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 Table of Contents  
CASE REPORT
Year : 2021  |  Volume : 8  |  Issue : 3  |  Page : 312-316

DRESS syndrome: a case report


Department of Geriatrics, MGM Medical College and Hospital, Navi Mumbai, Maharashtra, India

Date of Submission21-May-2021
Date of Acceptance12-Jun-2021
Date of Web Publication03-Sep-2021

Correspondence Address:
Dr. Tushar Kanti Biswas
Department of Geriatrics, MGM Medical College and Hospital, Kamothe, Navi Mumbai 410209, Maharashtra.
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mgmj.mgmj_29_21

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  Abstract 

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare adverse drug reaction. We report a rare case of DRESS syndrome secondary to antitubercular treatment (ATT). A 65-year-old male patient with pulmonary tuberculosis (TB) presented with fever, cough and breathlessness, flushing of the face, and itchy erythematous maculopapular rashes over the abdomen, thorax, upper and lower extremities for 3 days, about 4 weeks after starting fixed-dose combination (FDC) of antitubercular drugs-intensive phase therapy as recommended under the Revised National TB Control Programme (RNTCP). Investigations revealed eosinophilia, severe thrombocytopenia, cholestatic hepatitis, and acute kidney injury (AKI) with metabolic acidosis. FDC was withheld and the patient was managed as DRESS syndrome fulfilling diagnostic criteria. The patient showed gradual improvement with progressive return of laboratory parameters towards normal levels. DRESS syndrome following ATT is very rare with fewer case reports from India. Physicians prescribing ATT need to be aware of this severe hypersensitivity reaction to anti-TB drugs.

Keywords: DRESS syndrome, eosinophilia, fixed-dose combination (FDC)


How to cite this article:
Gudi S, Biswas TK, Kane S. DRESS syndrome: a case report. MGM J Med Sci 2021;8:312-6

How to cite this URL:
Gudi S, Biswas TK, Kane S. DRESS syndrome: a case report. MGM J Med Sci [serial online] 2021 [cited 2021 Sep 21];8:312-6. Available from: http://www.mgmjms.com/text.asp?2021/8/3/312/325538




  Introduction Top


Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, which is also termed as drug-induced hypersensitivity syndrome (DIHS), is a distinct severe adverse drug reaction to certain medications characterized by a long latent period. Clinically, DRESS/DIHS presents with a prodrome of fever and flu-like symptoms for several days, followed by the appearance of a diffuse morbilliform eruption usually involving the face. Systemic manifestations include lymphadenopathy, fever, and leucocytosis, eosinophilia, or atypical lymphocytosis, as well as hepatitis, nephritis, pneumonitis, myositis, and gastroenteritis, in descending order.

The symptoms of DRESS syndrome usually begin 2–8 weeks after exposure to an offending drug. The aromatic anticonvulsants (phenytoin, phenobarbital, carbamazepine) and sulphonamides are the most common cause of DRESS syndrome (incidence ranging between 1 in 1,000 and 1 in 10,000 exposures) but a variety of other drugs have been associated with this clinical entity. Very few cases of DRESS syndrome associated with first- or second-line anti-tuberculosis (anti-TB) drugs have been reported. The pathogenesis of DRESS is not fully understood. Most patients with DRESS syndrome recover completely in weeks to months after causative drug withdrawal.[1],[2],[3] We report a case of DRESS syndrome secondary to anti-TB drugs.


  Case history Top


A 65-year-old male patient presented to the geriatric outpatient department (OPD) with complaints of fever, flushing of the face, itchy rash on the upper limb, thorax, abdomen, and lower extremities for 3 days. He also had cough with breathlessness for 3 days. Fever was insidious, high grade, more so during the evening, and relieved on taking medication. Cough was associated with scanty mucoid sputum, nonblood stained. Breathlessness was grade 3 (MMRC/Modified Medical Research Council scale) and had progressed over the last 3 days. There was no history of orthopnea, paroxysmal nocturnal dyspnoea, chest pain, or palpitation. There was no history of joint pain, retro-orbital pain, or any bleeding manifestations.

