PURPOSE:Primary HIV-1 infection (PHI) can present with protean clinical manifestations. We report a rare presentation of PHI that underscores that a high index of suspicion is required for diagnosis of PHI. METHODS:We report on a 54-yearold previously healthy woman of African descent who presented with sudden-onset nephrotic-range proteinuria and acute kidney injury (AKI) requiring hemodialysis in the setting of febrile multiple organ dysfunction syndrome. Both the epidemiological and clinical features initially pointed to imported Lassa fever, but this was ruled out. She was eventually diagnosed with PHI. We reviewed the literature for other patients who presented with PHI and AKI requiring hemodialysis. RESULTS:Kidney biopsy evaluation, including conventional and electron microscopy, revealed minimal change disease (MCD) and diffuse tubular damage leading to AKI. To date, MCD has not been reported to be associated with PHI and severe AKI. A literature search revealed six additional cases of severe PHI-associated AKI requiring hemodialysis. In four cases, severe rhabdomyolysis with tubulotoxic myoglobinuria played the primary causative role, while in one case each AKI was associated with HIV-associated nephropathy (HIVAN) and hemolytic uremic syndrome, respectively. CONCLUSIONS:Severe AKI requiring hemodialysis is a rare manifestation of PHI and may be associated with several conditions, most commonly PHI-associated rhabdomyolysis with tubulotoxic myoglobinuria. Severe AKI in PHI may also occur as a complication of MCD manifesting with nephrotic-range proteinuria. PHI should be considered in the differential diagnosis in patients presenting with severe proteinuria and AKI in the setting of febrile multiple organ dysfunction syndromes, including hemorrhagic fever diseases.

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.

Objective: To assess the antiviral activity, pharmacokinetics, and safety of MK-6186 in HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI)-naïve, HIV-1-infected male participants. Design: Double-blind, randomized, two-panel study. Methods: In 2 sequential panels, 18 participants received MK-6186 (40 mg [Panel A] or 150 mg [Panel B]) or matching placebo once daily for 7 days. Plasma samples were collected for measurement of HIV-1 RNA levels and MK-6186 pharmacokinetics. Results: For the mean change from baseline in HIV-1 RNA (log10 copies/mL) at 24 h post Day 7 dose, the mean difference (90% confidence interval) between MK-6186 and placebo was -1.54 (-1.73, -1.34) in the 40-mg group and -1.28 (-1.81, -0.75) in the 150-mg group. One participant in the 150-mg group had viral rebound at 24 h after Day 6 dosing (Day 7 predose) associated with outgrowth of the V106A minority variant. Ultra-deep sequencing confirmed expansion of this predose minority variant from 0.26% to 63.67%. No outgrowth or rebound was seen in another participant in whom a V106A minority variant was also detected. MK-6186 was generally well tolerated. MK-6186 was rapidly absorbed with peak concentrations at 2 h followed by a biphasic decline. The effective t½ of MK-6186 was 43.9 to 48.7 h. Steady state was not achieved. Conclusions: Daily monotherapy with MK-6186 demonstrated robust antiviral activity with maximal antiviral activity at a dose of 40 mg. One participant in the 150-mg group exhibited viral rebound with outgrowth of the resistant V106A minority variant, demonstrating a risk of resistance development typical of NNRTIs. The reason for this outgrowth remains unclear as no outgrowth occurred in a participant in the 40-mg group in whom the V106A minority variant was also detected. MK-6186 may be an alternative next-generation NNRTI in combination therapy, in that combination antiretroviral therapy could prevent outgrowth of resistant minority variants.

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.

"Unilateral Endobronchial Vascular Hypertrophy in a Young Patient with Hemoptysis." American Journal of Respiratory and Critical Care Medicine, 207(2), pp. e1–e3

The risk of foreign body aspiration associated with uncapped handheld metered-dose inhalers (MDIs) is underestimated. We report a case in which a plastic cable clip accidentally lodged in the mouthpiece of an uncapped pressurized MDI was aspirated during its use. A literature search revealed 16 other cases of foreign body aspiration associated with uncapped handheld inhalers, all but one of which were pressurized inhalers. Patients should be informed of the risk of foreign body aspiration associated with uncapped pocket inhalers. The use of an uncuffed armoured tracheal tube with a separate oxygen tubing during flexible bronchoscopy for foreign body removal ensures a safe airway. Foreign bodies that exceed the lumen size of the tracheal tube can be pulled to the distal opening with forceps and removed when the tube is withdrawn.

