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1.
J Clin Immunol ; 39(1): 81-89, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30607663

RESUMO

The association of immunodeficiency-related vaccine-derived rubella virus (iVDRV) with cutaneous and visceral granulomatous disease has been reported in patients with primary immunodeficiency disorders (PIDs). The majority of these PID patients with rubella-positive granulomas had DNA repair disorders. To support this line of inquiry, we provide additional descriptive data on seven previously reported patients with Nijmegen breakage syndrome (NBS) (n = 3) and ataxia telangiectasia (AT) (n = 4) as well as eight previously unreported patients with iVDRV-induced cutaneous granulomas and DNA repair disorders including NBS (n = 1), AT (n = 5), DNA ligase 4 deficiency (n = 1), and Artemis deficiency (n = 1). We also provide descriptive data on several previously unreported PID patients with iVDRV-induced cutaneous granulomas including cartilage hair hypoplasia (n = 1), warts, hypogammaglobulinemia, immunodeficiency, myelokathexis (WHIM) syndrome (n = 1), MHC class II deficiency (n = 1), Coronin-1A deficiency (n = 1), X-linked severe combined immunodeficiency (X-SCID) (n = 1), and combined immunodeficiency without a molecular diagnosis (n = 1). At the time of this report, the median age of the patients with skin granulomas and DNA repair disorders was 9 years (range 3-18). Cutaneous granulomas have been documented in all, while visceral granulomas were observed in six cases (40%). All patients had received rubella virus vaccine. The median duration of time elapsed from vaccination to the development of cutaneous granulomas was 48 months (range 2-152). Hematopoietic cell transplantation was reported to result in scarring resolution of cutaneous granulomas in two patients with NBS, one patient with AT, one patient with Artemis deficiency, one patient with DNA Ligase 4 deficiency, one patient with MHC class II deficiency, and one patient with combined immunodeficiency without a known molecular etiology. Of the previously reported and unreported cases, the majority share the diagnosis of a DNA repair disorder. Analysis of additional patients with this complication may clarify determinants of rubella pathogenesis, identify specific immune defects resulting in chronic infection, and may lead to defect-specific therapies.


Assuntos
Reparo do DNA/genética , Granuloma/complicações , Granuloma/virologia , Síndromes de Imunodeficiência/complicações , Vírus da Rubéola/patogenicidade , Dermatopatias/etiologia , Dermatopatias/virologia , Adolescente , Ataxia Telangiectasia/genética , Ataxia Telangiectasia/virologia , Criança , Pré-Escolar , Feminino , Granuloma/genética , Cabelo/anormalidades , Cabelo/virologia , Transplante de Células-Tronco Hematopoéticas/métodos , Doença de Hirschsprung/genética , Doença de Hirschsprung/virologia , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/virologia , Masculino , Síndrome de Quebra de Nijmegen/genética , Síndrome de Quebra de Nijmegen/virologia , Osteocondrodisplasias/congênito , Osteocondrodisplasias/genética , Osteocondrodisplasias/virologia , Rubéola (Sarampo Alemão)/genética , Rubéola (Sarampo Alemão)/virologia , Pele/virologia , Dermatopatias/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/virologia
2.
J Clin Immunol ; 39(1): 112-117, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30680653

RESUMO

PURPOSE: Nitazoxanide was recently reported as having in vitro effectiveness against the rubella virus. Immunodeficiency-related vaccine-derived rubella occurs in some patients who have an inherited immunodeficiency and who received the MMR vaccine. This study investigated the in vivo effectiveness of nitazoxanide therapy. METHODS: This is a retrospective analysis of seven patients treated with nitazoxanide as salvage therapy for immunodeficiency-related vaccine-derived rubella infection. The patients were recruited from an ongoing rubella detection surveillance project. RESULTS: Seven patients with persistent rubella were treated with nitazoxanide and one demonstrated significant clinical improvement. Two additional patients exhibited diminished viral capsid production with one patient having transient slowing of progression. The cohort overall generally had low T cell counts and had a high burden of comorbidities. There were three deaths. Two deaths were from PML and one was related to hematopoietic stem cell transplantation. CONCLUSIONS: Nitazoxanide has limited in vivo anti-viral effects for immunodeficiency-related vaccine-derived rubella. Most patients did not exhibit clinical improvement.


