DRESS syndrome.pdf

DRESS Syndrome
Natasorn Lek-Uthai,MD.
Allergy and Immunology Fellowship year 2

Introduction
• Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome or drug-induced
hypersensitivity reaction (DIHS) is a severe cutaneous drug reaction characterized by fever,
lymphadenopathy, hematologic abnormalities, multisystem involvement, and viral reactivation
• The true incidence of DRESS/DIHS is still unknown, but it has been reported at around 10 per
million.
• A female predominance has been reported in some registries and series but not others.
• The onset is delayed, typically 2 to 3 weeks from the initial exposure of the drug but can lag up to
3 months or longer after starting the culprit medication.
Clinics in Dermatology (2020) 38, 702–711

• Some authors have estimated the mortality from DRESS/DIHS to be around 10%, although other
series and registries report mortality to be closer to 5%.
• The typical course of DRESS is one that is long and drawn out, and may sometimes experience a
paradoxical worsening of signs and clinical manifestations in the immediate period after drug
withdrawal.
• Relapses or flares are common in DRESS/DIHS. In a retrospective study of 60 patients with DRESS,
25% of patients had recurrence of their DRESS.
Introduction

Manieri E, Dondi A, Neri I and Lanari M (2023) Drug rash with eosinophilia and
systemic symptoms (DRESS) syndrome in childhood: a narrative review.

Associated drugs
• Allopurinol has been implicated in more severe disease, and it is more likely than some other
medications to be associated with the development of renal and hepatic involvement.
• Carbamazepine, another commonly implicated drug in DRESS/DIHS, is associated with hepatic
involvement, lymphadenopathy, and atypical lymphocytes.
• Vancomycin may be more frequently associated with renal involvement and even death.
• In a retrospective series of 29 patients with DRESS, the 4 patients who had vancomycin-
associated DRESS had a 4.98-fold median increase in their baseline creatinine, compared with a
2.25-fold median increase in the rest of the cohort.

Descriptive retrospective study of hospitalized patients at
the King Chulalongkorn Memorial Hospital between
January 2004 and December 2014 due to DRESS
- 52 patients were included in this study
- 28 patients : possible case
- 18 patients : probable case
- 6 patients : definite case
Allergol Int. 2016 Oct;65(4):432-438

• Phenytoin, nevirapine, allopurinol, and cotrimoxazole were the major causes.
• Allopurinol-induced DRESS had the longest onset time, and was associated with higher
eosinophilia and incidence of renal involvement.
Allergol Int. 2016 Oct;65(4):432-438

Viral Reactivation; Herpesviridae family
• The reactivation of viruses of the Herpesviridae family appears to be a feature of the DRESS
syndrome.
• Human herpesvirus (HHV)-6 is the most frequently reactivated, followed by cytomegalovirus
(CMV), Epstein–Barr virus (EBV), and HHV-7.
• The actual role, mechanisms, and timing of viral reactivation in the drug-specific immune response
and DRESS syndrome pathogenesis have not been clarified yet, but there seems to be an
association between it and the flaring-up of clinical symptoms , greater severity, or longer duration
of disease.

Human Herpesviruses (HHVs-6)
• Associated with a more severe disease course and a later onset following drug exposure
• Most frequent HHV to be associated with DRESS
HHV-6 DNA can be found in the skin, lymph nodes, kidney, and liver + microRNAs in
• serum → suggesting the potential concurrent role of reactivated HHV-6 in the development of
DRESS-related rash, lymphadenopathy, and organ failure
• Detection of HHV-6 DNA : associated with symptom flare-ups
• Increase in HHV-6 DNA levels : correlated with the severities
Microorganisms 2023, 11(2), 346;

• Acute stage; the population of T regulatory cells is expanded, number of B cells and the
plasma levels of Ig are reduced ,which may facilitate viral reactivation.
• Alternative hypothesis is that certain drugs (i.e., amoxicillin, valproic acid) may directly increase
HHV-6 replication
• T lymphocytes developed after exposure to the causal drug are virus-specific memory T cells,
reactivated following an incorrect recognition of the HLA-drug complexes.
Viral Reactivation; Herpesviridae family

EXPERT OPINION ON DRUG SAFETY, 2017
VOL. 16, NO. 2, 139–147

Manieri E, Dondi A, Neri I and Lanari M (2023) Drug rash with eosinophilia and systemic symptoms (DRESS)
syndrome in childhood: a narrative review.

