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Featured Articles
Improving the diagnosis of pulmonary tuberculosis in hard-to-reach patients in London, UK
Developed countries have not escaped the rise in cases of multidrug-resistant tuberculosis. In the UK a mobile X-ray unit has been operating in London since 2005 and this service has been augmented with point-of-care testing (POCT) since 2011. POCT has been well received by patients and has greatly reduced the number of unnecessary hospital visits.
by Dr R. J. Shorten and Dr A. Story
Background
Tuberculosis (TB) is an infectious disease caused by the bacterium Mycobacterium tuberculosis. TB is primarily a respiratory disease, although it can affect any part of the body and it is spread from person to person via expectorated droplets by individuals with active pulmonary disease. TB is a significant international problem and in 1993 the World Health Organization declared tuberculosis a global emergency [1]. In 2012 there were 8.6 million new cases and 1.3 million deaths, the vast majority of these occurring in Asia and sub-Saharan Africa [2].
Multidrug-resistant TB
This global epidemic is further complicated by the increase in drug resistant M. tuberculosis. Multidrug-resistant TB (MDR-TB) is a form of TB caused by bacteria that do not respond to, at least, isoniazid and rifampicin, the two most effective, first-line anti-TB drugs. There were approximately 450 000 cases of MDR-TB globally in 2012. More than half of these cases were in India, China and the Russian Federation [2].
This epidemic has not been avoided in developed countries and following a century of decline, the incidence of TB in the UK has been rising since 1988. Data from Public Health England [3] shows that the majority of these cases are concentrated in urban areas, with almost 40% being in London (3426 cases in 2012). Additionally, one or more of the following risk factors were present in 7.3% of cases; history of problem drug use, alcohol misuse/abuse, homelessness or imprisonment. Furthermore, some of these individual risk factors are associated with smear positivity (those patients who are more likely to be contagious), drug resistance, poor adherence to treatment and loss to follow up [4]. Indeed, the growing problem of TB in these hard-to-reach groups has led to specific UK guidance [5].
Searching for patients
Find & Treat was established in 2005 to strengthen TB control in the socially excluded communities of London by working with over 200 partner organizations. The service has been evaluated as an innovative and cost-effective health and social care model [6]. The mobile X-ray unit (MXU) has been operating in London since this time and screens approximately 8000 patients per year (Fig. 1). It is staffed by TB nurse specialists, reporting radiographers, social workers and outreach workers and former TB patients with a lived experience of homelessness who work are Peer Educators. Its role is to identify hard-to-reach patients with suspected TB using digital chest radiographs. These patients are then linked into local healthcare provision via Accident & Emergency (A&E) departments or community TB programmes. In December 2011 the service was augmented with the Xpert MTB/RIF assay (Cepheid, Sunnyvale, California, USA), which was used as a point-of-care test (POCT) for the molecular detection of M. tuberculosis in sputum [7].
Point-of-care testing
Prior to the implementation of the Xpert assay, if a digital chest radiograph indicated active pulmonary TB (seen in 1–2% of patients screened), then the patient underwent immediate referral to the nearest hospital with a TB service. This involved a TB nurse specialist or outreach worker accompanying the patient to an A&E department for assessment, conventional microbiological investigation and possible admission. Approximately 20% of referred patients are subsequently confirmed to have TB and are initiated on a complex course of multiple antibiotics over a period of at least 6 months [8].
The Xpert MTB/RIF assay is a nucleic acid amplification test (NAAT). The easy to use analyser extracts, amplifies and detects DNA of M. tuberculosis in the patients’ sputum. The assay also detects approximately 95% of the common rifampicin resistance-conferring mutations in the rpoB gene (a surrogate marker of multidrug resistant TB) [9].
The hands-on time of the assay is minimal and a specimen container with a rubber septum in the lid allows the staff on the MXU to safely process sputum samples without the need for containment facilities or a microbiological safety cabinet (Fig. 2). MXUs exist in other European cities, but we believe that this is the first example of a NAAT POCT being used in this way anywhere in Europe.
