Cytotoxic therapy for severe avian influenza A (H5N1) infection

Henter, Jan‐Inge; Chow, C.W.; Leung, Chi‐Wai; Lau, Yu Lung

doi:10.1016/s0140-6736(06)68232-9

Cited by 83 publications

(53 citation statements)

References 28 publications

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“…Deaths in these somewhat older patients without verified FHL were significantly overrepresented during days 11 to 28, and many of these deaths may be associated with toxicity, suggesting that reduced early cytotoxic therapy might be beneficial for these patients (such as etoposide once weekly instead of twice). 46 The results of HLH-2004 compare well with the largest study reported on ATG-based therapy with an overall survival of 21 of 38 (55%) obtained in a highly experienced center. 25 Nevertheless, despite the reduced pre-HSCT mortality in HLH-2004 from 27% to 19%, there is still a need for improved pre-HSCT survival; interesting trials with alternative therapeutic approaches for HLH have been initiated, including ATG in combination with etoposide (clinicaltrials.gov identifier: NCT01104025), alemtuzumab (NCT02472054), 47 tocilizumab (NCT02007239), 48,49 ruxolitinib (NCT02400463), 50,51 and a targeted anti-IFN-g monoclonal antibody (NCT01818492).…”

Section: Patients Alive Without Hsctsupporting

confidence: 59%

Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study

Bergsten

Horne

Aricò

et al. 2017

Blood

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Key Points• Early introduction of cyclosporine did not improve HLH outcome in patients treated with the HLH-94 etoposide-dexamethasone backbone (P 5 .06).• HLH-2004 may be improved by risk-group stratification, less therapy reduction weeks 7 to 8 for verified FHL patients, and earlier HSCT.Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome comprising familial/genetic HLH (FHL) and secondary HLH. In the HLH-94 study, with an estimated 5-year probability of survival (pSu) of 54% (95% confidence interval, 48%-60%), systemic therapy included etoposide, dexamethasone, and, from week 9, cyclosporine A (CSA). Hematopoietic stem cell transplantation (HSCT) was indicated in patients with familial/genetic, relapsing, or severe/persistent disease. In HLH-2004, CSA was instead administered upfront, aiming to reduce pre-HSCT mortality and morbidity. At median follow-up of 5.2 years, 230 of 369 patients (62%) were alive (5-year pSu, 61%; 56%-67%). Five-year pSu in children with (n 5 168) and without (n 5 201) family history/ genetically verified FHL was 59% (52%-67%) and 64% (57%-71%), respectively (familial occurrence [n 5 47], 58% [45%-75%]). Comparing with historical data (HLH-94), using HLH-94 inclusion criteria, pre-HSCT mortality was nonsignificantly reduced from 27% to 19% (P 5 .064 adjusted for age and sex). Time from start of therapy to HSCT was shorter compared with HLH-94 (P 5 .020 adjusted for age and sex) and reported neurological alterations at HSCT were 22% in HLH-94 and 17% in HLH-2004 (using HLH-94 inclusion criteria). Five-year pSu post-HSCT overall was 66% (verified FHL,(70)(71)(72)(73)(74)(75)(76)(77)(78)). Additional analyses provided specific suggestions on potential pre-HSCT treatment improvements. HLH-2004 confirms that a majority of patients may be rescued by the etoposide/dexamethasone combination but intensification with CSA upfront, adding corticosteroids to intrathecal therapy, and reduced time to HSCT did not improve outcome significantly. (Blood. 2017;130(25):2728-2738 Medscape Continuing Medical Education onlineIn support of improving patient care, this activity has been planned and

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Section: Patients Alive Without Hsctsupporting

confidence: 59%

Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study

Bergsten

Horne

Aricò

et al. 2017

Blood

Self Cite

488

444

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“…Although EBV is the most common cause of infection-associated HLH, recognition that at least some of the deaths associated with avian flu and severe acute respiratory syndrome are due to HLH may lead to a reduced mortality in those conditions. 5 Despite recent gains in knowledge, the pathogenesis of HLH is as yet unclear, but primary HLH is thought to involve defective termination of the immune response that results in persistent activation of macrophages and cytotoxic T cells. An alternative hypothesis involves failure to remove Ag, which results in ongoing stimulation of the immune effector cells.…”

Section: Introduction: Background and Pathogenesismentioning

confidence: 99%

Approach to Hemophagocytic Syndromes

2011

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Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal hyperinflammatory condition. It may occur as a primary (genetic) condition due to mutations in genes important in the cytolytic secretory pathway that cause perforin and granzymes to induce apoptosis in target cells. Primary HLH is divided into familial HLH (FHLH1-5), in which HLH is the only manifestation of disease, and other genetic causes in which HLH is one of several clinical manifestations. The identical clinical findings may arise secondary to infectious, rheumatologic, malignant, or metabolic conditions. Whether primary or secondary, HLH therapy needs to be instituted promptly to prevent irreversible tissue damage. It is helpful to think of HLH as the severe end of the spectrum of hyperinflammatory disorders when the immune system starts to damage host tissues (immunopathology). Therefore, no single clinical feature alone is diagnostic for HLH, and it is important that the entire clinical presentation be considered in making the diagnosis. This article contains a discussion of the genetic background, clinical presentation, diagnostic dilemmas, and features that are helpful in making the diagnosis of HLH, along with a discussion of common problems in its management.

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“…A dysregulation of pro-inXammatory responses in patients with H5N1 infection may promote a development of secondary haemophagocytic lymphohistiocytosis (HLH) [71]. Investigators from Hong Kong have reported that two patients with fatal H5N1 disease in 1997 had a reactive haemophagocytic syndrome as the most prominent feature [8].…”

Section: Immune Dysregulation and Inxammationmentioning

confidence: 99%

The threat of avian influenza a (H5N1): part II: Clues to pathogenicity and pathology

Cinatl

Michaelis

2007

Med Microbiol Immunol

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Among emerging and re-emerging infectious diseases, influenza constitutes one of the major threats to mankind. In this review series epidemiologic, virologic and pathologic concerns raised by infections of humans with avian influenza virus A/H5N1 are discussed. The second part focuses on experimental and clinical results, which give insights in the pathogenic mechanisms of H5N1 infection in humans. H5N1 is poorly transmitted to humans. However, H5N1-induced disease is very severe. More information on the role entry barriers, H5N1 target cells and on H5N1-induced modulation of the host immune response is needed to learn more about the determinants of H5N1 pathogenicity.

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Cytotoxic therapy for severe avian influenza A (H5N1) infection

Cited by 83 publications

References 28 publications

Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study

Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study

Approach to Hemophagocytic Syndromes

The threat of avian influenza a (H5N1): part II: Clues to pathogenicity and pathology

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