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Exceptional LAS Requests in Eurotransplant: Analysis of an 8-year Effort to Improve Lung Allocation for Precarious Patients.

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Exceptional LAS Requests in Eurotransplant: Analysis of an 8-year Effort to Improve Lung Allocation for Precarious Patients.

J Heart Lung Transplant. 2020 Apr;39(4S):S375-S376

Authors: Vos R, Smits JM, Hoek R, Green D, Evrard P, Knoop C, Verleden GM, Rondelet B, Kwakkel-vanErp JM, Seghers L, van Kessel DA, Luijk B, Verschuuren EA, Lang G, Hoetzenecker K, Laufer G, Hoefer D, Langer F, Schramm R, Deuse T, Buhl R, Witt C, Gottlieb J

Abstract
PURPOSE: Following introduction of the lung allocation score (LAS) in 2011, Eurotransplant member centers can apply for an exceptional LAS (eLAS) if the calculated LAS insufficiently reflects the perceived transplant benefit for a patient, specifically in case of primary pulmonary hypertension group 1 and 4; combined lung+non-renal transplantation; rare diseases; or extracorporeal support. Each eLAS proposal is evaluated by a LAS Review Board, consisting of ≥3 lung transplant experts, which subsequently declines or approves the eLAS request in consensus of ≥3 votes. In case of a lower than accepted score, predefined business rules to assign LAS percentiles are used.
METHODS: A retrospective analysis of all eLAS requests in Eurotransplant from December 2011 until September 2019.
RESULTS: Overall, 5183 lung transplants (deceased donors) were performed and 420 eLAS requests were made (Germany 52%, Netherlands 18%, Austria 18%, Belgium 13%), of which 116 (28%) were approved. Most eLAS requests concerned group B/Pulmonary vascular disease (44%), followed by group C/Cystic fibrosis or immunodeficiency disorder (28%), then group D/Restrictive lung disease (15%) and finally group A/Obstructive lung disease (11%); whereas 10 patients (2%) were not classified. The proportion of accepted eLAS requests significantly differed between countries (Germany 25%, Netherlands 37%, Austria 20%, Belgium 36%) (p=0.042). eLAS requests decreased in the Netherlands following its LAS introduction in 2014 (2011-2014 mean 13/yr vs. 2015-2019 mean 4.6/yr; p=0.060). However, since 2015 an overall annual increasing number of eLAS requests is seen, with doubling of the eLAS requests in 2018 vs. 2015, but no difference in acceptance rate (2015-2018: 22.4%) (Figure). Acceptance rates were 38% for Group B, 21% for Group C, 20% for Group D and 11% for Group A.
CONCLUSION: The observed variations require further investigation to optimize lung allocation for specific patient populations in Eurotransplant.

PMID: 32465561 [PubMed – in process]

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Lentiviral gene therapy corrects platelet phenotype and function in patients with Wiskott-Aldrich syndrome.

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Lentiviral gene therapy corrects platelet phenotype and function in patients with Wiskott-Aldrich syndrome.

J Allergy Clin Immunol. 2019 09;144(3):825-838

Authors: Sereni L, Castiello MC, Di Silvestre D, Della Valle P, Brombin C, Ferrua F, Cicalese MP, Pozzi L, Migliavacca M, Bernardo ME, Pignata C, Farah R, Notarangelo LD, Marcus N, Cattaneo L, Spinelli M, Giannelli S, Bosticardo M, van Rossem K, D’Angelo A, Aiuti A, Mauri P, Villa A

Abstract
BACKGROUND: Thrombocytopenia is a serious issue for all patients with classical Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT) because it causes severe and life-threatening bleeding. Lentiviral gene therapy (GT) for WAS has shown promising results in terms of immune reconstitution. However, despite the reduced severity and frequency of bleeding events, platelet counts remain low in GT-treated patients.
OBJECTIVE: We carefully investigated platelet defects in terms of phenotype and function in untreated patients with WAS and assessed the effect of GT treatment on platelet dysfunction.
METHODS: We analyzed a cohort of 20 patients with WAS/XLT, 15 of them receiving GT. Platelet phenotype and function were analyzed by using electron microscopy, flow cytometry, and an aggregation assay. Platelet protein composition was assessed before and after GT by means of proteomic profile analysis.
RESULTS: We show that platelets from untreated patients with WAS have reduced size, abnormal ultrastructure, and a hyperactivated phenotype at steady state, whereas activation and aggregation responses to agonists are decreased. GT restores platelet size and function early after treatment and reduces the hyperactivated phenotype proportionally to WAS protein expression and length of follow-up.
CONCLUSIONS: Our study highlights the coexistence of morphologic and multiple functional defects in platelets lacking WAS protein and demonstrates that GT normalizes the platelet proteomic profile with consequent restoration of platelet ultrastructure and phenotype, which might explain the observed reduction of bleeding episodes after GT. These results are instrumental also from the perspective of a future clinical trial in patients with XLT only presenting with microthrombocytopenia.

