7例影像学表现为弥漫肺间质性病变的肺结核报道及文献复习

目的:通过对7例高分辨CT(High Resolution Computed Tomography,HRCT)表现为弥漫肺间质性病变的肺结核患者的相关资料进行分析,结合相关文献,提高对该类肺结核的认识。方法:分析本院2012.2~2015.3确诊的7例HRCT表现为弥漫肺间质性病变的肺结核的临床症状、体征、影像学资料及痰抗酸杆菌、结核菌素纯蛋白衍生物(Purified Protein Derivative,PPD)试验、T细胞斑点试验(T-SPOT.TB)、抗结核抗体、血常规、血沉(Erythrocyte Sedimentation Rate,ESR)等实验室检查、病理检查等资料。结果:6例经2次以上痰涂片阳性确诊为肺结核,1例抗结核治疗有效诊断为肺结核;弥漫肺间质性病变的肺结核患者HRCT上间质性病变的范围与抗酸杆菌的检出及发热症状的出现有关联;与盗汗、乏力、咯血等结核中毒症状及PPD、结核抗体、ESR等指标无明显相关关系。结论:弥漫肺间质性病变也可为肺结核的一种特殊表现,极易误诊为其他间质病变。当患者临床表现及实验室检查无特殊发现时,需考虑肺结核的可能并进行结核病相关检查,尤其是抗酸杆菌及肺组织病理检查,以尽早明确诊断。     

Paleopathological and biomolecular study of tuberculosis in a medieval skeletal collection from England

Nine human skeletons of medieval date from a rural English burial site show signs of skeletal tuberculosis. They were subject to polymerase chain reaction (PCR) assays aimed at detecting traces of DNA from infecting mycobacteria, with the purpose both of confirming the paleopathological diagnosis of tuberculosis and determining in individual cases whether disease was due to M. tuberculosis or M. bovis. In all nine cases, evidence for M. tuberculosis complex DNA was found, and in all instances it appeared that disease was due to M. tuberculosis rather than M. bovis. The significance of the findings for understanding tuberculous infection in rural agrarian communities in medieval England is discussed.     

Molecular evidence for different stages of tuberculosis in ancient bone samples from Hungary

This paleomicrobiologic study was conducted on osseous tissue specimens from ancient Hungarian skeletal samples from the 7-8th and the 17th centuries AD with typical macromorphologic evidence of osseous tuberculosis (n = 3), morphologic alterations probably due to tuberculosis (n = 6), or with nontypical osseous changes of vertebral bodies suggestive of inflammatory reaction (n = 5). From these bone samples, DNA was extracted and amplified by polymerase chain reaction (PCR) by using various primer pairs recognizing DNA segments of different mycobacterial species. To confirm specificity of the analysis, the amplification products of several samples were subjected to restriction enzyme digestion and/or direct sequencing. Of the analyzed 14 cases, 8 were unambiguously positive for mycobacterial DNA of the Mycobacterium tuberculosis complex, as shown by the amplification of the IS6110 sequence. In 13 cases we found a PCR product with primers specific for the 65-kDa antigen gene, including 2 cases without genomic DNA. We conclude that the application of other mycobacterial DNA primers may reveal contamination of bones with atypical saprophytic mycobacteria. A positive result for typical mycobacteria was seen in 2 of 3 cases with typical morphologic signs of tuberculosis and amplifiable DNA, in 3 of 6 probable cases, but also in 3 of 6 cases with nontypical bone changes. This indicates that minor osseous reactions of the surface of vertebral bodies may be due-at least in several cases-to infections with bacteria of the M. tuberculosis complex. In these cases the disease may have proceeded rapidly, and the morphologic osseous changes may represent "early" stages of tuberculous infection of the vertebrae.     

Sources of infection in childhood tuberculosis in a region of east Croatia

Possible sources of tuberculosis (TBC) infection in children have been assessed in a retrospective epidemiological study covering a north-east region of Croatia in which the incidence of childhood tuberculosis has been increasing since the war in 1991-1995. During the past decade (1993-2003), 271 children up to 18 years of age have been referred for hospital care because of known contacts with tuberculosis (142 children, group A) or because of indicative clinical signs and symptoms (129 children, group B). Possible sources of infection were identified on the basis of medical documentation and field investigations. Frequencies of source identification for different age groups were compared. In group A, the exposure took place most often within the family (parents, grandparents, siblings, 129 of 142 children, 90.87%). Relatives, neighbors, friends and schoolmates accounted for 9.2%. In group B, possible sources of infection were identified for 44 of 129 children (34.1%) and were within the family for 16 of those 44 (36.4%). Evidenced contact with tuberculosis was more usual among younger children (0-9 years of age, 65.5%) in group A than among the older ones (10-18 years of age, 34.5%). In group B, contacts with tuberculosis were equally distributed (50.0%) among younger and older children. High proportion of unrecognized contacts in children having clinical signs and symptoms indicative of tuberculosis (group B, 85 of 129, 65.9%) opens the possibility that extra-familial exposure to tuberculosis occurs more often than expected regardless of the age of children.     

