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3.
J Clin Immunol ; 38(2): 204-213, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29423883

RESUMO

BACKGROUND: Immunologists are increasingly being asked to assess patients with non-classical and secondary antibody deficiency to determine their potential need for immunoglobulin replacement therapy (IGRT). Immunoglobulin is a limited, expensive resource and no clear guidance exists for this broad patient group. The purpose of this survey is to establish what factors influence the decision to commence IGRT in adult patients, when diagnostic criteria for primary antibody deficiency are not fulfilled. METHODS: Under the auspices of the United Kingdom Primary Immunodeficiency Network (UKPIN), a study group was established which circulated an online questionnaire to the consultant body across the UK and Ireland. Results provided a snapshot of the current clinical practice of 71% of consultant immunologists, from 30 centers. RESULTS: In order of importance, factors which influence the decision to commence IGRT include number of hospital admissions with infection, serum IgG level, bronchiectasis, radiologically proven pneumonia, number of positive sputum cultures, number of antibiotic courses, and results of immunization studies. The commonest test vaccine used was Pneumovax 23 with measurement of serotype-specific responses at 4 weeks, with a threshold of 0.35 µg/ml in 2/3 of serotypes measured. Eighty-six percent of patients are treated with a trial of prophylactic antibiotics prior to consideration of IGRT. Efficacy of IGRT trial is assessed at between 6 and 12 months. CONCLUSIONS: There was consistency in clinical practice using a combination of clinical history, evidence of infections, and vaccination testing for diagnosis. However, there was some variation in the implementation of this practice, particularly in vaccine choice and assessment of response to vaccination.

4.
Liver Transpl ; 24(2): 171-181, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29156507

RESUMO

Common variable immunodeficiency (CVID) is the most common form of primary immunodeficiency characterized by antibody deficiency, recurrent bacterial infections, and autoimmunity. Advanced chronic liver disease occurs in a subset of patients with CVID and manifests with various histological features, such as nodular regenerative hyperplasia, inflammation, fibrosis, and cholangiopathy. We present a case series characterizing the outcomes in adult patients transplanted for primary CVID-related liver disease. We discuss the unique transplantation challenges faced in this primary immunodeficiency group including susceptibility to infections and early disease recurrence. There is a statistically significant decrease in 3-year and 5-year survival after liver transplantation in those with CVID-related liver disease (55% at 3 and 5 years) compared with all-comers (89% at 3 years, 81% at 5 years), prompting a need for discussion of suitability of transplantation in this group of patients as well as methods for reducing posttransplantation risk such as scrupulous search for infectious agents and reduction of immunosuppression. Liver Transplantation 24 171-181 2018 AASLD.


Assuntos
Imunodeficiência de Variável Comum/imunologia , Hepatopatias/cirurgia , Transplante de Fígado/efeitos adversos , Adulto , Doença Crônica , Imunodeficiência de Variável Comum/complicações , Imunodeficiência de Variável Comum/diagnóstico , Evolução Fatal , Feminino , Humanos , Hospedeiro Imunocomprometido , Imunossupressores/efeitos adversos , Hepatopatias/diagnóstico , Hepatopatias/imunologia , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Recidiva , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
8.
J Allergy Clin Immunol ; 137(1): 204-213.e3, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26365387

RESUMO

BACKGROUND: Anti-cytokine autoantibodies (ACAAs) are pathogenic in a handful of rare immunodeficiencies. However, the prevalence and significance of other ACAAs across immunodeficiencies have not yet been described. OBJECTIVE: We profiled ACAAs in a diverse cohort of serum samples from patients with immunodeficiency and assessed the sensitivity and specificity of protein microarrays for ACAA identification and discovery. METHODS: Highly multiplexed protein microarrays were designed and fabricated. Blinded serum samples from a cohort of 58 immunodeficiency patients and healthy control subjects were used to probe microarrays. Unsupervised hierarchical clustering was used to identify clusters of reactivity, and after unblinding, significance analysis of microarrays was used to identify disease-specific autoantibodies. A bead-based assay was used to validate protein microarray results. Blocking activity of serum containing ACAAs was measured in vitro. RESULTS: Protein microarrays were highly sensitive and specific for the detection of ACAAs in patients with autoimmune polyendocrine syndrome type I and pulmonary alveolar proteinosis, detecting ACAA levels consistent with those reported in the published literature. Protein microarray results were validated by using an independent bead-based assay. To confirm the functional significance of these ACAAs, we tested and confirmed the blocking activity of select ACAAs in vitro. CONCLUSION: Protein microarrays are a powerful tool for ACAA detection and discovery, and they hold promise as a diagnostic for the evaluation and monitoring of clinical immunodeficiency.


