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Drug Eruptions

Dermatitis Medicamentosa

Drug eruptions constitute adverse events associated with medications. Clinical presentation of drug eruptions is as diverse as the variety of substance classes that may induce such lesions.


Presentation

Clinical presentation of drug eruptions varies largely. In most cases, they are bilateral and symmetric. The most common drug-induced cutaneous lesions are urticaria and exanthems, whereby the latter may also be referred to as morbilliform or maculopapular rash [4] [10]. These shall be described in further detail.

Urticaria typically manifests in form of slightly elevated, itching papules or plaques that are commonly referred to as hives or wheals. These lesions may develop within minutes after drug administration, but symptom onset may also be delayed for hours or days. In most cases, they remit spontaneously within a few hours. However, dependent on the frequency of application, re-induction may occur before remission. Complete recovery is usually achieved as soon as drug therapy is discontinued. Urticaria may be a symptom of a type I hypersensitivity reaction or may be mediated by direct effects of causative drugs on mast cells. The former commonly happens after application of beta-lactam antibiotics, the latter may be triggered by opiates. Of note, urticaria may precede anaphylaxis and should therefore be taken very seriously.

Morbilliform or maculopapular rash may not manifest until days after initiation of therapy. Usually, first lesions become apparent on the trunk, and may spread to other areas of the body. Pressure-stressed skin areas are also predisposed for exanthems. They generally remit spontaneously within one or two weeks.

Other dermatoses that may be related to drug application are:

Stevens-Johnson syndrome, toxic epidermal necrolysis and warfarin-induced skin necrosis are potentially life-threatening adverse events. The interested reader is referred to the respective articles.

Of note, a patient may develop dermatological diseases while receiving treatment for any previously diagnosed disorder, but this does not necessarily indicate the presence of drug eruptions. In fact, premature diagnosis of drug eruptions may cause physician and patient to overlook a second primary disease, as in a case of chronic urticaria that was erroneously ascribed to penicillin treatment [11].

