Gregory Calligaro

Are interferon-γ release assays useful for diagnosing active tuberculosis in a high-burden setting?

Although interferon-&ggr; release assays (IGRAs) are intended for diagnosing latent tuberculosis (TB), we hypothesised that in a high-burden setting: 1) the magnitude of the response when using IGRAs can distinguish active TB from other diagnoses; 2) IGRAs may aid in the diagnosis of smear-negative TB; and 3) IGRAs could be useful as rule-out tests for active TB. We evaluated the accuracy of two IGRAs (QuantiFERON®-TB Gold In-tube (QFT-GIT) and T-SPOT®.TB) in 395 patients (27% HIV-infected) with suspected TB in Cape Town, South Africa. IGRA sensitivity and specificity (95% CI) were 76% (68–83%) and 42% (36–49%) for QFT-GIT and 84% (77–90%) and 47% (40–53%) for T-SPOT®.TB, respectively. Although interferon-&ggr; responses were significantly higher in the TB versus non-TB groups (p<0.0001), varying the cut-offs did not improve discriminatory ability. In culture-negative patients, depending on whether those with clinically diagnosed TB were included or excluded from the analysis, the negative predictive value (NPV) of QFT-GIT, T-SPOT®.TB and chest radiograph in smear-negative patients varied between 85 and 89, 87 and 92, and 98% (for chest radiograph), respectively. Overall accuracy was independent of HIV status and CD4 count. In a high-burden setting, IGRAs alone do not have value as rule-in or -out tests for active TB. In smear-negative patients, chest radiography had better NPV even in HIV-infected patients.

Accuracy and impact of Xpert MTB/RIF for the diagnosis of smear-negative or sputum-scarce tuberculosis using bronchoalveolar lavage fluid

Rationale The accuracy and impact of new tuberculosis (TB) tests, such as Xpert MTB/RIF, when performed on bronchoalveolar lavage fluid (BALF) obtained from patients with sputum-scarce or smear-negative TB is unclear. Methods South African patients with suspected pulmonary TB (n=160) who were sputum-scarce or smear-negative underwent bronchoscopy. MTB/RIF was performed on uncentrifuged BALF (1 ml) and/or a resuspended pellet of centrifuged BALF (∼10 ml). Time to TB detection and anti-TB treatment initiation were compared between phase one, when MTB/RIF was performed as a research tool, and phase two, when it was used for patient management. Results 27 of 154 patients with complete data had culture-confirmed TB. Of these, a significantly lower proportion were detected by smear microscopy compared with MTB/RIF (58%, 95% CI 39% to 75% versus 93%, 77% to 98%; p<0.001). Of the 127 patients who were culture negative, 96% (91% to 98%) were MTB/RIF negative. When phase two was compared with phase one, MTB/RIF reduced the median days to TB detection (29 (18–41) to 0 (0–0); p<0.001). However, more patients initiated empirical therapy (absence of a positive test in those commencing treatment) in phase one versus phase two (79% (11/14) versus 28% (10/25); p=0.026). Consequently, there was no detectable difference in the overall proportion of patients initiating treatment (26% (17/67; 17% to 37%) versus 36% (26/73; 26% to 47%); p=0.196) or the days to treatment initiation (10 (1–49) versus 7 (0–21); p=0.330). BALF centrifugation, HIV coinfection and a second MTB/RIF did not result in detectable changes in accuracy. Conclusions MTB/RIF detected TB cases more accurately and more rapidly than smear microscopy and significantly reduced the rate of empirical treatment.

