Chronic cough with weight loss

Chronic cough with weight loss is a cough lasting 8 weeks or more in an adult (3 weeks or more when tuberculosis is possible) together with unintentional loss of body weight.

It signals chronic infection (most of all tuberculosis), malignancy or advanced chronic lung disease until proven otherwise. Infectious tuberculosis must be identified and isolated while lung cancer is excluded.

Definitions.

• Acute cough lasts under 3 weeks, subacute 3 to 8 weeks and chronic over 8 weeks.
• Significant weight loss is 5% or more of body weight over 6 months, or any loss with a body mass index under 18.5 kg/m2.
• Presumptive tuberculosis is a cough of 2 weeks or more, or any cough with fever, night sweats or weight loss in a person with HIV, a close contact of a case, or a person from a high burden setting.

Classification by cause.

• Infective: pulmonary tuberculosis, nontuberculous mycobacterial disease, chronic pulmonary aspergillosis, endemic mycoses, bronchiectasis with chronic infection, lung abscess, empyema, HIV related infection, parasitic disease.
• Neoplastic: bronchogenic carcinoma, lymphoma, metastases, mesothelioma, Kaposi sarcoma.
• Chronic cardiorespiratory disease with cachexia: COPD, interstitial lung disease, heart failure.
• Systemic and other causes.

Mechanisms of weight loss. Raised cytokines (tumour necrosis factor, interleukin 6) cause anorexia, hypermetabolism and muscle wasting. Malabsorption, reduced intake from dyspnoea and cough, and increased work of breathing add to loss.

Pattern clues.

• Cough with fever, night sweats and haemoptysis over weeks suggests tuberculosis.
• Cough with smoking history, haemoptysis, hoarseness and chest pain suggests lung cancer.
• Daily large volume purulent sputum over years suggests bronchiectasis.
• A dry cough with exertional dyspnoea and finger clubbing suggests interstitial lung disease.

Key distinctions. Smear negative and extrapulmonary tuberculosis are common in HIV, and the chest radiograph may be atypical or normal. Cancer and tuberculosis can coexist. A diagnosis of tuberculosis does not remove the need to biopsy a mass that fails to respond.

History

• Duration and pattern of cough, sputum volume, colour and smell, haemoptysis (volume and frequency), pleuritic pain, dyspnoea, wheeze, hoarseness, dysphagia and chest wall pain.
• Systemic features: fever, night sweats, anorexia, fatigue, weight lost (kilograms and time), and loose clothing.
• Contact with tuberculosis, previous tuberculosis treatment, prison, shelter, mining, healthcare work and household crowding.
• HIV status and risk, diabetes, alcohol, tobacco (pack years), biomass fuel exposure, occupational dust (silica, asbestos, coal), injecting drug use and immunosuppressive drugs.
• Travel and exposure: endemic fungi (caves, soil, bird droppings), freshwater crustaceans or raw crab (paragonimiasis), dogs and sheep (hydatid disease), and residence in Southeast Asia or northern Australia (melioidosis).
• Previous pneumonia, childhood infections, recurrent chest infection, sinus disease, and aspiration risk (alcohol, stroke, reflux, swallowing difficulty).
• Drugs: ACE inhibitors (cough without weight loss), amiodarone, methotrexate, nitrofurantoin and checkpoint inhibitors (pneumonitis).
• Other symptoms: dysphagia, bone pain, headache, neurological symptoms, lumps, skin lesions, diarrhoea and thyroid symptoms.
• Psychological impact, food access and ability to take treatment.

Examination

• Weight, height, body mass index, mid upper arm circumference, temperature, pulse, blood pressure, respiratory rate and oxygen saturation (at rest and on exertion).
• Cachexia, pallor, finger clubbing, hypertrophic osteoarthropathy, nicotine staining, oral candidiasis, hairy leucoplakia, skin lesions (Kaposi sarcoma), and lymph nodes (cervical, supraclavicular, axillary).
• Chest: crackles, bronchial breathing, wheeze, dullness and reduced air entry (effusion or collapse), signs of pleural thickening, and tracheal deviation.
• Signs of superior vena cava obstruction, Horner syndrome, hoarseness (recurrent laryngeal nerve palsy), and cardiac signs (right heart failure, murmur).
• Abdomen: hepatosplenomegaly, masses and ascites.
• Neurological: focal deficits, papilloedema and meningism.
• Bedside tests: pulse oximetry, glucose, urine dipstick, peak flow, and sputum collection with visual inspection.