Watanabe, H. (2018). Recent advances in drug-induced hypersensitivity syndrome/drug
reaction with eosinophilia and systemic symptoms. Journal of immunology
research, 2018.

Pathophysiology
• Viral reactivation, particularly HHV6, Epstein Barr virus, and CMV, is not only common among
patients with DRESS/DIHS and has been implicated in the pathophysiology of this disease.
• Early in the course of the disease, peripheral Tregs are greatly expanded in patients with DIHS
compared with patients with TEN, maculopapular drug reaction, or normal controls. Toward
resolution of the disease, however, this Treg compartment contracts and becomes
functionally deficient. At the same time, there is a shift toward an increase in Th17 cells. This
dynamics may explain the lag in the onset of DIHS clinical manifestations, as well as the
predisposition for late autoimmune sequelae
• In addition, ILC2, serum soluble ST2 (sST2), and IL-5 may be increased or elevated in peripheral
blood of patients with DRESS in the acute phase,and decreased after steroid treatment. Levels of
sST2 also correlated with alanine aminotransferase levels.

Biomarkers
• The average serum level of thymus and activation-regulated chemokine/chemokine ligand 17
(TARC/CCL17) among a cohort of 8 patients with DRESS was more than 10 times higher compared
with the average serum levels among 7 patients with SJS/TEN or 14 patients with a maculopapular
drug reaction.
• TARC levels were markedly elevated among the patients with DRESS during the acute phase of
their disease but decreased with lessening of the eruption.
• Serum levels of the high mobility group box 1 protein (HMGB1) were elevated in 17 patients
with DRESS and 17 patients with SJS/TEN compared with 11 patients with a maculopapular drug
eruption and 14 healthy volunteers. Serum HMGB1 levels among patients with DRESS, however,
were significantly higher compared with those in the SJS/TEN group. Although TARC and HMGB1 are
promising as a markers for DRESS, their use has not yet been sufficiently validated in a larger cohort.

Genetic factors
• Polymorphisms that affect N- acetylation and detoxification of toxic drug metabolites are
thought to increase susceptibility to developing DRESS/DIHS from specific drugs such as
sulfonamides and anticonvulsants.
• HLA molecules on antigen presenting cells are responsible for presenting the drug antigens to
their corresponding effector immune cells.
• HLA variants on viral reactivation may explain their association with DRESS.

• HLA-B*5801 has been identified as a genetic marker for allopurinol-associated DRESS in the Han
Chinese as well as the Japanese population.
• HLA-A*32:01 has been associated with vancomycin-induced DRESS after comparison of 32
patients with DRESS of predominantly European ancestry and 46 matched vancomycin-tolerant
controls.
• Smaller studies have suggested a link between HLA-B*56:02 and phenytoin- associated DRESS
among indigenous Australian.
• HLA-A*3101 and carbamazepine-associated DRESS in Han Chinese and Japanese patients.
Genetic factors

Specific HLA alleles
Dermatology,Fourth Edition :348-375

Histopathology
• A variety of histologic changes in the epidermis and dermis can be found in the skin of patients
with DRESS/DIHS, and histology is not specific for DRESS/DIHS.
• Not surprisingly, the epidermis from patients with clinically more severe DRESS/ DIHS is associated
with increased confluent keratinocyte necrosis on histology. Spongiotic epidermal change is
more likely to be found in those with milder disease.