The medical and surgical treatment of drug-resistant tuberculosis

Multi drug-resistant tuberculosis (MDR-TB) and extensively drug-resistant TB (XDR-TB) are burgeoning global problems with high mortality which threaten to destabilise TB control programs in several parts of the world. Of alarming concern is the emergence, in large numbers, of patients with resistance beyond XDR-TB (totally drug-resistant TB; TDR-TB or extremely drug resistant TB; XXDR-TB). Given the burgeoning global phenomenon of MDR-TB, XDR-TB and TDR-TB, and increasing international migration and travel, healthcare workers, researchers, and policy makers in TB endemic and non-endemic countries should familiarise themselves with issues relevant to the management of these patients. Given the lack of novel TB drugs and limited access to existing drugs such as linezolid and bedaquiline in TB endemic countries, significant numbers of therapeutic failures are emerging from the ranks of those with XDR-TB. Given the lack of appropriate facilities in resource-limited settings, such patients are being discharged back into the community where there is likely ongoing disease spread. In the absence of effective drug regimens, in appropriate patients, surgery is a critical part of management. Here we review the diagnosis, medical and surgical management of MDR-TB and XDR-TB.

Pulmonary manifestations of the immune reconstitution inflammatory syndrome.

Purpose of review Immune reconstitution inflammatory syndrome (IRIS) is a common occurrence in HIV patients starting antiretroviral therapy (ART), and pulmonary involvement is an important feature of tuberculosis-IRIS and pneumocystis-IRIS. Pulmonologists need an awareness of the timing, presentation and treatment of pulmonary IRIS. Recent findings Case definitions for tuberculosis-IRIS and cryptococcal-IRIS have been published by the International Network for the Study of HIV-associated IRIS (INSHI). A number of studies have addressed validation of clinical case definitions and the optimal time to commence ART after diagnosis of an opportunistic infection in HIV patients. The pathogenesis of IRIS is being assessed at a molecular level, increasing our understanding of mechanisms and possible targets for future preventive and therapeutic strategies. Summary Tuberculosis-IRIS, nontuberculosis mycobacterial-IRIS and pneumocystis-IRIS occur within days to weeks of starting ART, causing substantial morbidity, but low mortality. Cryptococcal-IRIS usually occurs later in the course of ART, and may be associated with appreciable mortality. Early recognition of unmasking and paradoxical IRIS affecting the lung allows timely initiation of antimicrobial and/or immunomodulatory therapies.

Effect of new tuberculosis diagnostic technologies on community-based intensified case finding: a multicentre randomised controlled trial

BACKGROUND Inadequate case detection results in high levels of undiagnosed tuberculosis in sub-Saharan Africa. Data for the effect of new diagnostic tools when used for community-based intensified case finding are not available, so we investigated whether the use of sputum Xpert-MTB/RIF and the Determine TB LAM urine test in two African communities could be effective. METHODS In a pragmatic, randomised, parallel-group trial with individual randomisation stratified by country, we compared sputum Xpert-MTB/RIF, and if HIV-infected, the Determine TB LAM urine test (novel diagnostic group), with laboratory-based sputum smear microscopy (routine diagnostic group) for intensified case finding in communities with high tuberculosis and HIV prevalence in Cape Town, South Africa, and Harare, Zimbabwe. Participants were randomly assigned (1:1) to these groups with computer-generated allocation lists, using culture as the reference standard. In Cape Town, participants were randomised and tested at an Xpert-equipped mobile van, while in Harare, participants were driven to a local clinic where the same diagnostic tests were done. The primary endpoint was the proportion of culture-positive tuberculosis cases initiating tuberculosis treatment in each study group at 60 days. This trial is registered at ClinicalTrials.gov, number NCT01990274. FINDINGS Between Oct 18, 2013, and March 31, 2015, 2261 individuals were screened and 875 (39%) of these met the criteria for diagnostic testing. 439 participants were randomly assigned to the novel group and 436 to the routine group. 74 (9%) of 875 participants had confirmed tuberculosis. If late culture-based treatment initiation was excluded, more patients with culture-positive tuberculosis were initiated on treatment in the novel group at 60 days (36 [86%] of 42 in the novel group vs 18 [56%] of 32 in the routine group). Thus the difference in the proportion initiating treatment between groups was 29% (95% CI 9-50, p=0·0047) and 53% more patients initiated therapy in the novel diagnostic group than in the routine diagnostic group. One culture-positive patient was treated based only on a positive LAM test. INTERPRETATION Compared with traditional tools, Xpert-MTB/RIF for community-based intensified case finding in HIV and tuberculosis-endemic settings increased the proportion of patients initiating treatment. By contrast, urine LAM testing was not found to be useful for intensive case finding in this setting. FUNDING European and Developing Countries Clinical Trials Partnership and South African Medical Research Council.

