You are in: eMedicine Specialties > Dermatology > INTERNAL MEDICINE Dermatologic Manifestations of Pulmonary DiseaseArticle Last Updated: Jul 10, 2006AUTHOR AND EDITOR INFORMATIONSection 1 of 11
 
Author: Paul B Cornia, MD, Staff physician, Assistant Professor of Medicine, University of Washington, Department of Medicine, Veterans Affairs Puget Sound Health Care System Coauthor(s): Gregory J Raugi, MD, PhD, Professor, Department of Internal Medicine, Division of Dermatology, University of Washington at Seattle; Chief, Dermatology Section, Primary and Specialty Care Service, Veterans Administration Medical Center of Seattle Editors: Kathleen David-Bajar, MD, Former Consultant to the Army Surgeon General, Department of Dermatology, Brooke Army Medical Center; Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University School of Medicine; Consulting Staff, Mountain View Dermatology, PA; Jeffrey P Callen, MD, Professor of Medicine, Chief, Division of Dermatology, University of Louisville School of Medicine; Joel M Gelfand, MD, MSCE, Medical Director, Clinical Studies Unit, Assistant Professor, Department of Dermatology, Associate Scholar, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania; William D James, MD, Paul R Gross Professor of Dermatology, University of Pennsylvania School of Medicine; Vice-Chair, Program Director, Department of Dermatology, University of Pennsylvania Health System Author and Editor Disclosure Synonyms and related keywords: skin, cutaneous, pulmonary, cyanosis, clubbing, lung cancer, hypertrophic osteoarthropathy, HOA, primary hypertrophic osteoarthropathy, primary HOA, secondary hypertrophic osteoarthropathy, secondary HOA, superior vena cava syndrome, SVC syndrome, sarcoidosis, papular sarcoidosis, lupus pernio, erythema nodosum, EN, Wegener granulomatosis, Churg-Strauss syndrome, relapsing polychondritis, pulmonary arteriovenous malformations, PAVM, alpha-1 antitrypsin deficiency, fat embolism syndrome, yellow nail syndrome INTRODUCTIONSection 2 of 11
 
The recognition and correct interpretation of cutaneous signs of diseases that primarily affect the bronchopulmonary system may aid the clinician in diagnosis and assessment of prognosis. This article reviews selected pulmonary diseases with distinctive cutaneous findings. CYANOSIS AND CLUBBINGSection 3 of 11
CyanosisThe distinctive blue or purple skin discoloration of cyanosis indicates the presence of at least 5 g/dL of desaturated hemoglobin. Severely anemic patients (regardless of degree of desaturation) are, therefore, unable to manifest cyanosis. Cyanosis may be classified as central or peripheral, referring to the etiology of the hemoglobin desaturation, not to the anatomic location of the cyanosis. Central cyanosis is often a manifestation of congenital heart disease characterized by right-to-left pulmonary shunts. Central cyanosis typically involves the entire body but may be best appreciated on warm areas of the body (eg, tongue, oral mucosa, conjunctiva, skin). Peripheral cyanosis is a manifestation of diminished tissue perfusion with resultant increased local oxygen extraction leading to high levels of desaturated hemoglobin. Shock, heart failure, and peripheral vascular disease are conditions that may result in peripheral cyanosis. ClubbingClubbing describes the bulbous, clublike deformation of the distal portion of the fingers and toes resulting from connective-tissue proliferation (see Media File 1). The condition was first described by Hippocrates; an alternate term is Hippocratic fingers. Clubbing may be hereditary, but, more often, it is acquired and is associated with a number of infectious, inflammatory, neoplastic, and vascular disorders. Although it may occur with several lung diseases (ie, lung cancer, tuberculosis, lung abscess, bronchiectasis, cystic fibrosis, idiopathic pulmonary fibrosis), clubbing is a distinctly unusual finding in chronic obstructive pulmonary disease and should prompt a search for other causes (particularly lung cancer). Pathophysiology The pathogenesis of clubbing is poorly understood; however, increased blood flow to the distal phalanges appears to play a role. Histopathologic studies have not shown an increase in the number or length of blood vessels; therefore, local vasodilation is probably responsible. Clubbing results from the proliferation of the connective tissue of the distal digits. Histologic findings correspond to the duration and severity of disease. Early findings include dermal fibroplasia. Later, mucoid degeneration of the ground substances occurs. Severe long-standing clubbing is characterized by interstitial edema and infiltration by plasma cells and lymphocytes. Connective-tissue proliferation and interstitial edema results in a characteristic spongy quality to the proximal nail fold—as if the nail were floating in the nail bed. Clinical findings Clinical examination findings may