Pediatrics

Drug Hypersensitivity syndrome

OVERVIEW: What every practitioner needs to know

Are you sure your patient has drug hypersensitivity syndrome? What are the typical findings for this disease?

Skin eruptions from medications are common. These reactions can occasionally be severe and have systemic manifestations.

The more severe form of medication reaction is termed drug hypersensitivity syndrome (DHS) and is associated with systemic symptoms of fever, fatigue, and feeling ill and can involve multiple organs, especially the liver. DHS can be life-threatening, and withdrawal of the offending medication and prompt therapy are vital.

DHS has many synonyms or alternative names such as drug reaction with eosinophilia and systemic symptoms, anticonvulsant hypersensitivity syndrome, dilantin hpersensitivity syndrome, and dapsone hypersensitivity syndrome.

DHS should be suspected especially when there is a morbilliform rash and associated fever. Although there are many causes for fever and rash, the following findings help to differentiate DHS from infections and malignancies.

Skin findings

Morbilliform (measles-like) eruption of red macules and papules, which often coalesce.

The eruption typically starts on the trunk and then generalizes to cover the majority of the body surface.

DHS is classically associated with facial, and often hand and foot, edema.

There can be some lip redness and fissuring, but only rarely is it severe enough to consider an overlap between Stevens-Johnson syndrome and DHS.

Other physical examination findings

Generally, patients appear ill.

Lymphadenopathy can be severe, making DHS difficult to distinguish from lymphoma.

Tachycardia and tachypnia can be present.

Key Laboratory findings

Elevated enzymes on liver function tests (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase) and possibly coagulopathy, especially if long standing

Elevated eosinphils but this does not occur in all cases and in one Japanese series, eosinophilia was only present in approximately half of the patients

Elevated atypical lymphocytes. Again, this occurs only in approximately half of the patients but often makes it difficult to rule out Epstein-Barr virus (EBV) infection or lymphoma

Human herpesvirus 6 (HHV-6) reactivation may be found uncommonly but is very helpful if present

Which medications are the most common culprits?

DHS can be caused by a long list of medications, but there is a smaller list that accounts for the majority of cases of DHS. When one of the high-risk DHS medications has been started within 2-6 weeks of onset of symptoms, including a rash and fevers and systemic symptoms, DHS should be highly suspected. In other words, if a fever, rash, hepatic dysfunction, and systemic symptoms occur within 2-6 weeks of starting a high-risk DHS medication it is much less likely that the symptoms and signs are due to another cause such as lymphoma.

High-risk medications (those most commonly associated with DHS)

Sulfa medications: trimethoprim-sulfamethoxazole, sulfasalazine, sulfadoxine, and others

Anticonvulsant agents: lamotrigine, carbamazepine, phenytoin, phenobarbital, oxcarbazepine, zonisamide

Antibiotics and antiviral agents: fluoroquinolones, minocycline, dapsone, abacavir

Cardiac medications: atenolol, captopril, diltiazem

Other medications: allopurinol, piroxicam

What other disease/condition shares some of these symptoms?

Patients with DHS often have fever, lymphadenopathy, eosinophilia, and/or atypical lymphocytosis. Therefore the following diseases are the most likely to be in the differential diagnosis of DHS:

Infection such as acute EBV, cytomegalovirus, HIV, or other viral syndromes

Lymphoma: Note that DHS has actually been called "pseudolymphoma" because it can mimic so many of the signs and symptoms of lymphoma, but again if a high-risk DHS drug was started within 2-6 weeks of symptom onset, this helps favor DHS over lymphoma.

Hemophagocytic lymphohistiocytosis

Parasitic infection

What caused this disease to develop at this time?

There is some data for medication reactions being more common in people with certain HLA subtypes, so DHS likely requires an immune system response. Therefore DHS typically presents 2-6 weeks after the medication is started.

Examples of drugs and HLA associations:

Abacavir: HLA B*5701

Allopurinol: HLA B*5801

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Complete blood count with differential, liver function tests, coagulation studies, erythrocyte sedimentation rate, kidney function tests, urinalysis with microscopy, human herpesvirus-6 serologic assay or polymerase chain reaction are important to help in the diagnosis.

If necessary, EBV determination, stool for ova and parasites, specific parasitic serologic tests, or lymph node biopsy (to rule out lymphoma) may be necessary if the diagnosis is not clear.

Would imaging studies be helpful? If so, which ones?

DHS can be associated with dysfunction in many organs but often requires no imaging tests. In some cases the following may be useful:

Liver ultrasonogram (to evaluate for hepatitis)

Echocardiogram (to evaluate for carditis)

Chest roentgenogram or computed tomographic scan (to evaluate for pneumonitis)

Confirming the diagnosis

DHS should be high on the differential diagnosis if the following are present:

A medication implicated in DHS

Widespread rash especially with facial edema and fever

Elevated liver enzymes, eosinophils or atypical lymphocytes

If you are able to confirm that the patient has drug hypersensitivity syndrome, what treatment should be initiated?

