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1.
Lancet ; 402(10417): 2077-2090, 2023 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-37931634

RESUMO

BACKGROUND: Sparsentan, a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist, significantly reduced proteinuria versus irbesartan, an angiotensin II receptor blocker, at 36 weeks (primary endpoint) in patients with immunoglobulin A nephropathy in the phase 3 PROTECT trial's previously reported interim analysis. Here, we report kidney function and outcomes over 110 weeks from the double-blind final analysis. METHODS: PROTECT, a double-blind, randomised, active-controlled, phase 3 study, was done across 134 clinical practice sites in 18 countries throughout the Americas, Asia, and Europe. Patients aged 18 years or older with biopsy-proven primary IgA nephropathy and proteinuria of at least 1·0 g per day despite maximised renin-angiotensin system inhibition for at least 12 weeks were randomly assigned (1:1) to receive sparsentan (target dose 400 mg oral sparsentan once daily) or irbesartan (target dose 300 mg oral irbesartan once daily) based on a permuted-block randomisation method. The primary endpoint was proteinuria change between treatment groups at 36 weeks. Secondary endpoints included rate of change (slope) of the estimated glomerular filtration rate (eGFR), changes in proteinuria, a composite of kidney failure (confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality), and safety and tolerability up to 110 weeks from randomisation. Secondary efficacy outcomes were assessed in the full analysis set and safety was assessed in the safety set, both of which were defined as all patients who were randomly assigned and received at least one dose of randomly assigned study drug. This trial is registered with ClinicalTrials.gov, NCT03762850. FINDINGS: Between Dec 20, 2018, and May 26, 2021, 203 patients were randomly assigned to the sparsentan group and 203 to the irbesartan group. One patient from each group did not receive the study drug and was excluded from the efficacy and safety analyses (282 [70%] of 404 included patients were male and 272 [67%] were White) . Patients in the sparsentan group had a slower rate of eGFR decline than those in the irbesartan group. eGFR chronic 2-year slope (weeks 6-110) was -2·7 mL/min per 1·73 m2 per year versus -3·8 mL/min per 1·73 m2 per year (difference 1·1 mL/min per 1·73 m2 per year, 95% CI 0·1 to 2·1; p=0·037); total 2-year slope (day 1-week 110) was -2·9 mL/min per 1·73 m2 per year versus -3·9 mL/min per 1·73 m2 per year (difference 1·0 mL/min per 1·73 m2 per year, 95% CI -0·03 to 1·94; p=0·058). The significant reduction in proteinuria at 36 weeks with sparsentan was maintained throughout the study period; at 110 weeks, proteinuria, as determined by the change from baseline in urine protein-to-creatinine ratio, was 40% lower in the sparsentan group than in the irbesartan group (-42·8%, 95% CI -49·8 to -35·0, with sparsentan versus -4·4%, -15·8 to 8·7, with irbesartan; geometric least-squares mean ratio 0·60, 95% CI 0·50 to 0·72). The composite kidney failure endpoint was reached by 18 (9%) of 202 patients in the sparsentan group versus 26 (13%) of 202 patients in the irbesartan group (relative risk 0·7, 95% CI 0·4 to 1·2). Treatment-emergent adverse events were well balanced between sparsentan and irbesartan, with no new safety signals. INTERPRETATION: Over 110 weeks, treatment with sparsentan versus maximally titrated irbesartan in patients with IgA nephropathy resulted in significant reductions in proteinuria and preservation of kidney function. FUNDING: Travere Therapeutics.


Assuntos
Glomerulonefrite por IGA , Falência Renal Crônica , Feminino , Humanos , Masculino , Antagonistas de Receptores de Angiotensina/efeitos adversos , Método Duplo-Cego , Glomerulonefrite por IGA/tratamento farmacológico , Irbesartana/efeitos adversos , Proteinúria/tratamento farmacológico , Resultado do Tratamento , Adulto
2.
N Engl J Med ; 382(7): 622-631, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-32053298

RESUMO

BACKGROUND: More effective and safer treatments are needed for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. METHODS: We conducted a randomized trial with a 2-by-2 factorial design to evaluate the use of plasma exchange and two regimens of oral glucocorticoids in patients with severe ANCA-associated vasculitis (defined by an estimated glomerular filtration rate of <50 ml per minute per 1.73 m2 of body-surface area or diffuse pulmonary hemorrhage). Patients were randomly assigned to undergo plasma exchange (seven plasma exchanges within 14 days after randomization) or no plasma exchange (control group). Patients were also randomly assigned to follow either a standard-dose regimen or a reduced-dose regimen of oral glucocorticoids. Patients were followed for up to 7 years for the primary composite outcome of death from any cause or end-stage kidney disease (ESKD). RESULTS: Death from any cause or ESKD occurred in 100 of 352 patients (28.4%) in the plasma-exchange group and in 109 of 352 patients (31.0%) in the control group (hazard ratio, 0.86; 95% confidence interval [CI], 0.65 to 1.13; P = 0.27). The results were similar in subgroup analyses and in analyses of secondary outcomes. We also assessed the noninferiority of a reduced-dose regimen of glucocorticoids to a standard-dose regimen, using a noninferiority margin of 11 percentage points. Death from any cause or ESKD occurred in 92 of 330 patients (27.9%) in the reduced-dose group and in 83 of 325 patients (25.5%) in the standard-dose group (absolute risk difference, 2.3 percentage points; 90% CI, -3.4 to 8.0), which met the criterion for noninferiority. Serious infections at 1 year were less common in the reduced-dose group than in the standard-dose group (incidence rate ratio, 0.69; 95% CI, 0.52 to 0.93), but other secondary outcomes were similar in the two groups. CONCLUSIONS: Among patients with severe ANCA-associated vasculitis, the use of plasma exchange did not reduce the incidence of death or ESKD. A reduced-dose regimen of glucocorticoids was noninferior to a standard-dose regimen with respect to death or ESKD. (Funded by the U.K. National Institute for Health Research and others; PEXIVAS Current Controlled Trials number, ISRCTN07757494; ClinicalTrials.gov number, NCT00987389.).