Patients with abnormal X-rays that indicate active pulmonary TB are asked whether they can produce sputum. Those who can, expectorate a sample into the specific sample container. They seal the container and return it to the team on the MXU who assess the sputum for quality (sputum, rather than watery saliva is required). The sample reagent is carefully added through the rubber septum in the lid and swirled gently to allow homogenization of the sample. This process ensures that minimal aerosols are generated and that they are not released to cause exposure to the operator. The assay takes approximately 2 hours in total and the result will determine whether the patient requires immediate referral to a TB service. Patients with negative NAAT are followed up by two further sputum samples, including one early morning specimen, collected in the community and processed for routing smear microscopy and culture in hospital laboratories. Due to the high negative predictive value of the assay (94%) and the increased sensitivity compared to sputum microscopy [10], it is highly unlikely that any infectious cases will go undetected using this algorithm.
Considerations and advantages of POCT for TB
As the POCT is performed by non-laboratory staff, it is imperative that the MXU staff are comprehensively trained and assessed for competence. None of the staff had any laboratory or analytical experience prior to the implementation of this assay. Registered clinical laboratory staff are involved in all stages of implementation and training. A close working relationship between the MXU team and the clinical laboratory is required to ensure appropriate refresher training and review of standard operating procedures and risk assessments.
The assay has been well received by patients, particularly as a negative result prevents a referral to hospital. This allows MXU staff to focus resources on screening more patients, rather than accompanying patients to hospital who subsequently are confirmed to be clear of TB. The MXU regularly screens in custodial settings where capacity to effectively isolate suspected cases is limited and significant resources are required accompanying patients with suspected TB to hospital appointments for further investigations. The value of the assay in determining which patients are potentially infectious is especially useful in these settings. The ability of the Xpert MTB/RIF to detect most cases of rifampicin resistant (and therefore likely to be MDR) TB, allows the MXU team to initiate appropriate second-line therapy more rapidly. Additionally, the simplicity and safe use of the assay has been well adopted by the MXU staff. We have demonstrated the potential of this technology in focussing resources on the most appropriate individuals and therefore improving the quality of care in this vulnerable group of patients. A randomized controlled trial to assess the benefit of using this assay on patients with an abnormal chest X-ray against them being referred to secondary care is underway to accurately quantify the benefits of this assay in tackling TB in this group of patients.
Summary
The epidemiology of TB in 21st century big cities is characterized by a concentration of disease in hard-to-reach medically underserved populations. Capacity to outreach effective diagnostic platforms directly to high risk populations is likely to become an increasingly important feature of TB control [11].
References
1. World Health Organization (WHO). Tuberculosis. Fact sheet 104, 2012. 2. WHO. Tuberculosis. Media centre; Fact sheet 104, 2014.
3. Tuberculosis in the UK: Annual report on tuberculosis surveillance in the UK, 2013. London: Public Health England 2013.
4. Story A, Murad S, Roberts W, et al. Tuberculosis in London: the importance of homelessness, problem drug use and prison Thorax 2007; 62(8): 667–671.
5. National Institute for Health and Clinical Excellence (NICE): Public health guidance. Tuberculosis – hard-to-reach groups. PH37 2012.
6. Jit M, Stagg HR, Aldridge RW, et al. Dedicated outreach service for hard to reach patients with tuberculosis in London: observational study and economic evaluation. BMJ 2011; 343: d5376.
7. Boehme CC, Nabeta P, Hillemann D, et al. Rapid molecular detection of tuberculosis and rifampin resistance. N Engl J Med. 2010; 363: 1005–1015
8. NICE: Clinical guidelines. Tuberculosis: Clinical diagnosis and management of tuberculosis, and measures for its prevention and control. CG117 2011. (http://guidance.nice.org.uk/CG117)
9. Zhang Y, Yew WW. Mechanisms of drug resistance in Mycobacterium tuberculosis. Int Tuberc Lung Dis. 2009; 13(11): 1320–1330.
10. O’Grady et al. Evaluation of the Xpert MTB/RIF assay at a tertiary care referral hospital in a setting where tuberculosis and HIV infection are highly endemic. J Clin Infect Dis. 2012; 55(9): 1171–1178.
11. van Hest NA, et al. Tuberculosis control in big cities and urban risk groups in the European Union: a consensus statement. Euro Surveill. 2014;19(9): Article 7.
