Manish Butte

Survival Trends in Infants Undergoing Allogeneic Hematopoietic Cell Transplant.

February 15, 2020 By Manish Butte

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Survival Trends in Infants Undergoing Allogeneic Hematopoietic Cell Transplant.

JAMA Pediatr. 2019 05 01;173(5):e190081

Authors: Parikh SH, Satwani P, Ahn KW, Sahr NA, Fretham C, Abraham AA, Agrawal V, Auletta JJ, Abdel-Azim H, Copelan E, Diaz MA, Dvorak CC, Frangoul HA, Freytes CO, Gadalla SM, Gale RP, George B, Gergis U, Hashmi S, Hematti P, Hildebrandt GC, Keating AK, Lazarus HM, Myers KC, Olsson RF, Prestidge T, Rotz SJ, Savani BN, Shereck EB, Williams KM, Wirk B, Pasquini MC, Loren AW

Abstract
Importance: Studies demonstrating improved survival after allogeneic hematopoietic cell transplant generally exclude infants.
Objective: To analyze overall survival trends and other outcomes among infants who undergo allogeneic hematopoietic cell transplant.
Design, Setting, and Participants: In this cohort study, we used time-trend analysis to evaluate 3 periods: 2000 through 2004, 2005 through 2009, and 2010 through 2014. The study was conducted in a multicenter setting through the Center for International Blood and Marrow Transplant Research, which is made up of a voluntary working group of more than 450 transplant centers worldwide. Two groups of infants aged 1 year or younger in 2 cohorts were included: those with malignant conditions, such as leukemia, and those with nonmalignant disorders, including immunodeficiencies. Data analysis was conducted from July 2017 to December 2018.
Exposures: Allogeneic hematopoietic cell transplant.
Main Outcomes and Measures: Survival trends, disease relapse, and toxicity.
Results: A total of 2498 infants with a median age of 7 months (range, <1-12 months) were included. In the nonmalignant cohort (n = 472), survival rates improved from the first to the second period (hazard ratio, 0.77 [95% CI, 0.63-0.93]; P = .007) but did not change after 2004. Compared with infants with nonmalignant diseases (n = 2026; 3-year overall survival: 2000-2004, 375/577 [65.0%]; 2005-2009, 503/699 [72.0%]; and 2010-2014, 555/750 [74.0%]), those with malignant conditions had poorer survival rates, without improvement over time (3-year overall survival: 2000-2004, 109/199 [54.8%]; 2005-2009, 104/161 [64.6%]; and 2010-2014, 66/112 [58.9%]). From 2000 through 2014, relapse rates increased in infants with malignant conditions (3-year relapse rate: 2000-2004, 19% [95% CI, 14%-25%]; 2005-2009, 23% [95% CI, 17%-30%]; 2010-2014, 36% [95% CI, 27%-46%]; P = .01). Sinusoidal obstruction syndrome was frequent, occurring with a cumulative incidence of 13% (95% CI, 11%-16%) of infants with nonmalignant diseases and 32% (95% CI, 22%-42%) of those with malignant diseases. Generally, recipients of human leukocyte antigen-identical sibling bone marrow grafts had the best outcomes.
Conclusions and Relevance: Survival rates have not improved for infants with malignant diseases over the 15-year study period. Infants with nonmalignant diseases had improved survival rates in the earlier but not the later study period. Higher relapses for the malignant cohort and toxicities for all infants remain significant challenges. Strategies to reduce relapse and toxicity and optimize donor and graft selection may improve outcomes in the future.

PMID: 30882883 [PubMed – indexed for MEDLINE]

Impact of graft-versus-host disease on the clinical outcome of allogeneic hematopoietic stem cell transplantation for non-malignant diseases.

February 14, 2020 By Manish Butte

Impact of graft-versus-host disease on the clinical outcome of allogeneic hematopoietic stem cell transplantation for non-malignant diseases.

