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Original source: eMedicine Medscape

Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/ARVC)

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/ARVC) is an inherited cardiomyopathy characterized by structural and functional abnormalities in the right ventricle (RV) resulting in ventricular arrhythmias. ^[1] This primary disease of heart muscle leads to fibrofatty replacement of the RV and the subepicardial region of the left ventricle. It is an important cause of sudden cardiac death (SCD) in young adults, accounting for 11% of all cases and 22% of cases among athletes. ^{[2, 3]} (See the image below.)

ARVD was first described in 1977 and was included in the World Health Organization (WHO) classification of cardiomyopathies in 1996. ^[4] Since then, there have been significant advances in the understanding of its etiopathogenesis, diagnosis, and management. ^[5]

The structural abnormalities in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/ARVC) result from the fatty infiltration and fibrosis of the RV myocardium. This leads to progressive RV dilatation and dysfunction. The left ventricle (LV) is less commonly involved, and the septum is relatively spared. ^[6] However, in a cohort of 200 probands, Sen-Chowdhry et al found that LV involvement may even precede the onset of significant RV dysfunction. ^[7] The prognosis is worse in patients with LV involvement. ^[8]

The mechanisms for myocardial loss include the following:

Apoptosis (programmed cell death)

Inflammation, enhanced fibrosis, and loss of function

Fatty replacement of myocardium

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/ARVC) is an inherited disorder, as it is already present in the fetus. Familial cases account for 30-90% of cases. ^[9] In other cases, it may result from an acquired etiology such as viral infection (myocarditis) or unidentified inheritance. It is also likely that patients with a genetic predisposition are more likely to develop myocarditis.

The disease manifests more frequently in active individuals, when mechanical sheer stress can cause cell membrane damage, inflammation, and fibrosis in genetically predisposed RV.

ARVD is considered a genetic disorder, as most cases are familial, and there is geographical clustering. The most common pattern of inheritance is autosomal dominance, with a variable penetrance ranging from 20-35% of family members. ^{[10, 11]} People living in the Veneto region of Italy have a higher penetrance. The autosomal-recessive (Naxos disease) pattern of inheritance is localized to the Greek island of Naxos and is associated with palmoplantar keratosis and wooly hair. The genetic mutation occurs on chromosome 17q21, and penetrance is almost 100%. ^{[12, 13]}

Genetic abnormalities in ARVD are located on chromosomes 1, 2, 3, 6, 7, 10, 12, and 14. There is no single unique genetic abnormality, posing a challenge in evaluation of patients and families with suspected ARVD. The responsible genes include plakoglobin (JUP), desmoplakin (DSP), plakophilin-2 (PKP2), desmoglein-2 (DSG2), desmocollin-2 (DSC2), and others. ^{[14, 15, 16]} In some cases, mutation in the SCN5A gene may cause dysfunction in the cardiac voltage-gated sodium channel (Na_v1.5), resulting in cardiomyopathy. ^[17]

The Heart Rhythm Society and the European Heart Rhythm Association published a consensus statement on genetic testing for cardiomyopathies. ^[18]

Because of the diagnostic challenge, the exact incidence and prevalence of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/ARVC) remains unknown, as clinically silent cases may go unrecognized. ^[19] It is estimated that it affects 1 in 2000 to 1 in 5000 in the general population ^{[19, 20]} and is more common in individuals of Greek and Italian origin. ^[21]

In a cohort of 100 patients from the United States, the median age at presentation was 26 years, and 51% were males. The median time to diagnosis was one year from the initial presentation, and median survival in the entire cohort was 60 years. ^[22]

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/ARVC) is an important cause of sudden cardiac death in young adults, accounting for 11% of all cases and 22% of cases among athletes.

The prognosis is worse in patients with left ventricular (LV) involvement.

Pregnancy is mostly well tolerated, but Hodes et al found 13% of pregnancies in women with ARVD/ARVC were complicated by ventricular arrhythmias and 5% by heart failure. ^[23]

Sustained ventricular arrhythmias are more common in men, and they have significantly abnormal electrocardiograms. ^[24]

Cardiac magnetic resonance imaging (CMRI) to assess tissue characteristics and a 5-year risk score model has been proposed. ^[25] In a study of 140 patients with ARVC, CMRI was normal in 14 patients who did not have any major events. LV-dominant abnormalities were found in 16 patients (12%). ^[26] Isolated RV involvement was seen in 41% patients and biventricular involvement was seen in 37% patients. LV involvement had a worse prognosis than RV involvement alone. However, the risk score model underestimated the risk in those who had LV involvement. ^[26]

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Gyanendra K Sharma, MD, FACC, FASE Professor of Medicine and Radiology, Director, Adult Echocardiography Laboratory, Section of Cardiology, Medical College of Georgia at Augusta University

Gyanendra K Sharma, MD, FACC, FASE is a member of the following medical societies: American Association of Cardiologists of Indian Origin, American Association of Physicians of Indian Origin, American College of Cardiology, American Society of Echocardiography, Society for Cardiovascular Magnetic Resonance, Society of Cardiovascular Computed Tomography

Disclosure: Nothing to disclose.

Jose M Dizon, MD Professor of Clinical Medicine, Clinical Electrophysiology Laboratory, Division of Cardiology, Columbia University College of Physicians and Surgeons; Attending Physician, Department of Medicine, New York-Presbyterian/Columbia University Medical Center

Jose M Dizon, MD is a member of the following medical societies: American College of Cardiology, Heart Rhythm Society

Disclosure: Nothing to disclose.

Allen Patrick Burke, MD Professor, Department of Pathology, University of Maryland School of Medicine; Pulmonary and Cardiovascular Pathologist, University of Maryland Medical Center; Urologic Pathologist, Joint Pathology Center

Allen Patrick Burke, MD is a member of the following medical societies: Pulmonary Pathology Society, Society for Cardiovascular Pathology, United States and Canadian Academy of Pathology

Disclosure: Nothing to disclose.

Jagdish Butany, MBBS, MS, FRCPC Professor of Pathology, University of Toronto Faculty of Medicine; Consultant Cardiovascular Pathologist, Director, Autopsy Service, Director, Division of Pathology, Department of Laboratory Medicine and Pathobiology, Toronto Medical Laboratories, Toronto General Hospital, University Health Network

Jagdish Butany, MBBS, MS, FRCPC is a member of the following medical societies: Canadian Cardiovascular Society, Society for Cardiovascular Pathology, United States and Canadian Academy of Pathology

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Edwards Life Sciences.

I sincerely thank Dr. Vernon Barnes (Georgia Preventive Institute, GHSU, Augusta) for a thorough review of the manuscript. I would also thank Mr. Chinmaya Sharma for providing the editorial assistance in the manuscript preparation.

Source: eMedicine Medscape

This article is provided for informational purposes only and is not a substitute for professional medical advice. Always consult with a qualified healthcare provider for diagnosis and treatment.

Original source: eMedicine Medscape

Ashman Phenomenon

Ashman phenomenon is an aberrant ventricular conduction due to a change in QRS cycle length, and it can be seen in any supraventricular arrhythmia. ^[1]  It is gnerally described as a wide QRS complex that follows a short R-R interval preceded by a long R-R interval. ^[2]

In 1947, Gouaux and Ashman ^[2] reported that in atrial fibrillation, when a relatively long cycle was followed by a relatively short cycle, the beat with a short cycle often has right bundle-branch block (RBBB) morphology, ^{[3, 4]}  although left BBB (LBBB) morphology can also occur. ^{[1, 2]} This causes diagnostic confusion with premature ventricular complexes (PVCs) or, rarely, ventricular tachycardia. ^[1] If a sudden lengthening of the QRS cycle occurs, the subsequent impulse with a normal or shorter cycle length may be conducted with aberrancy.

No geographic variations occur. ^[2] Ashman phenomenon is related to the underlying pathology of the cardiac conduction system and is a common electrocardiographic (ECG) finding in clinical practice.

No treatment is needed for isolated complexes. ^[2] Treat the underlying cardiac condition as appropriate.

As Ashman phenomenon is simply an ECG manifestation of the underlying condition, not a disease process itself, morbidity and mortality is related to the underlying condition (often, atrial fibrillation). ^[2]

Ashman phenomenon is an intraventricular conduction abnormality caused by a change in the heart rate. This is dependent on the effects of rate on the electrophysiological properties of the heart and can be modulated by metabolic and electrolyte abnormalities and the effects of drugs.

The aberrant conduction depends on the relative refractory period of the components of the conduction system distal to the atrioventricular node. The refractory period depends on the heart rate. Action potential duration (ie, refractory period) changes with the R-R interval of the preceding cycle; shorter duration of action potential is associated with a short R-R interval and prolonged duration of action potential is associated with a long R-R interval. A longer cycle lengthens the ensuing refractory period, and, if a shorter cycle follows, the beat ending it is likely to be conducted with aberrancy.

