COUGH

Cough provides an essential protective function for human airways

and lungs. Without an effective cough reflex, we are at risk

for retained airway secretions and aspirated material, predisposing

to infection, atelectasis, and respiratory compromise. At the

other extreme, excessive coughing can be exhausting; can be

complicated by emesis, syncope, muscular pain, or rib fractures;

and can aggravate abdominal or inguinal hernias and urinary

incontinence. Cough is often a clue to the presence of respiratory

disease. In many instances, cough is an expected and accepted

manifestation of disease, such as during an acute respiratory tract

infection. However, persistent cough in the absence of other respiratory

symptoms commonly causes patients to seek medical attention,

accounting for as many as 10—30% of referrals to pulmonary

specialists.

COUGH MECHANISM

Spontaneous cough is triggered by stimulation of sensory nerve

endings that are thought to be primarily rapidly adapting receptors

and C-fibers. Both chemical (e.g., capsaicin) and mechanical (e.g.,

particulates in air pollution) stimuli may initiate the cough reflex. A

cationic ion channel, called the type-1 vanilloid receptor, is found

on rapidly adapting receptors and C-fibers; it is the receptor for

capsaicin, and its expression is increased in patients with chronic

cough. Afferent nerve endings richly innervate the pharynx, larynx,

and airways to the level of terminal bronchioles and into the

lung parenchyma. They may also be found in the external auditory

meatus (the auricular branch of the vagus nerve, called the Arnold

nerve) and in the esophagus. Sensory signals travel via the vagus

and superior laryngeal nerves to a region of the brainstem in the

nucleus tractus solitarius, vaguely identified as the "cough center."

Mechanical stimulation of bronchial mucosa in a transplanted

lung (in which the vagus nerve has been severed) does not produce

cough.

The cough reflex involves a highly orchestrated series of involuntary

muscular actions, with the potential for input from cortical

pathways as well. The vocal cords adduct, leading to transient

upper-airway occlusion. Expiratory muscles contract, generating

positive intrathoracic pressures as high as 300 mm Hg. With

sudden release of the laryngeal contraction, rapid expiratory

flows are generated, exceeding the normal "envelope" of maximal

expiratory flow seen on the flow-volume curve ( Fig. 34-1 ).

Bronchial smooth muscle contraction together with dynamic

compression of airways narrows airway lumens and maximizes

the velocity of exhalation (as fast as 50 miles per hour).The

kinetic energy available to dislodge mucus from the inside of

airway walls is directly proportional to the square of the velocity

of expiratory airflow. A deep breath preceding a cough optimizes

the function of the expiratory muscles; a series of repetitive

coughs at successively lower lung volumes sweeps the point of

maximal expiratory velocity progressively further into the lung periphery.

IMPAIRED COUGH

Weak or ineffective cough compromises the ability to clear lower

respiratory tract infections, predisposing to more serious infections

and their sequelae. Weakness, paralysis, or pain of the expiratory

(abdominal and intercostal) muscles is foremost on the list of

causes of impaired cough ( Table 34-1 ). Cough strength is generally

assessed qualitatively; peak expiratory flow or maximal expiratory

pressure at the mouth can be used as a surrogate marker for cough

strength. A variety of assistive devices and techniques have been

developed to improve cough strength, spanning the gamut from

simple (splinting the abdominal muscles with a tightly-held pillow

to reduce post-operative pain while coughing) to complex (a

mechanical cough-assist device applied via face mask or tracheal

tube that applies a cycle of positive pressure followed rapidly by

negative pressure). Cough may fail to clear secretions despite a preserved

ability to generate normal expiratory velocities, either due to

abnormal airway secretions (e.g., bronchiectasis due to cystic fibrosis)

or structural abnormalities of the airways (e.g., tracheomalacia

with expiratory collapse during cough).

SYMPTOMATIC COUGH

The cough of chronic bronchitis in long-term cigarette smokers

rarely leads the patient to seek medical advice. It lasts only seconds

to a few minutes, is productive of benign-appearing mucoid sputum,

and is not discomforting. Similarly, cough may occur in the context

of other respiratory symptoms that, together, point to a diagnosis,

such as when cough is accompanied by wheezing, shortness of

breath, and chest tightness after exposure to a cat or other sources of

allergens. At times, however, cough is the dominant or sole symptom

of disease, and it may be of sufficient duration and severity

that relief is sought. The duration of cough is a clue to its etiology.