Fever
  • We observed fever (76%), lymphadenopathy (31.5%), eosinophilia (35%), and visceral involvement (50%). Twelve patients died directly related to the ACDR.[ncbi.nlm.nih.gov]
  • Reveno 1 reported 1 case of drug fever. McGavack et al . 2 reported, from over 100 cases treated, 1 case in which drug fever and urticaria were reproduced by propylthiouracil five weeks after withdrawal of thiouracil.[mdedge.com]
  • This refers to a condition which includes the presence of a morbilliform rash, fever and signs of damage to internal organs, and has a mortality of approximately 10%.[news-medical.net]
  • These patients are normally systemically ill with a fever. Skin pain is a feature, as opposed to itch that accompanies MDE. Occasionally, duskiness may be seen in the resolving phases of MDE- here, the areas are not tender. Scarlet fever.[dermatologyadvisor.com]
  • EBV, enteroviruses, adenovirus, early HIV, cytomegalovirus, human herpes virus type 6, human parvovirus B19, measles); bacteria (scarlet fever, mycoplasma infection); and streptococcal or staphylococcal toxins.[basicmedicalkey.com]
Chills
  • A Herxheimer reaction feels like a worsening of illness symptoms and can include fever, sweating and chills, rapid heart rate or palpitations, shortness of breath, muscle and joint aches and pains, headache, brain fog, insomnia, swollen glands, ringing[genevadermatology.ch]
  • […] epidermal necrolysis are often caused by infections, especially herpes simplex virus but, when caused by drugs, it is usually penicillins or sulfonamides. [ 8 ] Clinical features are similar in all causes: The reaction often starts with fever, sore throat, chills[patient.info]
  • Call your doctor at once if you have: blood in urine or stools; a seizure (convulsions); loss of movement in any part of your body; a blood cell disorder--sudden weakness or ill feeling, fever, chills, sore throat, mouth sores, pale skin, feeling tired[drugs.com]
Wound Infection
  • Prevention of wound infection and reduction of pruritus are often indicated and may be achieved by topical or systemic application of antibiotics, antihistamines and corticosteroids.[symptoma.com]
Excessive Daytime Sleepiness
  • Modafinil is a psychostimulant drug, which has been approved by the US Food and Drug Administration for the treatment of narcolepsy associated excessive daytime sleepiness, sleep disorder related to shift work, and obstructive sleep apnea syndrome.[ncbi.nlm.nih.gov]
Eruptions
  • A few types of drug eruption do not present such problems, and the fixed drug eruption is one of those whose clinical findings are specific enough to allow a diagnosis. The fixed drug eruption is a commonly reported type of drug eruption.[ncbi.nlm.nih.gov]
  • We obtained 10 skin biopsy specimens from patients with drug eruption by STI571, 6 from the antibiotics-induced drug eruption group, and 5 from normal skin (control).[ncbi.nlm.nih.gov]
  • The main clinical patterns of the eruptions seen were urticaria, maculopapular rash, fixed drug eruption and erythema multiforme.[ncbi.nlm.nih.gov]
  • Two distinct eruptions to mesna have been induced in these patients during cyclophosphamide/corticosteroid therapy; these eruptions are not thought to share a common pathogenic mechanism.[ncbi.nlm.nih.gov]
Erythema
  • OBJECTIVE: To determine if the existence of anti-SSA/Ro antibody may be a risk factor for FU-agent-induced DLE-like eruptions and acral erythema.[ncbi.nlm.nih.gov]
  • The confusion between erythema multiforme major and SJS means that erythema multiforme major is the main differential diagnosis. Skin disorders involving desquamation, in particular after pustulosis, are also common differential diagnoses.[ncbi.nlm.nih.gov]
  • Clinically, 3 of 4 patients had facial erythema, 3 of 4 had generalized macular erythema, 3 of 4 had widespread follicular-based papular eruption, and 4 of 4 had palmoplantar erythrodysesthesia.[ncbi.nlm.nih.gov]
  • The patient contacted her provider in tears two weeks into treatment for severe facial erythema at which time the patient’s use of Mirvaso was discontinued resulting in improvement of erythema and flushing thereafter.[omicsonline.org]
  • A 71-year-old man with aplastic anemia developed widespread erythema and reticulation with violaceous papules and pigmentation after receiving intramuscular injections of Demelon weekly for 2 months.[ncbi.nlm.nih.gov]
Urticaria
  • Indeed, acute urticaria has been reported to be the most common type of cutaneous reaction to drug therapy.[symptoma.com]
  • Fixed drug eruption was the commonest reaction, seen in 61 patients; other reactions being urticaria and angioedema,morbilliform rash in 37, pruritus in 25, Stevens Johnson Syndrome (SJS) in 6, purpura in 6, exfoliative dermatitis in 5,photosensitivity[ncbi.nlm.nih.gov]
  • Maculopapular rash was the most common type of drug eruption followed by urticaria and photosensitivity reaction.[ncbi.nlm.nih.gov]
  • Exanthematous drug eruptions, drug hypersensitivity syndrome, urticaria and angioedema, serum sickness-like reactions, fixed drug eruptions, drug-induced autoimmune blistering diseases, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug-induced[ncbi.nlm.nih.gov]
  • The main clinical patterns of the eruptions seen were urticaria, maculopapular rash, fixed drug eruption and erythema multiforme.[ncbi.nlm.nih.gov]
Photosensitivity
  • Besides piroxicam (a well-known photosensitizer) and carbamazepine, isoniazid and triflusal were identified as the causes of the reactions.[ncbi.nlm.nih.gov]
  • Fixed drug eruption was the commonest reaction, seen in 61 patients; other reactions being urticaria and angioedema,morbilliform rash in 37, pruritus in 25, Stevens Johnson Syndrome (SJS) in 6, purpura in 6, exfoliative dermatitis in 5,photosensitivity[ncbi.nlm.nih.gov]
  • Maculopapular rash was the most common type of drug eruption followed by urticaria and photosensitivity reaction.[ncbi.nlm.nih.gov]
  • […] angioedema, serum sickness-like reactions, fixed drug eruptions, drug-induced autoimmune blistering diseases, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug-induced acne, acute generalized exanthematous pustulosis, lichenoid drug eruptions and photosensitivity[ncbi.nlm.nih.gov]
  • RESULTS: Fixed drug eruption was seen in 61 patients; others being urticaria and angioedema, morbilliform rash in 37, pruritus in 25, Stevens Johnson (SJ) syndrome in six, purpura in six, exfoliative dermatitis in five, photosensitivity in five, Toxic[ncbi.nlm.nih.gov]
Pruritus
  • Fixed drug eruption was the commonest reaction, seen in 61 patients; other reactions being urticaria and angioedema,morbilliform rash in 37, pruritus in 25, Stevens Johnson Syndrome (SJS) in 6, purpura in 6, exfoliative dermatitis in 5,photosensitivity[ncbi.nlm.nih.gov]
  • Drug avoidance is the mainstay of treatment, and antihistamines can reduce associated pruritus.[ncbi.nlm.nih.gov]
  • RESULTS: Fixed drug eruption was seen in 61 patients; others being urticaria and angioedema, morbilliform rash in 37, pruritus in 25, Stevens Johnson (SJ) syndrome in six, purpura in six, exfoliative dermatitis in five, photosensitivity in five, Toxic[ncbi.nlm.nih.gov]
  • If therapy becomes necessary, it usually consists in symptomatic treatment of pruritus and wound care.[symptoma.com]
  • Mid- or high potency topical steroids (such as triamcinolone acetonide 0.1%, fluocinonide 0.05%, bethamethasone diproprionate 0.05% or clobetasol 0.05%) may help to relieve pruritus. Creams or lotions are useful for large surface areas.[dermatologyadvisor.com]