correlate with the severity of clubbing. The earliest finding may be the Schamroth sign, first described by a South African physician when he developed clubbing secondary to infective endocarditis. In healthy individuals, a rhombus is observed when the dorsal surfaces of the right and left second fingers are placed against each other with the distal interphalangeal (DIP) joints and distal aspect of the nails touching. An absence of this rhombus is consistent with clubbing. The accuracy of this sign has not been examined. The phalangeal depth ratio (see Media File 2) appears to be the simplest, validated bedside test. If the depth of the finger at the proximal nail fold equals or exceeds that of the DIP joint (a ratio greater than or equal to 1), clubbing may be diagnosed. Clubbed fingers also exhibit changes in nail-fold angles. Lovibond first observed that in healthy individuals, the nail exits the nail bed at an angle of approximately 160°. The Lovibond (also called profile) angle approaches 180° in persons with clubbing. The hyponychial angle is formed by a line joining the dorsal surface of the DIP joint with the dorsal surface of the proximal nail fold and a line joining the dorsal surface of the proximal nail fold with the hyponychium (thickened skin under the distal end of the nail). A normal hyponychial angle is approximately 180°; mean values of approximately 195° have been obtained in children with clubbing secondary to cystic fibrosis. LUNG CANCER, HYPERTROPHIC OSTEOARTHROPATHY, AND SUPERIOR VENA CAVA SYNDROMESection 4 of 11
Lung cancerAlthough breast and prostate cancer are more prevalent in women and men, respectively, lung cancer remains the leading cause of cancer death in both sexes. Cutaneous, subcutaneous, or superficial lymph node metastases are relatively uncommon events in the pathobiology of lung cancer. However, these metastases may be encountered in clinical practice because of the high prevalence of lung cancer. Of patients treated for lung cancer at a large referral center, 17% were noted to have either a skin metastasis or an involved superficial lymph node, but only in rare instances did the skin nodule lead to the diagnosis of lung cancer. The most common sites for cutaneous metastases were the chest, neck, and scalp. The cutaneous nodules were solitary and fast growing but lacked a characteristic gross appearance (variable size, color, and consistency). The superficial lymph node metastases were typically "rock" hard, tender, and fixed to the adjacent skin and were most often found in the supraclavicular (mimicking the Virchow node seen in gastrointestinal malignancy) and anterior cervical lymph node chains, ipsilateral to the primary tumor. See Media File 3. Of the non–small cell histologic subtypes of lung cancer, adenocarcinoma had the greatest propensity to spread to the skin, while the large cell subtypes rarely did so. Small cell cancer, which typically metastasizes early in the course of disease, may also metastasize to the skin. Hypertrophic osteoarthropathyClubbing associated with periostitis and arthritis is termed hypertrophic osteoarthropathy (HOA). HOA was described independently by E. von Bamberger in 1889 and Pierre Marie in 1890. HOA includes 2 distinctive clinical conditions. Primary HOA Primary HOA, also termed pachydermoperiostosis, is an autosomal dominant condition usually diagnosed in the second decade (typically around puberty), characterized by coarsening of the facial features as a result of sebaceous hyperplasia, cutis verticis gyrata, hyperhidrosis (especially of palms and soles), and severe seborrhea. Arthritis is notably absent in persons with pachydermoperiostosis. Secondary HOA Secondary HOA is most frequently associated with lung cancer. Symptoms of HOA commonly precede the diagnosis of underlying lung cancer by several months. HOA is more frequently associated with non–small cell lung cancer, particularly squamous cell carcinoma and adenocarcinoma. Other conditions less frequently associated with secondary HOA include lung abscess, mesothelioma, primary biliary cirrhosis, ulcerative colitis, and Hodgkin disease. Clinical findings Patients often report bone or joint pain. Periostitis typically affects the distal portions of the long bones of the leg or forearm, and bony tenderness is found in these areas during the physical examination. Patients who present with acute polyarthritis may initially be misdiagnosed with rheumatoid arthritis (RA). Similar to RA, the knees, ankles, wrists, metacarpophalangeal joints, and proximal interphalangeal joints are most often affected. In contrast to RA, the rheumatoid factor is rarely positive and synovial joint fluid is noninflammatory (ie, <500 leukocytes/µL, with few neutrophils and a low protein concentration). Plain radiographs of symptomatic bones reveal periostitis in persons with well-established disease. However, early in the