Introduction:

Drug-induced hematological disorders can affect all the hematological elements including red blood cells, white blood cells, platelets, and the coagulation system.[1] Drug reaction with eosinophilia and systemic symptom (DRESS) syndrome is a rare severe drug-induced idiosyncratic hypersensitivity response characterized by maculopapular and/or erythrodermic eruption, fever, peripheral lymphadenopathy, eosinophilia or atypical lymphocytosis, and visceral organ involvement. It usually occurs 2 to 8 weeks after initiating the offending drug. Of the potential causative agents, the most common drugs to cause this reaction are aromatic antiepileptic drugs (especially phenytoin, carbamazepine, and phenobarbital). The estimated incidence of this syndrome ranges from 1/1000 to 1/10,000 drug exposures.[2,3]

In this report, we describe a case of DRESS syndrome in a young female with a unique presentation.

Case Report

A 22 years female presented to the OPD with fever, rashes over body and swelling over face since 1 week. Patient also experienced difficulty in breathing in the form of orthopnoea and yellowish discoloration of eyes. She was suffering from last 2 years with pain and swelling in different joints and was diagnosed case of Rheumatoid arthritis. Patient was started with Sulfasalazine following which after 1 week patient developed these symptoms. The complete blood count results revealed hemoglobin level was 11.1 g/dL; platelet count, 296,000/mm³; and leukocyte count, 55,000 cells per mm³ with eosinophilia and lymphocytosis. A peripheral smear showed atypical lymphocytosis, shift to left and eosinophilia with absolute eosinophil count of 8,250 cells per mm³ (Fig. 1).

Figure 1: Peripheral blood smear showing leucocytosis with atypical lymphocyte (red arrow) and eosinophils (green arrows)((Leishman X100).

Other investigations revealed raised serum bilirubin with total bilirubin level of 2.99 mg/dl, direct was 1.75 mg/dl and indirect was 1.24 mg/dl, mild elevation of liver transaminases, and lactate dehydrogenase (aspartate aminotransferase, 64 U/L; alanine aminotransferase, 168 U/L; lactate dehydrogenase, 625 U/L) were detected. Other biochemistry test results and coagulation studies were within normal limits. The chest x ray was normal. She was hospitalized. Hemoculture, urine culture, and viral serological tests including hepatitis A, B, and C, human immunodeficiency virus were all negative. On further review of the patient’s history, it was noted that the patient had received a course of sulfasalazine to treat rheumatoid arthritis, beginning approximately one week prior to admission.

The patient's condition was diagnosed with DRESS syndrome. Sulfasalazine was stopped. Systemic corticosteroid (methylprednisolone, 2 mg/kg per day for 7 days) along with oral antihistamine was initiated. Her clinical and laboratory findings returned to normal gradually within the first week of treatment, and she was discharged with a normal white blood cell count (10,800 cells per mm³) and normal differential cell count and absence of atypical lymphocytes in peripheral blood smear examination.

Discussion

Various drug induced hematological syndromes are Immunohemolytic anemia, Nonimmune hemolytic anemia, Methhemoglobinemia, Megaloblastic anemia, Sideroblastic anemia, Aplastic anemia, Pure red cell aplasia, Immune thrombocytopenia, Thrombotic microangiopathy, Platelet dysfunction, Hypercoagulability, Hypoprothrombinemia, Neutropenia, Neutrophilia, Eosinophilia, Polycythemia, Acute leukemia/myelodyplasia.[1]

The diagnosis in our patient was sulfasalazine -induced DRESS syndrome. Among various diagnostic criteria for DRESS syndrome, Bocquet et al. were the first to propose a diagnostic criteria based on the presence of (a) drug-induced cutaneous eruption, (b) hematological abnormalities (eosinophilia ≥1.5 × 10[9] /l or atypical lymphocytes), and (c)systemic abnormalities which include lymphadenopathy > 2 cm in diameter or hepatitis (transaminases > 2 times the reference value) or interstitial nephritis or interstitial lung disease, or myocardial involvement.[4] Various reports are available of Sulfasalazine-induced DRESS syndrome.[5]