Workup

Unequivocal confirmation of a causative relation between drug therapy and cutaneous lesions may be very challenging. Although anamnestic data are of utmost importance to achieve that aim, they may also be misleading [11].

Patients should undergo complete and thorough physical examination in order to rule out distinct primary diseases and to assess if drug eruptions are associated with systemic complications. A laboratory analysis of blood samples serves the same purpose. Inflammatory, hepatic and renal parameters are most interesting at the time of diagnosing cutaneous adverse events. Eosinophilia may indicate a hypersensitivity reaction or autoimmune disorders. Skin tests and patch tests may reveal if a patient suffers from hypersensitivity to a particular drug, but such tests are only available for selected drugs; the same applies for serological tests aiming at detection of drug-specific antibodies. Histopathological analysis of tissue samples may be very helpful in establishing a diagnosis [12].

Although discontinuation of drug administration and re-induction of symptoms by restarting therapy may be a tempting diagnostic approach, the possibility of severe adverse reactions should not be underestimated. According to a recently published study, the presence of skin pain and mucosal lesions as well as the use of anticonvulsants are independent prognostic factors of such severe events [10].

Treatment

Treatment mainly consists in eliminating the trigger of drug eruptions and providing supportive therapy for present symptoms.

With regards to the former, discontinuation of drug administration may be the safest way to stop the chain of pathophysiological events leading to cutaneous lesions. In case of severe adverse events, this is the only recommended therapeutic approach. However, complete cessation of therapy may not be possible (due to lack of alternatives) or not necessary. If dose or frequency of medication can be reduced, this should be attempted. In some cases, drug-drug-interactions account for drug eruptions. Here, adjustment of dose and/or frequency of other drugs may be sufficient to prevent adverse events. If that is not the case and drug withdrawal is not an option, administration of antihistamines or corticosteroids prior to drug application may be considered.

Treatment of lesions has to be adjusted to the needs of the individual patient. Prevention of wound infection and reduction of pruritus are often indicated and may be achieved by topical or systemic application of antibiotics, antihistamines and corticosteroids.

Prognosis

Prognosis is very good for simple drug eruptions, i.e., for patients who present cutaneous adverse events but don't suffer from damage to internal organs. Most affected individuals achieve full recovery.

In case of complex drug eruptions, hepatic or renal lesions as well as damage to other internal organs may be associated with significant morbidity and mortality. Here, early diagnosis is of the utmost importance to terminate exposure to the causative agent and initiate treatment before the start of irreversible damage or infection. This applies particularly to Stevens-Johnson syndrome, toxic epidermal necrolysis and warfarin-induced skin necrosis, which comprise extensive skin lesions, possibly involve internal organs, and may claim fatalities [8] [9].

Etiology

Drug eruptions are among the most common adverse events and can be induced by virtually all kinds of medication, albeit with differing probability and severity. It is beyond the scope of this article to name all compounds that have been related to drug eruptions; a relation between drug therapy and the onset of dermatological disorders should be considered in every patient treated that unexpectedly develops cutaneous eruptions, even though such an adverse effect is not described here or in renowned reviews [3] [4].

Substance classes that are known to frequently induce drug eruptions are:

Antibiotics are assumed to account for about half of all drug eruptions, non-steroidal anti-inflammatory drugs for about one out of four.