Acute cough (<3 weeks) is most commonly due to a respiratory

tract infection, aspiration event, or inhalation of noxious chemicals

or smoke. Subacute cough (3—8 weeks duration) is frequently the

residuum from a tracheobronchitis, such as in pertussis or "postviral

tussive syndrome." Chronic cough (>8 weeks) may be caused

by a wide variety of cardiopulmonary diseases, including those of

inflammatory, infectious, neoplastic, and cardiovascular etiologies.

When initial assessment with chest examination and radiograph is

normal, cough-variant asthma, gastroesophageal reflux, nasopharyngeal

drainage, and medications (angiotensin converting enzyme

[ACE] inhibitors) are the most common causes of chronic cough.

Cough of less than 8 weeks' duration may be the early manifestation

of a disease causing chronic cough.

ASSESSMENT OF CHRONIC COUGH

Details as to the sound, time of occurrence during the day, and

pattern of coughing infrequently provide useful etiology clues.

Regardless of cause, cough often worsens when one first lies down

at night or with talking or in association with the hyperpnea of exercise;

it frequently improves with sleep. Exceptions might include

the characteristic inspiratory whoop after a paroxysm of coughing

that suggests pertussis or the cough that occurs only with certain

allergic exposures or exercise in cold air, as in asthma. Useful historical

questions include the circumstances surrounding the onset

of cough, what makes the cough better or worse, and whether or not

the cough produces sputum.

The physical examination seeks clues to the presence of cardiopulmonary

disease, including findings such as wheezing or crackles

on chest examination. Examination of the auditory canals and

tympanic membranes (for irritation of the tympanic membrane

resulting in stimulation of Arnold's nerve), the nasal passageways

(for rhinitis), and nails (for clubbing) may also provide etiologic

clues. Because cough can be a manifestation of a systemic disease,

such as sarcoidosis or vasculitis, a thorough general examination is

equally important.

In virtually all instances, evaluation of chronic cough merits a

chest radiograph. The list of diseases that can cause persistent coughing

without other symptoms and without detectable abnormality

on physical examination is long. It includes serious illnesses such as

Hodgkin's disease in young adults and lung cancer in an older population.

An abnormal chest film leads to evaluation of the radiographic

abnormality to explain the symptom of cough. A normal chest image

provides valuable reassurance to the patient and the patient's family,

who may have imagined the direst explanation for the cough.

In a patient with chronic productive cough, examination of

expectorated sputum is warranted. Purulent-appearing sputum

should be sent for routine bacterial culture and, in certain circumstances,

mycobacterial culture as well. Cytologic examination of

mucoid sputum may be useful to assess for malignancy and to distinguish

neutrophilic from eosinophilic bronchitis. Expectoration

of blood—whether streaks of blood, blood mixed with airway secretions,

or pure blood—deserves a special approach to assessment and

management, as discussed below.

CHRONIC COUGH WITH A NORMAL CHEST RADIOGRAPH

It is commonly held that use of an angiotensin-converting enzyme

inhibitor; post-nasal drainage; gastroesophageal reflux; and asthma,

alone or in combination, account for more than 90% of patients

who have chronic cough and a normal or noncontributory chest

radiograph. However, clinical experience does not support this contention,

and strict adherence to this concept discourages the search

for alternative explanations by both clinicians and researchers. On

the one hand, chronic idiopathic cough is common and its management

deserves study and discussion. On the other hand, serious

pulmonary diseases, including inflammatory lung diseases, chronic

infections, and neoplasms, may remain occult on plain chest imaging

and require additional testing for detection.

ACE inhibitor-induced cough occurs in 5—30% of patients taking

ACE inhibitors and is not dose-dependent. Any patient with

chronic unexplained cough who is taking an ACE inhibitor should

be given a trial period off the medication, regardless of the timing

of the onset of cough relative to the initiation of ACE inhibitor therapy.

In most instances, a safe alternative is available; angiotensinreceptor

blockers do not cause cough. Failure to observe a decrease

in cough after one month off medication argues strongly against

this diagnosis. ACE metabolizes bradykinin and other tachykinins,

such as substance P. The mechanism of ACE inhibitor cough may

involve sensitization of sensory nerve endings due to accumulation

of bradykinin. In support of this hypothesis, polymorphisms in the

neurokinin-2 receptor gene are associated with ACE inhibitor—

induced cough.