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/terapia , Glucocorticoides/administração & dosagem , Falência Renal Crônica/prevenção & controle , Troca Plasmática , Administração Oral , Adulto , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/mortalidade , Terapia Combinada , Ciclofosfamida/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Glucocorticoides/efeitos adversos , Humanos , Imunossupressores/uso terapêutico , Incidência , Quimioterapia de Indução , Nefropatias/complicações , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/etiologia , Masculino , Pessoa de Meia-Idade , Troca Plasmática/efeitos adversos , Rituximab/uso terapêutico
3.
Ann Rheum Dis ; 82(7): 937-944, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36958796

RESUMO

OBJECTIVE: Following induction of remission with rituximab in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) relapse rates are high, especially in patients with history of relapse. Relapses are associated with increased exposure to immunosuppressive medications, the accrual of damage and increased morbidity and mortality. The RITAZAREM trial compared the efficacy of repeat-dose rituximab to daily oral azathioprine for prevention of relapse in patients with relapsing AAV in whom remission was reinduced with rituximab. METHODS: RITAZAREM was an international randomised controlled, open-label, superiority trial that recruited 188 patients at the time of an AAV relapse from 29 centres in seven countries between April 2013 and November 2016. All patients received rituximab and glucocorticoids to reinduce remission. Patients achieving remission by 4 months were randomised to receive rituximab intravenously (1000 mg every 4 months, through month 20) (85 patients) or azathioprine (2 mg/kg/day, tapered after month 24) (85 patients) and followed for a minimum of 36 months. The primary outcome was time to disease relapse (either major or minor relapse). RESULTS: Rituximab was superior to azathioprine in preventing relapse: HR 0.41; 95% CI 0.27 to 0.61, p<0.001. 19/85 (22%) patients in the rituximab group and 31/85 (36%) in the azathioprine group experienced at least one serious adverse event during the treatment period. There were no differences in rates of hypogammaglobulinaemia or infection between groups. CONCLUSIONS: Following induction of remission with rituximab, fixed-interval, repeat-dose rituximab was superior to azathioprine for preventing disease relapse in patients with AAV with a prior history of relapse. TRIAL REGISTRATION NUMBER: NCT01697267; ClinicalTrials.gov identifier.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Azatioprina , Humanos , Azatioprina/uso terapêutico , Rituximab/uso terapêutico , Imunossupressores/uso terapêutico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Recidiva , Indução de Remissão , Resultado do Tratamento , Ciclofosfamida/uso terapêutico , Anticorpos Anticitoplasma de Neutrófilos
4.
Nephrology (Carlton) ; 27(1): 35-43, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34392579

RESUMO

AIM: There is no clear consensus on how best to treat primary membranous nephropathy (PMN). This study aimed to ascertain prevailing views among nephrologists on their choice of immunosuppressive agents to treat this disease. METHODS: The Australasian Kidney Trials Network conducted a multinational online survey among nephrologists from the South Asia-Pacific region to identify prescribing practices to treat PMN. Survey questions focused on the types of immunosuppressive therapies used, preferred first-line and second-line therapies, indications for starting immunosuppressive therapy, the preferred mode of combining corticosteroid and cyclophosphamide, the use of serum phospholipase A2 receptor antibody testing in clinical practice, indications for anticoagulation, and interest in participating in future clinical trials in PMN. RESULTS: One hundered fifty-five nephrologists from eight countries responded to the online survey. The majority of them were senior nephrologists from Australia and India with significant experience managing patients with PMN. The combination of cyclophosphamide and corticosteroid was the preferred first-line therapy. Of those who used this combination, only 34.8% followed the Kidney Disease Improving Global Outcomes (KDIGO) 2012 guidelines by adding intravenous methylprednisolone. The combination of calcineurin inhibitor with corticosteroid was the most common second-line therapy. Most respondents considered prophylactic anticoagulation if serum albumin was less than 25 g/L. Most nephrologists were keen to participate in a clinical trial with a control arm consisting of cyclophosphamide and corticosteroids. CONCLUSION: The combination of corticosteroid with cyclophosphamide (without intravenous methylprednisolone) is the most commonly reported first-line immunosuppressive therapy for the management of PMN.


Assuntos
Inibidores de Calcineurina/uso terapêutico , Ciclofosfamida/uso terapêutico , Glomerulonefrite Membranosa/tratamento farmacológico , Metilprednisolona/uso terapêutico , Padrões de Prática Médica/estatística & dados numéricos , Anticoagulantes/uso terapêutico , Australásia/epidemiologia , Quimioprevenção/métodos , Consenso , Glomerulonefrite Membranosa/epidemiologia , Glomerulonefrite Membranosa/imunologia , Humanos , Imunossupressores/uso terapêutico , Nefrologistas/estatística & dados numéricos , Inquéritos e Questionários
5.
Ann Rheum Dis ; 79(9): 1243-1249, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32581088

RESUMO

OBJECTIVES: Evaluation of rituximab and glucocorticoids as therapy to induce remission after relapse in ANCA-associated vasculitis (AAV) in a prospective observational cohort of patients enrolled into the induction phase of the RITAZAREM trial. METHODS: Patients relapsing with granulomatosis with polyangiitis or microscopic polyangiitis were prospectively enrolled and received remission-induction therapy with rituximab (4×375 mg/m2) and a higher or lower dose glucocorticoid regimen, depending on physician choice: reducing from either 1 mg/kg/day or 0.5 mg/kg/day to 10 mg/day by 4 months. Patients in this cohort achieving remission were subsequently randomised to receive one of two regimens to prevent relapse. RESULTS: 188 patients were studied: 95/188 (51%) men, median age 59 years (range 19-89), prior disease duration 5.0 years (range 0.4-34.5). 149/188 (79%) had previously received cyclophosphamide and 67/188 (36%) rituximab. 119/188 (63%) of relapses had at least one major disease activity item, and 54/188 (29%) received the higher dose glucocorticoid regimen. 171/188 (90%) patients achieved remission by 4 months. Only six patients (3.2% of the study population) did not achieve disease control at month 4. Four patients died in the induction phase due to pneumonia (2), cerebrovascular accident (1), and active vasculitis (1). 41 severe adverse events occurred in 27 patients, including 13 severe infections. CONCLUSIONS: This large prospective cohort of patients with relapsing AAV treated with rituximab in conjunction with glucocorticoids demonstrated a high level of efficacy for the reinduction of remission in patients with AAV who have relapsed, with a similar safety profile to previous studies.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Antirreumáticos/administração & dosagem , Glucocorticoides/administração & dosagem , Rituximab/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/patologia , Quimioterapia Combinada , Feminino , Humanos , Quimioterapia de Indução , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recidiva , Resultado do Tratamento , Adulto Jovem
6.
Ann Rheum Dis ; 78(3): 399-405, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30612116

