Developing a next level integrated genomic surveillance: Advances in the molecular epidemiology of HIV in Germany.

Advances in the molecular epidemiological studies of the Human Immunodeficiency Virus (HIV) at the Robert Koch Institute (RKI) by laboratory and bioinformatic automation should allow the processing of larger numbers of samples and more comprehensive and faster data analysis in order to provide a higher resolution of the current HIV infection situation in near real-time and a better understanding of the dynamic of the German HIV epidemic. The early detection of the emergence and transmission of new HIV variants is important for the adaption of diagnostics and treatment guidelines. Likewise, the molecular epidemiological detection and characterization of spatially limited HIV outbreaks or rapidly growing sub-epidemics is of great importance in order to interrupt the transmission pathways by regionally adapting prevention strategies. These aims are becoming even more important in the context of the SARS-CoV2 pandemic and the Ukrainian refugee movement, which both have effects on the German HIV epidemic that should be monitored to identify starting points for targeted public health measures in a timely manner. To this end, a next level integrated genomic surveillance of HIV is to be established.

Survival after cryptococcosis in Germany: A retrospective multicenter cohort study of patients diagnosed between 2004 and 2021.

Cryptococcosis is the most prevalent fungal infection of the central nervous system worldwide. We performed a retrospective multicenter cohort study to gain insights into the epidemiology of cryptococcosis in Germany. We describe the use of diagnostic tests, clinical management and patient outcome. We included 64 patients with underlying HIV infection (55%) or other predispositions. Molecular typing by MLST documented 20 individual sequence types among 42 typed isolates. A fatal outcome was documented in 14% of patients in the first two months after diagnosis.

AIDS-defining events among people living with HIV who have been under continuous antiretroviral therapy for more than one year, a German cohort study 1999-2018.

PURPOSE: This study examined the characteristics, incidence and prognostic factors of the first AIDS-defining condition developed after more than one year of continuous antiretroviral therapy (ART) among people living with HIV (PLHIV). METHODS: We used data from two multicentre observational cohorts of PLHIV in Germany between 1999 and 2018. Our outcome was the first AIDS-defining event that occurred during follow-up after more than one year of continuous ART. Descriptive analyses at ART initiation, at the time of the AIDS event and of the most frequently observed types of AIDS-defining illnesses were performed. We calculated the incidence rate (IR) per 1000 person-years (PY) and used a bootstrap stepwise selection procedure to identify predictors of the outcome. RESULTS: A total of 12,466 PLHIV were included in the analyses. 378 developed the outcome, constituting an overall IR of 5.6 (95% CI 5.1-6.2) AIDS events per 1000 PY. The majority of PLHIV was virally suppressed at the time of the event. Oesophageal candidiasis and wasting syndrome were the most frequently diagnosed AIDS-defining illnesses. We found a low CD4 count at ART initiation, a previous AIDS-defining condition and transmission through intravenous drug use to be meaningful prognostic factors of the outcome. CONCLUSION: The overall rate of AIDS-defining events among PLHIV under long-term ART was low, highlighting the importance of continuous treatment. PLHIV who started ART with indicators of impaired immune functioning were more susceptible to disease progression, suggesting that the public health response should continue to focus on early and sustained treatment for all PLHIV.

Clinically inapparent mpox virus (MPXV) infections among clients of three anonymous Community Based Voluntary Counselling and Testing centres in Berlin, Germany, 2022-2023.

INTRODUCTION: Since the mpox outbreak in 2022, it was unclear if and how often infections with mpox virus (MPXV) were clinically inapparent, i.e. not presenting to clinical care with mpox symptoms. Moreover, it was hypothesized that MPXV circulated in the affected communities before the outbreak was officially detected. METHODS: We retrospectively tested rectal and urethral swabs, and pooled samples for presence of MPXV. Samples were obtained from routine STI testing of three anonymous Community Based Voluntary Counselling and Testing (CBVCT) centres in Berlin, in 2022 and 2023. Testing results were linked to anonymously provided behavioural data. RESULTS: Overall, 9,053 samples from 6,600 client visits were included. Clinically inapparent MPXV infections were detectable in 1.1% of the samples. We did not find MPXV infections in the month before the first cases appeared in Berlin or between October 2022 and January 2023 when case numbers were low in Germany. However, during the outbreak period in 2022, we found clinically inapparent MPXV infections among 2.2% of the clients and during summer/autumn 2023 among 0.3%. The number of condomless anal/vaginal intercourse partners within the previous 6 months and PrEP use were identified as predictors of clinically inapparent MPXV infection. CONCLUSION: Clinically inapparent MPXV infections occurred during the mpox outbreak in Berlin in 2022 and post-outbreak in summer/autumn 2023. Unrecognized MPXV circulation in Berlin before the recognition of the outbreak in May 2022 appears unlikely. However, low-level sustained circulation of clinically inapparent MPXV infections need to be acknowledged in mpox prevention strategies.