Assuntos
Granuloma/tratamento farmacológico , Síndromes de Imunodeficiência/virologia , Vírus da Rubéola/efeitos dos fármacos , Rubéola (Sarampo Alemão)/tratamento farmacológico , Tiazóis/uso terapêutico , Adolescente , Criança , Pré-Escolar , Feminino , Granuloma/virologia , Humanos , Lactente , Masculino , Estudos Retrospectivos , Rubéola (Sarampo Alemão)/virologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/virologia , Vacinação/métodos
3.
FEMS Microbiol Rev ; 43(2): 181-192, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30649299

RESUMO

Human γ-herpesviruses include the closely related tumor viruses Epstein Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV). EBV is the most growth-transforming pathogen known and is linked to at least seven human malignancies. KSHV is also associated with three human cancers. Most EBV- and KSHV-infected individuals fortunately remain disease-free despite persistent infection and this is likely due to the robustness of the immune control that they mount against these tumor viruses. However, upon immune suppression EBV- and KSHV-associated malignancies emerge at increased frequencies. Moreover, primary immunodeficiencies with individual mutations that predispose to EBV or KSHV disease allow us to gain insights into a catalog of molecules that are required for the immune control of these tumor viruses. Curiously, there is little overlap between the mutation targets that predispose individuals to EBV versus KSHV disease, even so both viruses can infect the same host cell, human B cells. These differences will be discussed in this review. A better understanding of the crucial components in the near-perfect life-long immune control of EBV and KSHV should allow us to target malignancies that are associated with these viruses, but also induce similar immune responses against other tumors.


Assuntos
Herpesviridae/imunologia , Interações Hospedeiro-Patógeno/imunologia , Síndromes de Imunodeficiência/virologia , Neoplasias/virologia , Vírus Oncogênicos/imunologia , Predisposição Genética para Doença , Herpesvirus Humano 4/imunologia , Herpesvirus Humano 8/imunologia , Humanos , Imunocompetência/genética
4.
Diagn Microbiol Infect Dis ; 93(1): 69-73, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30174143

RESUMO

OBJECTIVE: Predictive factors associated with clinical outcomes of chronic norovirus infection (CNI) in primary immunodeficiency diseases (PIDD) are lacking. METHOD: We sought to characterize CNI using a multi-institutional cohort of patients with PIDD and CNI using the Clinical Immunology Society's CIS-PIDD Listserv e-mail group. RESULTS: Thirty-four subjects (21 males and 13 females) were reported from centers across North America, Europe, and Asia. All subjects were receiving high doses (median IgG dose: 1200 mg/kg/month) of supplemental immunoglobulin therapy. Fifty-three percent had a complete absence of B cells (median B-cell count 0; range 0-139 cells/µL). Common Variable Immune Deficiency (CVID) subjects manifested a unique phenotype with B-cell lymphopenia, non O+ blood type, and villous atrophy (logistic regression model, P = 0.01). Five subjects died, all of whom had no evidence of villous atrophy. CONCLUSION: While Norovirus (NoV) is thought to replicate in B cells, in this PIDD cohort of CNI, B-cell lymphopenia was common, indicating that the presence of B lymphocytes is not essential for CNI.


Assuntos
Infecções por Caliciviridae/imunologia , Síndromes de Imunodeficiência/virologia , Norovirus/fisiologia , Adolescente , Adulto , Linfócitos B/patologia , Infecções por Caliciviridae/mortalidade , Infecções por Caliciviridae/patologia , Doença Crônica , Imunodeficiência de Variável Comum/imunologia , Imunodeficiência de Variável Comum/patologia , Imunodeficiência de Variável Comum/terapia , Imunodeficiência de Variável Comum/virologia , Feminino , Gastroenterite/imunologia , Gastroenterite/mortalidade , Gastroenterite/patologia , Humanos , Imunização Passiva , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/patologia , Síndromes de Imunodeficiência/terapia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Norovirus/genética , Estudos Retrospectivos , Adulto Jovem
5.
Nat Med ; 24(12): 1815-1821, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30397357

RESUMO

Human microbiome studies have revealed the intricate interplay of host immunity and bacterial communities to achieve homeostatic balance. Healthy skin microbial communities are dominated by bacteria with low viral representation1-3, mainly bacteriophage. Specific eukaryotic viruses have been implicated in both common and rare skin diseases, but cataloging skin viral communities has been limited. Alterations in host immunity provide an opportunity to expand our understanding of microbial-host interactions. Primary immunodeficient patients manifest with various viral, bacterial, fungal, and parasitic infections, including skin infections4. Dedicator of cytokinesis 8 (DOCK8) deficiency is a rare primary human immunodeficiency characterized by recurrent cutaneous and systemic infections, as well as atopy and cancer susceptibility5. DOCK8, encoding a guanine nucleotide exchange factor highly expressed in lymphocytes, regulates actin cytoskeleton, which is critical for migration through collagen-dense tissues such as skin6. Analyzing deep metagenomic sequencing data from DOCK8-deficient skin samples demonstrated a notable increase in eukaryotic viral representation and diversity compared with healthy volunteers. De novo assembly approaches identified hundreds of novel human papillomavirus genomes, illuminating microbial dark matter. Expansion of the skin virome in DOCK8-deficient patients underscores the importance of immune surveillance in controlling eukaryotic viral colonization and infection.