Assuntos
Autoanticorpos/sangue , Citocinas/imunologia , Síndromes de Imunodeficiência/imunologia , Humanos , Síndromes de Imunodeficiência/sangue , Análise Serial de Proteínas
9.
Neurology ; 81(10): 872-6, 2013 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-23925762

RESUMO

OBJECTIVE: To determine the immunocompetency of patients with multiple sclerosis treated with the lymphodepleting humanized monoclonal antibody alemtuzumab. METHODS: In this pilot case-control study, we assessed immunocompetence in 24 patients after alemtuzumab treatment by measuring antibody responses to 3 vaccines (diphtheria, tetanus, and poliomyelitis vaccine, Haemophilus influenzae type b and meningococcal group C conjugate vaccine, and pneumococcal polysaccharide vaccine). In 20 patients, antibodies to common viruses (mumps, rubella, varicella-zoster, and Epstein-Barr virus) were measured before alemtuzumab treatment, then at 1 and 9-11 months after treatment. Results were compared with well-defined historical controls. RESULTS: Serum antibodies against common viruses remained detectable after treatment, and vaccine responses were normal to T-cell-dependent recall antigens (tetanus, diphtheria, and polio), a T-cell-dependent novel antigen (meningococcus C), and T-cell-independent antigens (pneumococcal). There was no evidence for a diminished response to vaccinations in 5 patients studied within 6 months of alemtuzumab treatment. CONCLUSION: In this small historically controlled pilot study, we demonstrated i) retained humoral immunologic memory (in the form of antibodies against common viruses and response to recall antigens), and ii) the retained ability to mount a humoral immune response against a novel antigen after treatment with alemtuzumab. CLASSIFICATION OF EVIDENCE: This pilot study provides Class III evidence that patients with relapsing-remitting multiple sclerosis appear immunocompetent after treatment with alemtuzumab.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Imunocompetência/imunologia , Esclerose Múltipla/imunologia , Esclerose Múltipla/terapia , Adulto , Alemtuzumab , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Projetos Piloto , Resultado do Tratamento , Adulto Jovem
10.
Medicine (Baltimore) ; 92(2): 109-22, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23429356

RESUMO

Autosomal recessive interleukin (IL)-12 p40 (IL-12p40) deficiency is a rare genetic etiology of mendelian susceptibility to mycobacterial disease (MSMD). We report the genetic, immunologic, and clinical features of 49 patients from 30 kindreds originating from 5 countries (India, Iran, Pakistan, Saudi Arabia, and Tunisia). There are only 9 different mutant alleles of the IL12B gene: 2 small insertions, 3 small deletions, 2 splice site mutations, and 1 large deletion, each causing a frameshift and leading to a premature stop codon, and 1 nonsense mutation. Four of these 9 variants are recurrent, affecting 25 of the 30 reported kindreds, due to founder effects in specific countries. All patients are homozygous and display complete IL-12p40 deficiency. As a result, the patients lack detectable IL-12p70 and IL-12p40 and have low levels of interferon gamma (IFN-γ). The clinical features are characterized by childhood onset of bacille Calmette-Guérin (attenuated Mycobacterium bovis strain) (BCG) and Salmonella infections, with recurrences of salmonellosis (36.4%) more common than recurrences of mycobacterial disease (25%). BCG vaccination led to BCG disease in 40 of the 41 patients vaccinated (97.5%). Multiple mycobacterial infections were rare, observed in only 3 patients, whereas the association of salmonellosis and mycobacteriosis was observed in 9 patients. A few other infections were diagnosed, including chronic mucocutaneous candidiasis (n = 3), nocardiosis (n = 2), and klebsiellosis (n = 1). IL-12p40 deficiency has a high but incomplete clinical penetrance, with 33.3% of genetically affected relatives of index cases showing no symptoms. However, the prognosis is poor, with mortality rates of up to 28.6%. Overall, the clinical phenotype of IL-12p40 deficiency closely resembles that of interleukin 12 receptor ß1 (IL-12Rß1) deficiency. In conclusion, IL-12p40 deficiency is more common than initially thought and should be considered worldwide in patients with MSMD and other intramacrophagic infectious diseases, salmonellosis in particular.


