It would be good to have known the role of Mycoplasma genitalium in this population where asymptomatic infections by other pathogens were common and at least have mentioned it in the Discussion
Despite significant differences in testing opportunities, screening and access to care, this paper clearly sets out some important epidemiology of STIs accross Europe, particularly among MSM using PrEP. Despite this, there is no mention of sexually transmitted enteric infections, despite a recent outbreak of extensively drug resistant Shigella sonnei which has affected sexual networks of MSM accross Europe. There have been outbreaks of Shigella described in networks of MSM since the 1960s and can cause sugnificant morbidity. There are poor surveillance systems to monitor shigella outbreaks including transmssion of drug resistant organisms. More work is needed on both surveillance and shigella control strategies including awareness amongst both the communities affected and stakeholders including commissioners and public health.
The study by Dean et al. (1) on the treatment of PID was complicated and thought-provoking. Could it be that "mild" PID comprised many cases that were not PID at all? This issue bedevilled studies in the past, so why not here? Am I right in thinking that randomisation was used to try to maintain an evenness of disease severity between the two treatment arms, that is standard (SoC) with ofloxacin plus metronidazole, and an intervention arm (IA) with intramuscular ceftriaxone plus azithromycin and metronidazole? This is an important point when the outcome of each arm is to be compared. Presumably, after diagnosis treatment began without delay, not waiting for the results of microbiological tests which, in fact, showed M.genitalium in about 10% of cases in each arm, a proporttion seen by others (3) in acute PID. Standard treatment was judged to be slightly superior to the alternative treatment. Tests of microbiological cure 6 to 8 weeks after the study started showed a few azithromycin- resistant cases of M.genitalium, roughly comparable in the two arms. Not being aware of this at the start of treatment seems excusable. The reader must also realize that it was a situation experienced up to 9 years ago before an abrupt termination of the study. Today the scene is different, resistance of M.genitalium to azithromycin and other antibiotics being common (4). It has become clear that M.genitalium should be sought early followed rapidly by treatment guided by nothing othe...
The study by Dean et al. (1) on the treatment of PID was complicated and thought-provoking. Could it be that "mild" PID comprised many cases that were not PID at all? This issue bedevilled studies in the past, so why not here? Am I right in thinking that randomisation was used to try to maintain an evenness of disease severity between the two treatment arms, that is standard (SoC) with ofloxacin plus metronidazole, and an intervention arm (IA) with intramuscular ceftriaxone plus azithromycin and metronidazole? This is an important point when the outcome of each arm is to be compared. Presumably, after diagnosis treatment began without delay, not waiting for the results of microbiological tests which, in fact, showed M.genitalium in about 10% of cases in each arm, a proporttion seen by others (3) in acute PID. Standard treatment was judged to be slightly superior to the alternative treatment. Tests of microbiological cure 6 to 8 weeks after the study started showed a few azithromycin- resistant cases of M.genitalium, roughly comparable in the two arms. Not being aware of this at the start of treatment seems excusable. The reader must also realize that it was a situation experienced up to 9 years ago before an abrupt termination of the study. Today the scene is different, resistance of M.genitalium to azithromycin and other antibiotics being common (4). It has become clear that M.genitalium should be sought early followed rapidly by treatment guided by nothing other than the result of antibiotic sensitivity testing. This cannot be questioned and is an action with which the authors, according to their final comments, support. However, it is interesting that the authors of a recent publication (5) recommend using ceftriaxone, doxycycline and metronidazole as standard treatment for acute PID. Curiously, they found infection by M.genitalium was reduced considerably by metronidazole to which it is not sensitive in vitro. It seems the last word has not been said.
References
1. Dean G, Soni S, Pitt R, et al. Treatment of mild-to-moderate pelvic inflammatory disease with a short-course azithromycin-based regimen versus ofloxacin plus metronidazole : results of a multicentre, randomized control trial. Sex Transm Infect 2020
2..Taylor-Robinson D. Investigating the microbial aetiology of pelvic inflammatory disease. Sex Transm Infect. 2003; 79: 424-5.
3. Lewis J, Horner PJ, White PJ. Incidence of pelvic inflammatory disease associated with Mycoplasma genitalium infection : evidence synthesis of cohort study data. Clin Infect Dis. 2020
4. Durukan D, Doyle M, Murray G, et al. Doxycycline and sitafloxacin combination therapy for treating highly resistant Mycoplasma genitalium. Emerg Infect Dis.2020 ; 26: 1870-4.
5. Wiesenfeld HC, Meyn LA, Darville T, et al. A randomized controlled trial of ceftriaxone and doxycycline, with or without metronidazole, for the treatment of acute pelvic inflammatory disease. Clin Infect Dis. 2020: xx (xx) :1-9.
Dear editor,
We thank Dr. Latini et al. for providing the data for the potential effects of SARS-CoV-2 pandemic on sexual lifestyle and epidemiology of sexually transmitted infections (STIs).1 In the study the author highlighted the importance to check the lasting effects of SARS-CoV-2 on STIs. As China is the first country to generally alleviate lockdown of most cities since beginning of April and the returns to usual lifestyle for nearly 6 months, we’re able to tract the epidemiology of STIs during the post-outbreak period in China.
According to the monthly report disclosed by Chinese Center for Disease Control and Prevention (Accessed from http://www.nhc.gov.cn/jkj/pqt/new_list.shtml), during the lockdown period of the first quarter, the number of newly diagnosed cases of HIV, syphilis and gonorrhea were 9695, 102273 and 16439, which reduced substantially by 27.3%, 19.3% and 38.2% compared to the previous year. After lockdown alleviation, the number of new cases returned, but not exceeding the previous years. The total new cases of HIV, syphilis and gonorrhea changed by -4.4%, -5.6% and -18.9% in the second quarter and -7.8%, -9.5% and +0.7% in the third quarter compared with 2019, respectively. As the number of new STIs in China is constantly growing in the past years, the reduction of new cases of STIs in 2020 after lockdown alleviation indicates a lasting effect of SARS-CoV-2. This may result from...
Dear editor,
We thank Dr. Latini et al. for providing the data for the potential effects of SARS-CoV-2 pandemic on sexual lifestyle and epidemiology of sexually transmitted infections (STIs).1 In the study the author highlighted the importance to check the lasting effects of SARS-CoV-2 on STIs. As China is the first country to generally alleviate lockdown of most cities since beginning of April and the returns to usual lifestyle for nearly 6 months, we’re able to tract the epidemiology of STIs during the post-outbreak period in China.
