may cause most oids. [13, 93, 94] The first-generation antihistamines may harm. The main adverse effects of antitussive agents have a stronger antitussive action than the second-are mental confusion, nausea and constipation, espegeneration drugs, since they have central nervous cially for the opioids, and effects that are especially sedative effects that could depress cough. In general, undesirable in the elderly. Respiratory depression is if any of these agents inhibit the nasal pathology that also claimed to be an adverse effect of the opioids, is producing cough, one would expect them also to although there seems to be little evidence to support inhibit cough. this view in humans; this may have arisen from the sedation, drowsiness and ease of sleep in patients. In ic acute cough accurately in relation to therapy, but animals, very large doses of opioids are needed to the former is conducted under closely defined laborcause respiratory depression. [97] atory conditions, while the latter is notoriously variable between patients and during the course of ill-It is believed that antitussive medication should ness. In addition, there is growing evidence that the not be used if the cough is 'wet', because this will cough reflex is quantitatively different in health lead to the accumulation of mucus in the chest. This compared to airways' disease. [101, 102] There have is an axiom taught to all medical students. There is been few studies in the elderly. little evidence to support it. Cough, airway mucocil-While it is convenient and conventional to divide iary transport and possibly mucus secretion are deantitussive agents into centrally-and peripherallypressed during sleep without adverse effect. [98] If a acting, many drugs, including those in current use, patient with a 'wet' cough sleeps through the night can be shown to act at both sites, at least in animal there is usually no adverse effect when they wake, models. This is not surprising since the nerve fibres although more mucus may be coughed up, as in responsible for cough stretch from the airway wall smokers. Patients with cough, including the elderly, to the 'cough centre' in the brainstem, and they spend a fortune at the pharmacy for OTC antituscontain the same mediators and pharmacological sives, probably without paying any attention to the membrane receptors along its entire course. The wet or dry nature of their cough.

antitussive agents ability to cross the blood-brain A final consideration, that will be developed barrier remains unclear. Most of the studies on localfurther, is with regard to the dosage of antitussive isation of the actions of antitussive drugs have been drugs. The doses of antitussive agents, either predone on experimental animals and its application to scribed or bought OTC, are so low that their effechumans is questionable. tiveness is little better than placebo; [98] [99] [100] yet pa-

The names of the antitussive agents available on tients and their partners believe that they work, prescription and those sold OTC, vary greatly from based mainly on relief of unpleasant soreness and country-to-country, and the following account canthe enhancement of sleep.

not make allowance for this. The list of available antitussive drugs, both prescribed and OTC, acting either centrally or peripher-5.1 Centrally-Acting Antitussive Agents ally, has changed little over the last decade or two. However, over the last few years there has been an

The central nervous generation of cough takes explosion of research into the peripheral (sensory) place in the medulla of the brainstem, in what used and central nervous mechanisms of antitussive to be called the 'cough centre'. Detailed neuronal drugs, which should have a profound influence on circuitry of this complex has been elucidated recentthe pharmacotherapy of cough. The pharmaceutical ly. [103, 104] Two aspects are important in relation to industry is investing heavily in antitussive research, cough therapy. Some agents that are powerful cough which is not surprising in view of the potential suppressants, such as dextromethorphan, do not inmarket.

fluence breathing and therefore may not act as Most clinical tests with antitussives have been respiratory depressants in effective antitussive with animal models, on patients with chronic cough doses. Secondly, central nervous pathways for or on healthy patients with cough induced by tus-cough from the larynx have distinct brainstem neusigenic aerosols. While qualitative application of ronal connections from those innervating the trachethese results to patients with acute cough is largely obronchial tree. [105] This opens up the prospect of accepted, more direct studies would be preferable. drugs being developed with specific actions on dif-One might expect an aerosol-induced cough to mim-ferent types of acute cough.

Other potential centrally-acting antitussive Codeine and pholcodine are among the most agents include antagonists to serotonin, substance P popular prescribed and OTC antitussive drugs, at (neurokinin), opioid receptor-like (ORL1) receptors, least in the UK, surpassed only by dextromethorglycine and glutamate. The involvement of these phan. Both (especially codeine) have potential receptors in cough and the effectiveness of appropriadverse effects, including addiction. Opioid analate antitussive drugs against them, have been studgesics, such as hydrocodone, hydromorphone, dihyied extensively in experimental animals. [105, 106, 116] drocodeine, methadone and even morphine, have 5.2 Peripherally-Acting Antitussive Agents been used as antitussives, but are usually restricted to the severely distressed and terminally ill patient.

