A hipogamaglobulinemia é uma alteração da imunidade humoral caracterizada por baixos níveis séricos de anticorpos podendo ter causas primárias e secundárias. Estes pacientes apresentam uma susceptibilidade a infecções bacterianas de repetição ou crônicas, principalmente do trato respiratório. Além disso, há alta prevalência de doenças gastrointestinais infecciosas e inflamatórias, hepatite C, doenças auto-imunes, doenças linfoproliferativas e granulomatosas. Ainda que a doença seja conhecida desde 1954 há poucos trabalhos na literatura sobre manifestações bucais nestes pacientes. Alguns estudos sugerem uma maior prevalência de lesões liquenóides, doença periodontal, candidíase pseudomembranosa, úlcera aftosa recorrente e hipoplasia de esmalte. Desta forma, o objetivo deste trabalho foi avaliar a prevalência das manifestações e alterações bucais, e caracterizar a saúde bucal de pacientes com hipogamaglobulinemias e correlacioná-las com o estado imunológico do paciente, comparativamente a um grupo de pacientes saudáveis. Para tanto avaliamos 100 pacientes com hipogamaglobulinemias atendidos no Ambulatório de Imunologia e Alergia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo e 93 pacientes normorreativos da Clínica Odontológica da Faculdade de Odontologia da Universidade de São Paulo, sendo realizado exame clínico bucal, anamnese e compilação de exames laboratoriais recentes. Do total de pacientes com hipogamaglobulinemias, 59 pacientes apresentaram alguma alteração bucal, sendo as mais frequentes lesões de cárie (21), hipoplasia de esmalte (21), gengivite (18), periodontite (8), boca seca (6), língua geográfica (5) e úlcera aftosa recorrente (2). Vinte e sete pacientes apresentaram queixas de úlcera aftosa recorrente com frequência. Dos 93 pacientes do grupo controle, 84 (90,3%) apresentaram alguma alteração bucal, sendo as mais frequentes lesões de cárie (66), gengivite (31), periodontite (44) e candidíase (3). Dezoito pacientes apresentaram queixas de úlcera aftosa recorrente com freqüência. Concluímos que os pacientes com hipogamaglobulinemias, apesar de apresentarem diminuição das imunoglobulinas do sangue, e alguns pacientes apresentarem uma diminuição de células da imunidade celular, não se encontrou relação positiva entre a incidência de cárie e IgA, doença periodontal e IgA e doença periodontal e CD4. / The hypogammaglobulinemia is an alteration in humoral immunity characterized by low levels of antibodies may have primary and secondary causes. These patients have a susceptibility to recurrent bacterial infections or chronic diseases, mainly respiratory tract. Moreover, there is a high prevalence of infectious and inflammatory gastrointestinal diseases, hepatitis C, autoimmune diseases, lymphoproliferative diseases and granulomatous disease. Although the disease is known since 1954 there are few available studies on oral manifestations in these patients. Some studies suggest a higher prevalence of lichenoid lesions, periodontal disease, pseudomembranous candidiasis, recurrent aphthous ulcer and enamel hypoplasia. Thus, the objective was to assess the prevalence of manifestations diseases and to characterize the oral health of patients with hypogammaglobulinemia and correlate with the immune status, compared with healthy patients. For that evaluated 100 patients with hypogammaglobulinemia in the Outpatient Immunology and Allergy Hospital of the Faculty of Medicine, University of São Paulo and 93 healthy patients of School of Dentistry, University of São Paulo, and was conducted oral clinical examination, medical history and compilation of recent laboratory tests. Of all patients with hypogammaglobulinemia, 59 patients showed abnormalities of the mouth, with 21 patients exhibited caries, 21 enamel hypoplasia, 18 gingivitis, 8 periodontitis, 6 dry mouth, 5 geographic tongue and 2 recurrent aphthous ulcer. Twenty-seven patients complained of frequent recurrent aphthous ulcer. Of the 93 control group patients, 84 (90.3%) showed abnormalities, being the most frequent caries (66), gingivitis (31), periodontitis (44) and candidiasis (3). Eighteen patients complained of recurrent aphthous ulcers frequently. We conclude that patients with hypogammaglobulinemia, despite showing decreased blood immunoglobulins, and some patients had a decrease of cells in cellular immunity, we did not find a positive relationship between the incidence of caries and IgA, IgA and periodontal disease and periodontal disease and CD4.