The patient was diagnosed as a case of pulmonary TB (though sputum-reports not available) by an outside physician 1 month ago and started on fixed-dose combination (FDC)-intensive phase therapy as recommended under the RNTCP program. The patient had no other comorbidities. On examination, the patient’s vitals were stable. He had dry skin with erythematous maculopapular lesions over the abdomen, thorax [Figure 1] and [Figure 2], upper and lower extremities. There was no mucosal or conjunctival involvement or lymphadenopathy. The findings of the abdominal examination did not reveal any hepato-splenomegaly. The findings of the examination of cardiovascular, respiratory, and central nervous systems were unremarkable.
Figure 1: Widespread maculopapular rashes over the abdomen and thorax (front)

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Figure 2: Widespread maculopapular rashes over the abdomen and thorax (back)

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Lab investigations revealed that the patient had eosinophilia, severe thrombocytopenia with a platelet count of 11,000/c.mm, and evidence of cholestatic hepatitis with raised total and direct serum bilirubin, raised serum alkaline phosphatase (ALP), aspartate aminotransferase (AST), and AST/ALP ratio less than 2. The patient also had acute kidney injury (AKI) with low urine output and serum creatinine of 4. mg/dL and blood urea of  mg/dL with ABG (arterial blood gas) analysis suggestive of high anionic gap metabolic acidosis. On peripheral smear, the patient had a normocytic normochromic picture with thrombocytopenia and eosinophilia [Table 1].
Table 1: Laboratory investigations

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Serology for dengue, leptospirosis, widal, HIV, HbsAg, and HCV were all negative.

Chest X-ray PA view [Figure 3] showed bilateral lower and mid zones nonhomogenous opacities.
Figure 3: Bilateral lower and mid zones nonhomogenous opacities

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The patient’s antitubercular treatment (ATT) was put on hold after the lab investigations and he was treated for metabolic acidosis and the AKI with bicarbonate infusion and ringer lactate solution. The patient did not undergo a skin biopsy. The patient was started on ethambutol and levofloxacin regimen for pulmonary TB. The patient’s lab investigations improved significantly over 5 days. ABG returned to normal, and platelets increased to 2 lakhs/c.mm, LFT (liver function test) showed a decrease in the enzyme levels; urine output improved, serum creatinine value came down to 1. mg/dL with blood urea  mg/dL. He showed regression of skin lesions and fever subsided. The patient was advised for follow-up with repeat investigations.


  Discussion Top


Anti-TB therapy, especially the fixed drug combination (FDC) therapy, is said to be more efficacious and more tolerable by the patient. As much as the usefulness of the regime, and the potential that it has to save lives, there is an undeniable prominence of adverse reaction that occurs due to these drugs from skin manifestations to severe disabling neurological disturbances.

DRESS syndrome is one such manifestation, which is a severe, idiosyncratic, multisystem reaction characterized by a triad of fever, rash, and multiorgan system involvement (which includes hepatitis, carditis, nephritis, and/or pneumonitis).[1] Mortality ranges between 8% and 10% in this condition especially if there is liver involvement, hence early diagnosis and treatment are crucial.[1],[3],[4],[5] Aromatic anticonvulsants (phenytoin, phenobarbital, carbamazepine) are the most common cause of DRESS, but a variety of other drugs, such as allopurinol, minocycline, dapsone, sulfasalazine, and mexiletine, have also been associated with DRESS.[1],[3]

But, DRESS syndrome following ATT is very rare and there are only a few case reports in the literature.[1],[2],[6] Furthermore, there have been fewer case reports from India that have shown DRESS syndrome secondary to ATT.[5] The drug most often associated with DRESS was rifampicin, whereas the most well-tolerated drugs upon re-administration were levofloxacin, ethambutol, cyclosporine, and streptomycin (streptomycin was also associated with skin reactions).