According to the monthly report disclosed by Chinese Center for Disease Control and Prevention (Accessed from http://www.nhc.gov.cn/jkj/pqt/new_list.shtml), during the lockdown period of the first quarter, the number of newly diagnosed cases of HIV, syphilis and gonorrhea were 9695, 102273 and 16439, which reduced substantially by 27.3%, 19.3% and 38.2% compared to the previous year. After lockdown alleviation, the number of new cases returned, but not exceeding the previous years. The total new cases of HIV, syphilis and gonorrhea changed by -4.4%, -5.6% and -18.9% in the second quarter and -7.8%, -9.5% and +0.7% in the third quarter compared with 2019, respectively. As the number of new STIs in China is constantly growing in the past years, the reduction of new cases of STIs in 2020 after lockdown alleviation indicates a lasting effect of SARS-CoV-2. This may result from changes of sexual lifestyle or reduced hospital visits. More studies focusing on sex behaviors after lockdown alleviation are needed.
Reference：
1. Latini A, Magri F, Donà MG, et alIs COVID-19 affecting the epidemiology of STIs? The experience of syphilis in RomeSexually Transmitted Infections Published Online First: 27 July 2020. doi: 10.1136/sextrans-2020-054543
Peter J White, MRC Centre for Outbreak Analysis & Modelling and NIHR Health Protection Research Unit in Modelling and Health Economics, Imperial College London.
Other Contributors:
Joanna Lewis, MRC Centre for Outbreak Analysis & Modelling, Imperial College London.
Paddy J Horner, Population Health Sciences, and NIHR Health Protection Research Unit in Behavioural Science and Evaluation, University of Bristol.
Pitt et al. commented “asymptomatic patients are not recommended for M. genitalium testing except sexual contacts... The current approach might need rethinking if asymptomatic infections are found to be an important reservoir for AMR and/or a source of infection and disease”.[1]
Recent analysis of the POPI cohort found 4.9% (95%CrI 0.4%–14.1%) of M. genitalium infections in women progressed to pelvic inflammatory disease, compared with 14.4% (5.9%–24.6%) of Chlamydia trachomatis infections.[2] Combined with its lower prevalence this means that M. genitalium is a much less important cause of disease in women than C. trachomatis.[2]
There is considerable uncertainty in the natural history and epidemiology of M. genitalium,[3] and we don’t know the importance of asymptomatic infection in transmission. Low bacterial load might limit infectivity but a long duration of infection[2,3] means there may be many potentially-infectious sex-acts. In fact, the BASHH guidelines are motivated by concern about transmission from asymptomatic...
Peter J White, MRC Centre for Outbreak Analysis & Modelling and NIHR Health Protection Research Unit in Modelling and Health Economics, Imperial College London.
Other Contributors:
Joanna Lewis, MRC Centre for Outbreak Analysis & Modelling, Imperial College London.
Paddy J Horner, Population Health Sciences, and NIHR Health Protection Research Unit in Behavioural Science and Evaluation, University of Bristol.
Pitt et al. commented “asymptomatic patients are not recommended for M. genitalium testing except sexual contacts... The current approach might need rethinking if asymptomatic infections are found to be an important reservoir for AMR and/or a source of infection and disease”.[1]
Recent analysis of the POPI cohort found 4.9% (95%CrI 0.4%–14.1%) of M. genitalium infections in women progressed to pelvic inflammatory disease, compared with 14.4% (5.9%–24.6%) of Chlamydia trachomatis infections.[2] Combined with its lower prevalence this means that M. genitalium is a much less important cause of disease in women than C. trachomatis.[2]
There is considerable uncertainty in the natural history and epidemiology of M. genitalium,[3] and we don’t know the importance of asymptomatic infection in transmission. Low bacterial load might limit infectivity but a long duration of infection[2,3] means there may be many potentially-infectious sex-acts. In fact, the BASHH guidelines are motivated by concern about transmission from asymptomatic infections. If asymptomatic infections are not treated then one expects a greater average number of transmission events per infection than if they were treated, but those transmitted infections that cause symptoms will tend to be treatable. Alternatively, if asymptomatic infections were treated routinely with current regimens then the short-term effect would be reduced transmission, but at the cost of increased drug resistance – which frequently arises de novo on azithromycin treatment, even after doxycycline pre-treatment – leading to more hard-to-treat (or even untreatable) infections in the future. In 2010–12 16.1% of infections had AMR-conferring mutations,[1] and with widespread use of azithromycin this is likely to have increased since, considering the large and rapid increases in resistance seen elsewhere.
Ultimately, we need effective regimens and testing for resistance. We agree more modelling is required,[1] and hope a future Natsal survey will provide valuable up-to-date information on M. genitalium prevalence and drug-resistance.
References
1. Pitt R, Unemo M, Sonnenberg P, et al. Antimicrobial resistance in Mycoplasma genitalium sampled from the British general population. Sex Transm Infect 2020; 96(6):464-468.
2. Lewis J, Horner PJ, White PJ. Incidence of Pelvic Inflammatory Disease Associated with Mycoplasma genitalium Infection: Evidence Synthesis of Cohort Study Data. Clin Infect Dis 2020; [online 23 July 2020] doi.org/10.1093/cid/ciaa419
3. Birger R, Saunders J, Estcourt C, et al. Should we screen for the sexually-transmitted infection Mycoplasma genitalium? Evidence synthesis using a transmission-dynamic model. Sci Rep 2017; 7: 16162.
Competing interests None declared.
Disclaimer The views expressed are those of the authors and not necessarily those of the Department of Health and Social Care, MRC, NHS, NIHR, or Public Health England.
We apologise for the delay in responding to your letter. We were only recently notified of this by email. Thank you for taking the time to construct your letter in response to our published short report, to which you raise several points which require addressing.
Firstly we feel it is important to highlight that although this service evaluation focussed specifically on HIV, we acknowledged that the HIV sampling kit was part of a more comprehensive STI kit (syphilis, chlamydia, and gonorrhoea tests). We were upfront with this fact in our report, and therefore refute the claim by the responder that our paper failed to consider the wider test portfolio required by sexual health screening services.
