Search

Background Capnocytophaga canimorsus is a Gram-negative capnophilic rod and part of dogs/cats’ normal oral flora. It can be transmitted by bites, scratches, or even by contact of saliva with injured skin. Asplenic patients and patients with alcohol abuse are at particular risk for fulminant C. canimorsus sepsis. However, also immunocompetent patients can have a severe or even fatal infection. This is the first case of a severe C. canimorsus infection in an immunocompromised host complicated by acute renal cortical necrosis with a “reverse rim sign” in contrast-enhanced computed tomography on hospital admission. Case presentation We report the case of a 44-year functionally asplenic patient after an allogeneic stem cell transplantation, who presented with septic shock after a minor dog bite injury 4 days prior. Because of abdominal complaints, epigastric pain with local peritonism, and radiological gallbladder wall thickening, an abdominal focus was suspected after the initial work-up. The patient underwent emergent open cholecystectomy, but the clinical suspicion of abdominal infection was not confirmed. Septic shock was further complicated by cardiomyopathy and disseminated intravascular coagulation. As a causative pathogen, C. canimorsus could be isolated. The clinical course was complicated by permanent hemodialysis and extensive acral necrosis requiring amputation of several fingers and both thighs. Conclusion We present a severe case of a C. canimorsus infection in a functionally asplenic patient after a minor dog bite. The clinical course was complicated by septic shock, disseminated intravascular coagulation, and the need for multiple amputations. In addition, the rare form of acute renal failure - bilateral acute renal cortical necrosis – was visible as “reverse rim sign” on computed tomography scan. This case is an example of the potential disastrous consequences when omitting pre-emptive antibiotic therapy in wounds inflicted by cats and dogs, particularly in asplenic patients.

Objectives SARS-CoV-2 may cause acute lung injury, and secondary infections are thus relevant complications in patients with COVID-19 pneumonia. However, detailed information on community- and hospital-acquired infections among patients with COVID-19 pneumonia is scarce. Methods We identified 220 SARS-CoV-2-positive patients hospitalized at the University Hospital Basel, Switzerland (between 25 February and 31 May 2020). We excluded patients who declined the general consent (n = 12), patients without clinical evidence of pneumonia (n = 29), and patients hospitalized for n = 17). We evaluated the frequency of community- and hospital-acquired infections using respiratory and blood culture materials with antigen, culture-based, and molecular diagnostics. For ICU patients, all clinical and microbial findings were re-evaluated interdisciplinary (intensive care, infectious disease, and clinical microbiology), and agreement reached to classify patients with infections. Results In the final cohort of 162 hospitalized patients (median age 64.4 years (IQR, 50.4–74.2); 61.1% male), 41 (25.3%) patients were admitted to the intensive care unit, 34/41 (82.9%) required mechanical ventilation, and 17 (10.5%) of all hospitalized patients died. In total, 31 infections were diagnosed including five viral co-infections, 24 bacterial infections, and three fungal infections (ventilator-associated pneumonia, n = 5; tracheobronchitis, n = 13; pneumonia, n = 1; and bloodstream infection, n = 6). Median time to respiratory tract infection was 12.5 days (IQR, 8–18) and time to bloodstream infection 14 days (IQR, 6–30). Hospital-acquired bacterial and fungal infections were more frequent among ICU patients than other patients (36.6% vs. 1.7%). Antibiotic or antifungal treatment was administered in 71 (43.8%) patients. Conclusions Community-acquired viral and bacterial infections were rare among COVID-19 pneumonia patients. By contrast, hospital-acquired bacterial or fungal infections were frequently complicating the course among ICU patients.

Background Patients with clinically suspected tuberculosis are often treated empirically, as diagnosis - especially of extrapulmonary tuberculosis - remains challenging. This leads to an overtreatment of tuberculosis and to underdiagnosis of possible differential diagnoses. Methods This open-label, parallel-group, superiority randomized controlled trial is done in a rural and an urban center in Tanzania. HIV-positive and -negative adults (≥18 years) with clinically suspected extrapulmonary tuberculosis are randomized in a 1:1 ratio to an intervention- or control group, stratified by center and HIV status. The intervention consists of a management algorithm including extended focused assessment of sonography for HIV and tuberculosis (eFASH) in combination with chest X-ray and microbiological tests. Treatment with anti-tuberculosis drugs is started, if eFASH is positive, chest X-ray suggests tuberculosis, or a microbiological result is positive for tuberculosis. Patients in the control group are managed according national guidelines. Treatment is started if microbiology is positive or empirically according to the treating physician. The primary outcome is the proportion of correctly managed patients at 6 months (i.e patients who were treated with anti-tuberculosis treatment and had definite or probable tuberculosis, and patients who were not treated with anti-tuberculosis treatment and did not have tuberculosis). Secondary outcomes are the proportion of symptom-free patients at two and 6 months, and time to death. The sample size is 650 patients. Discussion This study will determine, whether ultrasound in combination with other tests can increase the proportion of correctly managed patients with clinically suspected extrapulmonary tuberculosis, thus reducing overtreatment with anti-tuberculosis drugs. Trial registration PACTR, Registration number: PACTR201712002829221, registered December 1st 2017.

Background The burden and timeline of posttransplant infections are not comprehensively documented in the current era of immunosuppression and prophylaxis. Methods In this prospective study nested within the Swiss Transplant Cohort Study (STCS), all clinically relevant infections were identified by transplant–infectious diseases physicians in persons receiving solid organ transplant (SOT) between May 2008 and December 2014 with ≥12 months of follow-up. Results Among 3541 SOT recipients, 2761 (1612 kidney, 577 liver, 286 lung, 213 heart, and 73 kidney-pancreas) had ≥12 months of follow-up; 1520 patients (55%) suffered 3520 infections during the first year posttransplantation. Burden and timelines of clinically relevant infections differed between transplantations. Bacteria were responsible for 2202 infections (63%) prevailing throughout the year, with a predominance of Enterobacteriaceae (54%) as urinary pathogens in heart, lung, and kidney transplant recipients, and as digestive tract pathogens in liver transplant recipients. Enterococcus spp (20%) occurred as urinary tract pathogens in kidney transplant recipients and as digestive tract pathogens in liver transplant recipients, and Pseudomonas aeruginosa (9%) in lung transplant recipients. Among 1039 viral infections, herpesviruses predominated (51%) in kidney, liver, and heart transplant recipients. Among 263 fungal infections, Candida spp (60%) prevailed as digestive tract pathogens in liver transplant recipients. Opportunistic pathogens, including Aspergillus fumigatus (1.4%) and cytomegalovirus (6%), were rare, scattering over 12 months across all SOT recipients. Conclusions In the current era of immunosuppression and prophylaxis, SOT recipients experience a high burden of infections throughout the first year posttransplantation, with rare opportunistic pathogens and a predominance of bacteria., Data on burden and timeline of infections following solid organ transplantation are currently lacking. This Swiss nationwide cohort study found a high burden of infections throughout the first year posttransplantation, with rare opportunistic pathogens and a predominance of bacteria.

