[Neurosyphilis].

This review focuses on typical and atypical manifestations of neurosyphilis. The manifestations of neurosyphilis are manyfold and may involve many specialties. Today, clinicians have limited experience with the well-described manifestations of neurosyphilis. Many screening opportunities for men who have sex with men might catch the majority of cases of syphilis in this group. However, a concern could be if disclosure about heterosexuality or, in general, monosymptomatic neurosyphilis constitute a risk for delayed diagnosis.

Clinical Importance of Superior Sensitivity of the Aptima TMA-Based Assays for Mycoplasma genitalium Detection.

Mycoplasma genitalium (MG) is a common cause of nongonococcal cervicitis and urethritis. We investigated the demographic and clinical characteristics of patients tested in Denmark with the Conformité Européenne (CE)/in vitro diagnostics (IVD) Aptima Mycoplasma genitalium assay (CE/IVD AMG; Hologic) and examined the clinical significance of the higher sensitivity of the TMA-based MG assays. From March to June 2016, urogenital and extragenital specimens from consecutive attendees at a sexually transmitted infection clinic in Copenhagen, Denmark were tested with the CE/IVD AMG assay (TMA-based), the research-use-only MG Alt TMA-1 assay (Hologic), a laboratory-developed TaqMan mgpB quantitative real-time PCR (qPCR), and the Aptima Combo 2 (CT/NG; Hologic). Demographic characteristics and clinical symptoms were collected from the patient records. There were 1,245 patients included in the study. The MG prevalence among female subjects was 9.4%, and the MG prevalence among male subjects was 8.7%. Compared to the TMA-based assays, the sensitivity of the PCR-based MG assay was 64.52%, and 55 specimens from 48 individuals were missed in the mgpB qPCR. Of these, 26 individuals (54.2%) were symptomatic, whereas, among 64 individuals with concordant results, 30 individuals (46.9%) were symptomatic; no statistically significant difference was found between the groups (P = 0.567). The improved sensitivity of the TMA-based assays resulted in diagnoses of more patients with clinically relevant symptoms for which antibiotic treatment is indicated. However, approximately half of the MG-infected patients reported no symptoms, and future research is needed to investigate the pros and cons of diagnosing and treating MG in asymptomatic subjects.

Sex-associated Risk Factors for Co-infection with Chlamydia trachomatis and Neisseria gonorrhoea among Patients Presenting to a Sexually Transmitted Infection Clinic.

The aim of this study was to investigate the characteristics of patients co-infected with Chlamydia trachomatis and Neisseria gonorrhoea. A retrospective case-control study was performed, which included 399 co-infected patients seen at a sexually transmitted infection clinic in Copenhagen, Denmark. Case-control groups included 300 patients who tested positive only for N. gonorrhoea, 300 who tested positive only for C. trachomatis, and 300 who tested negative for both N. gonorrhoea and C. trachomatis in the same study period. For men, non-Danish origin (odds ratio (OR) 2.3, 95% confidence interval (Cl) 1.34-4.12), previous sexually transmitted infections with C . trachomatis (OR 3.3, 95% CI 1.94-5.92) and N. gonorrhoea (OR 10.6, 95% CI 6.36-17.76), and higher number of sex partners (OR 1.7, 95% Cl 1.40-2.28) were significantly associated with diagnosis of co-infection. For women, previous sexually transmitted infections with C. trachomatis (OR 6.7, 95% CI 3.89-11.78) and N. gonorrhoea (OR 10.4, 95% CI 4.99-21.71), and higher number of sex partners (OR 1.8, 95% CI 1.28-2.56) were significantly associated with a diagnosis of co-infection, whereas being of non-Danish origin was, in some cases, a protective factor (OR 0.3, 95% CI 0.17-0.69). Furthermore, this study demonstrated sex-associated characteristics that should raise concern about co- infection, including: for men, being of non-Danish origin, men who have sex with men status, and higher age, and, for women, young age, in particular, and previous sexually transmitted infections.

Syphilitic hepatitis and neurosyphilis: an observational study of Danish HIV-infected individuals during a 13-year period.