AIDS in the era of antiretroviral therapy: Changes in incidence rates and predictors of AIDS among people living with HIV under clinical care in Germany, a cohort study 1999-2018.

OBJECTIVES: This study examined the incidence rates and predictive utility of established prognostic factors for the progression to AIDS among people living with HIV under clinical care. METHODS: We used data from two observational cohorts of people living with HIV in Germany between 1999 and 2018. The outcome measure was the first AIDS-defining event that occurred during follow-up. Incidence rates (IRs) per 1000 person-years (PY) were calculated by years of follow-up and calendar periods. We used Cox models in our prediction analyses, including CD4 count, viral load, and age at baseline to estimate the predictive performance. Additionally, we included transmission mode to examine its predictive utility. RESULTS: A total of 23 299 people living with HIV were included in the analyses. Of these, 1832 developed a first AIDS event during follow-up, constituting an overall rate of 14.6/1000 PY (95% confidence interval [CI] 13.9-15.2). IRs were highest in the first year of follow-up (45.6/1000 PY, 95% CI 42.6-48.8) and then declined continuously. IRs were highest among people living with HIV who enrolled between 1999 and 2003 (36.1/1000 PY, 95% CI 32.6-40.0). A low CD4 count, high viral load, and older age at baseline increased the likelihood of progressing to AIDS. Adding transmission mode to the models did not improve the predictive performance. CONCLUSIONS: The rates of a first AIDS event among people living with HIV have continuously declined in Germany. Health outcomes depend on a person's CD4 count, viral load, and age but not on transmission mode. To further reduce the number of AIDS cases, the focus should be on groups more likely to present in progressed stages of their HIV infection.

Transmitted drug resistance and subtype patterns of viruses from reported new HIV diagnoses in Germany, 2017-2020.

BACKGROUND: The transmission of resistant HIV variants jeopardizes the effective use of antiretrovirals for therapy and prophylaxis. Molecular surveillance of new HIV diagnoses with a focus on prevalence and type of resistance associated mutations and the subtype of circulating viruses is mandatory. METHOD: From 2017 to 2020, 11,527 new HIV diagnoses were reported in Germany to the Robert Koch Institute (RKI). Protease (PR) and reverse-transcriptase (RT) sequences were obtained from 4559 (39.6%) cases, and PR, RT and integrase (IN) sequences were obtained from 3097 (26.9%) cases. The sequences were analyzed with data from the national HIV reports. RESULTS: Among all cases in the analysis, the proportion of primary resistance was 4.3% for nucleoside reverse-transcriptase inhibitors (NRTIs), 9.2% for non-NRTI (NNRTIs), 3.3% for protease inhibitors (PIs) and 1.4% for integrase inhibitors (INIs). Dual-class resistance was highest for NRTIs/NNRTIs with 1.2%. There was no trend in the proportion of viruses resistant to drug classes. Most individual key mutations associated with relevant resistance had a prevalence below 1% including K65R (0.1%) and M184V (0.6%). A notable exception was K103NS, with a prevalence of 2.9% and a significant increase (pTrend=0.024) during 2017-2020. In this period, diagnoses of infections with HIV-1 subtype B were the most common at 58.7%, but its prevalence was declining (pTrend=0.049) while the frequency of minority subtypes (each < 1%) increased (pTrend=0.007). Subtype B was highest (75.6%) in men who have sex with men (MSM) and lowest in reported heterosexual transmissions (HETs, 22.6%). CONCLUSION: The percentage of primary resistance was high but at a stable level. A genotypic determination of resistance is therefore still required before the start of therapy. The subtype diversity of circulating HIV-1 is increasing.

Disease severity in hospitalized COVID-19 patients: comparing routine surveillance with cohort data from the LEOSS study in 2020 in Germany.