Assuntos
Subunidade p40 da Interleucina-12/deficiência , Subunidade p40 da Interleucina-12/genética , Infecções por Micobactéria não Tuberculosa/genética , Infecções por Salmonella/genética , Adolescente , Adulto , Idade de Início , Ásia Ocidental/epidemiologia , Criança , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Efeito Fundador , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Infecções por Micobactéria não Tuberculosa/imunologia , Infecções por Micobactéria não Tuberculosa/mortalidade , Penetrância , Análise de Sobrevida , Tunísia/epidemiologia , Adulto Jovem
12.
J Exp Med ; 208(2): 227-34, 2011 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-21242295

RESUMO

Congenital or acquired cellular deficiencies in humans have the potential to reveal much about normal hematopoiesis and immune function. We show that a recently described syndrome of monocytopenia, B and NK lymphoid deficiency additionally includes the near absence of dendritic cells. Four subjects showed severe depletion of the peripheral blood HLA-DR(+) lineage(-) compartment, with virtually no CD123(+) or CD11c(+) dendritic cells (DCs) and very few CD14(+) or CD16(+) monocytes. The only remaining HLA-DR(+) lineage(-) cells were circulating CD34(+) progenitor cells. Dermal CD14(+) and CD1a(+) DC were also absent, consistent with their dependence on blood-derived precursors. In contrast, epidermal Langerhans cells and tissue macrophages were largely preserved. Combined loss of peripheral DCs, monocytes, and B and NK lymphocytes was mirrored in the bone marrow by complete absence of multilymphoid progenitors and depletion of granulocyte-macrophage progenitors. Depletion of the HLA-DR(+) peripheral blood compartment was associated with elevated serum fms-like tyrosine kinase ligand and reduced circulating CD4(+)CD25(hi)FoxP3(+) T cells, supporting a role for DC in T reg cell homeostasis.


Assuntos
Células Dendríticas/citologia , Suscetibilidade a Doenças/etiologia , Antígenos HLA-DR/sangue , Leucopenia/genética , Monócitos/citologia , Adulto , Antígenos CD/metabolismo , Células da Medula Óssea/citologia , Criança , Células Dendríticas/patologia , Suscetibilidade a Doenças/microbiologia , Suscetibilidade a Doenças/virologia , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Interferon gama/sangue , Leucopenia/sangue , Leucopenia/complicações , Microscopia de Fluorescência , Monócitos/patologia , Infecções por Mycobacterium/imunologia , Síndrome
13.
Medicine (Baltimore) ; 89(6): 381-402, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21057261

RESUMO

Interleukin-12 receptor ß1 (IL-12Rß1) deficiency is the most common form of Mendelian susceptibility to mycobacterial disease (MSMD). We undertook an international survey of 141 patients from 102 kindreds in 30 countries. Among 102 probands, the first infection occurred at a mean age of 2.4 years. In 78 patients, this infection was caused by Bacille Calmette-Guérin (BCG; n = 65), environmental mycobacteria (EM; also known as atypical or nontuberculous mycobacteria) (n = 9) or Mycobacterium tuberculosis (n = 4). Twenty-two of the remaining 24 probands initially presented with nontyphoidal, extraintestinal salmonellosis. Twenty of the 29 genetically affected sibs displayed clinical signs (69%); however 8 remained asymptomatic (27%). Nine nongenotyped sibs with symptoms died. Recurrent BCG infection was diagnosed in 15 cases, recurrent EM in 3 cases, recurrent salmonellosis in 22 patients. Ninety of the 132 symptomatic patients had infections with a single microorganism. Multiple infections were diagnosed in 40 cases, with combined mycobacteriosis and salmonellosis in 36 individuals. BCG disease strongly protected against subsequent EM disease (p = 0.00008). Various other infectious diseases occurred, albeit each rarely, yet candidiasis was reported in 33 of the patients (23%). Ninety-nine patients (70%) survived, with a mean age at last follow-up visit of 12.7 years ± 9.8 years (range, 0.5-46.4 yr). IL-12Rß1 deficiency is characterized by childhood-onset mycobacteriosis and salmonellosis, rare recurrences of mycobacterial disease, and more frequent recurrence of salmonellosis. The condition has higher clinical penetrance, broader susceptibility to infections, and less favorable outcome than previously thought.


