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| {{Infobox_Disease |
| | __NOTOC__ |
| Name = Wheeze |
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| ICD10 = {{ICD10|R|06|2|r|00}} |
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| ICD9 = {{ICD9|786.07}} |
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| }}
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| {{Wheeze}} | | {{Wheeze}} |
| {{CMG}} | | '''For patient information click [[{{PAGENAME}} (patient information)|here]]''' |
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| {{JFS}} | | {{CMG}}; {{JFS}} |
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| ==Overview== | | ==[[Wheeze overview|Overview]]== |
| A '''wheeze''' is a continuous, coarse, whistling sound produced in the respiratory [[airways]] during breathing. For wheezes to occur, some part of the respiratory tree must be narrowed or obstructed, or airflow velocity within the respiratory tree must be heightened. Wheezing is commonly experienced by persons with a [[lung]] [[disease]]; the most common cause of recurrent wheezing is [[asthma]], a form of [[reactive airway disease]].
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| == Pathophysiology == | | ==[[Wheeze pathophysiology|Pathophysiology]]== |
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| Wheezes occupy different portions of the [[respiration (physiology)|respiratory]] cycle depending on the site of airway obstruction and its nature. The proportion of the respiratory cycle occupied by the wheeze roughly corresponds to the degree of airway obstruction.{{rf|1|Baughman}}<sup>,</sup>{{rf|2|Pasterkamp}} [[Bronchiole|Bronchiolar]] disease usually causes wheezing that occurs in the expiratory phase of respiration. The presence of expiratory phase wheezing signifies that the patient's [[Spirometry|peak expiratory flow rate]] is less than 50% of normal.{{rf|3|Shim}} Wheezing heard in the inspiratory phase on the other hand is often a sign of a stiff stenosis, usually caused by [[tumor]]s, foreign bodies or scarring. This is especially true if the wheeze is monotonal, occurs throughout the inspiratory phase (ie. is "holoinspiratory"), and is heard more [[Anatomical position|distally]], in the [[Vertebrate trachea|trachea]]. Inspiratory wheezing also occurs in hypersensitivity pneumonitis.{{rf|4|Earis}} Wheezes heard at the end of both expiratory and inspiratory phases usually signify the periodic opening of deflated [[pulmonary alveolus|alveoli]], as occurs in some diseases that lead to collapse of parts of the [[lung]]s.
| | ==[[Wheeze causes|Causes]]== |
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| The location of the wheeze can also be an important clue to the diagnosis. Diffuse processes that affect most parts of the lungs are more likely to produce wheezing that may be heard throughout the [[chest]] via a stethoscope. Localized processes, such as the occlusion of a portion of the respiratory tree, are more likely to produce wheezing at that location, whence the sound will be loudest and radiate outwardly. The pitch of a wheeze does not reliably predict the degree of narrowing in the affected airway.{{rf|5|Meslier}}
| | ==[[Wheeze differential diagnosis|Differentiating Wheeze from other Conditions]]== |
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| Wheezing can also occur in people who are deconditioned.
| | == [[Wheeze epidemiology and demographics|Epidemiology and Demographics]] == |
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| ==Differentiating wheezing from the more serious condition of stridor== | | == [[Wheeze risk factors|Risk Factors]] == |
| A special type of wheeze is '''[[stridor]]'''. Stridor — the word is from the Latin, ''strīdor''{{rf|6|OED}} — is a harsh, high-pitched, vibrating sound that is heard in respiratory tract obstruction. Stridor heard solely in the expiratory phase of respiration usually indicates a lower respiratory tract obstruction, "as with aspiration of a foreign body (such as the fabled pediatric peanut)."{{rf|7|Sapira}} Stridor in the inspiratory phase is usually heard with obstruction in the upper airways, such as the trachea, epiglottis, or larynx; because a block here means that no air may reach either lung, this condition is a medical emergency.
