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1.
Virol J ; 21(1): 79, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38570803

RESUMO

BACKGROUND: No study has comparing hepatitis B virus (HBV) relapse rates among patients with both cancer and hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) who completed anti-viral prophylaxis for chemotherapy and then stopped taking entecavir or tenofovir alafenamide (TAF). METHODS: A total of 227 HBeAg-negative cancer patients without cirrhosis who previously took entecavir (n = 144) or TAF (n = 83) for antiviral prophylaxis were enrolled. RESULTS: The cumulative incidence of virological and clinical relapse at 2 years was 37% and 10.4%, respectively, in the entecavir group, and 46.7% and 19.5%, respectively, in the TAF group. The multivariate analysis revealed that the use of hematologic malignancy, TAF use, and high-viremia group at baseline were independent risk factors for virological relapse, and use of rituximab, TAF use, higher FIB-4 index and high-viremia group at baseline were independent risk factors for clinical relapse. After propensity score-matching, the patients who discontinued TAF therapy still exhibited higher virological (P = 0.031) and clinical relapse rates (P = 0.012) than did those who discontinued entecavir therapy. The patients were allocated to high- (> 2000 IU/mL), moderate- (between 20 and 2000 IU/mL) and low- (< 20 IU/mL) viremia groups. In the high-viremia group, those who had taken TAF for antiviral prophylaxis had higher rates of virological and clinical relapse than did those who had taken entecavir; in the moderate- and low-viremia groups, no significant difference in virological and clinical relapse rates was detected between the entecavir and TAF groups. Three patients experienced hepatic decompensation upon clinical relapse. All three patients were lymphoma and underwent rituximab therapy. One patient developed acute on chronic liver failure and died even though timely retreatment. CONCLUSIONS: In patients with both cancer and CHB who underwent antiviral prophylaxis, TAF use was associated with a higher chance of HBV relapse than entecavir use after nucleos(t)ide analogue cessation, particularly in the high-viremia group. Patients who are hematologic malignancy and undergo a rituximab-containing cytotoxic therapy should be monitored closely after withdrawal from prophylactic NA treatment.


Assuntos
Guanina/análogos & derivados , Neoplasias Hematológicas , Hepatite B Crônica , Humanos , Tenofovir/uso terapêutico , Antivirais , Antígenos E da Hepatite B , Viremia , Rituximab/uso terapêutico , Recidiva Local de Neoplasia/prevenção & controle , Recidiva Local de Neoplasia/induzido quimicamente , Recidiva Local de Neoplasia/tratamento farmacológico , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/prevenção & controle , Vírus da Hepatite B , Adenina/uso terapêutico , Neoplasias Hematológicas/induzido quimicamente , Neoplasias Hematológicas/tratamento farmacológico , Resultado do Tratamento , Recidiva , Antígenos de Superfície da Hepatite B
2.
J Pediatr Hematol Oncol ; 46(3): e244-e247, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38447094

RESUMO

Resistant and refractory cytomegalovirus (CMV) viremia can limit the provision of chemotherapy due to myelosuppression and end-organ dysfunction. Few therapies are available for children with clinically significant CMV viremia. We successfully used maribavir for a 4-year-old patient with lymphoma to complete his chemotherapy course. Resistance to maribavir did result after many months of therapy.


Assuntos
Infecções por Citomegalovirus , Diclororribofuranosilbenzimidazol , Neoplasias , Ribonucleosídeos , Pré-Escolar , Humanos , Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Infecções por Citomegalovirus/tratamento farmacológico , Diclororribofuranosilbenzimidazol/análogos & derivados , Neoplasias/tratamento farmacológico , Ribonucleosídeos/uso terapêutico , Viremia/tratamento farmacológico
3.
Pediatr Transplant ; 28(3): e14718, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38553815

