Manish Butte

Safety, Resistance, and Efficacy Results from a Phase IIIb Study of Conventional- and Double-Dose Oseltamivir Regimens for Treatment of Influenza in Immunocompromised Patients.

Infect Dis Ther. 2019 Oct 30;:

Authors: Mitha E, Krivan G, Jacobs F, Nagler A, Alrabaa S, Mykietiuk A, Kenwright A, Le Pogam S, Clinch B, Vareikiene L

Abstract
INTRODUCTION: Immunocompromised patients infected with influenza exhibit prolonged viral shedding and higher risk of resistance. Optimized treatment strategies are needed to reduce the risk of antiviral resistance. This phase IIIb, randomized, double-blind study (NCT00545532) evaluated conventional-dose or double-dose oseltamivir for the treatment of influenza in immunocompromised patients.
METHODS: Patients with primary or secondary immunodeficiency and influenza infection were randomized 1:1 to receive conventional-dose oseltamivir (75 mg adolescents/adults [≥ 13 years]; 30-75 mg by body weight in children [1-12 years]) or double-dose oseltamivir (150 or 60-150 mg, respectively), twice daily for an extended period of 10 days. Nasal/throat swabs were taken for virology assessments at all study visits. Co-primary endpoints were safety/tolerability and viral resistance. Secondary endpoints included time to symptom alleviation (TTSA) and time to cessation of viral shedding (TTCVS).
RESULTS: Of 228 patients enrolled between February 2008 and May 2017, 215 (199 adults) were evaluable for safety, 167 (151 adults) for efficacy, and 152 (138 adults) for resistance. Fewer patients experienced an adverse event (AE) in the conventional-dose group (50.5%) versus the double-dose group (59.1%). The most frequently reported AEs were nausea, diarrhea, vomiting, and headache. Fifteen patients had post-baseline resistance, more commonly in the conventional-dose group (n  = 12) than in the double-dose group (n  = 3). In adults, median TTSA was similar between arms, while median TTCVS was longer with conventional dosing.
CONCLUSIONS: Oseltamivir was well tolerated, with a trend toward better safety/tolerability for conventional dosing versus double dosing. Resistance rates were higher with conventional dosing in this immunocompromised patient population.
TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00545532.
FUNDING: F. Hoffmann-La Roche Ltd.

PMID: 31667696 [PubMed – as supplied by publisher]

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Primary immunodeficiency in Africa – a review.

S Afr Med J. 2019 Sep 10;109(8b):3-11

Authors: Erjaee A, Bagherpour M, Van Rooyen C, Van den Berg S, Kinnear CJ, Green RJ, Pepper M

Abstract
BACKGROUND: Efforts have been made worldwide to improve awareness and treatment of primary immunodeficiency (PID). This has also gained momentum on the African continent albeit at a slower pace. Objective. This review reports on the current status of PID on the African continent regarding its prevalence, distribution, genetic mutations and challenges in diagnosis and treatment of affected patients. Method. We evaluated all studies published from the African continent in the field of PID dealing with prevalence, epidemiology, case reports and genetic findings. Results. The prevalence of PID on the African continent has been estimated to be as high as 902 631 individuals. PID still is mostly underdiagnosed in Africa and although progress has been made in parts of the continent many challenges still remain regarding awareness, diagnosis, registration and care of these patients. Conclusion. Given the unique genetic mutations reported in PID patients on the African continent and the feasibility of hematopoietic stem cell transplantation and gene therapy, increased awareness should be encouraged and new therapeutic options considered.

PMID: 31662142 [PubMed – in process]

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Emergence and Persistence of Letermovir-Resistant Cytomegalovirus in a Patient With Primary Immunodeficiency.

