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Cough is the most common single reason for primary care physician visits and is a

common source of referrals to pulmonologists.1 In otherwise healthy persons, self-


limited cough can occur as part of local irritation due to a viral rhinitis or respiratory
infection. Chronic or persistent cough, defined as lasting more than 8 weeks, is
usually not caused by a life-threatening disorder. However, the frequency of this
complaint, its effect on quality of life, and concern about a serious underlying cause
make chronic cough an important problem.

Because cough is a symptom that is a common pathway for a variety of diverse conditions and has no reliable
objective monitoring tools, physicians' management of cough is actually quite variable. Clearly, a myriad of
pulmonary parenchymal and airway diseases (e.g., interstitial lung disease and bronchiectasis) which present
with abnormal chest imaging also have cough as one of the presenting symptoms. A common situation that
clinicians face is the presence of a cough of unclear cause in the setting of a normal chest x-ray and normal
spirometry, which is the focus of this section. A number of studies suggest that in addition to a history and
physical, a systematic diagnostic approach including a chest x-ray, spirometry, bronchoprovocation study, sinus
imaging, and esophageal pH monitoring yield a specific diagnosis in the vast majority of patients (>95%) with
chronic cough.2 However, routinely obtaining all these tests is cumbersome and expensive in clinical practice,
and some might not be readily available. Thus, it remains unclear whether most patients should undergo a trial of
empirical therapy (either sequential or concurrent) or an aggressive and targeted diagnostic evaluation. In clinical
practice, it is likely that these approaches are used in conjunction.

For a symptom such as cough, simply excluding certain serious causes can go a long way to reassuring the
patient as well as the clinician and allowing a period of observation. An optimal, cost-effective approach to the
management of chronic cough remains controversial. Because chronic cough is usually due to a benign cause,
we recommend a stepwise approach employing empirical therapy targeted at the most common diagnoses,
without extensive initial diagnostic testing (Figure 1). In some cases, a more aggressive approach may be
necessary. For instance, in patients with a normal chest x-ray who have persistent cough and hemoptysis after
antibiotic treatment, a fiberoptic bronchoscopic examination may be indicated to exclude endobronchial
malignancy. Similarly, new cough or a persistent change in the character of cough in a patient with heavy
smoking history may necessitate airway examination.

Definition and Pathophysiology


Cough is a protective physiologic reflex that augments mucociliary clearance of airway secretions. The cough
reflex is characterized by the generation of high intrathoracic pressures against a closed glottis, followed by
forceful expulsion of air and secretions on glottic opening. Intrathoracic pressures of up to 300 mm Hg and
expiratory velocities approaching 500 miles per hour may be achieved.2 These high velocities serve to tear off
mucus from the airway walls so the cough can effectively expel droplets into the air.3 Although it often serves a
protective role, cough can become harmful when it is excessive and nonproductive. The high intrathoracic
pressures and velocities generated during vigorous coughing produce hemodynamic changes analogous to chest
compressions.4
Although physiologic cough has a characteristic acoustic profile and is universally recognizable, there is no
clinical test that can document and confirm the presence of cough. This has hampered progress in the study of
cough, and most of our understanding of the neuronal regulation of cough is derived from animal studies. The
role of vagal afferent nerves in initiating the cough reflex is undisputed; however, the function of the various
afferent neuronal subtypes in the regulation of cough is not well understood. The symptom of cough involves a
reflex arc originating in peripheral cough receptors. Afferent nerves are most concentrated in the epithelia of the
upper and lower respiratory tracts, but they are also located in the external auditory meatus, tympanic
membrane, esophagus, stomach, pericardium, and diaphragm. For example, in a small percentage of patients,
mechanical stimulation of the ear can evoke cough by stimulating afferent nerves carried by the auricular branch
of the vagus nerve.5

Rapidly adapting receptors and C fibers are two afferent nerve subtypes that have been extensively studied and
are theorized to play important roles in the regulation of cough. Rapidly adapting receptors are activated by
mechanical forces such as lung inflation and deflation, whereas C fibers are much more sensitive to chemical
stimuli, primarily bradykinin. Signals from the receptors are carried by vagal afferents to a medullary cough
center, which then trigger cough activation via efferents mediated by the vagal, phrenic, and spinal motor nerves.
Irritation anywhere along the reflex arc by a disease process can cause cough. The exact role of each of the
various subtypes in the mediation of cough remains to be fully elucidated.5

Prevalence
Cough is the single most common symptom prompting outpatient medical visits in the United States.6 Persistent
cough is a common reason for referral to a pulmonologist or allergist. The population point-prevalence of chronic
cough depends on smoking status, ranging from 5% to 40%. Although cough can cause a variety of anatomic
and physiologic complications, 98% of patients in one series listed the suspicion of underlying disease to be the
major factor prompting them to seek medical attention. The aggregate cost of treatment for cough exceeds
several billion dollars in the United States alone. This estimate does not include resources expended for repeated
diagnostic studies.