Aberrant conduction results when a supraventricular impulse reaches the His-Purkinje system while one of its branches is still in the relative or absolute refractory period. This results in slow or blocked conduction through this bundle branch and delayed depolarization through the ventricular muscles, causing a bundle-branch block configuration (ie, wide QRS complex) on the surface ECG, in the absence of bundle-branch pathology. A RBBB pattern is more common than a left bundle-branch block (LBBB) pattern because of the longer refractory period of the right bundle branch.

Several studies have questioned the sensitivity and specificity of the long-short cycle sequence. Aberrant conduction with a short-long cycle sequence has also been documented.

Conditions causing an altered duration of the refractory period of the bundle branch or the ventricular tissue cause Ashman phenomenon. These conditions are commonly observed in atrial fibrillation, atrial tachycardia, and atrial ectopy.

A study by Sardar et al indicated that dofetilide, a delayed rectifier potassium current (I_Kr) blocker used to treat atrial fibrillation, can promote the development of Ashman phenomenon, possibly through a reverse use-dependence effect associated with prolongation of the ventricular refractory period. ^[5] The study involved 10 patients with atrial fibrillation who underwent dofetilide loading, receiving 250-500 micrograms of the drug every 12 hours. The investigators found that the total number of Ashman beats rose from 42±24 prior to the administration dofetilide to 93±79 after the first dose of the drug and 133±101 after the second dose. ^[5]

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Marriott HJL, Sandler JA. Criteria, old and new, for differentiating between ectopic ventricular beats and aberrant ventricular conduction in the presence of atrial fibrillation. Prog Cardiovasc Dis. 1966. 9:18.

Gulamhusein S, Yee R, Ko PT, Klein GJ. Electrocardiographic criteria for differentiating aberrancy and ventricular extrasystole in chronic atrial fibrillation: validation by intracardiac recordings. J Electrocardiol. 1985 Jan. 18(1):41-50. [QxMD MEDLINE Link].

Roger Freedman, MD Director of Clinical Cardiology, Professor, Department of Internal Medicine, Division of Cardiology, University of Utah School of Medicine

Roger Freedman, MD is a member of the following medical societies: American College of Cardiology, American College of Physicians, American Heart Association, Heart Rhythm Society, Phi Beta Kappa, Sigma Xi, The Scientific Research Honor Society

Disclosure: Received grant/research funds from St. Jude Medical for other; Received consulting fee from St. Jude Medical for consulting; Received ownership interest from St. Jude Medical for other; Received grant/research funds from Boston Scientific for other; Received consulting fee from Boston Scientific for consulting; Received grant/research funds from Medtronic for other; Received consulting fee from Medtronic for consulting; Received consulting fee from Sorin for consulting.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Brian Olshansky, MD, FESC, FAHA, FACC, FHRS Professor Emeritus of Medicine, Department of Internal Medicine, University of Iowa College of Medicine

Brian Olshansky, MD, FESC, FAHA, FACC, FHRS is a member of the following medical societies: American College of Cardiology, American Heart Association, Cardiac Electrophysiology Society, European Society of Cardiology, Heart Rhythm Society

Disclosure: Nothing to disclose.

Jeffrey N Rottman, MD Professor of Medicine, Department of Medicine, Division of Cardiovascular Medicine, University of Maryland School of Medicine; Cardiologist/Electrophysiologist, University of Maryland Medical System and VA Maryland Health Care System

Jeffrey N Rottman, MD is a member of the following medical societies: American Heart Association, Heart Rhythm Society

Disclosure: Nothing to disclose.

Russell F Kelly, MD Assistant Professor, Department of Internal Medicine, Rush Medical College; Chairman of Adult Cardiology and Director of the Fellowship Program, Cook County Hospital

Russell F Kelly, MD is a member of the following medical societies: American College of Cardiology

Disclosure: Nothing to disclose.

Ram C Sharma, MD, MRCP Assistant Professor of Medicine, Division of Cardiovascular Medicine, Department of Internal Medicine, University of Louisville

Ram C Sharma, MD, MRCP is a member of the following medical societies: American Academy of Sleep Medicine, American College of Cardiology, and Royal College of Physicians of the United Kingdom

Disclosure: Nothing to disclose.

Source: eMedicine Medscape

This article is provided for informational purposes only and is not a substitute for professional medical advice. Always consult with a qualified healthcare provider for diagnosis and treatment.

Original source: eMedicine Medscape

Accelerated Idioventricular Rhythm

Accelerated idioventricular rhythm (AIVR) was first described by Sir Thomas Lewis in 1910. ^[1] AIVR is currently defined as an enhanced ectopic ventricular rhythm with at least 3 consecutive ventricular beats, which is faster than normal intrinsic ventricular escape rhythm (≤40 bpm), but slower than ventricular tachycardia (at least 100-120 bpm). ^{[1, 2]}  Importantly, there is potential rate overlap between AIVR and some slow ventricular tachycardia. AIVR should not be diagnosed solely based on ventricular rate; context is important. Other characteristics of AIVR are helpful for its correct diagnosis (see Differentials).

AIVR is generally a transient rhythm, rarely causing hemodynamic instability and rarely requiring treatment. However, misdiagnosis of AIVR as slow ventricular tachycardia or complete heart block can lead to inappropriate therapies with potential complications. AIVR is often a clue to certain underlying conditions, like myocardial ischemia-reperfusion, digoxin toxicity, and cardiomyopathies. ^{[3, 4, 5]}

In most cases, the mechanism of AIVR appears to be related to the enhanced automaticity in His-Purkinje fibers and/or myocardium, ^[6] sometimes accompanied with vagal excess and decreased sympathetic activity. ^[7] Ischemia, reperfusion, hypoxia, drugs, and electrolyte abnormalities can all accelerate the phase 4 action potential depolarization rates in His-Purkinje fiber and myocardium, leading to faster spontaneous cell depolarization (enhanced automaticity). ^[8] When the enhanced automaticity in His-Purkinje fiber or myocardium surpasses that of sinus node, AIVR manifests as the dominant rhythm of the heart. Sinus bradycardia may facilitate the appearance of AIVR.

Under certain conditions such as acute ischemia and digoxin toxicity, triggered activity has been suggested as the mechanism for AIVR. ^[9]

Most AIVRs originate from a single focus. Occasionally, in patients with acute myocardial ischemia and myocarditis, AIVR can originate from multiple foci. ^{[10, 11]} The ventricular rate of AIVR is generally between 40 and 100-120 bpm.

Usually, AIVR is hemodynamically well tolerated due to its slow ventricular rate. It is self-limited and resolves as sinus rate surpasses the rate of AIVR. Rarely, AIVR can degenerate into ventricular tachycardia or ventricular fibrillation. In patients with severe myocardial dysfunction, AIVR may lead to hemodynamic instability due to the loss of AV synchrony or the ventricular rate.

Clinically, AIVR has been best studied in patients with acute ST-elevation myocardial infarction (STEMI). In the thrombolysis era, AIVR was noted to be a marker of reperfusion. ^[12] However, not all patients with reopened coronary artery have AIVR. In patients with acute myocardial infarction treated with primary percutaneous coronary intervention, the reported incidence of AIVR varied significantly, raging from 15-50%, depending on methods of monitoring. ^{[8, 13, 14]}

Studies in patients with STEMI treated with primary percutaneous coronary intervention support that AIVR is a marker of occluded coronary artery reopening, but is not necessarily a marker for complete reperfusion. In fact, AIVR seems to be associated with more extensive myocardial damage and delayed microvascular reperfusion, ^[13] although the mortality rates are similar in patients with and without AIVR.

Accelerated idioventricular rhythm (AIVR) can occur in people with and without apparent heart diseases. ^[15] The most common cause of AIVR is myocardial ischemia-reperfusion. Other causes include the following:

Congenital heart disease ^[17]

Dilated cardiomyopathy ^[5]

Drugs: Digoxin toxicity, ^[4] cocaine toxicity, ^[18] and various anesthesia agents ^{[19, 20, 21]}

Beach et al reported on the case of a boy aged 4 years who appeared to have developed AIVR from the administration of inhaled albuterol to treat his status asthmaticus. ^[23]

The true prevalence of accelerated idioventricular rhythm (AIVR) is unknown.

The true prevalence of AIVR is unknown.