Comparing Dynamic Hyperinflation and Associated Dyspnea Induced by Metronome-Paced Tachypnea Versus Incremental Exercise

Abstract Dynamic hyperinflation (DH) during exercise is associated with both dyspnea and exercise limitation in COPD. Metronome-paced tachypnoea (MPT) is a simple alternative for studying DH. We compared MPT with exercise testing (XT) as methods of provoking DH, and assessed their relationship with dyspnea. We studied 24 patients with moderate COPD (FEV1 59 ± 9% predicted) after inhalation of ipratropium/salbutamol combination or placebo in a double-blind, crossover design. Inspiratory capacity (IC) was measured at baseline and after 30 seconds of MPT with breathing frequencies (fR) of 20, 30 and 40 breaths/min and metronome-defined I:E ratios of 1:1 and 1:2, in random sequence, followed by incremental cycle ergometry with interval determinations of IC. DH was defined as a decline in IC from baseline (∆IC) for both methods. Dyspnea was assessed using a Borg CR-10 scale. ∆IC during MPT was greater with higher fR and I:E ratio of 1:1 versus 1:2, and less when patients were treated with bronchodilator rather than placebo (P = 0.032). DH occurred during 19 (40%) XTs, and during 35 (73%) tests using MPT. Eleven of 18 (61%) non-congruent XTs (where DH occurred on MPT but not XT) terminated before fR of 40 breaths/min was reached. Although greater during XT, the intensity of dyspnea bore no relationship to DH during either MPT and XT. MPT at 40 breaths/min and I:E of 1:1 elicits the greatest ∆IC, and is a more sensitive method for demonstrating DH. The relationship between DH and dyspnea is complex and not determined by DH alone.

Transthoracic ultrasound for the categorization of pleural effusions as malignant: an adjunct, but not the answer?

In this issue of Respiration , Bugalho et al. [6] report the findings of a prospective, observational study examining the diagnostic value of transthoracic ultrasonography for predicting malignancy in undiagnosed pleural effusions in a relatively large, unselected study population. Patients were scanned by chest physicians with expertise in thoracic ultrasound who were blinded to clinical and radiological details. Static images and video clips were reviewed by at least three chest physicians with similar expertise in order to generate a consensus opinion. A total of 133 patients with pleural effusion of unknown etiology were included; 66 were eventually diagnosed with malignant effusion and 67 had benign disease. Transthoracic ultrasound had an overall sensitivity of 80.3%, specificity of 83.6%, PPV of 82.8% and NPV of 81.2% for pleural malignancy. The study confirmed the strong association between malignant effusions and the presence of pleural and diaphragmatic nodularity (OR 29.02 and 95% CI 7.65– 110.01). However, unlike the report by Qureshi et al. [4] (where the pretest probability of malignancy was higher), these features were not 100% specific for malignant disease and were also found in 9% of benign effusions due to tuberculosis or pneumonia. The presence of chest wall invasion, a peripheral lung lesion associated with the effusion or hepatic metastasis were pathognomonic for malignancy, while air bronchograms and a septated pattern The detection, quantification and assessment of the nature of pleural effusions and the evaluation of associated pleural thickening and tumors remain the main indications for the use of transthoracic ultrasonography by respiratory physicians [1, 2] . The echogenicity of malignant pleural effusions is known to vary and is therefore considered nonspecific, but the ultrasonographic appearance of the pleura itself may often suggest a neoplastic etiology [2] . Several morphological criteria, based on those previously validated for contrast-enhanced computed tomography (CECT) [3] , were evaluated in a landmark study by Qureshi et al. [4] . The authors found that a radiologist, blinded to clinical and other radiological investigations, was able to correctively categorize 26 of 33 effusions as malignant and 19 of 19 as benign in patients referred under suspicion of malignancy. Ultrasound had an overall sensitivity of 79%, specificity of 100%, positive predictive value (PPV) of 100% and negative predictive value (NPV) of 73% [4] . The presence of parietal pleural thickening >10 mm, diaphragmatic nodularity or thickening >7 mm, visceral pleural thickening and pleural nodularity/irregularity were associated with malignancy. It was, however, suggested that these results may not be generalizable, given the high level of expertise at the author’s tertiary referral center and the low percentage of patients with benign disease [5] . Published online: February 13, 2014