Signs and Symptoms


Most patients seek medical attention because of complications of cough, either psychological or physical. The
most common complications include feeling that something is wrong (98%), exhaustion (57%), feeling self-
conscious (55%), insomnia (45%), lifestyle change (45%), musculoskeletal pain (45%), hoarseness (43%),
excessive perspiration (42%), and urinary incontinence (39%).2 A host of other physiologic symptoms occur
occasionally due to the high intrathoracic and intra-abdominal pressures achieved. The most prevalent symptoms
include cough syncope, cardiac dysrhythmias, headache, subconjuctival hemorrhage, inguinal herniation, and
gastroesophageal reflux. It is important to elicit which specific cough-related symptoms are bothersome for the
patient as a guide to the pace and scope of diagnostic testing.
Acute and Subacute Cough

The most common cause of acute cough, as defined by a time course of less than 3 weeks, is considered to be
the common cold. Although there are no case series addressing the frequency of the common cold as a cause of
acute cough, epidemiologic data support the relation. Acute and subacute cough are, by definition, self-limited.
Cough that lasts longer than 3 weeks but does not become chronic falls into the subacute category.
Postinfectious cough due to irritation of cough receptors accounts for most of these cases. Most commonly,
persistent bronchial or sinonasal inflammation caused by a preceding viral upper respiratory infection is the
culprit.

Acute bronchitis, as the term implies, is a lower respiratory tract syndrome and another common source of acute
cough. It manifests as a persistent cough, with or without sputum production, in patients with a normal chest
radiograph. Although it is much less prevalent than the common cold, acute bronchitis is the most common
diagnosis given to patients presenting to a physician with acute cough. It is caused by a respiratory virus more
than 90% of the time. Viral cultures and serologic assays are not routinely ordered; hence, the organism
responsible is rarely identified.

Distinction between the common cold and acute bronchitis is often impossible to make and usually clinically
irrelevant in otherwise healthy persons. Bacterial infections are implicated in less than 10% of cases of acute
bronchitis. Despite this, reports have indicated that more than two thirds of patients receive antibiotic therapy for
acute bronchitis. Elderly patients are more likely to receive broad-spectrum antibiotics, and nine out of ten
smokers receive antibiotics despite the lack of evidence that smoking itself is a risk factor for bacterial infection.
Treatment of self-limited bronchitis with antibiotics is often fueled by public expectation. In this circumstance, the
descriptors a physician uses can make a difference. Patients are less likely to feel that antibiotics are necessary
when the term "chest cold" is used as opposed to "bronchitis."7

A common diagnostic challenge encountered in the outpatient setting is determining the need for a chest
radiograph. Pneumonia can also manifest with acute cough, and its manifestation can be more subtle in the
elderly. Prospective studies have shown that the history and physical examination alone can predict the likelihood
of pneumonia and therefore the need for a chest radiograph. A diagnosis of pneumonia is unlikely in the absence
of tachycardia, tachypnea, fever, and evidence of focal consolidation on chest examination. The presence of
purulent sputum does not distinguish between acute bronchitis and pneumonia.7

The most common causes of acute cough are listed in Table 1. In the presence of a compatible history and
examination, further diagnostic testing is usually not necessary. Underrecognized causes of acute or subacute
cough include pertussis and mycoplasma infection. Rarely, life-threatening illnesses manifest primarily with acute
cough. Examples include pulmonary embolus, cardiogenic pulmonary edema, and pneumonia. The mainstay of
treatment includes nonspecific antitussive therapy. Newer generation nonsedating antihistamines are not as
effective in reducing cough compared with the older, first-generation antihistamine-plus-decongestant
preparations. Bronchodilators are not recommended as adjunctive treatment unless baseline airflow obstruction
is present. Expectorants and mucolytics, although commonly used, have not been proved beneficial.8
Table 1: Common Causes of Acute Cough

Cause Recommended Treatments Comments

Viral rhinosinusitis Antitussives Difficult to distinguish from acute


Decongestants sinusitis
First-generation antihistamines
Ibuprofen

Acute bronchitis Antitussives Antibiotics are not routinely


indicated

Acute sinusitis Antibiotics Treatment duration is 2-3 wk


Decongestants
First-generation antihistamines

Allergic or irritant Irritant avoidance Nasal corticosteroids are useful for


rhinitis Nonsedating antihistamines maintenance therapy

Acute exacerbation β Agonist or anticholinergic MDI with spacer


of COPD Antibiotics
Systemic corticosteroids

Pertussis Macrolides (if started within 8 days of Diagnosis is difficult (serologic or


symptom onset) TMP-SMX (macrolide allergy) nasopharyngeal culture)

