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CHRONIC COUGH

Jacqueline L. Olin, MS, PharmD, BCPS, CDE, FASHP,

FCCP Brian Hertz, MD J. Andrew Woods, PharmD,

BCPS

BASICS

DESCRIPTION

Chronic cough is defined as a cough that persists for >8 weeks in adults.

In children, chronic cough is often defined as a cough of >4 weeks in duration.

Subacute cough describes a cough lasting 3 to 8 weeks.

Patients present because of fear of the causative illness (e.g., cancer), annoyance, self-consciousness, and hoarseness.

System(s) affected: gastrointestinal (GI), pulmonary

EPIDEMIOLOGY

Predominant age: all age groups

Predominant sex: male = female, with females more likely to seek out medical attention

Incidence

Persistent unexplained cough occurs in up to 10% of patients presenting with chronic cough and up to 46% referred to specialty cough clinics (1).

Prevalence

Chronic cough is one of the most common reasons for primary care visits.

ETIOLOGYAND PATHOPHYSIOLOGY

Varies with findings and disorders implicated

Often multiple etiologies, but most are related to bronchial irritation. Frequent etiologies (account for >90% of cases) in nonsmokers include the following:

–Upper airway cough syndrome (UACS) and other upper airway abnormalities, including allergic and vasomotor rhinitis syndromes

–Asthma

–Gastroesophageal reflux disease (GERD)

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Other causes:

–ACE inhibitors

–Chronic smoking or exposure to smoke or pollutants

–Aspiration

–Bronchiectasis

–Infections (e.g., pertussis, tuberculosis)

–Nonasthmatic eosinophilic bronchitis (NAEB)

–Cystic fibrosis

–Sleep apnea

–Restrictive lung diseases

–Neoplasms: bronchogenic or laryngeal

–Psychogenic (habit cough)

Cough hypersensitivity syndrome defines a syndrome of cough with characteristic trigger symptoms not adequately explained by other medical conditions.

Etiologies of chronic cough in young children differ from those in older children and adults (2).

RISK FACTORS

Although various conditions may contribute to chronic cough, the main causes include smoking and pulmonary diseases.

COMMONLYASSOCIATED CONDITIONS

Patients with UACS, asthma, and GERD may present with chronic cough as the only symptom and not the usual symptoms associated with the diagnoses.

DIAGNOSIS

HISTORY

Patient age, associated signs/symptoms, medical history, medication history (i.e., ACE inhibitors), environmental and occupational exposures, potential for aspiration, and smoking history may make some causes more likely.

The character of cough or description of sputum quality is rarely helpful in predicting the underlying cause.

Cough diaries have not correlated well with objective measures. Hemoptysis or signs of systemic illness preclude empiric therapy.

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PHYSICALEXAM

Signs and symptoms are variable and related to the underlying cause; usually, a nonproductive cough with no other signs or symptoms

Possible signs and symptoms of UACS, sinusitis, GERD, congestive heart failure, chronic stressors

Absence of additional signs/symptoms of a particular condition not necessarily helpful

–For example, 5% of patients with GERD have no other signs or symptoms and sometimes have poor response to empiric proton pump inhibitor (PPI) trials.

DIAGNOSTIC TESTS & INTERPRETATION

Evaluation often starts with empiric therapy directed at likely underlying etiology and/or simple testing such as a chest x-ray (CXR).

Extensive testing only if indicated by the history and physical

Pediatric Considerations

Children with chronic cough not responsive to an inhaled β-agonist and without overt stressors should undergo spirometry (if age-appropriate) and foreign body evaluation (CXR).

Initial Tests (lab, imaging)

Evaluation will be dictated by findings in the comprehensive history and physical.

Evaluation of peak flow may be indicated.

If considering neoplasm, heart failure, or infectious etiologies, CXR or B-type natriuretic peptide (BNP) may be indicated.

In cases of failure to respond to initial trial of empiric therapy, CXR may also be beneficial.

Follow-Up Tests & Special Considerations

Examples:

–If considering chronic obstructive pulmonary disease (COPD), asthma, or restrictive lung disease: spirometry

–If suspicious of cystic fibrosis: sweat chloride testing

–If suspicious of hypereosinophilic syndrome, tuberculosis, or malignancy: sputum for eosinophils and cytology

If abnormal CXR, suspected neoplasm, or underlying pulmonary disorder,

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consider a chest CT.

Consider pulmonary consultation.

Consider specialist cough clinic.

Refer to gastroenterologist for endoscopy.