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| ==Differential diagnosis of wheezing: Common causes== | | == [[Wheeze natural history|Natural History, Complications and Prognosis]] == |
| The [[differential diagnosis]] of wheezing is wide, and the cause of wheezing in a given patient is determined by considering the characteristics of the wheezes and the historical and clinical findings made by the examining physician. The most common cases in clinical practice are:
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| *[[Asthma]]
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| *[[Bronchitis]]
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| *[[Cardiac asthma]] or [[Congestive heart failure]]
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| *[[Chronic obstructive pulmonary disease]]: Chronic [[bronchitis]] and [[emphysema]]
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| *[[Gastroesophageal Reflux Disease]]
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| *Chronic [[sinusitis]]
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| *[[Infection]] ([[pneumonia]])
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| Medication-induced [[bronchoconstriction]]
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| ==Complete Differential Diagnosis of the Causes of Wheeze== | | == Diagnosis == |
| (In alphabetical order)
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| *Abnormal arytenoid movement
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| *[[Allergic bronchopulmonary aspergillosis]] ABPA
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| *[[Alpha 1-Antitrypsin Deficiency]]
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| *Amyloid deposition
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| *[[Anaphylaxis]]
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| *[[Angioedema]]
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| *[[Aspergillosis]] including [[aspergilloma]] and ABPA
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| *[[Aspiration]](foreign particles or foods)
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| *[[Asthma]] including status asthmaticus
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| *Benign airway [[tumors]] including:
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| **Bronchial adenomata syndrome
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| **Unknown ([[hamartoma]], [[clear cell]], [[teratoma]])
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| **Epithelial ([[papilloma]], [[polyps]])
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| **Mesodermal ([[fibroma]], [[lipoma]], [[leiomyoma]], [[chondroma]], granular cell tumor, sclerosing [[hemangioma]])
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| **Other (myofibroblastic tumor, xanthoma, [[amyloid]], mucosa-associated lymphoid tumor)
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| *[[Bronchiectasis]]
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| *[[Bronchiolitis]] (a common childhood disease)
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| *[[Bronchiolitis obliterans]]
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| *[[Bronchitis]] (usually viral, bacterial only in patients with tracheostomy or endotracheal intubation)
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| **[[influenza]] A and B
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| **[[parainfluenza]]
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| **[[coronavirus]] (types 1-3)
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| **[[rhinovirus]]
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| **[[respiratory syncytial virus]]
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| **human metapneumovirus
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| **Other:
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| ***[[Mycoplasma pneumoniae]]
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| ***[[Chlamydophila pneumoniae]]
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| ***[[Pertussis]]
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| *[[Bronchopulmonary dysplasia]]
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| *[[Byssinosis]] - cotton duct
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| *[[Carcinoid syndrome]]
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| *Cardiac asthma (including cardiogenic pulmonary edema)
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| *[[Cardiomegaly]] (severe cardiomegaly)
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| *Chemical poisoning (more than 50 substances have been linked to wheezing)
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| *[[Chondromalacia]]
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| *[[Chronic obstructive pulmonary disease]]: Chronic bronchitis and Emphysema
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| *Cold induced [[wheezing]] (Paediatrics)
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| *[[Ciliary dyskinesia]]-bronchiectasis
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| *[[Congenital abnormalities]] affecting the bronchial tree
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| *Cricoarytenoid arthritis
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| *[[Cystic fibrosis]]
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| *Descending aortic [[aneurysm]]
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| *Dialyzer hypersensitivity syndrome
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| *Esophageal foreign body
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| *Exercise-induced [[asthma]]
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| *Extrinsic allergic [[alveolitis]]
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| *Food allergies: numerous including:
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| **[[Peanut]] Allergy
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| *[[Gastroesophageal Reflux Disease]] (with aspiration)
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| *[[Graft-versus-host disease]]
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| *[[Hay fever]]
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| *[[Heart failure]] (see cardiogenic pulmonary edema and cardiac asthma)
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| *[[Hemorrhage]], pulmonary
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| *Hypertrophied [[tonsils]]
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| *[[Immunodeficiency]]
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| *[[Infection]] ([[pneumonia]])
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| *[[Interstitial lung disease]]
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| *Intrathoracic [[goiter]]
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| *[[Klebsiella]] rhinoscleroma
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| *[[Laryngeal edema]]
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| *[[Laryngocele]]
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| *Laryngostenosis
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| *[[Laryngotracheobronchitis]]
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| *[[Lymphadenopathy]] with large lymphnodes compressing the tracheal tree.
