European union standards for tuberculosis care.

The European Centre for Disease Prevention and Control (ECDC) and the European Respiratory Society (ERS) jointly developed European Union Standards for Tuberculosis Care (ESTC) aimed at providing European Union (EU)-tailored standards for the diagnosis, treatment and prevention of tuberculosis (TB). The International Standards for TB Care (ISTC) were developed in the global context and are not always adapted to the EU setting and practices. The majority of EU countries have the resources and capacity to implement higher standards to further secure quality TB diagnosis, treatment and prevention. On this basis, the ESTC were developed as standards specifically tailored to the EU setting. A panel of 30 international experts, led by a writing group and the ERS and ECDC, identified and developed the 21 ESTC in the areas of diagnosis, treatment, HIV and comorbid conditions, and public health and prevention. The ISTCs formed the basis for the 21 standards, upon which additional EU adaptations and supplements were developed. These patient-centred standards are targeted to clinicians and public health workers, providing an easy-to-use resource, guiding through all required activities to ensure optimal diagnosis, treatment and prevention of TB. These will support EU health programmes to identify and develop optimal procedures for TB care, control and elimination.

Bronchoscopy in suspected pulmonary TB with negative induced-sputum smear and MTD(®) Gen-probe testing.

INTRODUCTION: In our institution, patients with suspected pulmonary TB undergo multiple induced-sputum sampling for microscopy, culture and nucleic acid amplification (NAA) with the MTD(®) Gen-probe assay. Those with negative induced-sputum results still suspected with TB are then referred for bronchoscopy. We sought to determine the diagnostic yield of bronchoscopy in these patients with negative initial induced-sputum results both via smear and NAA testing. METHODS: We identified 30 consecutive cases of suspected pulmonary TB between 2001 and 2007, who had undergone a diagnostic bronchoscopy after negative results on induced-sputum smears and the MTD(®) Gen-probe on at least 2 samples. RESULTS: The cohort (M = 20 & F = 10) had a median age of 37 (range 16-85 yrs); were predominantly foreign born (27/30); HIV-negative (29/30) individuals with strongly positive TST's (mean 18 + 5 mm). Induced-sputum cultures were negative for M-TB in all patients after a full 60-day incubation period. BAL was culture positive for M-TB in 3/30 cases (10%) with 2 strains being pan-sensitive and the third being INH resistant. BAL microscopy with acid-fast smear (n = 30) and BAL Gen-probe (n = 23) were negative in all cases. A third of the patients (9/27, 33%) with negative bronchoscopy results were treated for culture negative TB. Treatment for latent TB was initiated in 5/27 (18%) individuals whereas 13/27 (48%) received no further treatment. CONCLUSION: Bronchoscopy provided diagnostic confirmation of pulmonary TB in 10% of subjects at least 2 negative induced-sputum samples by smear microscopy and NAA testing.

Diagnosis and treatment of allergic bronchopulmonary aspergillosis.

Allergic bronchopulmonary aspergillosis (ABPA) is an underdiagnosed pulmonary disorder in asthmatic patients and patients with cystic fibrosis. Its clinical and diagnostic manifestations arise from an allergic response to multiple antigens expressed by fungi, most commonly Aspergillus fumigatus, colonizing the bronchial mucus. The clinical course is one of recurrent exacerbations characterized by chest infiltrates evident on chest x-ray films and associated with cough, wheeze, and sputum production that usually respond to oral corticosteroid treatment. Specific immunologic and radiologic markers of disease include elevation of the total serum IgE levels, presence of aspergillus IgE antibodies, and the occurrence of central bronchiectasis. Long-term treatment with corticosteroids is often required for effective management. The adverse effects of chronic corticosteroid use have led to attempts at treatment with antifungal agents such as itraconazole. Itraconazole has been reported anecdotally to be effective, and evidence for its effectiveness in randomized trials is still accruing. Consideration should be given to its use as a corticosteroid-sparing agent or for treatment of patients in whom corticosteroid response is poor. The natural history and prognosis of ABPA are not well characterized but may be complicated by progression to bronchiectasis and pulmonary fibrosis. If ABPA is diagnosed and treated before the development of bronchiectasis and fibrosis, these complications may be prevented.