Histopathology
• The histopathologic findings of DRESS are nonspecific
-Spongiosis, acanthosis, vacuolization, lymphocytic infiltrate in the papillary dermis, and perivascular,
• variable presence of eosinophils, atypical lymphocytes, or even granulomas
British Journal of Dermatology (2015)173, pp50–58

Histopathology
• Dyskeratosis (97%), epidermal spongiosis (78%), interface vacuolization (91%), perivascular
lymphocytic infiltration (97%) and eosinophilic infiltration (72%). Many pathological features were
common to both MPE and DRESS. However, severe dyskeratosis, epidermal spongiosis and
severe interface vacuolization were significantly more prominent in cases of DRESS (P < 005).
• Severe dyskeratosis, observed in DRESS, may correlate with a greater extent of systemic
involvement compared with that noted in MPE.
British Journal of Dermatology (2014) 170, pp866–873

Histopathology

Clinical presentation
• Data from the multinational registry RegiSCAR have shown that
• a polymorphous maculopapular eruption (85%) and facial edema (76%) were the most commonly seen
morphologies of the cutaneous involvement,
• 15% of their patients had a monomorphic maculopapular dermatitis.
• As part of the polymorphous maculopapular dermatitis
- pustules, purpura, infiltrated plaques, blisters, target-like lesions, urticarial lesions, an exfoliative
dermatitis, eczema-like lesions, and lichenoid lesions.

• The liver is the most frequently involved organ (70%), followed by kidney and lung: liver
abnormalities are characterized by a marked increase in serum alanine aminotransferase value.
• Neurologic symptoms manifesting as limbic encephalitis, gastroenteritis, interstitial pneumonia, and
myocarditis may also occur long after resolution of rashes:
VOL. 16, NO. 2, 139–147

• Develops 2 to 8 weeks after drug initiation - Re-exposure : shorter time to onset
• Fever (85%), cutaneous eruption (75%): most common • Cutaneous lesion usually begins as
morbilliform eruption
• → then becomes edematous, often with a follicular accentuation → followed by exfoliation and
desquamation
• Edema of the face is a frequent finding + hallmark
J Family Med Prim Care. 2022 Jul;11(7):3992-
3995 Dermatology, Fourth Edition : 348-375

• Less common: vesicles, follicular or non-follicular pustules (~20%), erythroderma, and purpuric
lesions
• Initial sites of involvement : Face, upper trunk, extremities
• Mucosal involvement: if present usually mild
J Family Med Prim Care. 2022 Jul;11(7):3992-
3995 Dermatology, Fourth Edition : 348-375

British Association of Dermatologists 2013 168,
pp391–401

Clinical presentation: Hepatitis
• Most prevalent systemic manifestation : hepatic involvement
- followed by renal, pulmonary, neurological, and cardiac involvement
- endocrine involvement is uncommon (thyroid gland is the most typically impacted gland)
• Symptoms may persist for several weeks or months after drug withdrawal - Average time to recovery
is 6 –9 weeks
- May persist for several months, with a succession of remissions and relapses
- Additional sites of involvement (e.g. cardiac, thyroid) may develop weeks or months later, including
following a taper of corticosteroids
Dermatology, Fourth Edition : 348-375 Front
Pharmacol. 2022 Apr 20;13:832048

Management
• Identification and discontinuation of the offending drug
• Identification and management of comorbidities
• Supportive measures to control clinical manifestations such as itching
• Control of inflammation with topical and/or systemic medications
• Monitoring for and management of long-term sequelae

Differential diagnosis
Immunol Allergy Clin N Am 29 (2009) 481–501

Diagnosis : RegiSCAR
Morphology rash
• Suggestive for DRESS at presence of 2 of following criteria:
- scaling/desquamation, eg, exfoliative dermatitis
- edema, especially facial edema (excluding lower leg edema)
- purpura (excluding lower leg)
- infiltration
J Am Acad Dermatol. 2014 Nov;71(5):1000-1000