Red flags

• Haemoptysis over 200 mL in 24 hours, or any haemoptysis with instability (massive haemoptysis).
• Stridor, hoarseness, superior vena cava obstruction or Horner syndrome.
• Hypoxia, respiratory distress or tracheal deviation.
• Severe cachexia (body mass index under 16 kg/m2) or rapid loss of over 10% of body weight.
• Headache, neck stiffness, confusion or focal deficit (tuberculous meningitis, cryptococcosis, metastases).
• Bone pain, spinal cord compression symptoms or hypercalcaemia.
• HIV with CD4 under 200 cells/microlitre.
• Smear positive disease in a household with young children or an immunocompromised person.
• Immunosuppression or biological therapy (reactivation risk).

Special groups

• Children: weight loss with chronic cough suggests tuberculosis, foreign body, cystic fibrosis or HIV, and needs age specific assessment and doses.
• Pregnancy: treat tuberculosis early, avoid streptomycin, and give pyridoxine.
• Older adults: tuberculosis reactivation, lung cancer, aspiration and heart failure are common, and sputum production may be poor.
• Kidney and liver impairment: adjust antituberculous therapy and monitor liver tests.
• Region specific: tuberculosis, HIV related disease, paragonimiasis, melioidosis, histoplasmosis, hydatid disease, silicosis with tuberculosis, and exposure to biomass smoke.

Mycobacterial infection

• Pulmonary tuberculosis (primary progressive, reactivation, miliary).
• Drug resistant tuberculosis.
• Tuberculous pleural effusion and empyema.
• Tuberculosis with HIV (smear negative, cavitation absent).
• Nontuberculous mycobacterial lung disease (Mycobacterium avium complex, Mycobacterium abscessus, Mycobacterium kansasii).
• Silicotuberculosis.

Other infections

• Chronic pulmonary aspergillosis (aspergilloma, chronic cavitary and fibrosing disease).
• Allergic bronchopulmonary aspergillosis.
• Histoplasmosis, coccidioidomycosis, blastomycosis, paracoccidioidomycosis and talaromycosis.
• Cryptococcosis.
• Pneumocystis pneumonia in HIV (subacute).
• Nocardiosis and actinomycosis.
• Lung abscess and empyema.
• Bronchiectasis with chronic infection (Pseudomonas aeruginosa, Haemophilus influenzae, Staphylococcus aureus).
• Cystic fibrosis.
• Melioidosis (chronic form).
• Paragonimiasis and strongyloidiasis.
• Hydatid cyst.
• Amoebic liver abscess with pulmonary extension.
• Cytomegalovirus pneumonitis.
• Persistent pneumonia from airway obstruction.

Neoplastic

• Primary bronchogenic carcinoma (squamous, adenocarcinoma, small cell, large cell).
• Lung metastases.
• Lymphoma.
• Mesothelioma.
• Kaposi sarcoma of the lung.
• Carcinoid tumour.
• Oesophageal and laryngeal cancer with aspiration.
• Mediastinal tumour and thymoma.
• Superior sulcus tumour.

Chronic cardiorespiratory disease

• COPD with cachexia.
• Interstitial lung disease and idiopathic pulmonary fibrosis.
• Sarcoidosis.
• Heart failure with cardiac cachexia.
• Hypersensitivity pneumonitis.
• Pneumoconiosis (silicosis, asbestosis, coal workers).
• Granulomatosis with polyangiitis and other vasculitis.
• Pulmonary hypertension.
• Aspiration and gastro-oesophageal reflux disease.
• Tracheo-oesophageal fistula.

Systemic and other causes

• HIV infection with wasting.
• Diabetes mellitus (with infection).
• Hyperthyroidism.
• Chronic kidney disease.
• Chronic liver disease.
• Malabsorption and coeliac disease.
• Depression or an eating disorder with an unrelated chronic cough.
• Alcohol use disorder.
• Drug induced lung disease (amiodarone, methotrexate, nitrofurantoin, checkpoint inhibitors).
• Upper airway cough syndrome, asthma and chronic bronchitis (cough without weight loss, relevant when weight loss has another cause).