INTRODUCTION: Studies investigating risk factors for severe COVID-19 often lack information on the representativeness of the study population. Here, we investigate factors associated with severe COVID-19 and compare the representativeness of the dataset to the general population. METHODS: We used data from the Lean European Open Survey on SARS-CoV-2 infected patients (LEOSS) of hospitalized COVID-19 patients diagnosed in 2020 in Germany to identify associated factors for severe COVID-19, defined as progressing to a critical disease stage or death. To assess the representativeness, we compared the LEOSS cohort to cases of hospitalized patients in the German statutory notification data of the same time period. Descriptive methods and Poisson regression models were used. RESULTS: Overall, 6672 hospitalized patients from LEOSS and 132,943 hospitalized cases from the German statutory notification data were included. In LEOSS, patients above 76 years were less likely represented (34.3% vs. 44.1%). Moreover, mortality was lower (14.3% vs. 21.5%) especially among age groups above 66 years. Factors associated with a severe COVID-19 disease course in LEOSS included increasing age, male sex (adjusted risk ratio (aRR) 1.69, 95% confidence interval (CI) 1.53-1.86), prior stem cell transplantation (aRR 2.27, 95% CI 1.53-3.38), and an elevated C-reactive protein at day of diagnosis (aRR 2.30, 95% CI 2.03-2.62). CONCLUSION: We identified a broad range of factors associated with severe COVID-19 progression. However, the results may be less applicable for persons above 66 years since they experienced lower mortality in the LEOSS dataset compared to the statutory notification data.

COVID-19 cross-border case and contact tracing activities - experiences and lessons learnt, Germany, April-December 2020.

BACKGROUND: Interruption of transmission chains has been crucial in the COVID-19 response. The Emergency Operations Centre (EOC) at the Robert Koch Institute (RKI) coordinated cross-border case and contact tracing activities at the national level by sharing data with German public health authorities (PHA) and other countries. Data on these activities were not collected in the national surveillance system, and thus were challenging to quantify. Our aim was to describe cross-border COVID-19 case and contact tracing activities including lessons learnt by PHA to adapt the procedures accordingly. METHODS: Case and contact tracing events were recorded using unique identifiers. We collected data on cases, contacts, dates of exposure and/or SARS-CoV-2 positive test results and exposure setting. We performed descriptive analyses of events from 06.04.-31.12.2020. We conducted interviews with PHA to understand experiences and lessons learnt, applying a thematic approach for qualitative analysis. RESULTS: From 06.04.-31.12.2020 data on 7,527 cross-border COVID-19 case and contact tracing activities were collected. Germany initiated communication 5,200 times, and other countries 2,327 times. Communication from other countries was most frequently initiated by Austria (n = 1,184, 50.9%), Switzerland (n = 338, 14.5%), and the Netherlands (n = 168, 7.2%). Overall, 3,719 events (49.4%) included information on 5,757 cases (median 1, range: 1-42), and 4,114 events (54.7%) included information on 13,737 contacts (median: 1, range: 1-1,872). The setting of exposure was communicated for 2,247 of the events (54.6%), and most frequently included private gatherings (35.2%), flights (24.1%) and work-related meetings (20.3%). The median time delay between exposure date and contact information receipt at RKI was five days. Delay between positive test result and case information receipt was three days. Main challenges identified through five interviews were missing data or delayed accessibility particularly from flights, and lack of clear and easy to use communication channels. More and better trained staff were mentioned as ideas for improving future pandemic response preparedness. CONCLUSION: Cross-border case and contact tracing data can supplement routine surveillance but are challenging to measure. We need improved systems for cross-border event management, by improving training and communication channels, that will help strengthen monitoring activities to better guide public health decision-making and secure a good future pandemic response.

[Evaluating the introduction of HIV pre-exposure prophylaxis as a benefit of statutory health insurance (EvE-PrEP) : Highly effective protection against HIV without an increase in sexually transmitted infections]. / Evaluation der Einführung der HIV-Präexpositionsprophylaxe als Leistung der gesetzlichen Krankenversicherung (EvE­PrEP) : Hocheffektiver Schutz vor HIV und keine Zunahme von sexuell übertragbaren Infektionen.