RESUMO

BACKGROUND: Urinary CXCL10/creatinine (uCXCL10/Cr) is proposed as an effective biomarker of subclinical rejection in pediatric kidney transplant recipients. This study objective was to model implementation in the clinical setting. METHODS: Banked urine samples at a single center were tested for uCXCL10/Cr to validate published thresholds for rejection diagnosis (>80% specificity). The positive predictive value (PPV) for rejection diagnosis for uCXCL10/Cr-indicated biopsy was modeled with first-positive versus two-test-positive approaches, with accounting for changes associated with urinary tract infection (UTI), BK and CMV viremia, and subsequent recovery. RESULTS: Seventy patients aged 10.5 ± 5.6 years at transplant (60% male) had n = 726 urine samples with n = 236 associated biopsies (no rejection = 167, borderline = 51, and Banff 1A = 18). A threshold of 12 ng/mmol was validated for Banff 1A versus no-rejection diagnosis (AUC = 0.74, 95% CI = 0.57-0.92). The first-positive test approach (n = 69) did not resolve a clinical diagnosis in 38 cases (55%), whereas the two-test approach resolved a clinical diagnosis in the majority as BK (n = 17/60, 28%), CMV (n = 4/60, 7%), UTI (n = 8/60, 13%), clinical rejection (n = 5/60, 8%), and transient elevation (n = 18, 30%). In those without a resolved clinical diagnosis, PPV from biopsy for subclinical rejection is 24% and 71% (p = .017), for first-test versus two-test models, respectively. After rejection treatment, uCXCL10/Cr level changes were all concordant with change in it-score. Sustained uCXCL10/Cr after CMV and BK viremia resolution was associated with later acute rejection. CONCLUSIONS: Urinary CXCL10/Cr reliably identifies kidney allograft inflammation. These data support a two-test approach to reliably exclude other clinically identifiable sources of inflammation, for kidney biopsy indication to rule out subclinical rejection.


Assuntos
Infecções por Citomegalovirus , Transplante de Rim , Criança , Feminino , Humanos , Masculino , Aloenxertos , Biomarcadores/urina , Quimiocina CXCL10 , Creatinina/urina , Infecções por Citomegalovirus/diagnóstico , Rejeição de Enxerto/patologia , Inflamação/patologia , Rim/patologia , Transplantados , Viremia , Pré-Escolar , Adolescente
4.
Sci Immunol ; 9(93): eadi4926, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38457515

RESUMO

Lymph node (LN) germinal centers (GCs) are critical sites for B cell activation and differentiation. GCs develop after specialized CD169+ macrophages residing in LN sinuses filter antigens (Ags) from the lymph and relay these Ags into proximal B cell follicles. Many viruses, however, first reach LNs through the blood during viremia (virus in the blood), rather than through lymph drainage from infected tissue. How LNs capture viral Ag from the blood to allow GC development is not known. Here, we followed Zika virus (ZIKV) dissemination in mice and subsequent GC formation in both infected tissue-draining and non-draining LNs. From the footpad, ZIKV initially disseminated through two LN chains, infecting LN macrophages and leading to GC formation. Despite rapid ZIKV viremia, non-draining LNs were not infected for several days. Non-draining LN infection correlated with virus-induced vascular leakage and neutralization of permeability reduced LN macrophage attrition. Depletion of non-draining LN macrophages significantly decreased GC B cells in these nodes. Thus, although LNs inefficiently captured viral Ag directly from the blood, GC formation in non-draining LNs proceeded similarly to draining LNs through LN sinus CD169+ macrophages. Together, our findings reveal a conserved pathway allowing LN macrophages to activate antiviral B cells in LNs distal from infected tissue after blood-borne viral infection.


Assuntos
Infecção por Zika virus , Zika virus , Camundongos , Animais , Linfonodos , Viremia , Centro Germinativo , Macrófagos , Antígenos
5.
Ann Hematol ; 103(4): 1353-1362, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38430226

RESUMO

During hematopoietic stem cell transplantation (HSCT), ATG depletes T cells in-vivo to improve engraftment and prevent graft-versus-host disease (GVHD). Here, we compared the clinical efficacy of two different types of ATGs: thymoglobulin and anti-human T-lymphocyte immunoglobulin (Grafalon). A total of 469 patients who received haploidentical transplantation were enrolled in this retrospective study. We applied a propensity score (PS)-matched analysis and 209 patients were assigned to each group. Clinical outcomes were compared between two groups and primary outcome was overall survival (OS). There was no significant difference in OS between two groups. Within the first 180 days after HSCT, Grafalon was associated with lower incidences of Epstein-Barr virus (EBV) viremia (31.6 vs. 54.5%, P < 0.0001) and cytomegalovirus viremia (CMV) viremia (54.5 vs. 67.9%, P = 0.005) compared to thymoglobulin. Patients receiving Grafalon had a higher rate of moderate/severe chronic GVHD (26.3 vs. 18.2%, P = 0.046). However, the incidences of engraftment failure, grade II-IV acute GVHD, relapse, non-relapse mortality (NRM), and GVHD-free relapse-free survival (GRFS) did not differ greatly between groups. In the subgroup analysis, Grafalon improved the OS of lymphoid malignancies with young ages (< 40 years old) (HR, 0.55; P = 0.04) or with a high/very high disease risk index (HR, 0.36; P = 0.04). In the myeloid cohort, Grafalon reduced NRM in the patients who received non-female for male transplantation grafts (HR, 0.17; P = 0.02). Our results suggest the two types of ATG may differentially influence transplant outcomes and it may optimize ATG selection according to the condition of patients.


