Advances in the Understanding and Treatment of Male Urethritis

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1 SUPPLEMENT ARTICLE Advances in the Understanding and Treatment of Male Urethritis Laura H. Bachmann, 1 Lisa E. Manhart, 2 David H. Martin, 3 Arlene C. Seña, 4 Jordan Dimitrakoff, 5,6,7 Jørgen Skov Jensen, 8 and Charlotte A. Gaydos 9 1 Division of Infectious Diseases, Department of Medicine, Wake Forest University Health Sciences, Winston-Salem, North Carolina; 2 Departments of Epidemiology and Global Health, University of Washington, Seattle; 3 Division of Infectious Diseases, Department of Medicine, Louisiana State University, New Orleans; 4 Division of Infectious Diseases, School of Medicine, University of North Carolina at Chapel Hill; 5 Division of Obstetrics/Gynecology and Reproductive Biology, Beth Israel Deaconess Hospital, and 6 Harvard School of Public Health, Boston, Massachusetts; 7 Division of Bone, Reproductive and Urologic Products, United States Food and Drug Administration, Silver Spring, Maryland; 8 Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark; and 9 Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland Neisseria gonorrhoeae and Chlamydia trachomatis are well-documented urethral pathogens, and the literature supporting Mycoplasma genitalium as an etiology of urethritis is growing. Trichomonas vaginalis and viral pathogens (herpes simplex virus types 1 and 2 and adenovirus) can cause urethritis, particularly in specific subpopulations. New data are emerging regarding the potential role of bacterial vaginosis associated bacteria in urethritis, although results are inconsistent regarding the pathogenic role of Ureaplasma urealyticum in men. Mycoplasma hominis and Ureaplasma parvum do not appear to be pathogens. Men with suspected urethritis should undergo evaluation to confirm urethral inflammation and etiologic cause. Although nucleic acid amplification testing would detect N. gonorrhoeae and C. trachomatis (or T. vaginalis if utilized), there is no US Food and Drug Administration approved clinical test for M. genitalium available in the United States at this time. The varied etiologies of urethritis and lack of diagnostic options for some organisms present treatment challenges in the clinical setting. Keywords. urethritis; men; Chlamydia trachomatis; Mycoplasma genitalium; Neisseria gonorrhoeae. Urethritis is a common genitourinary syndrome encountered in men in clinical practice. This entity is associated with a variety of etiologic agents including Neisseria gonorrhoeae (GC), Chlamydia trachomatis (CT), Mycoplasma genitalium (MG), Trichomonas vaginalis (TV), Ureaplasma urealyticum (UU), herpes simplex virus (HSV), and adenovirus [1]. Although seemingly a minor condition, urethritis cases are estimated to be 2.8 million in the United States each year [2] and can be associated with complications including acute epididymitis, orchitis, and prostatitis. This article summarizes new data on the etiology of male urethritis and its diagnosis and clinical management, using the Correspondence: Laura H. Bachmann, MD, MPH, Medical Center Blvd, Wake Forest University Health Sciences, Winston-Salem, NC (lbachman@wakehealth. edu). Clinical Infectious Diseases 2015;61(S8):S763 9 The Author Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please journals.permissions@oup.com. DOI: /cid/civ755 background material that informed the most recent update of the US Centers for Disease Control and Prevention (CDC) sexually transmitted diseases (STD) treatment guidelines. METHODS A PubMed (US National Library of Medicine and the National Institutes of Health) search was conducted of all literature published between 2 February 2009 and 8 January 2013 using the search term urethritis (249 articles), limited to human studies published in English. Given the increasing recognition of MG as a urethral pathogen, the search term M. genitalium was also added (224 articles). Subsequent to the dates of the literature review, the National Center for Biotechnology Information sent notifications of all publications with the keyword(s) urethritis and/or M. genitalium. Abstracts from relevant conferences (conferences focused on STDs, infectious diseases, and/or microbiology Treatment of Male Urethritis CID 2015:61 (Suppl 8) S763