Epidemiology

It has been estimated that drug eruptions account for about 2% of dermatological disorders referred for dermatologic evaluation [4]. Thus, they are rather common. Nevertheless, precise data regarding the incidence of drug eruptions cannot be provided. Because they are generally mild and remit upon termination of drug application, they may not be reported to the attending physician or the corresponding authorities. If considering those cases of cutaneous adverse events that have been reported, predilection for gender, age and determined comorbidities can be observed:

  • Drug eruptions more commonly affect women.
  • Highest incidence rates are observed in the elderly. This may be explained with a higher prevalence of comorbidities (see next two points) and an increased probability of drug-drug-interactions due to medication administered to treat those diseases [6].
  • Underlying diseases that interfere with pharmacokinetic, i.e., with liberation, absorption, distribution, metabolization and excretion, predispose for adverse events. Due to their important role in drug metabolization and excretion, disorders of liver, kidneys and intestines often contribute to adverse drug reactions.
  • The immune system plays a major role in the pathogenesis of drug eruptions. Consequently, immune disorders and immunodeficiency predispose for drug eruptions.

Less than 1% of cutaneous adverse events are severe.

Sex distribution
Age distribution

Pathophysiology

As has been implied in the previous section, interference with drug metabolization and excretion as well as induction of an immune response against medication may lead to drug eruptions.

Under pathological conditions, drugs may not be adequately metabolized. On the one hand, toxic metabolites may be generated due to malfunction of certain enzymes. On the other hand, toxic metabolites may accumulate because a subsequent step cannot be carried out or because their elimination via kidneys or intestines is impaired.

A significant share of drug eruptions is mediated by the immune system. Indeed, acute urticaria has been reported to be the most common type of cutaneous reaction to drug therapy [4]. This clinical presentation usually corresponds to a type I hypersensitivity reaction: Here, exposure to the antigen - the drug or any of its metabolites - leads to the activation of B lymphocytes which produce antibodies, namely immunoglobulin E. These bind to mast cells and basophils, rendering them sensitized, and upon renewed exposure to the antigen, these cells degranulate and release mediators like histamine, which, in turn, cause urticaria. In sum, this reaction requires repeated application of a drug, but occurs within minutes after drug administration. Of note, mast cell degranulation may also be triggered by the drug itself and occur independent of immunoglobulin E production. In this case, previous drug exposure and sensitization are not required.

In case of a type II hypersensitivity reaction, cells are marked with antibodies induced by determined drugs, and subsequently, cytolysis occurs. Type III reactions are based on the deposition of immune complexes. Such reactions are less common adverse effects, but have been observed after application of antimalarials and thyreostatics, respectively.

Single drugs may induce hypersensitivity reactions of distinct types. Penicillin, for instance, typically causes type I reactions but has also been related to cell-mediated type IV reactions. Affected patients may present after days or weeks with contact dermatitis or Stevens-Johnson Syndrome instead of acute urticaria.

Several other pathomechanisms have been reported to account for cutaneous adverse events:

  • Exposure to ultraviolet light, for instance, may activate the drug or any of its metabolites and cause photosensitivity and dermatitis [7]. This is commonly observed in patients treated with tetracycline antibiotics.
  • Administration of antibiotics may cause massive bacterial death and release of endotoxins, thus provoking Jarisch-Herxheimer phenomenon.
  • Furthermore, application of certain drugs may trigger reactivation of latent viral infections, particularly infections with herpesviridae. Those pathogens may cause dermatological lesions.

Prevention

Prevention of drug eruptions essentially consists in avoiding the causative medication. In case of severe reactions to particular kinds of drugs, patients should wear an emergency bracelet and/or autoinjectors carrying antidotes.

Patients are strongly recommended to inform their physicians about any observed adverse effect; physicians, in turn, should report to the corresponding authorities.

Summary

In general, an adverse event to drug therapy is defined as an undesired effect mediated by any type of medication. Adverse events are usually distinguished from side effects that rather correspond to more or less expected effects that differ from the therapeutic one. Predictable side effects are usually dose-dependent, adverse events aren't. A patient's reaction to penicillin administration may serve as an example to illustrate the difference between adverse events and side effects: penicillin allergy, in severe cases associated with life-threatening anaphylaxis, is unequivocally an adverse event. In contrast, gastrointestinal complaints, resulting from penicillin interfering with the gut flora, are commonly observed side effects to such antibiotic treatment. The fact that penicillin allergy may also comprise cutaneous adverse events is less known - possibly because the respective dermatological lesions are less threatening than anaphylaxis and less common than penicillin-induced diarrhea. Publications dealing with drug eruptions due to beta-lactam antibiotics describe both acute and delayed onset of cutaneous lesions that vary in clinical presentation [1]. Thus, penicillin-induced cutaneous adverse events represent the wide variety of drug eruptions that may be observed in patients receiving any kind of medication. Affected individuals may also present disorders of skin appendages like nails and hair. In the broader sense of the word, disorders of mucous membranes may also be considered as drug eruptions.