RESUMO

OBJECTIVES: Cyclophosphamide induction regimens are effective for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but are associated with infections, malignancies and infertility. Mycophenolate mofetil (MMF) has shown high remission rates in small studies of AAV. METHODS: We conducted a randomised controlled trial to investigate whether MMF was non-inferior to cyclophosphamide for remission induction in AAV. 140 newly diagnosed patients were randomly assigned to MMF or pulsed cyclophosphamide. All patients received the same oral glucocorticoid regimen and were switched to azathioprine following remission. The primary endpoint was remission by 6 months requiring compliance with the tapering glucocorticoid regimen. Patients with an eGFR <15 mL/min were excluded from the study. RESULTS: At baseline, ANCA subtype, disease activity and organ involvement were similar between groups. Non-inferiority was demonstrated for the primary remission endpoint, which occurred in 47 patients (67%) in the MMF group and 43 patients (61%) in the cyclophosphamide group (risk difference 5.7%, 90% CI -7.5% to 19%). Following remission, more relapses occurred in the MMF group (23 patients, 33%) compared with the cyclophosphamide group (13 patients, 19%) (incidence rate ratio 1.97, 95% CI 0.96 to 4.23, p=0.049). In MPO-ANCA patients, relapses occurred in 12% of the cyclophosphamide group and 15% of the MMF group. In PR3-ANCA patients, relapses occurred in 24% of the cyclophosphamide group and 48% of the MMF group. Serious infections were similar between groups (26% MMF group, 17% cyclophosphamide group) (OR 1.67, 95% CI 0.68 to 4.19, p=0.3). CONCLUSION: MMF was non-inferior to cyclophosphamide for remission induction in AAV, but resulted in higher relapse rate. TRIAL REGISTRATION NUMBER: NCT00414128.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Ciclofosfamida/uso terapêutico , Imunossupressores/uso terapêutico , Quimioterapia de Indução/métodos , Ácido Micofenólico/uso terapêutico , Adolescente , Adulto , Azatioprina/uso terapêutico , Criança , Feminino , Humanos , Masculino , Recidiva , Resultado do Tratamento
7.
Kidney Int ; 89(6): 1337-45, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27165824

RESUMO

Patient outcomes in end-stage kidney disease (ESKD) secondary to lupus nephritis have not been well described. To help define this we compared dialysis and transplant outcomes of patients with ESKD due to lupus nephritis to all other causes. All patients diagnosed with ESKD who commenced renal replacement therapy in Australia and New Zealand (1963-2012) were included. Clinical outcomes were evaluated in both a contemporary cohort (1998-2012) and the entire 50-year cohort. Of 64,160 included patients, 744 had lupus nephritis as the primary renal disease. For the contemporary cohort of 425 patients with lupus nephritis, the 5-year dialysis patient survival rate was 69%. Of 176 contemporary patients with lupus nephritis who received their first renal allograft, the 5-year patient, overall renal allograft, and death-censored renal allograft survival rates were 95%, 88%, and 93%, respectively. Patients with lupus nephritis had worse dialysis patient survival (adjusted hazard ratio 1.33, 95% confidence interval 1.12-1.58) and renal transplant patient survival (adjusted hazard ratio 1.87, 95% confidence interval 1.18-2.98), but comparable overall renal allograft survival (adjusted hazard ratio 1.19, 95% confidence interval 0.84-1.68) and death-censored renal allograft survival (adjusted hazard ratio 1.05, 95% confidence interval 0.68-1.62) compared with ESKD controls. Similar results were found in the entire cohort and when using competing-risks analysis. Thus, the ESKD of lupus nephritis was associated with worse dialysis and transplant patient survival but comparable renal allograft survival compared with other causes of ESKD.


Assuntos
Sobrevivência de Enxerto , Falência Renal Crônica/terapia , Transplante de Rim/mortalidade , Nefrite Lúpica/complicações , Sistema de Registros/estatística & dados numéricos , Diálise Renal/mortalidade , Adulto , Austrália/epidemiologia , Feminino , Seguimentos , Humanos , Falência Renal Crônica/etiologia , Masculino , Pessoa de Meia-Idade , Nova Zelândia/epidemiologia , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Taxa de Sobrevida , Transplante Homólogo/mortalidade
8.
Nephrology (Carlton) ; 21(5): 387-96, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26393772