A hipogamaglobulinemia é uma alteração da imunidade humoral caracterizada por baixos níveis séricos de anticorpos podendo ter causas primárias e secundárias. Estes pacientes apresentam uma susceptibilidade a infecções bacterianas de repetição ou crônicas, principalmente do trato respiratório. Além disso, há alta prevalência de doenças gastrointestinais infecciosas e inflamatórias, hepatite C, doenças auto-imunes, doenças linfoproliferativas e granulomatosas. Ainda que a doença seja conhecida desde 1954 há poucos trabalhos na literatura sobre manifestações bucais nestes pacientes. Alguns estudos sugerem uma maior prevalência de lesões liquenóides, doença periodontal, candidíase pseudomembranosa, úlcera aftosa recorrente e hipoplasia de esmalte. Desta forma, o objetivo deste trabalho foi avaliar a prevalência das manifestações e alterações bucais, e caracterizar a saúde bucal de pacientes com hipogamaglobulinemias e correlacioná-las com o estado imunológico do paciente, comparativamente a um grupo de pacientes saudáveis. Para tanto avaliamos 100 pacientes com hipogamaglobulinemias atendidos no Ambulatório de Imunologia e Alergia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo e 93 pacientes normorreativos da Clínica Odontológica da Faculdade de Odontologia da Universidade de São Paulo, sendo realizado exame clínico bucal, anamnese e compilação de exames laboratoriais recentes. Do total de pacientes com hipogamaglobulinemias, 59 pacientes apresentaram alguma alteração bucal, sendo as mais frequentes lesões de cárie (21), hipoplasia de esmalte (21), gengivite (18), periodontite (8), boca seca (6), língua geográfica (5) e úlcera aftosa recorrente (2). Vinte e sete pacientes apresentaram queixas de úlcera aftosa recorrente com frequência. Dos 93 pacientes do grupo controle, 84 (90,3%) apresentaram alguma alteração bucal, sendo as mais frequentes lesões de cárie (66), gengivite (31), periodontite (44) e candidíase (3). Dezoito pacientes apresentaram queixas de úlcera aftosa recorrente com freqüência. Concluímos que os pacientes com hipogamaglobulinemias, apesar de apresentarem diminuição das imunoglobulinas do sangue, e alguns pacientes apresentarem uma diminuição de células da imunidade celular, não se encontrou relação positiva entre a incidência de cárie e IgA, doença periodontal e IgA e doença periodontal e CD4. / The hypogammaglobulinemia is an alteration in humoral immunity characterized by low levels of antibodies may have primary and secondary causes. These patients have a susceptibility to recurrent bacterial infections or chronic diseases, mainly respiratory tract. Moreover, there is a high prevalence of infectious and inflammatory gastrointestinal diseases, hepatitis C, autoimmune diseases, lymphoproliferative diseases and granulomatous disease. Although the disease is known since 1954 there are few available studies on oral manifestations in these patients. Some studies suggest a higher prevalence of lichenoid lesions, periodontal disease, pseudomembranous candidiasis, recurrent aphthous ulcer and enamel hypoplasia. Thus, the objective was to assess the prevalence of manifestations diseases and to characterize the oral health of patients with hypogammaglobulinemia and correlate with the immune status, compared with healthy patients. For that evaluated 100 patients with hypogammaglobulinemia in the Outpatient Immunology and Allergy Hospital of the Faculty of Medicine, University of São Paulo and 93 healthy patients of School of Dentistry, University of São Paulo, and was conducted oral clinical examination, medical history and compilation of recent laboratory tests. Of all patients with hypogammaglobulinemia, 59 patients showed abnormalities of the mouth, with 21 patients exhibited caries, 21 enamel hypoplasia, 18 gingivitis, 8 periodontitis, 6 dry mouth, 5 geographic tongue and 2 recurrent aphthous ulcer. Twenty-seven patients complained of frequent recurrent aphthous ulcer. Of the 93 control group patients, 84 (90.3%) showed abnormalities, being the most frequent caries (66), gingivitis (31), periodontitis (44) and candidiasis (3). Eighteen patients complained of recurrent aphthous ulcers frequently. We conclude that patients with hypogammaglobulinemia, despite showing decreased blood immunoglobulins, and some patients had a decrease of cells in cellular immunity, we did not find a positive relationship between the incidence of caries and IgA, IgA and periodontal disease and periodontal disease and CD4.