Open Forum Infect Dis. 2019 Sep;6(9):ofz375

Authors: Popping S, Dalm VASH, Lübke N, Cristanziano VD, Kaiser R, Boucher CAB, Van Kampen JJA

Abstract
Background: Letermovir is a novel cytomegalovirus antiviral that is approved for prophylaxis in hematopoietic stem cell transplantation recipients.
Methods: After obtaining informed consent, letermovir prophylaxis was started in a patient with a presumed late-onset primary, combined T- and B-cell immunodeficiency. Plasma CMV DNAemia was monitored with real-time polymerase chain reaction, and letermovir resistance analyses were performed using Sanger sequencing and Illumina MiSeq next-generation sequencing.
Results: A letermovir-resistant cytomegalovirus variant (C325Y mutation in UL56) emerged 17 weeks after start of prophylaxis. The letermovir-resistant variant was able to reactivate without drug selective pressure as this variant was again detected in plasma 20.6 weeks after stopping of letermovir.
Conclusions: This case indicates that the C325Y mutation in UL56 does not significantly alter fitness of cytomegalovirus in vivo.

PMID: 31660414 [PubMed]

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Infectious vaccine-derived rubella viruses emerge, persist, and evolve in cutaneous granulomas of children with primary immunodeficiencies.

PLoS Pathog. 2019 Oct 28;15(10):e1008080

Authors: Perelygina L, Chen MH, Suppiah S, Adebayo A, Abernathy E, Dorsey M, Bercovitch L, Paris K, White KP, Krol A, Dhossche J, Torshin IY, Saini N, Klimczak LJ, Gordenin DA, Zharkikh A, Plotkin S, Sullivan KE, Icenogle J

Abstract
Rubella viruses (RV) have been found in an association with granulomas in children with primary immune deficiencies (PID). Here, we report the recovery and characterization of infectious immunodeficiency-related vaccine-derived rubella viruses (iVDRV) from diagnostic skin biopsies of four patients. Sequence evolution within PID hosts was studied by comparison of the complete genomic sequences of the iVDRVs with the genome of the vaccine virus RA27/3. The degree of divergence of each iVDRV correlated with the duration of persistence indicating continuous intrahost evolution. The evolution rates for synonymous and nonsynonymous substitutions were estimated to be 5.7 x 10-3 subs/site/year and 8.9 x 10-4 subs/site/year, respectively. Mutational spectra and signatures indicated a major role for APOBEC cytidine deaminases and a secondary role for ADAR adenosine deaminases in generating diversity of iVDRVs. The distributions of mutations across the genes and 3D hotspots for amino acid substitutions in the E1 glycoprotein identified regions that may be under positive selective pressure. Quasispecies diversity was higher in granulomas than in recovered infectious iVDRVs. Growth properties of iVDRVs were assessed in WI-38 fibroblast cultures. None of the iVDRV isolates showed complete reversion to wild type phenotype but the replicative and persistence characteristics of iVDRVs were different from those of the RA27/3 vaccine strain, making predictions of iVDRV transmissibility and teratogenicity difficult. However, detection of iVDRV RNA in nasopharyngeal specimen and poor neutralization of some iVDRV strains by sera from vaccinated persons suggests possible public health risks associated with iVDRV carriers. Detection of IgM antibody to RV in sera of two out of three patients may be a marker of virus persistence, potentially useful for identifying patients with iVDRV before development of lesions. Studies of the evolutionary dynamics of iVDRV during persistence will contribute to development of infection control strategies and antiviral therapies.

PMID: 31658304 [PubMed – as supplied by publisher]

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Deep learning-based model for predicting progression in patients with head and neck squamous cell carcinoma.

Cancer Biomark. 2019 Oct 18;:

Authors: Zhao Z, Li Y, Wu Y, Chen R

Abstract
PURPOSE: This study endeavors to build a deep learning (DL)-based model for predicting disease progression in head and neck squamous cell carcinoma (HNSCC) patients by integrating multi-omics data.
METHODS: RNA sequencing, miRNA sequencing, and methylation data from The Cancer Genome Atlas (TCGA) were used as input for autoencoder, a DL approach. An autoencoder-based prognosis model for PFS was built by SVM algorithm and tested in three confirmation sets. Predictive performance of the model was compared to two alternative approaches. Differential expression analysis for mRNAs, microRNAs (miRNA) and methylation was conducted. Moreover, functional annotation of differentially expressed genes (DEGs) was achieved through function enrichment analysis.
RESULT: The DL-based prognosis model identified two subgroups of patients with significantly different PFS, and showcased a good model fitness (C-index = 0.73). The two identified PFS subtypes were successfully validated in three confirmation sets. The DL-based model was more accurate and efficient than principal component analysis (PCA) or individual Cox-PH-based models. There were 348 DEGs, 23 differentially expressed miRNAs and 55 differentially methylated genes between the two PFS subtypes. These genes were significantly involved in several immune-related biological processes and primary immunodeficiency, cell adhesion molecules (CAMs), B cell receptor signaling and leukocyte transendothelial migration pathways.
CONCLUSION: The DL-based model introduced in this study is reliable and robust in predicting disease progression in HNSCC patients. A number of pathways and genes targets are unraveled to be implicated in cancer progression. Utility of this model would facilitate development of more individualized therapy for HNSCC patients and improve prognosis.