Berlin is amongst the cities most affected by the current monkeypox outbreak. Here, we report clinical characteristics of the first patients with confirmed monkeypox admitted to our center. We analyzed anamnestic, clinical, and laboratory data. Within a period of 2 weeks, six patients were hospitalized in our unit. All were MSM and had practiced condomless receptive anal intercourse in the weeks preceding admission. The chief complaint in all patients but one was severe anal pain unprecedented in severity. Investigations revealed proctitis, as well as anal and rectal ulcers with detection of monkeypox virus. Our findings support the hypothesis that sexual transmission plays a role in the current outbreak.

Background Rapid and reliable diagnostic work-up of tuberculosis (TB) remains a major healthcare goal. In particular, discrimination of TB infection from TB disease with currently available diagnostic tools is challenging and time consuming. This study aimed at establishing a standardised blood-based assay that rapidly and reliably discriminates TB infection from TB disease based on multiparameter analysis of TB antigen-reactive CD4(+) T-cells acting as sensors for TB stage-specific immune status. Methods 157 HIV-negative subjects with suspected TB infection or TB disease were recruited from local tertiary care hospitals in Berlin (Germany). Peripheral blood mononuclear cells were analysed for CD4(+) T-cells reactive to the Mycobacterium tuberculosis antigens purified protein derivative and early secretory antigenic target 6 kDa/culture filtrate protein 10. The activation state of TB antigen-reactive T-cells, identified by surface expression of CD154, was evaluated according to the expression profile of proliferation marker Ki-67 and activation markers CD38 and HLA-DR. Using data from 81 subjects with clinically confirmed TB infection (n=34) or culture-proven pulmonary or extrapulmonary TB disease (n=47), 12 parameters were derived from the expression profile and integrated into a scoring system. Results Using the scoring system, our assay (TB-Flow Assay) allowed reliable discrimination of TB infection from both pulmonary and extrapulmonary TB disease with high sensitivity (90.9%) and specificity (93.3%) as was confirmed by Monte-Carlo cross-validation. Conclusion With low time requirement, ease of sample collection, and high sensitivity and specificity both for pulmonary and extrapulmonary TB disease, we believe this novel standardised TB-Flow Assay will improve the work-up of patients with suspected TB disease, supporting rapid TB diagnosis and facilitating treatment decisions.

Background: MK-8507 is a novel HIV-1 non-nucleoside reverse transcriptase inhibitor being developed for treatment of HIV-1 infection. MK-8507 has high antiviral potency in vitro and pharmacokinetic (PK) properties that support once-weekly dosing. Setting: A phase 1, open-label, proof-of-concept study was conducted in treatment-naive adults with HIV-1 infection to assess monotherapy antiviral activity. Methods: In 3 sequential panels, participants aged 18–60 years with baseline plasma HIV-1 RNA ≥10,000 copies/mL and CD4 + T-cell count >200/mm 3 received a single oral dose of 40, 80, or 600 mg MK-8507 in the fasted state. Participants were assessed for HIV-1 RNA for at least 7 days, PKs for 14 days, and safety and tolerability for 21 days postdose. Results: A total of 18 participants were enrolled (6 per panel). The mean 7-day postdose HIV-1 RNA reduction ranged from ∼1.2 to ∼1.5 log 10 copies/mL across the doses assessed. One patient had a viral rebound associated with emergence of an F227C reverse transcriptase variant (per chain-termination method sequencing) 14 days postdose; this variant was found in a second participant by ultra-deep sequencing as an emerging minority variant. MK-8507 PKs were generally dose-proportional and similar to observations in participants without HIV-1 infection in prior studies; mean MK-8507 half life was 56–69 hours in this study. MK-8507 was generally well tolerated at all doses. Conclusions: The robust antiviral activity, PK, and tolerability of MK-8507 support its continued development as part of a complete once weekly oral regimen for HIV-1 treatment; combination therapy could mitigate the emergence of resistance-associated variants.

