Current Medical Diagnosis & Treatment 2015


Common Symptoms

Ralph Gonzales, MD, MSPH
Paul L. Nadler, MD



 Age, tobacco use history, and duration of cough.

 Dyspnea (at rest or with exertion).

 Vital signs (heart rate, respiratory rate, body temperature).

 Chest examination.

 Chest radiography when unexplained cough lasts more than 3–6 weeks.

 General Considerations

Cough adversely affects personal and work-related interactions, disrupts sleep, and often causes discomfort of the throat and chest wall. Most people seeking medical attention for acute cough desire symptom relief; few are worried about serious illness. Cough results from stimulation of mechanical or chemical afferent nerve receptors in the bronchial tree. Effective cough depends on an intact afferent–efferent reflex arc, adequate expiratory and chest wall muscle strength, and normal mucociliary production and clearance.

 Clinical Findings

  1. Symptoms

Distinguishing acute (< 3 weeks), persistent (3–8 weeks), and chronic (> 8 weeks) cough illness syndromes is a useful first step in evaluation. Postinfectious cough lasting 3–8 weeks has also been referred to as subacute cough to distinguish this common, distinct clinical entity from acute and chronic cough.

  1. Acute cough—In healthy adults, most acute cough syndromes are due to viral respiratory tract infections. Additional features of infection such as fever, nasal congestion, and sore throat help confirm the diagnosis. Dyspnea (at rest or with exertion) may reflect a more serious condition, and further evaluation should include assessment of oxygenation (pulse oximetry or arterial blood gas measurement), airflow (peak flow or spirometry), and pulmonary parenchymal disease (chest radiography). The timing and character of the cough have not been found to be very useful in establishing the cause of acute cough syndromes, although cough-variant asthma should be considered in adults with prominent nocturnal cough, and persistent cough with phlegm increases the patient’s likelihood of chronic obstructive pulmonary disease (COPD). The presence of post-tussive emesis or inspiratory whoop modestly increases the likelihood of pertussis, and the absence of paroxysmal cough decreases the likelihood of pertussis in adolescents and adults with cough lasting more than 1 week. Uncommon causes of acute cough should be suspected in those with heart disease (heart failure [HF]) or hay fever (allergic rhinitis) and those with environmental risk factors (such as farm workers).
  2. Persistent and chronic cough—Cough due to acute respiratory tract infection resolves within 3 weeks in the vast majority of patients (over 90%). Pertussis infection should be considered in adolescents and adults with persistent or severe cough lasting more than 3 weeks. In selected geographic areas, the prevalence of pertussis approaches 20% when cough has persisted beyond 3 weeks, although the exact prevalence of pertussis is difficult to ascertain due to the limited sensitivity of diagnostic tests.

When angiotensin-converting enzyme (ACE) inhibitor therapy, acute respiratory tract infection, and chest radiograph abnormalities are absent, most cases of persistent and chronic cough are due to or exacerbated by postnasal drip, asthma, or gastroesophageal reflux disease (GERD), or some combination of these three entities. A history of nasal or sinus congestion, wheezing, or heartburn should direct subsequent evaluation and treatment, though these conditions frequently cause persistent cough in the absence of typical symptoms. Dyspnea at rest or with exertion is not commonly reported among patients with persistent cough; dyspnea requires assessment for chronic lung disease, HF, or anemia.

Bronchogenic carcinoma is suspected when cough is accompanied by unexplained weight loss and fevers with night sweats, particularly in persons with significant tobacco or occupational exposures (asbestos, radon, diesel exhaust, and metals). Persistent and chronic cough accompanied by excessive mucus secretions increases the likelihood of COPD, particularly among smokers, or bronchiectasis in a patient with a history of recurrent or complicated pneumonia; chest radiographs are helpful in diagnosis.

  1. Physical Examination

Examination can direct subsequent diagnostic testing for acute cough. Pneumonia is suspected when acute cough is accompanied by vital sign abnormalities (tachycardia, tachypnea, fever). Findings suggestive of airspace consolidation (rales, decreased breath sounds, fremitus, egophony) are significant predictors of community-acquired pneumonia but are present in the minority of cases. Purulent sputum is associated with bacterial infections in patients with structural lung disease (eg, COPD, cystic fibrosis), but it is a poor predictor of pneumonia in the otherwise healthy adult. Wheezing and rhonchi are frequent findings in adults with acute bronchitis and do not represent consolidation or adult-onset asthma in most cases.

Examination of patients with persistent cough should look for evidence of chronic sinusitis, contributing to postnasal drip syndrome or asthma. Chest and cardiac signs may help distinguish COPD from HF. In patients with cough and dyspnea, a normal match test (ability to blow out a match from 25 cm away) and maximum laryngeal height > 4 cm (measured from the sternal notch to the cricoid cartilage at end expiration) substantially decrease the likelihood of COPD. Similarly, normal jugular venous pressure and no hepatojugular reflux decrease the likelihood of biventricular HF.

  1. Diagnostic Studies
  2. Acute cough—Chest radiography should be considered for any adult with acute cough whose vital signs are abnormal or whose chest examination suggests pneumonia. The relationship between specific clinical findings and the probability of pneumonia is shown inTable 2–1. A large, multicenter randomized clinical trial found that an elevated serum C-reactive protein (levels > 30 mg/dL) improves diagnostic accuracy of clinical prediction rules for pneumonia in adults with acute cough illness. In patients with dyspnea, pulse oximetry and peak flow help exclude hypoxemia or obstructive airway disease. However, a normal pulse oximetry value (eg, > 93%) does not rule out a significant alveolar–arterial (A–a) gradient when patients have effective respiratory compensation. During documented outbreaks, clinical diagnosis of influenza has a positive predictive value of ˜70%; it usually obviates the usefulness of rapid diagnostic tests.

Table 2–1. Positive and negative likelihood ratios for history, physical examination, and laboratory findings in the diagnosis of pneumonia.

  1. Persistent and chronic cough—Chest radiography is indicated when ACE inhibitor therapy–related and postinfectious cough are excluded by history or further diagnostic testing. If pertussis infection is suspected, polymerase chain reaction testing should be performed on a nasopharyngeal swab or nasal wash specimen—although the ability to detect pertussis decreases as the duration of cough increases. When the chest film is normal, postnasal drip, asthma, and GERD are the most likely causes. The presence of typical symptoms of these conditions directs further evaluation or empiric therapy, though typical symptoms are often absent. Definitive tests for determining the presence of each are available (Table 2–2). However, empiric treatment with a maximum-strength regimen for postnasal drip, asthma, or GERD for 2–4 weeks is one recommended approach since documenting the presence of postnasal drip, asthma, and GERD does not mean they are the cause of the cough. Alternative approaches to identifying patientswho have asthma with its corticosteroid-responsive cough include examining induced sputum for increased eosinophil counts (> 3%); measuring increased exhaled nitric oxide levels; or providing an empiric trial of prednisone, 30 mg daily orally for 2 weeks. Spirometry may help identify large airway obstruction in patients who have persistent cough and wheezing and who are not responding to asthma treatment. When empiric treatment trials are not successful, additional evaluation with pH manometry, endoscopy, barium swallow, sinus CT or high-resolution chest CT may identify the cause.

Table 2–2. Empiric treatments or tests for persistent cough.

 Differential Diagnosis

  1. Acute Cough

Acute cough may be a symptom of acute respiratory tract infection, asthma, allergic rhinitis, and HF, as well as many less common causes.

  1. Persistent and Chronic Cough

Causes of persistent cough include environmental exposures (cigarette smoke, air pollution), pertussis infection, postnasal drip (upper airway cough syndrome), asthma (including cough-variant asthma), GERD, COPD, bronchiectasis, eosinophilic bronchitis, tuberculosis or other chronic infection, interstitial lung disease, and bronchogenic carcinoma. COPD is a common cause of persistent cough among patients > 50 years of age. Persistent cough may also be psychogenic.


  1. Acute Cough

Treatment of acute cough should target the underlying etiology of the illness, the cough reflex itself, and any additional factors that exacerbate the cough. There is substantial evidence showing that antibiotics do not improve cough severity or duration in patients with uncomplicated acute bronchitis. Cough duration is typically 1–3 weeks; yet patients frequently expect cough to last less than 10 days. When influenza is diagnosed (including H1N1 influenza), treatment with oseltamivir or zanamivir is equally effective (1 less day of illness) when initiated within 30–48 hours of illness onset, although treatment is recommended regardless of illness duration when patients present with severe illness requiring hospitalization. In the setting of Chlamydophila or Mycoplasma-documented infection or outbreaks, first-line antibiotics include erythromycin, 250 mg orally four times daily for 7 days, or doxycycline, 100 mg orally twice daily for 7 days. In patients diagnosed with acute bronchitis, inhaled beta-2-agonist therapy reduces severity and duration of cough in some patients. Evidence supports a modest benefit of dextromethorphan, but not codeine, on cough severity in adults with cough due to acute respiratory tract infections. Treatment of postnasal drip (with antihistamines, decongestants, or nasal corticosteroids) or GERD (with H2-blockers or proton-pump inhibitors), when accompanying acute cough illness, can also be helpful. There is good evidence that vitamin C and echinacea are not effective in reducing the severity of acute cough after it develops; however, evidence does support vitamin C (at least 1 g daily) for prevention of colds among persons with major physical stressors (eg, post-marathon) or malnutrition. Treatment with zinc lozenges, when initiated within 24 hours of symptom onset, reduces the duration and severity of cold symptoms.

  1. Persistent and Chronic Cough

Evaluation and management of persistent cough often requires multiple visits and therapeutic trials, which frequently lead to frustration, anger, and anxiety. When pertussis infection is suspected early in its course, treatment with a macrolide antibiotic (azithromycin 500 mg on day 1, then 250 mg once daily for days 2–5; clarithromycin 500 mg twice daily for 7 days; erythromycin 250 mg four times daily for 14 days) is appropriate to reduce shedding and transmission of the organism. When pertussis infection has lasted more than 7–10 days, antibiotic treatment does not affect the duration of cough, which can last up to 6 months. Early identification, revaccination with Tdap, and treatment of adult patients who work or live with persons at high-risk for complications from pertussis is encouraged (pregnant women, infants [particularly younger than 1 year], and immunosuppressed individuals). Table 2–2 outlines empiric treatments for persistent cough. There is no evidence to guide how long treatment for persistent cough due to postnasal drip, asthma, or GERD should be continued. Studies have not found a consistent benefit of inhaled corticosteroid therapy in adults with persistent cough.

When empiric treatment trials fail, consider other causes of chronic cough such as obstructive sleep apnea, tonsillar enlargement, and environmental fungi. The small percentage of patients with idiopathic chronic cough should be managed in consultation with an otolaryngologist or a pulmonologist; consider high-resolution CT scan of the lungs. Treatment options include nebulized lidocaine therapy and morphine sulfate, 5–10 mg orally twice daily.

 When to Refer

  • Failure to control persistent or chronic cough following empiric treatment trials.
  • Patients with recurrent symptoms should be referred to an otolaryngologist or a pulmonologist.
  • Adults needing Tdap vaccination to enable “cocooning” of at-risk individuals (eg, infants age < 1 year).

 When to Admit

  • Patient at high risk for tuberculosis for whom compliance with respiratory precautions is uncertain.
  • Need for urgent bronchoscopy, such as suspected foreign body.
  • Smoke or toxic fume inhalational injury.
  • Intractable cough despite treatment, when cough impairs gas exchange, or in patients at high risk for barotrauma (eg, recent pneumothorax).

Benich JJ 3rd et al. Evaluation of the patient with chronic cough. Am Fam Physician. 2011 Oct 15;84(8):887–92. [PMID: 22010767]

Birring SS. Controversies in the evaluation and management of chronic cough. Am J Respir Crit Care Med. 2011 Mar 15;183(6):t708–15. [PMID: 21148722]

Broekhuizen BD et al. Undetected chronic obstructive pulmonary disease and asthma in people over 50 years with persistent cough. Br J Gen Pract. 2010 Jul;60(576):489–94. [PMID: 20594438]

Centers for Disease Control and Prevention (CDC). Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Tdap) in pregnant women and persons who have or anticipate having close contact with an infant aged <12 months—Advisory Committee on Immunization Practices (ACIP), 2011. MMWR Morb Mortal Wkly Rep. 2011 Oct 21;60(41):1424–6. [PMID: 22012116]

Centers for Disease Control and Prevention (CDC). Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine in adults aged 65 years and older—Advisory Committee on Immunization Practices (ACIP), 2012. MMWR Morb Mortal Wkly Rep. 2012 Jun 29;61(25):468–70. Erratum in: MMWR Morb Mortal Wkly Rep. 2012 Jul 13;61(27):515. [PMID: 22739778]

Cornia PB et al. Does this coughing adolescent or adult patient have pertussis? JAMA. 2010 Aug 25;304(8):890–6. [PMID: 20736473]

Held U et al. Diagnostic aid to rule out pneumonia in adults with cough and feeling of fever. A validation study in the primary care setting. BMC Infect Dis. 2012 Dec 17;12:355. [PMID: 23245504]

Johnstone KJ et al. Inhaled corticosteroids for subacute and chronic cough in adults. Cochrane Database Syst Rev. 2013 Mar 28;3:CD009305. [PMID: 23543575]

Lim KG et al. Long-term safety of nebulized lidocaine for adults with difficult-to-control chronic cough: a case series. Chest. 2013 Apr;143(4):1060–5. [PMID: 23238692]

van Vugt SF et al. Use of serum C reactive protein and procalcitonin concentrations in addition to symptoms and signs to predict pneumonia in patients presenting to primary care with acute cough: diagnostic study. BMJ. 2013 Apr 30;346:f2450. [PMID: 23633005]



 Fever, cough, and chest pain.