Isoniazid Chemoprophylaxis of Tuberculosis

A major step toward the eradication of tuberculosis in the United States has been the use of isoniazid for chemoprophylaxis in certain persons who have positive tuberculin skin tests but no other evidence of active infection. Chemical trials have demonstrated the effectiveness of chemoprophylaxis in groups where there is a relatively high risk of active tuberculosis. However, only the practicing physician can identify and offer chemoprophylaxis to many other susceptible persons. Even if the patient is a candidate for isoniazid, the risk of developing tuberculosis must be weighed against the cost and possible adverse effects of the drug. If isoniazid is given, the physician must be alert to the signs of possible drug toxicity. If isoniazid is not given, he must anticipate the development of active tuberculosis in susceptible persons.     

Shifts in the heart left ventricle function in patients with pulmonary tuberculosis during adequate chemotherapy

To investigate the hemodynamics and myocardic contraction of the heart left ventricle, 61 patients with pulmonary tuberculosis (main group) and 26 healthy subjects (control group) were observed. Higher ultimate systolic and diasystolic volumes of the left ventricle and lower levels of the efflux fraction in the patients with active pulmonary tuberculosis were stated. There was shown inverse correlation of the systemic systolic arterial pressure and the left ventricle efflux fraction with ESR, evident of the tuberculosis intoxication. The most pronounced aggravation of the left ventricle function was recorded in the patients with the most severe tuberculosis process. The impairments in the left ventricle in the patients with active pulmonary tuberculosis were of functional nature. Due to intensive therapy of the tuberculosis, the indices of the left ventricle efflux function improved and the systemic arterial pressure came to normal, along with elimination of the tuberculosis intoxication signs.     

Surveillance of Elderly Hospital Patients for Pulmonary Tuberculosis

A restrospective study of pulmonary tuberculosis in a general hospital showed that the diagnosis had been frequently overlooked in the middleaged or elderly because the patient also suffered from a more acute condition which preoccupied the attention of the doctor. The commonest error was to discount chest x-ray abnormalities by omitting sputum culture or serial radiography.Surveillance was carried out on all patients aged 60 or over admitted to a large general hospital whose routine chest radiograph showed signs of possible pulmonary tuberculosis whether apparently active or inactive. Three sputum samples from each patient were examined for Mycobacterium tuberculosis without reference to the clinical presentation. In a nine-month period six out of 81 patients proved to have active pulmonary tuberculosis (7·4%). It is suggested that this may be a useful method of screening the elderly hospital population for pulmonary tuberculosis.     

Disseminated pulmonary tuberculosis: significance of high-resolution computerized tomography]

Clinical and X-Ray studies were performed in 85 patients with disseminated pulmonary tuberculosis. All the patients underwent routine computerized tomography (CT) and high-resolution CT. According to the pathogenetic process, the authors identified hematogenic (n = 38), lymphogenic (n = 19), bronchogenic (n = 18) and mixed (n = 10) disseminations. High-resolution CT was found to have great advantages in detecting various types of tuberculous disseminations and in assessing the pattern of pulmonary abnormalities. Disseminated tuberculosis was revealed in 7 patients who had no pathological changes on routine lung X-ray films. The specific signs of hematogenic, lymphogenic disseminations and bronchgenic inoculations were identified in other forms of pulmonary tuberculosis. CT symptomatology is shown to be determined by the pathogenetic variant of its development and the stage of the process. Small focal changes in the lung were prevalent in patients with acute and subacute hematogenic forms of the disease. Infiltrates with decay cavities, thin-wall caverns, emphysema and bronchoectases were detected over the chronic course. Lymphogenic disseminations were characterized by the predominance of interstitial changes along with multiple minor foci. High-resolution CT had advantages in identifying decay cavities, signs of fibrosis and in evaluating mediastinal lymph nodes. CT data are of great significance for differential diagnosis of disseminated tuberculosis with lung metastases and diffuse interstitial diseases.     

Outbreak of tuberculosis after minimal exposure to infection.