Patients can develop malignancies due to various reasons including genetic factors, chemical carcinogens, radiation, and defects in their immune system. The immune system is postulated to carry out routine surveillance for malignancy. Patients who have defective immune responses may be susceptible to malignancies due to complicated underlying mechanisms. These include defective immune response to cancer-causing bacteria, transforming viruses, and concomitant molecular, cellular and immunoregulatory defects. Common variable immune deficiency (CVID) is characterized by hypogammaglobulinemia, impaired antibody responses and an increased susceptibility to infections. A disorderly immune response, or immune dysregulation, may also lead to autoimmune complications and possibly to malignancy. The treatment of CVID involves infusion of replacement doses of immunoglobulin, either intravenously (IGIV) or subcutaneously (SCIG). However, it is unclear whether adequate replacement of immunoglobulins is sufficient to prevent the increased risk of malignancy seen in this disease. We present two cases of unusual solid tumors complicating CVID treated with adequate doses of intravenous immunoglobulins. In this study we review the occurrence of malignancy in patients with CVID and postulate mechanisms that may be involved indigent to this disease. We will also review the role of replacement immunoglobulin and discuss cancer screening in these high risk individuals.

As imunodeficiências primárias são um grupo heterogêneo de doenças hereditárias do sistema. Aqui nós descrevemos 4 famílias (2 Turcas e 2 Brasileiras), que apresentaram infecções recorrentes desde os primeiros dias de vida. Após uma análise clínica bem detalhada, combinamos as técnicas de sequenciamento de alta geração para identificar novos defeitos genéticos que levam ao fenótipo de IDP. Finalizamos com a identificação e caracterização de três IDP, sendo que duas inéditas. A primeira identificada (P1) foi causada por uma mutação bialélica no sítio de splice do gene PRKCD (c.1352+1G>A). A segunda (P2 e P3) foi causada por uma mutação bialélica no gene que codifica NIK (c. C1694G; p. Pro565Arg). A terceira (P4) foi causada uma mutação no gene IL7Rα (c.G353A). Finalizamos a análise da P5, mas nenhum dos genes candidatos foi confirmado. A análise genética e a identificação do defeito genético, permite que nossos pacientes possam ter uma melhor sobrevida, podendo realizar um tratamento correto e permite o aconselhamento genético na família. / Primary immunodeficiencies are a heterogeneous group of inherited diseases of the immune system. Here we describe 5 patients from 4 families (2 Turks and 2 Brazilian), all patients had recurrent infections since the firsts days of life. After a very detailed clinical analysis, we applied the Next Generation Sequencing to identify new genes that could be lead to PID phenotype. We finished with the identification and characterization of 3 PID, where 2 of them was new. The first identified (P1) was a biallelic mutation in the splice site of the gene PRKCD (c.1352 + 1G>A). The second (P2 and P3) was a biallelic mutation in the gene encoding NIK (MAP3K14; c.C1694G;. p.Pro565Arg). The third (P4) has a mutation in the gene IL7Rα (c.G353A). We finished the analysis of P5, but no candidate gene was confirmed to be the defect cause. Genetic analysis and identification of the genetic defect allows our patients may have a better survival and can perform a proper treatment and genetic counseling allows the family.