PMID: 30926529 [PubMed – indexed for MEDLINE]

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Influenza-related hospitalizations due to acute lower respiratory tract infections in a tertiary care children’s hospital in Turkey.

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Influenza-related hospitalizations due to acute lower respiratory tract infections in a tertiary care children’s hospital in Turkey.

J Clin Virol. 2020 Apr 18;128:104355

Authors: Böncüoğlu E, Kıymet E, Çağlar İ, Tahta N, Bayram N, Ayhan FY, Genel F, Ecevit ÇÖ, Apa H, Çelik T, Devrim İ

Abstract
BACKGROUND: The influenza virus is a significant cause of acute lower respiratory tract infections (LRTI) requiring hospitalization in childhood and leads to severe morbidity and mortality, especially in certain risk groups.
OBJECTIVES: The study aims to evaluate acute LRTI due to influenza in a tertiary care hospital and the risk factors for hospitalization among Turkish children.
STUDY DESIGN: Children between 1 month and 18 years of age who were hospitalized at Dr. Behçet Uz Children’s Hospital between January 2016 and March 2018 with lower respiratory tract infection that tested positive for influenza by PCR were included. Children with viral coinfections were excluded. Patient files were retrospectively scanned from the hospital computerized system in terms of age, underlying diseases, whether antiviral therapy was used, and length of hospital stay. Statistical analysis was performed using SPSS statistical software.
RESULTS: The study included 131 patients with a median age of 2 years (1 month-15 years). Sixty-seven (51,1%) patients were younger than two years. Influenza A was isolated in 129 patients and B in 2 patients. Fifty-two patients (39,7%) had underlying medical conditions, and the most common one was malignancies (12/52, 23%). This was followed by neurodevelopmental diseases (9/52, 17,3%), prematurity (9/52 patients, 17,3%), primary immunodeficiency (8/52, 15,4%), asthma (7/52, 13,4%), Down syndrome (4/52, 7,7%), chronic renal disease (2/52, 3,8%) and congenital heart diseases (1/52, 1,9%). The mean length of stay (LOS) was 12,3 ± 9,5 days (2-60 days). The LOS was found to be statistically longer (15,2 ± 12,1 days, 3-60 days) in patients with an underlying disease compared to previously healthy patients (10,4 ± 6,7 days, 2-35 days) (p = 0.01).
CONCLUSIONS: Hospitalization due to influenza-related acute LRTI is not an issue only for patients with an underlying medical condition. Vaccination should be considered not only for those with underlying medical conditions but also for healthy children.

PMID: 32464308 [PubMed – as supplied by publisher]

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Jeffrey’s insights: Jeffrey Modell Foundation’s global genetic sequencing pilot program to identify specific primary immunodeficiency defects to optimize disease management and treatment.

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Jeffrey’s insights: Jeffrey Modell Foundation’s global genetic sequencing pilot program to identify specific primary immunodeficiency defects to optimize disease management and treatment.

Immunol Res. 2020 May 27;:

Authors: Quinn J, Modell V, Holle J, Truty R, Aradhya S, Johnson B, Orange J, Modell F

Abstract
Primary immunodeficiencies (PI) are genetic defects of the immune system that result in chronic and often life-threatening infections and/or life-threatening autoimmunity if not diagnosed and treated. Patients with a suspected PI, but without a genetic diagnosis, commonly undergo a diagnostic odyssey that is costly, time-consuming, and arduous. This delay in diagnosis prevents appropriate disease management and treatment, contributing to prolonged suffering and decreased quality of life. Although next generation sequencing (NGS) can provide these patients with relief from such a diagnostic odyssey, it is often unavailable, mainly due to cost and inaccessibility. In January 2019, the Jeffrey Modell Foundation (JMF) launched a free genetic sequencing pilot program for Jeffrey Modell Centers Network (JMCN) patients clinically diagnosed with an underlying PI. A total of 21 sites within the JMCN were invited to participate. JMF collaborated with Invitae, and testing was comprised of Invitae’s Primary Immunodeficiency Panel, which currently includes 207 genes. A questionnaire was disseminated to each participating physician to evaluate barriers to access to genetic sequencing and changes in disease management and treatment after testing. One hundred fifty-eight patients and 29 family members were tested in this pilot study. Twenty-one percent of patients with a suspected monogenic disorder received a molecular diagnosis, and others received potentially useful diagnostic leads. Based on the results of genetic sequencing, clinical diagnosis was altered in 45% of patients, disease management was altered in 40%, treatment was altered in 36%, and genetic counseling was altered in 62%. The results of this pilot program demonstrate the utility, cost-efficiency, and critical importance of NGS for PI and make the case for broad scale sequence-based diagnostics for PI patients when requested by expert immunologists.

PMID: 32462469 [PubMed – as supplied by publisher]

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Emergence of azole resistant-Aspergillus fumigatus infections during STAT3-deficiency.

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Emergence of azole resistant-Aspergillus fumigatus infections during STAT3-deficiency.