BACKGROUND: We investigated the impact of HIV pre-exposure prophylaxis (PrEP) as a new service of the statutory health insurance (SHI) on the incidence of HIV and other sexually transmitted infections (STIs) in Germany. In addition, PrEP needs and access barriers were analyzed. METHODS: The following data were evaluated as part of the evaluation project: HIV and syphilis notification data and extended surveillance by the Robert Koch Institute (RKI), pharmacy prescription data, SHI routine data, PrEP use in HIV-specialty care centers, Checkpoint, the BRAHMS and PrApp studies, as well as a community board. RESULTS: The majority of PrEP users were male (98-99%), primarily aged between 25-45 years, and predominantly of German nationality or origin (67-82%). The majority were men who have sex with men (99%). With regard to HIV infections, PrEP proved to be highly effective. There were only isolated cases of HIV infections (HIV incidence rate 0.08/100 person years); in most cases the suspected reason was low adherence. The incidences of chlamydia, gonorrhea, and syphilis did not increase but remained almost the same or even decreased. A need for information on PrEP for people in trans*/non-binary communities, sex workers, migrants, and drug users emerged. Needs-based services for target groups at increased risk of HIV are necessary. DISCUSSION: PrEP proved to be a very effective HIV prevention method. The partly feared indirect negative influences on STI rates were not confirmed in this study. Due to the temporal overlap with the containment measures during the COVID-19 pandemic, a longer observation period would be desirable for a conclusive assessment.

The impact of regional socioeconomic deprivation on the timing of HIV diagnosis: a cross-sectional study in Germany.

BACKGROUND: HIV infections which are diagnosed at advanced stages are associated with significantly poorer health outcomes. In Germany, the proportion of persons living with HIV who are diagnosed at later stages has remained continuously high. This study examined the impact of regional socioeconomic deprivation on the timing of HIV diagnosis. METHODS: We used data from the national statutory notification of newly diagnosed HIV infections between 2011 and 2018 with further information on the timing of diagnosis determined by the BED-Capture-ELISA test (BED-CEIA) and diagnosing physicians. Data on regional socioeconomic deprivation were derived from the German Index of Socioeconomic Deprivation (GISD). Outcome measures were a non-recent infection based on the BED-CEIA result or an infection at the stage of AIDS. The effect of socioeconomic deprivation on the timing of diagnosis was analysed using multivariable Poisson regression models with cluster-robust error variance. RESULTS: Overall, 67.5% (n = 10,810) of the persons were diagnosed with a non-recent infection and 15.2% (n = 2746) with AIDS. The proportions were higher among persons with heterosexual contact compared to men who have sex with men (MSM) (76.8% non-recent and 14.9% AIDS vs. 61.7% non-recent and 11.4% AIDS). MSM living in highly deprived regions in the countryside (< 100 k residents) were more likely to have a non-recent infection (aPR: 1.16, 95% CI: 1.05-1.28) as well as AIDS (aPR: 1.41, 95% CI: 1.08-1.85) at the time of diagnosis compared to MSM in less deprived regions in the countryside. No differences were observed among MSM from towns (100 k ≤ 1 million residents) or major cities (≥ 1 million residents), and no differences overall in the heterosexual transmission group. CONCLUSIONS: An effect of socioeconomic deprivation on the timing of HIV diagnosis was found only in MSM from countryside regions. We suggest that efforts in promoting HIV awareness and regular HIV testing are increased for heterosexual persons irrespective of socioeconomic background, and for MSM with a focus on those living in deprived regions in the countryside.

HIV, STI and renal function testing frequency and STI history among current users of self-funded HIV pre-exposure prophylaxis, a cross-sectional study, Germany, 2018 and 2019.

IntroductionUsers of pre-exposure prophylaxis (PrEP) require periodic testing for HIV, sexually transmitted infections (STI) and renal function. Before PrEP was made free of charge through statutory health insurance in late 2019, PrEP users in Germany had to pay for testing themselves.AimWe investigated self-reported HIV, STI and renal function testing frequencies among self-funded PrEP users in Germany, factors associated with infrequent testing, and STI diagnoses.MethodsA cross-sectional anonymous online survey in 2018 and 2019 recruited current PrEP users via dating apps for men who have sex with men (MSM), a PrEP community website, anonymous testing sites and friends. We used descriptive methods and logistic regression for analysis.ResultsWe recruited 4,848 current PrEP users. Median age was 37 years (interquartile range (IQR): 30-45), 88.7% identified as male, and respectively 26.3%, 20.9% and 29.2% were tested less frequently for HIV, STI and renal function than recommended. Participants with lower STI testing frequency were significantly less likely to report STI diagnoses during PrEP use, especially among those with many partners and inconsistent condom use. Factors most strongly associated with infrequent testing included not getting tested before starting PrEP, using PrEP from informal sources and on-demand/intermittent PrEP use.DiscussionIn a setting of self-funded PrEP, many users obtained medical tests less frequently than recommended, which can lead to missed diagnoses. Barriers to testing should be addressed to enable proper medical supervision. The suitability of testing frequencies to PrEP users with less frequent risk exposures needs to be evaluated.