 Vital sign measurements; pulse oximetry.

 Cardiac and chest examination.

 Chest radiography and arterial blood gas measurement in selected patients.

 General Considerations

Dyspnea is a subjective experience or perception of uncomfortable breathing. However, the relationship between level of dyspnea and the severity of underlying disease varies widely across individuals. Dyspnea can result from conditions that increase the mechanical effort of breathing (eg, COPD, restrictive lung disease, respiratory muscle weakness), conditions that produce compensatory tachypnea (eg, hypoxemia or acidosis), or psychogenic conditions. The following factors play a role in how and when dyspnea presents in patients: rate of onset, previous dyspnea, medications, comorbidities, psychological profile, and severity of underlying disorder. In patients with established COPD, the patient-reported severity of dyspnea is superior to forced expiratory volume in 1 second (FEV1) in predicting quality of life and 5-year mortality.

 Clinical Findings

  1. Symptoms

The duration, severity, and periodicity of dyspnea influence the tempo of the clinical evaluation. Rapid onset, severe dyspnea in the absence of other clinical features should raise concern for pneumothorax,pulmonary embolism, or increased left ventricular end-diastolic pressure (LVEDP). Spontaneous pneumothorax is usually accompanied by chest pain and occurs most often in thin, young males, or in those with underlying lung disease. Pulmonary embolism should always be suspected when a patient with new dyspnea reports a recent history (previous 4 weeks) of prolonged immobilization or hospitalization, estrogen therapy, or other risk factors for deep venous thrombosis (DVT) (eg, previous history of thromboembolism, cancer, obesity, lower extremity trauma) and when the cause of dyspnea is not apparent. Silent myocardial infarction, which occurs more frequently in diabetic persons and women, can result in acute heart failure and dyspnea.

Accompanying symptoms provide important clues to causes of dyspnea. When cough and fever are present, pulmonary disease (particularly infections) is the primary concern; myocarditis, pericarditis, and septic emboli can present in this manner. Chest pain should be further characterized as acute or chronic, pleuritic or exertional. Although acute pleuritic chest pain is the rule in acute pericarditis and pneumothorax, most patients with pleuritic chest pain in the outpatient clinic have pleurisy due to acute viral respiratory tract infection. Periodic chest pain that precedes the onset of dyspnea suggests myocardial ischemia or pulmonary embolism. When associated with wheezing, most cases of dyspnea are due to acute bronchitis; however, other causes include new-onset asthma, foreign body, and vocal cord dysfunction.

When a patient reports prominent dyspnea with mild or no accompanying features, consider noncardiopulmonary causes of impaired oxygen delivery (anemia, methemoglobinemia, cyanide ingestion, carbon monoxide), metabolic acidosis due to a variety of conditions, panic disorder, neuromuscular disorders, and chronic pulmonary embolism.

  1. Physical Examination

A focused physical examination should include evaluation of the head and neck, chest, heart, and lower extremities. Visual inspection of the patient can suggest obstructive airway disease (pursed-lip breathing, use of accessory respiratory muscles, barrel-shaped chest), pneumothorax (asymmetric excursion), or metabolic acidosis (Kussmaul respirations). Patients with impending upper airway obstruction (eg, epiglottitis, foreign body), or severe asthma exacerbation, sometimes assume a tripod position. Focal wheezing raises the suspicion for a foreign body or other bronchial obstruction. Maximum laryngeal height (the distance between the top of the thyroid cartilage and the suprasternal notch at end expiration) is a measure of hyperinflation. Obstructive airway disease is virtually nonexistent when a nonsmoking patient younger than 45 years has a maximum laryngeal height > 4 cm (Table 2–3). Absent breath sounds suggests a pneumothorax. An accentuated pulmonic component of the second heart sound (loud P2) is a sign of pulmonary hypertension and pulmonary embolism.

Table 2–3. Clinical findings suggesting obstructive airway disease.

Table 2–4 shows clinical predictors of increased LVEDP in dyspneic patients with no prior history of HF. When none is present, there is a very low probability (< 10%) of increased LVEDP, and when two or more are present, there is a very high probability (> 90%) of increased LVEDP.

Table 2–4. Clinical findings suggesting increased left ventricular end-diastolic pressure.

  1. Diagnostic Studies

Causes of dyspnea that can be managed without chest radiography are few: ingestions causing lactic acidosis, anemia, methemoglobinemia, and carbon monoxide poisoning. The diagnosis of pneumonia should be confirmed by chest radiography in most patients. When COPD exacerbation is severe enough to require hospitalization, results of chest radiography can influence management decisions in up to 20% of patients. Chest radiography is fairly sensitive and specific for new-onset HF (represented by redistribution of pulmonary venous circulation) and can help guide treatment of patients with other cardiac disease. End-expiratory chest radiography enhances detection of a small pneumothorax.

A normal chest radiograph has substantial diagnostic value. When there is no physical examination evidence of COPD or HF and the chest radiograph is normal, the major remaining causes of dyspnea include pulmonary embolism, Pneumocystis jirovecii infection (initial radiograph may be normal in up to 25%), upper airway obstruction, foreign body, anemia, and metabolic acidosis. If a patient has tachycardia and hypoxemia but a normal chest radiograph and electrocardiogram (ECG), then tests to exclude pulmonary emboli (see Chapter 9), anemia, or metabolic acidosis are warranted. High-resolution chest CT is particularly useful in the evaluation of pulmonary embolism and interstitial and alveolar lung disease.

Table 2–4 shows clinical findings suggesting increased LVEDP. Elevated serum or B-type natriuretic peptide (BNP or NT-proBNP) levels are both sensitive and specific for increased LVEDP in symptomatic persons. However, the systematic use of BNP in the evaluation of dyspnea in the emergency department does not appear to have clinically significant impact on patient or system outcomes and it does not conclusively affect hospital mortality rates.

Arterial blood gas measurement may be considered if clinical examination and routine diagnostic testing are equivocal. With two notable exceptions (carbon monoxide poisoning and cyanide toxicity), arterial blood gas measurement distinguishes increased mechanical effort causes of dyspnea (respiratory acidosis with or without hypoxemia) from compensatory tachypnea (respiratory alkalosis with or without hypoxemia or metabolic acidosis) from psychogenic dyspnea (respiratory alkalosis). An observational study, however, found that arterial blood gas measurement had little value in determining the cause of dyspnea in patients presenting to the emergency department. Carbon monoxide and cyanide impair oxygen delivery with minimal alterations in Po2; percent carboxyhemoglobin identifies carbon monoxide toxicity. Cyanide poisoning should be considered in a patient with profound lactic acidosis following exposure to burning vinyl (such as a theater fire or industrial accident). Suspected carbon monoxide poisoning or methemoglobinemia can also be confirmed with venous carboxyhemoglobin or methemoglobin levels.

Because arterial blood gas testing is impractical in most outpatient settings, pulse oximetry has assumed a central role in the office evaluation of dyspnea. Oxygen saturation values above 96% almost always correspond with a Po2 > 70 mm Hg, and values < 94% almost always represent clinically significant hypoxemia. Important exceptions to this rule include carbon monoxide toxicity, which leads to a normal oxygen saturation (due to the similar wavelengths of oxyhemoglobin and carboxyhemoglobin), and methemoglobinemia, which results in an oxygen saturation of about 85% that fails to increase with supplemental oxygen. A delirious or obtunded patient with obstructive lung disease warrants immediate measurement of arterial blood gases to exclude hypercapnia and the need for intubation, regardless of the oxygen saturation. If a patient reports dyspnea with exertion, but resting oximetry is normal, assessment of desaturation with ambulation (eg, a brisk walk around the clinic) can be useful for confirming impaired gas exchange.

Episodic dyspnea can be challenging if an evaluation cannot be performed during symptoms. Life-threatening causes include recurrent pulmonary embolism, myocardial ischemia, and reactive airway disease. When associated with audible wheezing, vocal cord dysfunction should be considered, particularly in a young woman who does not respond to asthma therapy. Spirometry is very helpful in further classifying patients with obstructive airway disease but is rarely needed in the initial or emergent evaluation of patients with acute dyspnea.

 Differential Diagnosis

Urgent and emergent conditions causing acute dyspnea include pneumonia, COPD, asthma, pneumothorax, pulmonary embolism, cardiac disease (eg, HF, acute myocardial infarction, valvular dysfunction, arrhythmia, cardiac shunt), metabolic acidosis, cyanide toxicity, methemoglobinemia, and carbon monoxide poisoning.


The treatment of urgent or emergent causes of dyspnea should aim to relieve the underlying cause. Pending diagnosis, patients with hypoxemia should be immediately provided supplemental oxygen unless significant hypercapnia is present or strongly suspected pending arterial blood gas measurement. Dyspnea frequently occurs in patients nearing the end of life. Opioid therapy, anxiolytics, and corticosteroids can provide substantial relief independent of the severity of hypoxemia. Oxygen therapy is most beneficial to patients with significant hypoxemia (Pao2 < 55 mm Hg) (see Chapter 5). In patients with severe COPD and hypoxemia, oxygen therapy improves mortality and exercise performance. It may relieve dyspnea in mildly and non-hypoxemic patients with COPD. Pulmonary rehabilitation programs are another therapeutic option for patients with moderate to severe COPD or interstitial pulmonary fibrosis. Noninvasive ventilation may be considered for patients with dyspnea caused by an acute COPD exacerbation, but the efficacy of this treatment is still uncertain.

 When to Refer

  • Following acute stabilization, patients with advanced COPD should be referred to a pulmonologist, and patients with HF or valvular heart disease should be referred to a cardiologist.
  • Cyanide toxicity or carbon monoxide poisoning should be managed in conjunction with a toxicologist.

 When to Admit

  • Impaired gas exchange from any cause or high risk of pulmonary embolism pending definitive diagnosis.
  • Suspected cyanide toxicity or carbon monoxide poisoning.

Amimoto Y et al. Lung sound analysis in a patient with vocal cord dysfunction and bronchial asthma. J Asthma. 2012 Apr;49(3):227–9. [PMID: 22335255]

Burri E et al. Value of arterial blood gas analysis in patients with acute dyspnea: an observational study. Crit Care. 2011;15(3):R145. [PMID: 21663600]

Cranston JM et al. Oxygen therapy for dyspnoea in adults. Cochrane Database Syst Rev. 2008 Jul 16;(3):CD004769. [PMID: 18646110]

Gallagher R. The use of opioids for dyspnea in advanced disease. CMAJ. 2011 Jul 12;183(10):1170. [PMID: 21746829]

Jang TB et al. The predictive value of physical examination findings in patients with suspected acute heart failure syndrome. Intern Emerg Med. 2012 Jun;7(3):271–4. [PMID: 22094407]

Junker C et al. Are arterial blood gases necessary in the evaluation of acutely dyspneic patients? Crit Care. 2011 Aug 2;15(4):176. [PMID: 21892979]

Kamal AH et al. Dyspnea review for the palliative care professional: assessment, burdens, and etiologies. J Palliat Med. 2011 Oct;14(10):1167–72. [PMID: 21895451]

Lin RJ et al. Dyspnea in palliative care: expanding the role of corticosteroids. J Palliat Med. 2012 Jul;15(7):834–7. [PMID: 22385025]

Parshall MB et al; American Thoracic Society Committee on Dyspnea. An official American Thoracic Society statement: update on the mechanisms, assessment, and management of dyspnea. Am J Respir Crit Care Med. 2012 Feb 15;185(4):435–52. [PMID: 22336677]

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 Fever, cough, and other symptoms of lower respiratory tract infection.

 Smoking history.

 Nasopharyngeal or gastrointestinal bleeding.

 Chest radiography and complete blood count (and, in some cases, INR).

 General Considerations

Hemoptysis is the expectoration of blood that originates below the vocal cords. It is commonly classified as trivial, mild, or massive—the latter defined as more than 200–600 mL (about 1–2 cups) in 24 hours. Massive hemoptysis can be usefully defined as any amount that is hemodynamically significant or threatens ventilation. Its in-hospital mortality was 6.5% in a recent study. The initial goal of management of massive hemoptysis is therapeutic, not diagnostic.

