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Proceedings of the National Academy of... Jan 2024Human bone marrow failure (BMF) syndromes result from the loss of hematopoietic stem and progenitor cells (HSPC), and this loss has been attributed to cell death;...
Human bone marrow failure (BMF) syndromes result from the loss of hematopoietic stem and progenitor cells (HSPC), and this loss has been attributed to cell death; however, the cell death triggers, and mechanisms remain unknown. During BMF, tumor necrosis factor-α (TNFα) and interferon-γ (IFNγ) increase. These ligands are known to induce necroptosis, an inflammatory form of cell death mediated by RIPK1, RIPK3, and MLKL. We previously discovered that mice with a hematopoietic RIPK1 deficiency () exhibit inflammation, HSPC loss, and BMF, which is partially ameliorated by a RIPK3 deficiency; however, whether RIPK3 exerts its effects through its function in mediating necroptosis or other forms of cell death remains unclear. Here, we demonstrate that similar to a RIPK3 deficiency, an MLKL deficiency significantly extends survival and like Ripk3 deficiency partially restores hematopoiesis in mice revealing that both necroptosis and apoptosis contribute to BMF in these mice. Using mouse models, we show that the nucleic acid sensor Z-DNA binding protein 1 (ZBP1) is up-regulated in mouse RIPK1-deficient bone marrow cells and that ZBP1's function in endogenous nucleic acid sensing is necessary for HSPC death and contributes to BMF. We also provide evidence that IFNγ mediates HSPC death in mice, as ablation of IFNγ but not TNFα receptor signaling significantly extends survival of these mice. Together, these data suggest that RIPK1 maintains hematopoietic homeostasis by preventing ZBP1 activation and induction of HSPC death.
Topics: Animals; Humans; Mice; Apoptosis; Bone Marrow Failure Disorders; Cell Death; Hematopoietic Stem Cells; Necrosis; Nucleic Acids; Pancytopenia; Receptor-Interacting Protein Serine-Threonine Kinases
PubMed: 38227660
DOI: 10.1073/pnas.2309628121 -
Cureus Nov 2023We present a 29-year-old man admitted to our hospital with fatigue for two months of duration and recent palpitations, lightheadedness, blurred vision and nausea. Workup...
We present a 29-year-old man admitted to our hospital with fatigue for two months of duration and recent palpitations, lightheadedness, blurred vision and nausea. Workup showed pancytopenia with severe macrocytic anemia, laboratory and blood smear features of hemolysis, low reticulocyte percentage and a negative direct Coombs test. B12 and folate levels were normal. As bone marrow aspirate was suggestive of megaloblastic anemia and upper endoscopy showed atrophic gastritis, we ordered homocysteine (elevated) and intrinsic factor (IF) antibodies (positive). The workup led to the diagnosis of pernicious anemia with spuriously normal B12 levels. Replacement therapy allowed a rapid recovery. We highlight that the presence of IF antibodies can interfere with the competitive binding assays commonly used to measure B12 levels.
PubMed: 38106734
DOI: 10.7759/cureus.48937 -
Cureus Jul 2023Immune checkpoint inhibitors (ICIs) as standard of care have revolutionized the treatment of patients with metastatic melanoma. The combination of nivolumab and...
Immune checkpoint inhibitors (ICIs) as standard of care have revolutionized the treatment of patients with metastatic melanoma. The combination of nivolumab and ipilimumab improves treatment efficacy and prolongs survival compared to monotherapy alone. However, combination therapy is also associated with an increased incidence of adverse events. We report an uncommon yet important case of multi-organ failure in a patient following a single dose of nivolumab plus ipilimumab. A 60-year-old male with a history of ulcerative colitis in remission and metastatic melanoma was admitted on February 25, 2021, for presumed sepsis, after presenting with neutropenic fever. His brain metastases were previously resected on January 14, 2021, and he was started on dexamethasone 4 mg BID for six weeks. On February 11, 2021, he received one dose of nivolumab plus ipilimumab, per the CheckMate-067 protocol. He presented 14 days later with fever, diarrhea, pancytopenia, renal failure, drug-induced hepatitis, and myocarditis. The infectious workup was negative. His neutropenia responded to growth factors. He was diagnosed with interstitial nephritis due to immunotherapy and treated with corticosteroids. His symptoms resolved with concomitant improvement of his renal, hepatic, and cardiac function. He was discharged home in a stable condition. Although these specific immune-related adverse events (irAEs) are uncommon and rarely occur simultaneously, ICIs can trigger non-specific immune system activation, resulting in widespread inflammatory effects. Since irAEs can lead to multi-organ failure, as evidenced in this case, early recognition and institution of high-dose steroids are critical to preventing rapid deterioration. Given that ICI therapy is the standard of care for several cancers and is often studied in clinical trials, increased education on irAE toxicity and updated algorithms on the management of febrile cancer patients are warranted.
PubMed: 37575835
DOI: 10.7759/cureus.41781 -
Cureus Nov 2023Hematological disorders pose a diagnostic challenge due to overlapping clinical features, as demonstrated by the difficulty in differentiating between aplastic anemia...
