mercaptopurine and Lymphohistiocytosis--Hemophagocytic

Macrophage activation syndrome is a life-threatening syndrome of uncontrolled immune activation with variable clinical presentation making early diagnosis difficult. It is often manifested by the development of multi-organ failure due to systemic inflammatory response. Patients with ulcerative colitis (UC) on purine antimetabolites are at high risk for severe myelosuppression due to the mechanism of thiopurine toxicity which potentially contributes to the development of macrophage activation syndrome. We present a case of a 39-year-old woman with a 2-year history of UC previously treated with 6-mercaptopurine (6-MP) and recent COVID-19 infection, who was admitted to our emergency department for C. difficile infection and subsequently developed macrophage activation syndrome. This case report also raises the question of whether abrupt discontinuation of 6-MP may have contributed to the worsening of the patient's symptoms of underlying hemophagocytic lymphohistiocytosis (HLH) and her rapid deterioration. Both macrophage activation syndrome and COVID-19 infection can produce a large number of pro-inflammatory cytokines termed "cytokine storm," but a pro-inflammatory cytokine panel breakdown helps to differentiate between the two. Our case report emphasizes the importance of close monitoring of patients on purine antimetabolite therapy who present with signs and symptoms of systemic toxicity.

Topics: Adult; Clostridioides difficile; COVID-19; Female; Humans; Lymphohistiocytosis, Hemophagocytic; Macrophage Activation Syndrome; Mercaptopurine

The lymphoproliferative disorders (LDs) are a heterogeneous group of at least 70 conditions that result from the clonal proliferation of B, T, and NK cells. Inflammatory bowel disease (IBD)-associated lymphomas are typically B-cell LD, while T-cell or Hodgkin's lymphomas are rare. In IBD patients not on immunosuppression, the risk of LD seems to be similar or slightly higher than the background population risk. Thiopurine therapy is associated with an increased risk: the relative risk is increased four- to sixfold and the absolute risk varies between 1 in 4000-5000 for those aged 20-29 to 1 in 300-400 in those over 70. It is difficult to quantify the risk of anti- tumor necrosis factor (TNF) therapy alone; however, it appears to be less than for thiopurines alone. There is particular concern regarding the development of post-transplant-like LD in those with latent epstein-barr virus (EBV) infection exposed to immunosuppressives, the occurrence of hepatosplenic T cell lymphoma in patients treated with combination anti-TNF and thiopurine therapy, and the development of hemophagocytic lymphohistiocytosis in those who acquire a primary EBV or other infections while on immunosuppressive medication. There are currently no guidelines for monitoring EBV (or other virus) status in patients on immunosuppression, although it could be used to monitor those who have a prior history of lymphoma and are about to start a thiopurine or anti-TNF agent. In discussing the risks of lymphoproliferative disorders associated with agents used for the treatment of IBD, patients can often be reassured that the benefits of such therapy still outweigh the small, but real, risks.

Topics: Age Factors; Azathioprine; Epstein-Barr Virus Infections; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Lymphohistiocytosis, Hemophagocytic; Lymphoma; Lymphoproliferative Disorders; Mercaptopurine; Risk Factors; Tumor Necrosis Factor-alpha

Although thiopurine is a crucial drug for treating acute lymphoblastic leukemia, individual variations in intolerance are observed due to gene polymorphisms. A 3-year-old boy with B-cell precursor acute lymphoblastic leukemia who was administered thiopurine developed mucositis, sepsis, and hemophagocytic lymphohistiocytosis due to prolonged hematologic toxicity, chronic disseminated candidiasis, and infective endocarditis that triggered multiple brain infarctions. The patient was found to harbor 3 gene polymorphisms associated with thiopurine intolerance including homozygous NUDT15 R139C, heterozygous ITPA C94A, and homozygous MTHFR C677T and heterozygous RFC1 G80A. Thus, the combined effect of intolerance via multiple gene polymorphisms should be considered in case of unexpected adverse reactions.

Topics: Antimetabolites, Antineoplastic; Brain Infarction; Child, Preschool; Drug Hypersensitivity; Homozygote; Humans; Infections; Lymphohistiocytosis, Hemophagocytic; Male; Mercaptopurine; Mucositis; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Pyrophosphatases; Sepsis

We report the diagnostic and therapeutic challenges in an unusually fulminant presentation of measles, presenting as severe necrotizing bronchiolitis with secondary hemophagocytic lymphohistiocytosis (HLH) in the absence of classical clinical features in an immunocompromised host on maintenance chemotherapy. Our patient had presented with features of a viral pneumonitis without the classical exanthem, in combination with HLH. Although rhinovirus-induced HLH was highly unusual, the positive rhinovirus swab result had distracted us from the eventual diagnosis. This calls for greater impetus to increase awareness and public education to improve vaccination rates and herd immunity to curb outbreaks and protect the immunocompromised patients.