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| *Lymphangitic carcinomatosis
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| *[[Malignancy]] (bronchogenic)
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| **[[Squamous cell carcinoma]] with variants: papillary, clear cell, small cell, basaloid
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| **[[Small cell carcinoma]]
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| **[[Adenocarcinoma]]
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| ***Acinar
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| ***Papillary
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| ***Bronchioloalveolar carcinoma
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| ****Non-mucinous (Clara cell/type II pneumocyte type)
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| ****Mucinous (Goblet cell type)
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| ****Mixed mucinous and non-mucinous (Clara cell/type II pneumocyte/goblet cell type) or indeterminate
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| ***Solid adenocarcinoma with mucin formation
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| ***Mixed
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| ***Variants: well-differentiated fetal adenocarcinoma, mucinous ("colloid"), mucinous cystadenocarcinoma, signet ring, clear cell
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| **Large cell carcinoma with variants: large cell neuroendocrine carcinoma, combined large cell neuroendocrine carcinoma, basaloid carcinoma, lymphoepithelioma-like carcinoma, clear cell carcinoma, large cell carcinoma with rhaboid phenotype
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| **Adenosquamous carcinoma
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| **Carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements
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| ***Carcinomas with spindle and/or giant cells
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| ***Pleomorphic carcinoma
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| ***Spindle cell carcinoma
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| ***Giant cell carcinoma
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| ***Carcinosarcoma
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| ***Blastoma (Pulmonary blastoma)
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| **Carcinoid tumor
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| ***Typical carcinoid
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| ***Atypical carcinoid
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| **Carcinomas of salivary gland type
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| ***Mucoepidermoid carcinoma
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| ***Adenoid cystic carcinoma
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| **Unclassified carcinoma
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| **[[Mastocytosis]]
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| **[[Mendelson's syndrome]] (aspiration pneumonitis)
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| *Medication-induced bronchoconstriction
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| **[[ACE inhibitors]] ( cough or rarely Angioneurotic edema and wheeze)
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| **[[Sotalol]]
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| **[[Adenosine]]
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| **[[Beta blockers]]: Common; usually occurs in patients with asthma or COPD; 1-selective agents, [[labetalol]], [[esmolol]], and [[pindolol]] are better tolerated than nonselective agents.
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| **[[Dipyridamole]] (IV form only)
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| **[[Protamine]]
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| **[[NSAIDs]] includign aspirin
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| **[[Marijuana]] (chronic use)
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| *[[Milk allergy]]
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| *Mobile supraglottic soft tissue
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| *[[Obesity]]
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| *[[Parasitic infections]]
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| **[[Ascariasis]]
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| **[[Hookworm]]
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| **Paragonimiases - lung infection
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| **[[Strongyloidiasis]]
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| **[[Toxocariasis]]
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| *Paroxysmal vocal cord motion
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| *Postextubation [[granuloma]]
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| *Postlobectomy bronchial torsion
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| *Postnasal drip syndrome
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| *Postradiation [[stenosis]]
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| *[[Primary ciliary dyskinesia]]
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| *[[Psychogenic]] wheezing
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| *[[Pulmonary edema]] (cardiogenic or non-cardiogenic)
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| *[[Pulmonary embolism]]
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| *[[Pulmonary eosinophilia]]
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| *[[Relapsing polychondritis]]
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| *Retained [[foreign body]] (trachea or esophagus)
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| *[[Retropharyngeal abscess]]
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| *Right sided [[aortic arch]]
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| *[[Sinusitis]] ( chronic sinusitis )
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| *Supraglottitis
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| *[[Tracheal stenosis]]
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| *[[Tracheobronchitis]]
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| *[[Tracheobronchomegaly]]
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| *Tracheobronchopathia osteoplastica : a rare, benign condition and is characterized by the presence of bony and cartilaginous nodules in the tracheal and bronchial mucosa.
