Manish Butte

Longitudinal In Vivo Assessment of Host-Microbe Interactions in a Murine Model of Pulmonary Aspergillosis.

iScience. 2019 Sep 18;20:184-194

Authors: Saini S, Poelmans J, Korf H, Dooley JL, Liang S, Manshian BB, Verbeke R, Soenen SJ, Vande Velde G, Lentacker I, Lagrou K, Liston A, Gysemans C, De Smedt SC, Himmelreich U

Abstract
The fungus Aspergillus fumigatus is ubiquitous in nature and the most common cause of invasive pulmonary aspergillosis (IPA) in patients with a compromised immune system. The development of IPA in patients under immunosuppressive treatment or in patients with primary immunodeficiency demonstrates the importance of the host immune response in controlling aspergillosis. However, study of the host-microbe interaction has been hampered by the lack of tools for their non-invasive assessment. We developed a methodology to study the response of the host’s immune system against IPA longitudinally in vivo by using fluorine-19 magnetic resonance imaging (19F MRI). We showed the advantage of a perfluorocarbon-based contrast agent for the in vivo labeling of macrophages and dendritic cells, permitting quantification of pulmonary inflammation in different murine IPA models. Our findings reveal the potential of 19F MRI for the assessment of rapid kinetics of innate immune response against IPA and the permissive niche generated through immunosuppression.

PMID: 31581067 [PubMed – as supplied by publisher]

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Primary immunodeficiencies and lymphoma: a systematic review of literature.

Leuk Lymphoma. 2019 Oct 03;:1-11

Authors: Herber M, Mertz P, Dieudonné Y, Guffroy B, Jung S, Gies V, Korganow AS, Guffroy A

Abstract
The management of lymphoma in patients with primary immunodeficiency (PID) is challenging because of its poor prognosis and complex therapeutic approaches. We conducted a systematic literature review of case-reports, case-series, and cohorts indexed in MEDLINE reporting the association of lymphoma and PID. One hundred and eighty-two articles were selected out of 787. We identified 386 cases. Median age at diagnosis of PID and lymphoma was 9.5 and 12 years old, respectively. T-cell deficiencies were the main PIDs associated with lymphoma (57%). The most prevalent lymphoma was diffuse large B-cell lymphoma (33.5%). Epstein-Barr Virus-driven lymphomas were mostly observed in innate immunodeficiencies (when reported). Complete response to treatment was observed in 65.8% of the cases. Death occurred in 38.2%. Few allogenic stem cell transplantations were performed (29 cases). Our detailed analysis of the literature provides a landscape of lymphoma’s occurrence in PID. Devoted studies in specific sub-groups of patients at risk are needed to develop dedicated protocols.

PMID: 31580160 [PubMed – as supplied by publisher]

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Non-parametric Heat Map Representation of Flow Cytometry Data: Identifying Cellular Changes Associated With Genetic Immunodeficiency Disorders.

Front Immunol. 2019;10:2134

Authors: Ellyard JI, Tunningley R, Lorenzo AM, Jiang SH, Cook A, Chand R, Talaulikar D, Hatch AM, Wilson A, Vinuesa CG, Cook MC, Fulcher DA