COPD, chronic obstructive pulmonary disease; MDI, metered-dose inhaler; TMP-SMX, trimethoprim-sulfamethoxazole.
Chronic Cough

Determining the cause of chronic cough is often very challenging. As a general principle, the positive and
negative predictive values of tests for the cause of chronic cough are poor, implying that attribution of cause
depends on a response to specific therapy. Additionally, in 18% to 62% of patients, there are two significant
causes, and in up to 42% there are three.9–11 In studies from cough clinics, the data suggest that there is little or
no diagnostic value in descriptive features such as cough frequency, character, or sputum production. In addition,
the most common causes of chronic cough can manifest with cough as the sole presenting symptom.

Several prospective studies have attempted to delineate the causes of chronic persistent cough and have
reached the same conclusion. In the absence of smoking and angiotensin-converting enzyme (ACE) inhibitors,
upper airway cough syndrome (UACS), asthma, and gastroesophageal reflux disease (GERD) are the most
common causes of chronic cough in patients with a normal chest radiograph.12 The same triad applies in children
and the elderly.2,13 Outside the United States, nonasthmatic eosinophilic bronchitis (NAEB) is a recognized cause
of chronic cough, accounting for up to one third of cases in some series. Even in immunocompromised hosts and
areas where tuberculosis is endemic, UACS, asthma, GERD, and NAEB are the most common causes reported.
Chronic bronchitis, usually resulting from cigarette smoking, is believed to be the most common overall cause of
chronic cough, but most smokers with cough typically do not seek medical attention. All of these data are derived
from studies of patients referred to pulmonologists or cough clinics; however, it is likely that a similar spectrum of
causes accounts for most patients seen by primary care providers.

Upper Airway Cough Syndrome

In January of 2006, the American College of Chest Physicians published a guideline on the diagnosis and
management of cough. The review on postnasal drip (PND) addressed the unclear relation of PND to cough.
Given the lack of understanding about whether PND is the cause of cough or a consequence of airway
inflammation that is producing cough, the term upper airway cough syndrome was adopted as a more accurate
descriptor.

UACS is the single most common cause of chronic cough, accounting for 8% to 87% of cases, either exclusively
or in combination with other factors.2,13 Categories of UACS-induced cough include allergic rhinitis (seasonal or
perennial), perennial nonallergic rhinitis (vasomotor or nonallergic rhinitis with eosinophilia), postinfectious UACS,
bacterial sinusitis, allergic fungal rhinitis, occupational rhinitis, rhinitis medicamentosa, and pregnancy-associated
rhinitis. All patients should undergo evaluation for exposure to common allergens or chemical irritants. An
episodic rhinitis might suggest that an occupational factor is involved.14

The pathogenesis of cough in UACS involves stimulation of afferent receptors in the upper airway, rather than
run-off of secretions into the lower airway. Associated symptoms include rhinorrhea, nasal congestion, a
sensation of drainage or tickle in the oropharynx, and throat clearing. Physical examination can reveal nasal
congestion or discharge, nasal mucosal bogginess, mucous in the oropharynx, or a cobblestone appearance of
the oropharyngeal mucosa. The examination findings are nonspecific, however, and may be present in any of the
other major causes of chronic cough. Although most patients have at least one symptom or sign, UACS can
manifest as cough alone up to 20% of the time.12 Because it is highly prevalent and may be otherwise clinically
unapparent, it is reasonable to employ a brief trial of empirical treatment in the approach to diagnosis. Ultimately,
UACS is a syndrome without a clear definition, and its role in chronic cough is best proven by a response to
therapy. Because the recommended therapy (older generation antihistaminics) can suppress the cough reflex
centrally and peripherally, response to therapy may not necessarily confirm that the diagnosis is accurate.

The presence of copious sputum is associated with an increased likelihood of chronic sinusitis, but neither the
clinical examination nor historical features reliably differentiate it from other causes of UACS.11,13 Excessive
sputum production, defined as greater than 30 mL per day, can be a manifestation of asthma, GERD, and
bronchiectasis. Patients with chronic sinusitis can present with a nonproductive cough as their sole symptom.