Diagnostic Procedures/Other

If diagnosis suggested and inadequate response to initial measures, other procedures can be considered:

Pulmonary function testing

Purified protein derivative (PPD) skin testing

Allergen testing

24-hour esophageal pH monitor

Bronchoscopy, if history of hemoptysis or smoking with normal CXR

Endoscopic or video fluoroscopic swallow evaluation or barium esophagram

Sinus CT

Ambulatory cough monitoring and cough challenge with citric acid, capsaicin, or other bronchodilator (at specialized cough clinic)

Echocardiogram

Test Interpretation

Specific to underlying cause

TREATMENT

GENERALMEASURES

With chronic cough, empiric treatment should be directed at the most common causes as clinically indicated (UACS, asthma, GERD) (1,3)[C].

Empiric trial of nasal steroids and/or antihistamines should be considered if allergic symptoms or postnasal drip is present.

With concomitant complaints of heartburn and regurgitation, GERD should be considered as a potential etiology (3)[C].

In patients with cough associated with the common cold, nonsedating antihistamines were not found to be effective in reducing cough (1,3)[C]. 90% of patients will have resolution of cough after smoking cessation (3)[A]. When indicated, ACE inhibitor therapy should be switched in patients in whom intolerable cough occurs. It may take several days or weeks for cough to resolve after stopping ACE inhibitor therapy.

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Empirically treat postnasal drip and GERD.

In infants and children with nonspecific chronic cough, trials of empiric PPI therapy were not effective (3)[C]; empiric PPI not recommended for adults either (3)[C]

Multimodality speech pathology therapy had a positive benefit on cough severity in some adults (1)[C].

Attempt maximal therapy for single most likely cause for several weeks and then search for coexistent etiologies.

MEDICATION

Treatments (nasal steroids, classic antihistamines, antacids, bronchodilators, inhaled corticosteroids, PPIs, antibiotics) should be directed at the specific cause of cough.

If history and physical exam suggest GERD, may want to empiric PPI therapy prior to further diagnostic testing

The FDAissued a public health advisory stating that OTC cough and cold medicines, including antitussives, expectorants, nasal decongestants, antihistamines, or combinations, should not be given to children <2 years. Subsequently, manufacturers have changed labeling to state “do not use” in children <4 years. In 2017, the FDAissued a contraindication to codeine for cough treatment in children <12 years.

Routine empiric treatment of children with chronic cough with leukotriene receptor antagonists lacks evidence and cannot be recommended.

First Line

In adults:

Nasal steroids: fluticasone, budesonide, others, 1 spray BID for those with allergic rhinitis symptoms or postnasal drip or an empiric trial of PPI (omeprazole, others) once a day

Second Line

Aperipherally acting antitussive agent has been used:

–In patients >10 years, benzonatate (Tessalon Perles) 100 to 200 mg PO TID as needed (maximum 600 mg/day)

Gabapentin was evaluated in a randomized, double-blind, placebo-controlled trial of patients with refractory chronic cough. Gabapentin demonstrated improved cough-specific quality of life compared to placebo. Nausea and fatigue occurred in 31%. Atherapeutic trial with a risk-benefit assessment at 6

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months is suggested (1)[C].

Acomparative effectiveness review of 49 studies with common opioid and nonanesthetic antitussives stated there is some efficiency for treating cough in adults, but evidence is limited (4)[C].

Studies evaluating inhaled corticosteroid use in chronic cough for patients without additional indication such as asthma did not show consistent benefits (1)[C].

ISSUES FOR REFERRAL

Patients with chronic cough may benefit from evaluation by pulmonary, gastroenterology, ear/nose/throat (ENT), and/or allergy specialists. Consider specialist cough clinic.

SURGERY/OTHER PROCEDURES

Fundoplication may be effective for cough secondary to refractory GERD.

ONGOING CARE

FOLLOW-UPRECOMMENDATIONS

Consider stepwise withdrawal of medications after resolution of cough.

Patient Monitoring

Frequent follow-up is necessary to assess the effectiveness of treatment.

DIET

Dietary modification: Patients with GERD may benefit by avoiding ethanol, caffeine, nicotine, citrus, tomatoes, chocolate, and fatty foods.

PATIENT EDUCATION

Reassure patient that most cases of chronic cough are not life-threatening and that the condition can usually be managed effectively.

Counsel that several weeks to a month may be needed for significant reduction or elimination of cough.

Prepare the patient for the possibility of multiple diagnostic tests and therapeutic regimens because the treatment is very often empiric.

PROGNOSIS

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>80% of patients can be effectively diagnosed and treated using a systematic approach.

Cough from any cause may take weeks to months until resolution, and resolution depends greatly on efficacy of treatment directed at underlying etiology.

COMPLICATIONS

Cardiovascular: arrhythmias, syncope

Stress urinary incontinence

Abdominal and intercostal muscle strain

GI: emesis, hemorrhage, herniation

Neurologic: dizziness, headache, seizures

Respiratory: pneumothorax, laryngeal, or tracheobronchial trauma

Skin: petechiae, purpura, disruption of surgical wounds

Medication side effects

Other: negative impact on quality of life

REFERENCES

1.Gibson P, Wang G, McGarvey L, et al. Treatment of unexplained chronic cough: CHEST guideline and expert panel report. Chest. 2016;149(1):27–44.