disease course, plain radiograph findings may be normal (approximately 50% of the bone must be affected before changes are evident on plain radiographs). Bone scanning is a more sensitive modality to detect periostitis in the early stages because it relies on increased osteoblast activity. Differential diagnoses The differential diagnosis of HOA includes clubbing, pachydermoperiostosis, thyroid acropachy, and acromegaly. Thyroid acropachy is seen in approximately 1% of patients with Graves disease and is usually accompanied by exophthalmos and pretibial myxedema. Patients with thyroid acropachy also may have clubbing and periostitis, although the periostitis is usually limited to the hands and feet, and the joints are spared. Acromegaly is a result of a growth hormone excess and results in enlargement of the hands and feet in all patients. Overgrowth of bone and cartilage results in thick, blunted digits (without clubbing). Arthritis may occur but is due to degeneration of joints; radiographs reveal increased soft tissue along with tufting of the distal phalanges. Treatment HOA responds dramatically to treatment of the underlying neoplasm, particularly if curative resection is possible. Partial symptomatic relief of pain related to periostitis or arthritis may be achieved with aspirin or nonsteroidal anti-inflammatory drugs. Superior vena cava syndromeThe superior vena cava (SVC) arises from the confluence of the right and left brachiocephalic veins. It travels approximately 7 cm before emptying the venous drainage of the upper body (ie, head, neck, arms, chest) into the right atrium. SVC syndrome occurs when blood flow through the SVC is impeded, either by extrinsic compression or intraluminal narrowing. A 1992 review by Hirschmann and Raugi underscored the importance of observing and interpreting the dermatologic findings in this condition. Many patients with this syndrome were initially diagnosed by dermatologists after referral for evaluation of a rash on the upper chest. Malignant neoplasm is by far the most common cause. Thrombosis of the SVC is becoming more common in critically ill, hospitalized patients because of the widespread use of intravascular devices (eg, central venous catheters, pulmonary artery catheters, pacemakers). Etiology Lung cancer is the most common cause of SVC syndrome. Because of the tendency to arise centrally (near the SVC), small cell carcinoma is the most common histology. Lymphomas, specifically the non-Hodgkin variety, are the next most common etiology. Other, much less common etiologies for SVC syndrome include mediastinal fibrosis, most commonly secondary to histoplasmosis, and retrosternal goiter. Clinical findings Markedly dilated veins or venules (often in vertical parallel clusters on the chest above the level of the heart) constitute the earliest cutaneous finding in SVC syndrome (see Media File 4). These result from increased collateral flow through the subcutaneous vessels of the chest wall. The engorged vessels shrink or disappear with relief of the obstruction of blood flow. Other signs that may result from the venous congestion include hoarseness, facial edema, plethora of the head and neck, conjunctival suffusion, and proptosis. Treatment SVC syndrome has traditionally been viewed as an oncologic emergency that requires immediate radiation treatment, even before tissue diagnosis. Most experts now believe that emergent radiotherapy is rarely indicated and may in fact make diagnosis and future treatment difficult. Exceptions include patients with life-threatening laryngeal or cerebral edema or tracheal compression resulting in respiratory compromise. Initial conservative management, including elevation of the head of the bed and supplemental oxygen, often provides symptomatic improvement and allows sufficient time to obtain a tissue diagnosis. Diuretics and corticosteroids are often used, but their efficacy is not well established. Anticoagulants and thrombolytics may be used in the setting of intravascular thrombosis. Intraluminal stenting can also be considered for patients who require rapid symptomatic improvement. SARCOIDOSISSection 5 of 11
Sarcoidosis is a multisystem granulomatous disease of unknown etiology. Almost all patients have involvement of the respiratory tract at some point during the disease course. Patients often present with dyspnea, nonproductive cough, and pleuritic chest pain. Nonspecific symptoms, such as fatigue, malaise, anorexia, weight loss, and low-grade fevers, are also common. The disease is often first suspected when bilateral hilar adenopathy without parenchymal disease is discovered on a chest radiograph (see Media File 5). Chest radiographs may also show diffuse parenchymal disease with or without hilar adenopathy. The pattern of parenchymal disease is typically interstitial but also may be nodular. Pleural effusions are uncommon. Importantly, radiographic