Assuntos
Infecções por Vírus Epstein-Barr , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Transplante de Células-Tronco de Sangue Periférico , Animais , Coelhos , Humanos , Masculino , Adulto , Estudos Retrospectivos , Pontuação de Propensão , Viremia , Herpesvirus Humano 4 , Soro Antilinfocitário , Transplante de Células-Tronco Hematopoéticas/métodos , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Condicionamento Pré-Transplante/métodos
6.
Nat Commun ; 15(1): 2682, 2024 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-38538621

RESUMO

Mosquito-borne dengue (DENV) and Zika (ZIKV) viruses originated in Old World sylvatic (forest) cycles involving monkeys and canopy-living Aedes mosquitoes. Both viruses spilled over into human transmission and were translocated to the Americas, opening a path for spillback into Neotropical sylvatic cycles. Studies of the trade-offs that shape within-host dynamics and transmission of these viruses are lacking, hampering efforts to predict spillover and spillback. We infected a native, Asian host species (cynomolgus macaque) and a novel, American host species (squirrel monkey) with sylvatic strains of DENV-2 or ZIKV via mosquito bite. We then monitored aspects of viral replication (viremia), innate and adaptive immune response (natural killer (NK) cells and neutralizing antibodies, respectively), and transmission to mosquitoes. In both hosts, ZIKV reached high titers that translated into high transmission to mosquitoes; in contrast DENV-2 replicated to low levels and, unexpectedly, transmission occurred only when serum viremia was below or near the limit of detection. Our data reveal evidence of an immunologically-mediated trade-off between duration and magnitude of virus replication, as higher peak ZIKV titers are associated with shorter durations of viremia, and higher NK cell levels are associated with lower peak ZIKV titers and lower anti-DENV-2 antibody levels. Furthermore, patterns of transmission of each virus from a Neotropical monkey suggest that ZIKV has greater potential than DENV-2 to establish a sylvatic transmission cycle in the Americas.


Assuntos
Aedes , Vírus da Dengue , Dengue , Infecção por Zika virus , Zika virus , Animais , Humanos , Viremia
7.
Am J Trop Med Hyg ; 110(4): 738-740, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38471167

RESUMO

Asymptomatic dengue virus (DENV) infections have important public health implications but are challenging to identify. We performed a cross-sectional study of reverse transcription quantitative polymerase chain reaction on pooled sera of asymptomatic individuals from the south coast of Kenya at two time periods to identify cases of asymptomatic viremia. Among 2,460 samples tested in pools of 9 or 10, we found only one positive case (0.04% incidence). Although pooling of samples has the potential to be a cost-effective and time-efficient method for asymptomatic DENV detection, mass cross-sectional pooled testing may not provide accurate data on rates of asymptomatic infection, likely owing to a decrease in the sensitivity with pooling of samples, a short period of viremia, or testing in the absence of an outbreak.


Assuntos
Vírus da Dengue , Dengue , Humanos , Vírus da Dengue/genética , Dengue/diagnóstico , Dengue/epidemiologia , Estudos Transversais , Infecções Assintomáticas/epidemiologia , Quênia/epidemiologia , Viremia , Reação em Cadeia da Polimerase
8.
Clin Transplant ; 38(4): e15294, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38545881

RESUMO

BACKGROUND: Recent studies suggest the transplantation of Hepatitis C (HCV) hearts from viremic donors is associated with comparable 1 year survival to nonviremic donors. Though HCV viremia is a known risk factor for accelerated atherosclerosis, data on cardiac allograft vasculopathy (CAV) outcomes are limited. We compared the incidence of CAV in heart transplant recipients from HCV viremic donors (nucleic acid amplification test positive; NAT+) compared to non-HCV infected donors (NAT-). METHODS: We retrospectively reviewed annual coronary angiograms with intravascular ultrasound from April 2017 to August 2020 at two large cardiac transplant centers. CAV was graded according to ISHLT guidelines. Maximal intimal thickness (MIT) ≥ 0.5 mm was considered significant for subclinical disease. RESULTS: Among 270 heart transplant recipients (mean age 54; 77% male), 62 patients were transplanted from NAT+ donors. CAV ≥ grade 1 was present in 8.8% of the NAT+ versus 16.8% of the NAT- group at 1 year, 20% versus 28.8% at 2 years, and 33.3% versus 41.5% at 3 years. After adjusting for donor age, donor smoking history, recipient BMI, recipient, hypertension, and recipient diabetes, NAT+ status did not confer increased risk of CAV (HR.80; 95% CI.45-1.40, p = 0.43) or subclinical IVUS disease (HR.87; 95% CI.58-1.30, p = 0.49). Additionally, there was no difference in the presence of rapidly progressive lesions on IVUS. CONCLUSION: Our data show that NAT+ donors conferred no increased risk for early CAV or subclinical IVUS disease following transplantation in a cohort of heart transplant patients who were treated for HCV, suggesting the short-term safety of this strategy to maximize the pool of available donor hearts.