• Liver
- ALT > 2 times UNL on at least 2 successive dates
- Conjugated bilirubin > 2 times UNL on at least 2 successive dates - AST, total bilirubin, ALP all > 2
times UNL at least
• Kidney
- Serum creatinine more than 1.5 times above the base value for the patient on at least 2 successive
dates
- proteinuria above 1 g/day, hematuria, decreased creatinine clearance, decreased GFR
• Lungs
Cough and/or dyspnea in conjunction with
- evidence of interstitial involvement on imaging
- abnormal broncho-alveolar lavage fluid, or biopsy - abnormal blood gases
J Am Acad Dermatol. 2014 Nov;71(5):1000-1000.e2

• Muscle, heart
Muscle pain and/or weakness, myocarditis (often nonspecific symptoms: hypotension, fatigue, chest
pain, dyspnea, malaise, palpitations, tachycardia, cardiac dysfunction, cardiomegaly, sudden cardiac
death), with
- Raised serum (CPK) > 2 times UNL
- Raised isoenzymes: CPK-3/CPK-MM (for skeletal muscle), raised CPK-2/MB fraction (for heart) - Serum
troponin T > 0.01 mcg/L
- Abnormal imaging: chest X-ray/ECHO/CT/MRI/EMG including ECG: ST-T electrocardiogram
abnormalities or conduction defects (ST-segment depression, T-wave inversions, or nondiagnostic ECG
changes (paced or bundle branch block)
- Endomyocardial biopsy

• Pancreas:
- Amylase and/or lipase > 2 times UNL
• Other organs: spleen, thyroid, central nervous system, gastrointestinal tract - Clinical symptoms
and additional investigations: enlargement/imaging, including EEG
- Abnormal lab values: TSH, FT4, FT3
- Biopsy

Japanese Research Committee on Severe Cutaneous
Adverse [Drug] Reactions (J-SCAR)
• Typical DRESS
: presence of all 7 criteria
• Atypical DRESS
: presence of only the first 5
criteria

•Reviewed case records of patients who were
diagnosed as probable adverse cutaneous drug
reactions by the WHO causality assessment
from January 2011 to December 2018
•Applied the RegiSCAR scoring and the
Japanese consensus group criteria
• Total 138/390 (35.4%) patients who
had RegiSCAR score of 4 or more
(definite/probable DRESS) and/or
patients who satisfied the Japanese
consensus group criteria for atypical
DiHS
Indian Dermatol Online J. 2022 Jan 24;13(1):40-45.

Japanese criteria for atypical DiHS showed reduced sensitivity to diagnose definite/probable
DRESS
Indian Dermatol Online J. 2022 Jan 24;13(1):40-45

Diagnostic testing
• Diagnostic testing by patch testing, intradermal testing, or lymphocyte activation assays to confirm
the offending agent in delayed hypersensitivity drug reactions remains controversial.
• Some authors suggest that patch testing may have some utility when done 6 months after
resolution of the signs and clinical manifestations of DRESS for specific drugs.
• One group performed patch testing on 74 patients with DRESS and found a positive patch test in
64% of the patients; however, the utility of patch testing was dependent on the type of drug
that was being tested. The authors noted frequent positive patch testing for beta-lactams,
pristinamycin, and omeprazole, but not for allopurinol, a commonly identified culprit in
DRESS/DIH In addition, 18% of the patients with DRESS in the study had positive patch tests to
multiple medications

• We previously demonstrated that positive LTT reactions can only be obtained at the recovery stage,
2 months after onset, but not the acute stage of DiHS/DRESS, while in SJS/TEN and other types of
drug eruptions positive LTT reactions were only observed when the test was performed at the acute
stage
VOL. 16, NO. 2, 139–147
Diagnostic testing