Abstract
Genetic primary immunodeficiency diseases are increasingly recognized, with pathogenic mutations changing the composition of circulating leukocyte subsets measured by flow cytometry (FCM). Discerning changes in multiple subpopulations is challenging, and subtle trends might be missed if traditional reference ranges derived from a control population are applied. We developed an algorithm where centiles were allocated using non-parametric comparison to controls, generating multiparameter heat maps to simultaneously represent all leukocyte subpopulations for inspection of trends within a cohort or segregation with a putative genetic mutation. To illustrate this method, we analyzed patients with Primary Antibody Deficiency (PAD) and kindreds harboring mutations in TNFRSF13B (encoding TACI), CTLA4, and CARD11. In PAD, loss of switched memory B cells (B-SM) was readily demonstrated, but as a continuous, not dichotomous, variable. Expansion of CXCR5+/CD45RA- CD4+ T cells (X5-Th cells) was a prominent feature in PAD, particularly in TACI mutants, and patients with expansion in CD21-lo B cells or transitional B cells were readily apparent. We observed differences between unaffected and affected TACI mutants (increased B cells and CD8+ T-effector memory cells, loss of B-SM cells and non-classical monocytes), cellular signatures that distinguished CTLA4 haploinsufficiency itself (expansion of plasmablasts, activated CD4+ T cells, regulatory T cells, and X5-Th cells) from its clinical expression (B-cell depletion), and those that were associated with CARD11 gain-of-function mutation (decreased CD8+ T effector memory cells, B cells, CD21-lo B cells, B-SM cells, and NK cells). Co-efficients of variation exceeded 30% for 36/54 FCM parameters, but by comparing inter-assay variation with disease-related variation, we ranked each parameter in terms of laboratory precision vs. disease variability, identifying X5-Th cells (and derivatives), naïve, activated, and central memory CD8+ T cells, transitional B cells, memory and SM-B cells, plasmablasts, activated CD4 cells, and total T cells as the 10 most useful cellular parameters. Applying these to cluster analysis of our PAD cohort, we could detect subgroups with the potential to reflect underlying genotypes. Heat mapping of normalized FCM data reveals cellular trends missed by standard reference ranges, identifies changes associating with a phenotype or genotype, and could inform hypotheses regarding pathogenesis of genetic immunodeficiency.

PMID: 31572362 [PubMed – in process]

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Diagnostic Interpretation of Genetic Studies in Patients with Primary Immunodeficiency Diseases: A Working Group Report of the Primary Immunodeficiency Diseases Committee of the American Academy of Allergy, Asthma, and Immunology.

J Allergy Clin Immunol. 2019 Sep 27;:

Authors: Chinn IK, Chan A, Chen K, Chou J, Dorsey MJ, Hajjar J, Jongco AM, Keller MD, Kobrynski LJ, Kumanovics A, Lawrence MG, Leiding JW, Lugar PL, Orange JS, Patel K, Platt CD, Puck JM, Raje N, Romberg ND, Slack MA, Sullivan KE, Tarrant TK, Torgerson TR, Walter JE

Abstract
Genetic testing has become an integral component of the diagnostic evaluation of patients with suspected primary immunodeficiency diseases. Results of genetic testing can have profound impact on clinical management decisions. Clinical providers must therefore demonstrate proficiency in interpreting genetic data. Because of the need for increased knowledge regarding this practice, the American Academy of Allergy, Asthma, and Immunology Primary Immunodeficiency Diseases Committee established a Work Group that reviewed and summarized information concerning appropriate methods, tools, and resources for evaluating variants identified by genetic testing. Strengths and limitations of tests frequently ordered by clinicians were examined. Summary statements and tables were then developed to guide the interpretation process. Finally, the need for research and collaboration was emphasized. Greater understanding of these important concepts will improve the diagnosis and management of patients with suspected primary immunodeficiency diseases.

PMID: 31568798 [PubMed – as supplied by publisher]

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Generalized Verrucosis Revealing a Life-Threatening and Unlabeled T-Cell Lymphopenia Associated With Autoimmune Hemolytic Anemia: A Case Report and Review of Literature.

J Pediatr Hematol Oncol. 2019 Sep 19;:

Authors: Marxgut M, Adjaoud D, Aladjidi N, Armari C, Marxgut L, Rubio A

Abstract
Primary immunodeficiencies are inherited disorders, which may be revealed in the context of autoimmune hemolytic anemia (AIHA). We report the case of a girl presenting with an enterovirus-related AIHA. Despite being in complete remission for her anemia after treatment, the initial CD4/CD8 lymphopenia dramatically worsened with time. Its sole clinical presentation was generalized verrucosis. Cellular quantitative and functional immunodeficiency was evidenced but no known molecular defect was identified despite extensive workup. This unlabeled profound naive T-lymphopenia was cured by bone marrow transplantation. No similar case was ever described in the scientific literature. Patients with AIHA and/or generalized verrucosis should be screened for primary immunodeficiency, before initiating any immunomodulatory treatment.