The identification of a case of respiratory tuberculosis in a swimming-baths attendant whose sputum was smear positive was followed by intensive contact tracing of children aged 8-11 years who had visited the baths. An outbreak was discovered that otherwise might not have been detected. Out of 3764 children, 108 (2.9%) had evidence of infection: there were 16 cases of tuberculosis, of which 11 were symptomless but showed lesions on chest radiography, and a further 92 with tine test grade 3 or 4 without clinical or radiological signs. The contact of these children with the index case was apparently minimal. Early detection, isolation, and treatment of infectious cases of respiratory tuberculosis and vigorous contact tracing should be given more priority in tuberculosis control.     

Characteristics of the x-ray picture of pulmonary tuberculosis in alcoholics

Tuberculosis prevalence among alcoholics is high, and pathomorphological and clinical manifestations of the disease are marked. Altogether 84 chronic alcoholics with pulmonary tuberculosis (the 1st group) and 100 tuberculosis non-alcoholic patients (100 controls--the 2nd group) were investigated. X-ray signs of the disease progression, more prevalent changes and more frequent multiple disintegration cavity of larger size are noted in the 1st group. During x-ray investigation of such patients emphasis must be laid on a search for disintegration cavities and bronchogenic dissemination.     

Clinical and Radiographic Factors Do Not Accurately Diagnose Smear-Negative Tuberculosis in HIV-infected Inpatients in Uganda: A Cross-Sectional Study

Background

Although World Health Organization guidelines recommend clinical judgment and chest radiography for diagnosing tuberculosis in HIV-infected adults with unexplained cough and negative sputum smears for acid-fast bacilli, the diagnostic performance of this approach is unknown. Therefore, we sought to assess the accuracy of symptoms, physical signs, and radiographic findings for diagnosing tuberculosis in this population in a low-income country with a high incidence of tuberculosis.

Methodology

We performed a cross-sectional study enrolling consecutive HIV-infected inpatients with unexplained cough and negative sputum smears for acid-fast bacilli at Mulago Hospital in Kampala, Uganda. Trained medical officers prospectively collected data on standard symptoms and signs of systemic respiratory illness, and two radiologists interpreted chest radiographs in a standardized fashion. We calculated positive- and negative-likelihood ratios of these factors for diagnosing pulmonary tuberculosis (defined when mycobacterial cultures of sputum or bronchoalveolar lavage fluid were positive). We used both conventional and novel regression techniques to develop multivariable prediction models for pulmonary tuberculosis.

Principal Findings

Among 202 enrolled HIV-infected adults with negative sputum smears for acid-fast bacilli, 72 (36%) had culture-positive pulmonary tuberculosis. No single factor, including respiratory symptoms, physical findings, CD4+ T-cell count, or chest radiographic abnormalities, substantially increased or decreased the likelihood of pulmonary tuberculosis. After exhaustive testing, we were also unable to identify any combination of factors which reliably predicted bacteriologically confirmed tuberculosis.

Conclusions and Significance

Clinical and radiographic criteria did not help diagnose smear-negative pulmonary tuberculosis among HIV-infected patients with unexplained cough in a low-income setting. Enhanced diagnostic methods for smear-negative tuberculosis are urgently needed.     

Co-infection of Mycobacterium tuberculosis and Mycobacterium leprae in human archaeological samples: a possible explanation for the historical decline of leprosy

Both leprosy and tuberculosis were prevalent in Europe during the first millennium but thereafter leprosy declined. It is not known why this occurred, but one suggestion is that cross-immunity protected tuberculosis patients from leprosy. To investigate any relationship between the two diseases, selected archaeological samples, dating from the Roman period to the thirteenth century, were examined for both Mycobacterium leprae and Mycobacterium tuberculosis DNA, using PCR. The work was carried out and verified in geographically separate and independent laboratories. Several specimens with palaeopathological signs of leprosy were found to contain DNA from both pathogens, indicating that these diseases coexisted in the past. We suggest that the immunological changes found in multi-bacillary leprosy, in association with the socio-economic impact on those suffering from the disease, led to increased mortality from tuberculosis and therefore to the historical decline in leprosy.     

