Maria de Lourdes Bastos

Influence of HTLV-1 on the clinical, microbiologic and immunologic presentation of tuberculosis

BackgroundHTLV-1 is associated with increased susceptibility to Mycobacterium tuberculosis infection and severity of tuberculosis. Although previous studies have shown that HTLV-1 infected individuals have a low frequency of positive tuberculin skin test (TST) and decreasing in lymphoproliferative responses compared to HTLV-1 uninfected persons, these studies were not performed in individuals with history of tuberculosis or evidence of M. tuberculosis infection. Therefore the reasons why HTLV-1 infection increases susceptibility to infection and severity of tuberculosis are not understood.The aim of this study was to evaluate how HTLV-1 may influence the clinical, bacteriologic and immunologic presentation of tuberculosis.MethodsThe study prospectively enrolled and followed 13 new cases of tuberculosis associated with HTLV-1 (cases) and 25 patients with tuberculosis without HTLV-1 infection (controls). Clinical findings, bacterial load in the sputum, x-rays, immunological response and death were compared in the two groups.ResultsThere were no differences in the demographic, clinical and TST response between the two study groups. IFN-γ and TNF-α production was higher in unstimulated cultures of mononuclear cells of case than in control patients (p < 0.01). While there was no difference in IFN-γ production in PPD stimulated cultures, TNF-α levels were lower in cases than in controls (p = 0.01). There was no difference in the bacterial load among the groups but sputum smear microscopy results became negative faster in cases than in controls. Death only occurred in two co-infected patients.ConclusionWhile the increased susceptibility for tuberculosis infection in HTLV-1 infected subjects may be related to impairment in TNF-α production, the severity of tuberculosis in co-infected patients may be due to the enhancement of the Th1 inflammatory response, rather than in their decreased ability to control bacterial growth.

Perfil inflamatório e imunológico em pacientes com DPOC: relação com a reversibilidade do VEF 1

Objetivo: Determinar se a gravidade da DPOC se correlaciona com a contagem de celulas no escarro, atopia e asma. Metodos: Estudo transversal com 37 pacientes com DPOC e 22 individuos saudaveis com funcao pulmonar normal (controles). As contagens de celulas no escarro foram determinadas por microscopia apos a centrifugacao das amostras. Foram realizados testes cutâneos de puntura, e as citocinas sericas foram determinadas por ELISA. Resultados: Os pacientes foram estratificados pela resposta ao broncodilatador: o grupo de limitacao ao fluxo aereo nao reversivel (LFAnr) envolveu 24 pacientes sem alteracao significativa do VEF1 pos-broncodilatador, e o grupo de limitacao ao fluxo aereo parcialmente reversivel (LFApr) envolveu 13 pacientes com reversibilidade do VEF1 (aumento do VEF1 pos-broncodilatador ≥ 12%). A proporcao de eosinofilos no escarro foi maior no grupo LFApr do que no LFAnr (p < 0,01), e houve uma correlacao inversa entre a proporcao de eosinofilos e VEF1 (p < 0,05). Entretanto, nenhum dos pacientes apresentou historico de asma e os resultados dos testes cutâneos nao diferiram entre os dois grupos. Nas amostras de escarro dos pacientes, os neutrofilos predominaram. Os niveis sericos de TNF, IL-6, IL-8 e RANTES (CCL5) foram maiores nos pacientes que nos controles (p < 0,001), mas nao diferiram entre os dois grupos de pacientes. Conclusoes: Pacientes com DPOC e reversibilidade parcial do VEF1 parecem apresentar maiores contagens de eosinofilos no escarro e maior hiper-responsividade das vias aereas que aqueles sem reversibilidade do VEF1. Entretanto, a gravidade da DPOC nao se correlacionou com atopia ou perfil das citocinas.

Inflammatory and immunological profiles in patients with COPD: relationship with FEV 1 reversibility

ABSTRACT Objective: To determine whether COPD severity correlates with sputum cell counts, atopy, and asthma. Methods: This was a cross-sectional study involving 37 patients with COPD and 22 healthy subjects with normal lung function (controls). Sputum cell counts were determined by microscopy after centrifugation of samples. Skin prick tests were performed, and serum cytokines were determined by ELISA. Results: Patients were stratified by bronchodilator response: a non-reversible airflow limitation (nonRAL) group comprised 24 patients showing no significant post-bronchodilator change in FEV1; and a partially reversible airflow limitation (partialRAL) group comprised 13 patients showing FEV1 reversibility (post-bronchodilator FEV1 increase ≥ 12%). The proportion of eosinophils in sputum was higher in the partialRAL group than in the nonRAL group (p < 0.01), and there was an inverse correlation between the proportion of eosinophils and FEV1 (p < 0.05). However, none of the patients had a history of asthma and skin prick test results did not differ between the two groups. In the patient sputum samples, neutrophils predominated. Serum levels of TNF, IL-6, IL-8, and RANTES (CCL5) were higher in patients than in controls (p < 0.001) but did not differ between the two patient groups. Conclusions: COPD patients with partial FEV1 reversibility appear to have higher sputum eosinophil counts and greater airway hyperresponsiveness than do those with no FEV1 reversibility. However, we found that COPD severity did not correlate with atopy or with the cytokine profile.