Of greater concern to us, we note a major error in the calculations from the data provided by the responders for their “RRR” and “HIV result obtained/ STI kit requested” values. This is important, as the foundation of their concluding statement is based on this error. The responder's have incorrectly used the number of returned kits (256,717) instead of the number of requested kits (319,485) in calculating the RRR (request-to-return ratio) and the “HIV result obtained/STI kit requested” proportion. Applying the correct calculation, the RRR value using the responder's data is not 1.36 (256,717/188,187) but 1.70 (319,485/188,187). The “HIV result obtained/STI kit requested” proportion using the correct calculation is 58.9% (188,187/319,485) and not 73.3%...
We apologise for the delay in responding to your letter. We were only recently notified of this by email. Thank you for taking the time to construct your letter in response to our published short report, to which you raise several points which require addressing.
Firstly we feel it is important to highlight that although this service evaluation focussed specifically on HIV, we acknowledged that the HIV sampling kit was part of a more comprehensive STI kit (syphilis, chlamydia, and gonorrhoea tests). We were upfront with this fact in our report, and therefore refute the claim by the responder that our paper failed to consider the wider test portfolio required by sexual health screening services.
Of greater concern to us, we note a major error in the calculations from the data provided by the responders for their “RRR” and “HIV result obtained/ STI kit requested” values. This is important, as the foundation of their concluding statement is based on this error. The responder's have incorrectly used the number of returned kits (256,717) instead of the number of requested kits (319,485) in calculating the RRR (request-to-return ratio) and the “HIV result obtained/STI kit requested” proportion. Applying the correct calculation, the RRR value using the responder's data is not 1.36 (256,717/188,187) but 1.70 (319,485/188,187). The “HIV result obtained/STI kit requested” proportion using the correct calculation is 58.9% (188,187/319,485) and not 73.3% as they have presented. We note that using the data provided by the responder's, the successful processing proportions of their MT samples were lower than that from our DBS samples (84.6% vs 98.8% for the DBS). The data presented by the responder’s highlights there are MT processing issues once a sample has been successfully returned by the user, and we would be interested to know the reasons for these processing failures, which account for 15.4% of their returned samples (compared with 0.2% of returned DBS samples from our paper). For these reasons it becomes clear that the responder’s claims do not undermine the findings of our study.
We would like to address the responder's comments about the “low return rates for postal testing” to which the responder's regard as a shortfall within this research. As detailed in the report, data collection spanned a short 4-month period, where return rates were found to be 68.7% for MT and 66.5% for DBS. We do not accept that these rates are considered as “low”. The return rates are average when compared with other peer-reviewed published data with a STI kit return rate focus, with rates ranging from 32.8% - 84% (Osmond 2000, Elliot 2015, Cordwell 2015, Manavi 2017, Turner 2019). The impressive return rates described by the responder's are provided without much context (e.g. is this looking at a historic complete data-set of all their kit requests across the nation, or is this a snapshot over a short time period from a region, which included kits that may have been requested, but returns fell outside of the time-period?). Without this context to frame the responder's return rates to, it is impossible to make inferences on their return rates. Had they provided the same data, but stated it was from the same region as our study, these comments would have been more credible.
Some of the critiques made by the responder's were already addressed in the short report, and we fail to understand why these points have been raised again, and presented as new information. We clearly acknowledged our small sample size (550) in our limitations, and encouraged further comparative evaluations, of greater numbers, across different regions to test the robustness of our report. We additionally addressed the low processing rates of MT from our report by stating that a large proportion of samples were of insufficient volumes supplied by the kit user (accounting for 22.5% of all MT samples). Our report also addressed the disadvantages of DBS, citing a more complex extraction process, higher cost and fewer laboratories accredited to analyse these samples. The nature of the comparative review meant that assessing the “real-world true HIV negative results” was difficult in the context of service provision. Our clinical experience makes us certain that outside of the remit of prospective research, service providers would not ask its users to do two differing HIV tests (besides point-of care testing) for HIV negative results. Pragmatically, it is usually easier to verify reactive results, as most sexual health clinics will mandate repeat HIV testing with the gold standard venous blood sampling. Once again, we acknowledge this fact in our report.
Several criticisms raised by the responder's towards our laboratory methodology appear to be misplaced, and perhaps should have been directed towards the potential for operator-based (client-dependent) difficulties. We agree that MT samples used in a clinical setting and stored in controlled laboratory conditions may have remained stable in excess of 4 days (the responder's quoted 8 days for their laboratory). We know that in reality, these laboratory conditions cannot be replicated by the general public (e.g. users may leave samples on surfaces exposed to direct sunlight, or leave them in their bag for extended periods of time before posting). Furthermore, as part of the UKAS accredited laboratory validation process, the laboratory used for this report identified samples older than 4 days (stored in realistic conditions) were associated with a higher false positive HIV rate (compared to those which were under 4 days).
We would like to provide some clarity of some of the questions asked by the responder's. Regarding their comment on the lack of quantification of what was considered a haemolysed sample. We can confirm that this process was two-stage. Obviously haemolysed blood was rejected manually. Borderline samples however, were still put through the analyser, and those which were rejected by the instrument software were deemed to have been done so due to haemolysis.
Regarding the responder's commentary about the quoted sensitivities and specificities of the assays; these standardised references are explicitly with reference to venous blood samples and not capillary blood samples. The quoted sensitivities and specificities are not necessarily transferrable between the two, and laboratory-based validation processes are required to ensure test accuracy. The laboratory used in our report had previously conducted sensitivity and specificity studies to which they have validated the DBS assay, which was directly compared with known HIV-positive whole blood samples. From this, they found that an 8-fold reduction in concentration was acceptable in order to make a diagnosis. Furthermore, the process was accredited for routine use following a successful UKAS inspection. We would like to add that we do comment in our supplementary data that both DBS filter paper and MT containers were CE marked, as the responder's seemed to infer otherwise.