Anaerobic nitrate reductase (narGHJI) activity of Mycobacterium bovis BCG in vitro and its contribution to virulence in immunodeficient mice

Mycobacterium tuberculosis and Mycobacterium bovis cause tuberculosis, which is responsible for the deaths of more people each year than any other bacterial infectious disease. Disseminated disease with Mycobacterium bovis BCG, the only currently available vaccine against tuberculosis, occurs in immunocompetent and immunodeficient individuals. Although mycobacteria are obligate aerobes, they are thought to face an anaerobic environment during infection, notably inside abscesses and granulomas. The purpose of this study was to define a metabolic pathway that could allow mycobacteria to exist under these conditions. Recently, the complete genome of M. tuberculosis has been sequenced, and genes homologous to an anaerobic nitrate reductase (narGHJI), an enzyme allowing nitrate respiration when oxygen is absent, were found. Here, we show that the narGHJI cluster of M. tuberculosis is functional as it conferred anaerobic nitrate reductase activity to Mycobacterium smegmatis. A narG mutant of M. bovis BCG was generated by targeted gene deletion. The mutant lacked the ability to reduce nitrate under anaerobic conditions. Both mutant and M. bovis BCG wild type grew equally well under aerobic conditions in vitro. Histology of immunodeficient mice (SCID) infected with M. bovis BCG wild type revealed large granulomas teeming with acid-fast bacilli; all mice showed signs of clinical disease after 50 days and succumbed after 80 days. In contrast, mice infected with the mutant had smaller granulomas containing fewer bacteria; these mice showed no signs of clinical disease after more than 200 days. Thus, it seems that nitrate respiration contributes significantly to virulence of M. bovis BCG in immunodeficient SCID mice.     

Glutoxim in the complex treatment of tuberculosis]

Results of Glutoxim investigation are presented. Glutoxim is the the drug of the new class--thiopoietins. It is considered to be immunorehabilitator as it modulates intracellular process of thiols metabolism, initiates cytokins system, activates phagocytosis etc. Results of the glutoxim administration at the 42 patients with tuberculosis using traditional treatment regimes are presented. Results of the randomized study at the patients with severe disseminated drug-sensitive and drug-resistant pulmonary tuberculosis demonstrated high efficacy of the glutoxim and its good tolerability. Glutoxim administration allowed to shorten the period of tuberculosis intoxication signs disappearance, to shorten the period of sputum negativation and shortened the period of pulmonary inflammation reverse process. Glutoxim application was specially favorable at the patients with severe tuberculosis complicated by viral or medicamental hepatitis.     

Characterization of T cell antigens associated with the cell wall protein-peptidoglycan complex of Mycobacterium tuberculosis

Mycobacterium tuberculosis cell walls are likely to contain critical T cell Ag capable of inducing protective immunity against the development of tuberculosis in animal models. Therefore, we characterized cell wall-associated Ag that stimulate T lymphocytes in tuberculosis patients and clinically well tuberculin-positive individuals. A protein-peptidoglycan complex isolated from the M. tuberculosis cell wall had potent immunologic activity, evoking PBMC proliferative responses similar to those induced by sonicated whole M. tuberculosis. In order to characterize the immunoreactive protein determinants associated with the protein-peptidoglycan complex, T cell lines were established to cell wall Ag and used to probe M. tuberculosis proteins separated by SDS-PAGE. These T cell lines proliferated primarily to protein Ag of 10, 19, 23, 28, 30, 40 to 50, and 65 kDa. Cell wall-reactive T cell clones that recognized the 10-, 23-, 28-, and 30-kDa proteins as single bands on SDS-PAGE did so under reducing and nonreducing conditions, suggesting that these are not proteolytic fragments or subunits of larger protein aggregates. We propose that these protein monomers, when post-translationally complexed with peptidoglycan, are the key ingredients of the immunogenic protein-peptidoglycan complex. In order to assess the relationship of the cell wall-associated Ag to those secreted proteins from "early culture filtrates" of actively growing M. tuberculosis recently implicated in eliciting protective immunity, cell wall-reactive T cell clones were tested for their ability to recognize early culture filtrates. Results revealed that at least three proteins shared with the cell wall complex are contained within early culture filtrates. Our data indicate that antigenic determinants associated with the protein-peptidoglycan complex of the M. tuberculosis cell wall may be involved in protective immunity and hence are potential candidates for inclusion in an effective antituberculosis vaccine.     