Lung function in the absence of respiratory symptoms in overweight children and adolescents

OBJECTIVE: To describe lung function findings in overweight children and adolescents without respiratory disease. METHODS: This was a cross-sectional study involving male and female overweight children and adolescents in the 8-18 year age bracket, without respiratory disease. All of the participants underwent anthropometric assessment, chest X-ray, pulse oximetry, spirometry, and lung volume measurements. Individuals with respiratory disease were excluded, as were those who were smokers, those with abnormal chest X-rays, and those with an SpO2 = 92%. Waist circumference was measured in centimeters. The body mass index-for-age Z score for boys and girls was used in order to classify the individuals as overweight, obese, or severely obese. Lung function variables were expressed in percentage of the predicted value and were correlated with the anthropometric indices. RESULTS: We included 59 individuals (30 males and 29 females). The mean age was 11.7 ± 2.7 years. Lung function was normal in 21 individuals (35.6%). Of the 38 remaining individuals, 19 (32.2%), 15 (25.4%), and 4 (6.7%) presented with obstructive, restrictive, and mixed ventilatory disorder, respectively. The bronchodilator response was positive in 15 individuals (25.4%), and TLC measurements revealed that all of the individuals with reduced VC had restrictive ventilatory disorder. There were significant negative correlations between the anthropometric indices and the Tiffeneau index in the individuals with mixed ventilatory disorder. CONCLUSIONS: Lung function was abnormal in approximately 65% of the individuals evaluated here, all of whom were overweight. Obstructive ventilatory disorder and positive bronchodilator response predominated.

Impaired TNF, IL-1β, and IL-17 production and increased susceptibility to Mycobacterium tuberculosis infection in HTLV-1 infected individuals

IFN-γ and TNF play critical roles in the control of Mycobacterium tuberculosis infection. Despite leading to an exaggerated production of inflammatory cytokines, HTLV-1 infection increases the risk of developing tuberculosis (TB). However, the immune mechanisms accounting for this phenomenon are still unclear. The aim of this study was to evaluate immunological aspects of the HTLV-1/M. tuberculosis co-infection. In this cross-sectional study, the levels of TNF, IL-1β, and IL-17 were determined by ELISA in the supernatants of either unstimulated or tuberculin purified protein derivative (PPD) stimulated peripheral blood mononuclear cells. Cells from HTLV-1 infected individuals produced lower levels of TNF following PPD stimulation compared to unstimulated cells. IL-1β and IL-17 production by cells from HTLV-1/M. tuberculosis co-infected individuals was lower than in cells from patients with TB. Impairment in TNF, IL-1β, and IL-17 production upon stimulation with mycobacterial antigens may contribute to the increased susceptibility to M. tuberculosis infection observed in HTLV-1 infected individuals.

HTLV-1 infection interferes with immune responses to Mycobacterium tuberculosis antigens

Tuberculosis (TB) is still a major health problem. IFN-γ and TNF are critical cytokines in the control of Mycobacterium tuberculosis (Mtb) infection. It has already been demonstrated that human T cell lymphotropic virus type 1 (HTLV-1) infection leads to a spontaneous IFN- γ and TNF production, however HTLV-1 infected subjects possess a 2-4 fold increased risk of developing tuberculosis. Nevertheless, the immune mechanisms involved in this phenomenon are still unclear. The aim of this study was to evaluate immunological features of the association between HTLV-1/Mtb in order to better understand the events leading to higher susceptibility to TB observed in HTLV-1 infected subjects. This was a cross-sectional study evaluating four groups: healthy control (HC group), HTLV-1 infected subjects without TB (HTLV-1 group) or with TB (HTLV-1 + TB group), and individuals with only TB (TB group). TNF, IL-1β, and IL-17 levels were measured in supernatants of non-stimulated or PPD stimulated peripheral blood mononuclear cells (PBMCs) by ELISA. PBMCs from HTLV-1 infected individuals had a decrease (p<0.05) in TNF production following PPD stimulation (median 114.5 pg/ml, IQ range 47-189 pg/ml) compared to non-stimulated cells (202 pg/ml, IQ range 100-250 pg/ml). When we normalized the data to non-stimulated cells, IL-1β production following PPD stimulation by individuals in the HTLV-1 + TB group (3 pg/ml, IQ range 0-43 pg/ml) was lower (p<0.05) than in patients with TB (87 pg/ml, IQ range 14-151 pg/ml). Similarly, HTLV-1/Mtb co-infected individuals had lower (p<0.05) production of IL-17 (9 pg/ml, IQ range 0-41 pg/ml) when compared to TB patients (43 pg/ml, IQ range 13-150 pg/ml). Impairment in TNF, IL-1β, and IL-17 production upon stimulation with mycobacterial antigens may contribute to the higher susceptibility to Mtb infection observed in HTLV-1 infected subjects. Financial support: CNPq, CAPES.