A shift from travel-associated cases to autochthonous transmission with Berlin as epicentre of the monkeypox outbreak in Germany, May to June 2022.

By 22 June 2022, 521 cases of monkeypox were notified in Germany. The median age was 38 years (IQR: 32-44); all cases were men. In Berlin, where 69% of all cases occurred, almost all were men who have sex with men. Monkeypox virus likely circulated unrecognised in Berlin before early May. Since mid-May, we observed a shift from travel-associated infections to mainly autochthonous transmission that predominantly took place in Berlin, often in association with visits to clubs and parties.

Barriers to using HIV pre-exposure prophylaxis (PrEP) and sexual behaviour after stopping PrEP: a cross-sectional study in Germany.

BACKGROUND: Persistence of individuals at risk of HIV with Pre-Exposure Prophylaxis (PrEP) is critical for its impact on the HIV epidemic. We analysed factors associated with stopping PrEP, barriers that may deter people from continuing PrEP and investigated sexual behaviour after stopping PrEP. METHODS: Current and former PrEP users in Germany were recruited to complete an anonymous online survey on PrEP use and sexual behaviour. Participants were recruited through dating apps, a PrEP community website, anonymous testing sites and peers. The results were analysed using descriptive methods and logistic regression. RESULTS: We recruited 4848 current and 609 former PrEP users in two study waves (July-October 2018, April-June 2019). Former PrEP users were more likely 18-29 years old than current users (adjusted OR = 1.6, 95% confidence interval (CI) 1.1-2.3). Moreover, they were more often unhappy with their sex life, which was more pronounced in former daily PrEP users (aOR = 4.5, 95% CI 2.9-7.1) compared to former on-demand users (aOR = 1.8, 95% CI 1.1-2.9, pinteraction = 0.005). The most common reason for stopping PrEP was a reduced need for PrEP (49.1%). However, 31.4% of former users identified logistic reasons and 17.5% stopped due to side effects. Former PrEP users using PrEP < 3 months were more likely to stop PrEP due to concerns over long-term side effects (32.0% vs. 22.5%, p = 0.015) and not wanting to take a chemical substance (33.2% vs. 24.0%, p = 0.020) compared to former PrEP users who used PrEP for longer. After stopping PrEP, 18.7% of former PrEP users indicated inconsistent condom use while having ≥4 sex partners within the previous 6 months. Former PrEP users with many partners and inconsistent condom use more often indicated logistic reasons for stopping (46.5% vs. 27.9%, p < 0.001) than did other former PrEP users. CONCLUSIONS: To maximise persistence with PrEP we need to develop strategies for younger PrEP users, reduce logistic barriers to access PrEP, and to develop effective communication on side-effect management. Moreover, prevention strategies for people stopping PrEP are required, since some remain at high risk for HIV.

COVID-19: cross-border contact tracing in Germany, February to April 2020.

IntroductionThe Robert Koch Institute (RKI) managed the exchange of cross-border contact tracing data between public health authorities (PHA) in Germany and abroad during the early COVID-19 pandemic.AimWe describe the extent of cross-border contact tracing and its challenges.MethodsWe analysed cross-border COVID-19 contact tracing events from 3 February to 5 April 2020 using information exchanged through the European Early Warning Response System and communication with International Health Regulation national focal points. We described events by PHA, number of contacts and exposure context.ResultsThe RKI processed 467 events, initiating contact to PHA 1,099 times (median = 1; interquartile range (IQR): 1-2) and sharing data on 5,099 contact persons. Of 327 (70%) events with known exposure context, the most commonly reported exposures were aircraft (n = 64; 20%), cruise ships (n = 24; 7%) and non-transport contexts (n = 210; 64%). Cruise ship and aircraft exposures generated more contacts with authorities (median = 10; IQR: 2-16, median = 4; IQR: 2-11) and more contact persons (median = 60; IQR: 9-269, median = 2; IQR: 1-3) than non-transport exposures (median = 1; IQR: 1-6 and median = 1; IQR: 1-2). The median time spent on contact tracing was highest for cruise ships: 5 days (IQR: 3-9).ConclusionIn the COVID-19 pandemic, cross-border contact tracing is considered a critical component of the outbreak response. While only a minority of international contact tracing activities were related to exposure events in transport, they contributed substantially to the workload. The numerous communications highlight the need for fast and efficient global outbreak communication channels between PHA.