While the responder's rightly state a small sample (200-400microlitres of serum once centrifuge) is required for processing, they have omitted some key points. Firstly, the sample that the user provides is not serum, but whole blood; and therefore more than 400microlitres of blood will be required from the user. Insufficient samples in our study were in reference to whole blood volumes. In order to obtain 200-400microlitres of serum, you need to start off with 1ml of blood, which was not what was being achieved by many of the MT users in our report. We also dispute being able to carry out all the 5 tests mentioned (HIV, Syphilis Ab, Hepatitis B, Hepatitis C, and quantitative syphilis RPR and TPHA) with 200-400microlitres of serum, which the responder's have made an ambiguous reference to.
We strongly refute the claim of author bias considering that at the time the report was conducted, the service was offering both MT and DBS. We also refute the responder’s suggestion of inadequate procedural quality control, and have justified this in our report, supplementary details and in this response letter.
In summary, the data compiled by the responder's was inaccurate and misleading regarding their overall HIV result-to-STI kits requested, and RRR values. The data they have provided do not compare favourably to the performance the DBS from our report. Their data suggests that much of their success was driven by higher kit return rates compared to our paper (80.4% vs our papers 68.7% for MT and 66.5% for DBS). The responder's data suggests that they too experienced a drop in the successful processing rate for MT (84.6% compared with 98.8% for our papers DBS). This drop was also observed in our paper when comparing MT and DBS. This in essence, is the key message that our short paper concludes with, and the responder’s results seem to fit this narrative. With our report being a comparative evaluation (as opposed to a single arm evaluation), we were able to state that from our findings that return rates were not the deciding factor in the RRR values of the MT or DBS modalities, as they were the same. If we apply this logic to the responder’s data, it may be reasonable to suggest that should they use DBS, their RRR value would be nearing 1.00, when we factor in the high kit return rates that they have presented in their response letter.
We would encourage the responder's to fully publish their data in a peer-reviewed journal, in order for its readers to draw conclusions from their results. This is a rapidly expanding area and it has not been thoroughly explored through research.
Ang et al [1] discussed rising syphilis incidence among HIV positive men in Singapore. The diagnostic test used for syphilis in this study (RPR) is a non-specific treponemal antibody test. This limitation should be acknowledged while interpreting results. However, it is of good epidemiological value for public health programs for behavioural intervention. An important opportunity for sexual health promotion that can be missed if overlooked is post-treatment follow up for RPR titre monitoring. BASHH guidelines recommend follow up RPR titre post treatment until sero-fast or sustained 4 fold decrease in titre (at 3, 6 and 12 months).
An audit at our central London clinic showed that 31% of men had a bacterial STI when followed up for RPR monitoring post-treatment for syphilis [2]. Of 32 men (mean age 37 years; range 21- 75 years; 31 MSM), 11 were HIV positive. Six patients attended follow up visits at 3,6, and 12 months post treatment , 9 attended two follow up visits , 6 attended one follow up visit. Ten (31%) had a bacterial STI diagnosis (6 Chlamydia, 6 Gonorrhea, 1 LGV) during follow up. This highlighted the importance of STI screening and sexual health promotion for the MSM cohort during follow up for RPR monitoring in our clinic. Opportunistic screening for STI should be conducted across the globe where resources permit.
Reference:
[1] Ang LW, Wong C, Ng O et al. Incidence of syphilis among HIV-infected
men in Singapore, 2006–2017: temporal tren...
Ang et al [1] discussed rising syphilis incidence among HIV positive men in Singapore. The diagnostic test used for syphilis in this study (RPR) is a non-specific treponemal antibody test. This limitation should be acknowledged while interpreting results. However, it is of good epidemiological value for public health programs for behavioural intervention. An important opportunity for sexual health promotion that can be missed if overlooked is post-treatment follow up for RPR titre monitoring. BASHH guidelines recommend follow up RPR titre post treatment until sero-fast or sustained 4 fold decrease in titre (at 3, 6 and 12 months).
An audit at our central London clinic showed that 31% of men had a bacterial STI when followed up for RPR monitoring post-treatment for syphilis [2]. Of 32 men (mean age 37 years; range 21- 75 years; 31 MSM), 11 were HIV positive. Six patients attended follow up visits at 3,6, and 12 months post treatment , 9 attended two follow up visits , 6 attended one follow up visit. Ten (31%) had a bacterial STI diagnosis (6 Chlamydia, 6 Gonorrhea, 1 LGV) during follow up. This highlighted the importance of STI screening and sexual health promotion for the MSM cohort during follow up for RPR monitoring in our clinic. Opportunistic screening for STI should be conducted across the globe where resources permit.
Reference:
[1] Ang LW, Wong C, Ng O et al. Incidence of syphilis among HIV-infected
men in Singapore, 2006–2017: temporal trends and associated risk factors. Sex Transm Infect 2020;96:293–299
[2] Sivaraj V, Rajapaksha D, Fitzgerald N et al. STI events after syphilis diagnosis:
one year follow up of a subset cohort. BASHH annual conference; P 32; International Journal of STD & AIDS 2019, Vol. 30(7S) 1–114
The paper by Jordan SJ et al (1) is thought stimulating. The CDC guideline to regard 2-4 PMN/HPF as depicting NGU is possibly not widely observed, despite having been said 5 years ago (2). This and the inference that 1 or <1 PMN/HPF means no NGU must put a strain on those counting and poses the question of what variation might exist between observers.
When 5 different micro-organisms were sought but not found in urethritis, the invitation was there to consider the role of oral and anal bacteria and those occurring in BV. An association between this and NGU has been noted in the past (3). Unfortunately it was not taken into account here. It is also curious that when looking at the role of Ureaplasma species, the authors did not consider U.parvum. Admittedly, others have considered it to be less important than U.urealyticum (4) but not banished it to the graveyard completely.
Finally, the issue of bacterial load is important in considering pathogenicity. The authors state that they used quantitative PCRs but they did not provide ANY quantitative results. Why is that? These and longitudinal studies are required.
I believe the conclusion of the authors is not fully founded. Remember, Koch's postulates have been fulfilled for U.urealyticum (5).
REFERENCES
1. Jordan SJ, Toh E, Williams AJ, et al. Aetiology and prevalence of mixed-infections and mono-infections in non-gonococcal urethritis in men: a case-control study. Sex Transm Inf 2020;...
The paper by Jordan SJ et al (1) is thought stimulating. The CDC guideline to regard 2-4 PMN/HPF as depicting NGU is possibly not widely observed, despite having been said 5 years ago (2). This and the inference that 1 or <1 PMN/HPF means no NGU must put a strain on those counting and poses the question of what variation might exist between observers.