The authors
Rob J. Shorten1* BSc, MSc, PhD and A Story2 RGN MPH PhD
1Clinical Scientist, Department of Medical Microbiology, Central Manchester Foundation Trust and Honorary Research Associate, University College London Centre for Clinical Microbiology, UK
2Clinical Lead Find & Treat, University College Hospitals NHS Foundation Trust, London, UK
*Corresponding author
E-mail: rob.shorten@nhs.net
Fungal antigen detection as an aid for diagnosis of invasive fungal infections
Immunocompromised hosts are at special risk for invasive fungal infections (IFI). Traditional methods of diagnosis (e.g. culture and molecular methods) largely suffer from poor sensitivity, thus limiting their clinical utility. Enzyme immunoassay-based detection of fungal antigens represents an attractive, supplementary method for IFI identification and is the focus of this review.
by Phillip R. Heaton and Elitza S. Theel
Background
Invasive fungal infections (IFI) are a significant cause of morbidity and mortality in patients with hematologic malignancies and in hematopoietic stem cell transplant (HSCT) recipients. Although Aspergillus species and Candida albicans are among the most common agents of IFI, an increasing incidence of IFI due to other filamentous fungi (e.g. Fusarium, Zygomycetes) and non-albicans Candida (e.g. C. tropicalis, C. krusei, C. glabrata) has been reported. Currently, IFI diagnosis is based on clinical evaluation, radiologic imaging (both of which may lack clinical specificity) and culture-based laboratory findings. Unfortunately, culture of the aforementioned fungi from bronchoalveolar lavage fluid (BAL) and blood, the most commonly collected specimens in suspected IFI cases, suffers from poor sensitivity: only 45 to 60% of BAL specimens and up to 50% of blood cultures yield fungal growth [1]. Additionally, as some fungi are common in the environment (e.g. Aspergillus), providers must determine whether growth from BAL cultures is indicative of invasive disease or colonization of the respiratory tract. Finally, procedures to collect alternative specimens, including lung tissue, are often contra-indicated due to the critical state of the patient. These limitations have led to a clinical need for alternative methods to identify IFI – techniques independent of culture, which are both sensitive and specific. This demand has driven the development of novel assays to detect fungal biomarkers including the Aspergillus galactomannan (GM) antigen, the (1→3) β-D-glucan (BDG) polysaccharide common to many fungi, and the Candida mannan antigen (Mn-A). This brief review will discuss the clinical utility, advantages and limitations of GM, BDG and Mn-A detection assays in patients at risk for IFI.
Detection of the Aspergillus galactomannan antigen
Galactomannan, composed of a mannan core and highly immunogenic galactofuranosyl side chains, is a dominant cell wall component present in the majority of clinically relevant Aspergillus species and is released during hyphal growth into surrounding tissue (Fig. 1). Currently, the Platelia Aspergillus antigen (Bio-Rad, Marnes-la-Coquette, France) enzyme immunoassay (EIA) is the only FDA approved assay for GM detection of in serum and BAL fluid, though other kits are also available (e.g. Pastorex kit, Sanofi Diagnostics, Pasteur, Marnes-La-Coquette, France). The Platelia EIA is a quantitative assay with GM levels ≥0.5 ng/mL considered as positive. The presence of GM in patient specimens can be used as an aid, alongside other clinical studies, to specifically detect invasive aspergillosis (IA), a potentially devastating condition encountered in 5–20% of HSCT patients [2]. The performance characteristics of the Platelia GM assay have been widely evaluated with overall favorable outcomes. Briefly, one study reported a clinical sensitivity and specificity of 94.4% and 98.8% respectively, from serum of HSCT patients with proven or probable IA [as defined by the European Organization for Research and Treatment of Cancer (EORTC) criteria], with similar positive and negative predictive values [3]. While a subsequent meta-analysis of GM studies found a significantly lower sensitivity in this patient population (58%), specificity remained comparable at 95% [4]. Notably, these results are in stark contrast to the sensitivity of this assay in other immunocompromised (ICH) patient populations, specifically in solid organ transplant (SOT) recipients, where sensitivity can be as low as 22–41% [4]. Additionally, while the kinetics of GM clearance are not yet well defined, serial testing and trending of GM levels following initiation of antifungal therapy has been shown to correlate well with patient outcome. Specifically, while persistently elevated GM levels were associated with treatment failure, a decrease of GM levels by ≥35% between baseline and week one of antifungal treatment was associated with clinical improvement [5].