RESUMO

BACKGROUND: Clinical outcomes of patients with end-stage kidney disease (ESKD) receiving renal replacement therapy (RRT) secondary to IgA nephropathy (IgAN) have not been well described. AIM: To investigate the characteristics, treatments and outcomes of ESKD because of kidney-limited IgAN and Henoch-Schönlein purpura nephritis (HSPN) in the Australian and New Zealand RRT populations. METHODS: All ESKD patients who commenced RRT in Australia and New Zealand between 1971 and 2012 were included. Dialysis and transplant outcomes were evaluated in both a contemporary cohort (1998-2012) and the entire cohort (1971-2012). RESULTS: Of 63 297 ESKD patients, 3721 had kidney-limited IgAN, and 131 had HSPN. For the contemporary cohort of IgAN patients on dialysis (n = 2194), 10-year patient survival was 65%. Of 1368 contemporary IgAN patients who received their first renal allograft, 10-year patient, overall renal allograft and death-censored renal allograft survival were 93%, 82% and 88%, respectively. Using multivariable Cox regression analysis, patients with IgAN had favourable dialysis patient survival (adjusted hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.57-0.69), overall renal allograft survival (HR 0.67, 95% CI 0.57-0.79) and renal transplant patient survival (HR 0.58, 95% CI 0.45-0.74) compared with ESKD controls. Similar results were found in the entire cohort and when using competing-risks models. Compared with kidney-limited IgAN patients, those with HSPN had worse dialysis patient survival (HR 1.94, 95% CI 1.02-3.69), overall renal allograft survival (HR 3.40, 95% CI 1.00-11.55) and renal transplant patient survival (HR 3.50, 95% CI 1.03-11.92). CONCLUSION: IgAN ESKD was associated with better dialysis and renal transplant outcomes compared with other forms of ESKD. The survival outcomes of ESKD patients with HSPN were worse than kidney-limited IgAN.


Assuntos
Glomerulonefrite por IGA/terapia , Falência Renal Crônica/terapia , Transplante de Rim , Diálise Renal , Austrália/epidemiologia , Distribuição de Qui-Quadrado , Progressão da Doença , Glomerulonefrite por IGA/diagnóstico , Glomerulonefrite por IGA/mortalidade , Sobrevivência de Enxerto , Humanos , Vasculite por IgA/diagnóstico , Vasculite por IgA/mortalidade , Incidência , Estimativa de Kaplan-Meier , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/mortalidade , Transplante de Rim/efeitos adversos , Transplante de Rim/mortalidade , Análise Multivariada , Nova Zelândia/epidemiologia , Modelos de Riscos Proporcionais , Sistema de Registros , Diálise Renal/efeitos adversos , Diálise Renal/mortalidade , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
9.
Ann Rheum Dis ; 74(6): 1178-82, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25739829

RESUMO

OBJECTIVES: The RITUXVAS trial reported similar remission induction rates and safety between rituximab and cyclophosphamide based regimens for antineutrophil cytoplasm antibody (ANCA)-associated vasculitis at 12 months; however, immunosuppression maintenance requirements and longer-term outcomes after rituximab in ANCA-associated renal vasculitis are unknown. METHODS: Forty-four patients with newly diagnosed ANCA-associated vasculitis and renal involvement were randomised, 3:1, to glucocorticoids plus either rituximab (375 mg/m(2)/week×4) with two intravenous cyclophosphamide pulses (n=33, rituximab group), or intravenous cyclophosphamide for 3-6 months followed by azathioprine (n=11, control group). RESULTS: The primary end point at 24 months was a composite of death, end-stage renal disease and relapse, which occurred in 14/33 in the rituximab group (42%) and 4/11 in the control group (36%) (p=1.00). After remission induction treatment all patients in the rituximab group achieved complete B cell depletion and during subsequent follow-up, 23/33 (70%) had B cell return. Relapses occurred in seven in the rituximab group (21%) and two in the control group (18%) (p=1.00). All relapses in the rituximab group occurred after B cell return. CONCLUSIONS: At 24 months, rates of the composite outcome of death, end-stage renal disease and relapse did not differ between groups. In the rituximab group, B cell return was associated with relapse. TRIAL REGISTRATION NUMBER: ISRCTN28528813.


Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Azatioprina/uso terapêutico , Ciclofosfamida/uso terapêutico , Glucocorticoides/uso terapêutico , Granulomatose com Poliangiite/tratamento farmacológico , Imunossupressores/uso terapêutico , Poliangiite Microscópica/tratamento farmacológico , Insuficiência Renal Crônica/tratamento farmacológico , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Linfócitos B/citologia , Progressão da Doença , Intervalo Livre de Doença , Quimioterapia Combinada , Feminino , Granulomatose com Poliangiite/complicações , Granulomatose com Poliangiite/imunologia , Humanos , Falência Renal Crônica/etiologia , Contagem de Linfócitos , Masculino , Poliangiite Microscópica/complicações , Poliangiite Microscópica/imunologia , Pessoa de Meia-Idade , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/imunologia , Rituximab
10.
Nephrology (Carlton) ; 20(5): 343-51, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25656094

RESUMO

AIM: This study evaluated the safety and efficacy of influenza vaccination in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. METHODS: Thirty-one patients who were in remission were randomized to receive either a trivalent influenza vaccine or no vaccine. Vaccine efficacy was assessed at 28 days. Patients were followed for 6 months for signs of reactivation of disease. In addition, 67 healthy individuals were randomized to receive either the influenza vaccine or no vaccine to assess its potential for triggering the formation of autoantibodies. RESULTS: Compared with patients who did not receive the vaccine, vaccinated patients achieved effective responses to all three influenza vaccine antigens. There was no significant change in levels of anti-neutrophil cytoplasmic antibody post-vaccination. There was no significant change in disease activity in vaccinated patients compared with non-vaccinated patients. Among vaccinated healthy individuals, we did not observe any significant change in the level of autoantibodies measured. CONCLUSION: This study shows that the administration of influenza vaccine to patients in remission with anti-neutrophil cytoplasmic antibody-associated vasculitis is both safe and modestly efficacious.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H3N2/imunologia , Vírus da Influenza B/imunologia , Vacinas contra Influenza , Influenza Humana/prevenção & controle , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Anticitoplasma de Neutrófilos/sangue , Anticorpos Antivirais/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Adulto Jovem
11.
N Engl J Med ; 363(3): 211-20, 2010 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-20647198