When 5 different micro-organisms were sought but not found in urethritis, the invitation was there to consider the role of oral and anal bacteria and those occurring in BV. An association between this and NGU has been noted in the past (3). Unfortunately it was not taken into account here. It is also curious that when looking at the role of Ureaplasma species, the authors did not consider U.parvum. Admittedly, others have considered it to be less important than U.urealyticum (4) but not banished it to the graveyard completely.
Finally, the issue of bacterial load is important in considering pathogenicity. The authors state that they used quantitative PCRs but they did not provide ANY quantitative results. Why is that? These and longitudinal studies are required.
I believe the conclusion of the authors is not fully founded. Remember, Koch's postulates have been fulfilled for U.urealyticum (5).
REFERENCES
1. Jordan SJ, Toh E, Williams AJ, et al. Aetiology and prevalence of mixed-infections and mono-infections in non-gonococcal urethritis in men: a case-control study. Sex Transm Inf 2020; 306-11.
2. Workowski KA, Bolan GA, Papp JR. Sexually transmitted disease treatment guidelines, 2015.MMWR Recomm Rep 2015; 64: 1-137.
3. Keane FE, Thomas BJ, Whitaker L, et al. An association between non-gonococcal urethritis and bacterial vaginosis and the implications for
patients and their sexual partners. Genitourin. Med 1997; 73: 373-7.
4. Zhang N, Wang R, Li X, et al. Are Ureaplasma spp. a cause of nongonococcal urethritis ? A systematic review and meta-analysis. PLoS One
2014; 9: e113771.
5. Taylor-Robinson D, Csonka GW, Prentice MJ. Human intra-urethral inoculation of ureaplasmas. Quart J Med 1977; 183: 309-26.
We thank Richardson et al., for their response to our recent publication titled “Proctitis in gay and bisexual men. Are microscopy and proctoscopy worthwhile?”[1]. The authors have previously reported findings of men who have sex with men (MSM) with proctitis, highlighting the polymicrobial nature of proctitis and symptomatic presentations with negative nucleic acid amplification testing (NAAT). However, they observed 8% (6/78) of MSM had syphilis proctitis based on NAAT from rectal mucosa[2] in contrast; we did not identify any.
Our study and the Richardson study have three main differences. Firstly, in our study, only a small proportion of MSM were tested for rectal syphilis (10.5% (16/154), and all patients were syphilis NAAT negative. Data on syphilis serology was not collected. As per our local guidelines, NAAT for rectal syphilis is based on clinical signs. None of our remaining patients had an appropriate history or clinical signs (ulcers) which would have triggered targeted NAAT for anorectal syphilis.
Secondly, 43% of GBM in our study were using pre-exposure prophylaxis (PrEP)and undergoing three monthly serological screening for Human Immunodeficiency Virus (HIV) and syphilis delivered as part of comprehensive sexually transmissible infections (STIs) and PrEP package. We postulate that this may have had a “protective” benefit against ‘symptomatic rectal syphilis”, through frequent STI testing or treatment of sexual contacts and engagement with heal...
We thank Richardson et al., for their response to our recent publication titled “Proctitis in gay and bisexual men. Are microscopy and proctoscopy worthwhile?”[1]. The authors have previously reported findings of men who have sex with men (MSM) with proctitis, highlighting the polymicrobial nature of proctitis and symptomatic presentations with negative nucleic acid amplification testing (NAAT). However, they observed 8% (6/78) of MSM had syphilis proctitis based on NAAT from rectal mucosa[2] in contrast; we did not identify any.
Our study and the Richardson study have three main differences. Firstly, in our study, only a small proportion of MSM were tested for rectal syphilis (10.5% (16/154), and all patients were syphilis NAAT negative. Data on syphilis serology was not collected. As per our local guidelines, NAAT for rectal syphilis is based on clinical signs. None of our remaining patients had an appropriate history or clinical signs (ulcers) which would have triggered targeted NAAT for anorectal syphilis.
Secondly, 43% of GBM in our study were using pre-exposure prophylaxis (PrEP)and undergoing three monthly serological screening for Human Immunodeficiency Virus (HIV) and syphilis delivered as part of comprehensive sexually transmissible infections (STIs) and PrEP package. We postulate that this may have had a “protective” benefit against ‘symptomatic rectal syphilis”, through frequent STI testing or treatment of sexual contacts and engagement with health services, as observed in our cohort. Lastly, almost half of the patients in the authors’ study, 47%(37/78), were HIV positive compared with 17% (26/154) in our study. HIV seropositivity is a known risk factor for anorectal syphilis[3].
We agree that the rising incidence of infectious syphilis among GBM necessitate a tailored approach to facilitate early detection of anorectal syphilis. Further studies are required to establish the clinical utility of anoscopy in this setting.
References
1. Mwasakifwa GE, Nugent C, Varma R. Proctitis in gay and bisexual men. Are microscopy and proctoscopy worthwhile? Sex Transm Infect [Internet] 2020 [cited 2020 May 3];Available from: https://sti.bmj.com/content/early/2020/01/30/sextrans-2019-054197
2. Pinto-Sander N, Parkes L, Fitzpatrick C, Richardson D. Symptomatic sexually transmitted proctitis in men who have sex with men. Sex Transm Infect [Internet] 2019 [cited 2020 May 1];95(6):471–471. Available from: https://sti.bmj.com/content/95/6/471
3. Arando M, Fernandez-Naval C, Mota-Foix M, Martinez D, Armengol P, Barberá MJ, et al. Early syphilis: risk factors and clinical manifestations focusing on HIV-positive patients. BMC Infect Dis [Internet] 2019 [cited 2020 May 3];19(1):1–9. Available from: https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-019-4269-8
We thank Piñeiro et al for their interest in our study using data from Britain’s third National Survey of Sexual Attitudes and Lifestyle (Natsal-3).1 This was a probability sample survey undertaken in 2010-12, with Mycoplasma genitalium testing results from urine available for over 4,500 participants aged 16-44 years.2 In this follow-up paper, we reported genotypic data on mutations associated with macrolide and fluoroquinolone resistance.