2 that took place during the defined dates above) were also identified, searching hard copies and online, using the search terms urethritis and/or M. genitalium. All abstracts were reviewed, and pertinent published articles (n = 95) were evaluated. After each article was read, a determination was made as to whether it provided data relevant to the scope of the CDC treatment guidelines. Pertinent articles were summarized and entered into a table of evidence that was used to inform the key questions (Table 1) addressed in the guidelines document. Due to space limitations, not all of these questions are addressed in this article. Etiologies of Urethritis The role of GC and CT as etiologic agents in symptomatic and asymptomatic urethritis is well established. It is estimated that approximately 5% 20% of urethritis is caused by gonococcal infection, with prevalence varying by region of the United States, testing venue, age, and symptom status of the patient [1]. Nongonococcal urethritis (NGU) in men may be caused by a variety of different organisms. Chlamydia trachomatis causes a variable percentage of NGU cases, depending on the population studied, with ranges that vary from 15% to 40% in US populations. Among NGU cases with an identified etiology, CT is responsible for the highest proportion, particularly among younger individuals [3]. However, a significant proportion of men with NGU have no detectable pathogens [4, 5]. Table 1. Key Questions Addressed for the 2015 Centers for Disease Control and Prevention Sexually Transmitted Diseases Treatment Guidelines 1. How should the urethritis syndrome be characterized? 2. What are the specific microbial etiologies of urethritis/ngu and associated epidemiology? 3. Should asymptomatic men be screened for evidence of NGU? 4. What are the criteria for a clinical diagnosis of urethritis/ngu (in symptomatic men)? 5. What should be the recommended confirmatory diagnostic (and screening) tests for Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium, and Trichomonas vaginalis? 6. What are the currently recommended treatment regimens for NGU? 7. What should be the recommendations regarding empiric treatment of urethritis (ie, in situations when point-of-care diagnostic tools are unavailable)? 8. How should persistent/recurrent urethritis be managed? 9. What should be the partner management recommendations for NGU? 10. Are there special considerations for the management of urethritis in HIV-infected men? 11. What is the effect of medical male circumcision on urogenital Mycoplasma genitalium among men? Abbreviations: HIV, human immunodeficiency virus; NGU, nongonococcal urethritis. Mycoplasma genitalium is now recognized as a common etiologic agent of NGU; it is estimated in the published literature to cause 15% 25% of NGU cases overall, ranging from 13% to 31% in more recent randomized controlled NGU treatment studies [3, 5, 6]. Data support an association of the organism with symptoms of NGU as well as an association with microscopic evidence of inflammation (odds ratio > 4) [7]. Although the role of MG in causing acute and persistent urethritis in men is well established, the importance of this pathogen in causing short- or long-term health complications in men is not clear. For instance, MG was reported in 4% of men with prostatitis in one uncontrolled study [8], but additional studies are clearly needed to further define MG s role in male genitourinary tract complications. In contrast, Mycoplasma hominis is unlikely to be an important etiology of NGU based on the literature to date [1]. Studies of the role of Ureaplasma in the pathogenesis of urethritis have been inconsistent. Ureaplasmas can be isolated by culture from 30% 40% of asymptomatic men, and have been associated with NGU in some studies but not others. After the division of the ureaplasmas into 2 separate species (Ureaplasma urealyticum [UU], formerly U. urealyticum biovar 2, and Ureaplasma parvum [UP], formerly U. urealyticum biovar 1), it has become apparent that the inconsistencies may, to some extent, be explained by differences in pathogenicity between species. Newer studies suggest that UU is associated with nonchlamydial NGU in some cases. Using quantitative polymerase chain reaction (PCR), Frolund et al found UU in 13% of NGU cases (>5 polymorphonuclear cells per high-power field [PMNs/hpf]) and 12% of controls (<5 PMNs/hpf) (P = not significant). The median UU DNA load, however, was higher in men with NGU vs no NGU (median, 223 vs 10 genome equivalents; P =.002) [9]. Overall, UU as detected by species-specific PCR has been weakly associated with NGU, particularly among younger men and in men with fewer sexual partners [9]. UU should be considered in men without other identifiable etiologies of NGU. However, UP does not appear to be a urethral pathogen [9 12]. Rates of TV vary by age and geography, with ranges from 2% to 13% in the United States [5, 6, 13, 14]. For instance, a large internet-based study of self-collected penile swabs for the diagnosis of TV among men reported a TV prevalence of 6% overall, with higher rates among black men (9.2%) and men years of age (8%). Age >30 years, black race, younger age of sexual debut, and the presence of urethral symptoms were all significant predictors of TV infection in multivariate analyses [14]. Another study by Gaydos et al [13] found that TV was not associated with urethritis on multivariate analysis in a population of men attending a Baltimore STD clinic. There are few data on viruses, including HSV and adenovirus, as an etiology of NGU. Urethritis is commonly seen S764 CID 2015:61 (Suppl 8) Bachmann et al