Thromboembolism occurrence and diagnosis in the medical intensive care unit.

Venous thromboembolism (VTE) represents an unrelenting and formidable challenge in the critical care setting even for the most experienced clinician. The morbidity and mortality attributed to untreated VTE have been substantiated by increasing series of epidemiologic and postmortem studies. As a larger group of the general population grows older, with increasing requirements for critical care services, challenges for the intensivist in the diagnosis and management of VTE are expected to grow. Moreover, despite the tremendous development of many critical care technologies, complexities of medical conditions commonly encountered in the critically ill have detracted from suspicion of VTE and made prompt recognition difficult. The approach to diagnosis of VTE should optimize diagnostic yield and outcomes with responsible use of resources. Key to an appropriate approach of VTE diagnosis in the intensive care unit is an understanding of the predisposing risk factors--pretest probability and the strengths and weaknesses of available diagnostic tools. Rational use of ultrasound, impedance plethysmography, computed tomography (CT), echocardiography, contrast venography, angiography, and D-dimer assays have provided the clinicians with a more substantial armamentarium, albeit incomplete, to facilitate diagnosis of VTE. The best use of these diagnostic tests often are dependent on local availability and expertise as part of a multidisciplinary team. With application of sound clinical principles in identifying select patients at risk and disciplined use of diagnostic technologies using simple algorithms, improvements in the diagnosis and management of VTE in the intensive care unit may be expected.

Dexamethasone inhibits IL-1 and TNF activity in human lung fibroblasts without affecting IL-1 or TNF receptors.

Interleukin (IL-1) and tumor necrosis factor (TNF) activate human lung fibroblasts through interactions with specific receptors. One effect of this interaction of IL-1 and TNF with fibroblasts is an increased production of the cytokines, IL-6 and IL-8. Dexamethasone blocks the induction of IL-6 and IL-8 by IL-1 or TNF. In these studies, we determined whether dexamethasone interferes with the upregulation of IL-6 and IL-8 by downregulating expression of the IL-1 or TNF receptor genes. Confluent lung fibroblasts were treated with medium alone (control) or medium with dexamethasone (10(-6) M). Dexamethasone did not decrease the binding of IL-1 and TNF to their receptors, nor did it decrease amounts of IL-1 or TNF receptor RNA. Both IL-1 and TNF increased release of IL-6 and IL-8 from the cells in a dose-dependent manner and dexamethasone inhibited this effect. Dexamethasone also inhibited the induction of IL-6 and IL-8 RNA by IL-1 and TNF. The studies show that dexamethasone does not block the effects of IL-1 or TNF on fibroblasts by decreasing expression of IL-1 or TNF receptors.

Protein kinase C modulates the amounts of IL-1 receptor mRNA in human lung fibroblasts.

IL-1 activates human lung fibroblasts via IL-1-specific membrane receptors. The numbers of IL-1 binding sites on fibroblasts are increased after exposure to prostaglandin E2 (PGE2) or IL-1. Increases in binding sites are associated with changes in functional responses to IL-1. In these studies, we determined if alterations in numbers of IL-1 binding sites on human lung fibroblasts were associated with parallel changes in IL-1R mRNA. In addition, since IL-1 and PGE2 can activate protein kinase C (PKC) and protein kinase A (PKA), we exposed human lung fibroblasts to 1-(5-Isoquinoline sulfonyl)-2-methylpiperafine (H7) or staurosporine, which are relatively specific inhibitors of PKC, and N-[2-(methylamino)ethyl]-5-isoquinolinesulfomamide (H8), an inhibitor of PKA, to determine whether the IL-1 and PGE2 stimulated increases in binding sites were mediated by activation of PKC or PKA. H7 decreased the base line and PGE2-stimulated increases in numbers of IL-1 binding sites. Exposure of the fibroblasts to phorbol-12-myristate-13-acetate (PMA) for 24 h, which is known to deplete PKC, also decreased the numbers of base line IL-1 binding sites. These changes were paralleled by changes in amounts of IL-1R mRNA. H7 and staurosporine also blocked IL-1 and PGE2 stimulated increases in IL-1R mRNA. In contrast, H8 had no effect on the base line or PGE2-stimulated increases in numbers of IL-1 binding sites nor did it change the amounts of IL-1R mRNA. These studies show that changes in the numbers of IL-1 binding sites on human lung fibroblasts are paralleled by changes in IL-1R mRNA. In addition, PKC activity is necessary for the expression of both base line and stimulated increases in IL-1 binding sites and IL-1R mRNA. These studies suggest that PKC activity plays an important role in the modulation of IL-1R expression.