Hingorani et al analyzed drug-free ambulatory ECG recordings from 1273 healthy volunteers (who had normal screening ECGs) from 22 phase 1 studies that were analyzed in a core ECG laboratory. AIVR was observed in 0.3% of healthy volunteers, and other types of arrhythmias were observed in a higher percentage of healthy volunteers. The results suggest that some cardiac arrhythmias may be due to chance in early-phase studies. ^[24]

No racial preponderance exists, and men and women are equally affected.

No age predilection exists.

Accelerated idioventricular rhythm (AIVR) is a mostly self-limiting rhythm and typically has a benign prognosis when AIVR rather than a slow(ed) VT is the true underlying entity. ^[25] The prognosis of patients with AIVR largely depends on their underlying conditions.

In general, AIVR does not significantly affect the patients’ morbidity and mortality, which reflects that of the underlying condition causing the AIVR. In a very small retrospective observation study, AIVR was found to be associated with a lower 7-day survival rate in postresuscitation patients. ^[22]

Rarely, AIVR can result in hemodynamic instability, especially in patients with severe cardiomyopathy. Rarely, AIVR may degenerate into ventricular tachycardia or ventricular fibrillation.

Reassure patients that accelerated idioventricular rhythm (AIVR) per se does not significantly affect their prognosis. Educate patients that some of the underlying etiologies for AIVR should be treated accordingly.

For patient education, see the Heart Health Center as well as Heart Rhythm Disorders.

Grimm W, Marchlinski FE. Accelerated idioventricular rhythm and bidirectional ventricular tachycardia. In: Zipes DP, Jalife J, eds. Cardiac Electrophysiology: From Cell to Bedside. 4th ed. Philadelphia: Saunders; 2004. 700-4.

Jakkoju A, Jakkoju R, Subramaniam PN, Glancy DL. Accelerated idioventricular rhythm. Proc (Bayl Univ Med Cent). 2018 Oct. 31(4):506-7. [QxMD MEDLINE Link]. [Full Text].

Goldberg S, Greenspon AJ, Urban PL, et al. Reperfusion arrhythmia: a marker of restoration of antegrade flow during intracoronary thrombolysis for acute myocardial infarction. Am Heart J. 1983 Jan. 105(1):26-32. [QxMD MEDLINE Link].

Castellanos A, Azan L, Bierfield J, Myerburg RJ. Digitalis-induced accelerated idioventricular rhythms: revisited. Heart Lung. 1975 Jan-Feb. 4(1):104-10. [QxMD MEDLINE Link].

Grimm W, Hoffmann J, Menz V, Schmidt C, Muller HH, Maisch B. Significance of accelerated idioventricular rhythm in idiopathic dilated cardiomyopathy. Am J Cardiol. 2000 Apr 1. 85(7):899-904, A10. [QxMD MEDLINE Link].

Castellanos A Jr, Lemberg L, Arcebal AG. Mechanisms of slow ventricular tachycardias in acute myocardial infarction. Dis Chest. 1969 Dec. 56(6):470-6. [QxMD MEDLINE Link].

Bonnemeier H, Ortak J, Wiegand UK, et al. Accelerated idioventricular rhythm in the post-thrombolytic era: incidence, prognostic implications, and modulating mechanisms after direct percutaneous coronary intervention. Ann Noninvasive Electrocardiol. 2005 Apr. 10(2):179-87. [QxMD MEDLINE Link].

Hasin Y, Rogel S. Ventricular rhythms in acute myocardial infarction. Cardiology. 1976. 61(3):195-207. [QxMD MEDLINE Link].

Holzmann M, Reutter FW. [Accelerated idioventricular rhythm with second degree v.a.-block and reentry (author’s transl)]. Z Kardiol. 1977 Jan. 66(1):52-4. [QxMD MEDLINE Link].

Sclarovsky S, Strasberg B, Fuchs J, et al. Multiform accelerated idioventricular rhythm in acute myocardial infarction: electrocardiographic characteristics and response to verapamil. Am J Cardiol. 1983 Jul. 52(1):43-7. [QxMD MEDLINE Link].

Nakagawa M, Hamaoka K, Okano S, Shiraishi I, Sawada T. Multiform accelerated idioventricular rhythm (AIVR) in a child with acute myocarditis. Clin Cardiol. 1988 Dec. 11(12):853-5. [QxMD MEDLINE Link].

Hohnloser SH, Zabel M, Kasper W, Meinertz T, Just H. Assessment of coronary artery patency after thrombolytic therapy: accurate prediction utilizing the combined analysis of three noninvasive markers. J Am Coll Cardiol. 1991 Jul. 18(1):44-9. [QxMD MEDLINE Link].

Terkelsen CJ, Sorensen JT, Kaltoft AK, et al. Prevalence and significance of accelerated idioventricular rhythm in patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention. Am J Cardiol. 2009 Dec 15. 104(12):1641-6. [QxMD MEDLINE Link].

Delewi R, Remmelink M, Meuwissen M, et al. Acute haemodynamic effects of accelerated idioventricular rhythm in primary percutaneous coronary intervention. EuroIntervention. 2011 Aug. 7(4):467-71. [QxMD MEDLINE Link].

Chiale PA, Sicouri SJ, Elizari MV, Rosenbaum MB. Chronic idiopathic idioventricular tachycardia caused by slow response automaticity. Pacing Clin Electrophysiol. 1987 Nov. 10(6):1371-7. [QxMD MEDLINE Link].

Hsu PC, Lin TH, Su HM, Voon WC, Lai WT, Sheu SH. Frequent accelerated idioventricular rhythm in a young male of Buerger’s disease with acute myocardial infarction. Int J Cardiol. 2008 Jul 4. 127(2):e64-6. [QxMD MEDLINE Link].

Nakagawa M, Yoshihara T, Matsumura A, Fusaoka T, Hamaoka K. Accelerated idioventricular rhythm in three newborn infants with congenital heart disease. Chest. 1993 Jul. 104(1):322-3. [QxMD MEDLINE Link].

Jonsson S, O’Meara M, Young JB. Acute cocaine poisoning. Importance of treating seizures and acidosis. Am J Med. 1983 Dec. 75(6):1061-4. [QxMD MEDLINE Link].

Marret E, Pruszkowski O, Deleuze A, Bonnet F. Accelerated idioventricular rhythm associated with desflurane administration. Anesth Analg. 2002 Aug. 95(2):319-21, table of contents. [QxMD MEDLINE Link].

Chhabra A, Subramaniam R. Sudden appearance of idioventricular rhythm during inhalational induction with halothane in a child with congenital cataract. J Postgrad Med. 2008 Oct-Dec. 54(4):337-9. [QxMD MEDLINE Link].

Sato K, Miyamae Y, Kan M, et al. Accelerated idioventricular rhythm following intraoral local anesthetic injection during general anesthesia. Anesth Prog. 2021 Dec 1. 68(4):230-4. [QxMD MEDLINE Link]. [Full Text].

Tsai MS, Huang CH, Chen HR, et al. Postresuscitation accelerated idioventricular rhythm: a potential prognostic factor for out-of-hospital cardiac arrest survivors. Intensive Care Med. 2007 Sep. 33(9):1628-32. [QxMD MEDLINE Link].

Beach C, Marcuccio E, Beerman L, Arora G. Accelerated idioventricular rhythm in a child with status asthmaticus. Pediatrics. 2015 Aug. 136(2):e527-9. [QxMD MEDLINE Link].

Hingorani P, Karnad DR, Rohekar P, Kerkar V, Lokhandwala YY, Kothari S. Arrhythmias seen in baseline 24-hour holter ECG recordings in healthy normal volunteers during phase 1 clinical trials. J Clin Pharmacol. 2016 Jul. 56(7):885-93. [QxMD MEDLINE Link].

Gangwani MK, Nagalli S. Idioventricular Rhythm. StatPearls [Internet]. 2022 Jan. [QxMD MEDLINE Link]. [Full Text].

Hoffman I, Zolnick MR, Bunn C. Transient post-reperfusion left bundle branch block and accelerated idioventricular rhythm with paradoxical QRS narrowing. J Electrocardiol. 2014 Sep-Oct. 47(5):705-7. [QxMD MEDLINE Link].

Elizari MV, Conde D, Baranchuk A, Chiale PA. Accelerated idioventricular rhythm unmasking the brugada electrocardiographic pattern. Ann Noninvasive Electrocardiol. 2015 Jan. 20(1):91-3. [QxMD MEDLINE Link].