Post-nasal drainage of any etiology can cause cough as a response

to stimulation of sensory receptors of the cough-reflex pathway

in the hypopharynx or aspiration of draining secretions into the

trachea. Clues to this etiology include symptoms of post-nasal

drip, frequent throat clearing, and sneezing and rhinorrhea. On

speculum examination of the nose, one may see excess mucoid or

purulent secretions, inflamed and edematous nasal mucosa, and/

or nasal polyps; in addition, one might visualize secretions or a

cobblestoned appearance of the mucosa along the posterior pharyngeal

wall. Unfortunately, there is no means by which to quantitate

post-nasal drainage. In many instances, one is left to rely on a

qualitative judgment based on subjective information provided by

the patient. This assessment must also be counterbalanced by the

fact that many people who have chronic post-nasal drainage do not

experience cough.

Linking gastroesophageal reflux to chronic cough poses similar

challenges. It is thought that reflux of gastric contents into the

lower esophagus may trigger cough via reflex pathways initiated

in the esophageal mucosa. Reflux to the level of the pharynx

with consequent aspiration of gastric contents causes a chemical

bronchitis and possible pneumonitis that can elicit cough for days

after the aspiration event. Retrosternal burning after meals or on

recumbency, frequent eructation, hoarseness, and throat pain are

potential clues to gastroesophageal reflux. Reflux may also elicit

no or minimal symptoms. Glottic inflammation may be a clue to

recurrent reflux to the level of the throat, but it is a nonspecific

finding and requires direct or indirect laryngoscopy for detection.

Quantification of the frequency and level of reflux requires a somewhat

invasive procedure to measure esophageal pH directly (a catheter

with pH probe placed nasopharyngeally in the esophagus for

24 h, or pH monitoring using a radiotransmitter capsule placedendoscopically into the esophagus). Precise interpretation of test

results enabling one to link reflux and cough in a causative way

remains debated. Again, assigning the cause of cough to gastroesophageal

reflux must be weighed against the observation that

many people with chronic reflux (such as frequently occurs during

pregnancy) do not experience chronic cough.

Cough alone as a manifestation of asthma is common in children

but not in adults. Cough due to asthma in the absence of wheezing,

shortness of breath, and chest tightness is referred to as "coughvariant

asthma." A history suggestive of cough-variant asthma tiesthe onset of cough to typical triggers for asthma and resolution

of cough upon withdrawal from exposure to them. Objective

testing can establish the diagnosis of asthma (airflow obstruction

on spirometry that varies over time or reverses in response to

bronchodilator) or exclude it with certainty (negative response to

bronchoprovocation challenge, such as with methacholine). In a

patient capable of making reliable measurements, home expiratory

peak flow monitoring can be used as a cost-effective method to

support or discount a diagnosis of asthma.

Chronic eosinophilic bronchitis causes chronic cough with a

normal chest radiograph. This condition is characterized by sputum

eosinophilia in excess of 3% without airflow obstruction or bronchial

hyperresponsiveness and is successfully treated with inhaled

glucocorticoids.

Treatment of chronic cough in a patient with a normal chest

radiograph is often empiric and is targeted at the most likely cause

or causes of cough as determined by history, physical examination,

and possibly pulmonary-function testing. Therapy for post-nasal

drainage depends on the presumed etiology (infection, allergy, or

vasomotor rhinitis) and may include systemic antihistamines; antibiotics;

nasal saline irrigation; and nasal pump sprays with corticosteroids,

antihistamines, or anticholinergics. Antacids, histamine

type-2 (H2) receptor antagonists, and proton-pump inhibitors are

used to neutralize or decrease production of gastric acid in gastroesophageal

reflux disease; dietary changes, elevation of the head and

torso during sleep, and medications to improve gastric emptying

are additional therapies. Cough-variant asthma typically responds

well to inhaled glucocorticoids and intermittent use of inhaled betaagonist

bronchodilators.Patients who fail to respond to treatment of the common causes

of cough or who have had these causes excluded by appropriate

diagnostic testing should undergo chest CT. Examples of diseases

causing cough that may be missed on chest x-ray include carcinoid

tumor, early interstitial lung disease, bronchiectasis, and atypical

mycobacterial pulmonary infection. On the other hand, patients

with chronic cough who have normal chest examination, lung function,

oxygenation, and chest CT imaging can be reassured as to the

absence of serious pulmonary pathology.