findings may not correlate with clinical findings. Pulmonary function testing typically reveals a restrictive pattern of disease with reduced lung volumes and decreased diffusion capacity. Cutaneous involvement occurs in approximately a quarter to one third of patients but seldom is the sole manifestation of disease. The presence of cutaneous sarcoidosis should prompt physicians to undertake a thorough evaluation. Cutaneous manifestations are described as either specific (histologically revealing typical noncaseating granulomas) or nonspecific. Etiology Many theories have been proposed for the etiology of sarcoidosis, but none is universally accepted. Antigen exposure in genetically predisposed individuals is widely believed to be the common pathophysiologic pathway. Many believe that Mycobacterium subspecies are the causative agents, but definitive evidence is lacking. Although sarcoidosis may affect persons in any racial or ethnic group, it is more common in African Americans, Scandinavian populations, and Irish populations. Pathophysiology The pathologic hallmark of the disease is the noncaseating granuloma. Granulomas in the skin have the same histologic appearance as granulomas in the lung parenchyma. In patients with specific cutaneous manifestations, a skin biopsy may obviate the need for more invasive and expensive procedures. Other laboratory test results (eg, elevated serum angiotensin-converting enzyme levels, hypercalcemia, hypercalciuria) may be obtained, but sarcoidosis remains a diagnosis of exclusion. Specific cutaneous manifestations Papular sarcoidosis is the most common specific cutaneous manifestation of sarcoidosis. Lesions are red/brown-to-purple dermal papules and are typically seen on the face or extensor surfaces of the arms or legs. Papular sarcoidosis is usually associated with the acute forms of sarcoidosis and suggests a good overall prognosis. Lupus pernio is the most characteristic lesion of sarcoidosis and is often seen in older African American women. Lesions are violaceous, indurated plaques on the face and nose that resemble those seen in persons with an acute cold injury (hence the name pernio). The cosmetic effects of lupus pernio may be particularly distressing to patients and may prompt them to seek medical attention. Unfortunately, patients with lupus pernio tend to have a more indolent disease course with a poorer overall prognosis than those with papular sarcoidosis. Systemic disease manifestations, including pulmonary fibrosis specifically affecting the upper respiratory tract, chronic uveitis, and bone cysts, are also more common. Subcutaneous nodules may occur at any time during the disease course but most often are a manifestation of late-stage, chronic sarcoidosis. The subcutaneous nodules are firm, mobile, nontender, red/brown to purple, and 0.5-2 cm in diameter; they usually occur on the extremities and trunk. They do not offer any clue to the prognosis. Cutaneous plaques may be round or oval, annular or arciform, and red/brown to purple (see Media File 6). The dermal infiltrates may be strikingly thick and tend to occur on the trunk and limbs. Plaques are a common manifestation of sarcoidosis and are associated with persistent pulmonary disease. Preexisting well-healed scars from prior trauma or surgery may become red or purple and indurated as they are infiltrated with granulomas. Scar sarcoidosis may be seen in the acute phase, along with erythema nodosum (EN), but more often is associated with chronic disease. Nonspecific cutaneous manifestations EN lesions are poorly circumscribed, tender, reddish nodules that resemble bruises and are located in the anterior tibial region. EN is associated with a number of conditions, mostly infectious. A 1998 retrospective study by Cribier et al found sarcoidosis to be the second most common identifiable etiology for EN. The lesions tend to erupt in crops and often occur in young white females. Sarcoidosis-related EN in combination with fever and polyarthritis is termed Lofgren syndrome. The prognosis of Lofgren syndrome is good, with more than 80% of patients experiencing spontaneous resolution in less than 2 years. Extracutaneous manifestations Cardiac involvement occurs in only 5-10% of patients but is associated with a poor prognosis. Most patients have rhythm or conduction disturbances noted on electrocardiograms. Anterior uveitis usually manifests as photophobia and blurred vision. Approximately 5% of patients have nervous system involvement; unilateral cranial nerve VII palsy is the most common manifestation. Liver infiltration is relatively common but is rarely clinically relevant. A cholestatic picture with elevated alkaline phosphatase levels and mild elevations of serum transaminase levels is typical. Treatment Corticosteroids remain the mainstay of treatment for sarcoidosis and are generally reserved for patients with symptomatic pulmonary disease, hypercalcemia, uveitis, and neurologic or cardiac involvement. Severe, disfiguring cutaneous involvement may rarely require systemic corticosteroid therapy. Many other agents have been used (eg, topical corticosteroids, antimalarials, thalidomide, allopurinol, methotrexate) in the treatment of cutaneous sarcoid but none has been well studied. WEGENER GRANULOMATOSIS, CHURG-STRAUSS SYNDROME, AND RELAPSING POLYCHONDRITISSection 6 of 11