The diagnosis of DRESS syndrome can be challenging as it can mimic many other diseases due to its highly variable clinical presentation. The differential diagnosis of this syndrome should include acute viral infections, hepatitis, sepsis, autoimmune diseases, and hematologic disorders.[6]

The DRESS syndrome pathophysiology remains uncertain and is hypothesized as an immune response to the drug with expansion of T lymphocytes. In other studies pathophysiology has been linked to the reactivation of human herpes virus, cytomegalovirus and Epstein-Barr virus. Genetic association is also postulated as it is found that alleles of the human leukocyte antigen (HLA) have been associated with increased susceptibility to DRESS syndrome.[7]

The frequency of development of DRESS syndrome depends on the drug used and the immune status of the individual.[2] The period from drug exposure to onset of disease can last 2 to 6 weeks, and may persist with a series of remissions and relapses. After discontinuation of the drug, the average recovery time is 6-9 weeks. DRESS syndrome has an approximate mortality rate of 10%.[2,8,9].

In a retrospective study conducted by Peyriere et al, among hematological abnormalities found in 216 cases of DRESS syndrome, eosinophilia was the most frequently occurring hematological abnormality (>50% of the cases). Other hematological abnormalities observed in patients included anemia, thrombocytopenia, neutropenia, and the presence of atypical lymphocytes which were large, activated lymphocytes.[10]

Silva et al in a case report found anemia of normocytic normochromic type, thrombocytopenia, leukocytosis with mild neutropenia, atypical lymphocytosis and eosinophilia (AEC- 973/mm³), along with elevated levels of C-reactive protein (CRP), transaminases (2 times the reference value), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), bilirubin (direct and indirect) and abnormalities in kidney function.[7]

In our case, similar to study conducted by Peyriere et al and Silva et al there was eosinophilia and presence of atypical lymphocytes in peripheral blood additionally there was leucocytosis and shift to left also and there were changes in liver function tests also. Our patient presented with fever and blood cell count abnormalities which can raise a suspicion for a hematologic malignancy.

Conclusion

The DRESS syndrome can be difficult to diagnose as its clinical findings can mimic those of other systemic diseases. DRESS should be included in the differential diagnosis of patients presenting with fever, rash, and hematological findings as described above. This case emphasizes the importance of incorporation of the patient’s clinical and medication history in the interpretation of hematological investigations. Awareness of the clinical, radiologic, and pathologic findings of DRESS is essential to avoid a misdiagnosis of hematological malignancy and hence unnecessary invasive investigations such as bone marrow examination.

References

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2. Husain Z, Reddy BY, Schwartz RA. DRESS syndrome: Part I. Clinical perspectives. J Am Acad Dermatol. 2013;68(5):693.e1-14; quiz 706-8. doi: 10.1016/j.jaad.2013.01.033.
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4. Bocquet H, Bagot M, Roujeau JC. Drug-induced pseudolymphoma and drug hypersensitivity syndrome (Drug Rash with Eosinophilia and Systemic Symptoms: DRESS). Semin Cutan Med Surg. 1996;15(4):250-7. doi: 10.1016/s1085-5629(96)80038-1.
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8. Cacoub P, Musette P, Descamps V, Meyer O, Speirs C, Finzi L, et al. The DRESS syndrome: a literature review. Am J Med. 2011; 124(7):588-97.
9. Husain Z, Reddy BY, Schwartz RA. DRESS syndrome: Part II. Management and therapeutics. J Am Acad Dermatol. 2013; 68(5):709.e1-9.
10. Peyrière H, Dereure O, Breton H, Demoly P, Cociglio M, Blayac JP, Hillaire-Buys D. Network of the French Pharmacovigilance Centers. Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist? Br J Dermatol. 2006;155(2):422-8. doi: 10.1111/j.1365-2133.2006.07284.x.