Despite the advantage of rapid GM testing in serum, a readily available specimen source, and the potential to monitor response to therapy, a number of limitations affecting assay specificity have been described. First, false-positive GM reactions have been associated with prior (<12 hours) administration of piperacillin/tazobactam, a fungal-derived antibiotic [6]. Recently, however, Mikulska and colleagues demonstrated negligible GM levels in patients on piperacillin/tazobactam therapy, suggesting that modern day manufacturing practices may have improved antibiotic purity [7]. Nonspecific reactions have also been noted in patients with non-Aspergillus IFI, including Fusarium and Penicillium (an exceedingly rare agent of IFI which also expresses GM) species infections and in individuals with either graft versus host disease (GVHD) or a damaged intestinal wall through which GM from food products can translocate [8].
Detection of β-D-glucan, a pan-fungal biomarker
(1→3)-β-D-glucan (BDG) is an abundant cell wall polysaccharide found in most fungi with the exception of Cryptococcus species, the Zygomycetes and Blastomyces dermatitidis (Fig. 2). The most commonly used BDG detection method, the Fungitell assay (Associates of Cape Cod, East Falmouth, MA), is a quantitative EIA (values ≥60 pg/mL considered positive) which detects BDG in serum using a modified version of the Limulus (horseshoe crab) clotting cascade. As a pan-fungal biomarker, BDG detection in patients with hematologic malignancies and HSCT recipients has been associated with high clinical specificity (76–99%) and negative predictive values (87–96%) for the presence of proven or probable IFI [9]. Similar to the GM assay however, inclusion of other ICH groups (e.g. SOT patients) dramatically lowers the performance characteristics of this assay. Interestingly, regardless of the patient population, the associated clinical sensitivity and positive predictive value of the BDG assay are generally poor (range 38 – 80%), collectively indicating that a single, negative BDG result should not be used to exclude the diagnosis of IFI [9]. Serial BDG testing, however, can significantly improve the clinical sensitivity of this assay and trending BDG levels during antifungal therapy has some prognostic value with respect to treatment failure or response, particularly in patients with disseminated candidiasis [9, 10]. Furthermore, BDG was shown to be detectable in critically ill patients prior to development of clinical symptoms, radiological findings or culture positivity, suggesting that in patients at increased risk for IFI, the presence of BDG should warrant further evaluation to identify an infectious process [11]. Finally, in patients with Pneumocystis jirovecii pneumonia (PjP), for whom invasive BAL or biopsy procedures are often precluded due to safety concerns, the demonstration of elevated BDG levels has been associated with high clinical sensitivity (>95%) [12]. Though this data is encouraging, especially in light of the limited sensitivity of current diagnostic methods to detect P. jirovecii, due to the pan-fungal nature of BDG, a positive result cannot be used to diagnose PjP pneumonia; a negative BDG finding can, however, be used to potentially exclude P. jirovecii as the causative agent.
The greatest limitation of BDG assays is their poor specificity. Many studies have now documented the generation of false-positive results in patients who received or have been exposed to albumin, intravenous immunoglobulin, amoxicillin-clavulanic acid, gauze during surgery, or cellulose based filters during dialysis. Additionally, infection with certain bacterial agents, including Alcaligenes faecalis, can also lead to false-positive results. Therefore, providers using these assays must confidently exclude these confounding factors prior to interpreting BDG results.