Prevalence of adverse effects in corticosteroid dependent asthmatics.

Eighty-five corticosteroid dependent patients with respiratory diseases requiring alternate day prednisone were studied for certain adverse effects that have been reported to be associated with corticosteroid therapy. The mean age of the patients was 52 years, the average years of prednisone therapy was 5.3, and the mean dose of alternate day prednisone was 26.2 mg. In this group of 85 patients the prevalence of hypertension, peptic ulcer disease, pathologic fractures and psychosis was not statistically increased over that of the general population. None of the patients was diagnosed as having steroid-induced psychosis, pancreatitis or tuberculosis. One patient developed aseptic necrosis of the hip; however, she received daily prednisone for approximately 3.2 years before being converted to an alternate day schedule. Our results demonstrate that alternate day corticosteroid therapy can be used without significant risk of adverse effects in patients in whom it is essential for control of respiratory disease.

Paroxysmal hypertension due to sinoaortic baroreceptor denervation in humans.

A 41-year-old man with a remote history of neck and mediastinal radiation was seen with severe paroxysms of hypertension, headache, and cutaneous flushing after bilateral carotid bypass surgery. Investigation revealed marked parallel fluctuations in blood pressure and heart rate and elevation of plasma norepinephrine to 1164 pg/ml during a paroxysm. We systematically evaluated his arterial and cardiopulmonary baroreceptor reflex function by assessing changes in heart rate, arterial pressure, and efferent muscle sympathetic nerve activity, which was measured directly by the microneurographic technique. Elevating resting arterial pressure from 130/88 to 164/100 mm Hg with phenylephrine or lowering it to 88/56 mm Hg with nitroprusside produced no reflex changes in heart rate or efferent sympathetic nerve activity. In contrast, decreases in cardiac filling pressures with lower body negative pressure produced a marked increase in sympathetic nerve activity. These findings indicate complete loss of the afferent limb of the arterial baroreceptor reflex but preservation of the cardiopulmonary baroreceptor reflex. They suggest that both carotid and aortic baroreceptors were impaired by the previous radiation and surgery. Despite the loss of arterial baroreceptor function, the patient did not have sustained hypertension. The paroxysms of hypertension appear to be due to spontaneous fluctuations in central sympathetic drive not buffered by arterial baroreceptors in a manner similar to that seen in sinoaortic-denervated animals.

Effect of perfusion rate of cholinergic agonist on sinus node automaticity.

Recent evidence supports a complex relationship between pressure in the sinus node artery and heart rate. In addition, it has been suggested that acetylcholine effects vary depending upon the pressure at which the drug is injected. We examined the cardiac chronotropic responses to acetylcholine, delivered via the sinus node artery using a constant flow perfusion technique. Dogs were anesthetized with chloralose and prepared to record ECG, arterial pressure and bipolar electrograms from the sinus node, sulcus terminalis, right atrium, right ventricle and His bundle. The sinus node artery was catheterized, distribution verified and autologously perfused via the femoral artery. Both vagi and both stellate ganglia were transected. Analog data were processed by computer for each cycle length during perfusion with normal Tyrode solution or Tyrode solution containing acetylcholine. Perfusion of normal Tyrode solution (1-4ml/min) resulted in prolongation in cycle length which was greater at higher flow rates but rapidly dissipated at all flow rates. Beyond mechanically-induced bradycardia, acetylcholine initially prolonged cycle length but cycle length prolongation faded with time. Delivery of acetylcholine at higher flow rates resulted in significantly greater prolongation of cycle length. Cycle length always returned back toward control although perfusion of acetylcholine continued. Thus, responses to acetylcholine are influenced not only by drug concentration but also by the flow rate at which the drug is delivered. This suggests a coupling of mechanical and pharmacologic components of chronotropic influences at the sinus node.