Childhood-onset Takayasu arteritis.

PURPOSE OF REVIEW: Takayasu arteritis is a rare chronic granulomatous large vessel vasculitis that predominantly affects the aorta and its branches. The purpose of this review is to unite the current knowledge regarding the pathophysiology, cause, and epidemiology as well as diagnosis, prognosis, and treatment of this condition in children. RECENT FINDINGS: Although the etiopathogenesis is not fully understood, studies suggest an autoimmune basis for the disease as well as a genetic predisposition. It is a disease primarily affecting young women with up to a third of cases with onset in childhood. There are distinct features of childhood-onset Takayasu arteritis (cTA) that merit this separate review. Diagnostic criteria and clinical manifestations are unique in pediatric patients with renovascular hypertension being the most prevalent presentation. Traditional treatments involving high-dose corticosteroids and cytotoxic agents are being reconsidered for less toxic contemporary biologic agents. Current algorithms for treatment include early introduction of corticosteroid-sparing agents, such as methotrexate or mycophenolate as well as tumor necrosis factor-alpha (TNF-α) inhibitor (infliximab, adalimumab) and/or interleukin-6 (IL-6) receptor inhibitor (tocilizumab). SUMMARY: Early diagnosis of cTA with goals to develop effective and well tolerated treatment paradigms are essential to improve the long-term prognosis of this rare and devastating disease.

Case report: Bordetella holmesii: A rare pathogen causing infective endocarditis associated glomerulonephritis.

Infective endocarditis (IE) can cause multiorgan dysfunction and chronic kidney disease, in addition to cardiac sequelae. The presentation may be vague and can manifest as acute glomerulonephritis. While the most common pathogens of infective endocarditis are Staphylococcus and Streptococcus species, we report a rare pathogen Bordetella holmesii causing infective endocarditis associated glomerulonephritis. A 20-year-old male patient with tetralogy of Fallot with pulmonary atresia and aortopulmonary collaterals underwent several cardiac surgeries including prosthetic pulmonary valve replacement in the past. He was admitted for 3 days at an outside hospital for fever, cough, and hemoptysis, and diagnosed with streptococcal pharyngitis, for which he received antibiotics. Five weeks later, he presented to our institution with lower extremity edema and gross hematuria. On examination, he was afebrile, normotensive, had a 7-kg weight gain with anasarca, and a systolic murmur, without rash. Investigations revealed elevated serum creatinine, nephrotic range proteinuria, hematuria, and hypocomplementemia, consistent with acute glomerulonephritis. Given his cardiac history, blood cultures were collected from three sites. Broad-spectrum antibiotics were initiated when he subsequently developed fever. Renal pathology on biopsy showed diffuse proliferative immune complex-mediated glomerulonephritis. Transesophageal echocardiogram visualized a vegetation on the pulmonary valve. Bordetella holmesii was ultimately cultured from the prior and current hospitalization. A serum sample detecting microbial cell-free DNA sequencing confirmed Bordetella holmesii at very high levels. After completing 6 weeks of intravenous antibiotics with concurrent angiotensin receptor blockade, his kidney function recovered with improvement in hypocomplementemia and proteinuria. This case report highlights the early recognition and comprehensive evaluation of a rare organism causing IE-associated GN, which allowed for renal recovery and preserved cardiac function.

CXCR4 allows T cell acute lymphoblastic leukemia to escape from JAK1/2 and BCL2 inhibition through CNS infiltration.

Targeting the JAK/STAT and BCL2 pathways in patients with relapsed/refractory T cell acute lymphoblastic leukemia (T-ALL) may provide an alternative approach to achieve clinical remissions. Ruxolitinib and venetoclax show a dose-dependent effect on T-ALL individually, but combination treatment reduces survival and proliferation of T-ALL in vitro. Using a xenograft model, the combination treatment fails to improve survival, with death from hind limb paralysis. Despite on-target inhibition by the drugs, histopathology demonstrates increased leukemic infiltration into the central nervous system (CNS) as compared to liver or bone marrow. Liquid chromatography-tandem mass spectroscopy shows that ruxolitinib and venetoclax insufficiently cross into the CNS. The addition of the CXCR4 inhibitor plerixafor with ruxolitinib and venetoclax reduces clinical scores and enhances survival. While combination therapy with ruxolitinib and venetoclax shows promise for treating T-ALL, additional inhibition of the CXCR4-CXCL12 axis may be needed to maximize the possibility of complete remission.