We read with interest that Piñeiro et al also found relatively low levels (<20%) of macrolide resistance in a Spanish, mainly general population sample in 2014-17.3 However, the low macrolide resistance (16%) found in our study is probably due not only to the general population sample, but also to the specimens being collected nearly a decade ago. Since 2010-12, there is evidence that macrolide resistance in M. genitalium has rapidly increased globally, and we anticipate finding higher levels of genotypic macrolide resistance in the general population in Britain in 2022 when Natsal-4 is expected to report findings.4 These data will be important to inform national and international understanding of incidence and prevalence as well as updated management and infection control strategies.
We appreciate both the relatively low treatment failure rate in the referenced Spanish study by Piñeiro et al,3 and the treatment strategy...
We thank Piñeiro et al for their interest in our study using data from Britain’s third National Survey of Sexual Attitudes and Lifestyle (Natsal-3).1 This was a probability sample survey undertaken in 2010-12, with Mycoplasma genitalium testing results from urine available for over 4,500 participants aged 16-44 years.2 In this follow-up paper, we reported genotypic data on mutations associated with macrolide and fluoroquinolone resistance.
We read with interest that Piñeiro et al also found relatively low levels (<20%) of macrolide resistance in a Spanish, mainly general population sample in 2014-17.3 However, the low macrolide resistance (16%) found in our study is probably due not only to the general population sample, but also to the specimens being collected nearly a decade ago. Since 2010-12, there is evidence that macrolide resistance in M. genitalium has rapidly increased globally, and we anticipate finding higher levels of genotypic macrolide resistance in the general population in Britain in 2022 when Natsal-4 is expected to report findings.4 These data will be important to inform national and international understanding of incidence and prevalence as well as updated management and infection control strategies.
We appreciate both the relatively low treatment failure rate in the referenced Spanish study by Piñeiro et al,3 and the treatment strategy informed by initial detection of macrolide resistance-associated mutations followed by azithromycin 1.5 g given over 5 days (if no macrolide resistance mutations detected) or moxifloxacin (if macrolide resistance mutations detected). This is in line with the current European guidelines.5 A similar but modified regimen using resistance-guided sequential treatment with doxycycline followed by azithromycin 2.5 g given over four days (if no macrolide resistance mutations) or moxifloxacin (if macrolide resistance mutations) is also described by Piñeiro et al, referencing a paper using sitafloxacin instead of moxifloxacin.6 Sitafloxacin may be more effective against M. genitalium than moxifloxacin because the doxycycline-sitafloxacin arm in the study clinically failed in only 7.8% of patients despite the observation that 20% of patients had ParC fluoroquinolone resistance-associated mutations.6 Furthermore, the cure rate for patients with M. genitalium samples with ParC S83I mutations (a common “fluoroquinolone resistance mutation”), possibly further potentiated by a concomitant GyrA M95I or D99N mutation, has been shown to be significantly higher with sitafloxacin compared to moxifloxacin.7 However, Durukan et al8 subsequently evaluated the same resistance-guided sequential treatment with doxycycline-moxifloxacin instead of doxycycline-sitafloxacin and found similar high cure rates.
Initiating empirical treatment of patients with, for example, symptomatic non-gonococcal urethritis with doxycycline, before laboratory results are available, currently appears to be the best choice because doxycycline will, (1) cure Chlamydia trachomatis infections, (2) cure 30-40% of M. genitalium infections,5 and (3) significantly decrease the M. genitalium load in most cases not achieving cure,6 which improves the cure rate of subsequent treatment. As Piñeiro et al mention,3 the adherence and adverse events of treatments are also important. However, the reported adherence to the doxycycline regimen in the studies discussed above was high, i.e. at 90-94%,6,8 and the adverse events were mainly mild grade 1. In fact, Durukan et al8 reported even fewer adverse events with doxycycline compared to azithromycin. Clearly, the adherence to treatment regimens and frequency of adverse events can significantly differ by setting, study population, and study.
There are still major gaps in our understanding about the distribution, natural history and pathology of M. genitalium, particularly in different anatomical sites, and about the sequelae of asymptomatic infections. For the moment, the primary focus in clinical practice should be on detecting and treating symptomatic patients (particularly with non-gonococcal urethritis and symptoms and/or signs of pelvic inflammatory disease), even though this may not be effective as a means to reduce population prevalence. We whole-heartedly agree with the need for more M. genitalium research, including on the epidemiology; pathogenesis; serious complications and sequelae; treatment approaches (sequential resistance-guided, ideal azithromycin dose regimen (1.5,3,5 2.0 g,9 2.5 g,6,8 or other, and how the total dose should be divided), associations with “fluoroquinolone resistance mutations” and treatment outcomes with different fluoroquinolones, and the pharmacokinetics/pharmacodynamics, compliance and adverse effects of the treatments in different settings), particularly where evaluated using randomised controlled clinical trials; and other mechanisms to manage and control M. genitalium including how to suppress AMR emergence. Ultimately, new antimicrobials and ideally a vaccine are needed for sustainable management and control of M. genitalium infections.
Magnus Unemo1, Pam Sonnenberg2, Nigel Field3
1 WHO Collaborating Centre for Gonorrhoea and Other STIs, National Reference Laboratory for STIs, Department of Laboratory Medicine, Microbiology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
2 Centre for Population Research in Sexual Health and HIV, Institute for Global Health, UCL, London, United Kingdom
3 Centre for Molecular Epidemiology and Translational Research, Institute for Global Health, UCL, London, United Kingdom
Correspondence to Dr Nigel Field, Centre for Molecular Epidemiology and Translational Research, Institute for Global Health, UCL, London WC1E 6JB, UK; nigel.field@ucl.ac.uk
Competing interests None.
REFERENCES
Pitt R, Unemo M, Sonnenberg P, et al. Antimicrobial resistance in Mycoplasma genitalium sampled from the British general population. Sex Transm Infect 2020. pii: sextrans-2019-054129. doi: 10.1136/sextrans-2019-054129.
Sonnenberg P, Ison CA, Clifton S, et al. Epidemiology of Mycoplasma genitalium in British men and women aged 16–44 years: evidence from the third National Survey of Sexual Attitudes and Lifestyles (Natsal-3). Int J Epidemiol 2015;44:1982-94.
Piñeiro L, Idigoras P, de la Caba I, et al. Guided antibiotic therapy for Mycoplasma genitalium infections: Analysis of mutations associated with resistance to macrolides and fluoroquinolones. Enferm Infecc Microbiol Clin 2019;37:394-7.