Hematological disorders pose a diagnostic challenge due to overlapping clinical features, as demonstrated by the difficulty in differentiating between aplastic anemia (AA) and primary myelofibrosis (PM). Myeloproliferative disorders, characterized by aberrant proliferation of bone marrow stem cells, present complexities in diagnosis, often requiring a comprehensive evaluation to distinguish between disorders with similar manifestations. The distinctions between myelofibrosis and AA lie not only in clinical presentations but also in genetic and molecular markers, necessitating a nuanced diagnostic approach. We present a case of a 37-year-old male initially diagnosed with myelofibrosis based on a history of pancytopenia, warm submandibular and submental swelling, and negative BCR-ABL and JAK2 mutations. Further examination revealed empty fragmented cells, hypoplastic bone marrow, and suppressed erythropoiesis and myelopoiesis. Subsequent core biopsy showed increased megakaryocytes, prompting a revised diagnosis of AA. This case underscores the importance of a meticulous diagnostic journey, incorporating physical examination, genetic testing, and advanced imaging to unravel the complexities of hematological disorders. The intricacies of this case prompt a reevaluation of diagnostic paradigms, highlighting the limitations of relying solely on specific mutations for diagnosis. The absence of BCR-ABL and JAK2 mutations in AA raises questions about its genetic landscape, necessitating further exploration. Immunological considerations, given the immune-mediated nature of AA, provide a foundation for future research into immune dysregulation and potential therapeutic interventions. The clinical management challenges posed by AA underscore the need for personalized treatment strategies, guided by a deeper understanding of its underlying pathophysiology. Advanced imaging techniques, in conjunction with traditional diagnostic methods, emerge as crucial tools for enhancing diagnostic accuracy in hematological disorders. This case serves as a paradigm for ongoing medical education, multidisciplinary collaboration, and innovative approaches in the evolving landscape of hematology, emphasizing the imperative for continuous refinement in diagnostic strategies and patient care.
PubMed: 38149134
DOI: 10.7759/cureus.49445 -
Pathogens (Basel, Switzerland) Sep 2023Leishmaniasis is a vector-borne disease caused by protozoan parasites of the genus Leishmania and is transmitted through the bite of infected female sandflies. In the...
Leishmaniasis is a vector-borne disease caused by protozoan parasites of the genus Leishmania and is transmitted through the bite of infected female sandflies. In the Mediterranean region, visceral leishmaniasis is caused by and it is usually responsible for symptoms such as fever, pancytopenia and enlargement of the liver and spleen. Relapse is rare in immunocompetent patients as much as the mucous involvement. We present a rare case of mucosal relapse of visceral leishmaniasis in a child with SARS-CoV-2 infection and perform an extensive review of the literature about leishmaniasis relapses in children. Atypical mucosal involvement during Leishmaniasis relapse is an eventuality in pediatric patients. Clinical follow-up and periodic PCR tests must be considered essential for the early recognition and treatment of an eventual relapse.
PubMed: 37764934
DOI: 10.3390/pathogens12091127 -
Frontiers in Immunology 2023Paroxysmal nocturnal haemoglobinuria (PNH) is a rare acquired haematopoietic stem cell disease characterized by complement-mediated intravascular hemolysis, thrombosis,... (Review)
Review
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare acquired haematopoietic stem cell disease characterized by complement-mediated intravascular hemolysis, thrombosis, and bone marrow failure. Eculizumab and ravulizumab are anti-C5 monoclonal antibodies that reduce hemolysis, anaemia and thrombotic risk, but are associated with increased risk of infection with encapsulated bacteria, including We report a case of life-threatening infection by non-groupable in a young PNH patient treated with ravulizumab. Despite prompt admission to the intensive care unit, microbe isolation was delayed due to the negativity of capsular antigens, and the patient required intubation, dialysis, and transfusion support for pancytopenia. Notably, PNH disease activity remained controlled and no additional anti-C5 doses were administered. Increasing awareness regarding septic risk in PNH patients on complement inhibitors despite vaccinations is pivotal. A warning about serotypes generally not pathogenetic and not covered by vaccination, such as non-capsulated forms, is emerging.
Topics: Humans; Hemoglobinuria, Paroxysmal; Complement Inactivating Agents; Neisseria meningitidis; Hemolysis; Pancytopenia; Thrombosis; Sepsis
PubMed: 37854608
DOI: 10.3389/fimmu.2023.1269325 -
Melanoma Research Feb 2024The occurrence of bone marrow metastases (BMM) in melanoma patients is often underestimated, with only 7% detected during in-vivo staging procedures but rising to 45% in...