Wegener granulomatosisWegener granulomatosis is a systemic vasculitis of unknown etiology that may affect any organ but most commonly involves the upper and lower respiratory tracts and the kidneys. Cutaneous manifestations are relatively common but usually not diagnostic. Cutaneous findings Histopathologic findings fall into the 4 distinct categories: (1) necrotizing vasculitis, (2) granulomatous vasculitis, (3) lymphomatoid vasculitis, or (4) necrotizing palisading granuloma. Skin findings are noted in approximately 10% of patients at presentation and develop in approximately 50% throughout the course of disease. Oral mucosal lesions are also relatively common. Purpuric lesions, specifically palpable purpura, are most common. Palpable purpura is usually found on the lower extremities. The second most frequent skin finding is necrotic ulcers, also typically found on the lower extremities. These lesions may be mistaken for pyoderma gangrenosum, but they lack the classic heaped-up border. Other cutaneous findings include subcutaneous nodules, papules, petechiae, and hemorrhagic bullae. Up to 60% of patients may have oral mucosal disease; nonspecific oropharyngeal ulcer is the most common finding. A rare and unusual gingivitis is considered pathognomonic of Wegener granulomatosis and is described as gingival hyperplasia with red petechiae and a friable granular appearance. Patients report pain and bleeding from the gums. Some evidence suggests that patients with cutaneous lesions have a higher incidence of renal involvement and that this may serve as an important prognostic indicator. Clinical findings The classic clinical triad of findings for Wegener granulomatosis is upper respiratory tract involvement, lower respiratory tract involvement, and renal disease. Ear, nose, and throat involvement is present in more than 70% of patients at presentation, and lung involvement is present in approximately 50% of patients. Ear, nose, and throat findings include sinusitis, epistaxis, nasal septal perforation or saddle nose, or otitis. Pulmonary disease may manifest as a nonproductive cough with or without hemoptysis and dyspnea. Less commonly, patients present with diffuse alveolar hemorrhage and renal failure; diagnostic confusion may arise in such cases (ie, Goodpasture syndrome vs Wegener granulomatosis). The finding of antineutrophil cytoplasmic antibodies (ANCAs) with diffuse cytoplasmic staining rather than antiglomerular basement (anti-GBM) antibodies is useful to distinguish these between the 2 entities. Two types of (ANCAs) may be identified by indirect immunofluorescence. The diffuse cytoplasmic form of ANCA is characterized by granular staining with interlobular accentuation and is commonly detected in patients with Wegener granulomatosis. In most cases, the identified antigen is serine proteinase 3 (PR3). The test has a sensitivity of approximately 90% during active disease and a specificity of approximately 90%. Titers of cytoplasmic ANCA also correlate well with disease activity and may disappear in remission. The perinuclear ANCA staining pattern is associated with antibodies that bind primarily to myeloperoxidase. The perinuclear ANCA pattern is much less disease specific and may be seen in association with many different vasculitides, including polyarteritis nodosa (PAN), Churg-Strauss syndrome, microscopic polyarteritis, and Wegener granulomatosis. The classic chest radiographic finding in persons with Wegener granulomatosis is cavitary nodules, but less distinct parenchymal infiltrates or nodules are also commonly observed. See Media File 7 for a radiograph of a person with Wegener granulomatosis. Bronchoscopy is frequently performed and may reveal tracheobronchial stenosis, focal or diffuse hemorrhage, or inflammatory or ulcerative lesions. Biopsy samples of these lesions usually reveal an inflammatory infiltrate but rarely reveal vasculitis. The presence of renal disease defines classic or generalized Wegener granulomatosis. Patients who lack renal involvement are said to have limited Wegener granulomatosis. Treatment Standard therapy involves the combination of corticosteroids and cyclophosphamide and has dramatically improved long-term survival. Untreated disease typically progresses rapidly and is nearly uniformly fatal (approximately 90% mortality rate at 2 y). Most patients can expect complete remission of their disease with treatment, although relapses remain