The primary therapy is to withdraw the medication. If the medication is stopped early and has a short half-life and the patient does not have significant end-organ toxicity (elevated liver enzymes, carditis, pneumonitis, nephritis), withdrawal may be enough. Laboratory values should be rechecked 1-2 weeks after stopping the medication to ensure there is not late-onset damage, especially to the liver.

Systemic steroids are often needed and can lead to much more rapid clinical improvement. Dosing is typically 1-2 mg/kg/d of prednisone for a 2- to 3-week course, followed by a taper. Clinically, patients often improve dramatically within 24-48 hours of receiving steroids. Oral prednisone is activated by the liver to prednisolone, so if there is severe liver dysfunction, prednisone may be less effective than prednisolone or methylprednisolone.

Intravenous immunoglobulin (IVIG) has also been shown in small series to be effective in DHS. This may be particularly useful if an infection or malignancy (lymphoma) cannot be ruled out and treatment must be started while the work-up is ongoing, because systemic steroids may adversely affect the disease or work-up of infection or lymphoma, but IVIG should not.

What are the adverse effects associated with each treatment option?

Systemic steroids are imunosuppressive and can lead to hypertension, elevated blood glucose levels, psychosis, and aseptic necrosis, among other problems.

IVIG can be associated with severe allergic reaction, headache, volume overload, stroke, and other conditions.

What are the possible outcomes of drug hypersensitivity syndrome?

Patients with DHS will typically do well but death can occur, especially from severe hepatitis or carditis. There can also be late-onset autoimmune hypothyroidism.

What causes this disease and how frequent is it?

DHS is uncommon (approximately 1/10,000), is caused only by exposure to medications, and is likely underrecognized because medication rashes are common and the offending medication is withdrawn. If no laboratory tests are done, the elevation in liver enzymes and eosinophils may come and go without notice.

There are a few theories for the cause of DHS:

Inability to metabolize the primary medication or its toxic metabolites (slow acetylators)

Viral reactivation or coinfection (herpesvirus 6 or other)

Other clinical manifestations that might help with diagnosis and management

This reaction can occur after a medication has been stopped, so be sure to ask about all medications the patient is or has been taking in the past few weeks.

There are a few medications that deserve special mention:

Minocycline has been shown to bind to the skin with more affinity in darker-skinned patients and thus can lead to a more long-lasting reaction in darker-skinnned patients.

Fansidar (sulfadoxine and pyrimethamine) is an antimalarial therapy that can be purchased is over the counter in some countries, so be sure to ask about over-the-counter medications as well.

Abacavir causes DHS, which may be fatal if the medication is ever reintroduced.

What complications might you expect from the disease or treatment of the disease?

Liver failure or severe carditis or pneumonitis can occur rarely.

Are additional laboratory studies available; even some that are not widely available?

A late-onset autoimmune thyroiditis can be induced by DHS; thyroid stimulating hormone should be checked 4-6 weeks after the reaction starts.

How can drug hypersensitivity syndrome be prevented?

Avoidance of drug exposure in known allergic patients is key.

Medication cross-reaction is very important as well. For instance all sulfa medications should be avoided in a patient who had a drug sensitivity reaction to trimethoprim-sulfamethoxasole. Also there is cross-reactivity among anticonvulsant (phenobarbital, carbamazepine, oxcarbazepine, and phenytoin for instance) and all should be avoided if possible if a patient has a drug hypersensitivity reaction to one.

HLA B*5701 has been associated with a higher risk of DHS in patients exposed to abacavir. Pretesting may help avoid the reaction and in the future there may be other associations found and pretesting (when possible) may help providers avoid these reactions.

What is the evidence?

Viera, MH, Perez, OA, Patel, JK. "Phenytoin-associated hypersensitivity syndrome with features of DRESS and TEN/SJS". Cutis. vol. 85. 2010. pp. 312-7.

(This article details a case of DHS showing overlapping features with Stevens-Johnson syndrome.)

Shiohara, T, Iijima, M, Ikezawa, Z, Hashimoto, K. "The diagnosis of a DRESS syndrome has been sufficiently established on the basis of typical clinical features and viral reactivations". Br J Dermatol. vol. 156. 2007. pp. 1083-4.

(This article outlines a proposal for diagnosis of DHS based on signs/symptoms and laboratory values.)

"Medsafe: Information for health professionals". December 6, 2011. http://www.medsafe.govt.nz/profs/puarticles/dhs.htm.

(This is a government website from New Zealand with a useful list of high-risk DHS medications.)

Wolkenstein, P, Revuz, J. "Drug-induced severe skin reactions. Incidence, management and prevention". Drug Saf. vol. 13. 1995. pp. 56-68.

(This article details the epidemiology of severe drug reactions.)

Martin, AM, Krueger, R, Almeida, CA. "A sensitive and rapid alternative to HLA typing as a genetic screening test for abacavir hypersensitivity syndrome". Pharmacogenet Genomics. vol. 16. 2006. pp. 353-7.

(Article describing the association between HLA subtype and abacavir hypersensitivity)
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