OBJECTIVE: Syphilis is an STI that potentially affects any organ. Syphilitic hepatitis and neurosyphilis have been reported in both HIV-uninfected and HIV-infected individuals. The aim of this study was to investigate syphilitic hepatitis and neurosyphilis among HIV-infected individuals during a 13-year period. METHODS: This retrospective study included all HIV-infected individuals ≥18 years diagnosed with syphilis between 1 May 2004 and 31 December 2016 in Copenhagen, Denmark. We used the unique 10-digit personal identification number assigned to all individuals in Denmark to link data from two nationwide registers to identify the patients. Patient files were revised to obtain clinical and laboratory data. RESULTS: A total of 509 episodes of syphilis were diagnosed in 427 HIV-infected individuals attending three hospitals in Copenhagen, Denmark. The majority of the patients were men (99.5%), and the majority of men were men who have sex with men (96%). Twenty-seven patients (6%) met the criteria for neurosyphilis, and the neurological symptoms included ocular and auditory abnormalities, headache, paraesthesia, vertigo, facial paresis, motor weakness and unexplained pain in the legs. The patients with neurosyphilis were diagnosed in the secondary stage (84%) and in the early latent (8%) or late latent (8%) stage. Among the patients tested for liver affection, 41% met the criteria for syphilitic hepatitis. The patients with syphilitic hepatitis were diagnosed in the secondary stage (82%), primary stage (10%), and in the early latent (5%) or late latent (3%) stage. CONCLUSIONS: The study emphasises that patients with syphilis, also those seen at STI clinics, should undergo a thorough clinical examination and questioning to reveal neurological symptoms. Identification of patients with neurosyphilis is crucial since these patients undergo a different treatment. The study also emphasises that syphilis should be considered as a diagnosis in sexually active patients with liver .

[Syphilis].

Syphilis is a sexually transmitted infection caused by the spirochaete Treponema pallidum. Syphilis re-emerged worldwide in the late 1990s, and hereafter increasing rates of syphilis were seen also in Denmark. Currently, around 700 cases are diagnosed yearly in Denmark, and syphilis is mainly encountered among men, who have sex with men. However, because of the risk of congenital infection screening of pregnant women has been introduced. Syphilis gives rise to highly variable symptoms such as chancre, skin rashes and fever or latent infection. The recommended treatment is intramuscular administration of penicillin.

[Sexually transmitted Mycoplasma genitalium infection is difficult to treat].

Mycoplasma genitalium infection is sexually transmitted, and it is almost as common as chlamydia in most European settings. Symptoms are indistinguishable from those of chlamydia, and late sequelae are believed to be similar. Treatment of M. genitalium infection is complicated due to widespread antimicrobial resistance not only to first-line azithromycin but now also increasingly to second-line moxifloxacin, leaving no other antibiotics registered in Denmark available for effective treatment. In the absence of available antimicrobials, screening of asymptomatic individuals should be avoided.

Serological Response to Treatment of Syphilis with Doxycycline Compared with Penicillin in HIV-infected Individuals.

Serological response to treatment of syphilis with orally administered doxycycline or intramuscularly administered penicillin was assessed in patients with concurrent HIV. All HIV-infected individuals diagnosed with syphilis attending 3 hospitals in Copenhagen, Denmark were included. Odds ratios (ORs) with 95% confidence intervals (CI) associated with serological outcome were modelled using propensity-score-adjusted logistic regression analysis. In total, 202 cases were treated with doxycycline or intramuscular penicillin. At 12 months, serological failure was observed in 12 cases (15%) treated with doxycycline and in 8 cases (17%) treated with penicillin (OR 0.78 (95% CI 0.16-3.88), p = 0.76). The serological cure rate at 12 months was highest in patients with primary syphilis (100%), followed by patients with secondary (89%), early latent (71%) and late latent (67%) syphilis (p = 0.006). In conclusion, this study provides evidence for the use of doxycycline as a treatment option when treating a HIV-infected population for syphilis.

CIED infection with either pocket or systemic infection presentation--complete device removal and long-term antibiotic treatment; long-term outcome.