Safety of Resuming Tumor Necrosis Factor Inhibitors in Ankylosing Spondylitis Patients Concomitant with the Treatment of Active Tuberculosis: A Retrospective Nationwide Registry of the Korean Society of Spondyloarthritis Research

BackgroundsPatients who develop an active tuberculosis infection during tumor necrosis factor (TNF) inhibitor treatment typically discontinue TNF inhibitor and receive standard anti-tuberculosis treatment. However, there is currently insufficient information on patient outcomes following resumption of TNF inhibitor treatment during ongoing anti- tuberculosis treatment. Our study was designed to investigate the safety of resuming TNF inhibitors in ankylosing spondylitis (AS) patients who developed tuberculosis as a complication of the use of TNF inhibitors.MethodsThrough the nationwide registry of the Korean Society of Spondyloarthritis Research, 3929 AS patients who were prescribed TNF inhibitors were recruited between June 2003 and June 2014 at fourteen referral hospitals. Clinical information was analyzed about the patients who experienced tuberculosis after exposure to TNF inhibitors. The clinical features of resumers and non-resumers of TNF inhibitors were compared and the outcomes of tuberculosis were surveyed individually.FindingsFifty-six AS patients were treated for tuberculosis associated with TNF inhibitors. Among them, 23 patients resumed TNF inhibitors, and these patients were found to be exposed to TNF inhibitors for a longer period of time and experienced more frequent disease flare-up after discontinuation of TNF inhibitors compared with those who did not resume. Fifteen patients resumed TNF inhibitors during anti-tuberculosis treatment (early resumers) and 8 after completion of anti-tuberculosis treatment (late resumers). Median time to resuming TNF inhibitor from tuberculosis was 3.3 and 9.0 months in the early and late resumers, respectively. Tuberculosis was treated successfully in all resumers and did not relapse in any of them during follow-up (median 33.8 [IQR; 20.8–66.7] months).ConclusionsInstances of tuberculosis were treated successfully in our AS patients, even when given concomitantly with TNF inhibitors. We suggest that early resumption of TNF inhibitors in AS patients could be safe under effective coverage of tuberculosis.     

Dichotomous role of the macrophage in early Mycobacterium marinum infection of the zebrafish

In tuberculosis, infecting mycobacteria are phagocytosed by macrophages, which then migrate into deeper tissue and recruit additional cells to form the granulomas that eventually contain infection. Mycobacteria are exquisitely adapted macrophage pathogens, and observations in the mouse model of tuberculosis have suggested that mycobacterial growth is not inhibited in macrophages until adaptive immunity is induced. Using the optically transparent and genetically tractable zebrafish embryo-Mycobacterium marinum model of tuberculosis, we have directly examined early infection in the presence and absence of macrophages. The absence of macrophages led rapidly to higher bacterial burdens, suggesting that macrophages control infection early and are not an optimal growth niche. However, we show that macrophages play a critical role in tissue dissemination of mycobacteria. We propose that residence within macrophages represents an evolutionary trade-off for pathogenic mycobacteria that slows their early growth but provides a mechanism for tissue dissemination.     

肺外结核病微生物学诊断方法的研究和应用进展

肺外结核病指由结核分枝杆菌（Mycobacterium tuberculosis, MTB）感染所引起的发生在肺部以外器官和部位的结核病。近年来肺外结核的发病率逐渐升高,未能得到早期有效治疗的肺外结核病患者可能并发畸形、截瘫甚至死亡等严重后果。微生物学检测方法对从病原学角度诊断肺外结核病至关重要。基于此,总结了近年来肺外结核病细菌学检查方法、结核分枝杆菌的抗原检测与分子生物学检测等微生物学诊断方法的概况及应用进展,并对这些检测方法的优缺点及适用范围进行了分析、比较,以期为今后肺外结核病病原学诊断的研究提供相关信息。     

Efficacy of cow's kumiss in the treatment of large intestine dysbacteriosis and its impact on tolerability of antituberculosis agents in patients with respiratory tract tuberculosis]

Dysbacteriosis of the large intestine is one of severe complications of long-term use of antituberculosis agents in the treatment of respiratory tract tuberculosis that results in a significant decrease of tolerability of antituberculosis agents, persistence of tuberculosis intoxication and slower involution of the tuberculosis process in the lungs. When the complex treatment with antituberculosis agents was accompanied by the use of cow's kumiss for correction of the large intestine dysbacteriosis, the intoxication signs disappeared in 12% of the patients in the main group, while in the patients of the control group the level of the intoxication syndrome increased twice. The rate of the tuberculosis lesions regression evident from the lung roentgenograms was 2.7-fold higher in the main group vs. the control (62 and 23% respectively). The indices of the lung functional capacity recovery in the patients of the main group vs. the control were also higher (41 and 33% respectively). Hepatic toxic reactions in the patients not given cow's kumiss for correction of dysbacteriosis were 8 times more frequent vs. the control. The results of the study made it possible to develop recommendations for phthisiologists in the use of cow's kumiss as one of the methods of pathogenetic therapy in complex treatment of patients with respiratory tract tuberculosis in sanatoria.