PMID: 31568177 [PubMed – as supplied by publisher]

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Preoperative Risk Factors for Opioid Utilization After Total Hip Arthroplasty.

J Bone Joint Surg Am. 2019 Sep 18;101(18):1670-1678

Authors: Prentice HA, Inacio MCS, Singh A, Namba RS, Paxton EW

Abstract
BACKGROUND: Opioid prescriptions following orthopaedic procedures may contribute to the opioid epidemic in the United States. Risk factors for greater and prolonged opioid utilization following total hip arthroplasty have yet to be fully elucidated. We sought to determine the prevalence of preoperative and postoperative opioid utilization in a cohort of patients who underwent total hip arthroplasty and to identify preoperative risk factors for prolonged utilization of opioids following total hip arthroplasty.
METHODS: A cohort study of patients who underwent primary elective total hip arthroplasty at Kaiser Permanente from January 2008 to December 2011 was conducted. The number of opioid prescriptions dispensed per 90-day period after total hip arthroplasty (up to 1 year) was the outcome of interest. The risk factors evaluated included preoperative analgesic medication use, patient demographic characteristics, comorbidities, and other history of chronic pain. Poisson regression models were used, and relative risks (RRs) and 95% confidence intervals (CIs) are presented.
RESULTS: Of the 12,560 patients who underwent total hip arthroplasty and were identified, 58.5% were female and 78.6% were white. The median age was 67 years (interquartile range, 59 to 75 years). Sixty-three percent of patients filled at least 1 opioid prescription in the 1 year prior to the total hip arthroplasty. Postoperative opioid use went from 88.6% in days 1 to 90 to 24% in the last quarter. An increasing number of preoperative opioid prescriptions was associated with a greater number of prescriptions over the entire postoperative period, with an RR of 1.10 (95% CI, 1.10 to 1.11) at days 271 to 360. Additional factors associated with greater utilization over the entire year included black race, chronic pulmonary disease, anxiety, substance abuse, and back pain. Factors associated with greater utilization in days 91 to 360 (beyond the early recovery phase) included female sex, higher body mass index, acquired immunodeficiency syndrome, peripheral vascular disease, and history of non-specific chronic pain.
CONCLUSIONS: We identified preoperative factors associated with greater and prolonged opioid utilization long after the early recovery period following total hip arthroplasty. Patients with these risk factors may benefit from targeted multidisciplinary interventions to mitigate the risk of prolonged opioid use.
CLINICAL RELEVANCE: Opioid prescriptions following orthopaedic procedures are one of the leading causes of chronic opioid use; strategies to reduce the risk of misuse and abuse are needed. At 1 year postoperatively, almost one-quarter of patients who underwent total hip arthroplasty used opioids in the last 90 days of the first postoperative year, which makes understanding risk factors associated with postoperative opioid utilization imperative.

PMID: 31567804 [PubMed – in process]

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Primary immunodeficiencies and invasive fungal infection: when to suspect and how to diagnose and manage.

Curr Opin Infect Dis. 2019 Sep 20;:

Authors: Lionakis MS

Abstract
PURPOSE OF REVIEW: Invasive fungal infections (IFIs) most often occur secondary to acquired immunodeficiency states such as transplantation, AIDS or immune-modulatory treatment for neoplastic and autoimmune disorders. Apart from these acquired conditions, several primary immunodeficiency disorders (PIDs) can present with IFIs in the absence of iatrogenic immunosuppression. This review highlights recent advances in our understanding of PIDs that cause IFIs, which may help clinicians in the diagnosis and management of such infections.
RECENT FINDINGS: A growing number of PIDs that cause varying combinations of invasive infections by commensal Candida, inhaled molds (primarily Aspergillus), Cryptococcus, Pneumocystis, endemic dimorphic fungi, dermatophytes, and/or agents of phaeohyphomycosis has uncovered the organ- and fungus-specific requirements for effective antifungal host defense in humans. Employing certain diagnostic algorithms tailored to the infecting fungus can facilitate the genetic diagnosis of the underlying PID, which has implications for the optimal management of affected patients.
SUMMARY: Heightened clinical suspicion is required for the diagnosis of underlying genetic defects in patients who develop IFIs in the absence of acquired immunodeficiency. Early initiation of antifungal therapy followed by long-term secondary prophylaxis is typically needed to achieve remission, but hematopoietic stem-cell transplantation may sometimes be necessary to promote immune restoration and infection control.