Assuntos
Fatores de Troca do Nucleotídeo Guanina/genética , Síndromes de Imunodeficiência/virologia , Dermatopatias/virologia , Pele/virologia , Adolescente , Bacteriófagos/genética , Criança , Feminino , Genoma Viral/genética , Fatores de Troca do Nucleotídeo Guanina/deficiência , Voluntários Saudáveis , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Imunidade/genética , Síndromes de Imunodeficiência/microbiologia , Síndromes de Imunodeficiência/patologia , Linfócitos/virologia , Masculino , Metagenoma/genética , Metagenoma/imunologia , Microbiota/genética , Papillomaviridae/isolamento & purificação , Papillomaviridae/patogenicidade , Pele/microbiologia , Dermatopatias/genética , Dermatopatias/microbiologia , Dermatopatias/patologia
6.
Orphanet J Rare Dis ; 13(1): 207, 2018 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-30445974

RESUMO

BACKGROUND: Patients with cartilage-hair hypoplasia (CHH), a rare metaphyseal chondrodysplasia, manifest severe growth failure, variable immunodeficiency and increased risk of malignancies. The impact of CHH on gynecologic and reproductive health is unknown. Vulnerability to genital infections may predispose CHH patients to prolonged human papillomavirus (HPV) infections potentially leading to cervical, vaginal and vulvar cancer. METHODS: We carried out gynecologic evaluation, pelvic ultrasound and laboratory assessment in 19 women with genetically confirmed CHH. All patients were clinically examined and retrospective data were collected from hospital records. RESULTS: The women ranged in age from 19.2 to 70.8 years (median 40.8 years) and in height from 103 to 150 cm (median 123 cm). All women had undergone normal pubertal development as assessed by breast development according to Tanner scale and by age of menarche (mean 12.5 yrs., range 11-14 yrs). Despite significant short stature and potentially small pelvic diameters, a well-developed uterus with fairly normal size and shape was found by pelvic ultrasound in most of the patients. Ovarian follicle reserve, assessed by ultrasound was normal in relation to age in all premenopausal women it could be assessed (12 cases). Anti-Müllerian hormone was normal in relation to age in 17 women (89%). HPV was detected in 44% (8/18) and three women carried more than one HPV serotype; findings did not associate with immunological parameters. Three patients had a concurrent cell atypia in Pap smear. CONCLUSIONS: Pubertal development, reproductive hormones and ovarian structure and function were usually normal in women with CHH suggesting fairly normal reproductive health. However, the immunodeficiency characteristic to CHH may predispose the patients to HPV infections. High prevalence of HPV infections detected in this series highlights the importance of careful gynecologic follow up of these patients.


Assuntos
Cabelo/anormalidades , Doença de Hirschsprung/patologia , Doença de Hirschsprung/virologia , Síndromes de Imunodeficiência/patologia , Síndromes de Imunodeficiência/virologia , Osteocondrodisplasias/congênito , Papillomaviridae/patogenicidade , Adulto , Idoso , Feminino , Genótipo , Cabelo/patologia , Cabelo/virologia , Doença de Hirschsprung/genética , Humanos , Síndromes de Imunodeficiência/genética , Pessoa de Meia-Idade , Osteocondrodisplasias/genética , Osteocondrodisplasias/patologia , Osteocondrodisplasias/virologia , Folículo Ovariano/metabolismo , Folículo Ovariano/patologia , Estudos Retrospectivos , Sorogrupo
7.
BMC Res Notes ; 11(1): 717, 2018 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-30305145

RESUMO

OBJECTIVE: Primary immunodeficiency (PID) patients are prone to developing viral infections and should not be vaccinated with live vaccines. In such patients, prolonged excretion and viral divergence may occur and they may subsequently act as reservoirs in the community introducing mutated virus and jeopardizing polio eradication. One hundred and thirty PID cases were included for poliovirus detection in stool with assessment of divergence of detected polioviruses from oral polio vaccine (OPV) virus. Clinical presentations of PID patients with detectable poliovirus in stool specimens are described. RESULTS: Six PID patients (4.5%) had detectable vaccine-derived poliovirus (VDPV) excretion in stool specimens; of these, five patients had severe combined immunodeficiency (two with acute flaccid paralysis, one with meningoencephalitis and two without neurological manifestations), and one patient had X-linked agammaglobulinemia (paralysis developed shortly after diagnosis of immunodeficiency). All six case-patients received trivalent OPV. Five case-patients had type 2 immunodeficiency-related vaccine-derived polioviruses (iVDPV2) excretion; one had concomitant excretion of Sabin like type 3 virus and one was identified as iVDPV1 excretor. Surveillance for poliovirus excretion among PID patients is critical as these patients represent a potential source to reseed polioviruses into populations.