RESUMO

BACKGROUND: Cyclophosphamide induction regimens for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis are effective in 70 to 90% of patients, but they are associated with high rates of death and adverse events. Treatment with rituximab has led to remission rates of 80 to 90% among patients with refractory ANCA-associated vasculitis and may be safer than cyclophosphamide regimens. METHODS: We compared rituximab with cyclophosphamide as induction therapy in ANCA-associated vasculitis. We randomly assigned, in a 3:1 ratio, 44 patients with newly diagnosed ANCA-associated vasculitis and renal involvement to a standard glucocorticoid regimen plus either rituximab at a dose of 375 mg per square meter of body-surface area per week for 4 weeks, with two intravenous cyclophosphamide pulses (33 patients, the rituximab group), or intravenous cyclophosphamide for 3 to 6 months followed by azathioprine (11 patients, the control group). Primary end points were sustained remission rates at 12 months and severe adverse events. RESULTS: The median age was 68 years, and the glomerular filtration rate (GFR) was 18 ml per minute per 1.73 m(2) of body-surface area. A total of 25 patients in the rituximab group (76%) and 9 patients in the control group (82%) had a sustained remission (P=0.68). Severe adverse events occurred in 14 patients in the rituximab group (42%) and 4 patients in the control group (36%) (P=0.77). Six of the 33 patients in the rituximab group (18%) and 2 of the 11 patients in the control group (18%) died (P=1.00). The median increase in the GFR between 0 and 12 months was 19 ml per minute in the rituximab group and 15 ml per minute in the control group (P=0.14). CONCLUSIONS: A rituximab-based regimen was not superior to standard intravenous cyclophosphamide for severe ANCA-associated vasculitis. Sustained-remission rates were high in both groups, and the rituximab-based regimen was not associated with reductions in early severe adverse events. (Funded by Cambridge University Hospitals National Health Service Foundation Trust and F. Hoffmann-La Roche; Current Controlled Trials number, ISRCTN28528813.)


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Ciclofosfamida/uso terapêutico , Imunossupressores/uso terapêutico , Nefropatias/tratamento farmacológico , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/mortalidade , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Murinos , Linfócitos B/efeitos dos fármacos , Ciclofosfamida/efeitos adversos , Quimioterapia Combinada , Feminino , Taxa de Filtração Glomerular , Glucocorticoides/efeitos adversos , Glucocorticoides/uso terapêutico , Humanos , Imunossupressores/efeitos adversos , Incidência , Infusões Intravenosas , Análise de Intenção de Tratamento , Nefropatias/mortalidade , Masculino , Metilprednisolona/efeitos adversos , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Indução de Remissão , Rituximab
12.
J Immunol ; 184(3): 1425-35, 2010 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-20042575

RESUMO

LL-37 is a cationic antimicrobial peptide derived from neutrophils and keratinocytes. It plays an important role in protection against bacterial infection in the skin and mucosal surfaces. However, its role within the blood compartment remains unclear given that serum inhibits its bactericidal property. In this study, we show that LL-37 promotes very rapid and highly efficient sensing of CpG motifs in bacterial DNA by human B lymphocytes and plasmacytoid dendritic cells (pDCs) in serum-containing media and in whole blood. LL-37 allowed detection of CpG oligodeoxynucleotide (ODN) within minutes of exposure. Without LL-37, 20-30 times more CpG was required to produce the same effect. The promotion of CpG detection by LL-37 was independent of the backbone of the ODN, as the effect was observed not only in ODNs with modified phosphorothioate backbone, but also in ODNs with natural phosphodiester backbone, as found in genomic DNA. Unmethylated CpG motifs within the phosphodiester ODN and LL-37-mediated delivery are required for pDCs to respond. In keeping with the above, cells responded to CpG-rich bacterial DNA and LL-37, but not to human DNA and LL-37. The ability of LL-37 to enhance delivery of CpG to stimulate immune cells is independent of its amphipathic structure and its bactericidal property. LL-37 aids the delivery of CpG to B cells and pDCs, but not T cells. These findings are pertinent to rapid recognition of microbial DNA and are highly relevant to contemporary studies of CpG/TLR9 agonists in vaccines and cancer therapy.


Assuntos
Peptídeos Catiônicos Antimicrobianos/fisiologia , Linfócitos B/imunologia , Ilhas de CpG/imunologia , Células Dendríticas/imunologia , Oligodesoxirribonucleotídeos/sangue , Adjuvantes Imunológicos/sangue , Adjuvantes Imunológicos/metabolismo , Adjuvantes Imunológicos/fisiologia , Sequência de Aminoácidos , Peptídeos Catiônicos Antimicrobianos/sangue , Peptídeos Catiônicos Antimicrobianos/metabolismo , Linfócitos B/metabolismo , Linfócitos B/microbiologia , Atividade Bactericida do Sangue/imunologia , Células Cultivadas , DNA Bacteriano/sangue , Células Dendríticas/metabolismo , Células Dendríticas/microbiologia , Escherichia coli/imunologia , Escherichia coli/metabolismo , Humanos , Dados de Sequência Molecular , Receptor Toll-Like 9/sangue , Receptor Toll-Like 9/fisiologia , Catelicidinas
13.
Kidney Int Rep ; 7(8): 1745-1757, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35967106

RESUMO

The first European Vasculitis Society (EUVAS) meeting report was published in 2017. Herein, we report on developments in the past 5 years which were greatly influenced by the pandemic. The adaptability to engage virtually, at this critical time in society, embodies the importance of networks and underscores the role of global collaborations. We outline state-of-the-art webinar topics, updates on developments in the last 5 years, and proposals for agendas going forward. A host of newly reported clinical trials is shaping practice on steroid minimization, maintenance strategies, and the role of newer therapies. To guide longer-term strategies, a longitudinal 10-year study investigating relapse, comorbidity, malignancy, and survival rates is at an advanced stage. Disease assessment studies are refining classification criteria to differentiate forms of vasculitis more fully. A large international validation study on the histologic classification of anti-neutrophil cytoplasmic antibody (ANCA) glomerulonephritis, recruiting new multicenter sites and comparing results with the Kidney Risk Score, has been conducted. Eosinophilic granulomatosis with polyangiitis (EGPA) genomics offers potential pathogenic subset and therapeutic insights. Among biomarkers, ANCA testing is favoring immunoassay as the preferred method for diagnostic evaluation. Consolidated development of European registries is progressing with an integrated framework to analyze large clinical data sets on an unprecedented scale.