Among patients with chronic cough, up to 38% have some radiologic sinus abnormality.15 Thus, a finding of sinus
mucosal thickening on radiographs has only a 29% to 81% positive predictive value (PPV) for chronic sinusitis
that is responsible for cough.2,15 Additionally, mucosal thickening is seen in bacterial and viral infections and
cannot be used to distinguish between the two. The presence of air-fluid levels on four-view sinus x-rays is more
specific for diagnosing sinusitis, and one report documented a 100% PPV.15 Due to the poor PPV, CT scan of the
sinuses is not encouraged routinely for the diagnosis of UACS1.

Asthma
In most series, asthma is the second most common cause of chronic cough in adult nonsmokers, present in 14%
to 55% of cases.16,17 Historical features of wheezing, chest tightness, or exertional dyspnea in response to
triggers such as strong odors or perfumes, cold air, or allergens should suggest the diagnosis. However, the PPV
of a suggestive history is only 56%.18

Cough is a feature in nearly all cases of asthma. In a subset of asthmatic patients, cough is the primary or sole
symptom, a condition termed cough-variant asthma(CVA). CVA accounts for 6.5% to 57% of all asthmatic
patients.2 Many of these patients later develop classic asthma symptoms.18

The physical examination and spirometry can be entirely normal in patients with chronic cough due to asthma.
The most useful test to support the diagnosis is a bronchoprovocation test with inhaled methacholine. The
methacholine challenge test (MCT) is highly sensitive, and a negative test virtually excludes the diagnosis of
asthma. A 20% decrement in forced expiratory volume in 1 second (FEV1) after methacholine inhalation, although
indicating bronchial hyperresponsiveness, can have a PPV as low as 74% for diagnosing the cause of
cough.19 More recently, measurement of exhaled nitric oxide has proved useful in the evaluation of chronic
cough, presumably by identifying cases due to CVA. When 30 ppb was taken as the diagnostic threshold,
exhaled nitric oxide testing had a sensitivity and specificity of 75% and 87%, respectively.20 Frequently, however,
proof that asthma is the inciting factor in chronic cough requires demonstration of a response to directed therapy,
i.e., inhaled corticosteroids. The utility of using short-acting bronchodilators as empirical therapy for CVA is
unknown.

Gastroesophageal Reflux Disease

GERD, alone or in combination with other conditions, accounts for up to 40% of cases of chronic cough around
the world.16 It has been recognized as a contributor to cough with increasing frequency in observational studies;
in some series it has surpassed other etiologies as a cause for chronic cough.2,16 Recognition, diagnosis, and
treatment of GERD are among the most challenging of all cough etiologies, with a number of unclarified issues.
Patients with GERD are commonly asymptomatic, and it can be assumed that the condition is therefore
underrecognized.

In some cases, reflux-mediated irritation of laryngeal receptors or episodic microaspiration underlie GERD-
induced cough. This condition has been termed laryngopharyngeal reflux. Nevertheless, GERD-induced cough is
frequently attributable to a reflex loop involving vagal afferents in the distal esophagus, and proximal reflux is
unnecessary in the pathogenesis.21 Reflux into the distal esophagus alone can stimulate the esophageal-
bronchial cough reflex. It is important to recognize that nonacid reflux can cause chronic cough, and these
patients do not respond to acid-suppression therapy. Coughing itself can induce reflux by an unknown
mechanism potentially creating a vicious self-perpetuating cycle.22

Symptomatic heartburn occurs in only a minority (25%-50%) of patients.2 Other historical features such as
exacerbation at night, in the supine position, or after eating do not reliably differentiate GERD-induced cough
from other causes.16 GERD also commonly accompanies other causes of cough; up to 80% of asthmatic patients
have abnormal 24-hour pH probe findings.2 Recurrent elevations in abdominal pressure can contribute to this
phenomenon.
Ambulatory 24-hour esophageal pH monitoring is the most reliable test for GERD. It is important to include a
temporal symptom log when conducting pH monitoring so as to document the causality of reflux events vis-à-vis
cough. Often, close examination reveals that cough preceded the reflux event. A temporal symptom log can also
substantiate GERD as a cause of cough even when pH probe scores lie within the normal range. In untreated
patients, the pH probe carries a 90% to 100% sensitivity, but the PPV may be as low as 35% when using
therapeutic response as a gold standard.2,23

The esophageal pH monitoring study will be negative in patients with nonacid reflux, and if this condition is
suspected, barium esophagography may be helpful. Esophageal intraluminal impedance plethysmography may
also be able to identify patients with nonacid reflux. However, there are no published data to suggest that
outcomes are improved with this device.