Background Influenza vaccination efficacy is reduced after hematopoietic stem cell transplantation (HSCT) and patient factors determining vaccination outcomes are still poorly understood. Methods We investigated the antibody response to seasonal influenza vaccination in 135 HSCT patients and 69 healthy volunteers (HVs) in a prospective observational multicenter cohort study. We identified patient factors associated with hemagglutination inhibition titers against A/California/2009/H1N1, A/Texas/2012/H3N2, and B/Massachusetts/2012 by multivariable regression on the observed titer levels and on seroconversion/seroprotection categories for comparison. Results Both regression approaches yielded consistent results but regression on titers estimated associations with higher precision. HSCT patients required 2 vaccine doses to achieve average responses comparable to a single dose in HVs. Prevaccination titers were positively associated with time after transplantation, confirming that HSCT patients can elicit potent antibody responses. However, an unrelated donor, absolute lymphocyte counts below the normal range, and treatment with calcineurin inhibitors lowered the odds of responding. Conclusions HSCT patients show a highly heterogeneous vaccine response but, overall, patients benefited from the booster shot and can acquire seroprotective antibodies over the years after transplantation. Several common patient factors lower the odds of responding, urging identification of additional preventive strategies in the poorly responding groups. Clinical Trials Registration NCT03467074., The Journal of Infectious Diseases, 225 (8), ISSN:0022-1899, ISSN:1537-6613

Prospective cohort studies significantly contribute to answering specific research questions in a defined population. Since 2008, the Swiss Transplant Cohort Study (STCS) systematically enrolled >95 % of all transplant recipients in Switzerland, collecting predefined data at determined time points. Designed as an open cohort, the STCS has included >3900 patients to date, with a median follow-up of 2.96 years (IQR 1.44-4.73). This review highlights some relevant findings in the field of transplant-associated infections gained by the STCS so far. Three key general aspects have crystallized: (i) Well-run cohort studies are a powerful tool to conduct genetic studies, which are crucially dependent on a meticulously described phenotype. (ii) Long-term real-life observations are adding a distinct layer of information that cannot be obtained during randomized studies. (iii) The systemic collection of data, close interdisciplinary collaboration, and continuous analysis of some key outcome data such as infectious diseases endpoints can improve patient care.

Zusammenfassung. Eine Tuberkulose manifestiert sich normalerweise pulmonal, kann jedoch in jedes Organ disseminieren. Die häufigsten Manifestationsorte einer extrapulmonalen Tuberkulose sind Lymphknoten, die Pleura und die Knochen. Die Wahrscheinlichkeit der Dissemination einer Tuberkulose erhöht sich bei einem immunsupprimierten Patienten, z.B. durch HIV oder einen TNF-alpha-Inhibitor. Die Diagnose einer extrapulmonalen Tuberkulose ist schwierig. Oft ist eine invasive Herangehensweise zur Probengewinnung nötig, um den Tuberkuloseerreger M. tuberculosis durch Mikroskopie, Kultur, Mikrobiologie (z.B. Xpert® MTB/RIF) oder Histologie nachzuweisen. Die Behandlung einer extrapulmonalen Tuberkulose folgt den Richtlinien der Therapie einer pulmonalen Tuberkulose mit einer zweimonatigen antibiotischen Vierfachtherapie (Rifampicin, Isoniazid, Ethambuthol und Pyrazinamid), gefolgt von einer viermonatigen antibiotischen Zweifachtherapie (Rifampicin und Isoniazid). Die Dauer der antibiotischen Behandlung ist bei einer tuberkulösen Meningitis auf ein Jahr und bei einer skelettalen Dissemination auf sechs bis neun Monate verlängert. Kortikosteroide sind bei einer tuberkulösen Meningoenzephalitis und Perimyokarditis empfohlen.

Ultrasound Course in Ifakara (Tanzania) with Case Studies Abstract. Presentation of two practical cases from the ultrasound course in Ifakara, Tanzania. Case 1 shows the diagnostic value of abdominal and thorax ultrasound in a polytraumatized patient with splenic rupture. In case 2 the sonographic signs of pulmonary and extrapulmonary tuberculosis are presented.

HIV in Sub-Saharan Africa: Where Are We Today? Abstract. In sub-Saharan Africa the HIV epidemic has changed remarkedly due to expanded testing and easier access to antiretroviral medication. The rate of new infections has decreased substantially since 2005, the life expectancy of people living with HIV has increased and the mortality rate has declined. Yet still a lot needs to be achieved to stop the ongoing epidemic. Women are still at a higher risk to get infected and stigma and discrimination are a hindrance to further reduce the incidence. Challenges like the lack of technical capacities, especially to perform viral load and resistance testing, refusal of testing or condom use and increasing drug resistance to first-line therapies jeopardize the goal of 90-90-90: 90 % of people tested, 90 % of positives under care and 90 % of treated persons virologically controlled. New testing strategies and medication with higher efficacies which, when taken regularly, stop the transmission completely, provide hope in the fight against HIV.

BACKGROUND: Cryptococcal meningitis accounts for 15% of all AIDS-mortality globally. Most cases in low- and middle-income countries are treated with fluconazole monotherapy, which is associated with a high mortality. New available therapies are needed. Short course amphotericin B has been shown to be a safe and efficient therapeutic option. Sertraline has in vitro fungicidal activity against Cryptococcus and bi-directional synergy with fluconazole. METHODS: We conducted an open label clinical trial to assess the safety and efficacy of sertraline 400 mg/day and fluconazole 1200 mg/day (n=28) vs. sertraline, fluconazole and additional 5-days of amphotericin B deoxycholate 0.7-1 mg/kg (n=18) for cryptococcal meningitis. RESULTS: 2-week survival was 64% (18/28) without amphotericin and 89% (16/18) with amphotericin, and 10-week survival was 21% (6/28) vs. 61% (11/18), respectively (p=0.012). The cerebrospinal fluid (CSF) Cryptococcus clearance rate was 0.264 log(10) colony forming units (CFU)/mL of CSF/day (95%CI: 0.112-0.416) without amphotericin and 0.473 log(10) CFU/mL/day (95%CI: 0.344-0.60) with short-course amphotericin (p=0.03). Sertraline was discontinued in one participant due to side effects. Four participants receiving amphotericin B experienced hypokalemia

Daptomycin is commonly prescribed in combination with other antibiotics for treatment of enterococcal bacteremia. While a free drug area under the curve to minimum inhibitory concentration ( f AUC/MIC) ratio >27.4 was associated with 30-day survival when daptomycin was administered as monotherapy, it was unknown whether receipt of other antibiotics affects this threshold. We pooled data from 7 published trials assessing outcomes in daptomycin-treated enterococcal bacteremia and included patients who received daptomycin (≥72 hours) and any β-lactam, an intravenous aminoglycoside, linezolid, tigecycline, and/or vancomycin. Exposures were calculated using a published population pharmacokinetic model based on creatinine clearance, 90% protein binding, and daptomycin Etest MIC. The f AUC/MIC threshold predictive of 30-day survival was determined by classification and regression tree analysis. Following the pooling of data, 240 adults were included and 137 (57.1%) were alive at 30 days. A majority of patients (65.8%) were immunosuppressed and received a β-lactam (94.6%). Examining the threshold in low-acuity patients to control for comorbidities, these patients (n=135) were more likely to survive when f AUC/MIC >12.3 was achieved (63.2% versus 20.0%, p=0.015). The difference remained significant in a multivariable logistic regression model that controlled for infection source and immunosuppression (p=0.017). This threshold is 2-fold lower than that observed with daptomycin monotherapy. Probabilities of threshold attainment using a 10 mg/kg/day dose were 100% for isolates with MICs ≤2 mg/L and 95.2% for a 12 mg/kg/day dose for MICs of 4 mg/L. These data support the use of high-dose daptomycin in combination with another antibiotic for treatment of enterococcal bacteremia.