OBJECTIVE: Cardiovascular implantable electronic device (CIED) infections are increasing in numbers. The objective was to review the clinical presentation and outcome in patients affected with CIED infections with either local pocket or systemic presentation. DESIGN: All device removals due to CIED infection during the period from 2005 to 2012 were retrospectively reviewed. CIED infections were categorized as systemic or pocket infections. Treatment included complete removal of the device, followed by antibiotic treatment of six weeks. RESULTS: Seventy-one device removals due to infection (32 systemic and 39 pocket infections) were recorded during the study period. Median follow-up time was 26 (IQR 9-41) months, 30 day and 12 month mortality were 4% and 14%, respectively. There was no long-term difference in mortality between patients with pocket vs. systemic infection (p = 0.48). During follow-up no relapses and two cases of new infections were noted (2.8%). CONCLUSIONS: CIED infection with systemic or pocket infection was difficult to distinguish in clinical presentation and outcome. Complete device removal and antibiotic treatment of long duration was safe and without relapses.

Molecular Typing of Treponema pallidum in Denmark: A Nationwide Study of Syphilis.

The aim of this nationwide study is to determine the strain type diversity among patients diagnosed with syphilis by PCR during a 4-year period in Denmark. Epidemiological data, including HIV status, for all patients were obtained from the Danish national syphilis registration system. Molecular strain typing was based on characterization of 3 variable treponemal genes, arp, tpr and tp0548. A total of 278 specimens from 269 patients were included. Among the fully typeable specimens (n = 197), 22 strain types were identified, with 1 type, 14d/g, accounting for 54%. The majority (93%) of the patients reported acquiring syphilis in Denmark. Among patients with concurrent HIV, 9 full strain types were identified and no difference in strain type was found by HIV status (p = 0.197). In conclusion, the majority of patients were infected in Denmark and the HIV-infected syphilis patients were diagnosed with a wide spectrum of different strain types of Treponema pallidum.

Syphilis and HIV co-infection. Epidemiology, treatment and molecular typing of Treponema pallidum.

The studies included in this PhD thesis examined the interactions of syphilis, which is caused by Treponema pallidum, and HIV. Syphilis reemerged worldwide in the late 1990s and hereafter increasing rates of early syphilis were also reported in Denmark. The proportion of patients with concurrent HIV has been substantial, ranging from one third to almost two thirds of patients diagnosed with syphilis some years. Given that syphilis facilitates transmission and acquisition of HIV the two sexually transmitted diseases are of major public health concern. Further, syphilis has a negative impact on HIV infection, resulting in increasing viral loads and decreasing CD4 cell counts during syphilis infection. Likewise, HIV has an impact on the clinical course of syphilis; patients with concurrent HIV are thought to be at increased risk of neurological complications and treatment failure. Almost ten per cent of Danish men with syphilis acquired HIV infection within five years after they were diagnosed with syphilis during an 11-year study period. Interestingly, the risk of HIV declined during the later part of the period. Moreover, HIV-infected men had a substantial increased risk of re-infection with syphilis compared to HIV-uninfected men. As one third of the HIV-infected patients had viral loads >1,000 copies/ml, our conclusion supported the initiation of cART in more HIV-infected MSM to reduce HIV transmission. During a five-year study period, including the majority of HIV-infected patients from the Copenhagen area, we observed that syphilis was diagnosed in the primary, secondary, early and late latent stage. These patients were treated with either doxycycline or penicillin and the rate of treatment failure was similar in the two groups, indicating that doxycycline can be used as a treatment alternative - at least in an HIV-infected population. During a four-year study period, the T. pallidum strain type distribution was investigated among patients diagnosed by PCR testing of material from genital lesions. In total, 22 strain types were identified. HIV-infected patients were diagnosed with nine different strains types and a difference by HIV status was not observed indicating that HIV-infected patients did not belong to separate sexual networks. In conclusion, concurrent HIV remains common in patients diagnosed with syphilis in Denmark, both in those diagnosed by serological testing and PCR testing. Although the rate of syphilis has stabilized in recent years, a spread to low-risk groups is of concern, especially due to the complex symptomatology of syphilis. However, given the efficient treatment options and the targeted screening of pregnant women and persons at higher risk of syphilis, control of the infection seems within reach. Avoiding new HIV infections is the major challenge and here cART may play a prominent role.

Nevirapine, sodium concentration and HIV-1 RNA in breast milk and plasma among HIV-infected women receiving short-course antiretroviral prophylaxis.