The lungs are supplied with a dual circulation. The pulmonary arteries arise from the right ventricle to supply the pulmonary parenchyma in a low-pressure circuit. The bronchial arteries arise from the aorta or intercostal arteries and carry blood under systemic pressure to the airways, blood vessels, hila, and visceral pleura. Although the bronchial circulation represents only 1–2% of total pulmonary blood flow, it can increase dramatically under conditions of chronic inflammation—eg, chronic bronchiectasis—and is frequently the source of hemoptysis.

The causes of hemoptysis can be classified anatomically. Blood may arise from the airways in COPD, bronchiectasis, and bronchogenic carcinoma; from the pulmonary vasculature in left ventricular failure, mitral stenosis, pulmonary embolism, pulmonary arterial hypertension, and arteriovenous malformations; or from the pulmonary parenchyma in pneumonia, inhalation of crack cocaine, or granulomatosis with polyangiitis (formerly Wegener granulomatosis). Diffuse alveolar hemorrhage is due to small vessel bleeding usually caused by autoimmune or hematologic disorders and results in alveolar infiltrates on chest radiography. Most cases of hemoptysis presenting in the outpatient setting are due to infection (eg, acute or chronic bronchitis, pneumonia, tuberculosis). Hemoptysis due to lung cancer increases with age, accounting for up to 20% of cases among the elderly. Less commonly (< 10% of cases), pulmonary venous hypertension (eg, mitral stenosis, pulmonary embolism) causes hemoptysis. Most cases of hemoptysis that have no visible cause on CT scan or bronchoscopy will resolve within 6 months without treatment, with the notable exception of patients at high risk for lung cancer (smokers older than 40 years). Iatrogenic hemorrhage may follow transbronchial lung biopsies, anticoagulation, or pulmonary artery rupture due to distal placement of a balloon-tipped catheter. No cause is identified in up to 15–30% of cases.

 Clinical Findings

  1. Symptoms

Blood-tinged sputum in the setting of an upper respiratory tract infection in an otherwise healthy, young (age < 40 years) nonsmoker does not warrant an extensive diagnostic evaluation if the hemoptysis subsides with resolution of the infection. However, hemoptysis is frequently a sign of serious disease, especially in patients with a high prior probability of underlying pulmonary pathology. One should not distinguish between blood-streaked sputum and cough productive of blood alone with regard to the evaluation plan. The goal of the history is to identify patients at risk for one of the disorders listed above. Pertinent features include duration of symptoms, presence of respiratory infection, and past or current tobacco use. Nonpulmonary sources of hemorrhage—from the sinuses or the gastrointestinal tract—must be excluded.

  1. Physical Examination

Elevated pulse, hypotension, and decreased oxygen saturation suggest large volume hemorrhage that warrants emergent evaluation and stabilization. The nares and oropharynx should be carefully inspected to identify a potential upper airway source of bleeding. Chest and cardiac examination may reveal evidence of HF or mitral stenosis.

  1. Diagnostic Studies

Diagnostic evaluation should include a chest radiograph and complete blood count. Kidney function tests, urinalysis, and coagulation studies are appropriate in specific circumstances. Hematuria that accompanies hemoptysis may be a clue to Goodpasture syndrome or vasculitis. Flexible bronchoscopy reveals endobronchial cancer in 3–6% of patients with hemoptysis who have a normal (non-lateralizing) chest radiograph. Nearly all of these patients are smokers over the age of 40, and most will have had symptoms for more than 1 week. Bronchoscopy is indicated in such patients. High-resolution chest CT scan complements bronchoscopy and should be strongly considered in patients with normal chest radiograph and low risk for malignancy. It can visualize unsuspected bronchiectasis and arteriovenous malformations and will show central endobronchial lesions in many cases. High-resolution chest CT scanning is the test of choice for suspected small peripheral malignancies. Helical CT pulmonary angiography has become the initial test of choice for evaluating patients with suspected pulmonary embolism, although caution should be taken to avoid large contrast loads in patients with even mild chronic kidney disease (serum creatinine > 2.0 g/dL or rapidly rising creatinine in normal range). Helical CT scanning can be avoided in patients who are at “unlikely” risk for pulmonary embolism using the Wells score for pulmonary embolism and the sensitive D-dimer test. Echocardiography may reveal evidence of HF or mitral stenosis.


Management of mild hemoptysis consists of identifying and treating the specific cause. Massive hemoptysis is life-threatening. The airway should be protected with endotracheal intubation, ventilation ensured, and effective circulation maintained. If the location of the bleeding site is known, the patient should be placed in the decubitus position with the involved lung dependent. Uncontrollable hemorrhage warrants rigid bronchoscopy and surgical consultation. In stable patients, flexible bronchoscopy may localize the site of bleeding, and angiography can embolize the involved bronchial arteries. Embolization is effective initially in 85% of cases, although rebleeding may occur in up to 20% of patients during the following year. The anterior spinal artery arises from the bronchial artery in up to 5% of people, and paraplegia may result if it is inadvertently cannulated and embolized. There is limited evidence that antifibrinolytics may reduce the duration of bleeding.

 When to Refer

  • Patients should be referred to a pulmonologist when bronchoscopic evaluation of lower respiratory tract is required.
  • Patients should be referred to an otolaryngologist when an upper respiratory tract bleeding source is identified.
  • Patients with severe coagulopathy complicating management should be referred to a hematologist.

 When to Admit

  • To stabilize bleeding process in patients at risk for or experiencing massive hemoptysis.
  • To correct disordered coagulation (using clotting factors or platelets, or both).
  • To stabilize gas exchange.

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Hurt K et al. Haemoptysis: diagnosis and treatment. Acute Med. 2012;11(1):39–45. [PMID: 22423349]

Jeudy J et al; Expert Panel on Thoracic Imaging. ACR Appropriateness Criteria hemoptysis. J Thorac Imaging. 2010 Aug;25(3):W67–9. [PMID: 20711032]

Pasha SM et al. Safety of excluding acute pulmonary embolism based on an unlikely clinical probability by the Wells rule and normal D-dimer concentration: a meta-analysis. Thromb Res. 2010 Apr;125(4):e123–7. [PMID: 19942258]

Shigemura N et al. Multidisciplinary management of life-threatening massive hemoptysis: a 10-year experience. Ann Thorac Surg. 2009 Mar;87(3):849–53. [PMID: 19231404]



 Chest pain onset, character, location/size, duration, periodicity, and exacerbators; and shortness of breath.

 Vital signs; chest and cardiac examination.

 Electrocardiography and biomarkers of myocardial necrosis in selected patients.

 General Considerations

Chest pain (or chest discomfort) is a common symptom that can occur as a result of cardiovascular, pulmonary, pleural, or musculoskeletal disease, esophageal or other gastrointestinal disorders, or anxiety states. The frequency and distribution of life-threatening causes of chest pain, such as acute coronary syndrome (ACS), pericarditis, aortic dissection, pulmonary embolism, pneumonia, and esophageal perforation, vary substantially between clinical settings. Systemic lupus erythematosus, rheumatoid arthritis, and HIV are conditions that confer a strong risk for coronary artery disease. Because pulmonary embolism can present with a wide variety of symptoms, consideration of the diagnosis and rigorous risk factor assessment for venous thromboembolism (VTE) is critical. Classic VTE risk factors include cancer, trauma, recent surgery, prolonged immobilization, pregnancy, oral contraceptives, and family history and prior history of VTE. Other conditions associated with increased risk of pulmonary embolism include HF and COPD. Sickle cell anemia can cause acute chest syndrome. Patients with this syndrome often have chest pain, fever, and cough.

 Clinical Findings

  1. Symptoms

Myocardial ischemia is usually described as dull, aching sensation of “pressure,” “tightness,” “squeezing,” or “gas,” rather than as sharp or spasmodic. Ischemic symptoms usually subside within 5–20 minutes but may last longer. Progressive symptoms or symptoms at rest may represent unstable angina. Prolonged chest pain episodes might represent myocardial infarction, although up to one-third of patients with acute myocardial infarction do not report chest pain. When present, pain due to myocardial ischemia is commonly accompanied by a sense of anxiety or uneasiness. The location is usually retrosternal or left precordial. Because the heart lacks somatic innervation, precise localization of pain due to cardiac ischemia is difficult; the pain is commonly referred to the throat, lower jaw, shoulders, inner arms, upper abdomen, or back. Ischemic pain may be precipitated or exacerbated by exertion, cold temperature, meals, stress, or combinations of these factors and is usually relieved by rest. However, many episodes do not conform to these patterns; and atypical presentations of ACS are more common in the elderly, women, and persons with diabetes mellitus. Other symptoms that are associated with ACS include shortness of breath; dizziness; a feeling of impending doom; and vagal symptoms, such as nausea and diaphoresis. In the elderly, fatigue is a common presenting complaint of ACS. Likelihood ratios for cardinal symptoms considered in the evaluation of acute myocardial infarction are summarized in Table 2–5.

Table 2–5. Likelihood ratios (LRs) for clinical features associated with acute myocardial infarction.

Hypertrophy of either ventricle or aortic stenosis may also give rise to chest pain with less typical features. Pericarditis may produce pain that is greater when supine than upright and may increase with respiration, coughing, or swallowing. Pleuritic chest pain is usually not ischemic, and pain on palpation may indicate a musculoskeletal cause. Aortic dissection classically produces an abrupt onset of tearing pain of great intensity that often radiates to the back; however, this classic presentation occurs in a small proportion of cases. Anterior aortic dissection can also lead to myocardial or cerebrovascular ischemia.

Pulmonary embolism has a wide range of clinical presentations, with chest pain present in about 75% of cases. The chief objective in evaluating patients with suspected pulmonary embolism is to assess the patient’s clinical risk for VTE based on medical history and associated signs and symptoms (see above and Chapter 9). Rupture of the thoracic esophagus iatrogenically or secondary to vomiting is another cause of chest pain.

  1. Physical Examination

Findings on physical examination can occasionally yield important clues to the underlying cause of chest pain; however, a normal physical examination should never be used as the sole basis for ruling-out most diagnoses, particularly ACS and aortic dissection. Vital signs (including pulse oximetry) and cardiopulmonary examination are always the first steps for assessing the urgency and tempo of the subsequent examination and diagnostic work-up.

Findings that increase the likelihood of ACS include diaphoresis, hypotension, S3 or S4 gallop, pulmonary crackles, or elevated jugular venous pressure (see Table 2–5). Although chest pain that is reproducible or worsened with palpation strongly suggests a musculoskeletal cause, up to 15% of patients with ACS will have reproducible chest wall tenderness. Pointing to the location of the pain with one finger has been shown to be highly correlated with nonischemic chest pain. Aortic dissection can result in differential blood pressures (> 20 mm Hg), pulse amplitude deficits, and new diastolic murmurs. Although hypertension is considered the rule in patients with aortic dissection, systolic blood pressure < 100 mm Hg is present in up to 25% of patients.

A cardiac friction rub represents pericarditis until proven otherwise. It can best be heard with the patient sitting forward at end-expiration. Tamponade should be excluded in all patients with a clinical diagnosis of pericarditis by assessing pulsus paradoxus (a decrease in systolic blood pressure during inspiration > 10 mm Hg) and inspection of jugular venous pulsations. Subcutaneous emphysema is common following cervical esophageal perforation but present in only about one-third of thoracic perforations (ie, those most commonly presenting with chest pain).

The absence of abnormal physical examination findings in patients with suspected pulmonary embolism usually serves to increase the likelihood of pulmonary embolism, although a normal physical examination is also compatible with the much more common conditions of panic/anxiety disorder and musculoskeletal disease.

  1. Diagnostic Studies

Unless a competing diagnosis can be confirmed, an ECG is warranted in the initial evaluation of most patients with acute chest pain to help exclude ACS. ST segment elevation is the ECG finding that is the strongest predictor of acute myocardial infarction (see Table 2–5); however, up to 20% of patients with ACS can have a normal ECG. In the emergency department, patients with suspected ACS can be safely removed from cardiac monitoring if they are pain-free at initial physician assessment and have a normal or nonspecific ECG. This decision rule had 100% sensitivity for serious arrhythmia (95% confidence interval, 80–100%), but deserves further validation. Clinically stable patients with cardiovascular disease risk factors, normal ECG, normal cardiac biomarkers, and no alternative diagnoses (such as typical GERD or costochondritis) should be followed-up with a timely exercise stress test that includes perfusion imaging. The ECG can also provide evidence for alternative diagnoses, such as pericarditis and pulmonary embolism. Chest radiography is often useful in the evaluation of chest pain, and is always indicated when cough or shortness of breath accompanies chest pain. Findings of pneumomediastinum or new pleural effusion are consistent with esophageal perforation.

The ADAPT trial found that an accelerated diagnostic protocol that included a TIMI score, electrocardiography, and 0 + 2 hour values of troponin I could identify patients at low short-term risk for a major adverse cardiac event within 30 days.

The TIMI score was shown in a study to be useful for risk stratification of significant cardiac events in patients selected for an emergency department observation unit, with intermediate risk scores (3–5) requiring admission (15.4% vs 9.8%, P = 0.048).

