Microvesicles released from pneumolysin-stimulated lung epithelial cells carry mitochondrial cargo and suppress neutrophil oxidative burst.

Microvesicles (MVs) are cell-derived extracellular vesicles that have emerged as markers and mediators of acute lung injury (ALI). One of the most common pathogens in pneumonia-induced ALI is Streptococcus pneumoniae (Spn), but the role of MVs during Spn lung infection is largely unknown. In the first line of defense against Spn and its major virulence factor, pneumolysin (PLY), are the alveolar epithelial cells (AEC). In this study, we aim to characterize MVs shed from PLY-stimulated AEC and explore their contribution in mediating crosstalk with neutrophils. Using in vitro cell and ex vivo (human lung tissue) models, we demonstrated that Spn in a PLY-dependent manner stimulates AEC to release increased numbers of MVs. Spn infected mice also had higher levels of epithelial-derived MVs in their alveolar compartment compared to control. Furthermore, MVs released from PLY-stimulated AEC contain mitochondrial content and can be taken up by neutrophils. These MVs then suppress the ability of neutrophils to produce reactive oxygen species, a critical host-defense mechanism. Taken together, our results demonstrate that AEC in response to pneumococcal PLY release MVs that carry mitochondrial cargo and suggest that these MVs regulate innate immune responses during lung injury.

Immediate postoperative extubation in bilateral lung transplantation: predictive factors and outcomes.

BACKGROUND: We reviewed our experience with tracheal extubation in the operating room (E-OR) among cystic fibrosis patients requiring bilateral lung transplantation to evaluate safety and determine predictive factors of E-OR. METHODS: The charts of 89 recipients (from May 2007 to June 2013) were analysed. Patients were divided into E-OR and E-ICU (intensive care unit extubation) groups. Data are expressed as numbers (percentages) or medians [25th-75th percentiles]. RESULTS: There were 41 patients in the E-OR group (46%). Donor and recipient characteristics were similar between groups. Intraoperative complications occurred less frequently in the E-OR group, and fluid and transfusion requirements were lower. Postoperative courses were different in the E-OR group, including a lower rate of grade 3 primary graft dysfunction (0 compared with 19 patients, P<0.0001) and shorter ICU (5.0 [3.7-7.2] compared with 11.5 [7.0-15.5] days) and hospital stays (22.0 [18.0-25.5] compared with 33.0 [25.0-56.5] days, respectively; P<0.0001 for both). The 1 yr survival rates were similar: 95% in the E-OR group and 98% in the E-ICU group. A statistical model built on a development cohort of 60 randomly selected patients predicted 95% of E-OR instances in this cohort and 82% of E-OR instances in the validation cohort (28 patients). Predictive factors were complications during single-lung ventilation (second graft implantation), complications during bipulmonary ventilation (end of surgery), and the ratio of arterial partial pressure of oxygen to fractional inspired oxygen (end of surgery). CONCLUSIONS: Our protocol allowed for extubation of 46% of bilateral lung transplant patients without increased postoperative risks.

[Abdominal aorta lesion during surgical treatment of a foraminal disk hernia]. / Plaie de l'aorte abdominale au cours d'une cure de hernie discale.

We report a case of an abdominal aorta lesion on a 54-year-old woman, who underwent surgery for the treatment of a foraminal disk hernia. At the end of the hernia repair, a sudden hypovolaemic collapse occurred. A computed tomography revealed an abdominal aorta disruption and a retroperitoneal haematoma. An endovascular treatment was preferred to a surgical reintervention and an endoluminal stent-graft was inserted; the postoperative course was uneventful. This case report describes an example of vascular complications of disk hernia surgery which are rare but potentially serious. It emphasizes the increasing development of endovascular procedures and their utility in the treatment of acute contained aortic disruption.

[Obstetric analgesia in patients with Klippel-Trenaunay syndrome]. / Analgésie obstétricale chez des patientes atteintes d'un syndrome de Klippel-Trenaunay.

We report three cases of delivery in two parturients with a Klippel-Trenaunay syndrome. These patients have a rare hereditary disorder that results in three main features: haemangiomas, varicose veins, bone and soft tissue hypertrophy. In the absence of angiographic magnetic resonance imaging of the spinal cord and of perispinal tissues, arteriovenous malformations of the central nervous system could not been ruled out. Intravenous sufentanil and pudendal block were used for labour analgesia and vaginal delivery respectively; general anaesthesia was used for uterine revision and for caesarean section.