Nayereh G Pezeshkian, MD Assistant Professor of Medicine, Division of Cardiology and Electrophysiology, University of California, Davis, School of Medicine

Nayereh G Pezeshkian, MD is a member of the following medical societies: American College of Cardiology, American Society of Echocardiography, Heart Rhythm Society

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Ronald J Oudiz, MD, FACP, FACC, FCCP Professor of Medicine, University of California, Los Angeles, David Geffen School of Medicine; Director, Liu Center for Pulmonary Hypertension, Division of Cardiology, LA Biomedical Research Institute at Harbor-UCLA Medical Center

Ronald J Oudiz, MD, FACP, FACC, FCCP is a member of the following medical societies: American College of Cardiology, American College of Chest Physicians, American College of Physicians, American Heart Association, American Thoracic Society

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Actelion, Bayer, Gilead, United Therapeutics<br/>Received research grant from: Actelion, Arena, Gilead, GSK, Liquidia, Reata, United Therapeutics<br/>Received income in an amount equal to or greater than $250 from: Actelion, Complexa, Gilead, Medtronic, Reata, United Therapeutics.

Jeffrey N Rottman, MD Professor of Medicine, Department of Medicine, Division of Cardiovascular Medicine, University of Maryland School of Medicine; Cardiologist/Electrophysiologist, University of Maryland Medical System and VA Maryland Health Care System

Jeffrey N Rottman, MD is a member of the following medical societies: American Heart Association, Heart Rhythm Society

Disclosure: Nothing to disclose.

Robert E Fowles, MD Clinical Professor of Medicine, University of Utah College of Medicine; Consulting Staff, Intermountain Medical Center and LDS Hospital; Director and Consulting Staff, Department of Cardiology, Salt Lake Clinic

Robert E Fowles, MD is a member of the following medical societies: American College of Cardiology, American College of Physicians, and American Heart Association

Disclosure: Nothing to disclose.

Rakesh K Sharma, MD, FACC Adjunct Associate Professor of Medicine and Cardiology; University of Arkansas for Medical Sciences, Medical Center of South Arkansas

Disclosure: Nothing to disclose.

Vibhuti N Singh, MD, MPH, FACC, FSCAI Clinical Assistant Professor, Division of Cardiology, University of South Florida College of Medicine; Director, Cardiology Division and Cardiac Catheterization Lab, Chair, Department of Medicine, Bayfront Medical Center, Bayfront Cardiovascular Associates; President, Suncoast Cardiovascular Research

Vibhuti N Singh is a member of the following medical societies: American College of Cardiology, American College of Physicians, American Heart Association, American Medical Association, and Florida Medical Association

Disclosure: Nothing to disclose.

Source: eMedicine Medscape

This article is provided for informational purposes only and is not a substitute for professional medical advice. Always consult with a qualified healthcare provider for diagnosis and treatment.

Original source: eMedicine Medscape

Acquired Angioedema Due to C1 Inhibitor Deficiency

Acquired angioedema (AAE) due to acquired C1-inhibitor (C1-INH) deficiency (C1-INH-AAE) is a rare disorder caused by acquired consumption of C1-INH. It is clinically characterized by recurrent episodes of nonpitting asymmetric edema of the face, lips, tongue, limbs, and genitals; severe abdominal pain due to edema of the gastrointestinal mucosa; and life-threatening edema of the upper respiratory tract. It is not associated with urticaria and is not an immunoglobulin E (IgE)‒mediated process.

Acquired angioedema was first described by Caldwell et al in 1972. The three key elements that initially characterized acquired angioedema were acquired deficiency of C1-INH, hyperactivation of the classic pathway of human complement, and recurrent angioedema symptoms. ^[1]

Two distinct syndromes are described below. Both types of acquired angioedema (AAE) without urticaria are characterized by painless, nonpruritic, nonpitting swelling of the skin. They are classified into 2 forms: acquired angioedema type I (AAE-I) and acquired angioedema type II (AAE-II).

Acquired angioedema type I is associated with other diseases, most commonly B-cell lymphoproliferative disorders. Acquired angioedema type II is an autoimmune process defined by the presence of an autoantibody directed against the C1 inhibitor molecule (C1-INH).

Go to Angioedema, Pediatric Angioedema, Acute Angioedema, and Hereditary Angioedema for complete information on this topic.

C1-INH is a multifunctional serine protease inhibitor that is normally present in high concentrations in plasma. It is primarily synthesized by hepatocytes. Its synthesis is up-regulated by interferon-gamma, interleukin 6, and interleukin 1. Androgens may also have a role in stimulating C1-INH synthesis. The major functions of C1-INH include inhibition of activated C1r and C1s, inhibition of activated Hageman factor (XIIa), and inhibition of activated kallikrein, the contact system protease that cleaves kininogen and releases bradykinin. ^[2]

Bradykinin is an important mediator involved in tissue permeability and vascular dilatation. Its biological effect is exerted through activation of bradykinin B2 receptors, which are expressed in the membranes of endothelial and smooth muscles cells. Elevated blood bradykinin levels are found during clinical flares in patients with angioedema.  Other kinins may also be pathogenic. ^[2]

The specific trigger responsible for inducing the release of these vasoactive peptides is unclear. Activation of factor XII (Hageman factor) may be secondary to phospholipid release from damaged or apoptotic cells and may be important in the generation of bradykinin from endothelial activation. This hypothesis encompasses the role of illness or tissue injury in the generation of bradykinin.

Supporting the importance of bradykinin in acquired angioedema, vascular permeability has been shown to increase in mice deficient in C1-INH, but not in mice with a deficiency in both C1-INH and the bradykinin B2 receptor. ^[3] The precise pathophysiology of acquired angioedema type I remains to be defined. C1-INH levels diminish as a result of its increased catabolism and excessive activation of the classic complement pathway.

Although the current classification of acquired angioedema is being readdressed, in acquired angioedema type I, the associated disorders (usually lymphoproliferative malignancies) produce complement-activating factors, idiotype/anti-idiotype antibodies, or other immune complexes that destroy C1-INH function. Neoplastic lymphatic tissue has been found to play an active role in the consumption of C1-INH and the complement components of the classic pathway.

The most commonly associated malignancy, B-cell lymphoma, has shown that anti-idiotypic antibody attached to immunoglobulin on the surface of B-cells causes C1-INH deficiency. Increased consumption of C1q followed by C2 and C4 results in subsequent release of vasoactive peptides that act on postcapillary venules.

In acquired angioedema type II, a normal 105-kd C1-INH molecule is synthesized in adequate amounts but, because of an unknown event, a subpopulation of B cells secretes autoantibodies to the C1-INH molecule. This autoantibody, which may be of any of the major immunoglobulin classes, binds to the reactive center of C1-INH. After binding to C1-INH and altering its structure, its regulatory capacity is diminished or abrogated.

In all reported cases of C1-INH deficiency caused by an autoantibody, C1-INH circulates in the blood in a form that has been cleaved by target proteases from its native molecule to a 95-kd fragment. Because of the higher affinity of the autoantibody for native C1-INH, the 95-kd antibody/C1-INH complex dissociates, and the freed antibody can bind to another native C1-INH molecule, further depleting C1-INH.

The distinction between acquired angioedema type I and acquired angioedema type II may be difficult to make at times, and it is imperative to stress that overlap does occur. For instance, cases of monoclonal gammopathy of undetermined significance (MGUS) have shown the monoclonal immunoglobulin itself to be the C1-INH antibody. Patients with acquired angioedema type I may initially present with autoantibodies to C1-INH, or the autoantibodies may develop as the disease progresses. While measuring antibodies against C1-INH is useful, groups have also developed assays that can measure the antibody against C1-INH in complex with C1-INH. In one study, anti–C1-INH antibodies were detected in 9 of 20 patients, while the complex between anti–C1-INH and C1-INH was found in 18 of 20, suggesting that there could be greater numbers of patients with anti–C1-INH antibodies than is seen when measuring antibody alone. ^[4]

Acquired angioedema type I is most frequently associated with B-cell lymphoproliferative disease. To date, only three reports of a T-cell lymphoma associated with acquired angioedema type I have been documented. ^[5]

Other associated disorders have included the following:

Chronic lymphocytic leukemia

Waldenström macroglobulinemia

Essential cryoglobulinemia

Infection with Helicobacter pylori or Echinococcus granulosis

Acquired angioedema type II is not associated with any specific disorder but rather is characterized by the presence of autoantibody directed against C1-INH. Most of these antibodies work by binding the epitopes around the reactive center of INH. ^[6] However, the occasional existence of features of both acquired angioedema type I and acquired angioedema type-II has been noted, most notably with a MGUS.

A 2016 study reported that 33% of patients presenting with acquired angioedema had or would develop non-Hodgkin lymphoma, in particular marginal zone lymphoma. Of the studied patients, 62.5% were diagnosed with non-Hodgkin lymphoma at the onset of angioedema or up to 7 years later. Patients presenting with acquired angioedema and C1-INH deficiency should be monitored regularly for the development of malignancy. ^[7]

In addition to associations with MGUS, C1-INH–deficient AAE has also been reported in monoclonal gammopathy of renal significance (MGRS). ^[8] One case of acquired angioedema with C1-INH deficiency state was identified in association with liver transplantation. The status of the liver donor was unknown, but it is speculated that the donor may have been C1-INH deficient. Another case of acquired angioedema was reported with acute upper airway angioedema in association with the local anesthetic articaine.