Therapy choices for cystic echinococcisis (CE) are stage-specific: surgical, minimally invasive, medical or observation without intervention. PAIR (percutaneous aspiration, instillation of a scolicide, and re-aspiration) has been considered the treatment of choice for uncomplicated echinococcal liver cysts. However, PAIR carries the risk of toxic cholangitis or hypernatremia and that the cyst frequently refills with bile after withdrawing the catheter. We treated a patient with a giant CE 1 liver cyst with puncture drainage (PD) under albendazole coverage. Drainage enabled us to monitor the morphology of protoscolices under praziquantel (PZQ) co-medication. Protoscolices degenerated within 5 days of PZQ 50 mg/kg/d. The cyst cavity solidified with no evidence of reactivation or secondary spread. Percutaneous treatments can replace surgery in a significant number or cases with hepatic CE. PD allows to assess microscopically the viability of protoscolices under co-medication with PZQ–albendazole and to avoid the instillation of topical scolicides.

BACKGROUND:Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous disease, most often preceded by herpes simplex virus (HSV) infection or reactivation. Mycoplasma pneumoniae (Mp) is considered the second major trigger of EM and is often associated with an atypical and more severe presentation of disease, characterized by prominent mucosal involvement. However, contrary to HSV-associated Erythema multiforme (HAEM), immunological mechanisms of Mp-associated EM remain unclear.CASE PRESENTATION:We present the case of a 50-year-old male patient presenting with community-acquired pneumonia (CAP) and erythema multiforme majus (EMM). Acute Mp infection was diagnosed by seroconversion, with no evidence of HSV infection as a cause of EMM. We performed immune phenotyping of blister fluid (BF) and peripheral blood (PB) T cells and detected a clonally expanded TCRVβ2+ T cell population that was double positive for CD4 and CD8, and expressed the cytotoxic markers granulysin and perforin. This CD4+CD8+ population comprised up to 50.7% of BF T cells and 24.9% of PB T cells. Two years prior to the onset of disease, the frequency of PB CD4+CD8+T cells had been within normal range and it gradually returned to baseline levels with the resolution of symptoms, suggesting an involvement of this population in EMM disease pathophysiology.CONCLUSIONS:This report is the first to provide a phenotypic description of lesional T cells in Mp-associated EMM. Characterizing the local immune response might help to address pathophysiological questions and warrants further systematic research.

Human bocavirus (HBoV) has to be considered a life-threatening pathogen in adults with atypical pneumonia. Pulsed high-dose glucocorticoid treatment may be beneficial in patients suffering from severe pulmonary disease caused by HBoV or other viruses. https://bit.ly/3epiMyO.

Purpose Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide causing a global health emergency. Pa-COVID-19 aims to provide comprehensive data on clinical course, pathophysiology, immunology and outcome of COVID-19, to identify prognostic biomarkers, clinical scores, and therapeutic targets for improved clinical management and preventive interventions. Methods Pa-COVID-19 is a prospective observational cohort study of patients with confirmed SARS-CoV-2 infection treated at Charité - Universitätsmedizin Berlin. We collect data on epidemiology, demography, medical history, symptoms, clinical course, and pathogen testing and treatment. Systematic, serial blood sampling will allow deep molecular and immunological phenotyping, transcriptomic profiling, and comprehensive biobanking. Longitudinal data and sample collection during hospitalization will be supplemented by long-term follow-up. Results Outcome measures include the WHO clinical ordinal scale on day 15 and clinical, functional, and health-related quality-of-life assessments at discharge and during follow-up. We developed a scalable dataset to (i) suit national standards of care, (ii) facilitate comprehensive data collection in medical care facilities with varying resources, and (iii) allow for rapid implementation of interventional trials based on the standardized study design and data collection. We propose this scalable protocol as blueprint for harmonized data collection and deep phenotyping in COVID-19 in Germany. Conclusion We established a basic platform for harmonized, scalable data collection, pathophysiological analysis, and deep phenotyping of COVID-19, which enables rapid generation of evidence for improved medical care and identification of candidate therapeutic and preventive strategies. The electronic database accredited for interventional trials allows fast trial implementation for candidate therapeutic agents. Trial registration Registered at the German registry for clinical studies (DRKS00021688)