• Lymphocyte activation test/lymphocyte transformation test (LAT/LLT) has also been used in
identifying the causative agent in DRESS, but it also has significant limitations. This test has a high
specificity but low sensitivity and must be timed properly. This test is currently not
commercially available.
• As described earlier, the acute stage of DiHS/DRESS is characterized by expansion of Tregs. This
expansion of Tregs would occur to counteract activation of drug-specific effector T cells (Teffs),
thereby delaying the activation of Teffs and allowing sequential reactivations of herpesviruses.
Consistent with this explanation, in vitro proliferation of drug-specific Teffs as evidenced by a
positive LTT reaction can only be detected at the resolution stage, at which time expansions of
Tregs have been contracted and are associated with a gradual loss of Treg function . This scenario
can provide a reasonable explanation for why various autoimmune responses can develop after
clinical resolution of the disease, which will be described below. Clinics in Dermatology (2020) 38, 702–711
VOL. 16, NO. 2, 139–147
Diagnostic testing

Patch test
Patch testing : Test of choice
• • European Network on Drug Allergy : 3 weeks - 3 months after resolution
• European Society of Contact Dermatitis : 6 weeks - 6 months after resolution
• Not receiving immunosuppressive therapy or systemic corticosteroids > 4 weeks
• • Sensitivity 32-80%
- Antiepileptics, contrast media, beta-lactams, increase the sensitivity of PT
- Allopurinol and sulfasalazine frequently cause DRESS but never give positive patch tests
World Allergy Organ J. 2023 Apr 8;16(3):100673 Indian J Dermatol
Venereol Leprol 2013;79:836-841 Contact Dermatitis.2022;86:443–479

Concentration 10% in petroleum using commercial forms of the drug (most used and most
recommended)
• Initial reading 48 h after placing the patch and a second reading in 96 h - late readings (7–10 days)
may be recommended in some medication
• “Angry back” reaction — if the dermatitis is very active at the time of patch testing, multiple positive
patch tests may arise (maybe false positive)
→re-patch testing is usually required
World Allergy Organ J. 2023 Apr 8;16(3):100673 Indian J Dermatol
Venereol Leprol 2013;79:836-841 Contact Dermatitis.2022;86:443–479
Patch test

Clin Rev Allergy Immunol. 2022 Jun;62(3):548-561

Patch testing : Safety of patch testing in DRESS
• Considered to be a safe procedure
• Few studies have reported a flare-up of DRESS and none has threatened patients' health
• In a group of 12 patients with DRESS from antituberculosis drugs
- 8/9 of whom had HIV-infection had flare-up of DRESS after patch testing (mild-severe reaction)
• Another study; 39 patients who had positive patch tests
- 9/39 (21%) experienced DRESS in the form of a mild skin rash developing before the 72 hours reading
- 2 cases had generalized symptoms, 1 case had eosinophilia
Contact Dermatitis. 2022 Jun;86(6):443-479.
Patch test

Curr Allergy Asthma Rep. 2014 Jun;14(6):442

Patch testing:recommendation
J Dtsch Dermatol Ges. 2019 Oct;17(10):1076-1093

Irritant reaction
Contact Dermatitis. Springer, Berlin, Heidelberg

Intradermal test
• Considered to be contraindicated in SCARs→severe and fatal reactions -however, various authors
consider IDTs in DRESS to be potentially useful and safe when
• performed by specialists
• Increased sensitivity over the patch test
• May perform better than patches for some medications, such as beta-lactam
World Allergy Organ J. 2023 Apr 8;16(3):100673 Contact
Dermatitis.2022;86:443–479

• Read after 24 hours have given some positive results in DRESS
- However, drug concentration, test protocol, specificity, sensitivity, and safety are unknown
• Often proposed prior to IDTs; safer than IDTs
World Allergy Organ J. 2023 Apr 8;16(3):100673 Contact
Dermatitis.2022;86:443–479
Skin prick test

Contact Dermatitis. 2022 May;86(5):344-356

• A systematic literature search of skin tests performed in clearly defined DRESS cases • Total of 17
articles, 290 patients
• Result :
- PT results positive in 56.7% (n = 160 of 282) of cases
- IDT results positive in 50.0% (n = 18 of 36) of cases
- SPT results positive in 22.2% (n = 2 of 9) of cases
- 1 patient developed a maculopapular exanthem after skin testing
-In terms of proportion of systemic reactions , no differences were noted between SPT, PT, and IDT
J Allergy Clin Immunol Pract. 2023 Feb;11(2):481-491.e5.