The MIDAS study found that patients in whom ACS was suspected who sought medical attention within 8 hours of symptom onset could undergo 3 hours of serial testing with the point-of-care troponin I assay with similar diagnostic accuracy.

Patients presenting to the emergency department with chest pain of intermediate or high probability for ACS without electrocardiographic or biomarker evidence of a myocardial infarction can be safely discharged from an observation unit after stress cardiac magnetic resonance imaging. An alternative to stress testing in the emergency department, sixty-four–slice CT coronary angiography (CTA) has been studied for diagnosing ACS among patients with normal or nonspecific ECG and normal biomarkers. A meta-analysis of nine studies found ACS in 10% of patients, and an estimated sensitivity of CTA for ACS of 95%, specificity of 87%, yielding a negative likelihood ratio (LR) of 0.06 and positive LR of 7.4. A study that examined the prognostic implications of nonobstructing coronary artery disease determined by CTA during acute chest pain found a low incidence of major adverse cardiac events (0.6% vs 1.3%, for the normal and nonobstructive groups, respectively, P = 0.2). Multidetector CTA enables diagnosis (or exclusion) of coronary artery disease, ACS, and pulmonary emboli (so-called “triple rule-out”) but involves both radiation and contrast exposure. Helical CT is the study of choice at most centers for the diagnosis of aortic dissection as well as for esophageal perforation.

In the evaluation of pulmonary embolism, diagnostic test decisions and results must be interpreted in the context of the clinical likelihood of VTE. A negative D-dimer test is helpful for excluding pulmonary embolism in patients with low clinical probability of VTE (3-month incidence = 0.5%); however, the 3-month risk of VTE among patients with intermediate and high risk of VTE is sufficiently high in the setting of a negative D-dimer test (3.5% and 21.4%, respectively) to warrant further imaging given the life-threatening nature of this condition if left untreated. CT angiography (with helical or multidetector CT imaging) has replaced ventilation-perfusion scanning as the preferred initial diagnostic test, having approximately 90–95% sensitivity and 95% specificity for detecting pulmonary embolism (compared with pulmonary angiography). However, for patients with high clinical probability of VTE, lower extremity ultrasound or pulmonary angiogram may be indicated even with a normal helical CT.

Panic disorder is a common cause of chest pain, accounting for up to 25% of cases that present to emergency departments and a higher proportion of cases presenting in primary care office practices. Features that correlate with an increased likelihood of panic disorder include absence of coronary artery disease, atypical quality of chest pain, female sex, younger age, and a high level of self-reported anxiety.


Treatment of chest pain should be guided by the underlying etiology. The term “noncardiac chest pain” is used to describe patients who evade diagnosis after receiving extensive work-up. Almost half reported symptom improvement with high-dose proton-pump inhibitor therapy. A systematic review found modest benefit of antidepressants in reducing noncardiac chest pain and a meta-analysis of 15 trials suggested modest to moderate benefit for psychological (especially cognitive-behavioral) interventions. Hypnotherapy may have some benefit.

 When to Refer

  • Refer patients with poorly controlled, noncardiac chest pain to a pain specialist.
  • Refer patients with sickle cell anemia to a hematologist.

 When to Admit

  • Failure to adequately exclude (to a sufficient degree) life-threatening causes of chest pain, particularly myocardial infarction, dissecting aortic aneurysm, pulmonary embolism, and esophageal rupture.
  • Pain control for rib fracture that impairs gas exchange.

Beigel R et al. Prognostic implications of nonobstructive coronary artery disease in patients undergoing coronary computed tomographic angiography for acute chest pain. Am J Cardiol. 2013 Apr 1;111(7):941–5. [PMID: 23332596]

Diercks DB et al. Diagnostic accuracy of a point-of-care troponin I assay for acute myocardial infarction within 3 hours after presentation in early presenters to the emergency department with chest pain. Am Heart J. 2012 Jan;163(1):74–80.e4. [PMID: 22172439]

Geersing GJ et al. Excluding venous thromboembolism using point of care D-dimer tests in outpatients: a diagnostic meta-analysis. BMJ. 2009 Aug 14;339:b2990. [PMID: 19684102]

Goldstein JA et al; CT-STAT Investigators. The CT-STAT (Coronary Computed Tomographic Angiography for Systematic Triage of Acute Chest Pain Patients to Treatment) trial. J Am Coll Cardiol. 2011 Sep 27;58(14):1414–22. [PMID: 21939822]

Hoffmann U et al; ROMICAT-II Investigators. Coronary CT angiography versus standard evaluation in acute chest pain. N Engl J Med. 2012 Jul 26;367(4):299–308. [PMID: 22830462]

Holly J et al. Prospective evaluation of the use of the thrombolysis in myocardial infarction score as a risk stratification tool for chest pain patients admitted to an ED observation unit. Am J Emerg Med. 2013 Jan;31(1):185–9. [PMID: 22944539]

Kisely SR et al. Psychological interventions for symptomatic management of non-specific chest pain in patients with normal coronary anatomy. Cochrane Database Syst Rev. 2012 Jun 13;6:CD004101. [PMID: 22696339]

Kosowsky JM. Approach to the ED patient with “low risk” chest pain. Emerg Med Clin North Am. 2011 Nov;29(4):721–7. [PMID: 22040703]

McConaghy JR et al. Outpatient diagnosis of acute chest pain in adults. Am Fam Physician. 2013 Feb 1;87(3):177–82. [PMID: 23418761]

Mills NL et al. Implementation of a sensitive troponin I assay and risk of recurrent myocardial infarction and death in patients with suspected acute coronary syndrome. JAMA. 2011 Mar 23;305(12):1210–6. [PMID: 21427373]

Nguyen TM et al. Systematic review: the treatment of noncardiac chest pain with antidepressants. Aliment Pharmacol Ther. 2012 Mar;35(5):493–500. [PMID: 22239853]

Ranasinghe AM et al. Acute aortic dissection. BMJ. 2011 Jul 29;343:d4487. [PMID: 21803810]

Rogers IS et al. Usefulness of comprehensive cardiothoracic computed tomography in the evaluation of acute undifferentiated chest discomfort in the emergency department (CAPTURE). Am J Cardiol. 2011 Mar 1;107(5):643–50. [PMID: 21247533]

Scheuermeyer FX et al. Safety and efficiency of a chest pain diagnostic algorithm with selective outpatient stress testing for emergency department patients with potential ischemic chest pain. Ann Emerg Med. 2012 Apr;59(4):256–64. [PMID: 22221842]

Than M et al. 2-Hour accelerated diagnostic protocol to assess patients with chest pain symptoms using contemporary troponins as the only biomarker: the ADAPT trial. J Am Coll Cardiol. 2012 Jun 5;59(23):2091–8. [PMID: 22578923]

Yoon YE et al. Evaluation of acute chest pain in the emergency department: “triple rule-out” computed tomography angiography. Cardiol Rev. 2011 May–Jun;19(3):115–21. [PMID: 21464639]



 Forceful, rapid, or irregular beating of the heart.

 Rate, duration, and degree of regularity of heart beat; age at first episode.

 Factors that precipitate or terminate episodes.

 Light-headedness or syncope; neck pounding.

 Chest pain.

 General Considerations

Palpitations are defined as an unpleasant awareness of the forceful, rapid, or irregular beating of the heart. They are the primary symptom for approximately 16% of patients presenting to an outpatient clinic with a cardiac complaint. While palpitations are usually benign, they are occasionally the symptom of a life-threatening arrhythmia. To avoid missing a dangerous cause of the patient’s symptom, clinicians sometimes pursue expensive and invasive testing when a conservative diagnostic evaluation is sufficient. The converse is also true; in one study, 54% of patients with supraventricular tachycardia were initially wrongly diagnosed with panic, stress, or anxiety disorder. A disproportionate number of these misdiagnosed patients are women. Table 2–6 lists history, physical examination, and ECG findings suggesting a cardiovascular cause for the palpitations.

Table 2–6. Palpitations: Patients at high risk for a cardiovascular cause.

 Clinical Findings

  1. Symptoms

Although described by patients in a myriad of ways, guiding the patient through a careful description of their palpitations may indicate a mechanism and narrow the differential diagnosis. Pertinent questions include the age at first episode; precipitants; and the rate, duration, and degree of regularity of the heart beat during the subjective palpitations. Palpitations lasting less than 5 minutes, and a family history of panic disorder reduce the likelihood of an arrhythmic cause (LR = 0.38 and LR = 0.26, respectively). To better understand the symptom, the examiner can ask the patient to “tap out” the rhythm with their fingers. The circumstances associated with onset and termination can also be helpful in determining the cause. Palpitations that start and stop abruptly suggest supraventricular or ventricular tachycardias. Termination of palpitations using vagal maneuvers (eg, Valsalva maneuver) suggests supraventricular tachycardia.

Three common descriptions of palpitations are (1) “flip-flopping” (or “stop and start”), often caused by premature contraction of the atrium or ventricle, with the perceived “stop” from the pause following the contraction, and the “start” from the subsequent forceful contraction; (2) rapid “fluttering in the chest,” with regular “fluttering” suggesting supraventricular or ventricular arrhythmias (including sinus tachycardia) and irregular “fluttering” suggesting atrial fibrillation, atrial flutter, or tachycardia with variable block; and (3) “pounding in the neck” or neck pulsations, often due to “cannon” A waves in the jugular venous pulsations that occur when the right atrium contracts against a closed tricuspid valve.

Palpitations associated with chest pain suggests ischemic heart disease, or if the chest pain is relieved by leaning forward, pericardial disease is suspected. Palpitations associated with light-headedness, presyncope, or syncope suggest hypotension and may signify a life-threatening cardiac arrhythmia. Palpitations that occur regularly with exertion suggests a rate-dependent bypass tract or hypertrophic cardiomyopathy. If a benign etiology for these concerning symptoms cannot be ascertained at the initial visit, then ambulatory monitoring or prolonged cardiac monitoring in the hospital might be warranted.

Noncardiac symptoms should also be elicited since the palpitations may be caused by a normal heart responding to a metabolic or inflammatory condition. Weight loss suggests hyperthyroidism. Palpitations can be precipitated by vomiting or diarrhea that leads to electrolyte disorders and hypovolemia. Hyperventilation, hand tingling, and nervousness are common when anxiety or panic disorder is the cause of the palpitations.

  1. Physical Examination

Rarely does the clinician have the opportunity to examine a patient during an episode of palpitations. However, careful cardiovascular examination can find abnormalities that can increase the likelihood of specific cardiac arrhythmias. The midsystolic click of mitral valve prolapse can suggest the diagnosis of a supraventricular arrhythmia. The harsh holosystolic murmur of hypertrophic cardiomyopathy, which occurs along the left sternal border and increases with the Valsalva maneuver, suggests atrial fibrillation or ventricular tachycardia. The presence of dilated cardiomyopathy, suggested on examination by a displaced and enlarged cardiac point-of-maximal impulse, increases the likelihood of ventricular tachycardia and atrial fibrillation. In patients with chronic atrial fibrillation, in-office exercise (eg, a brisk walk in the hallway) may reveal an intermittent accelerated ventricular response as the cause of the palpitations. The clinician should also look for signs of hyperthyroidism (eg, tremulousness, brisk deep tendon reflexes, or fine hand tremor), or signs of stimulant drug use (eg, dilated pupils or skin or nasal septal lesions). Visible neck pulsations (LR, 2.68; 95% CI, 1.25–5.78) in association with palpitations increases the likelihood of atrioventricular nodal reentry tachycardia.

  1. Diagnostic Studies

Commonly used studies in the initial evaluation of a patient with palpitations are the 12-lead ECG and ambulatory ECG monitoring devices (eg, the Holter monitor or the event recorder).

A 12-lead ECG should be performed on all patients reporting palpitations because it can provide evidence for a wide variety of causes. Although in most instances a specific arrhythmia will not be detected on the tracing, a careful evaluation of the ECG can help the clinician deduce a likely etiology in certain circumstances.

For instance, bradyarrhythmias and heart block can be associated with ventricular ectopy or escape beats that may be experienced as palpitations by the patient. Evidence of prior myocardial infarction by history or on ECG (eg, Q waves) increases the patient’s risk for nonsustained or sustained ventricular tachycardia. Ventricular preexcitation (Wolff-Parkinson-White syndrome) is suggested by a short PR interval (< 0.20 ms) and delta waves (upsloping PR segments). Left ventricular hypertrophy with deep septal Q waves in I, AVL, and V4 through V6 is seen in patients with hypertrophic obstructive cardiomyopathy. The presence of left atrial enlargement as suggested by a terminal P-wave force in V1 more negative than 0.04 msec and notched in lead II reflects a patient at increased risk for atrial fibrillation. A prolonged QT interval and abnormal T-wave morphology suggests the long-QT syndrome, which puts patients at increased risk for ventricular tachycardia.

For high-risk patients (Table 2–6), further diagnostic studies are warranted. A step-wise approach has been suggested—starting with ambulatory monitoring devices (Holter monitoring if the palpitations are expected to occur within the subsequent 72-hour period, event monitoring if less frequent), followed by invasive electrophysiologic testing if the ambulatory monitor records a worrisome arrhythmia or if serious arrhythmias are strongly suspected despite normal findings on the appropriate ambulatory monitor.