As imunodeficiências primárias são um grupo heterogêneo de doenças hereditárias do sistema. Aqui nós descrevemos 4 famílias (2 Turcas e 2 Brasileiras), que apresentaram infecções recorrentes desde os primeiros dias de vida. Após uma análise clínica bem detalhada, combinamos as técnicas de sequenciamento de alta geração para identificar novos defeitos genéticos que levam ao fenótipo de IDP. Finalizamos com a identificação e caracterização de três IDP, sendo que duas inéditas. A primeira identificada (P1) foi causada por uma mutação bialélica no sítio de splice do gene PRKCD (c.1352+1G>A). A segunda (P2 e P3) foi causada por uma mutação bialélica no gene que codifica NIK (c. C1694G; p. Pro565Arg). A terceira (P4) foi causada uma mutação no gene IL7Rα (c.G353A). Finalizamos a análise da P5, mas nenhum dos genes candidatos foi confirmado. A análise genética e a identificação do defeito genético, permite que nossos pacientes possam ter uma melhor sobrevida, podendo realizar um tratamento correto e permite o aconselhamento genético na família. / Primary immunodeficiencies are a heterogeneous group of inherited diseases of the immune system. Here we describe 5 patients from 4 families (2 Turks and 2 Brazilian), all patients had recurrent infections since the firsts days of life. After a very detailed clinical analysis, we applied the Next Generation Sequencing to identify new genes that could be lead to PID phenotype. We finished with the identification and characterization of 3 PID, where 2 of them was new. The first identified (P1) was a biallelic mutation in the splice site of the gene PRKCD (c.1352 + 1G>A). The second (P2 and P3) was a biallelic mutation in the gene encoding NIK (MAP3K14; c.C1694G;. p.Pro565Arg). The third (P4) has a mutation in the gene IL7Rα (c.G353A). We finished the analysis of P5, but no candidate gene was confirmed to be the defect cause. Genetic analysis and identification of the genetic defect allows our patients may have a better survival and can perform a proper treatment and genetic counseling allows the family.

The overall aim of this thesis is to improve knowledge about the prevention of infectious and bleeding complications in patients with hematological malignancies, primarily in those with chronic lymphocytic leukemia (CLL) and myelodysplatic syndrome (MDS). Hypogammaglobulinemia, impaired production of immunoglobulins (Ig), is an established risk factor for infection, but the impact of IgG pure subclass deficiency (IgG subclass deficiency with adequate production of IgG, IgA, and IgM) has been debated. In a retrospective single institution study, we concluded that pure IgG subclass deficiency in CLL patients is rare and is not associated with an increased risk of infection. Hence, routine analysis of IgG subclasses in patients with CLL is not warranted. There is no consensus on recommending vaccination against Streptococcus pneumoniae to CLL patients mainly because comparative studies are lacking. In our randomized trial, the efficacy of a conjugated pneumococcal vaccine on immune response was superior or equal to a polysaccharide vaccine for all pneumococcal serotypes common for the two vaccines. A conjugate pneumococcal vaccine should therefore be included in vaccination programs for patients with CLL. Bronchoalveolar lavage (BAL) is a well-established invasive method to identify the cause of pulmonary infiltrates in immunocompromised patients. In a retrospective trial, we have studied the diagnostic yield of BAL in patients with hematological malignancies. We concluded that BAL is highly useful in either verifying or excluding some of the important respiratory tract infections affecting these patients, particularly invasive pulmonary aspergillosis (IPA) and Pneumocystis jirovecii pneumonia (PJP). However, standardized procedures for BAL sampling should be continually revised to avoid unnecessary microbiological tests. Thrombocytopenia, an adverse prognostic factor in patients with MDS, can be aggravated by azacitidine, first-line treatment for high-risk MDS. Eltrombopag, a thrombopoietin-receptor agonist (TPO-R), alleviates thrombocytopenia in patients with immune thrombocytopenic purpura (ITP). In a phase I clinical trial, we concluded that the combination of eltrombopag and azacitidine in high-risk MDS patients with thrombocytopenia is feasible and well tolerated in doses up to 200 mg eltrombopag daily.