Most patients with GERD do not have endoscopic findings that suggest acid reflux, such as esophagitis or
Barrett's epithelium, and a normal endoscopy does not rule out GERD as a source of cough. It is reasonable to
empirically treat patients who fit the clinical profile before testing. However, recent data indicate that empirical
treatment of patients with chronic cough who have rare or no heartburn may not improve cough related quality of
life or symptoms.24 Similar to other causes of chronic cough, a diagnosis is suggested only when the cough
resolves with treatment.

Nonasthmatic Eosinophilic Bronchitis

A subset of patients has been recognized with increased sputum eosinophils in the absence of demonstrable
bronchial hyperresponsiveness. These patients are typically nonsmokers and have a chronic cough that
responds to inhaled corticosteroids. The frequency of this syndrome has been reported to be as high as 10% to
30% in patients with chronic cough who are referred to a specialist.25 Diagnosis is usually made by demonstration
of induced sputum eosinophilia (>3%). If induced sputum cannot be obtained or is nondiagnostic, bronchoscopy
with bronchial wash can provide useful information. The pathogenesis of NAEB is not well understood, although,
similar to asthma, an inhaled allergen or environmental agent is theorized to play a role. Persistent eosinophilic
airway inflammation can lead to progressive airflow obstruction, and NAEB may be implicated as a causative
factor in chronic obstructive pulmonary disease (COPD).26 The frequency and significance of NAEB remain
incompletely understood.

Chronic Bronchitis

Chronic bronchitis is characterized by a productive cough on most days for 3 months in 2 consecutive years. It
may be caused by irritant-induced inflammation or by the need to mobilize excessive secretions. Although
chronic bronchitis is a common cause of cough in the population, it is present in only 5% of those seeking
medical attention for cough.9,10 Cigarette smoke is the most common irritant associated with chronic bronchitis.
There is a direct relation between the incidence of chronic bronchitis and the number of cigarettes smoked. As
the airflow obstruction becomes more severe, the incidence of cough increases. Clinicians should also inquire
about passive smoke exposure because it is linked to chronic productive cough. Occupational exposures or
inflammatory bowel disease can also trigger this syndrome.27
The cause of cough in chronic bronchitis is multifactorial, with bronchial secretions and airway inflammation
playing a primary role. Patients with airflow obstruction cannot generate an effective cough to clear secretions.
Retained secretions can worsen cough and incite a self-perpetuating cycle. Acute respiratory infections, whether
viral or bacterial, are a common cause of exacerbations in chronic bronchitis. Patients typically present with
increased cough, sputum production, and worsening dyspnea.27

The mainstay of treatment is avoiding the offending agent(s). Cough completely resolves or significantly
decreases in 90% of patients after smoking cessation. In contrast to acute bronchitis, exacerbation of chronic
bronchitis should be treated with antibiotics. Particular vigilance is warranted when there is a change in the
character of the cough or sputum, because this may be the manifesting feature of a superimposed bronchogenic
carcinoma.

Postinfectious Cough

Airway inflammation can follow any respiratory tract infection; up to one quarter of such infections may be
complicated by persistent cough.2 Increased cough receptor sensitivity or temporary bronchial
hyperresponsiveness, probably related to epithelial damage, likely account for this phenomenon. Postinfectious
cough is a diagnosis of exclusion, and by definition it eventually resolves, but its duration may be prolonged. For
this reason, 8 weeks is a more clinically useful working definition of chronic cough than 3 weeks. Postinfectious
cough is usually caused by respiratory viruses, Mycoplasma spp, Chlamydia pneumoniae (strain TWAR),
or Bordatella pertussis. Vigorous coughing can stimulate esophageal reflux, which has been implicated as a
cause of postinfectious cough.82

Pertussis, or whooping cough, is a severe and debilitating cough illness that can last for weeks to months. A
common misconception is that pertussis is a disease of infants and children. Active pertussis infection in
adolescents and adults is an underrecognized cause of chronic cough. One investigation found a 21% incidence
of pertussis in a group of patients with a cough duration of 2 weeks to 3 months.29 In recent years, the incidence
of pertussis has increased, most likely due to a combination of waning immunity and increased detection of the
illness. Patients experience periodic episodes of violent coughing, and post-tussive emesis is common. The
inspiratory whooping sound typical in children is generally not heard in adults.28,30 Diagnosis of cough due to
pertussis may be aided by demonstration of positive polymerase chain reaction in nasopharyngeal secretions in
the acute setting and serum immunoglobulin G analysis later on in the course.31

Angiotensin-Converting Enzyme Inhibitors

ACE normally degrades proinflammatory mediators, such as bradykinins and substance P. Inhibition of this action
lowers the threshold for cough sensitivity. Cough due to ACE inhibitors is a class effect and has been
documented with all ACE inhibitors. Switching to another agent will not ameliorate the symptoms. Usually, cough
begins within 1 week of starting the medication, but it can begin as late as 1 year later. Approximately 10% to
20% of patients develop cough, but in many it is not bothersome. Asthmatic patients are not at increased risk.
Cough resolution may be delayed for up to 1 month after discontinuing the drug. Angiotensin II receptor blockers
do not cause cough and therefore are useful therapeutic alternatives.