INTRODUCTION: Risk factors for breast milk transmission of HIV-1 from mother to child include high plasma and breast milk viral load, low maternal CD4 count and breast pathology such as mastitis. OBJECTIVE: To determine the impact of nevirapine and subclinical mastitis on HIV-1 RNA in maternal plasma and breast milk after intrapartum single-dose nevirapine combined with either 1-week tail of Combivir (zidovudine/lamivudine) or single-dose Truvada (tenofovir/emtricitabine). METHODS: Maternal plasma and bilateral breast milk samples were collected between April 2008 and April 2011 at 1, 4 and 6 weeks postpartum from HIV-infected Tanzanian women. Moreover, plasma samples were collected at delivery from mother and infant. RESULTS: HIV-1 RNA was quantified in 1,212 breast milk samples from 273 women. At delivery, 96% of the women and 99% of the infants had detectable nevirapine in plasma with a median (interquartile range, IQR) of 1.5 µg/mL (0.75-2.20 µg/mL) and 1.04 µg/mL (0.39-1.71 µg/mL), respectively (P < 0.001). At 1 week postpartum, 93% and 98% of the women had detectable nevirapine in plasma and breast milk, with a median (IQR) of 0.13 µg/mL (0.13-0.39 µg/mL) and 0.22 µg/mL (0.13-0.34 µg/mL), respectively. Maternal plasma and breast milk HIV-1 RNA correlated at all visits (R = 0.48, R = 0.7, R = 0.59; all P = 0.01). Subclinical mastitis was detected in 67% of the women at some time during 6 weeks, and in 38% of the breast milk samples. Breast milk samples with subclinical mastitis had significantly higher HIV-1 RNA at 1, 4 and 6 weeks (all P < 0.05). CONCLUSION: After short-course antiretroviral prophylaxis, nevirapine was detectable in most infant cord blood samples and the concentration in maternal plasma and breast milk was high through week 1 accompanied by suppressed HIV-1 RNA in plasma and breast milk.

Undetectable hepatitis C virus RNA during syphilis infection in two HIV/HCV-co-infected patients.

BACKGROUND: Treponema pallidum, the causative agent of syphilis, elicits a vigorous immune response in the infected host. This study sought to describe the impact of syphilis infection on hepatitis C virus (HCV) RNA levels in patients with HIV and chronic HCV infection. METHODS: Patients with chronic HIV/HCV and syphilis co-infection were identified by their treating physicians from 1 October 2010 to 31 December 2013. Stored plasma samples obtained before, during, and after syphilis infection were analysed for interleukin (IL)-2, IL-4, IL-6, IL-8, IL-10, tumour necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), and IFN-γ-inducible protein 10 kDa (IP-10). RESULTS: Undetectable HCV RNA at the time of early latent syphilis infection was observed in 2 patients with HIV and chronic HCV infection. After treatment of the syphilis infection, HCV RNA levels increased again in patient 1, whereas patient 2 initiated HCV therapy and remained HCV RNA-negative. Available plasma samples obtained before and after the episode with undetectable HCV RNA were phylogenetically identical, making the possibility of spontaneous clearance and HCV reinfection less likely. The IL-10, TNF-α, and IP-10 levels increased at the time of syphilis diagnosis in patient 1 and decreased again after treatment of the syphilis infection. CONCLUSIONS: We propose that T. pallidum-induced cytokine secretion resulted in an immune response hindering HCV replication during syphilis infection. We suggest that HIV/HCV-co-infected patients with unexpected undetectable HCV RNA are tested for syphilis infection and that the serological tests include both non-treponemal and treponemal tests to avoid false-positive results caused by HCV.

Mycoplasma genitalium testing pattern and macrolide resistance: a Danish nationwide retrospective survey.