J Med Microbiol. 2020 May 27;:

Authors: Danion F, Duréault A, Gautier C, Senechal A, Persat F, Bougnoux ME, Givel C, Couderc LJ, Lortholary O, Garcia-Hermoso D, Lanternier F

Abstract
Introduction. Signal transducer and activator of transcription 3 (STAT3) deficiency is a rare primary immunodeficiency associated with increased susceptibility to bacterial and fungal infections, notably pulmonary aspergillosis.Aim. We describe the emergence of azole-resistant Aspergillus fumigatus infections in STAT3-deficient patients.Methodology. During a retrospective study of 13 pulmonary aspergillosis cases in STAT3-deficient patients conducted in France, we identified patients infected with azole-resistant A. fumigatus isolates.Results. Two out of the 13 STAT3-deficient patients with aspergillosis had azole-resistant A. fumigatus infection, indicating an unexpectedly high prevalence of resistance. The first patient with STAT3 deficiency presented several flares of allergic bronchopulmonary aspergillosis-like episodes. He was chronically infected with two azole-resistant A. fumigatus isolates (TR34/L98). Despite prolonged antifungal treatment, including caspofungin and amphotericin B, the patient was not able to clear the azole-resistant A. fumigatus. The second patient had chronic cavitary pulmonary aspergillosis (CCPA). The A. fumigatus isolate was initially azole susceptible but harboured three F46Y, M172V and E427K point mutations. Despite prolonged antifungal therapies, lesions worsened and the isolate became resistant to all azoles. Surgery and caspofungin treatments were then required to cure CCPA. Resistance was probably acquired from the environment (TR34/L98) in the first case whereas resistance developed under antifungal treatments in the second case. These infections required long-term antifungal treatments and surgery.Conclusions. The emergence of azole-resistant A. fumigatus infections in STAT3-deficiency dramatically impacts both curative and prophylactic antifungal strategies. Physicians following patients with primary immune-deficiencies should be aware of this emerging problem as it complicates management of the patient.

PMID: 32459615 [PubMed – as supplied by publisher]

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Immune Defect in Adults With Down Syndrome: Insights Into a Complex Issue.

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Immune Defect in Adults With Down Syndrome: Insights Into a Complex Issue.

Front Immunol. 2020;11:840

Authors: Dieudonné Y, Uring-Lambert B, Jeljeli MM, Gies V, Alembik Y, Korganow AS, Guffroy A

Abstract
Children with Down syndrome (DS) suffer from recurrent respiratory infections, which represent the leading cause of mortality during childhood. This susceptibility to infections is usually considered multifactorial and related to both impaired immune function and non-immunological factors. Infections are also one of the top causes of death in DS at adulthood. DS is considered an immunodeficiency with syndromic features by some researchers because of this high rate of infection and the immunological characteristics observed in children with DS. Little is known about the immune status of adult patients. Herein, we report the clinical and immune phenotype of 44 adults with DS, correlated with their infectious history. We observed that these adults had an aberrant lymphocyte phenotype with decreased naïve/memory T cell ratios and reduced numbers of switched memory B cells. The lower incidence of infectious events at adulthood distinguish DS from other inborn errors of immunity. Primary immunodeficiency-related features in DS could explain the increased risk of developing autoimmunity, malignancies, and infections. During adulthood, this immune dysfunction may be compensated for in mid-life, and infection-related mortality observed in older patients might be favored by multiple factors such as neurological impairment or nosocomial antigen exposure. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT01663675 (August 13, 2012).

PMID: 32457756 [PubMed – in process]

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Cell Versus Cytokine – Directed Therapies for Hemophagocytic Lymphohistiocytosis (HLH) in Inborn Errors of Immunity.

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Cell Versus Cytokine – Directed Therapies for Hemophagocytic Lymphohistiocytosis (HLH) in Inborn Errors of Immunity.

Front Immunol. 2020;11:808

Authors: Wegehaupt O, Wustrau K, Lehmberg K, Ehl S

Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a heterogeneous hyperinflammatory syndrome with different pathways of pathogenesis resulting in similar clinical presentations. It is best defined and understood if presenting in the context of genetic immunodeficiencies associated with defects of lymphocyte cytotoxicity. In these “primary” forms of HLH, cellular and soluble immune effectors are relatively well characterized. While etoposide-based broad cell-directed therapies remain standard of care, more specific therapies targeting these effectors individually are increasingly available. Anti-CD52 as a cell-directed therapy and anti-IFN-gamma, IL-18BP, and JAK-inhibition as cytokine-directed therapies are expected to broaden the therapeutic options, but the precise role of these drugs in first-line and rescue treatment indications remains to be defined. A number of additional inborn errors of immunity are associated with episodes of immune activation fulfilling the clinical criteria of HLH. Impaired pathogen control is a key driver of hyperinflammation in some conditions, while others are characterized by a strong autoinflammatory component. This heterogeneity of disease-driving factors and the variable severity in disease progression in these conditions do not allow a simple adaptation of protocols established for “primary” HLH to HLH in the context of other inborn errors of immunity. Cytokine-directed therapies hold significant promise in these increasingly recognized disorders.

PMID: 32457750 [PubMed – in process]

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