Case Presentation

A 66-year-old female, known case of diabetes, hypertension and hypothyroidism for more than 10 years, presented with the following: 1) high-grade continuous fever with rashes which started on both forearms and spread to involve  a trunk associated with itching 2) Odynophagia since 10 days. There was past history of fever with thrombocytopenia before 6 months. Dengue IgM was positive, But platelet was persistently low even after 2 weeks of fever onset and reached a level of 2000 cells/ microlitre by third week, which was not consistent with natural history of dengue, and also previous medical records have shown low platelet counts (less than 1lakh) consistently. After extensive workup for thrombocytopenia, the patient was diagnosed to have ITP and started on steroid and azathioprine.

On Examination

Febrile (99.6⁰ F), blanching maculopapular rashes with target lesion were present predominantly over extremities and multiple firm non-tender non-matted mobile lymph nodes of greater than 1cm were palpated over bilateral anterior cervical, axillary and inguinal regions. Oral thrush was present.

Figure 1 – Skin Lesion

Investigations

Hb-9.9 g/dl, total count – 14000(N36%,L34%,E28%,M2%,B0%), Platelet – 165000, Peripheral smear – eosinophilia, no blast cells, Absolute eosinophil count – 3920 cells/ microlitre, serum IgE level normal,RFT, LFT, urine routine – no significant abnormality, CTchest and abdomen – multiple significant mediastinal, right hilar, peri gastric, peri-pancreatic iliac and aortic lymph nodes present with no central necrotic area. No splenomegaly or lung infiltrates.Dengue NS1/IgM, MPQBC, COVID 19 – negative, Blood culture – negative, Anti VCA IgM & IgG for EBV negative, IgM for leptospirosis and scrub typhus- negative.

Problem

• Recent History of Thrombocytopenia on Immunosuppressant
• Odynophagia / Oral candidiasis
• Fever with rashes – Erythema multiforme
• Generalized lymphadenopathy
• Peripheral eosinophilia without organ damage

Differential Diagnosis

1. Lymphoma
2. Dress (Drug Reaction With Eosinophilia And Systemic Symptoms)

Figure 2 – Evaluation Of Thrombocytopenia

Discussion

Immune thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by antibody-mediated platelet destruction. It has been reported that about 20% of cases of ITP are associated with secondary causes like other autoimmune diseases, drugs, viral infections, Helicobacter pylori infection, lymphocytic leukemia, Hodgkin’s lymphoma, and non-Hodgkin’s lymphoma (NHL).^1,2,3 Such cases are defined as dsecondary ITP.

Before 6 months, there was no clinically significant lymphadenopathy, and also workup for secondary causes of thrombocytopenia were negative ( peripheral smear – no fragmented RBC, normal renal parameters, normal coagulation profile, normal liver function test, USG abdomen – no splenomegaly and normal liver, PCR for EBV,CMV,HSV, VZV, adenovirus – negative, HBV,HCV, HIV – negative, ANA – negative). Chest x ray- no hilar lymphadenopathy.

One of the new findings during current presentation is generalised lymphadenopathy. So the first differential diagnosis was lymphoma which can explain thrombocytopenia, erythema multiforme and eosinophilia. The reported presence of ITP in NHL is 0.76% as per four studies including 1,850 patients.³ A cohort study using a Swedish nation-wide database showed an increased incidence ratio of 7.5 for NHL after diagnosis of ITP.⁴ Increased antiplatelet antibodies were observed in most cases of ITP with NHL. Various studies have shown the role of platelet-specific autoreactive T cells in  ITP. It is possible that T-cell origin lymphoma cells activate B cells to produce antiplatelet antibodies.⁵ Erythema multiforme in association with  NHL have been reported in literature.^6,7,8 The pathophysiology of erythema multiforme (EM) probably is immunologically mediated. Dysregulated production of cytokines such as IL-3 and IL-5 by non Hodgkin lymphoma cell can increase eosinophil production and prolong longivity by inhibiting apoptosis accounting for secondary hypereosinophilia.⁹

Another differantial diagnosis was DRESS associated with azathioprine. Eosinophilia, skin rash (often maculopapular or erythematous), fever, lymphadenopathy, and inflammation of one or more organs  is a feature of DRESS syndrome. It is a delayed hypersensitivity reaction that typically develops 2 to 8 weeks after starting a drug. Many drugs including anticonvulsants, antibiotics, and allopurino lhave been linked to DRESS. Other hematologic abnormalities may include thrombocytopenia and atypical lymphocytes.

Cervical lymph node excision biopsy and HPE/IHC showed features of peripheral T-cell lymphoma – not otherwise specified-  a type of non Hodgkin’s lymphoma. Stool for ova and cyst (samples from 3 consecutive days) and IgE were negative. Bone marrow biopsy was carried out which was negative for primary eosinophilia. Skin biopsy showed perivascular infiltration with inflammatory cell, which is very non-specific.

Final Diagnosis

Peripheral T cell lymphoma – Not otherwise specified with secondary eosinoplilia and erythema multiforme.

Figure 3 – Lymphnode Biopsy Report

Reference

1. 1. Cines DB, Bussel JB, Liebman HA, Luning Prak et al. The ITP syndrome: pathogenic and clinical diversity. Blood. 2009;113(26):6511-21.
   2. Rogers KA, Woyach JA. Secondary autoimmune cytopenias in chronic lymphocytic leukemia. Semin Oncol. 2016;43(2):300-10.
   3. Hauswirth A. W., Skrabs C., Schützinger C., et al. Autoimmune thrombocytopenia in non-Hodgkin’s lymphomas. Haematologica. 2008;93(3):447–50.
   4. Fallah M., Liu X., Ji J., Försti A., Sundquist K., Hemminki K. Autoimmune diseases associated with non-Hodgkin lymphoma: a nationwide cohort study. Annals of Oncology. 2014;25(10):2025–30.
   5. Liu B., Zhao H., Poon M.-C., et al. Abnormality of CD4+CD25+ regulatory T cells in idiopathic thrombocytopenic purpura. European Journal of Haematology. 2007;78(2):139–43.
   6. Williams PM, Conklin RJ. Erythema multiforme: a review and contrast from Stevens-Johnson syndrome/toxic epidermal necrolysis. Dent Clin North Am. 2005;49(1):67-76.
   7. Volcheck GW. Clinical evaluation and management of drug hypersensitivity. Immunol Allergy Clin North Am. 2004;24(3):357-71.
   8. Aurelian L, Ono F, Burnett J. Herpes simplex virus (HSV)-associated erythema multiforme (HAEM): a viral disease with an autoimmune component. Dermatol Online J. 2003;9(1):1.
   9. Desmirean M, Deak D, Rus I, Dima D, Iluta S, Preda A, et al. Paraneoplastic hypereosinophilia in a patient with peripheral T cell lymphoma, not otherwise specified. Med Pharm Rep. 2019 Oct;92(4):421-6.

Dr. A. Vishnu Prasanth
Critical Care Specialist
Kauvery Hospital