We report a case of a probable HIV-1 transmission by human bite. The analyzed data from ten previously reported suspected or allegedly confirmed HIV transmissions revealed a deep bleeding bite wound as the primary risk factor. A high HIV plasma viral load and bleeding oral lesions are present most of the time during HIV transmission by bite. HIV post-exposure prophylaxis (PEP) should be recommended in case of a bleeding wound resulting from a bite of an HIV-infected person. PEP was missed in this presented case.

Objective Combination antiretroviral therapy (cART) has markedly increased survival and quality of life in people living with HIV. With the advent of new treatment options, including single-tablet regimens, durability and efficacy of first-line cART regimens are evolving. Methods We analyzed data from the prospective multicenter German Clinical Surveillance of HIV Disease (ClinSurv) cohort of the Robert-Koch Institute. Kaplan–Meier and Cox proportional hazards models were run to examine the factors associated with treatment modification. Recovery after treatment initiation was analyzed comparing pre-cART viral load and CD4+ T-cell counts with follow-up data. Results We included 8788 patients who initiated cART between 2005 and 2017. The sample population was predominantly male ( n = 7040; 80.1%), of whom 4470 (63.5%) were reporting sex with men as the transmission risk factor. Overall, 4210 (47.9%) patients modified their first-line cART after a median time of 63 months (IQR 59–66). Regimens containing integrase strand transfer inhibitors (INSTI) were associated with significantly lower rates of treatment modification (adjusted hazard ratio 0.44; 95% CI 0.39–0.50) compared to protease inhibitor (PI)-based regimens. We found a decreased durability of first-line cART significantly associated with being female, a low CD4+ T-cell count, cART initiation in the later period (2011–2017), being on a multi-tablet regimen (MTR). Conclusions Drug class and MTRs are significantly associated with treatment modification. INSTI-based regimens showed to be superior compared to PI-based regimens in terms of durability.

Background Islatravir (also known as ISL and MK-8591) is a unique nucleoside reverse transcriptase translocation inhibitor in clinical development for treatment of people with HIV-1 infection. In preclinical studies, intracellular islatravir-triphosphate exhibits a long half-life and prolonged virological effects. In this study, we aimed to assess islatravir safety, pharmacokinetics, and antiretroviral activity in treatment-naive adults with HIV-1 infection. Methods This open-label, consecutive-panel, phase 1b trial was done at Charite Research Organisation (Berlin, Germany) and included men and women (aged 18-60 years, inclusive) with HIV-1 infection who were ART naive. Participants were required to have plasma HIV-1 RNA counts of at least 10 000 copies per mL within 30 days before the trial treatment phase, without evidence of resistance to nucleoside reverse transcriptase inhibitors. Participants were enrolled in one of five consecutive dosing panels, receiving a single oral dose of islatravir (0.5-30 mg). The primary outcomes were safety and tolerability of islatravir and change from baseline in HIV-1 plasma RNA; secondary outcomes were islatravir plasma and islatravir-triphosphate intracellular pharmacokinetics. We obtained descriptive safety and pharmacokinetics statistics, and estimated efficacy results from a longitudinal data analysis model. This study is registered with ClinicalTrials.gov, NCT02217904, and EudraCT, 2014-002192-28. Findings Between Sept 17, 2015, and May 11, 2017, we enrolled 30 participants (six per panel). Islatravir was generally well tolerated. 27 (90%) participants had 60 adverse events after receipt of drug, of which 21 (35%) were deemed to be drug related. The most common (n>1) drug-related adverse events were headache (in nine [30%] participants) and diarrhoea (in two [7%]). No serious adverse events were reported, and no participants discontinued due to an adverse event. Plasma islatravir pharmacokinetics and intracellular islatravir-triphosphate pharmacokinetics were approximately dose proportional. The islatravir-triphosphate intracellular half-life was 78.5-128.0 h. Least-squares mean HIV-1 RNA at 7 days after dose decreased from 1.67 log 10 copies per mL (95% CI 1.42-1.92) at 10 mg dose to 1.20 log 10 copies per mL (0.95-1.46) at 0.5 mg dose. No genetic changes consistent with development of viral resistance were detected. Interpretation Single doses of islatravir as low as 0.5 mg significantly suppressed HIV-1 RNA by more than 1.0 log at day 7 in treatment-naive adults with HIV-1 infection and were generally well tolerated, supporting the further development of islatravir as a flexible-dose treatment for individuals with HIV-1 infection. Copyright (C) 2020 Elsevier Ltd. All rights reserved.