Assuntos
Subunidade beta 1 de Receptor de Interleucina-12/deficiência , Adolescente , Adulto , Fatores Etários , Criança , Pré-Escolar , Citocinas/sangue , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Subunidade beta 1 de Receptor de Interleucina-12/genética , Masculino , Pessoa de Meia-Idade , Infecções por Micobactéria não Tuberculosa/epidemiologia , Infecções por Micobactéria não Tuberculosa/genética , Mycobacterium bovis/isolamento & purificação , Mycobacterium tuberculosis/isolamento & purificação , Micobactérias não Tuberculosas/isolamento & purificação , Análise de Sobrevida
14.
Medicine (Baltimore) ; 89(6): 403-25, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21057262

RESUMO

Autosomal recessive interleukin-1 receptor-associated kinase (IRAK)-4 and myeloid differentiation factor (MyD)88 deficiencies impair Toll-like receptor (TLR)- and interleukin-1 receptor-mediated immunity. We documented the clinical features and outcome of 48 patients with IRAK-4 deficiency and 12 patients with MyD88 deficiency, from 37 kindreds in 15 countries.The clinical features of IRAK-4 and MyD88 deficiency were indistinguishable. There were no severe viral, parasitic, and fungal diseases, and the range of bacterial infections was narrow. Noninvasive bacterial infections occurred in 52 patients, with a high incidence of infections of the upper respiratory tract and the skin, mostly caused by Pseudomonas aeruginosa and Staphylococcus aureus, respectively. The leading threat was invasive pneumococcal disease, documented in 41 patients (68%) and causing 72 documented invasive infections (52.2%). P. aeruginosa and Staph. aureus documented invasive infections also occurred (16.7% and 16%, respectively, in 13 and 13 patients, respectively). Systemic signs of inflammation were usually weak or delayed. The first invasive infection occurred before the age of 2 years in 53 (88.3%) and in the neonatal period in 19 (32.7%) patients. Multiple or recurrent invasive infections were observed in most survivors (n = 36/50, 72%).Clinical outcome was poor, with 24 deaths, in 10 cases during the first invasive episode and in 16 cases of invasive pneumococcal disease. However, no death and invasive infectious disease were reported in patients after the age of 8 years and 14 years, respectively. Antibiotic prophylaxis (n = 34), antipneumococcal vaccination (n = 31), and/or IgG infusion (n = 19), when instituted, had a beneficial impact on patients until the teenage years, with no seemingly detectable impact thereafter.IRAK-4 and MyD88 deficiencies predispose patients to recurrent life-threatening bacterial diseases, such as invasive pneumococcal disease in particular, in infancy and early childhood, with weak signs of inflammation. Patients and families should be informed of the risk of developing life-threatening infections; empiric antibacterial treatment and immediate medical consultation are strongly recommended in cases of suspected infection or moderate fever. Prophylactic measures in childhood are beneficial, until spontaneous improvement occurs in adolescence.