The pathogenesis of DRESS is not fully understood and may be multifactorial, involving immunological mechanisms and particular drug metabolism. Delayed hypersensitivity (Type IV) to reactive drug metabolites may be involved in the pathogenesis of DRESS, directed by drug-specific T cells. A genetic predisposition is evidenced by an increased risk in patients with a family history of DRESS syndrome, suggesting that genetic factors may also play roles in the pathomechanisms of DRESS syndrome. One such factor is the polymorphism in genes encoding metabolizing enzymes for drugs, such as cytochrome P (CYP) 450 enzyme and N-acetyltransferase. Reduced activities of these metabolizing enzymes cause the accumulation of drugs or their active metabolites, which can then interact with cellular proteins or peptides, in turn evoking immune responses.

Several emerging studies have revealed associations between polymorphisms in HLA alleles and the development of DRESS syndrome. However, some critical problems remain unresolved as for lots of the culprit drugs, a genetic predisposition for patients with DRESS syndrome is still unidentified.

Reactivation of herpesviruses, in particular human herpesviruses 6 and 7, EBV, and cytomegalovirus (CMV), has also been frequently reported in this syndrome, although the causal role of viral infection has been debated. Inciting drugs may reactivate quiescent herpes viruses, resulting in expansion of viral-specific CD8+ T lymphocytes and subsequent end-organ damage. The activated T cells in DRESS syndrome are complex. Hanselet al.[7] had reported a case of DRESS syndrome caused by ceftriaxone, which had been confirmed by patch testing. Immunohistochemical study of skin biopsies from both the exanthema and the patch test revealed positive results for interleukin (IL)-5, perforin, granzyme B, fatty-acid synthase ligand (FasL), and interferon (IFN), which supported the notion that DRESS syndrome belongs to type IVb/IVC hypersensitivity reaction.[3],[8]

DRESS is specifically complicated because of its variable latency period (commonly 3 weeks) and presentation. Not all symptoms and signs are always recognized, and asymptomatic systemic involvement such as eosinophilia and atypical lymphocytes are often not determined or are determined too late, leading to their under-reporting.

Rifampicin is one of the drugs used as a first-line treatment of TB- pulmonary or extrapulmonary. The most common drug reaction occurring due to this drug is hepatotoxicity. It is most often a cholestatic type of hepatitis with raised serum bilirubin and enzymes that resolve sometimes without stopping the drugs but most often the drug is discontinued. Dermatologically, the patient can manifest with flushing of the face with an erythematous maculopapular rash all over the body and sometimes also can manifest with thrombocytopenic purpura. The most common hematological manifestation includes thrombocytopenia which improves immediately as the drug is stopped. The patient can also present with flu-like symptoms and finally in the kidney, the patient can have three different types of manifestation such as interstitial tubular necrosis, acute interstitial nephritis, progressive interstitial nephritis. Patients usually present with one or more of these symptoms.

There is no conclusive or specific test to diagnose DRESS syndrome. Diagnosis is one of the clinical manifestations with abnormality in the hematological test (mainly eosinophilia) derangement of the liver and kidney functions if manifested with involvement of these systems. Skin biopsy is also not specific.[3] The Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) group suggested criteria for hospitalized patients with a drug rash to diagnose DRESS syndrome [Table 2].[9]
Table 2: Registry of severe cutaneous adverse reaction criteria for diagnosis of drug rash and eosinophilia with systemic symptoms

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The RegiSCAR group also proposes a scoring system that comprises the major features of DRESS syndrome, giving each item a score of minus one point, zero points, one point, or two points. The diagnosis of DRESS syndrome is then made based on the total score: <2 points: no case; 2–3 points: possible case; 4–5 points: probable case; >5 points: the definite case for diagnosing DRESS syndrome.[8]

The mainstay of treatment for this remains to be an immediate withdrawal of the offending drugs and treating the patient symptomatically, with corticosteroid (topical/oral-depending on the symptoms) and starting the patient with a different line of ATT. However, the use of systemic corticosteroids remains controversial, as it is associated with a higher incidence of relapse compared to topical glucocorticoid treatment and may be associated with a higher rate of opportunistic infection.[4],[8]