Background The extent to which drug–drug interactions (DDIs) between antiretrovirals (ARVs) and co-medications are recognized and managed has not been thoroughly evaluated in limited-resource settings. Objectives This prospective questionnaire-based study aimed to determine the prevalence and risk factors for unrecognized/incorrectly managed DDIs in people living with HIV followed-up at the Chronic Diseases Clinic of Ifakara (CDCI) and enrolled in the Kilombero and Ulanga Antiretroviral Cohort (KIULARCO). Methods We prospectively included ARV-treated adults receiving ≥1 co-medication coming for a follow-up visit at the CDCI between March and July 2017. Using a structured questionnaire, physicians were requested to identify potentially clinically significant DDIs in the prescribed treatment, to provide recommendations for their management and to indicate any hurdles to implement the recommendations. Prescriptions were subsequently screened for DDIs using the Liverpool DDIs database. Identified clinically significant DDIs and their recommended management according to the DDIs database were compared with the information provided in the questionnaires. Results Among 334 participants, the median age was 47 years (IQR = 40–56 years), 69% were female and 82% had ≥1 non-communicable disease (NCD). Overall, 129 participants had ≥1 clinically relevant DDI, which was not recognized and/or incorrectly managed in 56 participants (43%). Of those, 6 (11%) were due to limited monitoring options or medication affordability issues. In the multivariable logistic regression, the presence of ≥1 NCD was associated with an increased risk for unrecognized/incorrect DDI management (OR = 15.8; 95% CI = 1.8–139.6). Conclusions Recognition/appropriate management of DDIs is suboptimal, highlighting the need for educational programmes, pharmacovigilance activities and increased access to medications and monitoring options. This should become a focus of HIV programmes given the increasing burden of NCDs in sub-Saharan Africa.

Background Arterial hypertension is the most prevalent risk factor for cardiovascular disease in sub-Saharan Africa. Only a few and mostly small randomized trials have studied antihypertensive treatments in people of African descent living in sub-Saharan Africa. Methods In this open-label, three-arm, parallel randomized controlled trial conducted at two rural hospitals in Lesotho and Tanzania, we compare the efficacy and cost-effectiveness of three antihypertensive treatment strategies among participants aged ≥ 18 years. The study includes patients with untreated uncomplicated arterial hypertension diagnosed by a standardized office blood pressure ≥ 140/90 mmHg. The trial encompasses a superiority comparison between a triple low-dose antihypertensive drug combination versus the current standard of care (monotherapy followed by dual treatment), as well as a non-inferiority comparison for a dual drug combination versus standard of care with optional dose titration after 4 and 8 weeks for participants not reaching the target blood pressure. The sample size is 1268 participants with parallel allocation and a randomization ratio of 2:1:2 for the dual, triple and control arms, respectively. The primary endpoint is the proportion of participants reaching a target blood pressure at 12 weeks of ≤ 130/80 mmHg and ≤ 140/90 mmHg among those aged Discussion This trial will help to identify the most effective and cost-effective treatment strategies for uncomplicated arterial hypertension among people of African descent living in rural sub-Saharan Africa and inform future clinical guidelines on antihypertensive management in the region. Trial registration Clinicaltrials.govNCT04129840. Registered on 17 October 2019 (https://www.clinicaltrials.gov/).

Background Dengue and Chikungunya viruses can cause large-scale epidemics, with attack rates of up to 80%. In Tanzania, there have been repeated outbreaks of dengue fever, the most recent in 2018 and 2019, mostly affecting the coastal areas. Despite the importance of these viruses, there is limited knowledge on the epidemiology of dengue (DENV) and Chikungunya (CHIKV) in Tanzania. This study was conducted to investigate the prevalence of DENV and CHIKV in Kilombero Valley, Tanzania. Methods A cross-sectional study was conducted at Kibaoni Health Center in Kilombero Valley, Southeastern Tanzania, in the rainy and dry seasons of 2018. Febrile patients of any age and gender were enrolled from the outpatient department. Blood samples were taken and screened for DENV and CHIKV viral RNA by real-time reverse transcription polymerase chain reaction assays. Results Overall, 294 patients were recruited. Most were females (65%), and one-third of patients were aged 14–25 years. DENV and CHIKV were detected in 29 (9.9%) and 3 (1.0%) patients, respectively. DENV was detected across all age groups during both the dry and rainy seasons. Although all 4 DENV serotypes were detected, serotypes 1 and 3 dominated and were present in 14 patients (42.4%) each. Additionally, the study showed DENV-1 and DENV-3 co-infections. Conclusions This study reveals the co-circulation of all 4 DENV serotypes and CHIKV in Kilombero. Importantly, we report the first occurrence of DENV-4 in Tanzania. Unlike previous DENV outbreaks caused by DENV-2, the 2018 outbreak was dominated by DENV-1 and DENV-3. The occurrence of all serotypes suggests the possibility of severe clinical outcomes in future DENV epidemics in Tanzania.

Objectives Few studies have assessed cognitive impairment among healthy people living with HIV (PLWH) who are stable on antiretroviral treatment (ART) in sub-Saharan Africa. Methods We conducted a cross-sectional study among a random sample of stable adult PLWH from rural Tanzania on ART for more than 1 year and without immunological failure or pre-existing neurological disease. We evaluated the prevalence and risk factors for neurocognitive impairment (NCI), assessed through neuropsychological tests, functional and depression questionnaires and defined as a mean Z-score ≤ -1 in two or more cognitive domains. Results Among 243 participants [median age = 44.3 years (interquartile range: 36-52] and 71% female] we found a rate of NCI of 19.3% (95% confidence interval: 14.8-24.8%). Memory and psychomotor domains demonstrated the highest impairment. Independent predictors of NCI were age and self-reported alcohol use. Other classical risk factors were not associated with HIV-associated NCI. Conclusion Despite effective ART roll-out, NCI remained a prevalent condition in this healthy rural Tanzanian population of PLWH on ART. Age and alcohol use were key risk factors.

Background In people with human immunodeficiency virus (PWH), it is unknown whether genetic background associates with rapid progression of kidney dysfunction (ie, estimated glomerular filtration rate [eGFR] decrease of >5mL/min/1.73m2 per year for ≥3 consecutive years). Methods We obtained univariable and multivariable hazard ratios (HR) for rapid progression, based on the clinical D:A:D chronic kidney disease (CKD) risk score, antiretroviral exposures, and a polygenic risk score based on 14 769 genome-wide single nucleotide polymorphisms in white Swiss HIV Cohort Study participants. Results We included 225 participants with rapid progression and 3378 rapid progression-free participants. In multivariable analysis, compared to participants with low D:A:D risk, participants with high risk had rapid progression (HR = 1.82 [95% CI, 1.28–2.60]). Compared to the first (favorable) polygenic risk score quartile, participants in the second, third, and fourth (unfavorable) quartiles had rapid progression (HR = 1.39 [95% CI, 0.94–2.06], 1.52 [95% CI, 1.04–2.24], and 2.04 [95% CI, 1.41–2.94], respectively). Recent exposure to tenofovir disoproxil fumarate was associated with rapid progression (HR = 1.36 [95% CI, 1.06–1.76]). Discussion An individual polygenic risk score is associated with rapid progression in Swiss PWH, when analyzed in the context of clinical and antiretroviral risk factors.