Detection of the Candida mannan antigen
The Candida Mn-A is an oligomannan cell wall component which can be detected by multiple quantitative EIAs (Fig. 3). Currently, the Platelia Candida Ag Plus quantitative EIA (Bio-Rad) is most commonly used. A recent meta-analysis of 14 studies evaluating the utility of Mn-A detection found significant heterogeneity in clinical sensitivity for detection of invasive candidiasis (IC), which, interestingly, appeared to be species dependent. For example, among patients with disseminated C. albicans, C. glabrata or C. tropicalis, the sensitivities ranged from 58–70%, whereas for patients with invasive C. parapsilossis and C. krusei, sensitivity of the assay ranged between 25–30% [13]. Importantly, however, despite the low sensitivity of the assay, the majority of Mn-A positive patients were subsequently confirmed as culture positive, suggesting the utility of this assay as an early diagnostic marker in at risk patients. Notably, the specificity of this assay is high (>90%) with cross-reactivity reported in patients with Geotrichum or Fusarium species infections, both fairly uncommon [14]. Due to the described performance variability and the short duration of Mn-A circulation, many authors have suggested combination testing with anti-Mn antibodies (Platelia Candida Ab Plus, Bio-Rad), which are detectable in at risk patients >10 days prior to proven candidemia [15]. One study evaluated neutropenic patients using combination testing and found that Mn-A/anti-Mn outperformed traditional diagnostic methods (cultures, radiology, and histopathology) for detection of IC with a sensitivity and specificity of 89% and 84%, respectively [15]. Based on these and other studies, current ECIL-3 recommendations support using a combination of Mn-A and antibody testing as an aid to detect IC [13].
Conclusions
The diagnosis of IFI in ICHs remains a challenge, and despite the limited sensitivity and specificity of the various fungal antigen detection assays, in 2008 the EORTC included detection of GM and BDG as supportive evidence for proven or probable IFI in specific patient populations [3]. When used appropriately (i.e. serial testing of high risk patients) and by providers knowledgeable of the associated limitations, antigen detection can be crucial marker for the identification of IFI. Future advancement of IFI diagnostics lies in the molecular arena and real-time polymerase chain reaction (RT-PCR) assays to detect fungal nucleic acid.
References
1. Singh N, Paterson DL. Aspergillus infections in transplant recipients. Clin Microbiol Rev. 2005; 18: 44–69.
2. Tamma P. The Galactomannan antigen assay. Pediatr Infect Dis J. 2007; 26: 641-642 610.1097/INF.1090b1013e318070c318525.
3. De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T, Pappas PG, Maertens J, Lortholary O, Kauffman CA, Denning DW, Patterson TF, Maschmeyer G, Bille J, Dismukes WE, Herbrecht R, Hope WW, Kibbler CC, Kullberg BJ, Marr KA, Muñoz P, Odds FC, Perfect JR, Restrepo A, Ruhnke M, Segal BH, Sobel JD, Sorrell TC, Viscoli C, Wingard JR, Zaoutis T, Bennett JE. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis. 2008; 46: 1813–1821.
4. Pfeiffer CD, Fine JP, Safdar N. Diagnosis of invasive aspergillosis using a galactomannan assay: a meta-analysis. Clin Infect Dis. 2006; 42: 1417–1727.
5. Chai LY, Kullberg BJ, Johnson EM, Teerenstra S, Khin LW, Vonk AG, Maertens J, Lortholary O, Donnelly PJ, Schlamm HT, Troke PF, Netea MG, Herbrecht R. Early serum galactomannan trend as a predictor of outcome of invasive aspergillosis. J Clin Microbiol. 2012; 50: 2330–2336.
6. Machetti M, Majabo MJ, Furfaro E, Solari N, Novelli A, Cafiero F, Viscoli C. Kinetics of galactomannan in surgical patients receiving perioperative piperacillin/tazobactam prophylaxis. J Antimicrob Chemother. 2006; 58: 806–810.
7. Mikulska M, Furfaro E, Del Bono V, Raiola AM, Ratto S, Bacigalupo A, Viscoli C. Piperacillin/tazobactam (TazocinTM) seems to be no longer responsible for false-positive results of the galactomannan assay.
J Antimicrob Chemother. 2012; 67: 1746–1748.
8. Mennink-Kersten MASH, Donnelly JP, Verweij PE. Detection of circulating galactomannan for the diagnosis and management of invasive aspergillosis. Lancet Infect Dis. 2004; 4: 349–357.
9. Lamoth F, Cruciani M, Mengoli C, Castagnola E, Lortholary O, Richardson M, Marchetti O. Beta-Glucan antigenemia assay for the diagnosis of invasive fungal infections in patients with hematological malignancies: a systematic review and meta-analysis of cohort studies from the Third European Conference on Infections in Leukemia (ECIL-3). Clin Infect Dis. 2012; 54: 633–643.