Acquired angioedema is rare. Only approximately 150 cases have been reported in the medical literature worldwide.

Persons of any race can be affected by acquired angioedema. Men and women are equally affected.

The onset of acquired angioedema is most common after the fourth decade of life, whereas the usual onset of hereditary acquired angioedema (HAE) is in the second decade.

The prognosis for patients with acquired angioedema is variable, and, in most cases, it depends on control of the underlying disorder. However, even with appropriate treatment of the underlying disease, patients may be free of symptoms only temporarily. Additionally, some patients who have had their underlying disease treated will be free of symptoms related to angioedema but will continue to have biochemical abnormalities. ^[9]

Compared with the general population, patients with acquired angioedema have a higher incidence of B-cell malignancies. Patients with acquired angioedema and a concurrent diagnosis of monoclonal gammopathy of undetermined significance (MGUS) do not have an increased risk for progression to malignancy compared with patients with a sole diagnosis of MGUS.

Although mortality may occur because of laryngeal edema, it is more likely due to the complications of the associated disorder.

For patient education information, see the Allergy Center and Hives and Angioedema.

Caldwell JR, Ruddy S, Schur PH, Austen KF. Acquired C1 inhibitor deficiency in lymphosarcoma. Clin Immunol Immunopathol. 1972. 1:39-52.

Caballero T, Baeza ML, Cabañas R, et al. Consensus statement on the diagnosis, management, and treatment of angioedema mediated by bradykinin. Part I. Classification, epidemiology, pathophysiology, genetics, clinical symptoms, and diagnosis. J Investig Allergol Clin Immunol. 2011. 21(5):333-47; quiz follow 347. [QxMD MEDLINE Link].

Cugno M, Zanichelli A, Foieni F, Caccia S, Cicardi M. C1-inhibitor deficiency and angioedema: molecular mechanisms and clinical progress. Trends Mol Med. 2009 Feb. 15(2):69-78. [QxMD MEDLINE Link].

López-Lera A, Garrido S, Nozal P, Skatum L, Bygum A, Caballero T, et al. Serum complexes between C1INH and C1INH autoantibodies for the diagnosis of acquired angioedema. Clin Exp Immunol. 2019 Dec. 198 (3):341-350. [QxMD MEDLINE Link].

Bidkar VG, Rajan NR, Dasar S, Naik AS, Rao R. Acquired Angioedema: A Rare Manifestation of Angioimmunoblastic T Cell Lymphoma. Indian J Otolaryngol Head Neck Surg. 2019 Oct. 71 (Suppl 1):96-99. [QxMD MEDLINE Link].

Cugno M, Castelli R, Cicardi M. Angioedema due to acquired C1-inhibitor deficiency: a bridging condition between autoimmunity and lymphoproliferation. Autoimmun Rev. 2008 Dec. 8(2):156-9. [QxMD MEDLINE Link].

Castelli R, Wu MA, Arquati M, Zanichelli A, Suffritti C, Rossi D, et al. High prevalence of splenic marginal zone lymphoma among patients with acquired C1 inhibtor deficiency. Br J Haematol. 2016 Jan 5. [QxMD MEDLINE Link].

Roy S, Konala VM, Kyaw T, Chakraborty S, Naramala S, Gayam V, et al. An Unusual Case of Acquired Angioedema and Monoclonal Gammopathy of Renal Significance in a Middle-Aged Caucasian Female. J Investig Med High Impact Case Rep. 2020 Jan-Dec. 8:2324709620912096. [QxMD MEDLINE Link].

Banerji A, Sheffer AL. The spectrum of chronic angioedema. Allergy Asthma Proc. 2009 Jan-Feb. 30(1):11-6. [QxMD MEDLINE Link].

Cicardi M, Zanichelli A. Acquired angioedema. Allergy Asthma Clin Immunol. 2010 Jul 28. 6(1):14. [QxMD MEDLINE Link]. [Full Text].

Bouillet-Claveyrolas L, Ponard D, Drouet C, Massot C. Clinical and biological distinctions between type I and type II acquired angioedema. Am J Med. 2003 Oct 1. 115(5):420-1. [QxMD MEDLINE Link].

Engel R, Rensink I, Roem D, Brouwer M, Kalei A, Perry D, et al. ELISA to measure neutralizing capacity of anti-C1-inhibitor antibodies in plasma of angioedema patients. J Immunol Methods. 2015 Aug 28. [QxMD MEDLINE Link].

Bork K. An evidence based therapeutic approach to hereditary and acquired angioedema. Curr Opin Allergy Clin Immunol. 2014 Aug. 14 (4):354-62. [QxMD MEDLINE Link].

Zegers IH, Aaldering KN, Nieuwhof CM, Schouten HC. Non-myeloablative allogeneic stem cell transplantation: a new treatment option for acquired angioedema?. Neth J Med. 2015 Oct. 73 (8):383-5. [QxMD MEDLINE Link].

Bork K, Staubach-Renz P, Hardt J. Angioedema due to acquired C1-inhibitor deficiency: spectrum and treatment with C1-inhibitor concentrate. Orphanet J Rare Dis. 2019 Mar 13. 14 (1):65. [QxMD MEDLINE Link].

Gobert D, Paule R, Ponard D, Levy P, Frémeaux-Bacchi V, Bouillet L, et al. A nationwide study of acquired C1-inhibitor deficiency in France: Characteristics and treatment responses in 92 patients. Medicine (Baltimore). 2016 Aug. 95 (33):e4363. [QxMD MEDLINE Link].

Longhurst H, Cicardi M, Craig T, Bork K, Grattan C, Baker J, et al. Prevention of Hereditary Angioedema Attacks with a Subcutaneous C1 Inhibitor. N Engl J Med. 2017 Mar 23. 376 (12):1131-1140. [QxMD MEDLINE Link].

Levi M, Hack CE, van Oers MH. Rituximab-induced elimination of acquired angioedema due to C1-inhibitor deficiency. Am J Med. 2006 Aug. 119(8):e3-5. [QxMD MEDLINE Link].

Ziakas PD, Giannouli S, Psimenou E, Evangelia K, Tzioufas AG, Voulgarelis M. Acquired angioedema: a new target for rituximab?. Haematologica. 2004 Aug. 89(8):ELT13. [QxMD MEDLINE Link].

Klossowski N, Braun SA, von Gruben V, Losem C, Plewe D, Homey B, et al. [Acquired angioedema with C1-INH deficiency and accompanying chronic spontaneous urticaria in a patient with chronic lymphatic B cell leukemia]. Hautarzt. 2015 Sep 3. [QxMD MEDLINE Link].

Desai HG, Shah SS. Recurrent intestinal obstruction with acquired angio-oedema, due to C1-esterase inhibitor deficiency. J Assoc Physicians India. 2014 Jun. 62 (6):524-5. [QxMD MEDLINE Link].

Kaur R, Williams AA, Swift CB, Caldwell JW. Rituximab therapy in a patient with low grade B-cell lymphoproliferative disease and concomitant acquired angioedema. J Asthma Allergy. 2014. 7:165-7. [QxMD MEDLINE Link].

Dreyfus DH, Na CR, Randolph CC, Kearney D, Price C, Podell D. Successful rituximab B lymphocyte depletion therapy for angioedema due to acquired C1 inhibitor protein deficiency: association with reduced C1 inhibitor protein autoantibody titers. Isr Med Assoc J. 2014 May. 16 (5):315-6. [QxMD MEDLINE Link].

Levi M, Cohn D, Zeerleder S, Dziadzio M, Longhurst H. Long-term effects upon rituximab treatment of acquired angioedema due to C1-inhibitor deficiency. Allergy. 2019 Apr. 74 (4):834-840. [QxMD MEDLINE Link].

Rottem M, Mader R. Successful use of etanercept in acquired angioedema in a patient with psoriatic arthritis. J Rheumatol. 2010 Jan. 37(1):209. [QxMD MEDLINE Link].

Amanda T Moon, MD Clinical Assistant Professor of Dermatology, Children’s Hospital of Philadelphia

Amanda T Moon, MD is a member of the following medical societies: American Academy of Dermatology, Society for Pediatric Dermatology, Women’s Dermatologic Society

Disclosure: Nothing to disclose.

Melody Esmaeili MD Candidate, Perelman School of Medicine at the University of Pennsylvania

Disclosure: Nothing to disclose.