Int J Hematol. 2020 Feb 12;:

Authors: Umeda K, Imai K, Yanagimachi M, Yabe H, Kobayashi M, Takahashi Y, Kajiwara M, Yoshida N, Cho Y, Inoue M, Hashii Y, Atsuta Y, Morio T, Inherited Disease
Working Group of the Japan Society for Hematopoietic Cell Transplantation

Abstract
The impact of acute and chronic graft-versus-host disease (GVHD) on clinical outcomes was retrospectively analyzed in 960 patients with non-malignant diseases (NMD) who underwent a first allogeneic hematopoietic stem cell transplantation (HSCT). Grade III-IV acute GVHD (but not grade I-II) was significantly associated with a lower rate of overall survival (OS), and higher non-relapse mortality (NRM) than that seen in patients without acute GVHD. Extensive (but not limited) GVHD was significantly associated with a lower OS rate and higher NRM than that seen in patients without chronic GVHD. Any grade of acute (but not chronic) GVHD was significantly associated with a lower incidence of relapse and a lower proportion of patients requiring a second HSCT or donor lymphocyte infusion for graft failure or mixed chimerism, but its impact on OS was almost negligible. Acute GVHD was significantly associated with lower OS rates in all disease groups, whereas chronic GVHD was significantly associated with lower OS rates in the primary immunodeficiency and histiocytosis groups. In conclusion, acute and chronic GVHD, even if mild, was associated with reduced OS in patients receiving HSCT for NMD and effective strategies should, therefore, be implemented to minimize GVHD.

PMID: 32052319 [PubMed – as supplied by publisher]

Clinical and economic aspects of newborn screening for severe combined immunodeficiency: DEPISTREC study results.

February 14, 2020 By Manish Butte

Clinical and economic aspects of newborn screening for severe combined immunodeficiency: DEPISTREC study results.

Clin Immunol. 2019 05;202:33-39

Authors: Thomas C, Durand-Zaleski I, Frenkiel J, Mirallié S, Léger A, Cheillan D, Picard C, Mahlaoui N, Riche VP, Roussey M, Sébille V, Rabetrano H, Dert C, Fischer A, Audrain M

Abstract
PURPOSE: Severe combined immunodeficiency (SCID) refers to a group of genetic disorders characterized by greatly compromised cellular and humoral immunity. Children with SCID are asymptomatic at birth, but they die from infections within the first months of life if not treated. Quantification of T-cell receptor excision circles is an extremely sensitive screening method for detecting newborns who may have SCID.The goal of the DEPISTREC study was to evaluate the feasibility of nationwide newborn screening for severe T-cell lymphopenia in France as well as its economic and clinical utility.
METHODS: The test universally used for neonatal screening for SCID was the quantification of TRECs on Guthrie cards. We compared a group of 190,517 babies from 48 maternities across the country who underwent newborn SCID screening with a control group of 1.4 million babies out of whom 28 were diagnosed with SCID without such screening during the course of the study.
RESULTS: Within the screening group, 62 babies were found to be lymphopenic, including three with SCID. The cost of screening ranged from 4.7€ to €8.15 per newborn. The average 18-month cost was €257,574 vs €204,697 in the control group.
CONCLUSIONS: In this large-scale study, we demonstrate that routine SCID screening is feasible and effective. This screening offers the additional benefit of aiding in the diagnosis of non-SCID lymphopenia. Economic evaluation allowed us to calculate the cost per test. Newborn screening may also prevent death by SCID before any curative treatment can be administered. The difference in cost between screened and control children could not be ascertained because of the very low numbers and death of one of the children tested.

PMID: 30946917 [PubMed – indexed for MEDLINE]

Neutropenia Is an Underrecognized Finding in Pediatric Primary Immunodeficiency Diseases: An Analysis of the United States Immunodeficiency Network Registry.

February 13, 2020 By Manish Butte

Neutropenia Is an Underrecognized Finding in Pediatric Primary Immunodeficiency Diseases: An Analysis of the United States Immunodeficiency Network Registry.

J Pediatr Hematol Oncol. 2020 Feb 11;:

Authors: Michniacki TF, Connelly JA, Sturza J, Merz LE, Marsh R, Dale D, Garabedian E, Walkovich K

Abstract
BACKGROUND: The frequency of neutropenia in pediatric primary immunodeficiency disorders (PIDDs) is unknown and potentially underappreciated. Our study aimed to determine the overall frequency and severity of neutropenia in children diagnosed with a PIDD entered in the United States Immunodeficiency Network (USIDNET) patient registry.
PROCEDURE: Neutropenia data and demographic/clinical information from 1145 patients younger than 21 years of age was obtained from the USIDNET registry.
RESULTS: Neutropenia is more common in PIDD patients entered within the USIDNET registry than previously appreciated. There was a >10% occurrence rate of neutropenia in all broad primary immunodeficiency categories as well as in nearly all individual PIDDs. Neutropenia frequency was greater in African American pediatric PIDD patients than in white or Asian patients. The degree of neutropenia did not associate with mortality in pediatric patients with a PIDD.
CONCLUSION: Although our study did not assess the frequency of PIDD in patients presenting with neutropenia, the possibility of a primary immune disorder should be considered in patients with idiopathic neutropenia.