Coronavirus disease 2019 (COVID-19) leads to inflammatory cytokine release, which can downregulate the expression of metabolizing enzymes. This cascade affects drug concentrations in the plasma. We investigated the association between lopinavir (LPV) and hydroxychloroquine (HCQ) plasma concentrations and the levels of the acute-phase inflammation marker C-reactive protein (CRP). LPV plasma concentrations in 92 patients hospitalized at our institution were prospectively collected. Lopinavir-ritonavir was administered every 12 hours, 800/200 mg on day 1 and 400/100 mg on day 2 until day 5 or 7., Coronavirus disease 2019 (COVID-19) leads to inflammatory cytokine release, which can downregulate the expression of metabolizing enzymes. This cascade affects drug concentrations in the plasma. We investigated the association between lopinavir (LPV) and hydroxychloroquine (HCQ) plasma concentrations and the levels of the acute-phase inflammation marker C-reactive protein (CRP). LPV plasma concentrations in 92 patients hospitalized at our institution were prospectively collected. Lopinavir-ritonavir was administered every 12 hours, 800/200 mg on day 1 and 400/100 mg on day 2 until day 5 or 7. HCQ was given at 800 mg, followed by 400 mg after 6, 24, and 48 h. Hematological, liver, kidney, and inflammation laboratory values were analyzed on the day of drug level determination. The median age of study participants was 59 (range, 24 to 85) years, and 71% were male. The median durations from symptom onset to hospitalization and treatment initiation were 7 days (interquartile range [IQR], 4 to 10) and 8 days (IQR, 5 to 10), respectively. The median LPV trough concentration on day 3 of treatment was 26.5 μg/ml (IQR, 18.9 to 31.5). LPV plasma concentrations positively correlated with CRP values (r = 0.37, P

Background Poor adherence to antiretroviral drugs and viral resistance are the main drivers of treatment failure in HIV-infected patients. In sub-Saharan Africa, avoidance of treatment failure on second-line protease inhibitor therapy is critical as treatment options are limited. Methods In the prospective observational study of the Kilombero & Ulanga Antiretroviral Cohort in rural Tanzania, we assessed virologic failure (viral load ≥1,000 copies/mL) and drug resistance mutations in bio-banked plasma samples 6-12 months after initiation of a protease inhibitor-based treatment regimen. Additionally, viral load was measured before start of protease inhibitor, a second time between 1-5 years after start, and at suspected treatment failure in patients with available bio-banked samples. We performed resistance testing if viral load was ≥1000 copies/ml. Risk factors for virologic failure were analyzed using logistic regression. Results In total, 252 patients were included; of those 56% were female and 21% children. Virologic failure occurred 6-12 months after the start of a protease inhibitor in 26/199 (13.1%) of adults and 7/53 of children (13.2%). The prevalence of virologic failure did not change over time. Nucleoside reverse transcriptase inhibitors drug resistance mutation testing performed at 6-12 months showed a positive signal in only 9/16 adults. No cases of resistance mutations for protease inhibitors were seen at this time. In samples taken between 1-5 years protease inhibitor resistance was demonstrated in 2/7 adults. In adult samples before protease inhibitor start, resistance to nucleoside reverse transcriptase inhibitors was detected in 30/41, and to non-nucleoside reverse-transcriptase inhibitors in 35/41 patients. In 15/16 pediatric samples, resistance to both drug classes but not for protease inhibitors was present. Conclusion Our study confirms high early failure rates in adults and children treated with protease inhibitors, even in the absence of protease inhibitors resistance mutations, suggesting an urgent need for adherence support in this setting.

Introduction Lifelong antiretroviral therapy (ART) improves health outcomes for HIV‐positive individuals, but is jeopardized by irregular clinic attendance and hence poor adherence. Loss to follow‐up (LTFU) is typically defined retrospectively but this may lead to biased inferences. We assessed incidence of and factors associated with LTFU, prospectively and accounting for recurrent LTFU episodes, in the Kilombero and Ulanga Antiretroviral Cohort (KIULARCO) of HIV‐positive persons in rural Tanzania. Methods We included adults (≥15 years) enrolled in 2005 to 2016, regardless of ART status, with follow‐up through April 2017. LTFU was defined as >60 days late for a scheduled appointment. Participants could experience multiple LTFU episodes. We performed analyses based on the first (prospective) and last (retrospective) events observed during follow‐up, and accounting for recurrent LTFU episodes. Time to LTFU was estimated using cumulative incidence functions. We assessed factors associated with LTFU using cause‐specific proportional hazards, marginal means/rates, and Prentice, Williams and Peterson models. Results Among 8087 participants (65% female, 60% aged ≥35 years, 42% WHO stage 3/4, and 47% CD4 count

Mortality assessment in cohorts with high numbers of persons lost to follow-up (LTFU) is challenging in settings with limited civil registration systems. We aimed to assess mortality in a clinical cohort (the Kilombero and Ulanga Antiretroviral Cohort (KIULARCO)) of human immunodeficiency virus (HIV)-infected persons in rural Tanzania, accounting for unseen deaths among participants LTFU. We included adults enrolled in 2005–2015 and traced a nonrandom sample of those LTFU. We estimated mortality using Kaplan-Meier methods 1) with routinely captured data (method A), 2) crudely incorporating tracing data (method B), 3) weighting using tracing data to crudely correct for unobserved deaths among participants LTFU (method C), and 4) weighting using tracing data accounting for participant characteristics (method D). We investigated associated factors using proportional hazards models. Among 7,460 adults, 646 (9%) died, 883 (12%) transferred to other clinics, and 2,911 (39%) were LTFU. Of 2,010 (69%) traced participants, 325 (16%) were found: 131 (40%) had died and 130 (40%) had transferred. Five-year mortality estimates derived using the 4 methods were 13.1% (A), 16.2% (B), 36.8% (C), and 35.1% (D), respectively. Higher mortality was associated with male sex, referral as a hospital inpatient, living close to the index clinic, lower body mass index, more advanced World Health Organization HIV clinical stage, lower CD4 cell count, and less time since initiation of antiretroviral therapy. Adjusting for unseen deaths among participants LTFU approximately doubled the 5-year mortality estimates. Our approach is applicable to other cohort studies adopting targeted tracing.