Cough Hypersensitivity Syndrome


Chronic cough may be unexplained despite comprehensive workup and empirical treatment trials in a substantial
number of patients. In referral centers, the prevalence has been reported to be as high as 42% of cases.32 A
heightened sensitivity to cough challenge with capsaicin has been demonstrated in these patients. There is a
frequent history of viral illness preceding the onset of chronic cough. The syndrome appears to have a
predilection for females who have onset of cough around menopause. Interestingly, a high prevalence of vocal
cord dysfunction has been reported in association with cough hypersensitivity syndrome.33 It has also been
suggested that the otolaryngological disorders such as laryngeal sensory neuropathy overlap considerably with
the cough hypersensitivity syndrome.34 Treatment is challenging but speech therapy may hold
promise.35 Nebulized local anesthetics, gabapentin, and amitriptyline have also been used with variable results.

Psychosomatic Cough

Psychosomatic cough is rare, especially in adults. It is a diagnosis of exclusion and should not be entertained
until all other potential causes have been investigated, with therapeutic trials of adequate intensity and duration.
There are no distinguishing historical features to reliably differentiate it from other etiologies.16 Habit cough is a
syndrome of persistent, habitual throat clearing that might respond to biofeedback. In distinction, psychogenic
cough usually implies an underlying psychiatric disorder. Most patients with psychogenic cough harbor an
intractable fear of a serious underlying medical disease.

Other Causes of Chronic Cough

Disorders of any of the locations of cough receptors (external auditory canal, tracheobronchial tree, pleura,
pericardium, diaphragm, esophagus, stomach) can cause chronic cough. Recently, obstructive sleep apnea and
chronic tonsillar hypertrophy have been recognized as associations with chronic cough. In addition to ACE
inhibitors, drugs such as sitagliptin, inhaled corticosteroids, topiramate, erythromycin, ribavirin and methotrexate
have been associated with chronic cough. Beta blockers can aggravate CVA. Vitamin B12 deficiency has been
associated with chronic cough via induction of cough reflex hypersensitivity.

Diagnosis
The management of chronic cough typically involves some combination of simple screening studies (chest x-ray
and spirometry), additional specific diagnostic studies (methacholine provocation, sinus imaging, or a pH probe),
and empirical therapy for the three most common entities (rhinitis, asthma, GERD) (see Figure 1). Patients who
lack specific clues by history and examination and who have a normal chest x-ray and spirogram represent the
most common management dilemma for the clinician. A major decision involves the extent of specific diagnostic
testing as opposed to trials of empirical therapy. Randomized clinical trials do not provide adequate guidance to
help the clinician choose between these two strategies. The approach is usually negotiated with the patient,
partly based on the level of subjective distress and on the level of exasperation by the patient and the clinician.

Pinpointing the cause of chronic cough is often difficult. Cough may be the sole manifestation of disorders such
as asthma, GERD, or UACS, with a paucity of other historical features to suggest the correct diagnosis. Features
of cough, such as timing, associated sputum production, and cough character (e.g., brassy), are not helpful in
distinguishing causes.16 A high percentage of patients have two or more responsible causes. Finally, there are no
diagnostic tests with a sufficiently high PPV to reliably implicate any particular cause of cough. Thus, diagnosis
hinges on demonstration of a response to a specific therapy.

Evaluation and treatment using our algorithm (see Figure 1) assume that failure to remedy the cough using trials
of empirical therapy will precipitate appropriate diagnostic testing. A significant fraction of nonresponders fail
treatment due to inadequate intensity or duration of treatment. One study found that the diagnosis was correct in
14% of referred patients, but the treatment regimens were insufficient.10 In these cases, diagnostic testing
facilitates appropriate narrowing and intensification of treatment. Because the overwhelming majority of patients
have UACS, asthma, or GERD, it is crucial to assiduously investigate the roles of each before further
investigations.