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| *[[Tracheomalacia]]
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| *[[Tuberculosis]], Pulmonary
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| *Vascular compression and rings ( Aberrant subclavian artery abnormality )
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| *Vocal cord dysfunction
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| *Vocal cord hematoma
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| *Vocal cord paralysis (bilateral paralysis)
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| *[[Wegener's granulomatosis]]
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| | [[Wheeze history and symptoms|History and Symptoms]] | [[Wheeze laboratory findings|Laboratory Findings]] | [[Wheeze chest x ray|Chest X Ray]] | [[Wheeze other imaging findings|Other Imaging Findings]] | [[Wheeze other diagnostic studies|Other Diagnostic Studies]] |
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| | ==Treatment== |
| | [[Wheeze medical therapy|Medical Therapy]] | [[Wheeze secondary prevention|Secondary Prevention]] | [[Wheeze cost-effectiveness of therapy| Cost-Effectiveness of Therapy]] | [[Wheeze future or investigational therapies|Future or Investigational Therapies]] |
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| | ==Case Studies== |
| | [[Wheeze case study one|Case #1]] |
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| ===Complete Differential Diagnosis of the Causes of Wheeze=== | | ==Related Chapters== |
| (By organ system)
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| {|style="width:75%; height:100px" border="1"
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| |style="height:100px"; style="width:25%" border="1" bgcolor="LightSteelBlue" | '''Cardiovascular'''
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| |style="height:100px"; style="width:75%" border="1" bgcolor="Beige" | Cardiac asthma ( pulmonary edema), [[Cardiomegaly]], Descending aortic [[aneurysm]], [[Pulmonary edema]]
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| [[Pulmonary embolism]], Right sided aortic arch, Vascular compression/ rings, [[Heart failure]]
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Chemical / poisoning'''
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| |bgcolor="Beige"| Dialyzer hypersensitivity syndrome, [[Food allergies]], [[Peanut Allergy]], Chemical poisoning
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Dermatologic'''
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| |bgcolor="Beige"| No underlying causes
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Drug Side Effect'''
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| |bgcolor="Beige"| Medication-induced bronchoconstriction, [[ACE inhibitors]], [[Sotalol]]
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| ,[[Adenosine]], [[Beta blockers]], [[Dipyridamole]], [[Protamine]], [[NSAIDs]], [[Aspirin]], [[Marijuana]]
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Ear Nose Throat'''
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| |bgcolor="Beige"| [[Aspiration]](foreign particles or foods), Bilateral vocal cord paralysis, Hypertrophied [[tonsils]], Intrathoracic [[goiter]], [[Laryngeal edema]], [[Laryngocele]], Laryngostenosis, [[Laryngotracheobronchitis]], Mobile supraglottic soft tissue, Paroxysmal vocal cord motion, Postextubation [[granuloma]], Postlobectomy bronchial torsion, Postnasal drip syndrome, Postradiation [[stenosis]], [[Retropharyngeal abscess]], Supraglottitis, Vocal cord dysfunction, Vocal cord hematoma, [[Sinusitis]]
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Endocrine'''
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| |bgcolor="Beige"| Intrathoracic [[goiter]], Obesity,
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Environmental'''
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| |bgcolor="Beige"| [[asthma]], [[Byssinosis]], [[Hay fever]]
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Gastroenterologic'''
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| |bgcolor="Beige"| [[Gastroesophageal Reflux Disease]]
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Genetic'''
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| |bgcolor="Beige"| [[Cystic fibrosis]], [[Milk allergy]], Obesity, [[Primary ciliary dyskinesia]], Vascular compression/ rings, [[Alpha 1-Antitrypsin Deficiency]], [[Ciliary dyskinesia]]-bronchiectasis,
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Hematologic'''
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| |bgcolor="Beige"| [[Lymphadenopathy]]
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Iatrogenic'''
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| |bgcolor="Beige"| [[Aspiration]](foreign particles or foods), Esophageal foreign body, [[Mendelson's syndrome]] (aspiration pneumonitis),