Step 1. Isolate and stabilise. Place patients with presumptive tuberculosis in a ventilated single room or outdoors, and give a surgical mask for the patient. Treat massive haemoptysis as an emergency.

Step 2. Chest radiograph. Posteroanterior film in every patient. Look for upper lobe infiltrates and cavities, miliary pattern, hilar and mediastinal nodes, pleural effusion, mass, collapse, bronchiectasis, fibrosis and honeycombing. A normal film does not exclude tuberculosis in HIV (about a tenth of culture positive patients) or early cancer, and further tests are needed when suspicion persists.

Step 3. Microbiology for tuberculosis

• Sputum for a rapid molecular test with rifampicin resistance detection, as the first test. Collect 2 samples (one early morning). The test has high sensitivity in smear positive disease and lower sensitivity in smear negative disease, and the ultra generation assay improves detection.
• Sputum smear microscopy for acid fast bacilli (grade the smear) and culture (liquid medium for 6 weeks, solid medium for 8 weeks) with drug susceptibility testing, particularly after treatment failure or relapse, or when resistance is suspected.
• Induced sputum or gastric aspirate (children), and bronchoscopy with lavage when sputum is not available or negative.
• Urine lipoarabinomannan antigen in HIV with CD4 under 200 cells/microlitre or seriously ill HIV patients, which gives a result from urine within an hour.
• Interferon gamma release assays and tuberculin skin tests detect infection and do not diagnose active disease, and they are often negative in advanced HIV and malnutrition.
• Extrapulmonary samples when indicated: pleural fluid (adenosine deaminase over 40 U/L, lymphocytes, high protein), lymph node aspirate, biopsy, cerebrospinal fluid, ascitic fluid and urine.

Step 4. Tests in all patients

• HIV test, with CD4 count and viral load when positive.
• Full blood count with differential (anaemia, lymphopenia, eosinophilia suggests parasites or aspergillosis), ESR and CRP, urea, creatinine, electrolytes (hyponatraemia in small cell cancer and tuberculosis), calcium, albumin, liver tests, glucose and HbA1c.
• Hepatitis B and C serology before treatment, and baseline liver tests.
• Sputum culture for bacteria, fungi and nontuberculous mycobacteria when there is bronchiectasis, cavitation or persistent smear positivity.
• Spirometry once stable, for obstructive or restrictive disease.

Step 5. CT chest. Contrast CT is the next test for abnormal radiographs, a normal radiograph with high suspicion, unexplained haemoptysis, suspected cancer, bronchiectasis, interstitial disease, cavity and aspergilloma. CT shows tree in bud nodules, cavities, lymphadenopathy with necrotic centres and miliary nodules in tuberculosis, and spiculated masses, nodes and effusion in cancer.

Step 6. Tissue diagnosis

• Bronchoscopy with washings, brushings, lavage and transbronchial biopsy for suspected cancer, unexplained infiltrates and tuberculosis when sputum is negative.
• Endobronchial ultrasound with nodal sampling, percutaneous needle biopsy of lung masses under CT control, pleural biopsy, and lymph node biopsy (excision preferred for lymphoma).
• Cytology for pleural effusion (sensitivity limited), then thoracoscopy.
• Staging for confirmed cancer: CT of chest, abdomen and pelvis, PET-CT, and MRI of brain.
• Molecular testing of lung adenocarcinoma (EGFR, ALK, ROS1, KRAS, PD-L1) before treatment.

Step 7. Other tests

• Aspergillus IgG and galactomannan for chronic pulmonary aspergillosis.
• Serum cryptococcal antigen, histoplasma antigen, and fungal serology in endemic regions.
• Sweat chloride or genetic testing for cystic fibrosis when bronchiectasis is unexplained, immunoglobulins and specific antibody responses for primary antibody deficiency.
• Autoantibodies, ACE and imaging for sarcoidosis and vasculitis.
• Stool and sputum examination for ova (Strongyloides, Paragonimus), serology for hydatid disease and melioidosis culture.
• Echocardiography for heart failure and pulmonary hypertension.
• Thyroid function tests, and coeliac serology when malabsorption is suspected.

Interpretation. When 2 rapid molecular tests and cultures are negative but tuberculosis remains likely (immunocompromised, compatible CT, response to treatment), clinicians may start treatment on clinical grounds, with reassessment at 2 months. Failure to improve by 2 months should prompt review of resistance, adherence and alternative diagnoses including cancer.