J Allergy Clin Immunol Pract. 2023 Feb;11(2):481-491.e5.

Lymphocyte transformation test
• Often positive in DRESS
• Obtained 4 to 8 weeks after remission, but not in the acute phase of DRESS
• Detects memory T cells → will not give a positive result in non-immunologic hypersensitivity
reaction ex. mast cell activation via the MRGPRX2 receptor
• Sensitivity 27%-73%, specificity 82%-100%
World Allergy Organ J. 2023 Apr 8;16(3):100673 J Immunol
Methods. 2021 Jun;493:113036.
J Allergy Clin Immunol. 2023 Jul;152(1):39-41

J Immunol Methods. 2021 Aug;495:113062.

ELISPOT
• Solid-phase enzymatic immunosorbent assays
• Detect cells secreting cytokines of interest in response to suspect drugs
• Assays performed during the acute phase (≤30 days) of DHR had more than two times the
sensitivity of those performed in the recovery phase (>30 days after DHR) (75% vs 30%)
J Immunol Methods. 2021 Aug;495:113062.

Drug provocation test
• Contraindicated because of the risk of recurrence of the hypersensitivity reaction
• In special circumstances, drug provocation tests may be performed
- according to some authors
- compelling need for testing (e.g., treatment is necessary and there are no safe and efficacious
treatment alternatives
- benefit of the provocation is far greater than the risk - patients are carefully selected
Contact Dermatitis. 2022 Jun;86(6):443-479

Management : systemic corticosteroids
• Not been studied in randomized trials
• Currently the most accepted treatment
• Dose : minimum of 1 mg/kg/day of prednisolone
• Gradual tapering in 3 to 6 months to avoid relapses
- In some cases, protracted courses out to a year or longer are needed
• Fever/rashes rapidly resolve, and abnormal liver enzymes normalized within several days
World Allergy Organization Journal (2023) 16:100673

Systemic corticosteroids
• Systemic corticosteroids remain the systemic treatment of choice for DRESS/DIHS. Retrospective
studies have shown that systemic corticosteroid therapy is initiated in 34% to 57% of patients with
DRESS/DIH
• 40 to 60 mg orally daily, followed by a prolonged taper over 6 to 8 weeks. This allows for the
adequate control of cutaneous and systemic inflammation and the prevention of relapse that can
occur among patients with DRESS.
• Other experts recommend a more aggressive approach with intravenous methylprednisolone. In
a prospective, open-label, single-arm study, pulse IV methylprednisolone and oral prednisolone
were administered to 10 patients with DRESS patients who received oral corticosteroid therapy were
more likely to develop herpes virus infections and pneumonia, compared with those who did not,
although the later were more likely to develop autoimmune complications.

Topical and supportive treatment
• Milder forms of the disease, supportive and topical therapy alone may be sufficient.
• In a retrospective study, another group studied a cohort of 38 patients with a DRESS score of 4 or
more (at least probably DRESS) and observed that 66% of the patients in their cohort were treated
with high-potency topical steroids alone
• significantly lower rate of infections and intensive care unit admissions, shorter hospital stay, and
shorter duration of treatment, although one patient (4%) developed progressive disease and died.
None of the 13 patients who were treated with systemic corticosteroids died during the study
duration.
• Antihistamines
• Fluid replacement