common. Because of the toxicities related to long-term administration of cyclophosphamide, a less toxic immunosuppressive regimen with similar efficacy is desirable. Churg-Strauss syndromeChurg-Strauss syndrome is a rare multisystemic disorder that primarily affects the lungs, peripheral nervous system, and skin. Churg and Strauss' initial description of the syndrome in 1951 required that histologic criteria be met to establish the diagnosis. Clinical and laboratory criteria have been more difficult to establish. Asthma, peripheral blood eosinophilia, and extrapulmonary vasculitis affecting 2 or more organs are cardinal clinical manifestations of Churg-Strauss syndrome. The disease typically begins as allergic rhinitis in a patient without a prior atopic history. Mild asthma, a nearly invariable part of the clinical picture, then develops and progressively worsens. Cardiac disease, although less frequent than reactive airway disease, accounts for a substantial percentage of mortality. Cardiomyopathy results from endocardial and myocardial infiltration with granulomas or coronary arteritis. Mononeuritis multiplex, similar to that seen with PAN, may be seen in as many as 70% of patients and usually involves the peroneal nerve with resultant foot drop. Another feature shared with PAN is gastrointestinal disease. As many as 60% of patients may have abdominal pain, which most often results from mesenteric ischemia secondary to mesenteric vasculitis. Chest radiographs typically reveal characteristic bilateral, patchy, and nonsegmental fleeting infiltrates. Other less common intrathoracic manifestations include pleural and pericardial effusions. Laboratory findings include striking peripheral eosinophilia, usually more than 1.5 X 109 cells/L. Eosinophilia is also common in patients with asthma; however, the magnitude is greater in patients with the Churg-Strauss syndrome. Eosinophils are the dominant cell in pleural or pericardial effusions. Other laboratory findings may include a positive perinuclear ANCA serology and elevated immunoglobulin E levels. Cutaneous findings As many as 70% of patients with Churg-Strauss syndrome have cutaneous manifestations. A variety of lesions may be seen, the most common of which are palpable purpura, subcutaneous nodules, urticarial rashes, and livedo reticularis. Palpable purpura usually involves the lower extremities and is common but nonspecific. Biopsy of these lesions reveals leukocytoclastic vasculitis. The most distinctive lesions are tender subcutaneous nodules occurring on the limbs and scalp, or, less frequently, on the trunk. Biopsies of these lesions reveal an eosinophilic granuloma, characterized by a necrotic core surrounded by densely packed eosinophils. Treatment Patients with Churg-Strauss syndrome respond well to high-dose corticosteroids. After several weeks, the steroids may be tapered based on the patient's symptoms. Some patients do not respond adequately to steroids and require more aggressive immunosuppression. Azathioprine and cyclophosphamide are often used in such cases. Relapsing polychondritisRelapsing polychondritis is a rare multisystemic disorder of unknown etiology. The disease is characterized by recurrent, and typically progressive, bouts of inflammation of cartilaginous structures. The diagnosis is based on clinical findings' no specific test can be used for diagnosis of this disease. Relapsing polychondritis predominantly affects whites in the fifth and sixth decades of life. A number of associated conditions have been reported, including several systemic vasculitides (ie, Wegener granulomatosis, PAN, Churg-Strauss syndrome), collagen-vascular diseases (ie, RA, systemic lupus erythematosus, reactive arthritis [Reiter syndrome], scleroderma, Sjögren syndrome), hematologic diseases (ie, leukemia, lymphoma), thyroid disease, ulcerative colitis, primary biliary cirrhosis, and diabetes. Clinical findings External ear pain and inflammation is a frequent presentation and an almost universal finding at some point during the disease course. Patients are routinely misdiagnosed with an infectious process (ie, auricular cellulitis). The key to diagnosis is the physical examination. Only the cartilaginous portion of the external ear is affected in persons with relapsing polychondritis, and thus, the ear lobe is spared. Other cutaneous findings (as reported by Trentham and Le) include leukocytoclastic vasculitis, EN, and erythema multiforme. Most features of the disease share the common pathophysiologic pathway of cartilaginous inflammation. Saddle-nose deformity may occur as a result of destruction of the cartilage in the nasal septum (see Media File 8). A nonerosive nondeforming arthritis affecting both large and small peripheral joints occurs in as many as 85% of patients. Ocular inflammation is extremely common and may affect any part of the eye. Destruction of cartilage in