10. Jaijakul S, Vazquez JA, Swanson RN, Ostrosky-Zeichner L. (1,3)-β-D-Glucan as a prognostic marker of treatment response in invasive candidiasis. Clin Infect Dis. 2012; 55: 521–526.
11. Odabasi Z, Mattiuzzi G, Estey E, Kantarjian H, Saeki F, Ridge RJ, Ketchum PA, Finkelman MA, Rex JH, Ostrosky-Zeichner L. Beta-D-glucan as a diagnostic adjunct for invasive fungal infections: validation, cutoff development, and performance in patients with acute myelogenous leukemia and myelodysplastic syndrome. Clin Infect Dis. 2004; 39: 199–205.
12. Karageorgopoulos DE, Qu JM, Korbila IP, Zhu YG, Vasileiou VA, Falagas ME. Accuracy of β-D-glucan for the diagnosis of Pneumocystis jirovecii pneumonia: a meta-analysis. Clin Microbiol Infect. 2013; 19: 39–49.
13. Marchetti O, Lamoth F, Mikulska M, Viscoli C, Verweij P, Bretagne S. ECIL recommendations for the use of biological markers for the diagnosis of invasive fungal diseases in leukemic patients and hematopoietic SCT recipients. Bone Marrow Transplant. 2012; 47: 846–854.
14. Rimek D, Singh J, Kappe R. Cross-reactivity of the PLATELIA CANDIDA antigen detection enzyme immunoassay with fungal antigen extracts. J Clin Microbiol. 2003; 41: 3395–3398.
15. Prella M, Bille J, Pugnale M, Duvoisin B, Cavassini M, Calandra T, Marchetti O. Early diagnosis of invasive candidiasis with mannan antigenemia and antimannan antibodies. Diagn Microbiol Infect Dis. 2005; 51: 95–101.
The authors
Phillip R. Heaton PhD and Elitza S. Theel PhD*
Division of Clinical Microbiology,
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester,
Minnesota, USA
*Corresponding author
E-mail: theel.elitza@mayo.edu
How useful is screening by mammography?
Mammography was first utilized in a trial at the M.D. Anderson Cancer Center 45 years ago. After several randomized controlled trials in subsequent years demonstrated a reduction in mortality from breast cancer in screened women aged 50 to 69, mammography became the recommended approach in the US in 1976. The then European Community approved its use a decade later. Prior to this time, the majority of Western women were taught how to carry out breast self examination (BSE) and encouraged to do so on a monthly basis to allow early detection of breast cancer, a disease that one in eight women in the West will eventually develop. Mammography has remained the gold standard tool to screen for early breast cancer in symptomless older women, but its use has become increasingly controversial because of the high rate of over-diagnosis and the probably limited effect on mortality from the disease. For many women mammography is also extremely painful.
Now results from a 25 year follow-up of the Canadian National Breast Screening randomied controlled trial have been published. Approximately 90,000 women aged from 40 to 49 were allocated to either a mammography arm or a control arm; both groups were taught how to carry out BSE by a healthcare professional and were given annual physical breast examinations. The trial continued for five years, during which time 666 and 524 invasive breast cancers were diagnosed in the mammography and control arms respectively. However, during the 25 year follow-up, no difference in mortality from the disease was observed between the mammography and control arms (500 and 505 deaths respectively), demonstrating an over-diagnosis of 22% in the mammography arm. Several other studies reinforce this message. A recent report from Switzerland covering 28 years of data estimated that regular mammography prevented death from breast cancer in 0.01 to 0.02% of women, but resulted in 10% of women being recalled for further tests. Many other studies suggest that the decreasing mortality from breast cancer in recent years is the result of improvements in treatment rather than more effective diagnosis.
Authors of the Canadian study conclude that “the rationale for screening by mammography be urgently reassessed by policy makers”. Maybe the time has come to re-educate women about the benefits of BSE and how to carry out this examination, preferably with the use of one of the various clinging pads marketed for this purpose that reduce friction between breast and fingers, greatly enhancing sensitivity. And hopefully the technology of digital breast tomosynthesis will eventually replace mammography, finally offering women accurate and painless breast screening.