Transmission dynamics of tuberculosis in a high-incidence country: prospective analysis by PCR DNA fingerprinting.

We have prospectively analyzed the DNA fingerprints of Mycobacterium tuberculosis strains from a random sample of patients with newly diagnosed tuberculosis in Windhoek, Namibia. Strains from 263 smear-positive patients in whom tuberculosis was diagnosed during 1 year were evaluated, and the results were correlated with selected epidemiological and clinical data. A total of 163 different IS6110 fingerprint patterns were observed among the 263 isolates. Isolates from a high percentage of patients (47%) were found in 29 separate clusters, with a cluster defined as isolates with 100% matching patterns. The largest cluster included isolates from 39 patients. One predominant strain of M. tuberculosis caused 15% of cases of smear-positive pulmonary tuberculosis in Windhoek. That strain was also prevalent in the north of the country, suggesting that in contrast to other African countries with isolates with high levels of diversity in their DNA fingerprint patterns, only a restricted number of different strains significantly contribute to the tuberculosis problem in Namibia.

[Development of acute and chronic respiratory diseases during pregnancy]. / Evolution des pathologies respiratoires aiguës et chroniques au cours de la grossesse.

Physiological respiratory and hormonal changes occurring during pregnancy result in increased oxygen consumption related to fetal growth. The increase in the maternal basal metabolism leads to hyperventilation and increased cardiac output. This explains why pathological respiratory or cardiovascular conditions existing prior to pregnancy can rapidly worsen during the course of the pregnancy. However, even if no cardiorespiratory disease exists prior to pregnancy, an inhalation lung disease, pre-eclampsia or sepsis can lead to pulmonary edema due to the increased plasma volume in the pregnant woman. These different pathological situations as well as infectious lung diseases are discussed here. We examine the evolution of respiratory function during the course of labor, delivery and the post-partum period. In addition, pregnancy also has an effect on chronic respiratory disease, particularly asthma.

Childhood tuberculosis in Germany between 1985 and 1994: comparison of three selected patient groups.

SETTING: Clinical and epidemiologic features of childhood tuberculosis in Germany are unknown for recent years. The characteristics of patient groups may show typical differences, depending on the source of data. OBJECTIVE: To identify typical features of childhood tuberculosis in Germany, and to relate the characteristics of patient groups to the purpose of the reporting centres. DESIGN: Comparative, retrospective, descriptive analysis of clinical and notification records by standardized data sheet. Evaluation of cases of active tuberculosis in children recorded between 1985 and 1994 at three study centres. RESULTS: One clinical study centre was a referral centre for sick children with an unclear diagnosis, the second specialized in tuberculosis, and the third was a public health office. Almost two thirds (64%) of the 285 evaluated patients were four years of age and under. Between 73% and 96% of children suffered from pulmonary disease and 17% to 58% were culture positive (range between study centres). Source cases had been found for 23% to 52% of children, and the primary reason for clinical evaluation was a positive tuberculin test for between 12% and 57%. Foreign-born children showed characteristic differences. CONCLUSION: The characteristics of reported childhood tuberculosis differ depending on the reporting centre. A significant number of notified cases were probably wrongly diagnosed.

Childhood tuberculosis: an index measuring the ability to detect cases early.

SETTING: Tuberculosis control programmes are conventionally monitored using data from sputum smear positive adult patients. Good overall results may mask significant and avoidable shortcomings with tuberculosis control in children. OBJECTIVE: To develop a specific surveillance tool for child patients, using the ability to detect cases early as a parameter for the impact of control measures. DESIGN: A simple index of early detection was compiled with values ranging from 0 to 100. Three groups of tuberculous children diagnosed in Germany between 1985 and 1994 (n = 303), and five other groups from the literature, were used to make a preliminary assessment of the validity of the index. RESULTS: The index values of 10, 13 and 24 for the German groups correlate well with other analysed patient data and the different functions of the institutions where the patients were diagnosed. Comparable characteristics could be found when applying the index to published data of other cases, with values of between 12 and 74. CONCLUSION: The proposed index seems suitable for monitoring early detection of child cases. Unexpected trends can be disclosed or effects of changed programme activities assessed. Routine use of the index would help the health services focus their attention on problem areas and specific patient groups with extremely low or falling index values. Conclusions can be drawn regarding the overall impact of the control programme.

