DRESS Syndrome - Symptoms, Diagnosis, and Treatment

What Is DRESS Syndrome?

DRESS is a drug reaction with eosinophilia and systemic symptoms. It is a particularly adverse reaction that affects the skin and various organs of the body. It is a rare hypersensitivity reaction to certain medications that are potentially life-threatening. Studies show that about ten percent is the estimated mortality rate. This condition can affect both adults and children. It is seen in both males and females. The incidence of DRESS syndrome is uncommon, with a risk of one in 1000 to one in 10000 cases, based on the offending drug.

What Is the Etiology of DRESS Syndrome?

The exact cause of this syndrome is not entirely understood. It is known that a strong immune response to a specific category of drugs is the key reason. This immune reaction involves an early increase in T-cells of the immune system and has been shown to reactivate viral infections previously latent in the affected individual. It also includes viruses from many herpes virus families and infectious mononucleosis. Infectious mononucleosis (a contagious disease caused by the EBV (Epstein-Barr virus), is associated with DRESS syndrome in 40 % of cases. It is recorded by studies that several HLA (Human Leukocyte Antigen) haplotypes and genetic factors are associated with an increased risk of DRESS syndrome.

What Are the Potential Culprit Drugs Associated With DRESS Syndrome?

The potential culprit drugs that are associated with DRESS syndrome are:

• Antiviral drugs (drugs used to treat viral infections).

• Anticonvulsants (medications used to control fits and seizures).

• Antibiotics (drugs used to treat bacterial infections).

• Allopurinol (drugs used to treat gout and kidney problems).

• Biological agents.

• Mood stabilizers and antidepressants (drugs used to cure mental instability and depression).

• Mexiletine.

There are also other factors that lead to this condition, such as:

• Reduced capacity of the liver to metabolize drugs.

• Reactivation of certain viruses like EBV (Epstein-Barr virus) and herpesvirus 6.

• Genetic predisposition for DRESS syndrome.

What Are the Signs and Symptoms of DRESS Syndrome?

• This condition has a long latency between initiating the inciting drug and the onset of symptoms; this helps distinguish the condition from typical simple drug reactions. Classic symptoms include the triad of fever, rash, and involvement of internal organs.

• The most common clinical manifestations are fever and rash.

• It occurs in 85 to 75 % (approximately) of the population worldwide.

• Facial erythema (redness on the skin) and edema are common cutaneous lesions.

• Leukocytosis.

• Generalized lymphadenopathy (swelling of lymph nodes).

• Abnormal liver function tests.

• Peripheral eosinophilia is seen in more than half of the affected individuals.

• Many visceral organs are affected by this condition, like the liver and brain. Liver conditions like fulminant hepatitis (failed liver functioning leads to hepatic coma).

• Inflammatory reactions like erythroderma, SJS (Steven Johnson syndrome)/ TEN (toxic epidermolysis necrosis), erythema multiforme, and pruritic eruptions.

• Hematological abnormalities include thrombocytopenia, anemia, neutropenia, and large, activated lymphocytes.

• It also includes the involvement of vital organs such as the liver, lungs, and kidneys.

• About 10 % of people are affected by kidney disease, mainly moderate interstitial nephritis (a kidney condition brought on by inflammation and swelling in the gaps between renal tubules). Rarely does renal failure occur.

• Acute respiratory distress syndrome (a frequent clinical condition characterized by abrupt respiratory failure brought on by edema and widespread lung inflammation), pleuritis (inflammation of the lining of the chest cavity and the membranes around the lungs), or interstitial pneumonitis (lung inflammation) are manifestations of lung involvement.

What Drugs Cause DRESS Syndrome?

• Allopurinol - Dysfunction and eosinophilia without fever appear several months after the start of treatment.

• Minocycline - Peripheral adenopathies, eosinophilia, heart abnormalities, and eosinophilic pneumopathy.

• Abacavir - Gastrointestinal and acute viral pneumonia-like symptoms of rapid occurrence after treatment.

• Lamotrigine - Fever and toxic epidermal necrolysis.

What Are the Risk Factors of DRESS Syndrome?

The medications that are most frequently linked to DRESS syndrome are Allopurinol, beta-lactam antibiotics, and anticonvulsants. Antiretrovirals, mood stabilizers, Captopril, non-steroidal anti-inflammatory medicines, and mood stabilizers are other pharmaceuticals that have been linked to DRESS.

One in 1000 to one in 10,000 exposures has been described as the occurrence of DRESS with anticonvulsants. Patients with simultaneous use of Thiazide diuretics and renal insufficiency are more susceptible to Allopurinol-induced DRESS. The metabolite oxypurinol, which is produced when renal impairment occurs or when diuretics are administered, is hypothesized to be the cause of the syndrome.