Although some of these drugs have been in use The central action of opioid antitussive drugs has for a long time and are the constituents of many been extensively studied in experimental animals. OTC preparations, they are seldom prescribed. The-At least four different types and subtypes of opioid oretically, they should act locally in the airways and receptor have been distinguished in the neuronal therefore lack the adverse effects of centrally-acting circuitry for cough [106, 107] and the detailed pattern of antitussive drugs. action of several opioids has been studied.

Nearly all forms of cough are due to the excita-Although the effectiveness of codeine in the tion of sensory receptors in the walls of airways by treatment of chronic cough, and its suppression of inhaled irritants or by inflammatory mediators reaerosol-induced cough, have been shown to be staleased due to local tissue damage within the airtistically significant, [108] [109] [110] one study of patients ways. [116, 117] When stimulated they cause cough, with acute cough showed that it was no more effecamong other reflexes, and also lead to the release of tive than placebo [96] mediators, such as tachykinins, which further induce inflammatory changes in the airways. In airways'

disease (including infections) these receptors are This is a non-narcotic opioid derivative that lacks sensitised, so that cough and local effects are enmany of the adverse effects of opioids, such as hanced. [101, 102, 118, 119] There has been extensive study constipation, nausea, sedation and addiction; howof these sensory cough receptors, especially in reever, it may cause some confusion. It is effective cent years; unfortunately this research has been alagainst chronic and acute cough, [108, 109, 111] and in most entirely on animal models, but its results are aerosol-induced cough under experimental condibeginning to influence antitussive treatments in tions. It is believed to act on NMDA receptors, humans. [117] [118] [119] [120] rather than opioid receptors in the brainstem, which

may explain its failure to depress respiration. [107] Local anaesthetics include lidocaine (ligno-

caine), [121, 122] bupivacaine, [123] benzonatate, [124] am-Although most often used to treat spasticity rath-broxol [125] and mexiletine. [126] Given locally, either er than cough, baclofen also has antitussive proper-as aerosol or lozenge, they anaesthetise the sensory ties. [112] [113] [114] [115] In this respect it works by activating γcough receptors in the airway mucosa; they may aminobutyric acid receptors in the brainstem that therefore be effective for acute cough owing to PND facilitate cough. It is effective against aerosol-in-or laryngitis. They should also relieve any pain and duced cough under experimental conditions and ex-soreness. Given orally, they probably act both peperimental animals, and against idiopathic and ACE ripherally and centrally. Benzonatate is the only oral inhibitor-induced cough in patients, although there local anaesthetic commonly used, especially in OTC are few clinical trials. [114, 115] preparations. For acute bronchitis, the use of aer-osolised local anaesthetics may be risky in view of of mean results, which makes statistical significance the possibility of inducing bronchoconstriction. less likely. This is not surprising as acute cough is very variable between patients and with time; differ-While there have been few studies on the antitusences in bodyweight (for a standard dose of drug) sive actions of local anaesthetics in natural or inwill cause more variation; and gender difference in duced cough, they do support its effectivecough sensitivity has seldom been allowed for. [15, 16] ness. [119, 120, 123] Similar studies with induced cough in healthy par-

ticipants, with the same doses of antitussive agent These include levodropropizine, [127, 128] levoclophave shown that the drugs are statistically more erastine, [129] cloperastine [130] and moguiseffective than placebo; in these laboratory studies teine. [131] [132] [133] These are non-narcotic, non-opioids variance of results would be far smaller. A metathat act peripherally and can inhibit induced and analysis of 710 patients with acute cough because of natural cough. In most trials with cough in patients URTI showed that the standard dose of dextromeththey were as effective as dextromethorphan or codeorphan was statistically 17% more effective than ine, and better than placebo.

placebo. [111] Even if cough suppressants act mainly by a place-

bo effect, this is a poor reason not to use them. Extensive work with experimental animals, has Patients believe they work, judged by their enoridentified several different types of cough sensory mous popularity and by their facilitation of sleep. receptors in the airway mucosa, and analysed their And if their effectiveness is small and close to that membrane properties. [101, 117, 118, 134] This research has of a placebo, this lessens the likelihood of adverse led to development of a number of novel drugs effects including addiction. which are active in suppressing induced cough in experimental animals, but which have not been adequately assessed in human patients as yet. Their 6. Conclusion action involves neurokinin, opioid, nociceptin/ Acute cough can be caused by viral or bacterial orphanin, vanilloid, Na + -channel, dopamine and pu-(or both) infections of any part of the respiratory rine pharmacological receptors on the sensory neutract. Its diagnosis is usually based on patient history rone membranes. Some of the drugs may also act on and clinical examination. The causative agent may the central nervous system. be one or more of a number of viruses and bacteria,

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Acknowledgements sion has been disputed. [135] However, nearly all these studies have been withNo sources of funding were used to assist in the prepararather small cohorts of patients, with a high variance tion of this manuscript. The authors have no conflicts of