3 (15% 30%) in patients with primary HSV and less common, though documented, in recurrent HSV. In a recent study, Frolund and colleagues found HSV-1 in 3% of NGU cases and HSV-2 in 2% of cases [9]. Adenovirus has been identified in men with NGU associated with upper respiratory tract symptoms. Bradshaw et al [15] described 8 cases of adenovirusassociated urethritis in which no other causative organism was isolated. All of the cases reported recent insertive oral sex (7 reported recent insertive vaginal sex as well) and were clustered in autumn and winter of each year. The authors concluded that adenovirus is an uncommon cause of urethritis in men but should be considered in men presenting with dysuria, meatitis, and associated conjunctivitis or constitutional symptoms. There are some data on the role of enteric organisms in urethritis, especially from rectal exposure. Gram-negative rods may represent a urinary tract infection or be associated with insertive anal sex. Insertive oral sex is the only exposure in some cases of nonchlamydial NGU and respiratory tract pathogens such as Haemophilus species, Neisseria meningitidis, Moraxella catarrhalis, andstreptococcus pneumoniae have been associated with male NGU, although controlled studies are lacking [16]. Uncultured or fastidious organisms commonly found in bacterial vaginosis (BV) have also been associated with urethritis. For instance, Leptotrichia/Sneathia was significantly associated with nonchlamydial NGU in one study (25/157 [15.3%] vs 6/102 [5.9%]; P =.03), and BV-associated bacterium 2 (BVAB-2) was detected more often in cases than controls [17]. Frolund et al studied men (N = 58) with and without NGU ( 5PMNs/hpf), without GC, CT, MG, UU, or UP and tested them for BVassociated organisms by PCR (Atopobium vaginae, Sneathia sanguinegens, Leptotrichia amnionii, Gardnerella vaginalis, BVAB 1, 2, 3 and Megasphaera phylotype 1). They found G. vaginalis in 93% of cases with urethritis of unknown etiology vs 37% controls (P <.0001), but there was no difference in organism load between conditions [18]. Therefore, a small number of studies have shown that specific organisms associated with BV may be associated with urethritis, but further studies are needed. Recent studies utilizing high-throughput sequencing have contributed to knowledge of the urethral microbiome. Ahrens et al found a median of 60 genera in urethritis of unknown etiology, 67 genera in CT-positive or MG-positive individuals, and 45 genera in controls [19]. Nelson and colleagues found that urine from sexually active men often contains complex microbial communities and that the composition of the communities is related to sexually transmitted infections (STIs). Men with an STIweremorelikelytohaveSneathia, Gemella, Aerococcus, Anaerococcus, Prevotella, andveillonella, for instance [20]. Aerococcus, Anaerococcus, Prevotella, and Veillonella have previously been detected in the prostate tissue of men with category III chronic prostatitis/chronic pelvic pain syndrome [8]. These findings suggest a role for urethral bacterial communities in the natural history of urethritis and prostatitis. Unfortunately, despite progress in determining the etiology of urethritis, many cases of NGU (20% 40%) still have no identified pathogen [21]. Making the Diagnosis of Urethritis The clinical presentation of urethritis is characterized by urethral discharge, dysuria, urethral irritation, or meatal pruritus and is confirmed by evidence of inflammation and/or the presence of a known pathogen. Objective evidence of inflammation includes any of the following: (1) discharge on exam, (2) increased number of PMNs on Gram stain smear of urethral exudate, (3) positive leukocyte esterase on urine dipstick testing, or (4) increased PMNs in the sediment of first-void urine (with or without a Gram stain). Approximately 30% 50% of men with microscopic evidence of urethritis are asymptomatic. This proportion may be higher depending on the study setting and methods for documenting inflammation. It is unclear whether evidence of urethral inflammation in the absence of symptoms and a known pathogen has clinical significance. Traditionally, the