Marchiafava Micheli syndrome [keywords]
- Notes from the Field: Meningococcal Disease in an International Traveler on Eculizumab Therapy - United States, 2015. [Journal Article]
- MMWR Morb Mortal Wkly Rep 2016; 65(27):696-7.
On June 2, 2015, CDC was notified that a male airline passenger, aged 41 years, with a fever of 105.4°F, headache, nausea, photophobia, diarrhea, and vomiting, which began approximately 3 hours after departure, was arriving to San Francisco, California, on a flight from Frankfurt, Germany. His symptoms reportedly started with neck stiffness 1 day earlier. Upon arrival, the patient was immediately transported to a local hospital, where he was in septic shock, which was followed by multisystem organ failure. Cerebrospinal fluid, obtained approximately 12 hours after initiation of treatment, was Gram stain- and culture-negative. Blood cultures, which were drawn before antibiotic treatment, were positive for Neisseria meningitides of indeterminate serogroup. A review of the patient's medical records revealed a history of paroxysmal nocturnal hemoglobinuria and current biweekly eculizumab (Soliris) therapy.
- Paroxysmal Nocturnal Hemoglobinuria: The Future Of Complement-Based Therapies. [JOURNAL ARTICLE]
- Curr Drug Targets 2016 Jul 11.
Since its introduction in the clinic, the first complement inhibitor eculizumab has changed the paradigm of PNH treatment. However, a ten-year experience has also taught us that there are same pitfalls which represent a challenge to improve the current anti-complement treatment. The most obvious unmet clinical need remain residual anemia, because one third of patients remains transfusion-dependent, and an additional third still lives with moderate anemia. It has been demonstrated that uncontrolled activation of early steps of the complement plays a major role in this reduced clinical benefit, making C3-mediated extravascular hemolysis the next challenge of PNH treatment. Indeed, a number of novel complement therapeutics is currently under investigation. Novel anti-C5 agents exploiting different technologies of drug design are available; likely they parallel the safety and efficacy profile of eculizumab. However, there is a growing interest for agents which target early phases of complement activation, since they may result in clinical benefit by preventing C3-mediated extravascular hemolysis. These second-generation complement inhibitors include anti-C3 agents, which have as lead compound compstatin and its derivatives, as well as some inhibitors of the alternative pathway, which specifically target complement factor B and D. Here we review the plethora of preclinical data, and the few clinical experiences that will hopefully change in the near future the scenario of anti-complement treatment in PNH, leading to improved clinical outcome.
- Modeling complement-driven diseases in transgenic mice: Values and limitations. [REVIEW, JOURNAL ARTICLE]
- Immunobiology 2016 Jun 16.
Remarkable advances have been made over past decades in understanding the pathogenesis of complement-mediated diseases. This has led to development of new therapies for, and in some cases re-classification of, complement-driven diseases. This success is due to not only insight from human patients but also studies using transgenic animal models. Animal models that mimic human diseases are useful tools to understand the mechanism of disease and develop new therapies but there are also limitations due to species differences in their complement systems. This review provides a summary of transgenic animal models for three human diseases that are at the forefront of anti-complement therapy, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G). They are discussed here as examples to highlight the values and limitations of animal modeling in complement-driven diseases.
- Complement research in the 18th-21st centuries: Progress comes with new technology. [REVIEW, JOURNAL ARTICLE]
- Immunobiology 2016 Jun 15.
The complement system has been studied for about 120 years. Progress in defining this large and complex system has been dependent on the research technologies available, but since the introduction of protein chromatography, electrophoresis, and antibody-based assay methods in the 1950s and 60s, and sequencing of proteins and DNA in the 70s and 80s, there has been very rapid accumulation of data. With more recent improvements in 3D structure determination (nmr and X-ray crystallography), the structures of most of the complement proteins have now been solved. Complement research since 1990 has been greatly stimulated by the discoveries of the multiple proteins in the lectin pathway, the strong association of Factor H, C3, Factor B allelic variants with adult macular degeneration and atypical haemolytic uremic syndrome, and the introduction of the anti-C5 monoclonal antibody as a therapy for paroxysmal nocturnal hemoglobinuria and atypical haemolytic uremic syndrome. Potential new roles for complement in tissue development and the search for novel therapeutics suggest a very active future for complement research.
- Therapeutic complement inhibition in complement-mediated hemolytic anemias: Past, present and future. [REVIEW, JOURNAL ARTICLE]
- Semin Immunol 2016 Jun 23.