This patient received FDC therapy and it is not known, which antitubercular drug, in particular, is responsible for this syndrome. We might consider reintroducing sequentially the primary drugs such as INH, RIF, and PZN later under hospitalization to identify the likely agent but the patient should be monitored vigilantly and if the symptoms start to appear then the drugs should be stopped immediately. The causative drug of DRESS syndrome is mostly determined based on drug history and subjective clinical assessment. Consideration must be given to the likelihood of a particular drug to cause the syndrome when multiple drugs are involved. A culprit drug is identified by drug re-challenging test in only a handful of cases.[2] Patch tests and in vitro lymphocyte tests have been used, but the sensitivity and specificity of these tests are variable, depending on the drug.[4]


  Conclusion Top


DRESS syndrome, an important clinical condition that occurs as a triad of fever, rash, and eosinophilia with the involvement of systemic organs, is rarely reported secondary to anti-TB therapy, as in the present case. Knowledge, Identification of the condition, and removal of the offending drug are of utmost importance. There is no specific diagnostic test that can confirm DRESS syndrome. Patients should avoid re-exposure. Suitable treatment alternatives have to be found. Physicians who prescribe ATT need to be aware of this severe hypersensitivity reaction to anti-TB drugs. General awareness of DIHS/DRESS is very important due to the severity and life-threatening potential of this type of drug reaction.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Kaswala DH. Drug rash with eosinophilia and systemic symptoms syndrome due to anti-TB medication. J Family Med Prim Care 2013;2:83-5.  Back to cited text no. 1
[PUBMED]  [Full text]  
2.
Lee Jin-Yong, Seol Yun-Jae, Shin Dong-Woo, Kim Dae-Young, Chun Hong-Woo, Kim Bo-Young, et al. A case of the drug reaction with eosinophilia and systemic symptom (DRESS) following isoniazid treatment. Tuberc Respir Dis (Seoul) 2015;78:27-30.  Back to cited text no. 2
    
3.
Tas S, Simonart T. Management of drug rash with eosinophilia and systemic symptoms (DRESS syndrome): An update. Dermatology 2003;206:353-6.  Back to cited text no. 3
    
4.
Ghislain PD, Roujeau JC. Treatment of severe drug reactions: Stevens-Johnson syndrome, toxic epidermal necrolysis and hypersensitivity syndrome. Dermatol Online J 2002;8:5.  Back to cited text no. 4
    
5.
Bartakke S, Shinde V, Shrividya S. Antituberculosis treatment-induced Drug Rash with Eosinophilia and Systemic Symptoms syndrome. Med J DY Patil Univ 2016;9:271-3.  Back to cited text no. 5
  [Full text]  
6.
Kim JH, Jang SH, Kim DH, Park S, Kim DG, Jung KS. A case of DRESS syndrome induced by the antituberculosis drugs, prothionamide, and para-aminosalycilic acid. Ann Allergy Asthma Immunol 2013;110:118-9.  Back to cited text no. 6
    
7.
Hansel K, Bellini V, Bianchi L, Brozzi J, Stingeni L. Drug reaction with eosinophilia and systemic symptoms from ceftriaxone confirmed by positive patch test: An immunohistochemical study. J Allergy Clin Immunol Pract 2017;5:808-10.  Back to cited text no. 7
    
8.
Cho YT, Yang CW, Chu CY. Drug reaction with eosinophilia and systemic symptoms (DRESS): An interplay among drugs, viruses, and immune system. Int J Mol Sci 2017;18:1243.  Back to cited text no. 8
    
9.
Kardaun SH, Sidoroff A, Valeyrie-Allanore L, Halevy S, Davidovici BB, Mockenhaupt M, et al. Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: Does a DRESS syndrome really exist? Br J Dermatol 2007;156:609-11.  Back to cited text no. 9
    


    Figures

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