urethral Gram stain has been utilized as the point-of-care test to diagnose urethritis in many healthcare settings. A new technique (methylene blue/gentian violet [MB/ GV] smear) has been reported as an alternative to Gram staining. MB/GV does not require heat fixation and has very similar performance characteristics to Gram stain. Taylor et al [22] found the sensitivity of both Gram stain and MB/GV to be 97.3% for the detection of gonococcal infection compared with culture. The specificity of Gram stain and MB/GV was 99.6%, and 100% correlation was found between Gram stain and MB/GV for the detection of GC. Although the criteria for the clinical diagnosis of NGU are well accepted and commonly used to define NGU for research purposes, the high rates of CT and MG infection among those with <5 WBCs (the historical cutoff for a significant number of white cells required for the diagnosis of urethritis [23]) has been a cause for concern. Given the fact that the sensitivity of the urethral Gram stain is highly dependent upon collection technique (experience of provider as well as device utilized [ie, swab vs loop vs spatula with increasing yields in the same order]), several studies have demonstrated that a substantial number of pathogen-positive NGU cases are missed with current Gram stain criteria. An earlier study [24] found that treatment based on 5 PMNs on the Gram stain would treat 82% of CT cases and 94% of GC cases; among patients with <5 PMNs, treating those with symptoms or contact to disease would treat an additional 6% of CT and 1% of GC identified using nucleic acid amplification tests (NAATs). Rietmeijer and Mettenbrink [25] performed a recent study of Gram stains for CT analysis and Gram stains for GC analysis. Samples were collected Treatment of Male Urethritis CID 2015:61 (Suppl 8) S765

4 by directly collecting the discharge on a glass slide (if discharge was present spontaneously or after manual expression) or using calcium alginate swabs (if no obvious discharge was present). CT positivity rates correlated strongly with the number of PMNs/hpf in a stepwise fashion. Almost 5% of those with 0 PMNs/hpf had CT compared with 43.8% if there were >10 PMNs/hpf. There was a statistically significant increase in the CT infection rate between 1 (6.6%) and 2 (16.2%) PMNs/hpf. There was no trend in GC detection by PMN strata (only 2.3% had <10 PMNs). Couldwell et al [10], using rayon-tipped swabs in an Australian STD clinic based study, found that 35% of CT, 60% of UU, and 50% of MG infections had <5 PMNs/ hpf. Similarly, Berntsson et al [26], using a plastic loop collection method in an STD clinic in Sweden, found that 15% of CT cases and 12.5% MG cases had <5 PMNs/hpf. In contrast, Moi et al [27] obtained samples for microscopy from 8468 men using a spatula and detected 98% of all CT infections and 99% of all MG infections using a cutoff of 5 PMNs/hpf.In summary, depending on the sampling technique, the Gram stain threshold for NGU ( 5 PMNs/hpf), when applied to men in the STD clinic venue, may miss a significant proportion of individuals with CT and MG. Given the recent data, a threshold of 2 PMNs/hpf on the urethral Gram stain could now be considered as a criterion to diagnose NGU in highrisk settings, particularly in venues where the rate of loss to follow-up is high. Pathogen-Specific Screening Tests Among Men With Urethritis: Rationale and Recommended Tests Nucleic Acid Amplification Tests The CDC released permissive guidelines for CT screening in males in high-prevalence settings [28]. In general, males should be screened for CT ± GC based on risk (young age, sexual orientation, sexual risk, sexual contact, other STI diagnosis). The recent CDC laboratory testing guidelines now recommend the use of NAATs for testing men for both CT and GC, unless culture is desired to perform susceptibility testing for GC. Firstvoid urine is the specimen of choice for NAATs in men, though the urethral swab specimen remains an option [29]. In general, most NAATs find more pathogens from urine than urethral swabs, with no statistical difference in pathogen detection between urine and urethral swabs [29]. Microscopic tests for trichomonas in men (urine wet mount) are neither sensitive nor specific. Culture can be used to test males, but it has poor sensitivity and would require multiple specimen types. Newer NAATs have superior test performance for diagnosing TV in males [30], although none are cleared by the US Food and Drug Administration (FDA) for use in men. Several large reference laboratories have performed verification studies for TV NAAT tests for men using NAAT assays that are only FDA-cleared for use with female samples. However, the low