Limits. Radiographic features of tuberculosis, fungal disease and cancer overlap. Sputum tests are less sensitive in children, HIV and extrapulmonary disease. Cytology has limited sensitivity, and biopsy may be needed more than once.

Immediate

• Resuscitate when unstable. Give oxygen to a saturation of 94 to 98% (88 to 92% when at risk of hypercapnia).
• Massive haemoptysis: position the patient bleeding side down, protect the airway, give oxygen, and obtain intravenous access and blood for crossmatch.
• Massive haemoptysis, drugs: tranexamic acid 1 g intravenously every 8 hours (or 500 mg nebulised 3 times daily), with limited evidence. Correct coagulopathy.
• Massive haemoptysis, procedures: bronchial artery embolisation or bronchoscopic control, and surgery when these fail.
• Stridor or superior vena cava obstruction: airway control, dexamethasone 8 to 16 mg intravenously, and urgent oncology and thoracic review.
• Respiratory failure: high flow oxygen or noninvasive ventilation, and intensive care.
• Hypercalcaemia: intravenous 0.9% sodium chloride and zoledronic acid 4 mg over 15 minutes (adjust at creatinine clearance under 60 mL/min, avoid under 30 mL/min).

Antituberculous therapy (drug susceptible, adults, started when diagnosis is confirmed or strongly suspected)

• Intensive phase for 2 months: isoniazid 5 mg/kg (maximum 300 mg), rifampicin 10 mg/kg (maximum 600 mg), pyrazinamide 25 mg/kg (maximum 2 g) and ethambutol 15 mg/kg once daily orally. Take on an empty stomach.
• Fixed dose combination tablets (isoniazid 75 mg, rifampicin 150 mg, pyrazinamide 400 mg, ethambutol 275 mg): 2 tablets at 30 to 37 kg, 3 tablets at 38 to 54 kg, 4 tablets at 55 to 70 kg and 5 tablets at 71 kg or over.
• Continuation phase for 4 months: isoniazid 5 mg/kg and rifampicin 10 mg/kg once daily (2 to 5 tablets of isoniazid 75 mg with rifampicin 150 mg by the same weight bands).
• Extend to 7 months for cavitation with positive culture at 2 months. Extend to 9 to 12 months for bone, joint or central nervous system disease (12 months for meningitis).
• Pyridoxine 10 to 25 mg once daily with isoniazid, particularly in HIV, pregnancy, diabetes, alcohol use, malnutrition and kidney failure.
• Dexamethasone for tuberculous meningitis (0.4 mg/kg daily reducing over 6 to 8 weeks), and prednisolone 1 mg/kg for 4 to 8 weeks reducing for pericarditis with effusion, under specialist direction.
• Monitor liver tests before treatment, and at 2 and 4 weeks and when symptomatic. High risk: older age, alcohol, liver disease, hepatitis B or C, HIV, pregnancy, malnutrition.
• Stop hepatotoxic drugs when alanine aminotransferase exceeds 5 times the upper limit of normal, or 3 times the upper limit with symptoms or jaundice. Reintroduce one by one after recovery under specialist direction.
• Adjust for kidney impairment: give ethambutol and pyrazinamide 3 times weekly at creatinine clearance under 30 mL/min.
• Check visual acuity and colour vision (ethambutol), uric acid and joints (pyrazinamide), and neuropathy (isoniazid).
• Rifampicin is a strong enzyme inducer. It lowers levels of oral contraceptives, warfarin, antiretrovirals, anticonvulsants, ciclosporin, tacrolimus, azoles and methadone. It causes orange discolouration of fluids.
• Drug resistant disease (rifampicin resistance on rapid test): specialist treatment. A common 6 month oral regimen is bedaquiline 400 mg daily for 2 weeks then 200 mg 3 times weekly, pretomanid 200 mg daily, linezolid 600 mg daily and moxifloxacin 400 mg daily. Monitor ECG, blood count and neuropathy.
• Antiretroviral therapy in HIV: start within 2 weeks of antituberculous therapy when CD4 is under 50 cells/microlitre, and within 8 weeks otherwise. Delay in tuberculous meningitis (usually 4 to 8 weeks) under specialist direction.
• With rifampicin, dolutegravir is given at 50 mg twice daily. Give co-trimoxazole 960 mg once daily for prophylaxis when CD4 is under 350 cells/microlitre or in advanced disease.
• Directly observed or supported adherence, nutritional supplementation, treatment of diabetes, alcohol and tobacco counselling, and notification.
• Contact investigation and preventive therapy for household contacts and people with HIV who are without active disease. Options are isoniazid 300 mg daily for 6 months, rifampicin 600 mg daily for 4 months, or isoniazid 900 mg with rifapentine 900 mg once weekly for 12 weeks (dose by weight in children).