[COVID-19 patients in Germany: exposure risks and associated factors for hospitalization and severe disease]. / COVID-19-Patientinnen und -Patienten in Deutschland: Expositionsrisiken und assoziierte Faktoren für Hospitalisierungen und schwere Krankheitsverläufe.

The severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) spread worldwide in 2020. By the end of June 2021, over 3.7 million people had been infected in Germany. The spread of the infection, however, is not evenly distributed across all parts of the population. Some groups are at a higher risk for SARS-CoV­2 infections or severe coronavirus disease 2019 (COVID-19) trajectories than others.This narrative review provides an overview of the parts of the population in Germany that are most affected by COVID-19. In addition, risk factors associated with hospitalization or severe courses of COVID-19 are identified.SARS-CoV­2 transmission may occur in various locations and settings. Professional settings, e.g., in the meat-processing industry, but also leisure activities and large public events are particularly affected. In the course of the pandemic, certain comorbidities associated with an increased risk for hospitalization or severe courses of COVID-19 have been identified. These include preexisting pulmonary, cardiovascular, and metabolic diseases. Patients with organ transplants and people with Down syndrome (trisomy 21) have the highest risk for hospitalization after SARS-CoV­2 infection.The identified settings that contribute to the spread of SARS-CoV­2 and the knowledge about vulnerable groups with a higher risk for hospitalization or severe disease trajectories form an important evidence base for the planning of prevention strategies and the fight against the pandemic.

Serum-derived plasminogen is activated by apoptotic cells and promotes their phagocytic clearance.

The elimination of apoptotic cells, called efferocytosis, is fundamentally important for tissue homeostasis and prevents the onset of inflammation and autoimmunity. Serum proteins are known to assist in this complex process. In the current study, we performed a multistep chromatographic fractionation of human serum and identified plasminogen, a protein involved in fibrinolysis, wound healing, and tissue remodeling, as a novel serum-derived factor promoting apoptotic cell removal. Even at levels significantly lower than its serum concentration, purified plasminogen strongly enhanced apoptotic prey cell internalization by macrophages. Plasminogen acted mainly on prey cells, whereas on macrophages no enhancement of the engulfment process was observed. We further demonstrate that the efferocytosis-promoting activity essentially required the proteolytic activation of plasminogen and was completely abrogated by the urokinase plasminogen activator inhibitor-1 and serine protease inhibitor aprotinin. Thus, our study assigns a new function to plasminogen and plasmin in apoptotic cell clearance.

Streptococcus pneumoniae stimulates a STING- and IFN regulatory factor 3-dependent type I IFN production in macrophages, which regulates RANTES production in macrophages, cocultured alveolar epithelial cells, and mouse lungs.

Streptococcus pneumoniae is the leading cause of community-acquired pneumonia. In this study, we examine an innate immune recognition pathway that senses pneumococcal infection, triggers type I IFN production, and regulates RANTES production. We found that human and murine alveolar macrophages as well as murine bone marrow macrophages, but not alveolar epithelial cells, produced type I IFNs upon infection with S. pneumoniae. This response was dependent on the pore-forming toxin pneumolysin and appeared to be mediated by a cytosolic DNA-sensing pathway involving the adapter molecule STING and the transcription factor IFN regulatory factor 3. Indeed, DNA was present in the cytosol during pneumococcal infection as indicated by the activation of the AIM2 inflammasome, which is known to sense microbial DNA. Type I IFNs produced by S. pneumoniae-infected macrophages positively regulated gene expression and RANTES production in macrophages and cocultured alveolar epithelial cells in vitro. Moreover, type I IFNs controlled RANTES production during pneumococcal pneumonia in vivo. In conclusion, we identified an immune sensing pathway detecting S. pneumoniae that triggers a type I IFN response and positively regulates RANTES production.