Common causes for diagnostic frustration include inadequate diagnosis and inadequate treatment. All tests used
for evaluating chronic cough have a poor PPV. Over-reliance on historical features or cough characteristics can
thwart accurate diagnosis because these are often misleading. The cause of cough may be otherwise clinically
silent, and 18% to 62% of chronic coughs are due to two or more causes. Diagnostic testing that suggests an
underlying cause does not ensure that cough is caused by that etiology. Inadequate treatment regimens are a
common reason for failure to alleviate symptoms, and eradication of related symptoms (heartburn, nasal
congestion) does not ensure that an underlying cause is sufficiently treated. Treatments themselves can frustrate
the search. Central cough suppressants, such as dextromethorphan and codeine, should generally be avoided;
they might serve as a temporizing measure but can distract from the search for a specific cause. Pressurized
metered-dose inhalers (MDIs) can exacerbate CVA.

The American College of Chest Physicians and the British Thoracic Society advise obtaining a chest x-ray before
starting empirical therapy.36 Although most investigators recommend chest x-ray early in the evaluation of chronic
cough, only 4% to 11% of nonsmokers have culpable abnormalities.9,10 The yield of fiberoptic bronchoscopy is
similarly low, and only 4% of patients with normal chest x-rays have endobronchial abnormalities. Even with a
finding of endobronchial pathology, the PPV is only 50% to 89%.2 In assessing for the presence of uncommon
causes of chronic cough, chest CT scanning has a relatively higher diagnostic yield (abnormal in up to 42% of
patients with a normal chest radiograph) and should be performed before cardiac tests in the absence of cardiac
symptoms.36

Some situations merit special consideration. Consider foreign body inhalation in patients who present with
sudden-onset cough. Consider sinus imaging if a patient suspected of having rhinitis or UACS does not respond
to empirical therapy; chronic sinusitis can be otherwise clinically silent.14 In patients who do not respond to
empirical treatment for UACS and GERD and who have a normal chest x-ray, normal spirometry, and negative
MCT, it is reasonable to empirically treat with a short course of inhaled corticosteroids. Resolution of cough would
support the diagnosis of NAEB. Occupational and environmental exposures should be considered as
exacerbating factors in all patients who present with cough. Indoor allergens, such as pets and dust mites, and
secondhand exposure to cigarette smoke are common environmental causes that are easily modifiable.29

Treatment
Rhinitis and Upper Airway Cough Syndrome

Initial therapy for most postnasal drainage syndromes should include an antihistamine-decongestant combination
(Table 2). First- generation antihistamines, such as dexbrompheniramine maleate or azatadine maleate, have
been demonstrated to be superior to second-generation (nonsedating) drugs, due to their additional
anticholinergic activity.2 If drowsiness is problematic, therapy may be initiated with bedtime dosing before
instituting twice-daily dosing. Second-generation antihistamines are useful primarily in allergic rhinitis syndromes.
The role of bacteria in perpetuating chronic sinusitis is controversial, and treatment regimens are not well
defined. Except for chronic sinusitis, in most patients symptoms respond within 1 week. Long-term use of topical
decongestants should be discouraged to avoid rebound nasal congestion (rhinitis medicamentosa).

Table 2: Treatment for Postnasal Drainage Syndromes

Syndrome Treatment Examples Comments

Post-infectious First-generation Dexbrompheniramine Nasal corticosteroids are


antihistamine plus maleate 6 mg plus useful for maintenance
decongestant pseudoephedrine 120 mg bid therapy
combination Ipratropium nasal MDI is
also effective

Allergic rhinitis Second-generation Loratidine 10 mg/day Cromolyn, azelastine,


antihistamine Beclomethasone nasal 42 µg leukotrine inhibitors are
Nasal corticosteroid each nostril qid also useful
Allergen avoidance Consider allergy testing

Non-allergic Anticholinergic nasal Ipratropium 0.06% 2 Intranasal glucocorticoids


rhinopathy spray puffs/nostril 4-6 times/day and/or intranasal
(vasomotor antihistamine if congestion,
rhinitis) sneezing present

Chronic sinusitis First-generation Dexbrompheniramine Use antibiotic active


antihistamine plus Pseudoephedrine as above against H. influenzae, S.
decongestant (3 wk) Oxymetazoline 2 sprays bid pneumoniae, oral
Nasal decongestant (5 anaerobes
days) Nasal corticosteroids after
Appropriate antibiotics cough resolves
(≥3 wk)

MDI, metered-dose inhaler.

Initial empirical therapy with an antihistamine-decongestant has been shown to be effective in a large percentage
of patients who present with chronic cough. This reflects the prevalence of UACS among patients with chronic
cough.19
Asthma

Inhaled corticosteroids are generally required to optimize therapy for most patients. Using a pressurized MDI can
aggravate cough which may be alleviated by the addition of a spacer. Mast cell stabilizers, such as cromolyn
sodium, are also effective. A few patients require oral corticosteroids for symptom control. Zafirlukast, a
leukotriene inhibitor, has been shown to have an antitussive effect in patients with CVA.

