Continuing Education Activity

A cough is an essential protective and defensive reflex that the body uses to remove mucus, noxious substances, and irritants from the larynx, trachea, and bronchi; an impaired or absent cough reflex can be dangerous. Nocturnal coughs are common and can result from a variety of etiologies. This activity describes the causes of nocturnal coughs, reviews the workup, and highlights the role of the interprofessional team in the management of affected patients.

Objectives:

• Identify the differential diagnosis of nocturnal cough.
• Describe the presentation of a patient with a nocturnal cough.
• Summarize the management options for nocturnal cough.
• Explain interprofessional team strategies for improving care coordination and communication to advance the management of nocturnal cough and improve patient outcomes.

Introduction

A cough is a symptom and a reflex action that is an essential protective and defensive act that secures the removal of mucus, noxious substances, and infections from the larynx, trachea, and larger bronchi. Impairment or absence of the coughing mechanism can be dangerous and even fatal in disease. Women tend to have a chronic cough more often and have heightened cough reflex sensitivity compared to men. Nocturnal cough is distressing and may cause disturbances in sleep.[1]

The cough reflex has three components:[2]

• Afferent sensory limb
• Central processing center
• Efferent limb

This cough reflex has neuroplasticity in such a way that hypersensitive response is triggered over time because of the cough itself causing chronic irritation and inflammation and leading to tissue remodeling.[3]

Asthma is a highly prevalent chronic respiratory disease with nocturnal cough as one of the presenting features. In asthma, symptoms usually worsen at night and cause awakenings affecting the quality of life. Marsden et al reported that the parameter of nocturnal cough could be a valid indicator for asthma control.[4] However, still, more information is needed regarding cause-effect relationships and longitudinal trends of nocturnal cough in asthma.

Etiology

Causes of a nocturnal cough can be categorized as respiratory, non-respiratory, and systemic.

• The most common respiratory causes of a chronic cough include postnasal drip, postinfectious, and asthma.
• Environmental factors include smoking, both active and passive; this is the most frequent environmental factor.
• Drugs include angiotensin-converting enzyme inhibitors (ACEIs), beta-blockers, and non-steroidal anti-inflammatory drugs (NSAIDs).[5]
• Drugs causing pulmonary fibrosis are bleomycin, busulphan, methotrexate, carmustine, amiodarone, cyclophosphamide, and hydralazine.[6]
• Other respiratory causes include bronchiectasis, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, interstitial lung disease (ILD), primary or secondary lung tumors, sarcoidosis, and tuberculosis.
• Other upper airway conditions to be ruled out are chronic tonsillar enlargement, obstructive sleep apnea, gastroesophageal reflux disease (GERD), laryngeal problems, and foreign bodies in the large airways.[7]
• Non-respiratory causes are GERD, recurrent aspiration, left ventricular failure, mitral stenosis, pulmonary infarction, and psychogenic cough, which is a diagnosis of exclusion.[8]
• Very rare conditions include cardiac arrhythmias, aortic aneurysm, cough only when supine (due to a collapse of large airways), following complex involuntary tics (Tourette syndrome), and vitamin B12 deficiency (probably due to sensory neuropathy).
• Of all these conditions, cough variant asthma, GERD, and upper airway cough syndrome (UACS) are called the pathogenic triad, and they constitute 90% of cases.[8][9][10]

Coronavirus disease 2019 (COVID-19) could result in long-standing symptoms, most importantly cough.[11] 'Post-COVID-19 syndrome' is referred to as signs and symptoms developing during or after COVID-19 and continuing for over twelve weeks.[12] More data is required and keeps emerging regarding incidence, the natural course of illness, and etiology.