Assuntos
Portador Sadio/virologia , Síndromes de Imunodeficiência/virologia , Poliomielite/transmissão , Vacina Antipólio Oral/efeitos adversos , Vacinação/efeitos adversos , Eliminação de Partículas Virais , Portador Sadio/imunologia , Portador Sadio/patologia , Erradicação de Doenças , Egito/epidemiologia , Fezes/virologia , Feminino , Humanos , Síndromes de Imunodeficiência/epidemiologia , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/mortalidade , Lactente , Masculino , Poliomielite/epidemiologia , Poliomielite/imunologia , Poliomielite/prevenção & controle , Poliovirus/imunologia , Poliovirus/patogenicidade , Vacina Antipólio Oral/administração & dosagem , Vigilância em Saúde Pública
8.
Pediatr Transplant ; 22(8): e13301, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30338638

RESUMO

Rhinoviruses are commonly detected in symptomatic and asymptomatic children prior to HCT. Unlike pre-HCT detection of other respiratory viruses, it is not known whether RV detection, with or without clinical symptoms, is associated with worse outcomes in children post-HCT. In a retrospective study of children undergoing allogeneic HCT from January 2009 to February 2015, 91 children underwent allogeneic HCT, and 62 children had RPP testing within 30 days pre-HCT. Fifty-six (90%) children had either no pathogen (n = 34, 55%) or single RV detection (n = 22, 35%), which was the most common pathogen identified. Compared with virus negative children, children with pre-HCT RV detection were not more likely to require ventilated support and did not have longer length of stay, higher mortality, or less days alive and out of the hospital within the first 100 days post-HCT. In a secondary analysis of all 56 patients with RPP testing and no pathogen or RV alone detected, the seven children with LRTI had less days alive and out of the hospital within the first 100 days post-HCT compared with the 49 children who were either asymptomatic or had URTI (10 vs 60 days, P = 0.002). In a bootstrapped regression model, presence of LRTI, not RV detection, was significantly associated with decreased days alive and out of the hospital within the first 100 days post-HCT. Thus, pre-HCT detection of RV, without associated LRTI, does not always warrant HCT delay.


Assuntos
Doenças Hematológicas/complicações , Transplante de Células-Tronco Hematopoéticas , Síndromes de Imunodeficiência/complicações , Neoplasias/complicações , Infecções por Picornaviridae/complicações , Rhinovirus/isolamento & purificação , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Doenças Hematológicas/terapia , Doenças Hematológicas/virologia , Humanos , Síndromes de Imunodeficiência/terapia , Síndromes de Imunodeficiência/virologia , Tempo de Internação , Masculino , Doenças Metabólicas/complicações , Doenças Metabólicas/terapia , Doenças Metabólicas/virologia , Neoplasias/terapia , Neoplasias/virologia , Análise de Regressão , Estudos Retrospectivos , Resultado do Tratamento
9.
J Gen Virol ; 99(7): 927-936, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29767614

RESUMO

Marek's disease virus (MDV) is a herpesvirus that induces lymphoma and a variety of non-neoplastic syndromes in chickens. Furthermore, very virulent plus (vv+) MDVs induce a form of immunosuppression (late-MDV-IS) that might involve both neoplastic and non-neoplastic mechanisms. The objective of this study was to evaluate whether the attenuation of MDV-induced tumours and late-MDV-IS occurs simultaneously or can be dissociated. The immunosuppressive ability of three viruses derived from vv+ MDV strain 686 (wild-type 686, the somewhat attenuated molecular clone 686-BAC, and the nononcogenic molecular clone lacking the two copies of the oncogene meq 686-BACΔMEQ) was evaluated. Late-MDV-IS was evaluated indirectly by assessing the negative effect of MDV strains on the protection conferred by infectious laryngotracheitis (ILT) vaccines. Our results showed that the ability to induce late-MDV-IS was attenuated before the ability to induce tumours. Strain 686 induced both tumours and late-MDV-IS, 686-BAC induced tumours but did not induce late-MDV-IS and 686-BACΔMEQ did not induce either tumours or late-MDV-IS. Further comparison of strains 686 and 686-BAC revealed that strain 686 reduced the humoral immune responses to ILTV (1132 vs 2167) more severely, showed higher levels of meq transcripts (2.1E+09 vs 4.98E+8) and higher expression of MDV microRNAs (mdv1-miR-M4-5p and mdv1-miR-M2-3p) in the spleen, and further reduced the percentage of CD45+-MHC-I+splenocytes (13 vs32 %) compared to molecular clone 686-BAC. This study suggests that the immunosuppressive ability of MDV might follow a continuous spectrum and only the most virulent MDVs can overcome a certain threshold level and induce clinical MDV-IS in the ILT model.