PMID: 32049770 [PubMed – as supplied by publisher]

Identification of Novel Genetic Variants in CVID Patients With Autoimmunity, Autoinflammation, or Malignancy.

February 13, 2020 By Manish Butte

Identification of Novel Genetic Variants in CVID Patients With Autoimmunity, Autoinflammation, or Malignancy.

Front Immunol. 2019;10:3022

Authors: Christiansen M, Offersen R, Jensen JMB, Petersen MS, Larsen CS, Mogensen TH

Abstract
Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by recurrent bacterial infections and defined by reduced levels of IgG, IgA, and/or IgM, insufficient response to polysaccharide vaccination, and an abnormal B-cell immunophenotype with a significantly reduced fraction of isotype-switched memory B cells. In addition to this infectious phenotype, at least one third of the patients experience autoimmune, autoinflammatory, granulomatous, and/or malignant complications. The very heterogeneous presentation strongly suggests a collection of different disease entities with somewhat different pathogeneses and most likely diverse genetic etiologies. Major progress has been made during recent years with the advent and introduction of next-generation sequencing, initially for research purposes, but more recently in clinical practice. In the present study, we performed whole exome sequencing on 20 CVID patients with autoimmunity, autoinflammation, and/or malignancy from the Danish CVID cohort with the aim to identify gene variants with a certain, possible, or potential disease-causing role in CVID. Through bioinformatics analyses, we identified variants with possible/probable disease-causing potential in nine of the patients. Of these, three patients had four variants in three different genes classified as likely pathogenic (NFKB1, TNFAIP3, and TTC37), whereas in six patients, we identified seven variants of possible pathogenic potential classified as variants of unknown significance (STAT3, IL17F, IRAK4, DDX41, NLRC3, TNFRSF1A, and PLCG2). In the remaining 11 patients, we did not identify possible genetic causes. Genetic findings were correlated to clinical disease presentation, clinical immunological phenotype, and disease complications. We suggest that the variants identified in the present work should lay the ground for future studies to functionally validate their disease-causing potential and to investigate at the mechanistic and molecular level their precise role in CVID pathogenesis. Overall, we believe that the present work contributes important new insights into the genetic basis of CVID and particular in the subset of CVID patients with a complex phenotype involving not only infection, but also autoimmunity, autoinflammation, and malignancy.

PMID: 32047491 [PubMed – in process]

Infection by Leishmania (Leishmania) infantum chagasi causes intestinal changes B-1 cells dependent.

February 13, 2020 By Manish Butte

Infection by Leishmania (Leishmania) infantum chagasi causes intestinal changes B-1 cells dependent.

Parasite Immunol. 2019 09;41(9):e12661

Authors: Souza KD, Fernandes EPA, Dos Santos AGA, de Lima LL, Gonzaga WFKM, Xander P, Nogueira-Melo GA, Sant’Ana DMG

Abstract
Evaluating the histopathological and morphometric changes caused by Leishmania (Leishmania) infantum chagasi infection either in the presence or absence of B-1 cells. Wild-type Balb/c and XID mice were used. Half of XID mice received B-1 cells adoptive transfer (XID + B1). Five animals from each group were infected (Balb/c I, XID I and XID + B1 I), totalizing six groups (n = 5). After 45 days of infection, the ileum was collected for histological processing and analysis. After infection, the XID animals showed an increase in the thickness of the intestinal layers, in the depth and width of the crypt and in the villi width. However, the Balb/c I group showed a reduction in almost all these parameters, whereas the villi width was increased. The villi height decreased in the infected XID animals; however, it was increased in the XID + B1 I group. Leishmania (L) infantum chagasiinfection caused a decrease in the number of Paneth cells; however, their area was increased. Finally, goblet cells and enterocytes presented different change profiles among groups. This study showed that the parasite infection causes structural and histopathological alterations in the intestine. These changes might be influenced by the absence of B-1 cells.

PMID: 31267529 [PubMed – indexed for MEDLINE]

[Ileitis as presentation of lymphoma in Wiskott-Aldrich syndrome].