Mercer CH, Clifton S, Prior G, et al. Collecting and exploiting data to understand a nation's sexual health needs: Implications for the British National Surveys of Sexual Attitudes and Lifestyles (Natsal). Sex Transm Infect 2019;95:159–61.
Jensen JS, Cusini M, Gomberg M, et al. 2016 European guideline on Mycoplasma genitalium infections. J Eur Acad Dermatol Venereol 2016;30:1650–6.
Read TRH, Fairley CK, Murray GL, et al. Outcomes of resistance-guided sequential treatment of Mycoplasma genitalium infections: A prospective evaluation. Clin Infect Dis 2019;68:554-60.
Murray GL, Bodiyabadu K, Danielewski J, et al. Moxifloxacin and sitafloxacin treatment failure in Mycoplasma genitalium infection: Association with parC mutation G248T (S83I) and concurrent gyrA mutations. J Infect Dis. 2019;jiz550. doi:10.1093/infdis/jiz550
Durukan D, Read TRH, Murray G, et al. Resistance-guided antimicrobial therapy using doxycycline-moxifloxacin and doxycycline-2.5g azithromycin for the treatment of Mycoplasma genitalium infection: efficacy and tolerability. Clin Infect Dis 2019;ciz1031. doi:10.1093/cid/ciz1031
Soni S, Horner P, Rayment M, et al. British Association for Sexual Health and HIV national guideline for the management of infection with Mycoplasma genitalium (2018). Int J STD AIDS. 2019;30:938–50.
It would be good to have known the role of Mycoplasma genitalium in this population where asymptomatic infections by other pathogens were common and at least have mentioned it in the Discussion
Despite significant differences in testing opportunities, screening and access to care, this paper clearly sets out some important epidemiology of STIs accross Europe, particularly among MSM using PrEP. Despite this, there is no mention of sexually transmitted enteric infections, despite a recent outbreak of extensively drug resistant Shigella sonnei which has affected sexual networks of MSM accross Europe. There have been outbreaks of Shigella described in networks of MSM since the 1960s and can cause sugnificant morbidity. There are poor surveillance systems to monitor shigella outbreaks including transmssion of drug resistant organisms. More work is needed on both surveillance and shigella control strategies including awareness amongst both the communities affected and stakeholders including commissioners and public health.
The study by Dean et al. (1) on the treatment of PID was complicated and thought-provoking. Could it be that "mild" PID comprised many cases that were not PID at all? This issue bedevilled studies in the past, so why not here? Am I right in thinking that randomisation was used to try to maintain an evenness of disease severity between the two treatment arms, that is standard (SoC) with ofloxacin plus metronidazole, and an intervention arm (IA) with intramuscular ceftriaxone plus azithromycin and metronidazole? This is an important point when the outcome of each arm is to be compared. Presumably, after diagnosis treatment began without delay, not waiting for the results of microbiological tests which, in fact, showed M.genitalium in about 10% of cases in each arm, a proporttion seen by others (3) in acute PID. Standard treatment was judged to be slightly superior to the alternative treatment. Tests of microbiological cure 6 to 8 weeks after the study started showed a few azithromycin- resistant cases of M.genitalium, roughly comparable in the two arms. Not being aware of this at the start of treatment seems excusable. The reader must also realize that it was a situation experienced up to 9 years ago before an abrupt termination of the study. Today the scene is different, resistance of M.genitalium to azithromycin and other antibiotics being common (4). It has become clear that M.genitalium should be sought early followed rapidly by treatment guided by nothing othe...
Show MoreDear editor,
Show MoreWe thank Dr. Latini et al. for providing the data for the potential effects of SARS-CoV-2 pandemic on sexual lifestyle and epidemiology of sexually transmitted infections (STIs).1 In the study the author highlighted the importance to check the lasting effects of SARS-CoV-2 on STIs. As China is the first country to generally alleviate lockdown of most cities since beginning of April and the returns to usual lifestyle for nearly 6 months, we’re able to tract the epidemiology of STIs during the post-outbreak period in China.
According to the monthly report disclosed by Chinese Center for Disease Control and Prevention (Accessed from http://www.nhc.gov.cn/jkj/pqt/new_list.shtml), during the lockdown period of the first quarter, the number of newly diagnosed cases of HIV, syphilis and gonorrhea were 9695, 102273 and 16439, which reduced substantially by 27.3%, 19.3% and 38.2% compared to the previous year. After lockdown alleviation, the number of new cases returned, but not exceeding the previous years. The total new cases of HIV, syphilis and gonorrhea changed by -4.4%, -5.6% and -18.9% in the second quarter and -7.8%, -9.5% and +0.7% in the third quarter compared with 2019, respectively. As the number of new STIs in China is constantly growing in the past years, the reduction of new cases of STIs in 2020 after lockdown alleviation indicates a lasting effect of SARS-CoV-2. This may result from...
Peter J White, MRC Centre for Outbreak Analysis & Modelling and NIHR Health Protection Research Unit in Modelling and Health Economics, Imperial College London.
Other Contributors:
Joanna Lewis, MRC Centre for Outbreak Analysis & Modelling, Imperial College London.
Paddy J Horner, Population Health Sciences, and NIHR Health Protection Research Unit in Behavioural Science and Evaluation, University of Bristol.
Pitt et al. commented “asymptomatic patients are not recommended for M. genitalium testing except sexual contacts... The current approach might need rethinking if asymptomatic infections are found to be an important reservoir for AMR and/or a source of infection and disease”.[1]
Show MoreRecent analysis of the POPI cohort found 4.9% (95%CrI 0.4%–14.1%) of M. genitalium infections in women progressed to pelvic inflammatory disease, compared with 14.4% (5.9%–24.6%) of Chlamydia trachomatis infections.[2] Combined with its lower prevalence this means that M. genitalium is a much less important cause of disease in women than C. trachomatis.[2]
There is considerable uncertainty in the natural history and epidemiology of M. genitalium,[3] and we don’t know the importance of asymptomatic infection in transmission. Low bacterial load might limit infectivity but a long duration of infection[2,3] means there may be many potentially-infectious sex-acts. In fact, the BASHH guidelines are motivated by concern about transmission from asymptomatic...