Management IVIg
• • For cases with ongoing relapse or who are recalcitrant
• • Dose : 1–2 g/kg for 5 days
• • IVIG contain antibodies that regulate immune responses by inhibiting cytotoxic T cells
• • Interferes with the generation and activation of cytotoxic T cells and decreases activity by blocking
cell surface molecules like antigen-specific T cell receptor
J Allergy Clin Immunol Pract. 2022 May;10(5):1155-1167.e5

IVIg
• IVIG compensate for the patient’s decreased immunoglobulin concentration, support immune
defense against HHV-6 infection, and have a substantial anti-inflammatory effect.
• Their use is controversial
• At an early stage of the disease, however, IVIG are thought to accelerate rapid B cell recovery,
resulting in an increase of autoantibodies production; the development of these autoantibodies
could be prevented by using systemic corticosteroids, leading to a consensus that corticosteroids
and IVIG should be used together in severe forms.
• Intravenous immunoglobulin (IVIG) has been reported as treatment for DRESS in case reports, case
series, and retrospective studies.
• High dose IVIG 200mg/kg/d for 5 days
• IVIG 1-2 mg/kg/d

• Retrospectively reviewed patients with DRESS syndrome who received IVIG
in addition to systemic steroids during 2012– 2017
• 18 DRESS patients were included
• IVIG treatment was added within a median time of 7 days from the
• commencement of systemic steroid therapy
• After IVIG treatment (total dosage: 1– 2 g/kg)
• - fever resolved within a median time of 1 day (range 0– 3)
- liver enzymes improved within a median time of 13 days (range 0– 27)
• = IVIg may be helpful in cases refractory to systemic steroid
treatment
Clin Transl Sci. 2022 Mar;15(3):782-788

Cyclosporine
• Cyclosporine appears to be an alternative to corticosteroids, with much shorter treatment times and
with an adequate safety profile (case reports)
• Dose : cyclosporine 3-5 mg/kg divided twice daily for 7 days, tapered to 1.5-2.5 mg/kg divided twice
daily for 7 days

Others
• Su et al. recently demonstrated the efficacy of cyclosporine in 8 cases of corticosteroid-dependent
DRESS syndrome. The mechanism of action is linked to the inhibition by cyclosporine of various
cytokines (IL-2, IL-3, IL-4, IL-5, and TNF) implicated in the pathogenesis of DRESS syndrome;
• Cyclosporine, plasmapheresis, cyclophosphamide, mycophenolate mofetil, rituximab, and
tofacitinib have been successfully used in the treatment of steroid refractory DRESS/DIHS, including
those with myocarditis.
• Plasma exchange, which contributes to the reduction in circulating cytokine levels. There are cases
in the literature where plasma exchange has been successfully used in pediatric patients with
corticosteroid- resistant DRESS syndrome, however, further investigation and more scientific.
• Blocking IL-5 and/or its receptor, namely mepolizumab and reslizumab, monoclonal antibodies
active against IL-5, and benralizumab, active against the IL-5 receptor.

Sequelae
- Risk of developing systemic autoimmune
sequelae, from months - 4 years after resolution
- Loss of regulatory T lymphocyte function and
a loss of tolerance to autoantigens
- Most common : autoimmune thyroiditis
J Allergy Clin Immunol Pract. 2022 May;10(5):1155-1167.e5

Sequelae
• Acute sequelae
• Hepatitis ; transminitis
• Renal insufficiency ; mild elevation of creatinine to severe intstitial nephritis
• Myocarditis ;
• The likelihood of death was 10 times higher among patients with DRESS-associated
myocarditis who were not treated with corticosteroids compared with those who were.
• minocycline, allopurinol, ampicillin, dap- sone, and trimethoprim-sulfamethoxazole

• Long-term sequelae
• These sequelae may appear after a long, symptom-free interval after complete resolution
can be as long as 4 years of the acute- phase DRESS/DIHS or may be a continuation
• autoimmune thyroiditis, but they also observed diabetes, autoimmune hemolytic anemia, and
alopecia.
• autoimmune blistering disorders, sclerodermoid cutaneous changes, systemic lupus
erythematosus, and enteropathy.
Sequelae