the laryngotracheal tree occurs in half to two thirds of patients and is the most feared disease manifestation. Respiratory distress results from destruction of the cartilaginous tracheal rings and subsequent tracheal collapse or from inflammation of cartilaginous tissue and subsequent tracheal edema. Some patients may develop recurrent pneumonia because of insufficient clearance of secretions. Aortic root dilatation and subsequent aortic valve regurgitation is a less common, but potentially morbid, intrathoracic manifestation. Treatment Corticosteroids are the mainstay of therapy. Tracheal collapse has traditionally been treated with tracheostomy, but this may be insufficient without continuous positive airway pressure. The development of metallic tracheal stents offers an alternative approach to this complication. PULMONARY ARTERIOVENOUS MALFORMATIONS AND ALPHA-1 ANTITRYPSIN DEFICIENCYSection 7 of 11
Pulmonary arteriovenous malformationsPulmonary arteriovenous malformations (PAVMs) are abnormal communications between pulmonary arteries and pulmonary veins. Most PAVMs are congenital. Approximately 70-80% of patients with a PAVM have hereditary hemorrhagic telangiectasia (HHT), also termed Osler-Weber-Rendu syndrome. HHT is a caused by a mutation in the endoglin (HHT type 1) or ALK1 (HHT type 2) gene; the phenotypic expression of these 2 mutations is indistinguishable. PAVMs are typically multiple, bilateral, and located in the lower lobes. Most persons with PAVMs have HHT; however, only approximately 10% of patients with HHT have PAVMs. HHT affects multiple organ systems, including the skin, mucosal membranes, lungs, brain, and gastrointestinal tract. Recurrent epistaxis is frequently the earliest symptom and occurs in nearly all patients. Other extrapulmonary manifestations include notoriously difficult to manage gastrointestinal hemorrhages from arteriovenous malformations and central nervous system complications (eg, stroke, brain abscess) caused by paradoxical embolization through the PAVM. Clinical findings Pulmonary symptoms of PAVM result from the right-to-left shunting of blood. Patients may report fatigue, dyspnea, and platypnea (dyspnea worsens while upright and improves when supine). Although less common, hemoptysis is often the first symptom to prompt patients to seek medical attention. Physical examination may reveal nonspecific signs (eg, clubbing, cyanosis, occasional pulmonary bruit). Orthodeoxia (ie, decreased oxygenation while upright and improved when supine) is the physical examination correlate of platypnea and is the result of gravitational redistribution of blood flow to the lung bases (thus through the PAVM) while the patient is upright. Chest radiographs may reveal oval or round, homogeneous, nodular lesions several millimeters to several centimeters in diameter in the lung bases. A clinical diagnosis of HHT can be established by examination of the skin. Telangiectasias of the face, hands, feet, chest, lips, tongue, and oral, nasal, and conjunctival mucosa become apparent in the second and third decades (see Media File 9). Lesions typically range from one to several millimeters in diameter, but they may grow much larger. Three-dimensional reconstructions of serial sections of skin biopsy specimens have established the nature of these lesions as arteriovenous malformations. Treatment The treatment of PAVMs consists of surgical resection or obliteration of the shunt by catheter embolization with coils (see Media File 10). Alpha-1 antitrypsin deficiencySynthesized by hepatocytes, alpha-1 antitrypsin is the principal serum protease inhibitor. A single amino acid substitution results in a profound structural alteration of the enzyme, preventing its release from hepatocytes. Although perceived as a rare disease, newborn screening studies estimate that the prevalence of the homozygous phenotype ZZ may be as high as 1 case per 3000 births in the United States. Clinical findings The major organ systems affected by alpha-1 antitrypsin deficiency are the lungs, liver, and skin. The effects are the result of unchecked proteinase activity that damages the parenchyma of these organs. Emphysema is the primary pulmonary manifestation of alpha-1 antitrypsin deficiency. Patients with alpha-1 antitrypsin deficiency develop severe fixed airflow obstruction at an early age, usually before age 50 years. Cigarette smoking greatly accelerates the progression of disease. Alpha-1 antitrypsin deficiency–associated emphysema occurs predominantly in the lung bases, as opposed to the upper lobe predominance seen in smoking-induced emphysema. Diagnostic testing includes quantitative tests (ie, determination of plasma alpha-1-antitrypsin levels) and qualitative tests (commonly referred to as phenotyping). Approximately 10% of children with the ZZ phenotype develop clinically significant liver disease; adults with cirrhosis of unknown