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Infectious Disease'''
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| |bgcolor="Beige"| [[Allergic bronchopulmonary aspergillosis]], Cold induced [[wheezing]], [[Bronchitis]], [[Bronchiolitis]], [[pneumonia]], [[Lymphadenopathy]], [[Retropharyngeal abscess]], [[Tuberculosis]], [[Ascariasis]], [[Hookworm]], Paragonimiases - lung infection, [[Strongyloidiasis]], [[Toxocariasis]], [[Aspergillosis]]
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Musculoskeletal / Ortho'''
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| |bgcolor="Beige"| Cricoarytenoid arthritis,
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Neurologic'''
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| |bgcolor="Beige"| No underlying causes
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Nutritional / Metabolic'''
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| |bgcolor="Beige"| Obesity
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Obstetric/Gynecologic'''
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| |bgcolor="Beige"| No underlying causes
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Oncologic'''
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| |bgcolor="Beige"| [[Carcinoid syndrome]], [[Lymphadenopathy]], Lymphangitic carcinomatosis, [[Malignancy]] (bronchogenic tumors), Bronchial adenomata syndrome, [[Mastocytosis]]
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Opthalmologic'''
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| |bgcolor="Beige"| No underlying causes
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Overdose / Toxicity'''
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| |bgcolor="Beige"| chemical poisoning
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Psychiatric'''
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| |bgcolor="Beige"| [[Psychogenic]] wheezing
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Pulmonary'''
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| |bgcolor="Beige"| [[Bronchiectasis]], [[Bronchiolitis]], [[Bronchiolitis obliterans]], [[Bronchitis]], [[Bronchopulmonary dysplasia]], [[Carcinoid syndrome]], [[Chronic obstructive pulmonary disease]]: Chronic bronchitis and Emphysema, Cold induced [[wheezing]], [[Cystic fibrosis]], Pulmonary [[hemorrhage]], [[pneumonia]], [[Interstitial lung disease]], Postlobectomy bronchial torsion, Postradiation [[stenosis]], [[Primary ciliary dyskinesia]], [[Pulmonary edema]], [[Pulmonary embolism]], [[Tracheal stenosis]], [[Tracheobronchitis]], [[Tracheobronchomegaly]], [[Tracheomalacia]], [[Wegener's granulomatosis]], [[Pulmonary eosinophilia]], [[Tuberculosis]], [[Alpha 1-Antitrypsin Deficiency]], Extrinsic allergic alveolitis, Bronchial adenomata syndrome, [[Ciliary dyskinesia]]-bronchiectasis, Tracheobronchopathia osteoplastica, [[Aspergillosis]]
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Renal / Electrolyte'''
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| |bgcolor="Beige"| No underlying causes
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Rheum / Immune / Allergy'''
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| |bgcolor="Beige"| [[Allergic bronchopulmonary aspergillosis]], [[Anaphylaxis]], [[Angioedema]], [[Asthma]], Cricoarytenoid arthritis, [[Immunodeficiency]], [[Interstitial lung disease]], [[Lymphadenopathy]], [[Milk allergy]], [[Relapsing polychondritis]], [[Wegener's granulomatosis]], [[Pulmonary eosinophilia]], Extrinsic allergic alveolitis, [[Graft-versus-host disease]], [[Hay fever]], [[Mastocytosis]],
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|
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Sexual'''
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| |bgcolor="Beige"| No underlying causes
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Trauma'''
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| |bgcolor="Beige"| No underlying causes
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Urologic'''
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| |bgcolor="Beige"| No underlying causes
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| |-
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| |-bgcolor="LightSteelBlue"
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| | '''Miscellaneous'''
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| |bgcolor="Beige"| Amyloid deposition, Tracheobronchopathia osteochondroplastica
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| |-
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| |}
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| [[Image:Asthma before-after.png|thumb|center|350px|'''Inflamed airways and bronchoconstriction in asthma'''. Airways narrowed as a result of the inflammatory response cause wheezing.]]