Ru’aa Al Harithy, MBBS, FRCPC Clinical Fellow in Laser and Cosmetic Dermatology, Division of Dermatology, SunnyBrook Hospital, University of Toronto Faculty of Medicine, Canada

Ru’aa Al Harithy, MBBS, FRCPC is a member of the following medical societies: American Academy of Dermatology, Canadian Dermatology Association

Disclosure: Nothing to disclose.

Warren R Heymann, MD Head, Division of Dermatology, Professor, Department of Internal Medicine, Rutgers New Jersey Medical School

Warren R Heymann, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

William D James, MD Emeritus Professor, Department of Dermatology, University of Pennsylvania School of Medicine

William D James, MD is a member of the following medical societies: American Academy of Dermatology, American Contact Dermatitis Society, Association of Military Dermatologists, Association of Professors of Dermatology, American Dermatological Association, Women’s Dermatologic Society, Medical Dermatology Society, Dermatology Foundation, Society for Investigative Dermatology, Washington DC Dermatological Society, Atlantic Dermatologic Society, Philadelphia Dermatological Society, Pennsylvania Academy of Dermatology, College of Physicians of Philadelphia

Disclosure: Received income in an amount equal to or greater than $250 from: Elsevier<br/>Served as a speaker for various universities, dermatology societies, and dermatology departments.

Paul Krusinski, MD Director of Dermatology, Fletcher Allen Health Care; Professor, Department of Internal Medicine, University of Vermont College of Medicine

Paul Krusinski, MD is a member of the following medical societies: American Academy of Dermatology, American College of Physicians, and Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Kathleen M Rossy, MD Staff Physician, Department of Dermatology, New York Medical College, Metropolitan Hospital

Disclosure: Nothing to disclose.

Robert A Schwartz, MD, MPH Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, University of Medicine and Dentistry of New Jersey-New Jersey Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi

Disclosure: Nothing to disclose.

Michael J Wells, MD Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine

Michael J Wells, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, and Texas Medical Association

Disclosure: Nothing to disclose.

Source: eMedicine Medscape

This article is provided for informational purposes only and is not a substitute for professional medical advice. Always consult with a qualified healthcare provider for diagnosis and treatment.

Original source: eMedicine Medscape

Allergic Contact Dermatitis

Individuals with allergic contact dermatitis (see the image below) may have persistent or relapsing dermatitis, particularly if the material(s) to which they are allergic is not identified or if they practice inappropriate skin care. The longer an individual has severe dermatitis, the longer, it is believed, that the dermatitis will take to resolve once the cause is identified.

See 5 Body Modifications and Piercing: Dermatologic Risks and Adverse Reactions, a Critical Images slideshow, to help recognize various body modifications and the related potential complications.

Acute allergic contact dermatitis is characterized by pruritic papules and vesicles on an erythematous base. Lichenified pruritic plaques may indicate a chronic form of the condition.

Individuals with allergic contact dermatitis typically develop the condition within a few days of exposure, in areas that were exposed directly to the allergen. Certain allergens (eg, neomycin), however, penetrate intact skin poorly; in such cases, the onset of dermatitis may be delayed for up to a week following exposure.

Individuals may develop widespread dermatitis from topical medications applied to leg ulcers or from cross-reacting systemic medications administered intravenously.

Intraoral metal contact allergy may result in mucositis that mimics lichen planus, which has an association with intraoral squamous cell carcinoma.

See Clinical Presentation for more detail.

Diagnostic studies for allergic contact dermatitis include the following:

Potassium hydroxide preparation and/or fungal culture: To exclude tinea; these tests are often indicated for dermatitis of the hands and feet

Patch testing: To identify external chemicals to which the person is allergic

Repeat open application test (ROAT): To determine whether a reaction is significant in individuals who develop weak or 1+ positive reactions to a chemical

Dimethylgloxime test: To determine whether a metallic object contains enough nickel to provoke allergic dermatitis

Skin biopsy: May help to exclude other disorders, particularly tinea, psoriasis, and cutaneous lymphoma

See Workup for more detail.

The definitive treatment for allergic contact dermatitis is the identification and removal of any potential causal agents; otherwise, the patient is at increased risk for chronic or recurrent dermatitis. Treatments also include the following:

Corticosteroids: Topical corticosteroids are the mainstay of treatment, although acute, severe allergic contact dermatitis, such as from poison ivy, often needs to be treated with a 2-week course of systemic corticosteroids

Topical immunomodulators (TIMs): Approved for atopic dermatitis, but they are also prescribed for cases of allergic contact dermatitis when they offer safety advantages over topical corticosteroids

Phototherapy: Administered to individuals with chronic allergic contact dermatitis that is not controlled well by topical corticosteroids; these patients may benefit from treatment with a combination of psoralen (a photosensitizer) and ultraviolet-A (PUVA)

Immunosuppressive agents: Chronic immunosuppressive agents are, in rare instances, used to treat recalcitrant cases of severe, chronic, widespread allergic contact dermatitis or severe hand dermatitis that prevents a patient from working or performing daily activities

Disulfiram: Occasionally, an individual who is highly allergic to nickel and has severe vesicular hand dermatitis will benefit from treatment with disulfiram (Antabuse); the drug has a chelating effect

See Treatment and Medication for more detail.

Allergic contact dermatitis (ACD) is a delayed type of induced sensitivity (allergy) resulting from cutaneous contact with a specific allergen to which the patient has developed a specific sensitivity. This allergic reaction causes inflammation of the skin manifested by varying degrees of erythema, edema, and vesiculation.

The term contact dermatitis sometimes is used incorrectly as a synonym for allergic contact dermatitis. Contact dermatitis is inflammation of the skin induced by chemicals that directly damage the skin (see Irritant Contact Dermatitis) and by specific sensitivity in the case of allergic contact dermatitis.

Jadassohn first described allergic contact dermatitis in 1895. He developed the patch test to identify the chemicals to which the patient was allergic. Sulzberger popularized patch testing in the United States in the 1930s. The Finn chamber method for patch testing was designed in the 1970s; these chambers consist of small metal cups, typically attached to strips of tape, filled with allergens dispersed in either petrolatum or water. The thin-layer rapid use epicutaneous (TRUE) test for patch testing became available in the United States in the 1990s.

The importance of specific substances as causes of allergic contact dermatitis varies with the prevalence of that substance in the environment. Mercury compounds once were significant causes of allergic contact dermatitis but rarely are used as topical medications and, currently, are uncommon as a cause of allergic contact dermatitis. Ethylenediamine, which was present in the original Mycolog cream, declined as a primary cause of allergic contact dermatitis once Mycolog cream was reformulated to no longer contain this allergen.

A detailed history, both before and after patch testing, is crucial in evaluating individuals with allergic contact dermatitis. Before patch testing, the history identifies potential causes of allergic contact dermatitis and the materials to which individuals are exposed that should be included in patch testing. After patch testing, the history determines the clinical significance of the findings. (See Clinical.)

Topical corticosteroids are the mainstay of treatment, while a variety of symptomatic treatments can provide short-term relief of pruritus. However, the definitive treatment of allergic contact dermatitis is the identification and removal of any potential causal agents; otherwise, the patient is at increased risk for chronic or recurrent dermatitis. (See Treatment.)

Go to Irritant Contact Dermatitis, Pediatric Contact Dermatitis, and Protein Contact Dermatitis for complete information on these topics.

Approximately 3000 chemicals are well documented as specific causes of allergic contact dermatitis.

Compounds must be less than 500 d for efficient penetration through the stratum corneum barrier, which is the water-impermeable outer layer of the skin. Small organic molecules that are chemically reactive (chemical sensitizers) bind with self-proteins to generate immunogenic neoantigens through a process termed haptenization. Although haptens can penetrate through intact skin, patients with certain disease states that impair barrier function (eg, leg ulcers, perianal dermatitis) have an increased risk of sensitization to topically applied medications and their vehicle components.

Many patients with atopic dermatitis or allergic contact dermatitis to nickel harbor a defective form of the filaggrin gene. ^[1] Filaggrin helps aggregate cytoskeletal proteins that form the cornified cell envelope. In its absence, the barrier is defective.

Prehaptens are chemicals that are not activated by host proteins, but instead require chemical transformation by oxidative derivatization by ambient or air oxidation to form hydroperoxide. Examples include certain fragrance materials and dyes used in hair coloring, such as para-phenylenediamine.

Haptens activate Toll-like receptors (TLRs) and activate innate immunity. The importance of hapten-mediated activation of innate immunity is highlighted by the clinical observation that the irritancy of chemicals (ie, the ability of these chemicals to cause grossly visible skin inflammation upon primary exposure) correlates with their ability to act as contact sensitizers and to induce acute contact dermatitis.