Severe airflow obstruction in vertically acquired HIV infection

It is becoming increasingly clear that human immunodeficiency virus (HIV) infection, either independently or in concert with opportunistic infections like pulmonary tuberculosis, is a risk factor for the development of chronic airflow limitation. In the majority of patients the etiology of this obstructive ventilatory defect is multifactorial. Post‐infectious obliterative bronchiolitis, post‐tuberculous lung damage (including bronchiectasis), immune reconstitution and the direct effects of HIV viral infection may all play a role. With increases in life expectancy and decreases in infectious complications in patients taking antiretroviral medications, the importance of HIV‐associated chronic lung disease as a cause of pulmonary disability is likely to increase. This is particularly relevant in regions like sub‐Saharan Africa, where both HIV infection and tuberculosis are highly prevalent. Here, to illustrate the complexity of this interaction, we present the case of a 15‐year‐old girl with vertically acquired HIV infection, multiple episodes of pulmonary infection, and severe airflow obstruction.

Obstructive pulmonary disease in patients with previous tuberculosis : pathophysiology of a community-based cohort

BACKGROUND An association between chronic airflow limitation (CAL) and a history of pulmonary tuberculosis (PTB) has been confirmed in epidemiological studies, but the mechanisms responsible for this association are unclear. It is debated whether CAL in this context should be viewed as chronic obstructive pulmonary disease (COPD) or a separate phenotype. OBJECTIVE To compare lung physiology and high-resolution computed tomography (HRCT) findings in subjects with CAL and evidence of previous (healed) PTB with those in subjects with smoking-related COPD without evidence of previous PTB. METHODS Subjects with CAL identified during a Burden of Obstructive Lung Disease (BOLD) study performed in South Africa were studied. Investigations included questionnaires, lung physiology (spirometry, body plethysmography and diffusing capacity) and quantitative HRCT scans to assess bronchial anatomy and the presence of emphysema (<-950 HU), gas trapping (<-860 HU) and fibrosis (>-200 HU). Findings in subjects with a past history and/or HRCT evidence of PTB were compared with those in subjects without these features. RESULTS One hundred and seven of 196 eligible subjects (54.6%) were enrolled, 104 performed physiology tests and 94 had an HRCT scan. Based on history and HRCT findings, subjects were categorised as no previous PTB (NPTB, n=31), probable previous PTB (n=33) or definite previous PTB (DPTB, n=39). Subjects with DPTB had a lower diffusing capacity (Δ=-17.7%; p=0.001) and inspiratory capacity (Δ=-21.5%; p=0.001) than NPTB subjects, and higher gas-trapping and fibrosis but not emphysema scores (Δ=+6.2% (p=0.021), +0.36% (p=0.017) and +3.5% (p=0.098), respectively). CONCLUSIONS The mechanisms of CAL associated with previous PTB appear to differ from those in the more common smoking-related COPD and warrant further study.

A Case of Anti Glomerular Basement Membrane (GBM) Negative Goodpasture's Disease

Goodpastures disease is a fulminant rapidly progressive disease characterized by autoantibodies to the alpha-3 chain of type IV collagen (Goodpastures antigen). It can present as a glomerulonephritis alone, or as a pulmonaryrenal syndrome with alveolar haemorrhage. We report here a classical case of Goodpastures disease presenting as a pulmonary-renal syndrome with serum anti-glomerular basement membrane (GBM) antibody negativity and positive perinuclear anti-neutrophil cytoplasm antibodies (p-ANCA).