Epidemiology

A worldwide study from 16 countries has shown that a nocturnal cough was present in 30%, productive cough in 10%, and non-productive cough in 10%. Conditions such as chronic bronchitis are therefore grossly underrepresented, even though they cause considerable morbidity within the population. Similarly, such tertiary referral clinics are unlikely to represent the true prevalence of conditions such as asthma as a cause of a chronic cough, since at least in European practice, a therapeutic trial of anti-asthma medication is usually performed by the primary provider.[13][14]

Pathophysiology

The cough reflex has three components: an afferent sensory limb, a central processing center, and an efferent limb. Cough receptors are present in the pharynx and larynx, up to the segmental bronchi. Many types of sensory receptors respond to mechanical, inflammatory, thermal, and chemical stimuli. These are connected to the vagal afferent nerves. The cough center is located in the medulla and receives signals from these cough receptors. The efferent fibers reach the various muscles that produce the forced expiratory effort. Since the higher cortical centers influence the cough center, it is possible to produce or suppress a cough voluntarily. The stimulation of a complex reflex arc is needed for each cough.[15]

History and Physical

A nocturnal cough needs to be assessed in terms of intensity, severity, frequency, and sensitivity. Some clues in the assessment of a nocturnal cough:

• A cough worsening on supine posture: Postnasal drip, esophageal reflux, chronic bronchitis, bronchiectasis, and heart failure
• Presence of clear sputum: Hypersensitivity mechanism
• Purulent sputum: Sinusitis, bronchiectasis; rule out tuberculosis
• Blood tinged sputum: Malignancies, tuberculosis, and bronchiectasis
• A non-productive cough: Angiotensin-converting-enzyme inhibitor therapy
• Improvement of a cough with antihistaminic treatment confirms the diagnosis of upper airway cough syndrome (UACS)
• The red flag symptoms of chronic nocturnal cough are copious sputum (bronchiectasis), hemoptysis (malignancy, tuberculosis), systemic symptoms (tuberculosis, lymphoma, lung primary or secondaries), and significant dyspnoea (congestive heart failure, COPD, fibrotic lung disease).[16][9] Ask about a history of fever, weight loss, night sweats, and progressive fatigue.

General examination should evaluate clubbing (may be indicative of vasculitis, sarcoidosis, and malignancies), pedal edema, and lymphadenopathy. Physical examination includes:

• The search for a deviated nasal septum, turbinate hypertrophy, polyps, and sinusitis
• Ears: Inflammation of the tympanic membrane or the external canal
• Respiratory system: Bilateral wheeze in COPD, bronchial asthma, or even heart failure; localized wheeze may occur in case of obstruction with a foreign body or tumor
• Other systems should also be examined carefully

Evaluation

A chest x-ray is mandatory in all cases. A chronic cough with a normal chest x-ray occurs with ACE inhibitor therapy, postnasal drip, GERD, and asthma.[17] These account for 90% of the cases. Diseases causing chronic cough but missed on chest x-ray include tumors, early ILD, bronchiectasis, and atypical mycobacterial pulmonary infection.

Sputum examination is essential, whenever possible. Bacterial culture is needed if the sputum is purulent.[18] When feasible and in case of doubt, mycobacterial culture is also necessary. A cytological examination is to identify malignant cells and to rule out eosinophilic bronchitis.[19] ESR and CRP may give a clue to the presence of infection, malignancy, and connective tissue disorders. Cold agglutinin titer for mycoplasma pneumoniae, in suspected cases. HIV Elisa for AIDS. Possible further investigations include: Bordetella pertussis can be detected from the nasopharyngeal secretions. Induced sputum analysis when sputum is not easily available, and it is mandatory to examine the sputum.[20]

Bronchial provocation testing with methacholine or histamine is positive in bronchial asthma. Bronchoscopy should be performed after excluding all common causes if foreign body inhalation is suspected. Bronchoscopy is also indicated whenever there are abnormal chest x-ray, hemoptysis, obstructive lesions, and infiltrates, that otherwise elude diagnosis. Echocardiography for cardiac ailments. Twenty-four-hour ambulatory oesophageal pH or oesophageal manometry for diagnosing GERD. Radiology of the sinuses. HRCT–when no other diagnosis can be made.[8] Patients who have isolated chronic nocturnal cough, with a normal physical examination, chest x-ray, and spirogram, are unlikely to have serious pulmonary conditions.