Assuntos
Transplante de Coração , Hepatite C , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Doadores de Tecidos , Estudos Retrospectivos , Transplante de Coração/efeitos adversos , Viremia/epidemiologia , Viremia/etiologia , Seguimentos , Hepatite C/etiologia , Hepacivirus , Aloenxertos , Transplantados
9.
J Zoo Wildl Med ; 55(1): 182-194, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38453501

RESUMO

This study examined the viral shedding kinetics of elephant endotheliotropic herpesvirus (EEHV) in African elephants (Loxodonta africana) compared to viral shedding behavior in Asian elephants (Elephas maximus). Little is known about the transmission dynamics and epidemiology of this disease in African elephants. In light of recent clinical cases and mortalities, this paper aims to identify trends in viral biology. Trunk wash samples were collected from 22 African elephants from four North American zoological institutions that had recently experienced herd viremias or translocations. Processing of these samples included DNA extraction followed by qPCR to quantitate viral DNA load. The results were then compared with available literature that chronicled similar cases in Asian and African elephants. Minimal EEHV shedding was detected in response to varied herd translocations. Increased shedding was recorded in herds in which an elephant experienced an EEHV viremia when compared to baseline shedding. These index infections were followed by subsequent viremias in other elephants, although it is not known if these were recrudescence, transient controlled viremias, and/or primary infections via transmission to other elephants. When compared to historically published data, it was observed that EEHV3 cases in African elephants and EEHV1A cases in Asian elephants had consistently higher levels of viral DNA in the blood than were shed in trunk secretions, a fact that is seemingly inconsistent with such severe cases of disease and the high mortality rates associated with those respective types. The findings produced in this study highlight the need for more routine monitoring of viral shedding in African elephant herds to elucidate possible EEHV transmission and recrudescence factors for ex situ population management.


Assuntos
Elefantes , Infecções por Herpesviridae , Herpesviridae , Animais , Infecções por Herpesviridae/epidemiologia , Infecções por Herpesviridae/veterinária , DNA Viral/genética , Viremia/veterinária , Animais de Zoológico/genética , Herpesviridae/genética , Recidiva
10.
J Zoo Wildl Med ; 55(1): 290-294, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38453514

RESUMO

Multiple species of elephant endotheliotropic herpesvirus (EEHV) have caused fatal hemorrhagic disease in African (Loxodonta africana) and Asian (Elephas maximus) elephants. To date, EEHV7 has been detected only in benign pulmonary and skin nodules and in saliva of African elephants and has not been associated with clinical illness. Low-level viremia due to EEHV7A was detected via qPCR in two subadult African elephants during routine surveillance. Hematologic changes were noted in both elephants, including leukopenia, lymphopenia, monocytopenia, and band heterophilia. Treatment was initiated with famciclovir, antimicrobials, and rectal fluids, and one elephant received plasma transfusions due to a progressive decrease in platelet count. Both elephants remained asymptomatic throughout the viremias, with rapid resolution of hematologic abnormalities. These cases add to the current understanding of the epidemiology of EEHV in African elephants; to the authors' knowledge, they represent the first documentation of clinical disease due to EEHV7 infection in any elephant.