Summary Objectives Antibacterial chemoprophylaxis with fluoroquinolones (FQPx) has been commonly used in cancer patients with neutropenia, but its efficacy has been challenged by the emergence of fluoroquinolone resistance. Methods The impact of FQPx on bloodstream infections (BSI) during neutropenia after high-dose chemotherapy for haematologic malignancies was evaluated through a multicenter hospital infection surveillance system for the period 2009–2014. Results Among 8755 patients (4223 allogeneic [allo-] HSCT, 3602 autologous [auto-] HSCT, 930 high-dose chemotherapy for acute leukemia [HDC]), 5302 (61%) had received FQPx . Administration of FQPx was associated with fewer Gram-negative BSI in the overall study cohort patients (4.6% vs. 7.7%, adjusted subdistribution hazard ratio [aSHR] 0.59, 95%CI 0.50–0.70), in patients with HDC (3.7% vs. 9.2%, adjusted subdistribution hazard ratio [aSHR] 0.40, 95%CI 0.22–0.70) and auto-HSCT patients (4% vs. 9%, aSHR 0.43, 95%CI 0.33–0.56). In HDC patients, FQPx was associated with a marked reduction in all-cause mortality during neutropenia (2.3% vs. 7.8%, aSHR 0.30, 95%CI 0.15–0.58). Patients receiving FQPx had significantly more BSIs due to ESBL-positive Enterobacteriacea (0.8 vs. 0.3%, RR 2.2, 95%CI 1.17–4.26). BSIs by MRSA ( n = 5) and VRE ( n = 11) were rare in our cohort. Conclusions As used in the participating centers, FQPx was associated with reduced Gram-negative BSI and improved survival among HDC patients. Among HSCT patients, the benefits were less clear. If adapted to local resistance patterns and patient characteristics, FQPx still may be useful in the management of patients with haematologic malignancies.

Background Observational studies have shown that dressings containing chlorhexidine gluconate (CHX) lower the incidence external ventricular drain (EVD)-associated infections (EVDAIs). This prospective, randomized controlled trial (RCT) studies the efficacy of CHX-containing dressings in reducing bacterial colonization. Methods In this RCT, patients aged ≥18 years undergoing emergency EVD placement were randomly given either a CHX-containing or an otherwise identical control dressing at the skin exit wound. The primary end-point was bacterial regrowth in cultured skin swab samples of the EVD exit wound. The secondary end-points were catheters processed by sonication, clinically diagnosed EVDAI and surgical treatment of hydrocephalus. Results From October 2013 to January 2016, a total of 57 patients were randomized to receive either a CHX or a control dressing (29 and 28 patients, respectively). Cutaneous bacterial regrowth at the EVD exit wound was significantly reduced over time (geometric mean ratio, 0.18; 95% confidence interval, .08-.42; P < .001). The incidence of colonized catheters was lower in the CHX group (5 of 28; 18%) than in the control group (10 of 27; 33%), with less microbial colonization on the subcutaneous portion. The infection rate was 4 of 28 (14%) in the CHX group, compared with 7 of 27 (26%) in the control group, with a substantially lower hydrocephalus treatment rate (7 of 28 [25%] vs 14 of 27 [52%], respectively). Conclusion Our data support the use of CHX dressings to reduce EVD exit site contamination, potentially reducing EVDAIs and permanent cerebrospinal fluid diversion procedures for hydrocephalus. Clinical Trials Registration NCT02078830.

OBJECTIVES Patients with severe COVID-19 may be at risk of longer term sequelae. Long-term clinical, immunological, pulmonary and radiological outcomes of patients treated with anti-inflammatory drugs are lacking. METHODS In this single-centre prospective cohort study, we assessed 90-day clinical, immunological, pulmonary and radiological outcomes of hospitalised patients with severe COVID-19 treated with tocilizumab from March 2020 to May 2020. Criteria for tocilizumab administration were oxygen saturation 30/min, C-reactive protein levels >75 mg/l, extensive area of ground-glass opacities or progression on computed tomography (CT). Descriptive analyses were performed using StataIC 16. RESULTS Between March 2020 and May 2020, 50 (27%) of 186 hospitalised patients had severe COVID-19 and were treated with tocilizumab. Of these, 52% were hospitalised on the intensive care unit (ICU) and 12% died. Eleven (22%) patients developed at least one microbiologically confirmed super-infection, of which 91% occurred on ICU. Median duration of hospitalisation was 15 days (interquartile range [IQR] 10–24) with 24 days (IQR 14–32) in ICU patients and 10 days (IQR 7–15) in non-ICU patients. At day 90, 41 of 44 survivors (93%) were outpatients. No long-term adverse events or late-onset infections were identified after acute hospital care. High SARS-CoV-2 antibody titres were found in all but one patient, who was pretreated with rituximab. Pulmonary function tests showed no obstructive patterns, but restrictive patterns in two (5.7%) and impaired diffusion capacities for carbon monoxide in 11 (31%) of 35 patients, which predominated in prior ICU patients. Twenty-one of 35 (60%) CT-scans at day 90 showed residual abnormalities, with similar distributions between prior ICU and non-ICU patients. CONCLUSIONS In this cohort of severe COVID-19 patients, no tocilizumab-related long-term adverse events or late-onset infections were identified. Although chest CT abnormalities were highly prevalent at day 90, the majority of patients showed normal lung function. Trial registration ClinicalTrials.gov NCT04351503

AIMS The aim of this study was to analyse the demographics, risk factors and in-hospital mortality rates of patients admitted with coronavirus disease 2019 (COVID-19) to a tertiary care hospital in Switzerland. METHODS In this single-centre retrospective cohort study at the University Hospital Basel, we included all patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection hospitalised from 27 February 2020 to 10 May 2021. Patients’ characteristics were extracted from the electronic medical record system. The primary outcome of this study was temporal trends of COVID-19-related in-hospital mortality. Secondary outcomes were COVID-19-related mortality in patients hospitalised on the intensive care unit (ICU), admission to ICU, renal replacement therapy and length of hospital stay, as well as a descriptive analysis of risk factors for in-hospital mortality. RESULTS During the study period we included 943 hospitalisations of 930 patients. The median age was 65 years (interquartile range [IQR] 53–76) and 63% were men. The numbers of elderly patients, patients with multiple comorbidities and need for renal replacement therapy decreased from the first and second to the third wave. The median length of stay and need for ICU admission were similar in all waves. Throughout the study period 88 patients (9.3%) died during the hospital stay. Crude in-hospital mortality was similar over the course of the first two waves (9.5% and 10.2%, respectively), whereas it decreased in the third wave (5.4%). Overall mortality in patients without comorbidities was low at 1.6%, but it increased in patients with any comorbidity to 12.6%. Predictors of all-cause mortality over the whole period were age (adjusted odds ratio [aOR] per 10-year increase 1.81, 95% confidence interval [CI] 1.45–2.26; p