PMID: 31658045 [PubMed – as supplied by publisher]

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Prevalence of human T-cell lymphotropic virus and the socio-demographic and risk factors associated with the infection among post-natal clinics women in Zaria, Nigeria.

J Immunoassay Immunochem. 2019;40(5):485-494

Authors: Hananiya HS, Ella EE, Aminu M, Anyanwu NCJ

Abstract
Introduction: Human T-cell lymphotropic virus has long been associated with Adult T-cell leukemia/lymphoma, HTLV-associated myelopathy/tropical spastic paraparesis, and hairy cell leukemia. Aim: The aim was to determine the prevalence of HTLV antibodies as well as the socio-demographic and risk factors associated with HTLV among women attending postnatal clinics in Zaria. Methodology: A total of 190 samples were collected within the months of January and June 2017 and qualitative determination of antibodies for HTLV in serum was performed by an antigen sandwich enzyme immunoassay method. Results: The study established an HTLV infection prevalence of 3.2% (6/190). Higher prevalence was observed among women from polygamous families [6.2% (4/64)], the self-employed [6.5% (4/62)], those in age group of 15-25 years [6.2% (5/72)] and women with only primary education [5.9% (2/32)] although the associations were not statistically significant. Similarly, there was no significant association between HTLV infection and history of family cancer (P = .629), intravenous drug use (P = .682), sharing of sharp objects (P = .596,) and history of X-ray exposure (P = .366), except for history of previous blood transfusion which shows significant association (P = .010). Conclusion: The study established a prevalence an HTLV of 3.2% that HTLV in Zaria therefore routinely screened is necessary.

PMID: 31339431 [PubMed – indexed for MEDLINE]

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Provider Perceptions of Quality of Life, Neurocognition, Physical Well-being, and Psychosocial Health in Patients with Primary Immunodeficiency/Immune Dysregulation Conditions.

J Clin Immunol. 2019 Oct 26;:

Authors: Michniacki TF, Walkovich KJ, Merz LE, Sturza J, Abraham RS

Abstract
PURPOSE: Both pediatric and adult patients with a primary immunodeficiency/immune dysregulation (PID/PIDR) diagnosis report inferior quality of life (QOL) and patient-reported outcomes (PROs) as compared with their healthy peers. Recognition of the negative impact on QOL and PROs provides an opportunity for clinicians to intervene with supportive measures. However, provider perceptions of PID/PIDR patients’ quality of life, physical well-being, psychosocial health and neurocognition, and access to supportive resources have yet to be systematically evaluated.
METHODS: We report specialty providers’ perception of the QOL and psychosocial and physical well-being of their pediatric and adult patients with PID/PIDR through the utilization of an online survey assessing QOL and the impact of disease or its associated treatment on their physical well-being, mental health, social relationships, neurocognition, and work/school performance.
RESULTS: Clinicians trended towards believing adult PID/PIDR patients had worse overall QOL than children with PID/PIDR. Providers additionally identified their adult patients’ QOL to be more deleteriously affected by co-morbidities than their pediatric patients. Clinicians distinguished anxiety and social relationships as the psychosocial aspects most often affected by a complex immunological diagnosis in all patients. Of physical health considerations, energy, rather than mobility or pain, was perceived to be more negatively influenced by PID/PIDR in both adult and pediatric patients.
CONCLUSIONS: Knowledge of these clinician perceptions can affect communication of findings with patients, as well as ongoing management, and thus, it is important to understand these fully to improve healthcare delivery to, and clinical management of, these patients.

PMID: 31655959 [PubMed – as supplied by publisher]

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