Assuntos
Elefantes , Infecções por Herpesviridae , Herpesviridae , Humanos , Animais , Infecções por Herpesviridae/diagnóstico , Infecções por Herpesviridae/epidemiologia , Infecções por Herpesviridae/veterinária , Famciclovir/uso terapêutico , Antivirais/uso terapêutico , Viremia/veterinária
11.
Viruses ; 16(3)2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38543685

RESUMO

The early detection of classical swine fever (CSF) remains a key challenge, especially when outbreaks are caused by moderate and low-virulent CSF virus (CSFV) strains. Oral fluid is a reliable and cost-effective sample type that is regularly surveilled for endemic diseases in commercial pig herds in North America. Here, we explored the possibility of utilizing oral fluids for the early detection of CSFV incursions in commercial-size pig pens using two independent experiments. In the first experiment, a seeder pig infected with the moderately-virulent CSFV Pinillos strain was used, and in the second experiment, a seeder pig infected with the highly-virulent CSFV Koslov strain was used. Pen-based oral fluid samples were collected daily and individual samples (whole blood, swabs) every other day. All samples were tested by a CSFV-specific real-time RT-PCR assay. CSFV genomic material was detected in oral fluids on the seventh and fourth day post-introduction of the seeder pig into the pen, in the first and second experiments, respectively. In both experiments, oral fluids tested positive before the contact pigs developed viremia, and with no apparent sick pigs in the pen. These results indicate that pen-based oral fluids are a reliable and convenient sample type for the early detection of CSF, and therefore, can be used to supplement the ongoing CSF surveillance activities in North America.


Assuntos
Vírus da Febre Suína Clássica , Peste Suína Clássica , Suínos , Animais , Vírus da Febre Suína Clássica/genética , Viremia/diagnóstico , Viremia/veterinária , Viremia/epidemiologia , Surtos de Doenças/veterinária , Vacinação/veterinária
13.
Cell ; 187(5): 1223-1237.e16, 2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38428396

RESUMO

While CD4+ T cell depletion is key to disease progression in people living with HIV and SIV-infected macaques, the mechanisms underlying this depletion remain incompletely understood, with most cell death involving uninfected cells. In contrast, SIV infection of "natural" hosts such as sooty mangabeys does not cause CD4+ depletion and AIDS despite high-level viremia. Here, we report that the CARD8 inflammasome is activated immediately after HIV entry by the viral protease encapsulated in incoming virions. Sensing of HIV protease activity by CARD8 leads to rapid pyroptosis of quiescent cells without productive infection, while T cell activation abolishes CARD8 function and increases permissiveness to infection. In humanized mice reconstituted with CARD8-deficient cells, CD4+ depletion is delayed despite high viremia. Finally, we discovered loss-of-function mutations in CARD8 from "natural hosts," which may explain the peculiarly non-pathogenic nature of these infections. Our study suggests that CARD8 drives CD4+ T cell depletion during pathogenic HIV/SIV infections.


Assuntos
Infecções por HIV , Inflamassomos , Síndrome de Imunodeficiência Adquirida dos Símios , Animais , Humanos , Camundongos , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Progressão da Doença , Infecções por HIV/patologia , Inflamassomos/metabolismo , Proteínas de Neoplasias/metabolismo , Síndrome de Imunodeficiência Adquirida dos Símios/patologia , Vírus da Imunodeficiência Símia/fisiologia , Viremia , HIV/fisiologia
14.
Front Immunol ; 15: 1349611, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38533498

RESUMO

Objective: Clinical and prognostic features of Anti-MDA5-Positive Dermatomyositis (MDA5+ DM) are diverse. This study aimed to examine the peripheral immune cell profiles of patients with MDA5+ DM, identify disease endotypes related to the heterogeneous manifestations and prognosis, and guide individualized therapy regimen. Methods: This inpatient cohort included 123 patients with MDA5+ DM. Unsupervised hierarchical clustering analysis was used to derive disease endotypes from the circulating immune cell profiles on admission. Clinical symptoms, laboratory test results, inpatient treatments, and disease outcomes were then analyzed among the identified endotypes. Results: Three disease endotypes in MDA5+ DM were identified from peripheral immune cell profiles. Endotype1 had the highest percentages of CD4+ T cells and monocytes, and the lowest percentage of neutrophils; Endotype2 had the highest percentage of B cells; Endotype3 had the highest percentage of CD8+ T cells and NK cells. Clinical and prognostic heterogeneity of the endotypes were revealed. Endotype1 had the lowest 3-month mortality with the high incidence of periungual capillary changes. Endotype2 and Endotype3 had higher prevalence of rapidly progressive interstitial lung disease (RPILD) and mortality at 3 months than Endotype1. Meanwhile, Endotype3 had higher pneumocystis jiroveci and CMV viremia cases with significantly elevated of activated CD8+ T cells and multiple cytokines than Endotype1. Conclusion: Clustering analysis of peripheral immune cell profiles identified three different endotypes in MDA5+ dermatomyositis. Endotpye2 and 3 showed higher RPILD, 3-month mortality, pneumocystis jiroveci and CMV viremia.