Assuntos
Carcinogênese/imunologia , Herpesvirus Galináceo 1/imunologia , Herpesvirus Galináceo 2/imunologia , Síndromes de Imunodeficiência/veterinária , Linfoma/veterinária , Doença de Marek/imunologia , Animais , Anticorpos Antivirais/biossíntese , Carcinogênese/genética , Carcinogênese/patologia , Galinhas , Feminino , Herpesvirus Galináceo 1/genética , Herpesvirus Galináceo 1/patogenicidade , Herpesvirus Galináceo 2/genética , Herpesvirus Galináceo 2/patogenicidade , Imunidade Humoral/efeitos dos fármacos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/virologia , Linfoma/genética , Linfoma/imunologia , Linfoma/virologia , Doença de Marek/genética , Doença de Marek/patologia , Doença de Marek/virologia , MicroRNAs/genética , MicroRNAs/imunologia , RNA Viral/genética , RNA Viral/imunologia , Especificidade da Espécie , Vacinas Virais/administração & dosagem , Virulência
10.
Front Immunol ; 9: 237, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29599765

RESUMO

The phosphatidylinositol-3-kinase (PI3K)/Akt pathway is important for multiple stages of herpesvirus replication including virus entry, replication, latency, and reactivation. Recently, patients with gain-of-function mutations in the p110δ-catalytic subunit of PI3K or in the p85-regulatory subunit of PI3K have been reported. These patients have constitutively active PI3K with hyperactivation of Akt. They present with lymphoproliferation and often have infections, particularly recurrent respiratory infections and/or severe virus infections. The most frequent virus infections are due to Epstein-Barr virus (EBV) and cytomegalovirus (CMV); patients often present with persistent EBV and/or CMV viremia, EBV lymphoproliferative disease, or CMV lymphadenitis. No patients have been reported with CMV pneumonia, colitis, or retinitis. Other herpesvirus infections have included herpes simplex pneumonia, recurrent zoster, and varicella after vaccination with the varicella vaccine. Additional viral infections have included adenovirus viremia, severe warts, and extensive Molluscum contagiosum virus infection. The increased susceptibility to virus infections in these patients is likely due to a reduced number of long-lived memory CD8 T cells and an increased number of terminally differentiated effector CD8 T cells.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/imunologia , Infecções por Citomegalovirus/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Síndromes de Imunodeficiência/imunologia , Fosfatidilinositol 3-Quinases/imunologia , Viremia/imunologia , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Classe I de Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Citomegalovirus/imunologia , Citomegalovirus/isolamento & purificação , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/genética , Infecções por Citomegalovirus/virologia , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/virologia , Mutação com Ganho de Função , Predisposição Genética para Doença , Herpesvirus Humano 4/imunologia , Herpesvirus Humano 4/isolamento & purificação , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/virologia , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/imunologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Viremia/tratamento farmacológico , Viremia/genética , Viremia/virologia
11.
Vaccine ; 36(24): 3541-3554, 2018 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-29426658

RESUMO

Infectious complications are a major cause of morbidity and mortality in patients with primary or secondary immunodeficiency. Prevention of infectious diseases by vaccines is among the most effective healthcare measures mainly for these subjects. However immunocompromised people vary in their degree of immunosuppression and susceptibility to infection and, therefore, represent a heterogeneous population with regard to immunization. To date there is no well- established evidence for use of vaccines in immunodeficient patients, and indications are not clearly defined even in high-quality reviews and in most of the guidelines prepared to provide recommendations for the active vaccination of immunocompromised hosts. The aim of this document is to issue recommendations based on published literature and the collective experience of the Italian primary immunodeficiency centers, about how and when vaccines can be used in immunocompromised patients, in order to facilitate physician decisions and to ensure the best immune protection with the lowest risk to the health of the patient.


Assuntos
Infecções Bacterianas/prevenção & controle , Vacinas Bacterianas/administração & dosagem , Hospedeiro Imunocomprometido , Guias de Prática Clínica como Assunto , Vacinas Virais/administração & dosagem , Viroses/prevenção & controle , Adulto , Infecções Bacterianas/imunologia , Infecções Bacterianas/microbiologia , Infecções Bacterianas/virologia , Criança , Política de Saúde , Humanos , Esquemas de Imunização , Síndromes de Imunodeficiência/microbiologia , Síndromes de Imunodeficiência/virologia , Itália , Vacinação/métodos , Vacinas de Produtos Inativados , Viroses/imunologia , Viroses/virologia
12.
BMC Infect Dis ; 18(1): 33, 2018 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-29325543