BACKGROUND: Mycoplasma genitalium is a common cause of nongonococcal urethritis (NGU) and cervicitis. The aim of the study was to analyze the M. genitalium testing pattern and distribution of positive results according to sex and age in a 5-year period where all diagnostic M. genitalium testing in Denmark was centralized at the Statens Serum Institut. A secondary aim was to estimate the occurrence of macrolide resistance in a 3-year period. METHODS: The study was performed as a nationwide retrospective survey of specimens submitted from general practice, private specialists, and hospitals to Statens Serum Institut for detection of M. genitalium by polymerase chain reaction between 1 January 2006 and 31 December 2010. Macrolide resistance screening was introduced December 2007. RESULTS: A total of 31 600 specimens from 28 958 patients were tested for M. genitalium, with an increasing trend from 3858 per year in 2006 to 7361 in 2010. The majority (54%) of the patients were tested in general practice. For both sexes, the positive rate increased significantly, from 2.4% to 3.8% for women and from 7.9% to 10.3% for men (P < .0005). Macrolide resistance was detected in 38% (385/1008) of the M. genitalium-positive patients, and the highest rate was found in patients tested at sexually transmitted disease clinics (43%). CONCLUSIONS: Testing for M. genitalium has become important for clinicians treating sexually transmitted infections. In this nationwide survey, macrolide resistance was found in almost 40% of the specimens, raising concern about single-dose azithromycin treatment of NGU, and emphasizing that NGU treatment should be guided by etiologic diagnosis.

Risk of HIV or second syphilis infection in Danish men with newly acquired syphilis in the period 2000-2010.

OBJECTIVES: Risk of subsequent diagnosis of HIV in persons diagnosed with newly acquired syphilis, and syphilis in HIV-infected persons, are of interest as these infections are markers of unsafe sex. METHODS: From a nationwide register, all Danish men aged >16 years diagnosed with syphilis in the period 2000-2010 (n=1217) were identified, and subsequently data on HIV status was extracted from the Danish HIV Cohort Study. We used Kaplan-Meier analysis to estimate the 5-year risk of HIV and second syphilis infection, and Cox regression to determine incidence rate ratios (IRR). RESULTS: The 5-year risk of HIV diagnosis was 9.8% (95% CI 7.0% to 12.6%). Those with a second diagnosis of syphilis had a higher risk of being diagnosed with HIV (IRR=3.1, 95% CI 1.2 to 8.0). The 5-year risk for a second diagnosis of syphilis was 14.8% (95% CI 12.1% to 17.4%) and HIV-infected persons had a higher risk of a second syphilis diagnosis (IRR=4.0, 95% CI 2.8 to 5.9). Sixty-five percent of the persons were men having sex with men (MSM). Thirty-four percent of the HIV-infected persons had viral load >1000 copies/ml at time of syphilis diagnosis. CONCLUSIONS: The substantial risks of syphilis and HIV infection in men diagnosed with one of these sexually transmitted diseases indicate a high frequency of unsafe sex in the Danish MSM population. As one-third of the HIV-infected persons diagnosed with syphilis had high viral loads, our data support initiation of antiretroviral therapy in all HIV-infected MSM to reduce HIV transmission.

Good performance of an immunoassay based method for nevirapine measurements in human breast milk.

BACKGROUND: Understanding the distribution of antiretro-virals in breastfeeding HIV-positive mothers is essential, both for prevention of mother-to-child HIV transmission and for research on the development of drug resistance. The ARK nevirapine (NVP)-test is an immunoassay method for nevirapine measurements, developed and validated for plasma use. In this study, the ARK NVP-test was evaluated for measurement of nevirapine concentrations in breast milk. High performance liquid chromatography (HPLC) is the method currently used to determine nevirapine in breast milk. This method, however, requires complicated extraction techniques. The ARK method employs an immunoassay technology and requires a small sample volume (40 µL) and no pre-treatment of the samples. METHODS: Commercial enzyme and antibody were used and calibration standards and quality controls were prepared from pooled breast milk from HIV-uninfected women. Clinical samples from HIV-infected women receiving a single-dose of nevirapine were analyzed. RESULTS: Precision and accuracy were evaluated with two concentrations of quality control materials analyzed in three replicates on four different days and was <4%, and between 96.5% and 104.6%, respectively. Clinical samples were analyzed and CVs ranged from 0.0% to 11.1%. The median nevirapine concentration in breast milk 1 week post-partum was 0.29 µg/mL (range 0.11-0.90 µg/mL) in women treated with a single-dose of nevirapine. CONCLUSIONS: The ease of use and small sample volume makes the ARK assay an attractive alternative to HPLC analyses for determinations of nevirapine concentrations in breast milk.