Assuntos
Infecções por Citomegalovirus , Dermatomiosite , Doenças Pulmonares Intersticiais , Humanos , Helicase IFIH1 Induzida por Interferon , Linfócitos T CD8-Positivos , Viremia/complicações , Infecções por Citomegalovirus/complicações
15.
Pediatr Transplant ; 28(2): e14724, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38450793

RESUMO

BACKGROUND: BK viremia after kidney transplantation (KT) poses significant risk for BK virus-associated nephropathy and impacts graft survival. Conventional treatment involves reduction of immunosuppression, which in turn may increase risk for rejection. To address this dilemma, use of anti-viral therapy with immunosuppressive properties such as leflunomide is an attractive option. METHODS: We performed a multi-center, retrospective chart review to report tolerability and effectiveness of leflunomide use for the eradication of BK viremia and prevention of BK virus-associated nephropathy in pediatric KT recipients. RESULTS: Seventy patients prescribed leflunomide were included and were followed up from initiation until 1 year following leflunomide completion. BK viremia was eradicated in 64 (91.4%) patients including 8 of 11 with nephropathy (BKVN) on initial biopsy. Reduced anti-proliferative medication (AP) dosing was not associated with increase in biopsy proven rejection (BPAR). However, complete discontinuation of AP during leflunomide therapy was associated with increase in BPAR in uni- and multivariate logistic regression, as was targeted reduction in calcineurin inhibitor (CNI) trough goals. One graft was lost to BKVN. There was no significant association found between time to BK eradication and leflunomide trough concentration, mycophenolate dose reduction, or steroid use (univariate logistic regression). Few leflunomide adverse drug reactions (ADR) were reported (most commonly: gastrointestinal, hematologic). CONCLUSION: Leflunomide is a promising adjunctive treatment to immunosuppression reduction for BK virus eradication with minimal ADR. AP reduction, not discontinuation, and judicious reduction in CNI trough goals with close monitoring, is a promising strategy for treatment of BK viremia with concomitant use of leflunomide therapy.


Assuntos
Transplante de Rim , Nefrite Intersticial , Humanos , Criança , Leflunomida/uso terapêutico , Estudos Retrospectivos , Viremia/tratamento farmacológico , Imunossupressores/uso terapêutico , Inibidores de Calcineurina
16.
J Reprod Immunol ; 162: 104208, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38367478

RESUMO

High HBV DNA levels predispose to mother to child transmission (MTCT) of HBV. Early nucleotide analogue (NA) therapy can reduce HBV DNA and minimize MTCT. We analysed immune-metabolic profile in pregnant mothers who received NA from 2nd trimester compared with untreated mothers. In 2nd trimester, there was no difference in immune profiles between Gr.1 and Gr.2 but high viral load women had downregulated pyruvate, NAD+ metabolism but in 3rd trimester, Gr.1 had significant reduction in HBV-DNA, upregulated pyruvate and NAD with increased IFN-2αA, CD8Tcells, NK cells and decreased Tregs, IL15, IL18, IL29, TGFß3 compared to Gr.2. In Gr.1, three eAg-ve women showed undetectable DNA and HBsAg. At delivery, Gr.1 showed no MTCT, with undetectable HBV DNA, HBsAg, high CD8 and NK cells in two women. We conclude, that starting NA from second trimester, reduces HBV load and MTCT, modulates NAD, induces immunity and suggest use of NA in early gestation in future trials.


Assuntos
Vírus da Hepatite B , Hepatite B , Transmissão Vertical de Doenças Infecciosas , Complicações Infecciosas na Gravidez , Viremia , Criança , Feminino , Humanos , Gravidez , Linfócitos T CD8-Positivos , DNA Viral , Antígenos de Superfície da Hepatite B , Células Matadoras Naturais , NAD , Complicações Infecciosas na Gravidez/tratamento farmacológico , Segundo Trimestre da Gravidez , Piruvatos , Tenofovir , Viremia/imunologia , Hepatite B/imunologia , Hepatite B/transmissão
17.
J Clin Microbiol ; 62(3): e0090623, 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38349144