Haptens or haptenated self-proteins are recognized by innate immune mechanisms in the skin, and this leads to the elaboration of a number of proinflammatory mediators, including interleukin (IL)–1β. As a result, skin-resident dendritic cells (DCs) become activated. There are several populations of DCs. Langerhans cells are the only DC subtype in the epidermis. Like all skin-resident DCs, Langerhans cells efficiently acquire antigen in the periphery and migrate to regional lymph nodes where they present antigen to naïve and memory T cells. These DCs, which may have been directly haptenated or could have acquired haptenated proteins from their surroundings, migrate to skin-draining lymph nodes where they present peptides from haptenated proteins to activate memory and naïve T cells.

In the final step, hapten-induced inflammation recruits activated effector T cells back to the initial site of antigen encounter in the skin. The effector T cells release proinflammatory cytokines, such as interferon-γ, and promote the killing of haptenated cells, resulting in the development of the classic inflammatory rash seen in allergic contact dermatitis.

Keratinocytes are crucial for the development of allergic contact dermatitis. They constitute the vast majority of cells in the epidermis and form the anatomic barrier of the skin. Keratinocytes express most TLRs, and this allows them to respond to TLR4-triggering haptens, such as nickel. Keratinocytes are also a source of IL-10, an immunosuppressive cytokine that limits the extent of contact hypersensitivity

The initial sensitization typically takes 10-14 days from initial exposure to a strong contact allergen such as poison ivy. Some individuals develop specific sensitivity to allergens following years of chronic low-grade exposure; for example, sensitivity to chromate in cement can eventually develop in individuals with chronic irritant contact dermatitis resulting from the alkaline nature of cement. Once an individual is sensitized to a chemical, allergic contact dermatitis develops within hours to several days of exposure.

CD4⁺ CCR10⁺ memory T cells persist in the dermis after clinical resolution of allergic contact dermatitis.

Approximately 25 chemicals appear to be responsible for as many as one half of all cases of allergic contact dermatitis. These include nickel, preservatives, dyes, and fragrances.

Poison ivy (Toxicodendron radicans) is the classic example of acute allergic contact dermatitis in North America. Allergic contact dermatitis from poison ivy is characterized by linear streaks of acute dermatitis that develop where plant parts have been in direct contact with the skin.

Nickel is the leading cause of allergic contact dermatitis in the world. The incidence of nickel allergic contact dermatitis in North America is increasing; in contrast, new regulations in Europe have resulted in a decreasing prevalence of nickel allergy in young and middle-aged women. ^{[2, 3]}

Allergic contact dermatitis to nickel typically is manifested by dermatitis at the sites where earrings or necklaces (see the image below) containing nickel are worn or where metal objects (including the keypads of some cell phones ^[4] ) containing nickel are in contact with the skin.

Nickel may be considered a possible occupational allergen. Workers in whom nickel may be an occupational allergen primarily include hairdressers, retail clerks, caterers, domestic cleaners, and metalworkers. Individuals allergic to nickel occasionally may develop vesicles on the sides of the fingers (dyshidrotic hand eczema or pompholyx) from nickel in the diet.

Allergy to 1 or more chemicals in rubber gloves is suggested in any individual with chronic hand dermatitis who wears them, unless patch testing demonstrates otherwise. Allergic contact dermatitis to chemicals in rubber gloves typically occurs maximally on the dorsal aspects of the hand. Usually, a cutoff of dermatitis occurs on the forearms where skin is no longer in contact with the gloves. Individuals allergic to chemicals in rubber gloves may develop dermatitis from other exposures to the chemicals (eg, under elastic waistbands).

p-Phenylenediamine (PPD) is a frequent component of and sensitizer in permanent hair dye products and temporary henna tattoos ^[6] ; exposure in to it in hair dye products may cause acute dermatitis with severe facial edema. Severe local reactions from PPD may occur in black henna tattoos in adults and children. Epidemiologic data indicate that the median prevalence of positive patch test reactions to PPD among dermatitis patients is 4.3% (increasing) in Asia, 4% (plateau) in Europe, and 6.2% (decreasing) in North America. ^[7]

Individuals allergic to dyes and permanent press and wash-and-wear chemicals added to textiles typically develop dermatitis on the trunk, which occurs maximally on the lateral sides of the trunk but spares the vault of the axillae. Primary lesions may be small follicular papules or may be extensive plaques.

Individuals in whom this allergic contact dermatitis is suspected should be tested with a series of textile chemicals, particularly if routine patch testing reveals no allergy to formaldehyde. New clothing is most likely to provoke allergic contact dermatitis, since most allergens decrease in concentration in clothing following repeated washings.

Preservative chemicals added to cosmetics, moisturizers, and topical medications are major causes of allergic contact dermatitis (see the image below). The risk of allergic contact dermatitis appears to be highest to quaternium-15, followed by allergic contact dermatitis to isothiazolinones. Methylisothiazolinone is used as an individual preservative and may be a significant allergen. ^[8] Kathon CG is methylchloroisothiazolinone in combination with methylisothiazolinone.

Although parabens are among the most widely used preservatives, they are not a frequent cause of allergic contact dermatitis.

Schnuch et al estimated that preservatives found in leave-on topical products varied over 2 orders of magnitude in relative sensitization risk. ^[9]

Formaldehyde is a major cause of allergic contact dermatitis (see the image below). Certain preservative chemicals widely used in shampoos, lotions, other moisturizers, and cosmetics are termed formaldehyde releasers (ie, quaternium-15 [Dowicil 200], imidazolidinyl urea [Germall 115], and isothiazolinones ^[9] ). They are, in themselves, allergenic or may produce cross-sensitization to formaldehyde.

Individuals may develop allergy to fragrances. Fragrances are found not only in perfumes, colognes, aftershaves, deodorants, and soaps, but also in numerous other products, often as a mask to camouflage an unpleasant odor. Unscented products may contain fragrance chemicals used as a component of the product and not labeled as fragrance.

Individuals allergic to fragrances should use fragrance-free products. Unfortunately, the exact chemicals responsible for a fragrance in a product are not labeled. Four thousand different fragrance molecules are available to formulate perfumes. The fragrance industry is not required to release the names of ingredients used to compose a fragrance in the United States, even when individuals develop allergic contact dermatitis to fragrances found in topical medications.

Deodorants may be the most common cause of allergic contact dermatitis to fragrances because they are applied to occlude skin that is often abraded by shaving in women.

Massage and physical therapists and geriatric nurses are at higher risk of occupational allergic contact dermatitis to fragrances.

In the last decade, it has become clear that some individuals with chronic dermatitis develop allergy to topical corticosteroids. Most affected individuals can be treated with some topical corticosteroids, but an individual can be allergic to all topical and systemic corticosteroids. Budesonide and tixocortol pivalate are useful patch test corticosteroids for identifying individuals allergic to topical corticosteroids.

The risk of allergy to neomycin is related directly to the extent of its use in a population. The risk of allergy to neomycin is much higher when it is used to treat chronic stasis dermatitis and venous ulcers than when it is used as a topical antibiotic on cuts and abrasions in children. Assume that individuals allergic to neomycin are allergic to chemically related aminoglycoside antibiotics (eg, gentamicin, tobramycin). ^[12] Avoid these drugs both topically and systemically in individuals allergic to neomycin.

Avoid topical use of benzocaine. Benzocaine is included in most standard patch test trays. Individuals allergic to benzocaine may safely use or be injected with lidocaine (Xylocaine), which does not cross-react with benzocaine.

Many individuals complain of adverse reactions to sunscreens, but many of these individuals are not allergic to the sunscreen materials. They may be allergic to preservatives in these products or may have nonspecific cutaneous irritation from these products.

Occasionally, individuals develop photoallergic contact dermatitis. Allergic contact dermatitis may be accentuated by ultraviolet (UV) light, or patients may develop an allergic reaction only when a chemical is present on the skin and when the skin is exposed sufficiently to ultraviolet light A (UV-A; 320-400 nm).

Acrylates and methacrylates  ^{[13, 14]}

These agents are used in manufacturing, nail acrylics, and wound dressings, among other uses.

The National Health and Nutrition Examination Survey (NHANES) estimated the prevalence of contact dermatitis to be 13.6 cases per 1000 population, using physical examinations by dermatologists of a selected sample of patients. NHANES underreported the prevalence compared with the physical examination findings.

The National Ambulatory Medical Care Survey conducted in 1995 estimated 8.4 million outpatient visits to American physicians for contact dermatitis. This was the second most frequent dermatologic diagnosis. Of office visits to dermatologists, 9% are for dermatitis. At a student health center dermatology clinic, 3.1% of patients presented for allergic contact dermatitis, and 2.3% presented for irritant contact dermatitis.