prevalence of TV in NGU does not warrant using such tests in the initial workup, although consideration could be given to utilizing them among male sexual partners to women with trichomoniasis and in other male populations in highprevalence areas of the country. NAAT-based research tests for MG have been developed and are both sensitive and specific for identifying the organism, although there are no FDAcleared tests currently available in the United States. Several large reference laboratories offer male testing for MG after having internally validated NAAT assays previously restricted to research use. Overall, the value of additional tests (eg, NAATs) for other NGU etiologies such as the viral pathogens is unclear. Urethritis Treatment: What Is New? Despite the evolving data regarding the association of new pathogens with urethritis in men, the 2015 CDC-recommended treatment for urethritis will remain the same as the regimens recommended in The initial treatment for NGU should include azithromycin 1 g orally in a single dose or doxycycline 100 mg orally twice a day for 7 days. Alternative regimens include erythromycin base 500 mg orally 4 times a day for 7 days, or erythromycin ethylsuccinate 800 mg orally 4 times a day for 7 days, or levofloxacin 500 mg once daily for 7 days or ofloxacin 300 mg twice a day for 7 days. In clinical settings where diagnostic studies are not available to exclude GC (ie, Gram stain or MB/GV stain), patients should be treated with drug regimens effective against both GC and CT (Figure 1). Prior studies demonstrated good efficacy for azithromycin and doxycycline in the treatment of NGU caused by CT. However, recent data are conflicting regarding cure rates for CT in men with NGU, utilizing NAATs for CT detection. These data may be confounded by the use of clinical or microbiologic definitions of cure as well as by the timing of test of cure. Schwebke and colleagues reported a 95% clearance rate for CT with doxycycline compared to 77% for azithromycin [5], whereas Manhart found no differences based on microbiologic cure for CT [6]. A more recent study that harmonized definitions of NGU, time frames for follow-up test of cure, and controlled for sexual reexposure found the CT treatment failure rate for azithromycin to be only 6.6% [31]. The treatment of NGU is made more complicated by the challenge of effective treatment for MG. Doxycycline is only 20% 35% effective against MG, whereas azithromycin is estimated to be 70% effective. However, a recent US-based NGU treatment trial found that cure rates for MG were extremely low for both azithromycin and doxycycline (40% vs 30%, respectively; P =.41)[5, 6, 32, 33]. Unfortunately, there is increasing evidence that suboptimal treatment of MG may select for rapid macrolide resistance in those who fail [34, 35]. A survey of specimens in Denmark reported that almost 40% of MG specimens were resistant to macrolides, raising S766 CID 2015:61 (Suppl 8) Bachmann et al

5 Figure 1. Treatment algorithm for nongonococcal urethritis (NGU). Abbreviations: BID, twice daily; PO, per oral; QD, once daily; QID, 4 times daily. concerns about the future of azithromycin for NGU treatment [36]. For patients with macrolide-resistant MG infections, moxifloxacin is currently the only treatment option for which limited data are available [37 40]. In summary, MG treatment failure following the currently recommended NGU regimens is extremely common and NGU treatment should ideally be guided by etiologic diagnosis [36, 41]. In practice, this will be difficult until affordable licensed assays are on the market. Several recent studies have shed light on the question of whether initial TV treatment is beneficial in men presenting with NGU. Schwebke and colleagues [5] conducted an STD clinic based, multicenter randomized controlled trial to evaluate the addition of tinidazole to azithromycin or doxycycline for initial treatment of symptomatic men with NGU. The addition of tinidazole did not lead to increased clinical cure rates for NGU. Only 1 of 20 (5%) tinidazole-treated patients with TV at baseline remained positive at follow-up and of those with baseline TV who did not receive tinidazole, 5 of 16 (31%) remained positive. Thus, 69% of men with TV who did not receive tinidazole spontaneously resolved their infection (73% of these had cleared by first follow-up visit). At this time, the accumulated evidence fails to support empiric treatment of TV infection for an initial episode of NGU. Persistent/Recurrent NGU: Recommended Approach Persistent/recurrent NGU often represents a diagnostic and therapeutic challenge. It is estimated that 20% 40% of NGU does not respond to first-line treatment, with up to 