RESUMO

BACKGROUND: We report a rare case of Mammalian orthoreovirus (MRV) infection in a child with a primary immunodeficiency (PID). Infections with Mammalian orthoreovirus are very rare and probably of zoonotic origin. Only a few cases have been described so far, including one with similar pathogenesis as in our case. CASE PRESENTATION: The patient, age 11, presented with flu-like symptoms and persistent severe diarrhea. Enterovirus has been detected over several months, however, exact typing of a positive cell culture remained inconclusive. Unbiased metagenomic sequencing then detected MRV in stool samples from several time points. The sequencing approach further revealed co-infection with a recombinant Coxsackievirus and Adenovirus. MRV-specific antibodies detected by immunofluorescence proved that the patient seroconverted. CONCLUSION: This case highlights the potential of unbiased metagenomic sequencing in supplementing routine diagnostic methods, especially in situations of chronic infection with multiple viruses as seen here in an immunocompromised host. The origin, transmission routes and implications of MRV infection in humans merit further investigation.


Assuntos
Infecções por Adenoviridae/virologia , Infecções por Coxsackievirus/virologia , Síndromes de Imunodeficiência/complicações , Metagenômica/métodos , Infecções por Reoviridae/virologia , Infecções por Adenoviridae/etiologia , Criança , Coinfecção , Infecções por Coxsackievirus/etiologia , Diarreia/virologia , Enterovirus/genética , Enterovirus/patogenicidade , Infecções por Enterovirus/virologia , Feminino , Humanos , Síndromes de Imunodeficiência/virologia , Orthoreovirus de Mamíferos/genética , Orthoreovirus de Mamíferos/patogenicidade , Infecções por Reoviridae/etiologia
13.
EMBO Mol Med ; 10(2): 188-199, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29282224

RESUMO

Inherited CTPS1, CD27, and CD70 deficiencies in humans have revealed key factors of T-lymphocyte expansion, a critical prerequisite for an efficient immunity to Epstein-Barr virus (EBV) infection. RASGRP1 is a T-lymphocyte-specific nucleotide exchange factor known to activate the pathway of MAP kinases (MAPK). A deleterious homozygous mutation in RASGRP1 leading to the loss RASGRP1 expression was identified in two siblings who both developed a persistent EBV infection leading to Hodgkin lymphoma. RASGRP1-deficient T cells exhibited defective MAPK activation and impaired proliferation that was restored by expression of wild-type RASGRP1. Similar defects were observed in T cells from healthy individuals when RASGRP1 was downregulated. RASGRP1-deficient T cells also exhibited decreased CD27-dependent proliferation toward CD70-expressing EBV-transformed B cells, a crucial pathway required for expansion of antigen-specific T cells during anti-EBV immunity. Furthermore, RASGRP1-deficient T cells failed to upregulate CTPS1, an important enzyme involved in DNA synthesis. These results show that RASGRP1 deficiency leads to susceptibility to EBV infection and demonstrate the key role of RASGRP1 at the crossroad of pathways required for the expansion of activated T lymphocytes.


Assuntos
Proteínas de Ligação a DNA/genética , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/imunologia , Fatores de Troca do Nucleotídeo Guanina/genética , Doença de Hodgkin/genética , Doença de Hodgkin/imunologia , Proliferação de Células , Células Cultivadas , Criança , Proteínas de Ligação a DNA/metabolismo , Suscetibilidade a Doenças , Predisposição Genética para Doença , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Síndromes de Imunodeficiência/virologia , Linhagem
15.
J Clin Invest ; 127(12): 4415-4420, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29106381

RESUMO

Primary immunodeficiencies are often monogenic disorders characterized by vulnerability to specific infectious pathogens. Here, we performed whole-exome sequencing of a patient with disseminated Mycobacterium abscessus, Streptococcus viridians bacteremia, and cytomegalovirus (CMV) viremia and identified mutations in 2 genes that regulate distinct IFN pathways. The patient had a homozygous frameshift deletion in IFNGR2, which encodes the signal transducing chain of the IFN-γ receptor, that resulted in minimal protein expression and abolished downstream signaling. The patient also harbored a homozygous deletion in IFNAR1 (IFNAR1*557Gluext*46), which encodes the IFN-α receptor signaling subunit. The IFNAR1*557Gluext*46 resulted in replacement of the stop codon with 46 additional codons at the C-terminus. The level of IFNAR1*557Gluext*46 mutant protein expressed in patient fibroblasts was comparable to levels of WT IFNAR1 in control fibroblasts. IFN-α-induced signaling was impaired in the patient fibroblasts, as evidenced by decreased STAT1/STAT2 phosphorylation, nuclear translocation of STAT1, and expression of IFN-α-stimulated genes critical for CMV immunity. Pretreatment with IFN-α failed to suppress CMV protein expression in patient fibroblasts, whereas expression of WT IFNAR1 restored IFN-α-mediated suppression of CMV. This study identifies a human IFNAR1 mutation and describes a digenic immunodeficiency specific to type I and type II IFNs.