The TRUE test Web site can provide accurate basic information on common allergens. The Contact Allergen Management Program is provided as a service to the American Contact Dermatitis Society (ACDS) members and is particularly valuable for allergens found in topical skin care products. The Contact Allergen Management Program (CAMP) database contains more than 8100 known ingredients cataloged in more than 5500 commercial skincare products and is available as a Smartphone application.

A Swedish study found that prevalence of allergic contact dermatitis of the hands was 2.7 cases per 1000 population. A Dutch study found that prevalence of allergic contact dermatitis of the hands was 12 cases per 1000 population.

No racial predilection exists for allergic contact dermatitis. Allergic contact dermatitis is more common in women than in men. This predominantly is a result of allergy to nickel, which is much more common in women than in men in most countries.

Allergic contact dermatitis may occur in neonates. In elderly individuals, the development of allergic contact dermatitis may be delayed somewhat, but the dermatitis may be more persistent once developed. Contact allergy to topical medicaments is more common in persons older than 70 years. ^[15]

The prognosis depends on how well the affected individual can avoid the offending allergen. ^[16]

Individuals with allergic contact dermatitis may have persistent or relapsing dermatitis, particularly if the material(s) to which they are allergic is not identified or if they continue to practice skin care that is no longer appropriate (ie, they continue to use harsh chemicals to wash their skin, they do not apply creams with ceramides or bland emollients to protect their skin).

The longer an individual has severe dermatitis, the longer it is believed it will take the dermatitis to resolve once the cause is identified.

Some individuals have persistent dermatitis following allergic contact dermatitis, which appears to be true especially in individuals allergic to chromates.

A particular problem is neurodermatitis (lichen simplex chronicus), in which individuals repeatedly rub or scratch an area initially affected by allergic contact dermatitis.

Death from allergic contact dermatitis is rare in the United States. Allergic contact dermatitis to the weed wild feverfew caused deaths in India when the seeds contaminated wheat shipments to India. This plant then became widespread and a primary cause of severe airborne allergic contact dermatitis.

Patients have the best prognosis when they are able to remember the materials to which they are allergic and how to avoid further exposures. Provide patients with as much information as possible concerning the chemical to which they are allergic, including all known names of the chemical. Web sites, Smartphone applications, standard textbooks, and the TRUE test kit contain basic information about the chemicals.

Susceptible individuals need to read the list of ingredients before applying cosmetic products to their skin, since preservative chemicals are used widely in consumer, medical, and workplace products. The same chemical may have different names when used for consumer or industrial purposes.

Provide pamphlets with color pictures of poison ivy to individuals allergic to the plant. The American Academy of Dermatology also has pamphlets on allergic contact dermatitis and hand eczema.

For patient education information, see the Skin Conditions & Beauty Center, as well as Contact Dermatitis.

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Thomas N Helm, MD Professor of Dermatology, Hershey Medical Center, Penn State Health, Pennsylvania State University College of Medicine

Thomas N Helm, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Society for Dermatologic Surgery, American Society of Dermatopathology

Disclosure: Nothing to disclose.

William D James, MD Emeritus Professor, Department of Dermatology, University of Pennsylvania School of Medicine

William D James, MD is a member of the following medical societies: American Academy of Dermatology, American Contact Dermatitis Society, Association of Military Dermatologists, Association of Professors of Dermatology, American Dermatological Association, Women’s Dermatologic Society, Medical Dermatology Society, Dermatology Foundation, Society for Investigative Dermatology, Washington DC Dermatological Society, Atlantic Dermatologic Society, Philadelphia Dermatological Society, Pennsylvania Academy of Dermatology, College of Physicians of Philadelphia

Disclosure: Received income in an amount equal to or greater than $250 from: Elsevier<br/>Served as a speaker for various universities, dermatology societies, and dermatology departments.

Daniel J Hogan, MD Clinical Professor of Internal Medicine (Dermatology), Nova Southeastern University College of Osteopathic Medicine; Investigator, Hill Top Research, Florida Research Center

Daniel J Hogan, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Contact Dermatitis Society, Canadian Dermatology Association

Disclosure: Nothing to disclose.

Matthew F Helm, MD Assistant Professor of Dermatology, Pennsylvania State University College of Medicine

Disclosure: Nothing to disclose.

Donald Belsito, MD Professor of Clinical Dermatology, Department of Dermatology, Columbia University Medical Center

Donald Belsito, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Contact Dermatitis Society, Dermatology Foundation, New York County Medical Society, New York Dermatological Society, Noah Worcester Dermatological Society, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Barry E Brenner, MD, PhD, FACEP Professor of Emergency Medicine, Professor of Internal Medicine, Program Director for Emergency Medicine, Case Medical Center, University Hospitals, Case Western Reserve University School of Medicine

Barry E Brenner, MD, PhD, FACEP is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Chest Physicians, American College of Emergency Physicians, American College of Physicians, American Heart Association, American Thoracic Society, Arkansas Medical Society, New York Academy of Medicine, New York Academy of Sciences,and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Jeffrey P Callen, MD Professor of Medicine (Dermatology), Chief, Division of Dermatology, University of Louisville School of Medicine

Jeffrey P Callen, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and American College of Rheumatology

Disclosure: Amgen Honoraria Consulting; Celgene Honoraria Safety Monitoring Committee

Simon K Law, MD, PharmD Clinical Professor of Health Sciences, Department of Ophthalmology, Jules Stein Eye Institute, University of California, Los Angeles, David Geffen School of Medicine

Simon K Law, MD, PharmD is a member of the following medical societies: American Academy of Ophthalmology, American Glaucoma Society, and Association for Research in Vision and Ophthalmology

Disclosure: Nothing to disclose.

Mark Louden, MD Assistant Professor of Clinical Medicine, Division of Emergency Medicine, Department of Medicine, University of Miami, Leonard M Miller School of Medicine

Mark Louden, MD is a member of the following medical societies: American Academy of Emergency Medicine and American College of Emergency Physicians

Disclosure: Nothing to disclose.

R Scott Lowery, MD Associate Professor of Ophthalmology, Department of Pediatric Ophthalmology and Strabismus, University of Arkansas for Medical Sciences College of Medicine, Arkansas Children’s Hospital

R Scott Lowery, MD is a member of the following medical societies: American Academy of Ophthalmology and Arkansas Medical Society

Disclosure: Nothing to disclose.

Joshua May, MD Bend Dermatology Clinic

Disclosure: Nothing to disclose.

Disclosure: Nothing to disclose.

Christopher J Rapuano, MD Professor, Department of Ophthalmology, Jefferson Medical College of Thomas Jefferson University; Director of the Cornea Service, Co-Director of Refractive Surgery Department, Wills Eye Institute

Christopher J Rapuano, MD is a member of the following medical societies: American Academy of Ophthalmology, American Society of Cataract and Refractive Surgery, Contact Lens Association of Ophthalmologists, Cornea Society, Eye Bank Association of America, and International Society of Refractive Surgery

Disclosure: Allergan Honoraria Speaking and teaching; Allergan Consulting fee Consulting; Alcon Honoraria Speaking and teaching; RPS Ownership interest Other; Bausch & Lomb Honoraria Speaking and teaching; Merck Consulting fee Consulting; Bausch & Lomb Consulting; Merck Honoraria Speaking and teaching

Hampton Roy Sr, MD Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences

Hampton Roy Sr, MD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, and Pan-American Association of Ophthalmology

Disclosure: Nothing to disclose.

David Todd Schwartz, MD Associate Professor of Emergency Medicine, New York University School of Medicine; Attending Physician, Department of Emergency Medicine, Bellevue Hospital Center and New York University Medical Center

David Todd Schwartz, MD is a member of the following medical societies: American Academy of Emergency Medicine and American College of Emergency Physicians

Disclosure: Nothing to disclose.

Bradley D Shy, MD Staff Physician, Department of Emergency Medicine, Bellevue Hospital Center, New York University School of Medicine

Disclosure: Nothing to disclose.

Richard P Vinson, MD Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Association of Military Dermatologists, Texas Dermatological Society, and Texas Medical Association

Disclosure: Nothing to disclose.

Jack L Wilson, PhD Distinguished Professor, Department of Anatomy and Neurobiology, University of Tennessee Health Science Center College of Medicine

Jack L Wilson, PhD is a member of the following medical societies: American Association of Anatomists, American Association of Clinical Anatomists, and American Heart Association

Disclosure: Nothing to disclose.

Source: eMedicine Medscape

This article is provided for informational purposes only and is not a substitute for professional medical advice. Always consult with a qualified healthcare provider for diagnosis and treatment.