The presence of bronchial hyperresponsiveness should be demonstrated by provocation testing or reliable


history before initiating oral steroids. Caution is warranted when interpreting the results of empirical therapeutic
success with asthma therapy; NAEB and postinfectious cough might respond similarly. For this reason, we
recommend at least one attempt to taper therapy. Steroids should also be tapered in patients whose MCT was
obtained in the setting of a postinfectious cough.

Gastroesophageal Reflux Disease

Treatment of GERD should begin with maximal therapy. Patients should avoid reflux-predisposing foods (fatty
foods, chocolate, caffeine, alcohol), give up tobacco, elevate the head of the bed, and not eat within 2 or 3 hours
before lying down. These are important lifestyle adaptations that can significantly diminish cough. Proton pump
inhibitors (PPIs) should be used as the mainstay of medical therapy. In nonsmokers with a normal chest x-ray in
whom asthma, UACS, and NAEB have been ruled out, empirical treatment has been shown to be cost
effective.22 We recommend commencing treatment with twice-daily PPIs, dosed half to 1 hour before the morning
and evening meals; later, therapy may be de-escalated if proven effective. Onset of response can take up to 3
months, with maximal effects of treatment delayed for up to 6 months.2 Response rates of 70% to 100% have
been reported when the end point is improvement in cough.2 However, the true response rate is unknown,
because therapeutic response is the only indication; there is no objective gold standard to prove GERD is the
cause of cough. The role of nonacid reflux in cough pathogenesis is also currently unknown, but it probably
accounts for some of the nonresponders.

Ambulatory pH monitoring should be considered in patients who fail maximal therapy. Unfortunately, this test is
usually only available in larger academic centers. Treatment response in patients with GERD can be prolonged
and even take up to 6 months. Intensive treatment for at least several months should be attempted before
referral for further diagnostic testing. Documentation of persistent symptomatic acid reflux should prompt referral
to a specialist. Surgical correction with esophageal fundoplication is controversial and can result in significant
comorbidity.

Eosinophilic Bronchitis

Inhaled corticosteroids are usually effective, but a few patients require a short course of oral steroid therapy.25 A
2- to 3-week course of prednisone at 30 mg/day is sufficient; a small percentage of patients require maintenance
therapy, generally with inhaled corticosteroids.

Chronic Bronchitis
Smoking cessation markedly reduces symptoms in more than 50% of patients within a month. Cough frequency
and sputum production are most effectively decreased by ipratropium MDI (2 puffs qid). Mucolytics are not
helpful, and the symptomatic benefit of ICS has not been demonstrated.

Postinfectious Cough

Postinfectious cough usually responds to treatment analogous to asthma. Alternatively, ipratropium has proven
efficacy. Ongoing infections should be treated with appropriate antibiotic therapy (see Table 1).

Cough Suppression

Nonspecific cough suppression becomes necessary when the symptom impacts quality of life significantly or
when it is due to a disease process without effective treatment (e.g., idiopathic pulmonary fibrosis). Narcotics
(morphine, codeine and dextromethorphan) have traditionally been used for cough suppression but have well
known and prohibitive side effects with chronic use. Benzonatate is a valuable option for cough suppression;
however, side-effect profile includes seizures and cardiac arrhythmias. Effective pharmacotherapy for cough
suppression remains an unmet need. Recent introduction of central cough suppressants such as
cloperastin37 and peripheral cough suppressants such as levodrpropizine38 and moguisteine39 have been
welcome additions although not yet available in the United States. The discovery of upregulation of the transient
receptor potential (TRP) nociceptors in patients with cough reflex hypersensitivity promises new peripherally
active agents (TRP receptor antagonists) in the treatment of stubborn cough.

Conclusion

Evaluation of cough depends on a systematic review of potential causes. The balance between empiricism and
testing is often dictated by the patient's clinical course and quality of life. In most cases, empirical therapy
targeted at the most common diagnoses leads to significant improvement or resolution of cough, obviating the
need for extensive diagnostic testing. A chest radiograph and spirometry are recommended before referring a
patient to a specialist.

The cause of chronic cough may be otherwise clinically silent, and it is not uncommon for there to be more than
one contributing factor. Ultimately, the underlying cause may be inferred by demonstrating a response to therapy.
Complete resolution of chronic cough can take weeks to months, and both the physician and patient need to set
realistic treatment goals. Inadequate length of treatment, insufficient medication intensity, and patient
nonadherence are common reasons for treatment failure. For this reason, a combination of systematic
empiricism and limited adjunctive diagnostic testing are appropriate for most patients.