RESUMO

Human Cytomegalovirus (HCMV) infection is life-threatening for immunocompromised patients. Quantitative molecular assays on whole blood or plasma are the gold standard for the diagnosis of invasive HCMV infection and for monitoring antiviral treatment in individuals at risk of HCMV disease. For these reasons, an accurate standardization toward the WHO 1st International Standard among different centers and diagnostic kits represents an effort for better clinical management of HCMV-positive patients. Herein, we evaluate, for the first time, the performance of a new transcription-mediated amplification (TMA) assay versus quantitative polymerase chain reaction (qPCR) chemistry, used as a routine method, on whole blood samples. A total of 755 clinical whole blood specimens were collected and tested simultaneously with TMA and qPCR assays. The data showed a qualitative agreement of 99.27% for positive quantified samples and 89.39% for those undetected between the two tested methods. Evaluation of viremia in positive samples highlighted a good correlation between TMA and qPCR chemistries in terms of International Units (ΔLog10 IU/mL: -0.29 ± 0.40). The TMA assay showed a significant correlation with qPCR in patients monitored for up to 3 months, thus allowing an accurate assessment of viremia in transplant patients. Therefore, TMA chemistry showed good agreement with qPCR testing, used as a current diagnostic routine. It also offers important advantages, such as FDA approval on plasma and In Vitro Diagnostic (IVD) on both plasma and whole blood, automated workflow with minimal hands-on time, and random access loading, thus enabling a rapid and reliable diagnostic in HCMV-infected patients. IMPORTANCE: In this paper, we describe the clinical performance of a novel transcription-mediated amplification (TMA) assay for the detection and quantification of human Cytomegalovirus (HCMV) DNA from whole blood samples. This is a pivotal analysis in immunocompromised patients [transplanted, HIV-positive, and Hematopoietic Stem Cell (HSC) recipients], and molecular tests with high sensitivity and specificity are necessary to evaluate the HCMV viral load in these patients. To our knowledge, this is the first in-depth evaluation of TMA chemistry for HCMV diagnosis on whole blood samples. Moreover, also technical aspects of this assay make it suitable for clinical diagnostics.


Assuntos
Infecções por Citomegalovirus , Viremia , Humanos , Reação em Cadeia da Polimerase/métodos , Citomegalovirus/genética , Hospedeiro Imunocomprometido , DNA Viral/genética
18.
Microbiol Spectr ; 12(4): e0357023, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38364104

RESUMO

Phenotypic changes and functional impairment of natural killer (NK) cells occur early in HIV-1 infection. Antiretroviral therapy (ART) effectively restores CD4+ T cell counts and suppresses HIV-1 to undetectable levels. The role and efficacy of immediate ART initiation in mitigating NK cell aberrations remain to be elucidated comprehensively. This study hypothesized that HIV-1 infection negatively influences NK cell evolution and that early ART initiation restores these perturbations. Blood samples were collected longitudinally from five acutely HIV-1 infected men who have sex with men in Nairobi, Kenya. Participants were immediately initiated on ART after HIV-1 diagnosis. Blood samples were drawn pre-infection and at sequential bi-weekly post-infection time points. Peripheral blood mononuclear cells were stained with panel NK cells surface markers to assess HIV-induced phenotypic changes by flow cytometry. Some cells were also stimulated overnight with K562 cell line, IL-2, and IL-15 and stained for flow cytometry functionality. HIV-1 infection was associated with significant reductions in the production of IFN-γ (P = 0.0264), expression of CD69 (P = 0.0110), and expression of NK cell inhibitory receptor Siglec7 (P = 0.0418). We observed an increased NK cell degranulation (P = 0.0100) and an upregulated expression of cell exhaustion marker PD-1 (P = 0.0513) at post-infection time points. These changes mainly were restored upon immediate initiation of ART, except for Siglec7 expression, whose reduced expression persisted despite ART. Some HIV-associated changes in NK cells may persist despite the immediate initiation of ART in acute HIV-1 infections. Our findings suggest that understanding NK cell dynamics and their restoration after ART can offer insights into optimizing HIV-1 treatment and potentially slowing disease progression.IMPORTANCENatural killer (NK) cells play a crucial role in controlling of HIV-1 replication and progression to disease. Perturbations of their functionality may therefore result in deleterious disease outcomes. Previous studies have demonstrated reduced NK cell functionality in chronic HIV-1 infection that positively correlated to HIV-1 viral load. This may suggest that control of HIV-1 viremia in acute HIV-1 infection may aid in enhancing NK cell response boosting the inate immunity hence effective control of viral spread and establishment of viral reservoir. Antiretroviral therapy (ART) effectively supresses HIV-1 viremia to undectable levels and restores CD4+ T cell counts. Our study highlights the significant role of early ART initiation in mitigating NK cell disruptions caused by acute HIV-1 infection. Our results suggest that early initiation of ART could have benefits beyond suppressing viral load and restoring CD4+ T cell counts. In addition, it could boost the innate immunity necessary to control disease progression.