14.
Health Technol Assess ; 26(38): 1-60, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36155131

RESUMO

BACKGROUND: Anti-neutrophil cytoplasm antibody-associated vasculitis is a multisystem, autoimmune disease that causes organ failure and death. Physical removal of pathogenic autoantibodies by plasma exchange is recommended for severe presentations, along with high-dose glucocorticoids, but glucocorticoid toxicity contributes to morbidity and mortality. The lack of a robust evidence base to guide the use of plasma exchange and glucocorticoid dosing contributes to variation in practice and suboptimal outcomes. OBJECTIVES: We aimed to determine the clinical efficacy of plasma exchange in addition to immunosuppressive therapy and glucocorticoids with respect to death and end-stage renal disease in patients with severe anti-neutrophil cytoplasm antibody-associated vasculitis. We also aimed to determine whether or not a reduced-dose glucocorticoid regimen was non-inferior to a standard-dose regimen with respect to death and end-stage renal disease. DESIGN: This was an international, multicentre, open-label, randomised controlled trial. Patients were randomised in a two-by-two factorial design to receive either adjunctive plasma exchange or no plasma exchange, and either a reduced or a standard glucocorticoid dosing regimen. All patients received immunosuppressive induction therapy with cyclophosphamide or rituximab. SETTING: Ninety-five hospitals in Europe, North America, Australia/New Zealand and Japan participated. PARTICIPANTS: Participants were aged ≥ 16 years with a diagnosis of granulomatosis with polyangiitis or microscopic polyangiitis, and either proteinase 3 anti-neutrophil cytoplasm antibody or myeloperoxidase anti-neutrophil cytoplasm antibody positivity, and a glomerular filtration rate of < 50 ml/minute/1.73 m2 or diffuse alveolar haemorrhage attributable to active anti-neutrophil cytoplasm antibody-associated vasculitis. INTERVENTIONS: Participants received seven sessions of plasma exchange within 14 days or no plasma exchange. Oral glucocorticoids commenced with prednisolone 1 mg/kg/day and were reduced over different lengths of time to 5 mg/kg/day, such that cumulative oral glucocorticoid exposure in the first 6 months was 50% lower in patients allocated to the reduced-dose regimen than in those allocated to the standard-dose regimen. All patients received the same glucocorticoid dosing from 6 to 12 months. Subsequent dosing was at the discretion of the treating physician. PRIMARY OUTCOME: The primary outcome was a composite of all-cause mortality and end-stage renal disease at a common close-out when the last patient had completed 10 months in the trial. RESULTS: The study recruited 704 patients from June 2010 to September 2016. Ninety-nine patients died and 138 developed end-stage renal disease, with the primary end point occurring in 209 out of 704 (29.7%) patients: 100 out of 352 (28%) in the plasma exchange group and 109 out of 352 (31%) in the no plasma exchange group (adjusted hazard ratio 0.86, 95% confidence interval 0.65 to 1.13; p = 0.3). In the per-protocol analysis for the non-inferiority glucocorticoid comparison, the primary end point occurred in 92 out of 330 (28%) patients in the reduced-dose group and 83 out of 325 (26%) patients in the standard-dose group (partial-adjusted risk difference 0.023, 95% confidence interval 0.034 to 0.08; p = 0.5), thus meeting our non-inferiority hypothesis. Serious infections in the first year occurred in 96 out of 353 (27%) patients in the reduced-dose group and in 116 out of 351 (33%) patients in the standard-dose group. The rate of serious infections at 1 year was lower in the reduced-dose group than in the standard-dose group (incidence rate ratio 0.69, 95% confidence interval 0.52 to 0.93; p = 0.016). CONCLUSIONS: Plasma exchange did not prolong the time to death and/or end-stage renal disease in patients with anti-neutrophil cytoplasm antibody-associated vasculitis with severe renal or pulmonary involvement. A reduced-dose glucocorticoid regimen was non-inferior to a standard-dose regimen and was associated with fewer serious infections. FUTURE WORK: A meta-analysis examining the effects of plasma exchange on kidney outcomes in anti-neutrophil cytoplasm antibody-associated vasculitis is planned. A health-economic analysis of data collected in this study to examine the impact of both plasma exchange and reduced glucocorticoid dosing is planned to address the utility of plasma exchange for reducing early end-stage renal disease rates. Blood and tissue samples collected in the study will be examined to identify predictors of response to plasma exchange in anti-neutrophil cytoplasm in antibody-associated vasculitis. The benefits associated with reduced glucocorticoid dosing will inform future studies of newer therapies to permit further reduction in glucocorticoid exposure. Data from this study will contribute to updated management recommendations for anti-neutrophil cytoplasm antibody-associated vasculitis. LIMITATIONS: This study had an open-label design which may have permitted observer bias; however, the nature of the end points, end-stage renal disease and death, would have minimised this risk. Despite being, to our knowledge, the largest ever trial in anti-neutrophil cytoplasm antibody-associated vasculitis, there was an insufficient sample size to assess clinically useful benefits on the separate components of the primary end-point: end-stage renal disease and death. Use of a fixed-dose plasma exchange regimen determined by consensus rather than data-driven dose ranging meant that some patients may have been underdosed, thus reducing the therapeutic impact. In particular, no biomarkers have been identified to help determine dosing in a particular patient, although this is one of the goals of the biomarker plan of this study. TRIAL REGISTRATION: This trial is registered as ISRCTN07757494, EudraCT 2009-013220-24 and Clinicaltrials.gov NCT00987389. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 38. See the NIHR Journals Library website for further project information.