Assuntos
Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/imunologia , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Mutação , Receptor de Interferon alfa e beta , Receptores de Interferon , Bacteriemia/genética , Bacteriemia/imunologia , Bacteriemia/microbiologia , Citomegalovirus/imunologia , Infecções por Citomegalovirus/genética , Infecções por Citomegalovirus/imunologia , Feminino , Fibroblastos/imunologia , Fibroblastos/microbiologia , Fibroblastos/virologia , Doenças Genéticas Inatas/microbiologia , Doenças Genéticas Inatas/virologia , Humanos , Síndromes de Imunodeficiência/microbiologia , Síndromes de Imunodeficiência/virologia , Masculino , Infecções por Micobactéria não Tuberculosa/genética , Infecções por Micobactéria não Tuberculosa/imunologia , Mycobacterium abscessus/imunologia , Fosforilação/genética , Fosforilação/imunologia , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/imunologia , Receptores de Interferon/genética , Receptores de Interferon/imunologia , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/imunologia , Fator de Transcrição STAT2/genética , Fator de Transcrição STAT2/imunologia , Infecções Estreptocócicas/genética , Infecções Estreptocócicas/imunologia , Viremia/genética , Viremia/imunologia , Viremia/virologia , Estreptococos Viridans/imunologia
16.
Antiviral Res ; 147: 58-66, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28974385

RESUMO

Persistent rubella virus (RV) infection has been associated with various pathologies such as congenital rubella syndrome, Fuchs's uveitis, and cutaneous granulomas in patients with primary immune deficiencies (PID). Currently there are no drugs to treat RV infections. Nitazoxanide (NTZ) is an FDA-approved drug for parasitic infections, and has been recently shown to have broad-spectrum antiviral activities. Here we found that empiric 2-month therapy with oral NTZ was associated in the decline/elimination of RV antigen from lesions in a PID patient with RV positive granulomas, while peginterferon treatment had no effect. In addition, we characterized the effects of NTZ on cell culture models of persistent RV infection. NTZ significantly inhibited RV replication in a primary culture of human umbilical vein endothelial cells (HUVEC) and Vero and A549 epithelial cell lines in a dose dependent manner with an average 50% inhibitory concentration of 0.35 µg/ml (1.1 µM). RV strains representing currently circulating genotypes were inhibited to a similar extent. NTZ affected early and late stages of infection by inhibiting synthesis of cellular and RV RNA and interfering with intracellular trafficking of the RV surface glycoproteins, E1 and E2. These results suggest a potential application of NTZ for the treatment of persistent rubella infections, but more studies are required.


Assuntos
Antígenos Virais/metabolismo , Transporte Proteico/efeitos dos fármacos , Vírus da Rubéola/efeitos dos fármacos , Tiazóis/farmacologia , Tiazóis/uso terapêutico , Replicação Viral/efeitos dos fármacos , Células A549 , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Antivirais/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Feminino , Granuloma/complicações , Granuloma/tratamento farmacológico , Granuloma/virologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/virologia , Concentração Inibidora 50 , Rubéola (Sarampo Alemão)/complicações , Rubéola (Sarampo Alemão)/tratamento farmacológico , Rubéola (Sarampo Alemão)/virologia , Pele/patologia , Pele/virologia , Tiazóis/toxicidade , Resultado do Tratamento , Células Vero
17.
Medicine (Baltimore) ; 96(42): e7989, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29049190

RESUMO

RATIONALE: With the progress of sequencing technology, an increasing number of atypical primary immunodeficiency (PID) patients have been discovered, including Janus kinase 3 (JAK3) gene deficiency. PATIENT CONCERNS: We report a patient who presented with chronic active Epstein-Barr virus (CAEBV) infection but responded poorly to treatment with ganciclovir. DIAGNOSES: Next-generation sequencing (NGS) was performed, including all known PID genes, after which Sanger sequencing was performed to verify the results. Genetic analysis revealed that our patient had 2 novel compound heterozygous mutations of JAK3, a gene previously reported to cause a rare form of autosomal recessive severe combined immunodeficiency with recurrent infections. The p.H27Q mutation came from his father, while p. R222H from his mother. Thus, his diagnosis was corrected for JAK3-deficiency PID and CAEBV. INTERVENTIONS: Maintenance treatment of subcutaneous injection of recombinant human interferon α-2a was given to our patient with 2 MU, 3 times a week. OUTCOMES: Interferon alpha was applied and the EBV infection was gradually controlled and his symptoms ameliorated remarkably. Our patient is in good health now and did not have relapses. LESSONS: The diagnoses of PID should be taken into consideration when CAEBV patients respond poorly to conventional treatments. Good results of our patient indicate that interferon α-2a may be an alternative treatment for those who are unwilling to accept hematopoietic stem cell transplantation (HSCT) like our patient. Literature review identified 59 additional cases of JAK3 deficiency with various infections.