Efficacy and safety of rifabutin in the treatment of patients with newly diagnosed pulmonary tuberculosis.

The efficacy and safety of rifabutin (RBT) and rifampicin (RMP) were compared in 298 patients with newly diagnosed pulmonary tuberculosis. In the initial 8-wk phase, all patients received isoniazid 400 mg/d, ethambutol 1200 mg/d, and pyrazinamide 2 g/d and were randomly allocated to receive either RMP 600 mg/d or RBT 300 mg/d. In the 16-wk continuation phase, patients received intermittent treatment (twice weekly) with isoniazid 600 mg/d, ethambutol 2400 mg/d and either RMP 600 mg/d or RBT 300 mg/d. Two hundred twenty-five (RMP = 118; RBT = 107) patients completed the 24-wk treatment period (evaluable patient population). Bacteriologic conversion rates in the RMP and RBT groups were 87.7 versus 92.0% at Week 8, 99.1 versus 99.0% at Week 12, 93.5 versus 93.8% at Week 24, and 89.8 versus 95.3% at the last valid observation. The mean time to first bacteriologic conversion was 14.1 wk in the RMP group and 14.3 wk in the RBT group. None of these differences was significant. Adverse events were reported by four patients (five events) in the RMP group and six patients (six events) in the RBT group. Those events thought to be associated with RMP were increased SGOT and leucopenia and, with RBT, increased SGOT and thrombocytopenia. Two hundred four patients entered the follow-up phase, and, of these, 95 (RMP = 49; RBT = 46) completed the scheduled 24-mo period. The overall rate of relapse was 3.8% (4/106) for the RMP group and 5.1% (5/98) for the RBT group. These differences were not significant. All relapsed patients, except for two who could not be traced, were successfully retreated. We conclude that the efficacy and tolerability of RBT is equivalent to that of RMP in the treatment of newly diagnosed uncomplicated tuberculosis, and that RBT can be effectively administered in a part-daily, part-intermittent dosage schedule.

Prepacked kits for diagnosis and treatment of tuberculosis in former Yugoslavia.

SETTING: After the outbreak of armed conflicts in the republics of former Yugoslavia in 1991, basic health services deteriorated and shortages of essential medical supplies occurred. The World Health Organization (WHO) has taken part in emergency relief operations in the area since July 1992. There was a growing concern that poor living conditions and shortages of supplies could rapidly increase the tuberculosis problem. OBJECTIVE: To provide essential supplies, WHO included support of tuberculosis control in the emergency relief operations for former Yugoslavia. DESIGN: WHO designed a prepacked kit with anti-tuberculosis drugs and material for sputum smear examination for use in combination with policy recommendations and a treatment protocol. RESULTS: The initial distribution of the kits was completed by the end of April 1994. Medium term support from May 1994 onwards has included continued distribution of kits, together with assistance in adjusting tuberculosis control programmes according to the recommended WHO policy package. CONCLUSION: Support of tuberculosis control with essential supplies and strictly focusing on priority measures is proposed as the most adequate strategy, when dealing with a developed country dependent on humanitarian assistance.

Use of BCG in high prevalence areas for HIV.

Recommendations state that, where the risk of tuberculosis is high, BCG should be administered to infants as early in life as possible, even if the mother is known to be HIV-infected. BCG should be withheld from individuals with symptomatic HIV infections. However, continuing reports from sub-Saharan Africa and elsewhere of BCG complications in HIV-infected persons call for a re-assessment of current vaccination policies. For HIV-infected infants any benefit of BCG vaccination may be marginal because the prognosis is very poor. It is however not possible to exclude HIV-infected children from BCG vaccination at birth. HIV-uninfected infants born to HIV-infected mothers are at great risk of tuberculosis infection, which justifies routine vaccination. BCG rarely causes serious complications. Theoretically, persons with asymptomatic HIV infection may be at greater risk of complications from BCG vaccines, but available data are inconclusive in that respect. To vaccinate children with BCG at one year of age does not seem feasible and would increase the risk of tuberculosis especially for uninfected infants of HIV seropositive mothers. Available data seem to indicate that routine vaccination of newborns is indeed safe, even in areas with high prevalence of HIV infection.