Anti-neutrophil cytoplasm antibody vasculitis is a rare and severe disease in which the patient makes antibodies that damage their blood vessels. It can cause lung damage, kidney failure and early death. Treatment aims to suppress the harmful effects of the antibodies and associated inflammation. In particular: Plasma exchange aims to remove the antibodies from the bloodstream.Steroids aim to reduce the harmful activity of the antibodies. Unfortunately, plasma exchange is expensive and time-consuming, and we do not know if it really works long term to reduce kidney damage or the risk of death. We know steroids work, but they have many severe side effects that are related to higher doses. Again, we do not know if lower doses are equally effective. We conducted a randomised trial, PEXIVAS (Plasma Exchange In VASculitis), to measure the clinical effectiveness of plasma exchange and of reduced steroid doses. Anti-neutrophil cytoplasm antibody vasculitis patients with severe kidney or lung disease were allocated randomly to either plasma exchange or no plasma exchange. The same patients were then randomly allocated to a 'reduced' or 'standard' steroid dose. All patients received an immunosuppressive drug: cyclophosphamide or rituximab. The primary end point for both trials was the occurrence of either kidney failure or death. A total of 704 patients were recruited between 2010 and 2016, and they were followed up until the end of the trial in July 2017. Ninety-nine patients died and 138 developed kidney failure. Plasma exchange did not reduce the chances of death or kidney failure. There was also no difference between the two steroid dose groups in the number of deaths or patients developing kidney failure. However, there were fewer serious infections in the reduced steroid dose group. These results do not support the routine use of plasma exchange for all patients with severe vasculitis. They do show that the reduced-dose steroid regimen is just as effective as, and safer than, a 'standard'-dose steroid regimen. These results have the potential to save money and make the treatment of vasculitis patients safer in the future.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Falência Renal Crônica , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Autoanticorpos/uso terapêutico , Análise Custo-Benefício , Ciclofosfamida/uso terapêutico , Citoplasma , Glucocorticoides/uso terapêutico , Humanos , Falência Renal Crônica/terapia , Mieloblastina , Peroxidase/uso terapêutico , Prednisolona/uso terapêutico , Rituximab/uso terapêutico
15.
Am J Kidney Dis ; 57(4): 566-74, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21194817

RESUMO

BACKGROUND: Plasma exchange may be effective adjunctive treatment for renal vasculitis. We performed a systematic review and meta-analysis of randomized controlled trials of plasma exchange for renal vasculitis. STUDY DESIGN: Systematic review and meta-analysis of articles identified from electronic databases, bibliographies, and studies identified by experts. Data were abstracted in parallel by 2 reviewers. SETTING & POPULATION: Adults with idiopathic renal vasculitis or rapidly progressive glomerulonephritis. SELECTION CRITERIA FOR STUDIES: Randomized controlled trials that compared standard care with standard care plus adjuvant plasma exchange in adult patients with either renal vasculitis or idiopathic rapidly progressive glomerulonephritis. INTERVENTION: Adjuvant plasma exchange. OUTCOME: Composite of end-stage renal disease or death. RESULTS: We identified 9 trials including 387 patients. In a fixed-effects model, the pooled RR for end-stage renal disease or death was 0.80 for patients treated with adjunctive plasma exchange compared with standard care alone (95% CI, 0.65-0.99; P = 0.04). No significant heterogeneity was detected (P = 0.5; I(2) = 0%). The effect of plasma exchange did not differ significantly across the range of baseline serum creatinine values (P = 0.7) or number of plasma exchange treatments (P = 0.8). The RR for end-stage renal disease was 0.64 (95% CI, 0.47-0.88; P = 0.006), whereas the RR for death alone was 1.01 (95% CI, 0.71-1.4; P = 0.9). LIMITATIONS: Although the primary result was statistically significant, there is insufficient statistical information to reliably determine whether plasma exchange decreases the composite of end-stage renal disease or death. CONCLUSIONS: Plasma exchange may decrease the composite end point of end-stage renal disease or death in patients with renal vasculitis. Additional trials are required given the limited data available.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/terapia , Glomerulonefrite/terapia , Troca Plasmática , Adulto , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Progressão da Doença , Feminino , Glomerulonefrite/etiologia , Humanos , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/mortalidade , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Resultado do Tratamento
16.
Toxicon ; 203: 66-73, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34562496

RESUMO

Snakebite is an important problem in Myanmar. Regionally, bites by Eastern Russell's vipers, Daboia siamensis (Viperidae, Viperinae), and monocled cobras, Naja kaouthia are considered medically important, but those categorised as "green snake" bites are not. However, these may include bites by green pit vipers, Trimeresurus spp. (Viperidae, Crotalinae) for which no antivenom is available in Myanmar. Elsewhere in Southeast Asia, these snakes are reported to cause local and systemic envenoming. As part of the Myanmar Snakebite Project, prospective case data were collected over 3 years from five hospitals in the Mandalay region. These included 3803 snakebite cases reported from Mandalay region. Of these, 355 were listed as bites by a witnessed green-coloured snake. In 22 cases, the snakes responsible were retained and preserved, then expertly identified; 21 were medically important white-lipped pit vipers (Trimeresurus albolabris), and one as an Asian vine snake, Ahaetulla prasina (Colubridae, Ahaetuliinae) which is not of medical importance. Among confirmed Trimeresurus albolabris bites, 15/21 developed swelling of the bitten limb, and 3/21 coagulopathy, defined as a positive 20-min whole blood clotting test (20WBCT). None developed necrosis, blistering, thrombocytopenia or acute kidney injury (AKI). Of the remaining 333 patients bitten by green snakes that were not specifically identified, 241 (72%) developed swelling of the bitten limb, and 62 (19%) coagulopathy. AKI occurred in 21/333 patients, but only one required dialysis. At least 10/21 of the cases with AKI in this study were more likely to represent bites from Trimeresurus spp. than D. siamensis because the snake responsible was brought into the hospital, examined and described by the treating physician as "green-coloured". This study describes a previously unpublished case of AKI from envenoming by T. erythrurus in Yangon, and reviews cases of AKI following bites by this species and T. albolabris in Myanmar. This confirms that, at least on rare occasions, Trimeresurus spp. envenoming can cause AKI. This has important implications for snakebite management in Myanmar as the finding of local swelling, coagulopathy and AKI is generally considered pathognomonic of D. siamensis envenoming. Further collection of confirmed Trimeresurus spp. bites is required in Myanmar in order better to define the syndrome of envenoming and to assess the possible need for antivenom against Trimeresurus spp. in this country.