In patients with a prior myocardial infarction, ambulatory cardiac monitoring or signal-averaged-ECG are appropriate next steps to assess ventricular tachycardia. ECG exercise testing is appropriate in patients who have palpitations with physical exertion and patients with suspected coronary artery disease. Echocardiography is useful when physical examination or ECG suggests structural abnormalities or decreased ventricular function.

 Differential Diagnosis

When assessing a patient with palpitations in an urgent care setting, the clinician must ascertain whether the symptoms represent (1) an arrhythmia that is minor and transient, (2) significant cardiovascular disease, (3) a cardiac manifestation of a systemic disease such as thyrotoxicosis, or (4) a benign somatic symptom that is amplified by underlying psychosocial characteristics of the patient.

Palpitations in patients with a known history of cardiac disease or palpitations that occur during sleep increase the likelihood of a cardiac arrhythmia. A history of panic disorder or palpitations that last less than 5 minutes make a cardiac arrhythmia slightly less likely. Patients who seek medical attention in the emergency department instead of a medical clinic are more likely to have a cardiac etiology (47% versus 21%), whereas psychiatric causes are more common among patients with palpitations who seek medical attention in office practices (45% versus 27%). In a study of patients who went to a university medical clinic with the chief complaint of palpitations, etiologies were cardiac in 43%, psychiatric in 31%, and miscellaneous in 10% (including illicit drugs, medications, anemia, thyrotoxicosis, and mastocytosis).

Cardiac arrhythmias that can result in symptoms of palpitations include sinus bradycardia; sinus, supraventricular, and ventricular tachycardia; premature ventricular and atrial contractions; sick sinus syndrome; and advanced atrioventricular block.

Nonarrhythmic cardiac causes of palpitations include valvular heart diseases, such as aortic insufficiency or stenosis, atrial or ventricular septal defect, cardiomyopathy, congenital heart disease, and pericarditis.

Noncardiac causes of palpitations include fever, dehydration, hypoglycemia, anemia, thyrotoxicosis, and pheochromocytoma. Drugs such as cocaine, alcohol, caffeine, and pseudoephedrine can precipitate palpitations, as can prescription medications, including digoxin, phenothiazines, theophylline, and beta-agonists.

The most common psychiatric causes of palpitations are anxiety and panic disorder. The release of catecholamines during a panic attack or significant stress can trigger an arrhythmia. Asking a single question, “Have you experienced brief periods, for seconds or minutes, of an overwhelming panic or terror that was accompanied by racing heartbeats, shortness of breath, or dizziness?” can help identify patients with panic disorder.


After ambulatory monitoring, most patients with palpitations are found to have benign atrial or ventricular ectopy and nonsustained ventricular tachycardia. In patients with structurally normal hearts, these arrhythmias are not associated with adverse outcomes. Abstention from caffeine and tobacco may help. Often, reassurance suffices. If not, or in very symptomatic patients, a trial of a beta-blocker may be prescribed. A three-session course of cognitive behavioral therapy that includes some physical activity has proven effective for patients with benign palpitations with or without chest pain. For treatment of specific atrial or ventricular arrhythmias, see Chapter 10.

 When to Refer

  • For electrophysiologic studies.
  • For advice regarding treatment of atrial or ventricular arrhythmias.

 When to Admit

  • Palpitations associated with syncope or near-syncope, particularly when the patient is aged 75 years or older and has an abnormal ECG, hematocrit < 30%, shortness of breath, respiratory rate > 24/min, or a history of HF.
  • Patients with risk factors for a serious arrhythmia.

Indik JH. When palpitations worsen. Am J Med. 2010 Jun;123(6):517–9. [PMID: 20569756]

Jamshed N et al. Emergency management of palpitations in the elderly: epidemiology, diagnostic approaches, and therapeutic options. Clin Geriatr Med. 2013 Feb;29(1):205–30. [PMID: 23177608]

Jellins J et al. Brugada syndrome. Hong Kong Med J. 2013 Apr;19(2):159–67. [PMID: 23535677]

Jonsbu E et al. Short-term cognitive behavioral therapy for non-cardiac chest pain and benign palpitations: a randomized controlled trial. J Psychosom Res. 2011 Feb;70(2):117–23. [PMID: 21262413]

Misiri J et al. Evaluation of syncope and palpitations in women. J Womens Health (Larchmt). 2011 Oct;20(10):1505–15. [PMID: 21819232]

Thavendiranathan P et al. Does this patient with palpitations have a cardiac arrhythmia? JAMA. 2009 Nov 18;302(19):2135–43. [PMID: 19920238]

Vallès E et al. Diagnostic and prognostic value of electrophysiologic study in patients with nondocumented palpitations. Am J Cardiol. 2011 May 1;107(9):1333–7. [PMID: 21371684]

Wexler RK et al. Outpatient approach to palpitations. Am Fam Physician. 2011 Jul 1;84(1):63–9. [PMID: 21766757]



 History of venous thromboembolism.

 Symmetry of swelling.


 Change with dependence.

 Skin findings: hyperpigmentation, stasis dermatitis, lipodermatosclerosis, atrophie blanche, ulceration.

 General Considerations

Acute and chronic lower extremity edema present important diagnostic and treatment challenges. Lower extremities can swell in response to increased venous or lymphatic pressures, decreased intravascular oncotic pressure, increased capillary leak, and local injury or infection. Chronic venous insufficiency is by far the most common cause, affecting up to 2% of the population, and the incidence of venous insufficiency has not changed during the past 25 years. Venous insufficiency is a common complication of DVT; however, only a small number of patients with chronic venous insufficiency report a history of this disorder. Venous ulceration commonly affects patients with chronic venous insufficiency, and its management is labor-intensive and expensive. Other causes of lower extremity edema include cellulitis, musculoskeletal disorders (Baker cyst rupture, gastrocnemius tear or rupture), lymphedema, HF, cirrhosis, nephrotic syndrome, and medication side effects (eg, calcium channel blockers, minoxidil, or pioglitazone).

 Clinical Findings

  1. Symptoms and Signs

Normal lower extremity venous pressure (in the erect position: 80 mm Hg in deep veins, 20–30 mm Hg in superficial veins) and cephalad venous blood flow require competent bicuspid venous valves, effective muscle contractions, and normal respirations. When one or more of these components fail, venous hypertension may result. Chronic exposure to elevated venous pressure by the postcapillary venules in the legs leads to leakage of fibrinogen and growth factors into the interstitial space, leukocyte aggregation and activation, and obliteration of the cutaneous lymphatic network. These changes account for the brawny, fibrotic skin changes observed in patients with chronic venous insufficiency, and the predisposition toward skin ulceration, particularly in the medial malleolar area.

Among common causes of lower extremity swelling, DVT is the most life-threatening. Clues suggesting DVT include a history of cancer, recent limb immobilization, or confinement to bed for at least 3 days following major surgery within the past month (Table 2–7). A search for alternative explanations is equally important in excluding DVT. Bilateral involvement and significant improvement upon awakening favor systemic causes (eg, venous insufficiency, HF, and cirrhosis). The sensation of “heavy legs” is the most frequent symptom of chronic venous insufficiency, followed by itching. Pain, particularly if severe, is uncommon in uncomplicated venous insufficiency. Lower extremity swelling and inflammation in a limb recently affected by DVT could represent anticoagulation failure and thrombus recurrence but more often are caused by postphlebitic syndrome with valvular incompetence. Other causes of a painful, swollen calf include ruptured popliteal cyst (“pseudothrombophlebitis”), calf strain or trauma, and cellulitis.

Table 2–7. Risk stratification of adults referred for ultrasound to rule out DVT.

Lower extremity swelling is a familiar complication of therapy with calcium channel blockers (particularly felodipine and amlodipine), pioglitazone, and minoxidil. Bilateral lower extremity edema can be a presenting symptom of nephrotic syndrome or volume overload caused by renal failure or cirrhosis. Prolonged airline flights (> 10 hours) are associated with edema. In addition, among those with low to medium risk of thromboembolism (eg, women taking oral contraceptives), long flights are associated with a 2% incidence of asymptomatic popliteal DVT.

  1. Physical Examination

Physical examination should include assessment of the heart, lungs, and abdomen for evidence of pulmonary hypertension (primary, or secondary to chronic lung disease), HF, or cirrhosis. Some patients with cirrhosis have pulmonary hypertension without lung disease. There is a spectrum of skin findings related to chronic venous insufficiency that depends on the severity and chronicity of the disease, ranging from hyperpigmentation and stasis dermatitis to abnormalities highly specific for chronic venous insufficiency: lipodermatosclerosis (thick brawny skin; in advanced cases, the lower leg resembles an inverted champagne bottle) and atrophie blanche (small depigmented macules within areas of heavy pigmentation). The size of both calves should be measured 10 cm below the tibial tuberosity and elicitation of pitting and tenderness performed. Swelling of the entire leg or swelling of one leg 3 cm more than the other suggests deep venous obstruction. It is normal for the left calf to be slightly larger than the right as a result of the left common iliac vein coursing under the aorta.

An ulcer located over the medial malleolus is a hallmark of chronic venous insufficiency but can be due to other causes. Shallow, large, modestly painful ulcers are characteristic of venous insufficiency, whereas small, deep, and more painful ulcers are more apt to be due to arterial insufficiency, vasculitis, or infection (including cutaneous diphtheria). Diabetic vascular ulcers, however, may be painless. When an ulcer is on the foot or above the mid calf, causes other than venous insufficiency should be considered.

  1. Diagnostic Studies

Most causes of lower extremity swelling can be demonstrated with color duplex ultrasonography. Patients without an obvious cause of acute lower extremity swelling (eg, calf strain) should have an ultrasound performed, since DVT is difficult to exclude on clinical grounds. A predictive rule allows a clinician to exclude a lower extremity DVT in patients without an ultrasound if the patient has low pretest probability for DVT and has a negative sensitive D-dimer test (the “Wells prediction rule”). Assessment of the ankle-brachial pressure index (ABPI) is important in the management of chronic venous insufficiency, since peripheral arterial disease may be exacerbated by compression therapy. This can be performed at the same time as ultrasound. Caution is required in interpreting the results of ABPI in older patients and diabetics due to decreased compressibility of their arteries. A dipstick urine test that is strongly positive for protein can suggest nephrotic syndrome, and a serum creatinine can help estimate kidney function.


Treatment of lower extremity edema should be guided by the underlying etiology. See relevant chapters for treatment of edema in patients with HF (see Chapter 10), nephrosis (see Chapter 22), cirrhosis (see Chapter 16), and lymphedema (see Chapter 12). Edema resulting from calcium channel blocker therapy responds to concomitant therapy with ACE inhibitors or angiotensin receptor blockers.

In patients with chronic venous insufficiency without a comorbid volume overload state (eg, HF), it is best to avoid diuretic therapy. These patients have relatively decreased intravascular volume, and administration of diuretics may first enhance sodium retention through increased secretion of renin and angiotensin and then result in acute kidney injury and oliguria. Instead, the most effective treatment involves (1) leg elevation, above the level of the heart, for 30 minutes three to four times daily, and during sleep; (2) compression therapy; and (3) ambulatory exercise to increase venous return through calf muscle contractions. A wide variety of stockings and devices are effective in decreasing swelling and preventing ulcer formation. They should be put on with awakening, before hydrostatic forces result in edema. To control simple edema, 20–30 mm Hg is usually sufficient; whereas, 30–40 mm Hg is usually required to control moderate to severe edema associated with ulcer formation. Patients with decreased ABPI should be managed in concert with a vascular surgeon. Compression stockings (12–18 mm Hg at the ankle) are effective in preventing edema and asymptomatic thrombosis associated with long airline flights in low- to medium-risk persons. For lymphedema, new bandaging systems applied twice weekly can be effective. See Chapter 12 for treatment of venous stasis ulcers.

 When to Refer

  • Chronic lower extremity ulcerations requiring specialist wound care.
  • Refer patients with nephrotic syndrome to a nephrologist.
  • Refer patients with coexisting severe arterial insufficiency (claudication) that would complicate treatment with compression stockings to a vascular surgeon.

 When to Admit

  • Pending definitive diagnosis in patients at high risk for DVT despite normal lower extremity ultrasound.
  • Severe, acute swelling raising concern for an impending compartment syndrome.
  • Severe edema that impairs ability to ambulate or perform activities of daily living.

Hamdan A. Management of varicose veins and venous insufficiency. JAMA. 2012 Dec 26;308(24):2612–21. [PMID: 23268520]

Moffatt CJ et al. A preliminary randomized controlled study to determine the application frequency of a new lymphoedema bandaging system. Br J Dermatol. 2012 Mar;166(3):624–32. [PMID: 22059933]

Partsch H et al. Dose finding for an optimal compression pressure to reduce chronic edema of the extremities. Int Angiol. 2011 Dec;30(6):527–33. [PMID: 22233613]

Word R. Medical and surgical therapy for advanced chronic venous insufficiency. Surg Clin North Am. 2010 Dec;90(6):1195–214. [PMID: 21074036]



 Age; injection substance use.