BACKGROUND Prompt linkage to human immunodeficiency virus (HIV) care after diagnosis is of utmost importance for individual health and reduction of HIV transmission. Different definitions for “linkage to care” have challenged comparisons as a public health marker. Its meaning in the era of “universal test and treat” has transformed in all settings, but is most relevant in sub-Sahara Africa, where the burden of new HIV infection is still highest. METHODS For this narrative review on “linkage to care” definitions with a focus on sub-Saharan Africa, we searched PubMed/Medline between September and December 2020, restricted to the period 2000–2020 using Boolean operators: “HIV” AND (“linkage to care” OR “engagement in care”) and screened for institutional definitions of “linkage to care”. Additionally, as one example of a rural sub-Saharan African setting, we analysed linkage steps within the Chronic Diseases Clinic Ifakara (CDCI) and its associated Kilombero and Ulanga Antiretroviral Cohort (KIULARCO) in rural Tanzania between 1 January 2017 and 31 March 2019. RESULTS We analysed 81 articles that included “linkage to care” within different study settings and HIV organisations. Major differences in defining “linkage to care” exist, according to setting and location, patient populations and the timing of steps within the linkage process. We identified 16 different numerators and 10 denominators used to define linkage with time periods ranging from “same day as diagnosis” up to 12 months after diagnosis among 34 original articles from sub-Saharan Africa. At the CDCI, 1149/1671 (69%) newly diagnosed individuals were enrolled into care after diagnosis. Three months after enrolment into care, 94%, 86%, 85% and 71% of enrolled patients had a laboratory evaluation, a clinical evaluation, were initiated on treatment and had a first clinical follow-up visit after initiation of treatment, respectively. DUSCUSSION To address the inconsistency in defining “linkage to care” and in order to guarantee the comparability of “linkage to care” in the sub-Saharan Africa region, we support the definition from the European region with some adaptions. We suggest a priority list of care indicators if more than one care indicator is available for successful “linkage to care” in the era of “universal test and treat” for sub-Sahara Africa.

Antibacterial resistance is emerging in patients undergoing haematopoietic stem cell transplantation (HSCT), and most data on the epidemiology of bloodstream infections (BSI)-causing pathogens come from retrospective single-centre studies. This study sought to investigate trends in the epidemiology of BSI in HSCT patients from a prospective multicentre cohort.We investigated changes in the incidence of causative organisms of BSI during neutropenia among adult HSCT patients for 2002-2014. The data were collected from a prospective cohort for infection surveillance in 20 haematologic cancer centres in Germany, Austria and Switzerland (ONKO-KISS).A total of 2388 of 15 181 HSCT patients with neutropenia (1471 allogeneic (61.6%) and 917 autologous (38.4%) HSCT) developed BSI (incidence 15.8% per year). The incidence of Gram-negative BSI increased over time both in patients after allogeneic HSCT (allo-HSCT) and autologous HSCT (auto-HSCT). BSI caused by Escherichia coli in allo-HSCT patients increased from 1.1% in 2002 to 3.8% in 2014 (3/279 vs. 31/810 patients, p0.001), and the incidence of BSI caused by enterococci increased from 1.8% to 3.3% (5 vs. 27 patients, p0.001). In contrast, the incidence of BSI due to coagulase-negative staphylococci decreased in allo-HSCT patients from 8.2% to 5.1%, (23 vs. 40 patients, p0.001) and in auto-HSCT patients from 7.7% to 2.0% (13/167 vs. 30/540 patients; p = 0.028 for period 2002-2011). No significant trends were observed for the incidence of BSI due to methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci or extended-spectrum β-lactamase-producing Enterobacteriaceae. The BSI case fatality remained unchanged over the study period (total of 477 fatalities, 3.1%).The incidence of Gram-negative BSI significantly increased over time in this vulnerable patient population, providing evidence for reevaluating empiric therapy for neutropenic fever in HSCT patients.

Zusammenfassung. Vor dem Start unseres Projekts gab es im St. Francis Referral Hospital, Ifakara, Tansania, wie auch in den meisten Spitälern im südlichen Afrika keine Notfallstation. Durch eine Ausbildung in Notfallmedizin und Ultraschall, die Organisation eines Dreischichtbetriebes und einer Triage war die neu geschaffene Notfallstation weniger als sechs Monate nach Beginn des Projekts voll funktionstüchtig. Einige wenige Geräte (zwei Überwachungsmonitore, EKG-Gerät, Thoraxdrainagesystem, Vernebler, Defibrillator, Ultraschallgeräte) mussten angeschafft werden oder wurden gespendet. Derzeit werden täglich 80–100 Patienten betreut, etwa 20 % der Patienten sind schwer krank. Neben Anamnese und klinischer Untersuchung ist der Ultraschall das wichtigste diagnostische Instrument. Die klinische Arbeit steht im Mittelpunkt. In einer Studie werden mittels «Focused Assessment with Sonography for HIV-Associated Tuberculosis (FASH)» Patienten mit Verdacht auf Tuberkulose untersucht, mit Echokardiografie ermitteln wir die Häufigkeit von Herzkrankheiten.

Background. COVID-19, caused by the SARS-CoV-2 virus, is a pandemic disease with high morbidity and mortality. Currently, available therapeutic options for COVID-19 are limited. Prior experience in epidemics with convalescent plasma (CP) containing antibodies to viruses has demonstrated variable indications of therapeutic efficacy for: Influenza, Argentine Hemorrhagic Fever, and SARS. Characterizing antibody titers to viruses has indicated correlation with therapeutic efficacy. Convalescent COVID-19 patients with potent SARS-CoV-2 antibody responses can serve as plasma donors for immune therapy. However, antibody responses are variable, many donors are first-time higher risk blood donors, and rapid assays to select optimal CP immune efficacy are limited. Pathogen inactivation (PI) of CP can reduce the risk of transfusion-transmitted infection by unrecognized pathogens. Objectives. This study characterized COVID-19 PI-CP activity; and evaluated efficacy and safety of PI CP transfusion in a case matched controlled cohort of acute COVID-19 patients. Methods. COVID-19 apheresis CP (650 - 1300 mL) was collected from nasopharyngeal PCR + outpatients following 2 PCR negative tests or 28 days after symptom resolution. Amotosalen-UVA PI of CP (INTERCEPT Blood System for Plasma) was performed, and antibody efficacy before and after PI was characterized by: VSV reporter pseudo-virus plaque neutralization (RVPN) NT-50 titer (Vitalant Research Institute, San Francisco), antibody to S and N virus proteins by agglutination-dependent antibody PCR (ADAP, Enable Biosciences, San Francisco), virus ACE-2 soluble receptor neutralization assay (Enable Biosciences), and SARS-CoV-2 antibody profile by coronavirus microarray (University of California, Irvine). Patient inclusion criteria were: confirmed SARS-CoV-2 infection, hospitalization, pulmonary infiltrates, availability of ABO compatible CP, and informed consent. CP patients were matched with control patients (CTRL) for disease severity at diagnosis by standardized clinical risk score (W. Liang et al JAMA Intern Med 2020) and concomitant Tocilizumab use. CP Patients received a total of 400 mL of PI CP from 2 donors over 48 hours and standard therapy. CTRL patients received standard COVID-19 therapy without CP. The primary outcome was in-hospital death to day 28. Secondary outcomes included: progression to intubation, admission to ICU, time to discharge, serious adverse events, NP viral clearance, plasma viral clearance, and humoral immune responses. Differences between CP and CTRL patients were assessed by the Mann-Whitney test for continuous variables, and by Fisher's exact test for categorical variables. Progression to ICU and intubation were analyzed as odds ratios calculated by conditional logistic regression. Results. 15 CP and 30 CTRL patients were enrolled. One CP patient was admitted in cardiogenic shock. Only 2 of 15 CP cohort patients had detectable IgG antibody to SARS CoV-2 S1 antigen at study entry. 3 of 15 PI CP donors had negligible SARS CoV-2 IgG antibodies to all antigens, and demonstrated poor neutralization efficacy. 12/15 CP had effective RVPN titers (> 1:80), RVPN titers were correlated with ACE-2 neutralization antibody titers (r2 = 0.83), and had significant activity specific for S and RBD antigens by microarray profiling (Figure 1). SARS CoV-2 antibody levels were variable between CP donors, but not impacted by PI (Figure 1). Baseline characteristics of CP and matched CTRL patients were similar (Table 1). Sensitivity analysis was performed assessing mortality after exclusion of one CTRL patient admitted in cardiogenic shock and the 2 respective controls. In-hospital 28-day mortality was lower in the CP cohort (0/14) compared to 5/28 CTRL, p = 0.151, 2-sided Fisher's exact test. Progression to intubation, ICU admission, and days in hospital were not significantly different (Table 1). There was a trend toward decreased inflammatory response (CRP normalization) in CP patients. Conclusions. In hospital mortality of COVID-19 patients was lower in the PI-CP cohort, but not statistically significant. 15% of CP had ineffective antibody by multiple assays. However, PI did not impact CP anti-SARS-CoV-2 activity. PI of plasma provides reduced risk of transfusion transmitted infection from COVID-19 CP donors. In this study, PI CP was safe, and may be effective for early treatment of hospitalized COVID-19 patients. Disclosures von Goetz: Cerus Corporation: Current Employment, Current equity holder in publicly-traded company. Khan:Nanommune Inc.: Current equity holder in private company. Tsai:Enable Biosciences: Current Employment. Robinson:Enable Biosciences: Current Employment. Seftel:Enable Biosciences: Current Employment, Current equity holder in private company. Bagri:Cerus Corporation: Current Employment, Current equity holder in publicly-traded company. Corash:Cerus Corporation: Current Employment, Current equity holder in publicly-traded company.