Assuntos
Colubridae , Crotalinae , Mordeduras de Serpentes , Trimeresurus , Animais , Humanos , Mianmar , Mordeduras de Serpentes/tratamento farmacológico , Mordeduras de Serpentes/epidemiologia
17.
J Exp Med ; 200(1): 13-24, 2004 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-15226359

RESUMO

HLA class I polymorphism creates diversity in epitope specificity and T cell repertoire. We show that HLA polymorphism also controls the choice of Ag presentation pathway. A single amino acid polymorphism that distinguishes HLA-B*4402 (Asp116) from B*4405 (Tyr116) permits B*4405 to constitutively acquire peptides without any detectable incorporation into the transporter associated with Ag presentation (TAP)-associated peptide loading complex even under conditions of extreme peptide starvation. This mode of peptide capture is less susceptible to viral interference than the conventional loading pathway used by HLA-B*4402 that involves assembly of class I molecules within the peptide loading complex. Thus, B*4402 and B*4405 are at opposite extremes of a natural spectrum in HLA class I dependence on the PLC for Ag presentation. These findings unveil a new layer of MHC polymorphism that affects the generic pathway of Ag loading, revealing an unsuspected evolutionary trade-off in selection for optimal HLA class I loading versus effective pathogen evasion.


Assuntos
Apresentação de Antígeno , Suscetibilidade a Doenças , Genes MHC Classe I , Antígenos HLA-B/metabolismo , Polimorfismo Genético , Animais , Antiporters/genética , Antiporters/metabolismo , Linhagem Celular , Cristalografia por Raios X , Antígenos HLA-B/química , Antígenos HLA-B/genética , Herpes Simples , Humanos , Imunoglobulinas/genética , Imunoglobulinas/metabolismo , Proteínas de Membrana Transportadoras , Camundongos , Modelos Moleculares , Peptídeos/química , Peptídeos/metabolismo , Conformação Proteica , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Simplexvirus
18.
Toxicon ; 184: 39-47, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32504626

RESUMO

Examination of 18 cobras brought to three hospitals in the Mandalay Region by patients bitten or spat at by them distinguished 3 monocled cobras (Naja kaouthia) and 15 Mandalay spitting cobras (N. mandalayensis), based on their morphological characteristics. We confirm and extend the known distributions and habitats of both N. mandalayensis and N. kaouthia in Upper Myanmar. Clinical symptoms of local and systemic envenoming by N. mandalayensis are described for the first time. These included local swelling, blistering and necrosis and life-threatening systemic neurotoxicity. More information is needed about the clinical phenotype and management of bites by N. mandalayensis, the commoner of the two cobras in Upper Myanmar. Since the current cobra antivenom manufactured in Myanmar has lower pre-clinical efficacy against N. mandalayensis than N. kaouthia, there is a need for more specific antivenom therapy.


Assuntos
Venenos Elapídicos , Elapidae , Naja , Animais , Antivenenos , Endoftalmite , Mianmar , Mordeduras de Serpentes
19.
Respirol Case Rep ; 7(7): e00456, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31312454

RESUMO

Pulmonary calcification can develop as a complication of end-stage renal failure. Most patients are asymptomatic, with characteristic parenchymal changes incidentally detected on computed tomography (CT) imaging and a clinical course that is usually benign. In this report, we describe a 64-year-old female with a history of inadequate peritoneal dialysis who presented with severe chronic cough, a symptom that persisted despite treatment for respiratory tract infection. On follow-up bronchoscopic examination, white nodular tracheobronchial mucosal changes persisted. The presence of calcium deposits within these nodules was histologically confirmed, although CT imaging had not suggested the presence of calcific tracheobronchial changes. We believe that the bronchoscopic findings represent a highly unusual presentation of metastatic pulmonary calcification and an uncommon cause of chronic cough amongst patients with end-stage renal failure.

20.
Toxicon X ; 1: 100001, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32831344

RESUMO

Snakebite is predominantly an occupational disease affecting poor rural farmers in tropical regions and was recently added to the World Health Organisation list of Neglected Tropical Diseases (NTD). We document an overview of methodologies developed and deployed in the Myanmar Snakebite Project, a foreign aid project largely funded by the Australian Government, with the core aim to "improve outcomes for snakebite patients". A multidisciplinary team of experts was assembled that worked in a collaborative manner with colleagues in Myanmar, first to identify problems related to managing snakebite and then develop interventions aimed to improve selected problem areas. A broad approach was adopted, covering antivenom production, antivenom distribution and health system management of snakebite. Problems identified in antivenom production included poor snake husbandry resulting in poor survival of captive specimens, lack of geographical diversity; poor horse husbandry, resulting in high mortality, inadequate stock acquisition protocols and data collection, and inappropriate immunisation and bleeding techniques; and inadequate production capacity for freeze dried antivenoms and quality control systems. These problems were addressed in various ways, resulting in some substantial improvements. Antivenom distribution is being reorganised to achieve better availability and utilisation of stock. Health system management of snakebite was assessed across all levels within the area selected for the study, in Mandalay region. A comprehensive community survey indicated that hospital statistics substantially underestimated the snakebite burden, and that access to care by local villagers was delayed by transport and cost issues compounded by lack of antivenom at the most peripheral level of the health service. A health system survey confirmed under-resourcing at the local village level. Prospective case data collection initiated at tertiary hospitals indicated the extent of the snakebite burden on health resources. Interventions initiated or planned include training of health staff, development of a core of senior trainers who can "train the trainers" nationwide in a sustainable way, development and deployment of management guidelines and algorithms for snakebite and a distribution of solar powered fridges to remote health facilities to allow storage of antivenom and prompt treatment of snakebite cases before transfer to major hospitals, thereby reducing the "bite to needle" time.

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