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| ==Treatment of Wheeze==
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| === Management of chronic obstructive pulmonary disease (COPD)===
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| All patients with COPD should be on a short-acting bronchodilator to be used on as-needed basis for intermittent increases in dyspnea. The purpose of the short-acting bronchodilator is to reduce symptoms and improve lung function. It is recommended to use a short-acting beta agonist plus a short-acting anticholinergic, rather than either alone, to achieve greater benefit. However, monotherapy with either is acceptable. For patients in whom intermittent short-acting bronchodilators are insufficient to control symptoms, a regularly scheduled long-acting inhaled bronchodilator is recommended. The purpose of the long-acting inhaled bronchodilator is to improve symptoms, improve lung function, and reduce the frequency of exacerbations. The effects of the currently available once daily long acting anticholinergic are superior to the effects of the twice daily long acting beta agonists that are available. Theophylline is the least preferred long-acting bronchodilator option because its effects are modest and toxicity is a concern. For patients who continue to have symptoms or repeated exacerbations despite an optimal long-acting inhaled bronchodilator regimen, adding an inhaled glucocorticoid is recommended.
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| All patients with COPD should be advised to quit smoking, educated about COPD, and given a yearly influenza vaccination. In addition, the pneumococcal polysaccharide vaccine should be given to patients who are ≥65 years old, or who are younger than 65 years with a forced expiratory volume in one second (FEV1) less than 40 percent.
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| ===Management of asthma===
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| The optimal treatment of asthma involves the following steps:
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| #Monitoring of symptoms and lung function by formal periodic pulmonary function testing
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| #Patient education
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| #Controlling environmental and trigger factors and co-morbid conditions that contribute to asthma
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| #Pharmacologic therapy in a step wise fashion depending on the severity of asthma: intermittent (Step 1), mild persistent (Step 2, moderate persistent (Step 3), and severe persistent (Step 4 or 5).
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| Asthma severity is based upon current level of symptoms, FEV1 or PEFR values, and the number of exacerbations requiring oral glucocorticoids per year.
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| Medications include: quick-acting inhaled beta-2-selective adrenergic agonists, long-acting inhaled beta agonists, inhaled glucocorticoids, leukotriene receptor antagonists, theophylline, cromoglycates, anti-IgE therapy (omalizumab), and oral glucocorticoids on a daily or alternate-day basis.
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| <ref>Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:77 ISBN 1591032016</ref> <ref>Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:68 ISBN 140510368X</ref>:
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| ==See also==
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| * [[Rales]] | | * [[Rales]] |
| * [[Rhonchi]] | | * [[Rhonchi]] |
| | | {{WH}} |
| == References ==
| | {{WS}} |
| {{Reflist}}
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| ==Additional Resources==
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| {{ent|1|Baughman}} Baughman RP, Loudon RG. Quantitation of wheezing in acute asthma. ''Chest.'' 1984;86:718–722. PMID 6488909
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| {{ent|2|Pasterkamp}} Pasterkamp H, Asher T, Leahy F, et al. The effect of anticholinergic treatment on postexertional wheezing in asthma studied by phonopneumography and spirometry. ''Am Rev Respir Dis.'' 1985;132:16–21. PMID 3160273
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| {{ent|3|Shim}} Shim CS, Williams MH. Relationship of wheezing to the severity of obstruction in asthma. ''Arch Intern Med.'' 1983;143:890–892. PMID 6679232
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| {{ent|4|Earis}} Earis J, Marsh K, Pearson M, et al. The inspiratory squawk in extrinsic allergic alveolitis and other pulmonary fibrosis. ''Thorax.'' 1982;37:923–926. PMID 7170682
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| {{ent|5|Meslier}} Meslier N, Charbonneau G, Racineux JL. Wheezes. ''Eur Respir J.'' 1995;8(11):1942-8. PMID 8620967
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| {{ent|6|OED}} Simpson JA, Weiner ESC (eds). "''stridor, n. 2''." ''Oxford English Dictionary'' 2nd ed. Oxford: Clarendon Press, 1989. OED Online Oxford University Press. Accessed September 10, 2005. http://dictionary.oed.com.
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| {{ent|7|Sapira}} Orient JM. ''Sapira's Art & Science of Bedside Diagnosis'' 2nd ed. Philadelphia: Lippincott William Wilkins, 2000. ISBN 0-683-30714-2
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