Assuntos
Quinases Associadas a Receptores de Interleucina-1/deficiência , Fator 88 de Diferenciação Mieloide/deficiência , Adolescente , Antibacterianos/uso terapêutico , Infecções Bacterianas/epidemiologia , Infecções Bacterianas/prevenção & controle , Criança , Pré-Escolar , Suscetibilidade a Doenças , Feminino , Humanos , Imunidade , Lactente , Quinases Associadas a Receptores de Interleucina-1/genética , Masculino , Mutação , Fator 88 de Diferenciação Mieloide/genética , Receptores de Interleucina-1/metabolismo , Receptores Toll-Like/metabolismo
15.
J Allergy Clin Immunol ; 126(2): 332-7, 337.e1-2, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20621347

RESUMO

BACKGROUND: IL-1 receptor-associated kinase 4 (IRAK-4) is an effector of the Toll-like receptor and IL-1 receptor pathways that plays a critical role in innate immune responses. The role of IRAK-4 in adaptive immune functions in human subjects is incompletely understood. OBJECTIVE: We sought to evaluate T-cell function in IRAK-4 deficient patients. METHODS: We compared upregulation of CD25 and CD69 on T cells and production of IL-2, IL-6, and IFN-gamma after stimulation of PBMCs from 4 IRAK-4-deficient patients and healthy control subjects with anti-CD3 and anti-CD28. RESULTS: Upregulation of CD25 and CD69 on T cells and production of IL-6 and IFN-gamma, but not IL-2, was significantly reduced in IRAK-4-deficient patients. CONCLUSIONS: IRAK-4-deficient patients have defects in T-cell activation.


Assuntos
Doenças Genéticas Inatas , Síndromes de Imunodeficiência , Quinases Associadas a Receptores de Interleucina-1 , Ativação Linfocitária , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T , Imunidade Adaptativa/genética , Imunidade Adaptativa/imunologia , Antígenos CD/biossíntese , Antígenos CD/genética , Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/biossíntese , Antígenos de Diferenciação de Linfócitos T/genética , Antígenos de Diferenciação de Linfócitos T/imunologia , Estudos de Casos e Controles , Citocinas/biossíntese , Citocinas/genética , Citocinas/imunologia , Feminino , Doenças Genéticas Inatas/enzimologia , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/imunologia , Humanos , Síndromes de Imunodeficiência/enzimologia , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Quinases Associadas a Receptores de Interleucina-1/genética , Quinases Associadas a Receptores de Interleucina-1/imunologia , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Subunidade alfa de Receptor de Interleucina-2/biossíntese , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-2/imunologia , Lectinas Tipo C/biossíntese , Lectinas Tipo C/genética , Lectinas Tipo C/imunologia , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Masculino , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T/enzimologia , Linfócitos T/imunologia , Regulação para Cima/genética , Regulação para Cima/imunologia
18.
Blood ; 113(9): 1967-76, 2009 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-18981294

RESUMO

TNFRSF13B encodes transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), a B cell- specific tumor necrosis factor (TNF) receptor superfamily member. Both biallelic and monoallelic TNFRSF13B mutations were identified in patients with common variable immunodeficiency disorders. The genetic complexity and variable clinical presentation of TACI deficiency prompted us to evaluate the genetic, immunologic, and clinical condition in 50 individuals with TNFRSF13B alterations, following screening of 564 unrelated patients with hypogammaglobulinemia. We identified 13 new sequence variants. The most frequent TNFRSF13B variants (C104R and A181E; n=39; 6.9%) were also present in a heterozygous state in 2% of 675 controls. All patients with biallelic mutations had hypogammaglobulinemia and nearly all showed impaired binding to a proliferation-inducing ligand (APRIL). However, the majority (n=41; 82%) of the pa-tients carried monoallelic changes in TNFRSF13B. Presence of a heterozygous mutation was associated with antibody deficiency (P< .001, relative risk 3.6). Heterozygosity for the most common mutation, C104R, was associated with disease (P< .001, relative risk 4.2). Furthermore, heterozygosity for C104R was associated with low numbers of IgD(-)CD27(+) B cells (P= .019), benign lymphoproliferation (P< .001), and autoimmune complications (P= .001). These associations indicate that C104R heterozygosity increases the risk for common variable immunodeficiency disorders and influences clinical presentation.