Topics: Adrenal Cortex Hormones; Anti-Infective Agents; Antineoplastic Combined Chemotherapy Protocols; Cryptogenic Organizing Pneumonia; Diagnostic Errors; Extracorporeal Membrane Oxygenation; Fatal Outcome; Humans; Lymphohistiocytosis, Hemophagocytic; Maintenance Chemotherapy; Male; Measles; Mercaptopurine; Methotrexate; Multiple Organ Failure; Pancytopenia; Picornaviridae Infections; Plasma Exchange; Pneumonia, Viral; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Rhinovirus; Sepsis; Survivors

We report a case of Epstein-Barr virus (EBV)-driven haemophagocytic lymphohistiocytosis (HLH) in a man with Crohn's disease treated with 6-mercaptopurine and adalimumab therapy who was successfully treated with rituximab therapy alone. This is the first published case in an adult patient with EBV-driven HLH in the setting of thiopurine use and inflammatory bowel disease to be successfully treated with rituximab therapy alone. Here, we will discuss putative immunological mechanisms which may contribute to this potentially life-threatening complication.

Topics: Adalimumab; Anti-Inflammatory Agents; Crohn Disease; Epstein-Barr Virus Infections; Humans; Immunologic Factors; Immunosuppressive Agents; Lymphohistiocytosis, Hemophagocytic; Male; Mercaptopurine; Rituximab; Young Adult

We describe a 4-year-old female with pre-B-cell acute lymphoblastic leukemia on maintenance chemotherapy, who developed hemophagocytic lymphohistiocytosis (HLH) secondary to Epstein-Barr virus (EBV) infection, complicated by an aggressive lymphoproliferative disorder. Although there was no history of bone marrow transplant or underlying immunodeficiency, EBV triggered a post-transplant lymphoproliferative disease (PTLD)-like lymphoma. Multiple regimens of chemotherapy failed to induce remission and patient developed multiorgan failure. The association of HLH with EBV-related PTLD-like lymphoproliferative disorder is rare. We present this case to highlight this unusual association so that this highly fatal disease can be recognized and promptly addressed.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Child, Preschool; Cyclosporine; Dexamethasone; Epstein-Barr Virus Infections; Etoposide; Female; Humans; Immunocompromised Host; Infant; Lymphohistiocytosis, Hemophagocytic; Male; Mercaptopurine; Methotrexate; Multiple Organ Failure; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Rituximab; Treatment Failure; Vincristine; Viral Load

To assess the incidence of hemophagocytic lymphohistiocytosis (HLH) in a well-defined population of children with inflammatory bowel disease (IBD) and evaluate the common clinical and laboratory characteristics of individuals with IBD who developed HLH.. We conducted a retrospective study of all children who developed HLH over an 8-year period. The incidence of HLH in patients with IBD was calculated using US census data and a statewide project examining the epidemiology of pediatric IBD.. Among children in Wisconsin, 20 cases of HLH occurred during the study period; 5 cases occurred in children with IBD. Common characteristics include: Crohn's disease (CD), thiopurine administration, fever lasting more than 5 days, lymphadenopathy, splenomegaly, anemia, lymphopenia, and elevated serum triglycerides and ferritin. Of the patients, 4 had primary Epstein-Barr virus infections. The incidence of HLH among all children in Wisconsin was 1.5 per 100 000 per year. The risk was more than 100-fold greater for children with CD (P < .00001).. Pediatric patients with CD are at increased risk for developing HLH; primary Epstein-Barr virus infection and thiopurine administration may be risk factors.

Topics: Adolescent; Anemia; Azathioprine; Crohn Disease; Epstein-Barr Virus Infections; Ferritins; Fever; Humans; Immunosuppressive Agents; Incidence; Lymphatic Diseases; Lymphohistiocytosis, Hemophagocytic; Lymphopenia; Mercaptopurine; Retrospective Studies; Splenomegaly; Triglycerides; Wisconsin

A case of hemophagocytic syndrome associated with ulcerative colitis is very rare. A 32-year-old man visited the hospital complaining of fever and severe abdominal pain for 7 days. He was diagnosed to have ulcerative colitis 2 years ago and had been treated with sulfasalazine. Three months ago, he had abdominal pain, weight loss, and hematochezia, so prednisolone and mercaptopurine were added to the treatment. On admission, the physical examination showed splenomegaly. Peripheral blood counts revealed pancytopenia, and bone marrow aspirate smears showed many histiocytes with active hemophagocytosis. There was no evidence of viral and bacterial infections and other neoplasms, which were commonly associated with hemophagocytic syndrome. He was successfully treated with high dose steroid. We report this case along with a review of the related literatures.

Topics: Adult; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Bone Marrow Cells; Colitis, Ulcerative; Colonoscopy; Dexamethasone; Humans; Immunosuppressive Agents; Lymphohistiocytosis, Hemophagocytic; Male; Mercaptopurine; Prednisolone; Sulfasalazine; Syndrome; Tomography, X-Ray Computed