Jonathan C. Peter

Clinical Utility of a Commercial LAM-ELISA Assay for TB Diagnosis in HIV-Infected Patients Using Urine and Sputum Samples

Background The accurate diagnosis of TB in HIV-infected patients, particularly with advanced immunosuppression, is difficult. Recent studies indicate that a lipoarabinomannan (LAM) assay (Clearview-TB®-ELISA) may have some utility for the diagnosis of TB in HIV-infected patients; however, the precise subgroup that may benefit from this technology requires clarification. The utility of LAM in sputum samples has, hitherto, not been evaluated. Methods LAM was measured in sputum and urine samples obtained from 500 consecutively recruited ambulant patients, with suspected TB, from 2 primary care clinics in South Africa. Culture positivity for M. tuberculosis was used as the reference standard for TB diagnosis. Results Of 440 evaluable patients 120/387 (31%) were HIV-infected. Urine-LAM positivity was associated with HIV positivity (p = 0.007) and test sensitivity, although low, was significantly higher in HIV-infected compared to uninfected patients (21% versus 6%; p<0.001), and also in HIV-infected participants with a CD4 <200 versus >200 cells/mm3 (37% versus 0%; p = 0.003). Urine-LAM remained highly specific in all 3 subgroups (95%–100%). 25% of smear-negative but culture-positive HIV-infected patients with a CD4 <200 cells/mm3 were positive for urine-LAM. Sputum-LAM had good sensitivity (86%) but poor specificity (15%) likely due to test cross-reactivity with several mouth-residing organisms including actinomycetes and nocardia species. Conclusions These preliminary data indicate that in a high burden primary care setting the diagnostic usefulness of urine-LAM is limited, as a rule-in test, to a specific patient subgroup i.e. smear-negative HIV-infected TB patients with a CD4 count <200 cells/mm3, who would otherwise have required further investigation. However, even in this group sensitivity was modest. Future and adequately powered studies in a primary care setting should now specifically target patients with suspected TB who have advanced HIV infection.

Carotid and vertebral artery occlusion after blunt cervical injury : The role of MR angiography in early diagnosis

The early diagnosis of cervical vascular trauma is critical in the prevention of cerebral ischemia. Traumatic blunt carotid or vertebral artery dissection is rare and frequently associated with other injuries. Diagnosis is often delayed, limiting treatment options and contributing to a poor outcome. The clinical findings and investigation of 14 patients are presented with special reference to the last three who had magnetic resonance imaging angiography. Treatment options are discussed and it is suggested that with modern methods of investigation and management, the prognosis of this condition may be improved.

Selective posterior rhizotomy: a long-term follow-up study

Fifty-one spastic children who had undergone selective posterior lumbar rhizotomy between 1981 and 1984 were re-examined to determine whether the gains achieved had persisted and to look at other aspects that had not previously been explored in detail. The reduction of tone was maintained in all cases, while motor function continued to improve in 42 cases. Functional gains were greatest in children operated on under the age of 8, but pleasing results were also achieved in older children. Forty-five children continued to receive physiotherapy, particular attention being paid to building up muscle strength. Sensory disturbances were minimal, and there was no evidence of spinal instability. Post-rhizotomy orthopaedic surgery for fixed-joint contractures generally brought further improvement. Parents and older children were also questioned and almost all were enthusiastic about the outcome. Rhizotomy can be of considerable benefit to spastic children, but great care must be taken in the selection of suitable cases.

Point-of-care diagnosis of tuberculosis: past, present and future

Diagnosis represents only one aspect of tuberculosis (TB) control but is perhaps one of the most challenging. The drawbacks of current tools highlight several unmet needs in TB diagnosis, that is, necessity for accuracy, rapidity of diagnosis, affordability, simplicity and the ability to generate same‐day results at point‐of‐care (POC). When a return visit is required to access test results, time to treatment is prolonged, and default rates are significant. However, a good diagnostic tool is also critically dependent on obtaining an adequate biological sample. Here, we review the accuracy and potential impact of established and newer potential POC diagnostic tests for TB, including smear microscopy, the Xpert MTB/RIF assay (Cepheid) and the Determine TB lipoarabinomannan antigen test (Alere). Novel experimental approaches and detection technologies for POC diagnosis of active TB, including nucleic acid amplification tests, detection of volatile organic compounds or metabolites, mass spectroscopy, microfluidics, surface‐enhanced Raman spectroscopy, electrochemical approaches, and aptamers among others, are discussed. We also discuss future applications, including the potential POC diagnosis of drug‐resistant TB and presumed latent TB infection. Challenges to the development and roll‐out of POC tests for TB are also reviewed.

Urine for the diagnosis of tuberculosis: current approaches, clinical applicability, and new developments.