2.Chang AB, Oppenheimer JJ, Weinberger M, et al. Etiologies of chronic cough in pediatric cohorts: CHEST guideline and expert panel report. Chest. 2017;152(3):607–617.

3.Irwin RS, Baumann MH, Bolser DC, et al. Diagnosis and management of cough executive summary: ACCPevidence-based clinical practice guidelines. Chest. 2006;129(Suppl 1):1S–23S.

4.Yancy WS Jr, McCrory DC, Coeytaux RR, et al. Efficacy and tolerability of treatments for chronic cough: a systematic review and meta-analysis. Chest. 2013;144(6):1827–1838.

SEE ALSO

Asthma; Bronchiectasis; Eosinophilic Pneumonias; Gastroesophageal Reflux

Disease; Laryngeal Cancer; Lung, Primary Malignancies; Pertussis;

Pulmonary Edema; Rhinitis, Allergic; Sinusitis; Tuberculosis

Algorithm: Cough, Chronic

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CODES

ICD10

R05 Cough

J44.9 Chronic obstructive pulmonary disease, unspecified J41.0 Simple chronic bronchitis

CLINICALPEARLS

Chronic cough is defined as a cough that persists for >8 weeks in adults.

In patients with chronic cough, most frequent etiologies include a history of smoking, asthma, UACS, and GERD.

The FDAissued a public health advisory stating that OTC cough and cold medicines should not be given to children <2 years. OTC cough expectorant and suppressant product labels state “do not use” in children <4 years.

Codeine is contraindicated for cough treatment in children <12 years.

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CHRONIC FATIGUE SYNDROME (CFS)

Yow-Jeng Franny Pan, MB, BCh, BAO Naureen Rafiq, MBBS

BASICS

DESCRIPTION

Acomplex physical illness characterized by a new or definite onset of debilitating fatigue that persists for >6 months and significantly reduces a person’s ability to perform usual activities. Key features include:

–Impaired memory or concentration

–Joint and muscle pain

–Unrefreshing sleep

–Postexertional malaise

–Orthostatic intolerance (i.e., dizziness and light-headedness when standing

up)

Synonyms: myalgic encephalomyelitis, chronic Epstein-Barr virus syndrome, postviral fatigue syndrome, chronic fatigue immune dysfunction, and systemic exertion intolerance disease (1)

Fatigue is not relieved by rest and results in >50% reduction in previous activities (occupational, educational, social, and personal).

Other potential medical causes must be ruled out (2).

EPIDEMIOLOGY

Generally occurs as sporadic or isolated cases, although cluster outbreaks have occurred in different parts of the world—Iceland (1948), London, England (1955), New Zealand (1984), and the United States (1984 and 1985)

Onset usually between 30 and 50 years of age, can affect all ages (1)[B]

Females affected 3 to 4 times more than male

Estimated annual cost from loss of productivity and medical bills ranges from $17 to 24 billion in the United States.

Prevalence

Affects all racial and ethnic groups; more prevalent in minority and low socioeconomic groups

An estimated 836,000 to 2.5 million Americans suffer from chronic fatigue

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syndrome (CFS) (1)[B].

ETIOLOGYAND PATHOPHYSIOLOGY

Unknown and likely multifactorial

–Possible interaction between genetic predisposition, environmental factors, an initiating stressor, and perpetuating factors

Arecent theory attributes possible neuroendocrine immunologic and biochemical effects in CFS to dysbiosis of the gut microbiome.

Physiologic or environmental stressors are potential precipitants.

Many patients with chronic fatigue recall significant stressors (e.g., major medical procedure, loss of a loved one, loss of employment) in months before symptoms began. History of childhood trauma is common.

Systems hypothesized to contribute to altered physiology include:

–Neuroendocrine (e.g., diminished cortisol response to increased corticotropin concentrations)

–Immune (e.g., increased C-reactive protein and β-2 microglobulin)

–Neuromuscular (e.g., dysfunction of oxidative metabolism)

–Autonomic (Orthostatic hypotension is reported in a proportion of CFS patients.)

–Serotonergic (e.g., hyperserotonergic mechanisms or upregulation of serotonin receptors)

Genetics

Higher concordance among monozygotic twins compared with dizygotic twins

RISK FACTORS

Possible predisposing factors include (3):

Personality characteristics (neuroticism and introversion) Lifestyle

–Childhood inactivity or over activity

–Inactivity in adulthood after infectious mononucleosis

–Familial predisposition

–Comorbid depression or anxiety

Long-standing medical conditions in childhood

Childhood trauma (emotional, physical, sexual abuse)

Prolonged idiopathic chronic fatigue

Postinfectious fatigue and CFS have been noted to follow mononucleosis, Ross River virus, Coxiella burnetii, herpes zoster, Q fever, and Giardia

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