 Localizing symptoms; weight loss; joint pain.

 Immunosuppression or neutropenia; history of cancer.



 General Considerations

The average normal oral body temperature taken in mid-morning is 36.7°C (range 36–37.4°C). This range includes a mean and 2 standard deviations, thus encompassing 95% of a normal population (normal diurnal temperature variation is 0.5–1°C). The normal rectal or vaginal temperature is 0.5°C higher than the oral temperature, and the axillary temperature is 0.5°C lower. Rectal temperature is more reliable than oral temperature, particularly in patients who breathe through their mouth or in tachypneic states.

Fever is a regulated rise to a new “set point” of body temperature. When stimuli act on monocyte-macrophages, these cells elaborate pyrogenic cytokines, causing elevation of the set point through effects in the hypothalamus. These cytokines include interleukin-1 (IL-1), tumor necrosis factor (TNF), interferon-gamma, and interleukin-6 (IL-6). The elevation in temperature results from either increased heat production (eg, shivering) or decreased heat loss (eg, peripheral vasoconstriction). Body temperature in cytokine-induced fever seldom exceeds 41.1°C unless there is structural damage to hypothalamic regulatory centers.

 Clinical Findings

  1. Fever

Fever as a symptom provides important information about the presence of illness—particularly infections—and about changes in the clinical status of the patient. The fever pattern, however, is of marginal value for most specific diagnoses except for the relapsing fever of malaria, borreliosis, and occasional cases of lymphoma, especially Hodgkin disease. Furthermore, the degree of temperature elevation does not necessarily correspond to the severity of the illness. In general, the febrile response tends to be greater in children than in adults. In older persons, neonates, and in persons receiving certain medications (eg, NSAIDs or corticosteroids), a normal temperature or even hypothermia may be observed. Markedly elevated body temperature may result in profound metabolic disturbances. High temperature during the first trimester of pregnancy may cause birth defects, such as anencephaly. Fever increases insulin requirements and alters the metabolism and disposition of drugs used for the treatment of the diverse diseases associated with fever.

  1. Hyperthermia

Hyperthermia—not mediated by cytokines—occurs when body metabolic heat production or environmental heat load exceeds normal heat loss capacity or when there is impaired heat loss; heat stroke is an example. Body temperature may rise to levels (> 41.1°C) capable of producing irreversible protein denaturation and resultant brain damage; no diurnal variation is observed.

Neuroleptic malignant syndrome is a rare and potentially lethal idiosyncratic reaction to neuroleptic medications, particularly haloperidol and fluphenazine; however, it has also been reported with the atypical neuroleptics (such as olanzapine or risperidone) (see Chapter 25). Serotonin syndrome resembles neuroleptics malignant syndrome but occurs within hours of ingestion of agents that increase levels of serotonin in the central nervous system, including serotonin reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, meperidine, dextromethorphan, bromocriptine, tramadol, lithium, and psychostimulants (such as cocaine, methamphetamine, and MDMA) (see Chapter 38). Clonus and hyperreflexia are more common in serotonin syndrome, whereas “lead pipe” rigidity is more common in neuroleptic malignant syndrome. Neuroleptic malignant and serotonin syndromes share common clinical and pathophysiologic features to malignant hyperthermia of anesthesia (see Chapter 38).

  1. Fever of Undetermined Origin

See Fever of Unknown Origin, Chapter 30.


Most fever is well tolerated. When the temperature is > 40°C, symptomatic treatment may be required. A temperature > 41°C is likely to be hyperthermia and thus not cytokine mediated, and emergent management is indicated. (See Heat Stroke, Chapter 37.)

  1. General Measures for Removal of Heat

Regardless of the cause of the fever, alcohol sponges, cold sponges, ice bags, ice-water enemas, and ice baths will lower body temperature (see Chapter 37). They are more useful in hyperthermia, since patients with cytokine-related fever will attempt to override these therapies.

  1. Pharmacologic Treatment of Fever
  2. Antipyretic drugs—Antipyretic therapy is not needed except for patients with marginal hemodynamic status. Aspirin or acetaminophen, 325–650 mg every 4 hours, is effective in reducing fever. These drugs are best administered around-the-clock rather than as needed, since “as needed” dosing results in periodic chills and sweats due to fluctuations in temperature caused by varying levels of drug.
  3. Antimicrobial therapy—Antibacterial and antifungal prophylactic regimens are only recommended for patients expected to have < 100 neutrophils/mcL for more than 7 days, unless other factors increase risks for complications or mortality. In most febrile patients, empiric antibiotic therapy should be deferred pending further evaluation. However, empiric antibiotic therapy is sometimes warranted. Prompt broad-spectrum antimicrobials are indicated for febrile patients who are clinically unstable, even before infection can be documented. These include patients with hemodynamic instability, those with neutropenia (neutrophils < 500/mcL), others who are asplenic (surgically or secondary to sickle cell disease) or immunosuppressed (including individuals taking systemic corticosteroids, azathioprine, cyclosporine, or other immunosuppressive medications) (Tables 30–4and30–5), and those who are HIV infected (see Chapter 31).

Inpatient treatment is standard to manage febrile neutropenic episodes, although carefully selected patients may be managed as outpatients after systematic assessment beginning with a validated risk index (eg, Multinational Association for Supportive Care in Cancer [MASCC] score or Talcott rules). Patients with MASCC scores ≥ 21 or in Talcott group 4, and without other risk factors, can be managed safely as outpatients. Febrile neutropenic patients should receive initial doses of empiric antibacterial therapy within an hour of triage and should either be monitored for at least 4 hours to determine suitability for outpatient management or be admitted to the hospital.

The carefully selected outpatients determined to be at low risk by the MASCC score or Talcott rules can be managed with an oral fluoroquinolone plus amoxicillin/clavulanate (or clindamycin, if penicillin allergic), unless fluoroquinolone prophylaxis was used before fever developed. For treatment of fever during neutropenia following chemotherapy, outpatient parenteral antimicrobial therapy can be provided effectively and safely (in low-risk patients) with a single agent such as cefepime, piperacillin/tazobactam, imipenem, meropenem or doripenem; or (in high-risk patients) with a combination of agents such as an aminoglycoside plus one of the following agents: piperacillin/tazobactam, cefepime (or ceftazidime), imipenem, meropenem (or doripenem); or vancomycin plus one of the following: piperacillin/tazobactam, cefepime (or ceftazidime), imipenem, meropenem, aztreonam and an aminoglycoside, or ciprofloxacin and an aminoglycoside. If a fungal infection is suspected in patients with prolonged fever and neutropenia, fluconazole is an equally effective but less toxic alternative to amphotericin B.

  1. Treatment of Hyperthermia

Discontinuation of the offending agent is mandatory. Treatment of neuroleptic malignant syndrome includes dantrolene in combination with bromocriptine or levodopa (see Chapter 25). Treatment of serotonin syndrome includes administration of a central serotonin receptor antagonist—cyproheptadine or chlorpromazine—alone or in combination with a benzodiazepine (see Chapter 38). In patients for whom it is difficult to distinguish which syndrome is present, treatment with a benzodiazepine may be the safest therapeutic option.

 When to Admit

  • Neuroleptic malignant syndrome; serotonin syndrome; malignant hyperthermia of anesthesia.
  • Heat stroke.
  • For measures to control temperature when it is > 41°C or when associated with seizure or other mental status changes.

Affronti M et al. Low-grade fever: how to distinguish organic from non-organic forms. Int J Clin Pract. 2010 Feb;64(3):316–21. [PMID: 20456171]

Coburn B et al. Does this adult patient with suspected bacteremia require blood cultures? JAMA. 2012 Aug 1;308(5):502–11. [PMID: 22851117]

Flowers CR et al. Antimicrobial prophylaxis and outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2013 Feb 20;31(6):794–810. [PMID: 23319691]

Kim YJ et al. Diagnostic value of 18F-FDG PET/CT in patients with fever of unknown origin. Intern Med J. 2012 Jul;42(7):834–7. [PMID: 22805689]

Worth LJ et al; Australian Consensus Guidelines 2011 Steering Committee. Use of risk stratification to guide ambulatory management of neutropenic fever. Intern Med J. 2011 Jan;41(1b):82–9. [PMID: 21272172]



 Age; caloric intake; secondary confirmation (eg, changes in clothing size).

 Fever; change in bowel habits.

 Substance use.

 Age-appropriate cancer screening history.

 General Considerations

Body weight is determined by a person’s caloric intake, absorptive capacity, metabolic rate, and energy losses. Body weight normally peaks by the fifth or sixth decade and then gradually declines at a rate of 1–2 kg per decade. In NHANES II, a national survey of community-dwelling elders (age 50–80 years), recent involuntary weight loss (> 5% usual body weight) was reported by 7% of respondents, and this was associated with a 24% higher mortality.


Involuntary weight loss is regarded as clinically significant when it exceeds 5% or more of usual body weight over a 6- to 12-month period. It often indicates serious physical or psychological illness. Physical causes are usually evident during the initial evaluation. The most common causes are cancer (about 30%), gastrointestinal disorders (about 15%), and dementia or depression (about 15%). When an adequately nourished-appearing patient complains of weight loss, inquiry should be made about exact weight changes (with approximate dates) and about changes in clothing size. Family members can provide confirmation of weight loss, as can old documents such as driver’s licenses. A mild, gradual weight loss occurs in some older individuals. However, rapid involuntary weight loss is predictive of morbidity and mortality. In addition to various disease states, causes in older individuals include loss of teeth and consequent difficulty with chewing, alcoholism, and social isolation.

 Clinical Findings

Once the weight loss is established, the history, medication profile, physical examination, and conventional laboratory and radiologic investigations (such as complete blood count, serologic tests including HIV, thyroid-stimulating hormone [TSH] level, urinalysis, fecal occult blood test, chest radiography, and upper gastrointestinal series) usually reveal the cause. When these tests are normal, the second phase of evaluation should focus on more definitive gastrointestinal investigation (eg, tests for malabsorption; endoscopy) and cancer screening (eg, Papanicolaou smear, mammography, prostate specific antigen [PSA]). A prospective case study in patients with unintentional weight loss showed that colonoscopy did not find colorectal cancer if weight loss was the sole indication for the test.

If the initial evaluation is unrevealing, follow-up is preferable to further diagnostic testing. Death at 2-year follow-up was not nearly as common in patients with unexplained involuntary weight loss (8%) as in those with weight loss due to malignant (79%) and established nonmalignant diseases (19%). Psychiatric consultation should be considered when there is evidence of depression, dementia, anorexia nervosa, or other emotional problems. Ultimately, in approximately 15–25% of cases, no cause for the weight loss can be found.

 Differential Diagnosis

Malignancy, gastrointestinal disorders (poorly fitting dentures, cavities, swallowing or malabsorption disorders, pancreatic insufficiency), psychological problems (dementia, depression, paranoia), endocrine disorders (hyperthyroidism, hypothyroidism, hyperparathyroidism, hypoadrenalism), eating problems (dietary restrictions, lack of money for food), social problems (alcoholism, and social isolation), and medication side effects are all established causes.


Weight stabilization occurs in most surviving patients with both established and unknown causes of weight loss through treatment of the underlying disorder and caloric supplementation. Nutrient intake goals are established in relation to the severity of weight loss, in general ranging from 30 to 40 kcal/kg/d. In order of preference, route of administration options include oral, temporary nasojejunal tube, or percutaneous gastric or jejunal tube. Parenteral nutrition is reserved for patients with serious associated problems. A variety of pharmacologic agents have been proposed for the treatment of weight loss. These can be categorized into appetite stimulants (corticosteroids, progestational agents, dronabinol, and serotonin antagonists); anabolic agents (growth hormone and testosterone derivatives); and anticatabolic agents (omega-3 fatty acids, pentoxifylline, hydrazine sulfate, and thalidomide).

 When to Refer

  • Weight loss caused by malabsorption.
  • Persistent nutritional deficiencies despite adequate supplementation.
  • Weight loss as a result of anorexia or bulimia.

 When to Admit

  • Severe protein-energy malnutrition, including the syndromes of kwashiorkor and marasmus.
  • Vitamin deficiency syndromes.
  • Cachexia with anticipated progressive weight loss secondary to unmanageable psychiatric disease.
  • To carefully manage electrolyte and fluid replacement in protein-energy malnutrition and avoid “re-feeding syndrome.”