Prevalence and influence of tuberculosis in the neurologic manifestations of the Human T cell lymphotropic virus type 1 (HTLV-1)

HTLV-1 infects mainly T cells, leading to activation and cellular proliferation with exaggerated production of pro-inflammatory cytokines. The majority of HTLV-1 infected patients are considered as HTLV-1 carriers, but 5% will develop HTLV-1 associated myelopathy (HAM) and about 15% overactive bladder, an oligosymptomatic form of HAM. HTLV-1 is associated with increased susceptibility to Mycobacterium tuberculosis infection but up to now it is unknown if HTLV-1 influences the severity of tuberculosis and if tuberculosis may influence the outcome of HTLV-1. The aims of this study were to determine the prevalence and severity of tuberculosis (TB) in HTLV-1 infected patients and analyze whether TB influences the outcome of HTLV-1 infection. This is a cross-sectional study, in which the prevalence of tuberculosis was analyzed in 166 HTLV-1 infected individuals. Cytokine productions were determined by ELISA, the proviral load was evaluated by PCR. Tuberculosis occurred in 33 (22%) of cases and 70 (42%) had a positive tuberculin skin test (TST) (latent tuberculosis). The majority of the cases did not have severe tuberculosis. There was no difference in the proviral load, but there was a higher frequency of HAM/TSP in the group with tuberculosis than in HTLV-1 infected subjects without TB (P<0.05). This study shows that the prevalence of M.tuberculosis infection is 6 fold higher in HTLV-1 infected individuals than that described in the Brazilian population the majority of co-infected had latent tuberculosis and HTLV-1 may influence progression from infection to HAM/TSP.

Consequences of the association between HTLV-1 and tuberculosis

HTLV-1 modifies the immune response and clinical presentation of bacterial, fungal and helminthic infections. There are also evidences that helminthic infections may modify disease expression related to HTLV-1, increasing the occurrence of Adult T cell leukemia (ATL) and decreasing the development of HTLV-1 associated myelopathy or tropical spastic paraparesis (HAM/TSP). Recently it has been shown that HTLV-1 increases susceptibility for tuberculosis (TB) but the consequences of this co-infection in the clinical course of TB and HTLV-1 infection is not so clear. The aim of this study was to evaluate if TB influences neurologic disease in HTLV-1 infected subjects and to evaluate sequels of TB in HTLV-1 infected individuals. This is a nested case control study with the participation of 32 patients with previous diagnosis of TB and positivity sorology for HTLV-1 and 32 controls with HTLV-1 without TB paired by age, gender and time of admission in the clinic. Of the 32 patients with TB 29 had pulmonary TB, one had pleural TB, one laryngeal TB and the other lymphonode TB. Only 2 (6,2%) developed a second episode of TB. Among those who have been treated for TB 8 (25%) patients complained of dyspnea, 3 without evidence of pulmonary disease, 3 cases had chronic obstructive pulmonary disease (COPD) and two cases had bronchial overactivity. Regarding HTLV-1 associated disease probable HAM/TSP was diagnosed in 4 (12,5%) of the TB patients and in 6 (18,7%) of the patients who only have HTLV-1 infection (P > 0.05). Definitive HAM/TSP was diagnosed in 10 (31,2%) of the co-infected patients with HTLV-1 and TB and in 4 (12,5%) in the group who only had HTLV-1 (P < 0.05). While HTLV-1 appears to not influence the severity of Micobacterium tuberculosis infection TB was highly associated with HAM/TSP.

Influence of HTLV-1 in the clinic, microbiologic and immunologic features of tuberculosis.

Background HTLV-1 infection increases susceptibility and severity of tuberculosis. Despite the documentation of a decreased in vitro and in vivo T cells response to mycobacterial antigens, the reasons of the HTLV-1 infection increase the susceptibility and make worse the clinic course of tuberculosis are not understood. For instance, it is not known if HTLV-1 infection increases bacillary load and if severity of tuberculosis is due to the inability of these patients to control bacterial growth. The aim of the present study was to evaluate how HTLV-1 might influence the clinic, bacteriologic and immunologic features of tuberculosis.