Introduction Recurrent pleural effusion is a common cause of dyspnoea, cough and chest pain during the course of malignant diseases. Chemical pleurodesis had been the only definitive treatment option until two decades ago. Indwelling pleural catheters (IPC) emerged as an alternative, not only assuring immediate symptom relief but also potentially leading to pleurodesis in the absence of sclerosing agents. Methods In this single-centre retrospective observational study patient characteristics, procedural variables and outcome in a large population of patients with IPC in malignancy were evaluated and prognostic factors for pleurodesis were identified. Results From 2006 to 2016, 395 patients received 448 IPC, of whom 121 (30.6%) had ovarian, 91 (23.0%) lung and 45 (11.4%) breast cancer. The median length of IPC remaining in place was 1.2 months (IQR, 0.5–2.6), the median survival time after insertion 2.0 months (IQR, 0.6–6.4). An adequate symptom relief was achieved in 94.9% of all patients, with no need for subsequent interventions until last visit or death. In patients surviving ≥30 days after IPC insertion, pleurodesis was observed in 44.5% and was more common in patients < 60 years (HR, 1.72; 95% CI, 1.05–2.78; p = 0.03). The use of an additional talc slurry via the IPC was highly predictive for pleurodesis (HR 6.68; 95% CI, 1.44–31.08; p = 0.02). Complications occurred in 13.4% of all procedures ( n = 60), 41.8% concerning infections (local infections at the tunnel/exit site ( n = 14) and empyema ( n = 11)), and 98.3% being low or mild grade ( n = 59). Complication rates were higher in men than women (18.6 vs. 12.4%, p = 0.023). Conclusion High efficacy in symptom relief and a favourable safety profile confirm IPC as suitable first line option in most malignant pleural effusions. The study presents the largest dataset on IPC in gynaecologic cancer to date. Gender-specific differences in complication rates warrant further study.

Background To evaluate clinical outcomes after either immediate or deferred initiation of antiretroviral therapy in HIV-1-infected patients, presenting late with pneumocystis pneumonia (PCP) or toxoplasma encephalitis (TE). Methods Phase IV, multicenter, prospective, randomized open-label clinical trial. Patients were randomized into an immediate therapy arm (starting antiretroviral therapy (ART) within 7 days after initiation of OI treatment) versus a deferred arm (starting ART after completing the OI-therapy). All patients were followed for 24 weeks. The rates of clinical progression (death, new or relapsing opportunistic infections (OI) and other grade 4 clinical endpoints) were compared, using a combined primary endpoint. Secondary endpoints were hospitalization rates after completion of OI treatment, incidence of immune reconstitution inflammatory syndrome (IRIS), virologic and immunological outcome, adherence to proteinase-inhibitor based antiretroviral therapy (ART) protocol and quality of life. Results 61 patients (11 patients suffering TE, 50 with PCP) were enrolled. No differences between the two therapy groups in all examined primary and secondary endpoints could be identified: immunological and virologic outcome was similar in both groups, there was no significant difference in the incidence of IRIS (11 and 10 cases), furthermore 9 events (combined endpoint of death, new/relapsing OI and grade 4 events) occurred in each group. Conclusions In summary, this study supports the notion that immediate initiation of ART with a ritonavir-boosted proteinase-inhibitor and two nucleoside reverse transcriptase inhibitors is safe and has no negative effects on incidence of disease progression or IRIS, nor on immunological and virologic outcomes or on quality of life.