• Long-term sequelae are described in 10.8% of the pediatric population and are defined as
conditions observed 1–24 months after the DRESS syndrome
• The most common are autoimmune diseases, including hypothyroidism, type 1 diabetes mellitus,
systemic lupus erythematosus, systemic sclerosis, adrenal insufficiency, and autoimmune hemolytic
anemia, which can occur months to years after the resolution of the syndrome, highlighting the
importance of long-term follow-up and surveillance
• A recent study demonstrated that interferon-induced protein (IP)-10 is associated with HHV-6
reactivation and a higher incidence of long-term sequelae, which is why in the future it could be
used as a predictive marker for the development of sequelae
Sequelae

• Previous studies have shown that children have an increased risk of developing type 3 polyglandular
autoimmune syndrome as a sequela of DRESS syndrome. It has therefore been suggested to subject
patients with DRESS syndrome, especially children, to an autoantibody screening and in patients at
risk to carefully evaluate whether to subject them to therapies that induce a rapid increase in B and
T cells, such as IVIG and pulsed prednisolone
Sequelae

• Nine patients died before interview, whereas 43 patients completed a specially designed
questionnaire. The overall cumulative incidence of long-term sequelae was 11.5% (6 of 52
patients). Four patients developed autoimmune diseases, specifically Graves disease (n = 2),
type 1 diabetes mellitus (n = 1), and autoimmune hemolytic anemia (n = 1). Alopecia areata
was also noted in 1 of the 2 patients with Graves disease. The other 2 patients developed renal
failure after visceral involvement and required lifetime hemodialysis.
( J Am Acad Dermatol 2013;68:459-65.)
Sequelae

Prognosis
• Average recovery period 6-9 weeks
• More than 20% of cases the disease can persist for several months with relapses • Mortality is 3.8%,
mainly due to fulminant hepatitis and liver necrosis

Prognosis and recovery
• Complete recovery is not immediate but takes a few weeks for most patients.
• DRESS syndrome recurrence in the pediatric population appears to be strongly related to the
presence of fever, facial edema, lymph node enlargement, leukocytosis, pharyngeal and internal
organ involvement, and chronic medical conditions.
• The course of the DRESS syndrome frequently shows various episodes of complete or partial
recurrences, despite removing the culprit drug. Reactivation of cutaneous manifestations during the
first months after the episode often occurs in a milder form and in a shorter time window after drug
re-exposure.
• Relapses are more frequent in children who have comorbidities, including neuropsychiatric
conditions, and who require long-term therapy with anticonvulsants, which could induce a new
episode due to cross-reactivity between some molecules.

Drug-related relapses in DRESS
• Relapses of DRESS may be related to administration of new drugs or to previously tolerated drugs
after dose increase
• Unknown mechanism:
- Suspected from stimulation of already activated T cells → may tolerate the suspected drug after
complete recovery from the relapse
- Some patients showed a new T cell sensitization → multiple drug hypersensitivity syndrome (MDH)
Clin Transl Allergy. 2020 Nov 23;10(1):52

• A monocentric, retrospective analysis
• Patients with DRESS (RegiScar ≥4) between January 2011-
December 2018
• Skin tests and LTT were performed during the recovery
state within 24 months after diagnosis DRESS
• Relapses = transient re-occurrence of clinical symptoms
and/or laboratory signs occurring during or within 24
months after resolution of DRESS

• All drugs involved in relapses were different to the initial drugs causing DRESS
• 8/16 (50.0%) of drug-related relapses patients show sensitization to a suspected culprit drug

•
Conclusion :
- Patients with DRESS are at risk that new drugs may result in another severe DHR
- Advisable to be as restrictive as possible with administration of new drugs during a DRESS
reaction

DRESS syndrome.pdf

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DRESS syndrome.pdf