Genetic influences are also significant. Those who have a first-degree relative who has had this condition may be at risk for developing DRESS by as much as 25 percent.

What Is Regi Scar and What Are the Criteria Included to Receive a Diagnosis Under It?

To lessen the burden of severe cutaneous reactions, a cooperation called the European Registry of Severe Cutaneous Adverse Reactions to Drugs and Collection of Biological Samples (RegiSCAR) was established. This group has developed diagnostic criteria to aid in recognizing DRESS syndrome.

At least three of the following must be met by potential instances to meet the RegiSCAR inclusion criteria:

• Hospitalization.

• Acute rash.

• Drug-related reaction.

• Fever higher than 38°C.

• Enlarged lymph nodes at least at two sites.

• Involvement of at least one internal organ.

• Blood count abnormalities include low platelets, elevated eosinophils, or an unusual lymphocyte count.

Furthermore, reactivation of the Human Herpes Virus 6 (HHV-6) is seen as diagnostic by a Japanese group. Yet, if reactivation is not assessed appropriately, a diagnosis is noticed because this usually happens two to three weeks after the rash first appears. Experts disagree about whether reactivation is a characteristic of the disease or if it needs to be treated as a side effect.

How Is the Diagnosis Made For DRESS Syndrome?

This syndrome can mimic many diseases, including viral hepatitis, cellulitis, and systemic lupus erythematosus. Due to this, the diagnosis becomes tough. Investigations include:

• Skin Biopsy - It shows dense infiltration of inflammatory cells like eosinophils, lymphocytes, extravasated erythrocytes, and edema.

• Blood Tests - Include blood count.

• Coagulation Studies - A test that checks blood’s ability to clot.

• Viral Serology - Hepatitis B, C, EBV (Epstein-Barr virus), CMV (cytomegalovirus), HHV-6

• Endocrine Function - Thyroid, glucose levels.

• Biochemical Tests - Liver function tests, renal function tests, and muscle enzymes.

• Genetic Susceptibility Tests - Tests for checking the liability of getting genetic disorders.

• Urinalysis: The purpose of urinalysis is to evaluate kidney impairment.

• Imaging Tests: An echocardiography, a chest X-ray, and an electrocardiogram (ECG) may be part of a cardiac and pulmonary assessment. The evaluation of the liver, kidneys, and brain may involve scans contingent on the findings of preliminary testing and clinical manifestations.

What Is the Treatment Given for DRESS Syndrome?

• All questionable medications must be stopped at once as part of the treatment plan, which also includes close observation and supportive care.

• Blood testing should be done as soon as feasible for patients who appear with a high fever and rash since this is when drug hypersensitivity syndrome is suspected.

• The treatment plan's main goals are symptom management, relief, and support.

• Fluid, electrolytes, and calorie intake are taken into consideration.

• Fluid replacement (medical procedure to replace bodily fluids lost to perspiration, hemorrhage, disease processes, or fluid changes).

• Temperature regulation.

• Proper nutrition.

• Wound care and infection control.

• Such other treatments depend on the involved and affected organs.

• Systemic corticosteroids are widely used as a treatment for this condition. There is no bar for ideal dosage, timing, and route of administration. A combination of pulsed corticosteroids and oral corticosteroids together gives an effective treatment.

• Other potential therapies include intravenous immunoglobulin, topical corticosteroids for rashes, plasmapheresis, and immunosuppressants like Cyclosporin.

• Immunomodulatory drugs such as Cyclophosphamide, Rituximab, and Mycophenolate are used.

• Supportive treatments for skin rash like dressings, topical steroids, emollients, and oral antihistamines.

• Secondary infections require antibiotic therapy.

How Can This Syndrome Be Avoided?

Individuals who experience drug hypersensitivity syndrome are advised not to take the offending medication(s) ever again.

The three primary aromatic anticonvulsant medications—Phenytoin, Carbamazepine, and Phenobarbitone—frequently cause cross-reactions with one another. All three of these medications should be avoided by patients who have developed drug hypersensitivity syndrome with any one of them.

Genetic factors may influence drug hypersensitivity syndrome; thus, first-degree relatives should be made aware of their increased chance of experiencing hypersensitivity reactions to the same medication(s).

Conclusion:

DRESS syndrome is complex, rare, and potentially life-threatening. Early diagnosis and treatment are very important to avoid its progression and complications. It can lead to fatal conditions, even death. It occurs when the body’s immune system overreacts to specific drugs, resulting in type 4 hypersensitivity reactions that cause multiple symptoms in the individual's body, like fever, blood abnormalities, and organ inflammation. The important and primary treatment line is removing the causative drug for this condition. Treatment is done according to the symptoms revealed. The occurrence of liver failure in DRESS syndrome is rare, but an early diagnosis can avoid unwanted complications.