Besides beta-lactam antibiotics, cutaneous adverse events have been reported for nearly every substance class, ranging from antibiotics to vaccines to contrast agents used for diagnostic imaging. The likelihood of drug eruptions varies largely from common (in case of beta-lactam antibiotics and drugs prescribed for multiple sclerosis [2], for instance) to very rare.

In most cases, drug eruptions constitute mild cutaneous disorders that disappear after withdrawal of the causative agent. However, cutaneous adverse events may also be the first sign of systemic damage caused by the respective medication. In this sense, hepatic and renal lesions are most common. They may be associated with significant morbidity and mortality. Therefore, patients who present with dermatological lesions that may be associated with drug therapy should be thoroughly examined and worked up.

Patient Information

Drug eruptions are common adverse reactions to medical therapy. Virtually any kind of medication may induce the formation of cutaneous lesions, but these are most frequently seen in patients who receive antibiotics (e.g., beta-lactam antibiotics like penicillin) or non-steroidal anti-inflammatory drugs. They typically manifest within a short period of time after drug administration, but may also appear with a delay of several days or weeks. Although hives and rash are frequent types of drug eruptions, clinical presentation varies largely.

In most cases, drug eruptions go away spontaneously as soon as drug therapy is discontinued. However, they may also precede severe systemic complications like hepatic or renal damage or anaphylaxis. Thus, it is of utmost importance to register drug eruptions and report them to the treating physician.

If therapy becomes necessary, it usually consists in symptomatic treatment of pruritus and wound care.

References

Article

  1. Schnyder B, Pichler WJ. Skin and laboratory tests in amoxicillin- and penicillin-induced morbilliform skin eruption. Clin Exp Allergy. 2000; 30(4):590-595.
  2. Balak DM, Hengstman GJ, Hajdarbegovic E, van den Brule RJ, Hupperts RM, Thio HB. Prevalence of cutaneous adverse events associated with long-term disease-modifying therapy and their impact on health-related quality of life in patients with multiple sclerosis: a cross-sectional study. BMC Neurol. 2013; 13:146.
  3. Ahmed AM, Pritchard S, Reichenberg J. A review of cutaneous drug eruptions. Clin Geriatr Med. 2013; 29(2):527-545.
  4. Farshchian M, Ansar A, Zamanian A, Rahmatpour-Rokni G, Kimyai-Asadi A, Farshchian M. Drug-induced skin reactions: a 2-year study. Clin Cosmet Investig Dermatol. 2015; 8:53-56.
  5. Maldonado Cid P, Alonso de Celada RM, Noguera Morel L, Feito-Rodriguez M, Gomez-Fernandez C, Herranz Pinto P. Cutaneous adverse events associated with heparin. Clin Exp Dermatol. 2012; 37(7):707-711.
  6. Carneiro SC, Azevedo-e-Silva MC, Ramos-e-Silva M. Drug eruptions in the elderly. Clin Dermatol. 2011; 29(1):43-48.
  7. Drucker AM, Rosen CF. Drug-induced photosensitivity: culprit drugs, management and prevention. Drug Saf. 2011; 34(10):821-837.
  8. Harr T, French LE. Toxic epidermal necrolysis and Stevens-Johnson syndrome. Orphanet J Rare Dis. 2010; 5:39.
  9. Nazarian RM, Van Cott EM, Zembowicz A, Duncan LM. Warfarin-induced skin necrosis. J Am Acad Dermatol. 2009; 61(2):325-332.
  10. Manriquez J, Andino-Navarrete R, Cataldo-Cerda K, Downey C, Berroeta D. Progression of drug exanthemas to serious drug eruptions: A retrospective review identifying early determinants. Australas J Dermatol. 2015.
  11. Silverman S, Localio R, Apter AJ. Association between chronic urticaria and self-reported penicillin allergy. Ann Allergy Asthma Immunol. 2016; 116(4):317-320.
  12. Weyers W, Metze D. Histopathology of drug eruptions - general criteria, common patterns, and differential diagnosis. Dermatol Pract Concept. 2011; 1(1):33-47.

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Last updated: 2019-07-11 22:02