Chapman IM. Weight loss in older persons. Med Clin North Am. 2011 May;95(3):579–93. [PMID: 21549879]

Davis IJ et al. Unintentional weight loss as the sole indication for colonoscopy is rarely associated with colorectal cancer. J Am Board Fam Med. 2011 Mar–Apr;24(2):218–9. [PMID: 21383224]

Morley JE. Undernutrition in older adults. Fam Pract. 2012 Apr;29(Suppl 1):i89–i93. [PMID: 22399563]

Murphy RA et al. Nutritional intervention with fish oil provides a benefit over standard of care for weight and skeletal muscle mass in patients with nonsmall cell lung cancer receiving chemotherapy. Cancer. 2011 Apr 15;117(8):1775–82. [PMID: 21360698]

Schilp J et al. Early determinants for the development of undernutrition in an older general population: Longitudinal Aging Study Amsterdam. Br J Nutr. 2011 Sep;106(5):708–17. [PMID: 21450117]

Visvanathan R et al. Undernutrition and anorexia in the older person. Gastroenterol Clin North Am. 2009 Sep;38(3):393–409. [PMID: 19699404]



 Weight loss; fever.

 Sleep-disordered breathing.

 Medications; substance use.

 General Considerations

Fatigue, as an isolated symptom, accounts for 1–3% of visits to generalists. The symptom of fatigue is often poorly described and less well defined by patients than symptoms associated with specific dysfunction of organ systems. Fatigue or lassitude and the closely related complaints of weakness, tiredness, and lethargy are often attributed to overexertion, poor physical conditioning, sleep disturbance, obesity, undernutrition, and emotional problems. A history of the patient’s daily living and working habits may obviate the need for extensive and unproductive diagnostic studies.

Investigated causes of chronic fatigue syndrome include an occult retrovirus infection or an immune dysregulation mechanism, or both. Recent studies, however, have failed to show any differences in levels of xenotropic murine leukemia-virus-related virus in US patients with and without chronic fatigue syndrome. The diagnosis of chronic fatigue syndrome remains hotly debated because of the lack of a gold standard. Persons with chronic fatigue syndrome meeting specific criteria (such as those from the CDC) report a greater frequency of childhood trauma and psychopathology and demonstrate higher levels of emotional instability and self-reported stress than persons who do not have chronic fatigue. Neuropsychological and neuroendocrine studies reveal neurobiologic abnormalities in most patients, but none with a consistent pattern. A longitudinal MRI study showed that no abnormal patterns in rate and extent of brain atrophy, ventricle volume, white matter lesions, cerebral blood flow, or aqueductal cerebrospinal fluid flow were detected in the chronic fatigue syndrome population. Sleep disorders have been reported in 40–80% of patients with chronic fatigue syndrome, but their treatment has provided only modest benefit, suggesting that it is an effect rather than a cause of the fatigue. Veterans of the Gulf War show a tenfold greater incidence of chronic fatigue syndrome compared with nondeployed military personnel.

 Clinical Findings

  1. Fatigue

Clinically relevant fatigue is composed of three major components: generalized weakness (difficulty in initiating activities); easy fatigability (difficulty in completing activities); and mental fatigue (difficulty with concentration and memory). Important diseases that can cause fatigue include hyperthyroidism and hypothyroidism, HF, infections (endocarditis, hepatitis), COPD, sleep apnea, anemia, autoimmune disorders, irritable bowel syndrome, and cancer. Alcoholism, side effects from such drugs as sedatives, and beta-blockers may be the cause. Psychological conditions, such as insomnia, depression, anxiety, panic attacks, dysthmia, and somatization disorder, may cause fatigue. Common outpatient infectious causes include mononucleosis and sinusitis. These conditions are usually associated with other characteristic signs, but patients may emphasize fatigue and not reveal their other symptoms unless directly asked. The lifetime prevalence of significant fatigue (present for at least 2 weeks) is about 25%. Fatigue of unknown cause or related to psychiatric illness exceeds that due to physical illness, injury, medications, drugs, or alcohol.

  1. Chronic Fatigue Syndrome

A working case definition of chronic fatigue syndrome indicates that it is not a homogeneous abnormality, and there is no single pathogenic mechanism (Figure 2–1). No physical finding or laboratory test can be used to confirm the diagnosis of this disorder.

 Figure 2–1. Classification of chronic fatigue patients. ALT, alanine aminotransferase; BUN, blood urea nitrogen; Ca2+, calcium; CBC, complete blood count; ESR, erythrocyte sedimentation rate;  phosphate; TSH, thyroid-stimulating hormone; UA, urinalysis.

The evaluation of chronic fatigue syndrome includes a history and physical examination as well as complete blood count, erythrocyte sedimentation rate, serum chemistries—blood urea nitrogen (BUN), electrolytes, glucose, creatinine, and calcium; liver and thyroid function tests—antinuclear antibody, urinalysis, and tuberculin skin test; and screening questionnaires for psychiatric disorders. Other tests to be performed as clinically indicated are serum cortisol, rheumatoid factor, immunoglobulin levels, Lyme serology in endemic areas, and HIV antibody. More extensive testing is usually unhelpful, including antibody to Epstein-Barr virus. There may be an abnormally high rate of postural hypotension. MRI scans may show brain abnormalities on T2-weighted images—chiefly small, punctate, subcortical white matter hyperintensities, predominantly in the frontal lobes, although a 2010 study found no such abnormalities. Brain MRI is not recommended in the routine evaluation of chronic fatigue syndrome.


  1. Fatigue

Management of fatigue involves identification and treatment of conditions that contribute to fatigue, such as cancer, pain, depression, disordered sleep, weight loss, and anemia. Resistance training and aerobic exercise lessens fatigue and improves performance for a number of chronic conditions associated with a high prevalence of fatigue, including HF, COPD, arthritis, and cancer. Continuous positive airway pressure is an effective treatment for obstructive sleep apnea. Psychostimulants such as methylphenidate have shown inconsistent results in randomized trials of treatment of cancer-related fatigue. Modafinil and armodafinil appear to be effective and well-tolerated in HIV-positive patients with fatigue and with depression.

  1. Chronic Fatigue Syndrome

A variety of agents and modalities have been tried for the treatment of chronic fatigue syndrome. Acyclovir, intravenous immunoglobulin, nystatin, and low-dose hydrocortisone do not improve symptoms. Some patients with postural hypotension report response to increases in dietary sodium as well as fludrocortisone, 0.1 mg orally daily. In a phase III double-blind placebo-controlled randomized trial evaluating the experimental toll-like receptor 3-agonist rintatolimod, administered twice weekly intravenously to 243 cases of severe chronic fatigue syndrome, the patients receiving the rintatolimod were shown to improve exercise tolerance and reduce use of other medications; confirmation of these results is needed. There is a greater prevalence of past and current psychiatric diagnoses in patients with this syndrome. Affective disorders are especially common. Patients with chronic fatigue syndrome have benefited from a comprehensive multidisciplinary intervention, including optimal medical management, treating any ongoing affective or anxiety disorder pharmacologically, and implementing a comprehensive cognitive-behavioral treatment program. At present, cognitive-behavioral therapy and graded exercise are the treatments of choice for patients with chronic fatigue syndrome. Cognitive-behavioral therapy, a form of nonpharmacologic treatment emphasizing self-help and aiming to change perceptions and behaviors that may perpetuate symptoms and disability, is helpful. Although few patients are cured, the treatment effect is substantial. Response to cognitive-behavioral therapy is not predictable on the basis of severity or duration of chronic fatigue syndrome, although patients with low interest in psychotherapy rarely benefit. Graded exercise has also been shown to improve functional work capacity and physical function. A 2011 randomized trial (PACE trial) has confirmed the independent benefits of cognitive behavioral therapy and graded exercise, and found no benefit of adaptive pacing therapy.

In addition, the clinician’s sympathetic listening and explanatory responses can help overcome the patient’s frustrations and debilitation by this still mysterious illness. All patients should be encouraged to engage in normal activities to the extent possible and should be reassured that full recovery is eventually possible in most cases.

 When to Refer

  • Infections not responsive to standard treatment.
  • Difficult to control hyperthyroidism or hypothyroidism.
  • Severe psychological disease.
  • Malignancy.

 When to Admit

  • Failure to thrive.
  • Fatigue severe enough to impair activities of daily living.

Kerr CW et al. Effects of methylphenidate on fatigue and depression: a randomized, double-blind, placebo-controlled trial. J Pain Symptom Manage. 2012 Jan;43(1):68–77. [PMID: 22208450]

Kitai E et al. Fatigue as a first-time presenting symptom: management by family doctors and one year follow-up. Isr Med Assoc J. 2012 Sep;14(9):555–9. [PMID: 23101419]

McMillan EM et al. Exercise is an effective treatment modality for reducing cancer-related fatigue and improving physical capacity in cancer patients and survivors: a meta-analysis. Appl Physiol Nutr Metab. 2011 Dec;36(6):892–903. [PMID: 22067010]

Perrin R et al. Longitudinal MRI shows no cerebral abnormality in chronic fatigue syndrome. Br J Radiol. 2010 May;83(989):419–23. [PMID: 20223910]

Rabkin JG et al. Treatment of HIV-related fatigue with armodafinil: a placebo-controlled randomized trial. Psychosomatics. 2011 Jul–Aug;52(4):328–36. [PMID: 21777715]

Strayer DR et al; Chronic Fatigue Syndrome AMP-516 Study Group. A double-blind, placebo-controlled, randomized, clinical trial of the TLR-3 agonist rintatolimod in severe cases of chronic fatigue syndrome. PLoS One. 2012; 7(3):e31334. [PMID: 22431963]

White PD et al; PACE Trial Management Group. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomized trial. Lancet. 2011 Mar 5;377(9768):823–36. [PMID: 21334061]

Wiborg JF et al. Towards an evidence-based treatment model for cognitive behavioral interventions focusing on chronic fatigue syndrome. J Psychosom Res. 2012 May;72(5):399–404. [PMID: 22469284]



 Age > 50 years.

 Rapid onset and severe intensity (ie, “thunderclap” headache); trauma.

 Fever; vision changes.

 HIV infection.

 Current or past history of hypertension.

 Neurologic findings (mental status changes, motor or sensory deficits).

 General Considerations

Headache is a common reason that adults seek medical care, accounting for approximately 13 million visits each year in the United States to physicians’ offices, urgent care clinics, and emergency departments. A broad range of disorders can cause headache (see Chapter 24). This section deals only with acute nontraumatic headache in adolescents and adults. The challenge in the initial evaluation of acute headache is to identify which patients are presenting with an uncommon but life-threatening condition, approximately 1% of patients seeking care in emergency department settings and considerably less in office practice settings.

Diminution of headache in response to typical migraine therapies (such as serotonin receptor antagonists or ketorolac) does not rule out critical conditions such as subarachnoid hemorrhage or meningitis as the underlying cause.

 Clinical Findings

  1. Symptoms

A careful history and physical examination should aim to identify causes of acute headache that require immediate treatment. These causes can be broadly classified as imminent or completed vascular events (intracranial hemorrhage, thrombosis, vasculitis, malignant hypertension, arterial dissection, or aneurysm), infections (abscess, encephalitis, meningitis), intracranial masses causing intracranial hypertension, preeclampsia, and carbon monoxide poisoning. Having the patient carefully describe the onset of headache can be helpful in diagnosing a serious cause. Report of a sudden-onset headache that reaches maximal and severe intensity within seconds or a few minutes is the classic description of a “thunderclap” headache and should precipitate work-up for subarachnoid hemorrhage, since the estimated prevalence of subarachnoid hemorrhage in patients with “thunderclap” headache is 43%. Other historical features that raise the need for diagnostic testing include headache brought on by the Valsalva maneuver, cough, exertion, or sexual activity.

The general medical history can also guide the need for additional work-up. A new headache in a patient over the age of 50 or with a history of HIV disease under most circumstances (including a normal neurologic examination) warrants immediate neuroimaging (Table 2–8). When the patient has a medical history of hypertension—particularly uncontrolled hypertension—a complete search for criteria satisfying a diagnosis of “malignant hypertension” is appropriate to determine the correct urgency level of hypertension management (see Chapter 11). Headache and hypertension associated with pregnancy may be due to preeclampsia. Episodic headache associated with the triad of hypertension, heart palpitations, and sweats is suggestive of pheochromocytoma. In the absence of “thunderclap” headache, advanced age, and HIV disease, a careful physical examination and detailed neurologic examination will usually determine acuity of the work-up and need for further diagnostic testing.

Table 2–8. Clinical features associated with acute headache that warrant urgent or emergent neuroimaging.

Patient symptoms can also be useful for diagnosing migraine headache in the absence of the “classic” migraine pattern involving scintillating scotoma followed by unilateral headache, photophobia, and nausea and vomiting (Table 2–9). The presence of three or more of these features can establish the diagnosis of migraine (in the absence of other clinical features that warrant neuroimaging studies), and the presence of none or one of these features (provided it is not nausea) can help to rule out migraine.

Table 2–9. Summary likelihood ratios (LRs) for individual clinical features associated with migraine diagnosis.

  1. Physical Examination

Critical components of the physical examination of the patient with acute headache include vital signs, neurologic examination, and vision testing with funduscopic examination. The finding of fever with acute headache warrants additional maneuvers to elicit evidence of meningeal inflammation, such as Kernig and Brudzinski signs. Besides malignant hypertension, significant hypertension can also be a sign of intracranial hemorrhage, preeclampsia, and pheochromocytoma. Patients over 60 years of age should be examined for scalp or temporal artery tenderness.