Assuntos
Infecções por HIV , HIV-1 , Minorias Sexuais e de Gênero , Masculino , Humanos , Projetos Piloto , Estudos Transversais , Leucócitos Mononucleares , Viremia , Homossexualidade Masculina , Quênia , Antirretrovirais/uso terapêutico , Células Matadoras Naturais , Progressão da Doença , Carga Viral , Linfócitos T CD4-Positivos
19.
Front Immunol ; 15: 1328820, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38357545

RESUMO

Introduction: Bluetongue virus (BTV) is an arthropod-borne Orbivirus that is almost solely transmitted by Culicoides biting midges and causes a globally important haemorrhagic disease, bluetongue (BT), in susceptible ruminants. Infection with BTV is characterised by immunosuppression and substantial lymphopenia at peak viraemia in the host. Methods: In this study, the role of cell-mediated immunity and specific T-cell subsets in BTV pathogenesis, clinical outcome, viral dynamics, immune protection, and onwards transmission to a susceptible Culicoides vector is defined in unprecedented detail for the first time, using an in vivo arboviral infection model system that closely mirrors natural infection and transmission of BTV. Individual circulating CD4+, CD8+, or WC1+ γδ T-cell subsets in sheep were depleted through the administration of specific monoclonal antibodies. Results: The absence of cytotoxic CD8+ T cells was consistently associated with less severe clinical signs of BT, whilst the absence of CD4+ and WC1+ γδ T cells both resulted in an increased clinical severity. The absence of CD4+ T cells also impaired both a timely protective neutralising antibody response and the production of IgG antibodies targeting BTV non-structural protein, NS2, highlighting that the CD4+ T-cell subset is important for a timely protective immune response. T cells did not influence viral replication characteristics, including onset/dynamics of viraemia, shedding, or onwards transmission of BTV to Culicoides. We also highlight differences in T-cell dependency for the generation of immunoglobulin subclasses targeting BTV NS2 and the structural protein, VP7. Discussion: This study identifies a diverse repertoire of T-cell functions during BTV infection in sheep, particularly in inducing specific anti-viral immune responses and disease manifestation, and will support more effective vaccination strategies.


Assuntos
Arbovírus , Vírus Bluetongue , Bluetongue , Ceratopogonidae , Ovinos , Animais , Gado , Viremia , Linfócitos T CD8-Positivos , Ruminantes , Subpopulações de Linfócitos T , Bluetongue/prevenção & controle , Ceratopogonidae/fisiologia
20.
Dev Comp Immunol ; 154: 105145, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38316233

RESUMO

Spring viremia of carp virus (SVCV) is a globally distributed virus that causes severe clinical symptoms and high mortality in fish belonging to the families Cyprinidae and Siluridae. To protect the host against viral infection, understanding the relatedness between viral susceptibility and antiviral mechanisms must be crucial. Thus, we evaluated the viral suppression efficacy of ribavirin by measuring the transcription levels of viral and immune genes in vitro. The results showed that following ribavirin treatment after SVCV infection (MOI 0.1), ribavirin inhibited SVCV replication in epithelioma papulosum cyprini (EPC) cells and completely inhibited viral gene (G and N) expression at concentrations above 10 µg/mL at 48 h post-infection. Ribavirin does not directly damage SVCV particles but inhibits early viral replication. In the absence of SVCV infection, the immunological dynamics triggered by ribavirin resulted in upregulated pattern recognition receptors and proinflammatory cytokine-related genes (i.e., PI3K, MYD88, IRAK1, RIG-І, MAVS, Mx1, TNF-α, and NF-κB). Furthermore, EPC cells treated with ribavirin following SVCV infection showed upregulation of PI3K, MYD88, IRAK1, RIG-І, TNF-α, and NF-κB genes within 24 h post-SVCV infection, suggesting that ribavirin positively inhibits the SVCV infection in vitro.


Assuntos
Carpas , Doenças dos Peixes , Infecções por Rhabdoviridae , Rhabdoviridae , Humanos , Animais , Ribavirina/uso terapêutico , Ribavirina/farmacologia , Viremia/tratamento farmacológico , NF-kappa B , Fator de Necrose Tumoral alfa , Fator 88 de Diferenciação Mieloide/genética , Rhabdoviridae/fisiologia , Proteínas Adaptadoras de Transdução de Sinal , Fosfatidilinositol 3-Quinases
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