The occurrence of bone marrow metastases (BMM) in melanoma patients is often underestimated, with only 7% detected during in-vivo staging procedures but rising to 45% in autopsy cases. This systematic review aims to shed light on the clinical and laboratory features of BMM in melanoma by analyzing 73 studies selected from 2 482 initially retrieved from PubMed, Embase , and Cochrane CENTRAL databases. Our findings reveal a slight male predominance, with a median age at BMM diagnosis of 56 years. Primary melanoma sites included the skin (52%), mucosa (8.8%), uvea (20.5%) and unidentified (19%). BMM was preceded by lymph node involvement in 36.5% of cases, whereas 63% showed no nodal metastases, with direct BMM occurring in 22.5% and metastases to other sites in 41%. Common BMM symptoms included pain (60.7%), anemia (80%), thrombocytopenia, leukoerythroblastosis, pancytopenia and leukopenia, while disseminated intravascular coagulation was detected in 11% of cases. In 23.6% of cases, BMM was amelanotic. The prognosis for BMM is grim, with a median survival of only 2 months. Conventional therapies for BMM remain largely ineffective, emphasizing the importance of considering bone marrow as a potential metastatic site in melanoma patients.
Topics: Humans; Male; Middle Aged; Female; Melanoma; Bone Marrow; Skin Neoplasms; Bone Marrow Neoplasms; Prognosis
PubMed: 37939076
DOI: 10.1097/CMR.0000000000000942 -
Cureus Dec 2023Massive splenomegaly complicating pregnancy is a rare clinical entity that poses special difficulties, such as anemia, thrombocytopenia, ascites, and jaundice. This case...
Massive splenomegaly complicating pregnancy is a rare clinical entity that poses special difficulties, such as anemia, thrombocytopenia, ascites, and jaundice. This case report of a pregnant woman with large splenomegaly and pancytopenia highlights the value of prompt diagnosis and effective treatment. Splenomegaly can have a number of causes, including viral infections, hematological problems, portal hypertension, and metabolic abnormalities. A 29-year-old gravida 3 woman at 37 weeks of gestation who had massive splenomegaly was admitted and underwent a cesarean section to avoid complications of splenomegaly. The case report discusses the difficulties in obstetric management caused by enormous splenomegaly during pregnancy, including the choice of delivery method. Significant complications include splenic rupture and bleeding, particularly when pancytopenia is present. The need for several transfusions, the potential side effects of transfusion therapy, and factors related to the origin of splenomegaly when assessing maternal-fetal outcomes are discussed in this case report. The study concludes that in cases with pancytopenia splenomegaly during pregnancy, vigilant monitoring, prompt intervention, and a multidisciplinary approach are crucial to achieve positive outcomes for both the mother and the fetus.
PubMed: 38229813
DOI: 10.7759/cureus.50656 -
Journal of Medical Case Reports Jul 2023Vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic syndrome is a newly discovered inflammatory disease affecting male subjects, for which few data exist in the...
BACKGROUND
Vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic syndrome is a newly discovered inflammatory disease affecting male subjects, for which few data exist in the literature. Here, we describe the case of a patient with known Sweet's syndrome admitted to the intensive care unit and for whom a vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic syndrome was diagnosed, allowing for appropriate treatment and the patient's discharge and recovery.
CASE PRESENTATION
A 70-year-old male White patient was hospitalized in the intensive care unit following an intrahospital cardiac arrest. History started a year before with repeated deep vein thrombosis and episodes of skin eruption compatible with Sweet's syndrome. After a course of oral steroids, fever and inflammatory syndrome relapsed with onset of polychondritis, episcleritis along with neurological symptoms and pulmonary infiltrates. Intrahospital hypoxic cardiac arrest happened during patient's new investigations, and he was admitted in a critical state. During the intensive care unit stay, he presented with livedoid skin lesions on both feet. Vasculitis was not proven; however, cryoglobulinemia screening came back positive. Onset of pancytopenia was explored with a myelogram aspirate. It showed signs of dysmyelopoiesis and vacuoles in erythroid and myeloid precursors. Of note, new deep vein thrombosis developed, despite being treated with heparin leading to the diagnosis of heparin-induced thrombocytopenia. The course of symptoms were overlapping multiple entities, and so a multidisciplinary team discussion was implemented. Screening for UBA1-mutation in the blood came back positive, confirming the vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic syndrome. Corticosteroids and anti-IL1 infusion were started with satisfactory results supporting patient's discharge from intensive care unit to the internal medicine ward.
CONCLUSIONS
Vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic syndrome should be suspected in male patients presenting with inflammatory symptoms, such as fever, skin eruption, chondritis, venous thromboembolism, and vacuoles in bone marrow precursors. Patients with undiagnosed vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic syndrome may present with organ failure requiring hospitalization in intensive care unit, where screening for UBA1 mutation should be performed when medical history is evocative. Multidisciplinary team involvement is highly recommended for patient management, notably to start appropriate immunosuppressive treatments.
Topics: Humans; Male; Aged; Sweet Syndrome; Vacuoles; Hospitalization; Exanthema; Fever; Heart Arrest; Venous Thrombosis
PubMed: 37480098
DOI: 10.1186/s13256-023-04034-5 -
Pediatrics in Review Oct 2023
PubMed: 37777240
DOI: 10.1542/pir.2020-001016