Careful assessment of visual acuity, ocular gaze, visual fields, pupillary defects, optic disks, and retinal vein pulsations is crucial. Diminished visual acuity is suggestive of glaucoma, temporal arteritis, or optic neuritis. Ophthalmoplegia or visual field defects may be signs of venous sinus thrombosis, tumor, or aneurysm. Afferent pupillary defects can be due to intracranial masses or optic neuritis. Ipsilateral ptosis and miosis suggest Horner syndrome and in conjunction with acute headache may signify carotid artery dissection. Finally, papilledema or absent retinal venous pulsations are signs of elevated intracranial pressure—findings that should be followed by neuroimaging prior to performing lumbar puncture (Table 2–8). Nonmydriatic fundoscopy reveals up to 8.5% of patients who arrive at the emergency department complaining of headache show abnormalities, of which few had other significant physical examination findings and 41% had normal neuroimaging studies.

Mental status and complete neurologic evaluations are also critical and should include assessment of motor and sensory systems, reflexes, gait, cerebellar function, and pronator drift. Any abnormality on mental status or neurologic evaluation warrants emergent neuroimaging (Table 2–8).

  1. Diagnostic Studies

Neuroimaging is summarized in Table 2–8. Under most circumstances, a noncontrast head CT is sufficient to exclude intracranial hypertension with impending herniation, intracranial hemorrhage, and many types of intracranial masses (notable exceptions include lymphoma and toxoplasmosis in HIV-positive patients, herpes simplex encephalitis, and brain abscess). When needed, a contrast study can be ordered to follow a normal noncontrast study. A normal neuroimaging study does not sufficiently exclude subarachnoid hemorrhage and should be followed by lumbar puncture. In patients for whom there is a high level of suspicion for subarachnoid hemorrhage or aneurysm, a normal CT and lumbar puncture should be followed by angiography within the next few days (provided the patient is medically stable). Lumbar puncture is also indicated to exclude infectious causes of acute headache, particularly in patients with fever or meningeal signs. Cerebrospinal fluid tests should routinely include Gram stain, white blood cell count with differential, red blood cell count, glucose, total protein, and bacterial culture. In appropriate patients, also consider testing cerebrospinal fluid for VDRL (syphilis), cryptococcal antigen (HIV-positive patients), acid-fast bacillus stain and culture, and complement fixation and culture for coccidioidomycosis. Storage of an extra tube with 5 mL of cerebrospinal fluid is also prudent for conducting unanticipated tests in the immediate future. Polymerase chain reaction tests for specific infectious pathogens (eg, herpes simplex 2) should also be considered in patients with evidence of central nervous system infection but no identifiable pathogen.

In addition to neuroimaging and lumbar puncture, additional diagnostic tests for exclusion of life-threatening causes of acute headache include erythrocyte sedimentation rate (temporal arteritis; endocarditis), urinalysis (malignant hypertension; preeclampsia), and sinus CT or radiograph (bacterial sinusitis, independently or as a cause of venous sinus thrombosis).


Treatment should be directed at the cause of acute headache. In patients in whom migraine or migraine-like headache has been diagnosed, early treatment with NSAIDs or triptans can often abort or provide significant relief of symptoms (see Chapter 24). High-flow oxygen therapy may also provide effective treatment for all headache types in emergency department setting. Other causes of acute headache, such as subarachnoid hemorrhage, intracranial mass, or meningitis, usually require emergent treatment in the hospital.

 When to Refer

  • Frequent migraines not responsive to standard therapy.
  • Migraines with atypical features.
  • Chronic daily headaches due to medication overuse.

 When to Admit

  • Need for repeated doses of parenteral pain medication.
  • To facilitate an expedited work-up requiring a sequence of neuroimaging and procedures.
  • Monitoring for progression of symptoms and neurologic consultation when the initial emergency department work-up is inconclusive.
  • Pain severe enough to impair activities of daily living or limit participation in follow-up appointments or consultation.

De Luca GC et al. When and how to investigate the patient with headache. Semin Neurol. 2010 Apr;30(2):131–44. [PMID: 20352583]

Derry CJ et al. Sumatriptan (oral route of administration) for acute migraine attacks in adults. Cochrane Database Syst Rev. 2012 Feb 15;2:CD008615. [PMID: 22336849]

Edlow JA et al. Clinical policy: critical issues in the evaluation and management of adult patients presenting to the emergency department with acute headache. Ann Emerg Med. 2008 Oct;52(4):407–36. [PMID: 18809105]

Friedman BW et al. Headache in the emergency department. Curr Pain Headache Rep. 2011 Aug;15(4):302–7. [PMID: 21400252]

Friedman BW et al. Metoclopramide for acute migraine: a dose-finding randomized clinical trial. Ann Emerg Med. 2011 May;57(5):475–82.e1. [PMID: 21227540]

Jamshidi S et al. Clinical predictors of significant findings on head computed tomographic angiography. J Emerg Med. 2011 Apr;40(4):469–75. [PMID: 19854018]

Loder E. Triptan therapy in migraine. N Engl J Med. 2010 Jul 1;363(1):63–70. [PMID: 20592298]

Ozkurt B et al. Efficacy of high-flow oxygen therapy in all types of headache: a prospective, randomized, placebo-controlled trial. Am J Emerg Med. 2012 Nov;30(9):1760–4. [PMID: 22560101]

Thulasi P et al. Nonmydriatic ocular fundus photography among headache patients in an emergency department. Neurology. 2013 Jan 29;80(5):432–7. [PMID: 23284060]



 Fever; new back or flank pain; nausea or vomiting.

 Vaginal discharge.

 Pregnancy risk.

 Structural abnormalities.

 Instrumentation of urethra or bladder.

 General Considerations

Dysuria (painful urination) is a common reason for adolescents and adults to seek urgent medical attention. An inflammatory process (eg, infection; autoimmune disorder) underlies most causes of dysuria. In women, cystitis will be diagnosed in up to 50–60% of cases and has an incidence of 0.5–0.7% per year in sexually active young women. The key objective in evaluating women with dysuria is to exclude serious upper urinary tract disease, such as acute pyelonephritis, and sexually transmitted diseases. In elderly men, dysuria may be a symptom of prostatitis. In contrast, in younger men, urethritis accounts for the vast majority of cases of dysuria.

 Clinical Findings

  1. Symptoms

Well-designed cohort studies have shown that some women can be reliably diagnosed with uncomplicated cystitis without a physical examination or urinalysis, and randomized controlled trials show that telephone management of uncomplicated cystitis is safe and effective. An increased likelihood of cystitis is present when women report multiple irritative voiding symptoms (dysuria, urgency, frequency), fever, or back pain (LRs = 1.6–2.0). Inquiring about symptoms of vulvovaginitis is imperative. When women report dysuria and urinary frequency, and deny vaginal discharge and irritation, the likelihood ratio for culture-confirmed cystitis is 24.5. In contrast, when vaginal discharge or irritation is present, as well as dysuria or urinary frequency, the LR is 0.7. Gross hematuria in women with voiding symptoms usually represents hemorrhagic cystitis but can also be a sign of bladder cancer (particularly in older patients) or upper tract disease. Failure of hematuria to resolve with antibiotic treatment should prompt further evaluation of the bladder and kidneys. Chlamydial infection should be strongly considered among women age 25 years or younger who are sexually active and seeking medical attention for a suspected urinary tract infection for the first time or have a new partner.

Because fever and back pain, as well as nausea and vomiting, are considered harbingers of (or clinical criteria for) acute pyelonephritis, women with these symptoms should usually be examined by a clinician prior to treatment in order to exclude coexistent urosepsis, hydronephrosis, or nephrolithiasis. Other major risk factors for acute pyelonephritis (among women 18–49 years of age) relate to sexual behaviors (frequency of sexual intercourse three or more times per week, new sexual partner in previous year, recent spermicide use), as well as diabetes mellitus and recent urinary tract infection or incontinence. Finally, pregnancy, underlying structural factors (polycystic kidney disease, nephrolithiasis, neurogenic bladder), immunosuppression, diabetes mellitus, and a history of recent bladder or urethral instrumentation usually alter the treatment regimen (antibiotic choice or duration of treatment, or both) of uncomplicated cystitis.

  1. Physical Examination

Fever, tachycardia, or hypotension suggest the possibility of urosepsis and potential need for hospitalization. A focused examination in women, in uncomplicated circumstances, could be limited to ascertainment of costovertebral angle tenderness and to a lower abdominal and pelvic examination, if the history suggests vulvovaginitis or cervicitis.

  1. Diagnostic Studies
  2. Urinalysis—Urinalysis is probably overutilized in the evaluation of dysuria. The probability of culture-confirmed urinary tract infection among women with a history and physical examination compatible with uncomplicated cystitis is about 70–90%. Urinalysis is most helpful in atypical presentations of cystitis. Dipstick detection (> trace) of leukocytes, nitrites, or blood supports a diagnosis of cystitis. When both leukocyte and nitrite tests are positive, the LR is 4.2, and when both are negative, the LR is 0.3. The negative predictive value of urinalysis is not sufficient to exclude culture-confirmed urinary tract infection in women with multiple and typical symptoms; and randomized trial evidence shows that antibiotic treatment is beneficial to women with typical symptoms and negative urinalysis dipstick tests. Microscopy of unspun urine may also be helpful in diagnosis and reduce unnecessary use ofantibiotics. The combination of urgency, dysuria, and pyuria (assessed with the high power objective (40 ×) for pus cells (> 1 pus cell/7 high power fields) had a positive predictive value of 71.71 and LR of 2.97.
  3. Urine culture—Urine culture should be considered for all women with upper tract symptoms (prior to initiating antibiotic therapy), as well as those with dysuria and a negative urine dipstick test. In symptomatic women, a clean-catch urine culture is considered positive when 102–103colony-forming units/mL of a uropathogenic organism is detected.
  4. Renal imaging—When severe flank or back pain is present, the possibility of complicated kidney infection (perinephric abscess, nephrolithiasis) or of hydronephrosis should be considered. Renal ultrasound or CT scanning should be done to rule out abscess or hydronephrosis. To exclude nephrolithiasis, noncontrast helical CT scanning is more accurate than intravenous urography and is rapidly becoming the diagnostic test of choice. In a meta-analysis, the positive and negative likelihood ratios of helical CT scanning for diagnosis of nephrolithiasis were 23.2 and 0.05, respectively.

 Differential Diagnosis

The differential diagnosis of dysuria in women includes acute cystitis, acute pyelonephritis, vaginitis (Candida, bacterial vaginosis, Trichomonas, herpes simplex), urethritis/cervicitis (Chlamydia, gonorrhea), and interstitial cystitis/painful bladder syndrome. Nucleic acid amplification tests from first-void urine or vaginal swab specimens are highly sensitive for detecting chlamydial infection. Other infectious pathogens associated with dysuria and urethritis in men include Mycoplasma genitalium and Enterobacteriacea.


Definitive treatment is directed to the underlying cause of the dysuria. An evidence-informed algorithm for managing suspected urinary tract infection in women is shown in Figure 2–2. This algorithm supports antibiotic treatment of most women with multiple and typical symptoms of urinary tract infection without performing urinalysis or urine culture. Antibiotic selection should be guided by local resistance patterns; major options for uncomplicated cystitis include nitrofurantoin, cephalosporins, ciprofloxacin, and trimethoprim-sulfamethoxazole. Prolonged treatment of urinary tract infections (> 7 days) in men does not appear to reduce early or late recurrences. Symptomatic relief can be provided with phenazopyridine, a urinary analgesic that is available over-the-counter; it is used in combination with antibiotic therapy (when a urinary tract infection has been confirmed) but for no more than 2 days. Patients should be informed that phenazopyridine will cause orange/red discoloration of their urine and other bodily fluids (eg, some contact lens wearers have reported discoloration of their lenses). Rare cases of methemoglobinemia and hemolytic anemia have been reported, usually with overdoses or underlying renal dysfunction.

 Figure 2–2. Proposed algorithm for evaluating women with symptoms of acute urinary tract infection (UTI). (Modified and reproduced, with permission, from Bent S et al. Does this woman have an acute uncomplicated urinary tract infection? JAMA. 2002 May 22–29;287(20):2701–10.)

In cases of interstitial cystitis/painful bladder syndrome (see Chapter 23), patients will often respond to a multimodal approach that may include urethral/vesicular dilation, biofeedback, cognitive behavioral therapy, antidepressants, dietary changes, vaginal emollients, and other supportive measures.

 When to Refer

  • Anatomic abnormalities leading to repeated urinary infections.
  • Infections associated with nephrolithiasis.
  • Persistent interstitial cystitis/painful bladder syndrome.

 When to Admit

  • Severe pain requiring parenteral medication or impairing ambulation or urination (such as severe primary herpes simplex genitalis).
  • Dysuria associated with urinary retention or obstruction.
  • Pyelonephritis with ureteral obstruction.

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