Recognition of Streptococcus pneumoniae by the innate immune system.

Streptococcus pneumoniae is both a frequent colonizer of the upper respiratory tract and a leading cause of life-threatening infections such as pneumonia, meningitis and sepsis. The innate immune system is critical for the control of colonization and for defence during invasive disease. Initially, pneumococci are recognized by different sensors of the innate immune system called pattern recognition receptors (PRRs), which control most subsequent host defence pathways. These PRRs include the transmembrane Toll-like receptors (TLRs) as well as the cytosolic NOD-like receptors (NLRs) and DNA sensors. Recognition of S. pneumoniae by members of these PRR families regulates the production of inflammatory mediators that orchestrate the following immune response of infected as well as neighbouring non-infected cells, stimulates the recruitment of immune cells such as neutrophils and macrophages, and shapes the adaptive immunity. This review summarizes the current knowledge of the function of different PRRs in S. pneumoniae infection.

The NLRP3 inflammasome is differentially activated by pneumolysin variants and contributes to host defense in pneumococcal pneumonia.

Streptococcus pneumoniae is a leading cause of pneumonia, meningitis, and sepsis. Pneumococci can be divided into >90 serotypes that show differences in the pathogenicity and invasiveness. We tested the hypotheses that the innate immune inflammasome pathway is involved in fighting pneumococcal pneumonia and that some invasive pneumococcal types are not recognized by this pathway. We show that human and murine mononuclear cells responded to S. pneumoniae expressing hemolytic pneumolysin by producing IL-1ß. This IL-1ß production depended on the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome. Some serotype 1, serotype 8, and serotype 7F bacteria, which have previously been associated with increased invasiveness and with production of toxins with reduced hemolytic activity, or bacterial mutants lacking pneumolysin did not stimulate notable IL-1ß production. We further found that NLRP3 was beneficial for mice during pneumonia caused by pneumococci expressing hemolytic pneumolysin and was involved in cytokine production and maintenance of the pulmonary microvascular barrier. Overall, the inflammasome pathway is protective in pneumonia caused by pneumococci expressing hemolytic toxin but is not activated by clinically important pneumococcal sequence types causing invasive disease. The study indicates that a virulence factor polymorphism may substantially affect the recognition of bacteria by the innate immune system.

Optimization of HIV testing services in Germany using HIV indicator diseases: study protocol of the HeLP study.

BACKGROUND: Despite the potentially accompanying negative clinical, epidemiologic, and health economic effects, a large proportion of persons living with the human immunodeficiency virus (HIV) are diagnosed late. Internationally, numerous diseases are known to be HIV indicator diseases. Adequate HIV testing in the presence of HIV indicator diseases could help to diagnose unknown HIV infections earlier. The objective of the HeLP study is to validate published HIV indicator diseases for the German setting and to identify guidelines in terms of these indicator diseases in order to reduce knowledge gaps and increase HIV testing when HIV indicator diseases are diagnosed. METHODS: A mixed methods approach is used. In a first step, published HIV indicator diseases will be identified in a systematic literature review and subsequently discussed with clinical experts regarding their relevance for the German setting. For the validation of selected indicator diseases different data sets (two cohort studies, namely HIV-1 seroconverter study & ClinSurv-HIV, and statutory health insurance routine data) will be analyzed. Sensitivity analyses using different time periods will be performed. Guidelines of HIV indicator diseases validated in the HeLP study will be reviewed for mentioning HIV and for HIV testing recommendations. In addition, semi-standardized interviews (followed by a free discussion) with guideline creators will identify reasons why HIV testing recommendations were (not) included. Subsequently, a random sample of physicians in medical practices will be surveyed to identify how familiar physicians are with HIV testing recommendations in guidelines and, if so, which barriers are seen to perform the recommended tests in everyday care. DISCUSSION: The HeLP-study adopts the challenge to validate published HIV indicator diseases for the German setting and has the potential to close a knowledge gap regarding this objective. This has the potential to improve targeted HIV testing for patients with HIV indicator diseases and consequently lead to earlier HIV diagnosis. TRIAL REGISTRATION: DRKS00028743.