Purpose of review Urine is increasingly being investigated as a convenient clinical sample for the identification of mycobacterial products for the diagnosis of tuberculosis. The available literature on mycobacterial lipoarabinomannan (LAM) and urine mycobacterial DNA is reviewed. Recent findings The available data, despite being extracted from heterogeneous clinical populations and different clinical subgroups, indicate that urine LAM has little diagnostic utility in unselected tuberculosis suspects; however, test characteristics improve in HIV-infected patients, particularly those with advanced immunosuppression (CD4 cell count <200 cells/μl). Methodologies for urine PCR for detection of mycobacterial DNA vary across studies and focus is on standardizing assays with respect to specimen collection, assay design, and processing methodology. Summary Both the urine LAM and PCR for mycobacterial DNA are being evaluated in different geographical settings. Urine LAM currently offers little utility for the diagnosis of tuberculosis in unselected populations. However, urine LAM appears promising as a diagnostic tool in HIV-infected patients with CD4 cell counts less than 200 cells/μl in different clinical settings. Further developmental studies are required to enhance the performance of the assays, and their usefulness over sputum microscopy in HIV-infected patients with advanced immunosuppression requires definition in large cohort studies.

Transcranial Doppler pulsatility index is not a reliable indicator of intracranial pressure in children with severe traumatic brain injury

BACKGROUND The TCD-derived PI has been associated with ICP in adult studies but has not been well investigated in children. We examined the relationship between PI and ICP and CPP in children with severe TBI. METHODS Data were prospectively collected from consecutive TCD studies in children with severe TBI undergoing ICP monitoring. Ipsilateral ICP and CPP values were examined with Spearman correlation coefficient (mean values and raw observations), with a GEE, and as binary values (1 and 20 mm Hg, respectively). RESULTS Thirty-four children underwent 275 TCD studies. There was a weak relationship between mean values of ICP and PI (P = .04, r = 0.36), but not when raw observations (P = .54) or GEE (P = .23) were used. Pulsatility index was 0.76 when ICP was lower than 20 mm Hg and 0.86 when ICP was 20 mm Hg or higher. When PI was 1 or higher, ICP was lower than 20 mm Hg in 62.5% (25 of 40 studies), and when ICP was 20 mm Hg or higher, PI was lower than 1 in 75% (46 of 61 studies). The sensitivity and specificity of a PI threshold of 1 for examining the ICP threshold of 20 mm Hg were 25% and 88%, respectively. The relationship between CPP and PI was stronger (P = .001, r = -0.41), but there were too few observations below 50 mm Hg to examine PI at this threshold. CONCLUSION The absolute value of the PI is not a reliable noninvasive indicator of ICP in children with severe TBI. Further study is required to examine the relationship between PI and a CPP threshold of 50 mm Hg.

Comparison of Quantitative Techniques including Xpert MTB/RIF to Evaluate Mycobacterial Burden

Introduction Accurate quantification of mycobacterial load is important for the evaluation of patient infectiousness, disease severity and monitoring treatment response in human and in-vitro laboratory models of disease. We hypothesized that newer techniques would perform as well as solid media culture to quantify mycobacterial burden in laboratory specimens. Methods We compared the turn-around-time, detection-threshold, dynamic range, reproducibility, relative discriminative ability, of 4 mycobacterial load determination techniques: automated liquid culture (BACTEC-MGIT-960), [3H]-uracil incorporation assays, luciferase-reporter construct bioluminescence, and quantitative PCR(Xpert -MTB/RIF) using serial dilutions of Mycobacterium bovis and Mycobacterium tuberculosis H37RV. Mycobacterial colony-forming-units(CFU) using 7H10-Middlebrook solid media served as the reference standard. Results All 4 assays correlated well with the reference standard, however, bioluminescence and uracil assays had a detection threshold ≥1×103 organisms. By contrast, BACTEC-MGIT-960 liquid culture, although only providing results in days, was user-friendly, had the lowest detection threshold (<10 organisms), the greatest discriminative ability (1 vs. 10 organisms; p = 0.02), and the best reproducibility (coefficient of variance of 2% vs. 38% compared to uracil incorporation; p = 0.02). Xpert-MTB/RIF correlated well with mycobacterial load, had a rapid turn-around-time (<2 hours), was user friendly, but had a detection limit of ∼100 organisms. Conclusions Choosing a technique to quantify mycobacterial burden for laboratory or clinical research depends on availability of resources and the question being addressed. Automated liquid culture has good discriminative ability and low detection threshold but results are only obtained in days. Xpert MTB/RIF provides rapid quantification of mycobacterial burden, but has a poorer discrimination and detection threshold.