The introduction in the clinic of anti-complement agents represented a major achievement which gave to physicians a novel etiologic treatment for different human diseases. Indeed, the first anti-complement agent eculizumab has changed the treatment paradigm of paroxysmal nocturnal hemoglobinuria (PNH), dramatically impacting its severe clinical course. In addition, eculizumab is the first agent approved for atypical Hemolytic Uremic Syndrome (aHUS), a life-threatening inherited thrombotic microangiopathy. Nevertheless, such remarkable milestone in medicine has brought to the fore additional challenges for the scientific community. Indeed, the list of complement-mediated anemias is not limited to PNH and aHUS, and other human diseases can be considered for anti-complement treatment. They include other thrombotic microangiopathies, as well as some antibody-mediated hemolytic anemias. Furthermore, more than ten years of experience with eculizumab led to a better understanding of the individual steps of the complement cascade involved in the pathophysiology of different human diseases. Based on this, new unmet clinical needs are emerging; a number of different strategies are currently under development to improve current anti-complement treatment, trying to address these specific clinical needs. They include: (i) alternative anti-C5 agents, which may improve the heaviness of eculizumab treatment; (ii) broad-spectrum anti-C3 agents, which may improve the efficacy of anti-C5 treatment by intercepting the complement cascade upstream (i.e., preventing C3-mediated extravascular hemolysis in PNH); (iii) targeted inhibitors of selective complement activating pathways, which may prevent early pathogenic events of specific human diseases (e.g., anti-classical pathway for antibody-mediated anemias, or anti-alternative pathway for PNH and aHUS). Here we briefly summarize the status of art of current and future complement inhibition for different complement-mediated anemias, trying to identify the most promising approaches for each individual disease.
- Development of paroxysmal nocturnal hemoglobinuria in CALR-positive myeloproliferative neoplasm. [Journal Article]
- J Blood Med 2016.:107-10.
Paroxysmal nocturnal hemoglobinuria (PNH), a disease characterized by intravascular hemolysis, thrombosis, and bone marrow failure, is associated with mutations in the PIG-A gene, resulting in a deficiency of glycosylphosphatidylinositol-anchored proteins. Many hypotheses have been posed as to whether PNH and PIG-A mutations result in an intrinsic survival benefit of CD55(-)/CD59(-) cells or an extrinsic permissive environment that allows for their clonal expansion within the bone marrow compartment. Recent data have identified the concurrence of PIG-A mutations with additional genetic mutations associated with myeloproliferative disorders, suggesting that some presentations of PNH are the result of a stepwise progression of genetic mutations similar to other myelodysplastic or myeloproliferative syndromes. We report for the first time in the literature the development of clinically significant PNH in a patient with JAK2V617F-negative, CALR-positive essential thrombocythemia, providing further support to the hypothesis that the development of PNH is associated with the accumulation of multiple genetic mutations that create an intrinsic survival benefit for clonal expansion. This case study additionally highlights the utility of genomic testing in diagnosis and the understanding of disease progression in the clinical setting.
- Genetic variants of C5 and polymorphisms of C3 in Chinese patients with paroxysmal nocturnal hemoglobinuria. [Letter]
- Int J Lab Hematol 2016 Aug; 38(4):e84-5.
- Performance characteristics of a non-fluorescent aerolysin-based paroxysmal nocturnal hemoglobinuria (PNH) assay for simultaneous evaluation of PNH neutrophils and PNH monocytes by flow cytometry, following published PNH guidelines. [JOURNAL ARTICLE]
- Cytometry B Clin Cytom 2016 Jun 13.
CD157 has been recently reported as a useful glycosylphosphatidylinositol (GPI)-linked marker for the detection of paroxysmal nocturnal hemoglobinuria (PNH) clones in patients with suspected paroxysmal nocturnal hemoglobinuria by flow cytometry as it targets both neutrophils and monocytes. The aim of this study is to test the feasibility of a non-fluorescent aerolysin (FLAER) approach and propose an alternative for laboratories, where FLAER is not available.We validated a non-FLAER-based single-tube, 6-color assay targeting the GPI-linked structures CD157, CD24, and CD14. We determined its performance characteristics on 20 PNH patient samples containing a variety of clone sizes and compared results with a previously validated FLAER-based approach.Coefficient of variation (CV) for intra-/interassay precision analyses ranged from 0.1%/0.2% to 3.02%/7.58% for neutrophils and from 0.10%/0.3% to 5.39%/6.36% for monocytes. Coefficient of determination (r(2) ) for linear regression analysis of PNH clones from 20 patients ranging from 0.06% to 99.7% was 0.99 in all cases, Wilcoxon ranks test showed no statistically significant differences (P > 0.05), Bland-Altman analysis demonstrated performance agreement with mean bias ranging from 0.06 to 0.2.Our results confirm very good performance characteristics for both intra- and interassay precision analyses, favorable correlation, and agreement between the FLAER and non-FLAER-based approaches, using the CD157 GPI marker. Our experience suggests that a rapid and cost-effective simultaneous evaluation of PNH neutrophils and monocytes by flow cytometry without using FLAER is possible in areas where FLAER may not be widely available. © 2016 International Clinical Cytometry Society.
- Immune pathophysiology of acquired aplastic anemia. [Journal Article]
- Rinsho Ketsueki 2016 May; 57(5):525-30.
Acquired aplastic anemia (AA) is a hematopoietic dyscrasia characterized by pancytopenia and bone marrow hypoplasia. AA is considered to be caused mainly by T-cell attacks on hematopoietic stem cells, as assumption based on good responses to T-cell specific immunosuppressive therapy (IST). Several markers, such as HLA-DRB1(*)1501 and an increase in the percentage of paroxysmal nocturnal hemoglobinuria (PNH) phenotype cells, have been shown to represent the immune pathophysiology of AA. However, little is known about the pathogenesis of AA. This review article focuses on immune mechanisms underlying the development of AA and the roles of the aforementioned markers in the management of bone marrow failure.