Surveillance of resistance to antituberculosis drugs in developing countries.

Resistance to antituberculosis drugs is caused by poor management of tuberculosis control. It gives rise to treatment failure, relapse, further transmission of resistant tuberculosis, and multidrug-resistant tuberculosis. Widespread occurrence of multidrug-resistant tuberculosis would constitute a major threat to tuberculosis control in resource-poor countries. Although the impact of HIV on drug resistance is not yet fully understood, it is likely to exacerbate problems caused by drug resistance. In particular, HIV-related adverse effects of thiacetazone, together with the risks of transmission of HIV by parenteral administration of streptomycin, reduce the armamentarium available to tuberculosis control programmes in high HIV prevalence countries, and could encourage the development of resistance to the remaining drugs. While the prime need is to ensure, by good management and supervision, that resistance does not occur in the first place, surveillance of drug resistance is essential to determine the current scale and nature of the drug resistance problem, as well as to define the correct solutions.

PIP: Poor management of tuberculosis (TB) control is responsible for resistance to antituberculosis drugs. It leads to treatment failure, relapse, transmission of resistant TB, and multi-drug resistant TB. In developing countries, where resources are already limited, an epidemic of multi-drug resistant TB would jeopardize TB control. The effect of HIV infection is likely to worsen drug resistance-related problems. Specifically, streptomycin injections pose a risk of HIV transmission. It appears that withdrawal of thiacetazone from HIV infected TB patients causes resistance to more powerful drugs. If these 2 antibiotics cannot be used to treat TB patients, the armamentarium available to control TB in high HIV prevalence countries is reduced, which could foster resistance to the fewer remaining antibiotics. Good management and supervision is needed to prevent resistance to antituberculosis drugs. Surveillance of drug resistance is also needed to monitor the current level and characteristics of the drug resistance problem and to identify effective solutions. Specifically, at the national level, a TB surveillance system can assess the TB control program's performance and assess the need to modify the current treatment policy. It can identify districts or health centers with high levels of drug resistance and determine the risk factors for resistance. WHO will assist developing countries in developing their own surveillance systems. WHO and the International Union Against Tuberculosis and Lung Disease plan on setting up a network of supranational reference laboratories to determine the quality control and standardization of susceptibility testing needed for international comparison. WHO also plans on supporting national reference laboratories in developing countries.

The diagnosis of pulmonary tuberculosis by gaschromatographic detection of tuberculostearic acid using flame ionisation detectors.

It has been shown that the detection of tuberculostearic acid (TBSA) with gas chromatography-mass-spectrometry provides a highly specific, sensitive and rapid method for the diagnosis of various forms of tuberculosis. However, the need for complex and expensive equipment prevented the more widespread use of this method. We report on the application of conventional gas chromatography with flame ionization detectors in the detection of TBSA in sputum samples. TBSA was detected in all patients with proven pulmonary tuberculosis before treatment or under treatment for less than 4 weeks (n = 18). Six of these patients (33%) had a negative microscopy result at the time of the study. Sputum samples from patients under therapy for longer than 4 weeks (n = 20) were TBSA-positive in 15 cases (75%). Only in two cases was the diagnosis by microscopy and/or culture not met by TBSA-detection. All sputa of 20 control patients with lung diseases other than tuberculosis were TBSA negative. Additional analysis of patients' data showed a significant relationship (P < 0.005) between the relative amounts of TBSA detectable in the sputum samples and the duration of therapy. It is concluded that conventional capillary gaschromatography may be sensitive and specific enough to be used for the detection of TBSA in sputum of patients with pulmonary tuberculosis.

Drug-resistant tuberculosis: laboratory issues. World Health Organization recommendations.