Pressure autoregulation, intracranial pressure, and brain tissue oxygenation in children with severe traumatic brain injury

OBJECT Cerebral pressure autoregulation is an important neuroprotective mechanism that stabilizes cerebral blood flow when blood pressure (BP) changes. In this study the authors examined the association between autoregulation and clinical factors, BP, intracranial pressure (ICP), brain tissue oxygen tension (PbtO(2)), and outcome after pediatric severe traumatic brain injury (TBI). In particular we examined how the status of autoregulation influenced the effect of BP changes on ICP and PbtO(2). METHODS In this prospective observational study, 52 autoregulation tests were performed in 24 patients with severe TBI. The patients had a mean age of 6.3 +/- 3.2 years, and a postresuscitation Glasgow Coma Scale score of 6 (range 3-8). All patients underwent continuous ICP and PbtO(2) monitoring, and transcranial Doppler ultrasonography was used to examine the autoregulatory index (ARI) based on blood flow velocity of the middle cerebral artery after increasing mean arterial pressure by 20% of the baseline value. Impaired autoregulation was defined as an ARI < 0.4 and intact autoregulation as an ARI >or= 0.4. The relationships between autoregulation (measured as both a continuous and dichotomous variable), outcome, and clinical and physiological variables were examined using multiple logistic regression analysis. RESULTS Autoregulation was impaired (ARI < 0.4) in 29% of patients (7 patients). The initial Glasgow Coma Scale score was significantly associated with the ARI (p = 0.02, r = 0.32) but no other clinical factors were associated with autoregulation status. Baseline values at the time of testing for ICP, PbtO(2), the ratio of PbtO(2)/PaO(2), mean arterial pressure, and middle cerebral artery blood flow velocity were similar in the patients with impaired or intact autoregulation. There was an inverse relationship between ARI (continuous and dichotomous) with a change in ICP (continuous ARI, p = 0.005; dichotomous ARI, p = 0.02); that is, ICP increased with the BP increase when ARI was low (weak autoregulation). The ARI (continuous and dichotomous) was also inversely associated with a change in PbtO(2) (continuous ARI, p = 0.002; dichotomous ARI, p = 0.02). The PbtO(2) increased when BP was increased in most patients, even when the ARI was relatively high (stronger autoregulation), but the magnitude of this response was still associated with the ARI. There was no relationship between the ARI and outcome. CONCLUSIONS These data demonstrate the influence of the strength of autoregulation on the response of ICP and PbtO(2) to BP changes and the variability of this response between individuals. The findings suggest that autoregulation testing may assist clinical decision-making in pediatric severe TBI and help better define optimal BP or cerebral perfusion pressure targets for individual patients.

Incidence of spinal deformity in children after multiple level laminectomy for selective posterior rhizotomy

Fifty-five children with cerebral palsy had multiple-level laminectomies for selective posterior rhizotomies for the relief of spasticity. They were followed up clinically and radiologically to assess their spinal stability and the possible development of post-laminectomy deformity of the spine. The majority of the deformities found were related to cerebral palsy and did not appear to be due to the laminectomy: 16% had scoliosis, 5% kyphosis, 7% lordosis, and 9% spondylolysis/spondylolisthesis. Spondylolysis is the only abnormality that appeared to be more common in this group than in children with cerebral palsy.

Endoscopic third ventriculostomy in tuberculous meningitis

IntroductionWe report our preliminary experience with two cases of tuberculous meningitis (TBM) in which endoscopic third ventriculostomy (ETV) was performed to treat non-communicating hydrocephalus. For many years, the insertion of ventriculoperitoneal shunts has been the standard treatment for hydrocephalus in patients with TBM, although the indications for and timing of surgery are not uniformly accepted. Shunt insertion is associated with a high incidence of complications, particularly with long-term follow-up. An alternative treatment for hydrocephalus in this group of patients would clearly be of great benefit. The indications for ETV have increased in the last decade, and there are reports of some effectiveness of the procedure in patients with hydrocephalus due to bacterial meningitis. To our knowledge, ETV has not been described in the management of TBM.MethodsWe report the early results of our preliminary experience with ETV in two patients who presented with neurological compromise due to hydrocephalus and raised intracranial pressure. The clinical context and pre-operative investigation of these patients are presented. The emphasis is placed on the distinction between communicating and non-communicating pathologies as a guide to management options. We detail our surgical findings and the peculiar endoscopic challenges that the condition presented to us. Follow-up in these patients included clinical and investigational data suggesting early effectiveness of the procedure in converting non-communicating hydrocephalus into a communicating one, which can then be treated medically.DiscussionEndoscopic third ventriculostomy is presented as a new application of a procedure accepted for other indications in the treatment of non-communicating hydrocephalus. There are particular aspects of the use of this procedure related to the unique pathology of TBM that are significantly different. We explain our rationale for endoscopy in these patients, and suggest a protocol in which endoscopy may play a role in the management of patients with raised intracranial pressure due to tuberculous hydrocephalus.