CME: Extrapulmonary Tuberculosis Abstract. While tuberculosis mostly manifests as pulmonary infection, a dissemination in any extrapulmonary organ is possible. Extrapulmonary tuberculosis mostly affects lymph nodes, pleura and bones. Patients with immunosuppressive conditions such as an HIV co-infection or immunosuppressive therapies like TNF-alpha-inhibitors have a higher risk of a dissemination of tuberculosis. Diagnosis of extrapulmonary tuberculosis is difficult, as microbiological testing mostly requires invasive procedures to obtain a sample for direct proof of tuberculosis by microscopy, culture, molecular methods (e.g. Xpert(R) MTB/RIF) or histology. Treatment follows guidelines of pulmonary tuberculosis with a two-month regimen consisting of four drugs (rifampicin, isoniazide, pyrazinamide and ethambuthol), followed by a four-month therapy with two drugs (rifampicin and isoniazide). Duration of therapy is extended in tuberculous meningitis to one year and in a skeletal dissemination up to six to nine months. Corticosteroids are recommended in cerebral and pericardial tuberculosis.

Background In sub-Saharan Africa, diagnosis and management of extrapulmonary tuberculosis (EPTB) in people living with HIV (PLHIV) remains a major challenge. This study aimed to characterize the epidemiology and risk factors for poor outcome of extrapulmonary tuberculosis in people living with HIV (PLHIV) in a rural setting in Tanzania. Methods We included PLHIV >18 years of age enrolled into the Kilombero and Ulanga antiretroviral cohort (KIULARCO) from 2013 to 2017. We assessed the diagnosis of tuberculosis by integrating prospectively collected clinical and microbiological data. We calculated prevalence- and incidence rates and used Cox regression analysis to evaluate the association of risk factors in extrapulmonary tuberculosis (EPTB) with a combined endpoint of lost to follow-up (LTFU) and death. Results We included 3,129 subjects (64.5% female) with a median age of 38 years (interquartile range [IQR] 31–46) and a median CD4+ cell count of 229/μl (IQR 94–421) at baseline. During the median follow-up of 1.25 years (IQR 0.46–2.85), 574 (18.4%) subjects were diagnosed with tuberculosis, whereof 175 (30.5%) had an extrapulmonary manifestation. Microbiological evidence by Acid-Fast-Bacillus stain (AFB-stain) or Xpert® MTB/RIF was present in 178/483 (36.9%) patients with pulmonary and in 28/175 (16.0%) of patients with extrapulmonary manifestations, respectively. Incidence density rates for pulmonary Tuberculosis (PTB and EPTB were 17.9/1000person-years (py) (95% CI 14.2–22.6) and 5.8/1000 py (95% CI 4.0–8.5), respectively. The combined endpoint of death and LTFU was observed in 1058 (33.8%) patients, most frequently in the subgroup of EPTB (47.2%). Patients with EPTB had a higher rate of the composite outcome of death/LTFU after TB diagnosis than with PTB [HR 1.63, (1.14–2.31); p = 0.006]. The adjusted hazard ratios [HR (95% CI)] for death/LTFU in EPTB patients were significantly increased for patients aged >45 years [HR 1.95, (1.15–3.3); p = 0.013], whereas ART use was protective [HR 0.15, (0.08–0.27); p

Objective HIV-1 rapidly establishes a persistent infection that can be contained under life-long antiretroviral therapy (ART) but not cured. One major viral reservoir is the peripheral lymph node (LN) follicles. Studying the impact of novel HIV-1 treatment and vaccination approaches on cells residing in germinal centers is essential for rapid progress towards HIV-1 prevention and cure. Results We enrolled 9 asymptomatic adult volunteers with a newly diagnosed HIV-1 infection and CD4 T cell counts ≥ 350/ml. The patients underwent venous blood collection and inguinal lymph node excision surgery in parallel. Mononuclear cells were extracted from blood and tissues simultaneously. Participants were followed up regularly for 2 weeks until complete healing of the surgical wounds. All participants completed the lymph node excision surgery without clinical complications. Among the 9 volunteers, one elite controller was identified. The number of mononuclear cells recovered from lymph nodes ranged from 68 to 206 million and correlated positively with lymph node size. This is the first study to show that lymph node biopsy is a safe procedure and can be undertaken with local experts in rural settings. It provides a foundation for detailed immune response investigations during future clinical trials.

BackgroundIn human immunodeficiency virus (HIV), the relative contribution of genetic background, clinical risk factors, and antiretrovirals to chronic kidney disease (CKD) is unknown.MethodsWe applied a case-control design and performed genome-wide genotyping in white Swiss HIV Cohort participants with normal baseline estimated glomerular filtration rate (eGFR >90 mL/minute/1.73 m2). Univariable and multivariable CKD odds ratios (ORs) were calculated based on the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) score, which summarizes clinical CKD risk factors, and a polygenic risk score that summarizes genetic information from 86 613 single-nucleotide polymorphisms.ResultsWe included 743 cases with confirmed eGFR drop to ConclusionsGenetic score increased CKD risk similar to clinical D:A:D score and potentially nephrotoxic antiretrovirals. Irrespective of D:A:D score, individuals with the most favorable genetic background may be protected against CKD.