There is a suggestion that drug resistance rates decreased in developing countries over the period 1962-85, while recent data suggest that resistance may be increasing. The initial decrease in resistance appears to be associated with well-functioning National Tuberculosis Control Programmes (NTP), while the recently observed increase may be due either to understaffed, resource-poor programmes or to the effect of the HIV epidemic, or to both. It is possible that the HIV epidemic may overwhelm the NTP, resulting in decreased programme efficiency and ultimately increased drug resistance. Resistance surveillance appears to be a good measure of programme efficiency. For research purposes, primary drug resistance surveys should be done on a sample of relevant patients which includes and distinguishes between HIV-positive and HIV-negative patients. At this time, there is not enough information to warrant a recommendation regarding HIV testing of TB patients for surveillance purposes. In order for resistance surveys to be relevant from the public health perspective, one must know the proportion of patients presenting for treatment having previously received treatment. The meaningful denominator for drug resistance surveys from the programme evaluation perspective should be the number of patients presenting for treatment. For initial drug resistance surveys the measurement should be the number of people never having received prior TB treatment with resistant bacilli, divided by the number of new patients presenting for treatment. For acquired resistance, one should look at all patients who begin treatment with susceptible bacilli who become resistant 6 months later.

Random variation in tuberculin sensitivity in schoolchildren. Serial skin testing before and after preventive treatment for tuberculosis.

Schoolchildren were Mantoux-tested with 2 TU freeze-dried PPD RT23, and the strong reactors with indurations of 14.0 mm or more were selected for treatment with one of three different fixed drug combinations containing isoniazid or with placebo for 2 to 6 months. The initial tuberculin test was repeated after 8, 14, and 27 months. Of the 8,934 black schoolchildren initially tested, 5,165 did not react to the skin test, 2,898 had indurations up to 14.0 mm, and 871 reacted strongly. Of these strong reactors, 808 were allocated to four preventive treatment groups. On completion of treatment, the mean tuberculin reaction for all groups was significantly decreased. Because the placebo group showed changes similar to those seen in the other treatment groups, the tuberculin skin test is probably not suitable for monitoring the success of preventive therapy. Differences between skin test results before and after treatment when retesting only strong reactors are caused by a combination of effects that are difficult to distinguish. Assuming random variation in tuberculin sensitivity, the decrease can be explained as a combined effect of regression to the mean and some boosting. The increased reaction sizes in the subsequent Mantoux tests are explained by the booster phenomenon and possibly by reinfection. When using a cutting point for deriving a positive reactor, the chance of being selected for preventive treatment may depend primarily on the moment in time when the test is done. Thus, all reactors with no recent BCG vaccination should equally be considered for treatment.

Importance of rifampicin in combined daily/intermittent chemotherapy for tuberculosis.

Three different partly intermittent regimens were evaluated in order to assess the value of rifampicin (RMP) in the continuation phase of treatment for tuberculosis. Patients suffering from newly diagnosed culture-positive pulmonary tuberculosis were admitted to the trial. All were initially treated daily for 8 weeks with a quadruple combination including RMP. The intensive treatment phase was followed by twice-weekly intermittent treatment for 16 weeks with one of three different combinations, one containing RMP. Of 246 patients, 85 were withdrawn, 7 because of adverse events. At the end of treatment 127 of 135 patients (94,1%) from whom sputum results could be obtained, had negative sputum cultures, and 6 had one colony growth. Of 42 patients who had one or more positive sputum cultures during follow-up of 96 weeks, 6 belonged to the RMP group compared with 20 and 16 of the other groups (P = 0,0244). The results indicate that a combined daily/intermittent regimen containing RMP in both phases can be safely used, whereas a similar regimen with the same duration but not including RMP in the continuation phase, is inferior.

The need for co-operative operational research in tuberculosis control.

Progress in tuberculosis research and control is limited. Present control measures have seldom proved as successful as expected. Most of the problems encountered when implementing tuberculosis programmes are managerial and not technical. The only conceivable way to increase the impact of control measures is more effective application of conventional techniques. The data available seldom allow assessment, comparison and systematic improvement in the quality of control programmes. Similarly, the effectiveness of different techniques under specific conditions is difficult to assess. If the deficiencies in tuberculosis control schemes are to be overcome, research needs to be supplemented by co-operative operational research programmes. The aims of these programmes should always be to provide generally applicable guidelines and models for appropriate tuberculosis control schemes on a district level.