Assuntos
Agamaglobulinemia/genética , Predisposição Genética para Doença/genética , Mutação , Proteína Transmembrana Ativadora e Interagente do CAML/genética , Alelos , Substituição de Aminoácidos , Estudos de Casos e Controles , Células Cultivadas , Estudos de Coortes , Análise Mutacional de DNA , Frequência do Gene , Heterozigoto , Homozigoto , Humanos , Mutação/fisiologia , Linhagem , Polimorfismo de Nucleotídeo Único/fisiologia , Fatores de Risco , Síndrome
19.
Eur J Immunol ; 37(8): 2196-204, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17595676

RESUMO

Fas and Fas Ligand (FasL) expression, activation-induced cell death (AICD) and mycobacterial antigen-specific cytotoxicity of peripheral T cells from patients with complete inherited IFN-gamma receptor 1 binding chain deficiency (IFN-gammaR1-/-) were investigated. Fas was equally expressed in both normal and deficient T lymphoblasts and they underwent apoptosis when stimulated with agonist anti-Fas mAb. By contrast, T lymphoblasts and CD4+ T cell clones (TCC) from deficient patients displayed a reduced surface FasL expression and resistance to AICD. CD8+ TCC from healthy and deficient patients displayed similar high level of FasL and susceptibility to AICD. In Jurkat CD4+ T cells competent to transduce IFN-gamma signaling, IFN-gamma induced surface FasL export and their Fas-dependent apoptosis. Effector T cells generated from a patient with a dominant negative mutation of IFN-gammaR1 (IFN-gammaR1DN) following stimulation with mycobacterial antigens were unable to kill MHC class II-matched, mycobacterial antigen-pulsed macrophages. Normal Fas expression in T cells and FasL in CD8+ cells may account for the absence of autoimmune disorders in these patients. Conversely, defective FasL expression on IFN-gammaR1DN CD4+ T cells impairs their cytotoxic functions and highlights a novel role for IFN-gamma signaling in the control of mycobacterial infection in humans.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Citotoxicidade Imunológica , Proteína Ligante Fas/biossíntese , Interferon gama/imunologia , Infecções por Mycobacterium/imunologia , Apoptose/fisiologia , Linfócitos T CD4-Positivos/metabolismo , Citometria de Fluxo , Humanos , Interferon gama/metabolismo , Microscopia Confocal , Mycobacterium/imunologia , Receptores de Interferon/deficiência , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Receptor fas/biossíntese
20.
Lancet Infect Dis ; 7(3): 225-32, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17317604

RESUMO

A 12-year-old girl with protracted tuberculous meningitis received standard chemotherapy and dexamethasone and had a progressive cerebrospinal fluid neutrophilia, raised protein and depressed glucose levels. Her temperature was raised for 5 months until a second course of dexamethasone was given. At week 15, multiple tuberculomas and hydrocephalus were detected followed by acute hydrocephalus (week 58), which required a ventricular-peritoneal shunt. Tuberculomas resolved after a second course of dexamethasone but recurred 15 months later. Immunological investigations were normal including integrity of the type 1 cytokine pathway. From month 24, interferon-gamma was given subcutaneously (initially 50 microg/m(2)) and continued for 19 months. Within 2 weeks she responded clinically followed by a reduction in inflammatory signs on magnetic resonance imaging scan (but not in the tuberculomas). At month 44, when chemotherapy was stopped, the cerebrospinal fluid/serum albumin quotient was 57x10(-3) (normal <6.0x10(-3)), which supports continuing major impairment of the blood-brain barrier. Gene expression in peripheral blood mononuclear cells before and during treatment with interferon-gamma, assessed by gene array analysis, showed reduction in a number of cytokine and chemokine genes. The response to interferon-gamma might have been secondary to downregulation of certain cytokine and chemokine genes.


Assuntos
Antituberculosos/uso terapêutico , Interferon gama/uso terapêutico , Tuberculose Meníngea/tratamento farmacológico , Tuberculose Meníngea/fisiopatologia , Anti-Inflamatórios/uso terapêutico , Antituberculosos/administração & dosagem , Líquido Cefalorraquidiano/química , Líquido Cefalorraquidiano/citologia , Quimiocinas/biossíntese , Quimiocinas/genética , Criança , Dexametasona/uso terapêutico , Feminino , Febre , Expressão Gênica , Glucose/líquido cefalorraquidiano , Humanos , Hidrocefalia/cirurgia , Interferon gama/administração & dosagem , Leucócitos Mononucleares/imunologia , Neutropenia , Tuberculoma , Tuberculose Meníngea/complicações
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