Assuntos
Infecções por Vírus Epstein-Barr/genética , Herpesvirus Humano 4 , Síndromes de Imunodeficiência/genética , Janus Quinase 3/deficiência , Antivirais/uso terapêutico , Criança , Doença Crônica , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Infecções por Vírus Epstein-Barr/virologia , Ganciclovir/uso terapêutico , Herpesvirus Humano 4/efeitos dos fármacos , Humanos , Síndromes de Imunodeficiência/tratamento farmacológico , Síndromes de Imunodeficiência/virologia , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Masculino , Proteínas Recombinantes/administração & dosagem , Resultado do Tratamento
19.
Emerg Infect Dis ; 23(10): 1664-1670, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28930011

RESUMO

Prolonged excretion of poliovirus can occur in immunodeficient patients who receive oral polio vaccine, which may lead to propagation of highly divergent vaccine-derived polioviruses (VDPVs), posing a concern for global polio eradication. This study aimed to estimate the proportion of primary immunodeficient children with enterovirus infection and to identify the long-term polio/nonpolio enterovirus excreters in a tertiary care unit in Mumbai, India. During September 2014-April 2017, 151 patients received diagnoses of primary immunodeficiency (PID). We isolated 8 enteroviruses (3 polioviruses and 5 nonpolio enteroviruses) in cell culture of 105 fecal samples collected from 42 patients. Only 1 patient with severe combined immunodeficiency was identified as a long-term VDPV3 excreter (for 2 years after identification of infection). Our results show that the risk of enterovirus excretion among children in India with PID is low; however, systematic screening is necessary to identify long-term poliovirus excreters until the use of oral polio vaccine is stopped.


Assuntos
Síndromes de Imunodeficiência/virologia , Poliomielite/prevenção & controle , Vacina Antipólio Oral/administração & dosagem , Poliovirus/imunologia , Eliminação de Partículas Virais/imunologia , Criança , Pré-Escolar , Enterovirus Humano C/imunologia , Enterovirus Humano C/patogenicidade , Infecções por Enterovirus/imunologia , Infecções por Enterovirus/transmissão , Infecções por Enterovirus/virologia , Fezes/virologia , Feminino , Humanos , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/patologia , Índia , Lactente , Masculino , Poliomielite/imunologia , Poliomielite/transmissão , Poliomielite/virologia , Poliovirus/patogenicidade , Risco
20.
Am J Clin Pathol ; 147(2): 171-187, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-28395104

RESUMO

Objectives: The 2015 Workshop of the Society for Hematopathology/European Association for Haematopathology aimed to review immunodeficiency-related lymphoproliferative disorders with plasmablastic and plasma cell differentiation. Methods: The workshop panel reviewed human herpes virus 8 (HHV8)/Kaposi sarcoma herpesvirus (KSHV)-associated lesions and other lesions exhibiting plasma cell differentiation, including plasmablastic proliferations with features of myeloma/plasmacytoma, plasmablastic neoplasms presenting in extranodal sites and effusion-based lymphomas, and rendered a consensus diagnosis. Results: The spectrum of HHV8/KSHV-associated proliferations ranged from multicentric Castleman disease (MCD) to MCD with plasmablastic aggregates to HHV8+ diffuse large B-cell lymphoma and germinotrophic lymphoproliferative disorder. Comparisons across effusion-based lymphomas with and without HHV8/KSHV and plasmablastic lymphomas in immunodeficient and immunocompetent patients were discussed. Conclusions: The presence or absence of HHV8/KSHV is a defining feature in disorders associated with Castleman disease, although their differential diagnosis and recognition of progression may be challenging. Plasmablastic proliferations overlap with myeloma/plasmacytoma as well as extranodal and effusion-based lymphomas. The involvement of Epstein-Barr virus is typically variable.


Assuntos
Infecções por Herpesviridae/complicações , Síndromes de Imunodeficiência/patologia , Transtornos Linfoproliferativos/patologia , Neoplasias de Plasmócitos/patologia , Adulto , Idoso , Educação , Feminino , Herpesvirus Humano 8 , Humanos , Síndromes de Imunodeficiência/virologia , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/virologia , Masculino , Pessoa de Meia-Idade , Neoplasias de Plasmócitos/diagnóstico , Neoplasias de Plasmócitos/virologia
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