We apologise for the delay in responding to your letter. We were only recently notified of this by email. Thank you for taking the time to construct your letter in response to our published short report, to which you raise several points which require addressing.
Firstly we feel it is important to highlight that although this service evaluation focussed specifically on HIV, we acknowledged that the HIV sampling kit was part of a more comprehensive STI kit (syphilis, chlamydia, and gonorrhoea tests). We were upfront with this fact in our report, and therefore refute the claim by the responder that our paper failed to consider the wider test portfolio required by sexual health screening services.
Of greater concern to us, we note a major error in the calculations from the data provided by the responders for their “RRR” and “HIV result obtained/ STI kit requested” values. This is important, as the foundation of their concluding statement is based on this error. The responder's have incorrectly used the number of returned kits (256,717) instead of the number of requested kits (319,485) in calculating the RRR (request-to-return ratio) and the “HIV result obtained/STI kit requested” proportion. Applying the correct calculation, the RRR value using the responder's data is not 1.36 (256,717/188,187) but 1.70 (319,485/188,187). The “HIV result obtained/STI kit requested” proportion using the correct calculation is 58.9% (188,187/319,485) and not 73.3%...
Show MoreAng et al [1] discussed rising syphilis incidence among HIV positive men in Singapore. The diagnostic test used for syphilis in this study (RPR) is a non-specific treponemal antibody test. This limitation should be acknowledged while interpreting results. However, it is of good epidemiological value for public health programs for behavioural intervention. An important opportunity for sexual health promotion that can be missed if overlooked is post-treatment follow up for RPR titre monitoring. BASHH guidelines recommend follow up RPR titre post treatment until sero-fast or sustained 4 fold decrease in titre (at 3, 6 and 12 months).
An audit at our central London clinic showed that 31% of men had a bacterial STI when followed up for RPR monitoring post-treatment for syphilis [2]. Of 32 men (mean age 37 years; range 21- 75 years; 31 MSM), 11 were HIV positive. Six patients attended follow up visits at 3,6, and 12 months post treatment , 9 attended two follow up visits , 6 attended one follow up visit. Ten (31%) had a bacterial STI diagnosis (6 Chlamydia, 6 Gonorrhea, 1 LGV) during follow up. This highlighted the importance of STI screening and sexual health promotion for the MSM cohort during follow up for RPR monitoring in our clinic. Opportunistic screening for STI should be conducted across the globe where resources permit.
Reference:
Show More[1] Ang LW, Wong C, Ng O et al. Incidence of syphilis among HIV-infected
men in Singapore, 2006–2017: temporal tren...
The paper by Jordan SJ et al (1) is thought stimulating. The CDC guideline to regard 2-4 PMN/HPF as depicting NGU is possibly not widely observed, despite having been said 5 years ago (2). This and the inference that 1 or <1 PMN/HPF means no NGU must put a strain on those counting and poses the question of what variation might exist between observers.
Show MoreWhen 5 different micro-organisms were sought but not found in urethritis, the invitation was there to consider the role of oral and anal bacteria and those occurring in BV. An association between this and NGU has been noted in the past (3). Unfortunately it was not taken into account here. It is also curious that when looking at the role of Ureaplasma species, the authors did not consider U.parvum. Admittedly, others have considered it to be less important than U.urealyticum (4) but not banished it to the graveyard completely.
Finally, the issue of bacterial load is important in considering pathogenicity. The authors state that they used quantitative PCRs but they did not provide ANY quantitative results. Why is that? These and longitudinal studies are required.
I believe the conclusion of the authors is not fully founded. Remember, Koch's postulates have been fulfilled for U.urealyticum (5).
REFERENCES
1. Jordan SJ, Toh E, Williams AJ, et al. Aetiology and prevalence of mixed-infections and mono-infections in non-gonococcal urethritis in men: a case-control study. Sex Transm Inf 2020;...
We thank Richardson et al., for their response to our recent publication titled “Proctitis in gay and bisexual men. Are microscopy and proctoscopy worthwhile?”[1]. The authors have previously reported findings of men who have sex with men (MSM) with proctitis, highlighting the polymicrobial nature of proctitis and symptomatic presentations with negative nucleic acid amplification testing (NAAT). However, they observed 8% (6/78) of MSM had syphilis proctitis based on NAAT from rectal mucosa[2] in contrast; we did not identify any.
Our study and the Richardson study have three main differences. Firstly, in our study, only a small proportion of MSM were tested for rectal syphilis (10.5% (16/154), and all patients were syphilis NAAT negative. Data on syphilis serology was not collected. As per our local guidelines, NAAT for rectal syphilis is based on clinical signs. None of our remaining patients had an appropriate history or clinical signs (ulcers) which would have triggered targeted NAAT for anorectal syphilis.
Secondly, 43% of GBM in our study were using pre-exposure prophylaxis (PrEP)and undergoing three monthly serological screening for Human Immunodeficiency Virus (HIV) and syphilis delivered as part of comprehensive sexually transmissible infections (STIs) and PrEP package. We postulate that this may have had a “protective” benefit against ‘symptomatic rectal syphilis”, through frequent STI testing or treatment of sexual contacts and engagement with heal...
Show MoreWe thank Piñeiro et al for their interest in our study using data from Britain’s third National Survey of Sexual Attitudes and Lifestyle (Natsal-3).1 This was a probability sample survey undertaken in 2010-12, with Mycoplasma genitalium testing results from urine available for over 4,500 participants aged 16-44 years.2 In this follow-up paper, we reported genotypic data on mutations associated with macrolide and fluoroquinolone resistance.
We read with interest that Piñeiro et al also found relatively low levels (<20%) of macrolide resistance in a Spanish, mainly general population sample in 2014-17.3 However, the low macrolide resistance (16%) found in our study is probably due not only to the general population sample, but also to the specimens being collected nearly a decade ago. Since 2010-12, there is evidence that macrolide resistance in M. genitalium has rapidly increased globally, and we anticipate finding higher levels of genotypic macrolide resistance in the general population in Britain in 2022 when Natsal-4 is expected to report findings.4 These data will be important to inform national and international understanding of incidence and prevalence as well as updated management and infection control strategies.
We appreciate both the relatively low treatment failure rate in the referenced Spanish study by Piñeiro et al,3 and the treatment strategy...
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