20% of men with chlamydial NGU and 30% 50% of men with nonchlamydial NGU experiencing persistence/recurrence. These high rates are derived from research studies and are defined based on elevated white blood cells on urethral smear, often in the absence of symptoms, thus accounting for why the clinician does not encounter high numbers of men returning voluntarily complaining of persistent/recurrent disease [5, 6, 33]. The differential diagnosis for recurrence includes reinfection, nonadherence, drug resistance, a persistent postinfectious immunologic response, and complicated infection. A good history can guide the clinician s assessment regarding the likelihood of these scenarios. At the time of clinical presentation, the first priority is to determine whether or not reinfection is likely (in which case the patient should be re-treated with a recommended regimen for NGU) or if clinical failure is a possibility, in which case treatment approaches differ as discussed below. These patients should be documented to have objective evidence of inflammation on examination as described above. If the patient is not likely to have been reinfected and he has Treatment of Male Urethritis CID 2015:61 (Suppl 8) S767

6 etiologic agents continues to evolve as technology improves and new diagnostic tests continue to be developed. The evolving role of antibiotic-resistant MG as well as new data regarding the prevalence of TV and other new etiologic agents in male urethritis will continue to impact therapeutic strategies for this disease entity. Figure 2. Association of Chlamydia trachomatis (CT), Mycoplasma genitalium (MG), and Trichomonas vaginalis (TV) with microbiologic and clinical failure. V2, visit 2; V3, visit 3; clinical failure at V2, persistent symptoms and 5 polymorphonuclear cells per high-power field (PMNs/ hpf) on urethral smear or persistent urethral discharge; clinical failure at V3, 5 PMN/hpf on urethral smear or persistent urethral discharge regardless of symptoms. Adapted from Seña et al [44]. evidence of inflammation on exam, evaluation and therapy for persistent NGU are indicated. Cross-sectional studies of men seeking evaluation for persistent/ recurrent NGU suggest that CT and TV are responsible for some cases, while MG is responsible for 12% 41% of cases [38, 42, 43]. The contribution of viral pathogens to persistent/recurrent NGU is unclear at this time. Seña et al [44] conducted a secondary data analysis from a large NGU trial, and reported that 33 of 245 (13%) men with NGU who were reassessed at visit 2 (1 week after posttreatment) had clinical failure 9% were CT infected, 33% MG infected, and 12% TV infected. Among the men who returned for visit 3 (3 4 weeks posttreatment), 10% had CT, 25% MG, 10% TV, and 56% no pathogen (Figure 2). Therefore, CT and TV may be associated with persistent NGU, the prevalence of which likely varies by subpopulation and is based on the initial treatment regimen. Given the strong evidence that MG is associated with NGU and that failure to eradicate MG is associated with persistent urethritis, moxifloxacin 400 mg orally once daily for 7 days and treatment for TV with either metronidazole or tinidazole are recommended in the CDC guidelines for treatment of persistent NGU after initial azithromycin therapy. Men with persistent/recurrent NGU who received doxycycline, ofloxacin, or levofloxacin as initial therapy should receive azithromycin 1 g orally once and therapy for TV. Given the extremely low prevalence of TV in men who have sex only with men, this population has a low likelihood of benefiting from the addition of TV-directed therapy in this situation and should be treated with MG-active agents only (Figure 1). CONCLUSIONS Urethritis is an extremely common problem encountered in a variety of clinical settings. Knowledge regarding potential Notes Disclaimer. The views and opinions expressed in the present manuscript do not reflect the views and opinions of the United States Food and Drug Administration or the United States Government. Supplement sponsorship. This article appears as part of the supplement Evidence Papers for the CDC Sexually Transmitted Diseases Treatment Guidelines, sponsored by the Centers for Disease Control and Prevention. Potential conflicts of interest. L. E. M. is a board member for Qiagen, Inc, and Hologic/Gen-Probe and has received research supplies from Hologic/Gen-Probe. J. S. J. receives funding from Cempra Pharmaceuticals and NabrivaPharmaceuticals.D.H.M.isaconsultantforHologic,Inc. C. A. G. receives research support from Hologic, Inc and Becton Dickinson. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. References 1. 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