February 12, 2020 By Manish Butte

[Ileitis as presentation of lymphoma in Wiskott-Aldrich syndrome].

Medicina (B Aires). 2020;80(1):81-83

Authors: Odstrcil-Bobillo MS, Kohan D, Heller PG, Otero V, Russo MP, Basquiera AL

Abstract
Wiskott-Aldrich syndrome is a rare X chromosome-linked primary immunodeficiency syndrome associated with an increased incidence of infections, autoimmune disorders and neoplasms. We present the case of a 41-year-old man with a diagnosis of Wiskott-Aldrich syndrome with ileitis as a form of presentation of a lymphoproliferative syndrome. The ileitis, in the context of the patient, represents a clinical challenge given the large number of differential diagnoses (inflammatory bowel disease, infections, neoplasms and lymphoproliferative diseases), so it usually requires anatomopathological diagnosis and particular considerations regarding the subsequent specific treatment.

PMID: 32044744 [PubMed – in process]

An adult case of X-linked chronic granulomatous disease with skin ulcer on the nose and internal canthus.

February 12, 2020 By Manish Butte

An adult case of X-linked chronic granulomatous disease with skin ulcer on the nose and internal canthus.

J Eur Acad Dermatol Venereol. 2020 Feb 11;:

Authors: Inoue-Masuda Y, Hirai I, Yanagisawa E, Kurihara Y, Funakoshi T, Yamagami J, Amagai M, Kubo A

Abstract
Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disease in which phagocytes are unable to produce reactive oxygen species (ROS) due to an impaired NADPH oxidase complex. Beginning in infancy, patients suffer recurrent infections, especially catalase-positive bacteria and fungi, and the formation of tissue granulomas due to dysregulated inflammation.1 Antimicrobial prophylaxis has enabled CGD patients to survive into adulthood.

PMID: 32043662 [PubMed – as supplied by publisher]

Status Epilepticus as a Consequence of Hemophagocytic Lymphohistiocytosis in a Previously Healthy Infant.

February 12, 2020 By Manish Butte

Status Epilepticus as a Consequence of Hemophagocytic Lymphohistiocytosis in a Previously Healthy Infant.

Cureus. 2020 Jan 30;12(1):e6824

Authors: Nassar SM, AlBattah MA, Bukhari AA, Alslimah A, Nahass AA

Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a rare and fatal entity with an incidence rate of 1.2 cases per million people per year. HLH is explained as a highly destructive inflammatory consequence of rampant hypercytokinemia due to excessive lymphocyte-mediated activation of macrophages and histiocytes. Primary HLH is a product of genetic dysfunction and could be familial (five subtypes), syndromic immunodeficiency, or as a consequence of mutations predisposing a person to Epstein Barr Virus (EBV) infection. With secondary HLH, there is an identifiable cause provoking the inflammatory reaction, whether it is an infection, an autoimmune disease, or malignancy (particularly hematological). As a result of widespread cytokine deposition, systemic manifestations are seen with a variety of manifestations that can vary between cases. This is a case of a patient who initially presented to the emergency department with fever, altered mentation, and gastroenteritis. Initial investigations showed non-anion gap metabolic acidosis, high white cell count, and deteriorating renal function. Further laboratory tests, bone marrow biopsies, and neurological imaging were conducted throughout the course of admission as the patient further deteriorated systemically. However, it’s important to note the abundant neurological manifestations with a worsening level of consciousness and seizures, some of which were categorized as status epilepticus.

PMID: 32042537 [PubMed]

Hereditary Tumor Syndromes with Skin Involvement.

February 12, 2020 By Manish Butte

Hereditary Tumor Syndromes with Skin Involvement.

Dermatol Clin. 2019 Oct;37(4):607-613

Authors: Hamid RN, Akkurt ZM

Abstract
Cutaneous findings that appear in childhood may be the first sign of a hereditary tumor syndrome. Early detection of genodermatoses allows the patient and at-risk family members to be screened for associated malignancies. This article provides a brief description of the pathogenesis and clinical manifestations of various inherited disorders with skin involvement, along with treatment updates. Advances in molecular-based therapy have spurred development of novel treatment methods for various genodermatoses such as xeroderma pigmentosum (XP) and Gorlin-Goltz syndrome. Further studies are needed to better assess the efficacy of many of these new treatment options.

PMID: 31466598 [PubMed – indexed for MEDLINE]