Other causes

• Lung cancer: urgent multidisciplinary oncology review, with treatment by stage (surgery, stereotactic radiotherapy, chemoradiotherapy, targeted therapy, immunotherapy). Palliative care involvement, analgesia, and treatment of symptoms.
• Bronchiectasis: airway clearance (physiotherapy, hypertonic saline 7% nebulised twice daily).
• Bronchiectasis exacerbations: 14 days of a susceptible antibiotic (for example amoxicillin 500 mg to 1 g orally three times daily, doxycycline 200 mg then 100 mg daily, or ciprofloxacin 500 to 750 mg twice daily for Pseudomonas).
• Bronchiectasis with frequent exacerbations: long term azithromycin 250 mg daily or 500 mg three times weekly, after excluding nontuberculous mycobacteria (check ECG and hearing).
• Chronic pulmonary aspergillosis: itraconazole 200 mg orally twice daily for at least 6 months with drug levels (trough over 1 mg/L), liver tests and attention to cardiac failure and interactions, or voriconazole 200 mg twice daily. Surgery for localised aspergilloma with haemoptysis.
• Nontuberculous mycobacteria: specialist treatment with a macrolide, ethambutol and rifampicin for at least 12 months after culture conversion.
• Histoplasmosis (chronic): itraconazole 200 mg 3 times daily for 3 days then 200 mg once or twice daily for at least 12 months.
• Cryptococcosis: liposomal amphotericin B 3 to 4 mg/kg intravenously daily with flucytosine 25 mg/kg every 6 hours for 2 weeks, then fluconazole 400 to 800 mg daily.
• Pneumocystis pneumonia: co-trimoxazole 15 to 20 mg/kg daily (trimethoprim component) in 3 or 4 doses for 21 days.
• Add prednisolone when arterial oxygen tension is under 9.3 kPa (70 mmHg): 40 mg twice daily for 5 days, 40 mg once daily for 5 days and then 20 mg daily for 11 days.
• Lung abscess: amoxicillin with clavulanic acid 1.2 g intravenously every 8 hours then 625 mg orally three times daily for 4 to 6 weeks, with drainage when over 6 cm or not improving.
• Paragonimiasis: praziquantel 25 mg/kg orally 3 times daily for 2 days.
• Hydatid disease: albendazole 400 mg twice daily with surgery or percutaneous drainage by cyst type.
• Heart failure, COPD and interstitial lung disease: optimise treatment, including nutritional support and rehabilitation.

Symptom control. Treat cough with simple linctus. Avoid opioid cough suppressants in infectious cases with sputum retention. Codeine linctus 15 mg 3 to 4 times daily may be used short term in lung cancer. Give nutritional supplements and treat anorexia, with dietitian review. Smoking cessation.

Monitoring. Weekly review in the intensive phase when possible, with weight and symptom check. Sputum smear or culture at 2 months and at 5 months and the end of treatment. Smear positive at 2 months prompts review for resistance and adherence. Liver tests, and monthly review of adherence. Weight gain and cough settling are the first signs of response.

Referral and escalation. Chest or infectious diseases physician for suspected drug resistance, extrapulmonary disease, HIV, relapse and treatment failure. Oncology and thoracic surgery for suspected cancer. Interventional radiology or thoracic surgery for massive haemoptysis. Dietitian and social support. Public health notification and contact tracing for tuberculosis.

Admission criteria. Massive haemoptysis, respiratory failure, severe cachexia, central nervous system or miliary disease, infectious tuberculosis in settings where outpatient isolation is unsafe, and hepatotoxicity or severe drug reaction.

Discharge and follow up. Discharge when non infectious (usually after 2 weeks of effective treatment with clinical improvement) with supported adherence. Safety net advice: return for haemoptysis, breathlessness, vomiting, jaundice, visual change, rash, confusion or fever. Review for relapse for 12 months after treatment.