etiology are occasionally found to express this phenotype. Cutaneous manifestations Recurrent ulcerative, necrotizing panniculitis is a rare, extrapulmonary manifestation alpha-1 antitrypsin deficiency. The panniculitis is often preceded by trauma and is often mistaken for bacterial cellulitis. Crops of painful, red or violaceous, subcutaneous nodules occur on the trunk and proximal extremities. The nodules subsequently ulcerate and spontaneously drain a clear-to-yellow serosanguineous fluid, which may be oily as a result of liquefaction of fat. Biopsy specimens reveal lymphohistiocytic infiltrate with areas of acute neutrophilic panniculitis. Culture results for bacteria, fungi, and mycobacteria are routinely negative. Treatment Intravenous infusions of purified alpha-1 antitrypsin, corticosteroids, dapsone, and doxycycline have been used to treat the panniculitis. FAT EMBOLISM SYNDROMESection 8 of 11
Fat embolism syndrome is a systemic disease that follows trauma and fractures of the long bones or pelvis. Fat embolism (without systemic manifestations) may also occur in association with a variety of other conditions, including hemoglobinopathies (sickle cell anemia), pancreatitis, bone marrow transplantation, and sepsis, and as a surgical complication of total hip and knee arthroplasty. Clinical findings The classic triad of findings in persons with fat embolism syndrome includes respiratory distress, altered mental status, and thrombocytopenia, typically occurring within 24-72 hours of long bone or pelvic fracture. The classic cutaneous manifestation (occurring in approximately one third to one half of patients) is an evanescent petechial eruption on nondependent portions of the body (ie, upper chest, neck, axillae, conjunctivae). The finding is frequently overlooked but is an early key to diagnosis. Subsequent respiratory decompensation may range from mild hypoxemia to respiratory failure requiring intubation. Chest radiographs frequently show progressive, diffuse bilateral interstitial and alveolar infiltrates that are described as a "snowstorm pattern." Neurologic manifestations vary widely but typically are reversible upon resolution of the respiratory component. Pathophysiology The pathophysiology of respiratory compromise is uncertain but is believed to result either from direct mechanical occlusion of the pulmonary capillaries by fat droplets released from the bone marrow or from the biochemical toxicity of these droplets once they are hydrolyzed to free fatty acids by lung lipases. Distinguishing between fat embolism (the presence of fat globules in peripheral circulation) and fat embolism syndrome (a systemic disorder that may be life threatening) is critical. Fat embolism occurs in as many as 90% of patients with long bone fractures; fat embolism syndrome is much less common (estimated rate of 1-2%). TreatmentThe mortality rate for patients with fat embolism syndrome is substantial (approximately 5-10%), and therapy is primarily supportive. Some experts believe that early fracture fixation and corticosteroids may be beneficial. The prognosis is primarily dependent on the degree of respiratory compromise. YELLOW NAIL SYNDROMESection 9 of 11
First described in 1964 by Samman and White, yellow nail syndrome consists of the triad of yellow slow-growing nails, lymphedema, and pleural effusions. The disease is due to lymphatic impairment; lymphangiograms show a decreased number of hypoplastic and dilated lymphatics. Clinical findings The nails in persons with yellow nail syndrome are the most obvious clue to diagnosis. In addition to the yellow (occasionally green) discoloration, the nails are characteristically thick and dystrophic. Additional nail changes include onycholysis, transverse ridging on an otherwise smooth surface, and loss of the cuticle. Women with yellow nail syndrome often color their nails with polish. The growth rate of fingernails in patients with this syndrome is less than 0.5 mm/wk (approximately half the normal rate). The lymphedema involves the lower extremities to a greater extent than the upper extremities and is symmetrical and nonpitting. Pleural effusion is the classic pulmonary manifestation of yellow nail syndrome and usually the last in the triad to develop. The exudative effusions are characterized by a high concentration of protein (>3 g/dL) and lactate dehydrogenase (>200 IU/L), with fewer than 1000 leukocytes/µL, mostly lymphocytes. Effusions may be unilateral or bilateral and often recur after initial drainage. Other respiratory manifestations include bronchiectasis, recurrent pneumonias, bronchitis, and sinusitis. Treatment Treatment of pleural effusions may warrant pleurodesis (ie, instillation of a sclerosing agent into the pleural space), pleuroperitoneal shunts, or pleurectomy. MULTIMEDIASection 10 of 11
REFERENCESSection 11 of 11
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