PMID: 31567735 [PubMed – as supplied by publisher]

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Diagnosis of primary immunodeficiency diseases in the developing world: the need for education and networking with the developed world.

Curr Opin Pediatr. 2019 Sep 20;:

Authors: Villavicencio MF, Pedroza LA

Abstract
PURPOSE OF REVIEW: Even with the evident improvement in knowledge about clinical and molecular aspects and the technology used to diagnose primary immunodeficiency diseases (PIDs), there is still a significant delay in recognition of these diseases in the developing world, specifically in Latin America. In this review, the goal is to outline the challenges that need to overcome for the diagnosis of PIDs and the optimization of resources available based on our experience.
RECENT FINDINGS: We describe the advances achieved in the past decade in Latin America in terms of recognition of PIDs, as well as the need for improvement. We outline the need for continued medical education, the lack of resources for laboratory testing, and how genetic testing through next-generation sequencing (that is becoming a day-to-day tool) can be achieved in the developing world.
SUMMARY: We aim to gather information about the limitations and challenges for the diagnosis of PIDs in a low-resource environment and the opportunities to benefit from the available advanced tools for diagnosis.

PMID: 31567427 [PubMed – as supplied by publisher]

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Prevalence of Immunodeficiency in Children With Invasive Pneumococcal Disease in the Pneumococcal Vaccine Era: A Systematic Review.

JAMA Pediatr. 2019 Sep 30;:

Authors: Butters C, Phuong LK, Cole T, Gwee A

Abstract
Importance: Despite increasing access to vaccination, invasive pneumococcal disease (IPD) is responsible for approximately 826 000 deaths worldwide in children younger than 5 years each year. To allow early identification and prevention, an improved understanding of risk factors for IPD is needed.
Objectives: To review the literature on the prevalence of primary immunodeficiency (PID) in children younger than 18 years presenting with IPD without another predisposing condition and to inform guidelines for immunologic evaluation after the first episode of IPD based on published evidence.
Evidence Review: A literature search of PubMed, Embase (inception [1974] to February 28, 2019), and MEDLINE (inception [1946] to February 28, 2019) was conducted using the terms Streptococcus pneumonia, Streptococcus pneumoniae, pneumococcal infection, Streptococcus infection, pneumococcal meningitis, immunodeficiency, immune response, immunocompromised, susceptib*, precursor, predispose*, recurren*, newborn, neonat*, infan*, toddler, child, preschooler, adolescen*, and pediatric. Publications reporting original data on immunodeficiency in children with microbiologically confirmed primary or recurrent IPD were included. Strength of clinical data was graded according to the 5-point scale of the Oxford Centre for Evidence-Based Medicine.
Findings: In 6022 unique children with primary IPD, 5 of 393 (1.3%) to 17 of 162 (10.5%) of all children and 14 of 53 (26.4%) of those older than 2 years had a PID identified. Higher rates of PID, up to 10 of 15 (66.7%), were found in children with recurrent IPD. Antibody deficiency was the most common immunodeficiency, followed by complement deficiency, asplenia, and rarer defects in T-cell signaling. The site of infection was a key indicator for the risk of underlying PID, with the greatest risk of PID in children with meningitis or complicated pneumonia.
Conclusions and Relevance: Results of this study suggest that invasive pneumococcal disease, and particularly recurrent IPD, is an important marker of underlying PID in children without other risk factors. The findings also suggest that children older than 2 years with pneumococcal meningitis or complicated pneumonia and all children with recurrent IPD should be referred for an immune evaluation.
Trial Registration: PROSPERO identifier: CRD42017075978.

PMID: 31566672 [PubMed – as supplied by publisher]

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