Treatment / Management

Encourage smokers to cease smoking.[21][22] A cough should improve within eight weeks of smoking cessation. In the case of ACEI therapy, stop the therapy, improvement occurs within four weeks. The persistence of a cough after the withdrawal of ACEIs raises the possibility of other causes of a cough. The onset of asthma has been linked to its use. Advise the patient to keep away from known environmental and occupational pollutants and irritants.

Treatment of upper airway cough syndrome (UACS) depends on a presumed etiology (infection, allergy, or vasomotor rhinitis). So treatment includes first-generation antihistamines, antibiotics, nasal saline irrigation, nasal pump sprays with glucocorticoids with or without decongestants like pseudoephedrine.[23] Beta 2 agonists with inhaled corticosteroids give relief within a week in case of proven asthma. A negative response to a bronchoprovocation test, e.g., methacholine, rules out cough variant asthma. Peak expiratory flow meter can be used as a cost-effective method to assess therapeutic response.[24] A course of oral steroids for two weeks, or inhaled steroids, gives relief in the case of non-asthmatic eosinophilic bronchitis (NAEB). A postinfectious cough can be treated with inhaled ipratropium, inhaled corticosteroids. Macrolide antibiotics with or without antitussives may be needed. GERD therapy includes prokinetic agents, H2 antagonists, and proton pump inhibitors (PPIs). Appropriate dietary therapy and proper positioning of the patient in bed are important aspects of management. PPIs should be tried for 8 to 12 weeks.

Differential Diagnosis

Nocturnal cough can be due to the disease of the upper airway, lower airway, gastrointestinal system, or cardiovascular system. Following are the differential diagnoses of nocturnal cough.

• The most common cause of an acute/subacute cough is a viral respiratory tract infection
• Upper airway cough syndrome
• Asthma
• GERD[25]
• Non-asthmatic eosinophilic bronchitis[26]
• Bronchiectasis
• Bronchogenic carcinoma
• Chronic aspiration
• COPD
• Congestive heart failure
• Foreign body of the airway
• ILD
• Tracheoesophageal fistula

In adults with a cough longer than eight weeks, most of the cases are due to post-nasal drip, asthma, eosinophilic bronchitis, and GERD. The causes of chronic cough are the same in children with the addition of bacterial bronchitis.

Prognosis

The prognosis of nocturnal cough is dependent on the cause. A cough should improve within eight weeks of smoking cessation. In the case of ACEI therapy, improvement occurs within four weeks. Cough caused by GERD only improves after the underlying condition is treated. However, the cough of asthma may be present for years.

Complications

Nocturnal cough causes disturbed sleep, which may cause neuropsychiatric disorders in patients. A study by Won et al showed that in adults, chronic cough impacts health-related quality of life. Persons with a chronic cough had a significantly lower overall EQ-5D-3L index score than individuals without chronic cough, with the impact on quality of life being particularly large in women 65 years or older. A greater association was reported between chronic cough and anxiety/depression, pain/discomfort, and usual activities than with self-care or mobility.[27]

Consultations

Nocturnal cough has many etiologies, to identify the exact cause and then its management requires teamwork by different specialties. Following specialties may be required to reach the proper diagnosis:

• Pulmonology
• Gastroenterology
• Immunology
• Cardiology

Deterrence and Patient Education

Nocturnal cough is a common and distressing symptom. It is important to identify and treat the underlying cause for appropriate management.

In the case of cigarette smoking or the use of tobacco products, patients should be encouraged to quit in order to improve their symptoms and prevent other complications. They should be educated on the importance of smoking cessation and how nocturnal cough could be caused or exacerbated by smoking.

Patients who develop a cough after the use of ACEI should be switched to another medication.

An empiric approach is needed to evaluate and effectively treat patients with chronic cough.

Enhancing Healthcare Team Outcomes

Nocturnal cough is a common presentation with diverse etiology. When a patient presents with this symptom, it is best managed by an interprofessional team, including primary care providers, pulmonologists, immunologists, or addiction specialists. In case the nocturnal cough is caused by GERD, a gastroenterologist may need to be consulted to treat the underlying condition. There may also be a need to involve respiratory therapists, physician assistants, and nurse practitioners to more appropriately manage the patient.

To improve outcomes of nocturnal cough, prompt management by an interprofessional team is recommended.