Causes of morbidity and mortality of people living with HIV are changing with access to antiretroviral therapy and increased life expectancy. Age-related data on comorbidities and their impact on mortality in sub-Saharan Africa are scarce.This prospective analysis evaluated comorbidities, assessed by means of International Classification of Diseases and Related Health problems 10th revision codes and clinical variables, derived from data collected from the KilomberoUlanga antiretroviral cohort of people living with HIV in rural Tanzania.We calculated prevalences and incidences of comorbidities in patients enrolled from 2013 to 2017 and evaluated their association with a combined endpoint of death and loss to follow-up (LTFU) in various age groups (15-29, 30-49 and ≥50 years) using Cox regression analysis.Of 1622 patients [65% females, median age 38 years (interquartile range 31-46)], 11% were at least 50 years. During a median follow-up of 22.1 months (interquartile range 10.6-37.3), 48 (2.9%) patients died and 306 (18.9%) were LTFU. Anaemia was the most prevalent comorbidity (66.3%) irrespective of age and was associated with increased mortality/LTFU [hazard ratios 2.02 (95% confidence interval (CI) 1.57-2.60); P 0.001]. In patients aged at least 50 years, arterial hypertension was highly prevalent (43.8%), but not associated with mortality/LTFU [hazard ratios 1.04 (95% CI 0.56-1.93), P = 0.9]. Undernutrition ranged from 25.5% in the youngest to 29.1% in the oldest age group and contributed to mortality/LTFU [hazard ratios 2.24 (95% CI 1.65-3.04); P 0.001]. Prevalence of tuberculosis was 21.4% with hazard ratios of 2.54 (95% CI 1.72-3.75, P 0.001) for mortality/LTFU.We show that anaemia, arterial hypertension and undernutrition are the most relevant comorbidities with different age-associated frequencies and impact on death/LTFU in this population.

Background Patients with suspected tuberculosis are often overtreated with antituberculosis drugs. We evaluated the diagnostic value of the focused assessment with sonography for HIV-associated tuberculosis (FASH) in rural Tanzania. Methods In a prospective cohort study, the frequency of FASH signs was compared between patients with confirmed tuberculosis and those without tuberculosis. Clinical and laboratory examination, chest x-ray, Xpert MTB/RIF assay, and culture from sputum, sterile body fluids, lymph node aspirates, and Xpert MTB/RIF urine assay was done. Results Of 191 analyzed patients with a 6-month follow-up, 52.4% tested positive for human immunodeficiency virus, 21.5% had clinically suspected pulmonary tuberculosis, 3.7% had extrapulmonary tuberculosis, and 74.9% had extrapulmonary and pulmonary tuberculosis. Tuberculosis was microbiologically confirmed in 57.6%, probable in 13.1%, and excluded in 29.3%. Ten of eleven patients with splenic or hepatic hypoechogenic lesions had confirmed tuberculosis. In a univariate model, abdominal lymphadenopathy was significantly associated with confirmed tuberculosis. Pleural- and pericardial effusion, ascites, and thickened ileum wall lacked significant association. In a multiple regression model, abnormal chest x-ray (odds ratio [OR] = 6.19; 95% confidence interval [CI], 1.96–19.6; P < .002), ≥1 FASH-sign (OR = 3.33; 95% CI, 1.21–9.12; P = .019), and body temperature (OR = 2.48; 95% CI, 1.52–5.03; P = .001 per °C increase) remained associated with tuberculosis. A combination of ≥1 FASH sign, abnormal chest x-ray, and temperature ≥37.5°C had 99.1% sensitivity (95% CI, 94.9–99.9), 35.2% specificity (95% CI, 22.7–49.4), and a positive and negative predictive value of 75.2% (95% CI, 71.3–78.7) and 95.0% (95% CI, 72.3–99.3). Conclusions The absence of FASH signs combined with a normal chest x-ray and body temperature

Background Information on diagnoses made in emergency departments situated in rural sub-Saharan Africa is scarce. The aim was: to evaluate the frequency of different diagnoses made in a new emergency department to define relevant healthcare requirements; and to find out if in-hospital mortality rates would decrease after the implementation of the emergency department. Methods In this observational study, we prospectively collated diagnoses of all patients presenting to the emergency department of the St Francis Referral Hospital in Ifakara, Tanzania during 1 year. In addition, we compared in-hospital mortality rates before and after the implementation of the emergency department. Results From July 2016 through to June 2017, a total of 35,903 patients were included. The median age was 33.6 years (range 1 day to 100 years), 57% were female, 25% were children l5 years, 4% were pregnant and 9% were hospitalised. The most common diagnoses were respiratory tract infection (12.6%), urinary tract infection (11.4%), trauma (9.8%), undifferentiated febrile illness (5.4%), and malaria (5.2%). The most common clinical diagnoses per age group were: lower respiratory tract infection (16.1%) in children l5 years old; trauma (21.6%) in 5- to 17-year-olds; urinary tract infection (13.5%) in 18- to 50-year-olds; and hypertensive emergency (12.4%) in g50-year-olds. Respiratory tract infections peaked in April during the rainy season, whereas malaria peaked 3 months after the rainy season. In-hospital mortality rates did not decrease during the study period (5.6% in 2015 vs 7.6% in 2017). Conclusions The majority of diagnosed disorders were of infectious or traumatic origin. The majority of febrile illnesses were poorly defined because of the lack of diagnostic methods. Trauma systems and inexpensive accurate diagnostic methods for febrile illnesses are needed in rural sub-Saharan Africa.

OBJECTIVES Staphylococcus aureus bloodstream infection is associated with considerable mortality. Experimental models suggest a direct antistaphylococcal effect of acetylsalicylic acid, but evidence from human studies is scarce. We aimed to estimate the effect of low-dose acetylsalicylic acid therapy on mortality in bloodstream infections caused by S. aureus compared with Escherichia coli. DESIGN Retrospective cohort study based on observational data from 838 and 602 episodes of S. aureus and E. coli bloodstream infection, respectively. SETTING Swiss tertiary referral center. PATIENTS Adult patients with S. aureus and E. coli bloodstream infection, respectively, categorized according to low-dose acetylsalicylic acid therapy as outpatient or inpatient before bacteremia. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Thirty-day all-cause mortality was analyzed in a total of 314 propensity score-matched S. aureus bloodstream infection and in 268 E. coli bloodstream infection patients, respectively (1:1 match of low-dose acetylsalicylic acid users and nonusers). S. aureus bloodstream infection cases and controls were equally matched for relevant confounders except treatment with statins, which was strongly associated with a low-dose acetylsalicylic acid use (p < 0.001). At day 30, 12.1% of cases and 27.4% of controls had died (hazard ratio, 0.40; p < 0.001). Low-dose acetylsalicylic acid use was associated with a reduced 30-day all-cause mortality in multivariate analysis (hazard ratio, 0.38; 95% CI, 0.21-0.69; p = 0.001) of matched patients and also of the entire cohort (n = 689) after adjustment for the propensity score (hazard ratio, 0.58, 95% CI, 0.34-0.98; p = 0.04). In contrast, low-dose acetylsalicylic acid use was not associated with the primary endpoint in patients with E. coli bloodstream infection (hazard ratio, 0.78; 95% CI, 0.40-1.55; p = 0.8). CONCLUSIONS Low-dose acetylsalicylic acid at the time of bloodstream infection was strongly associated with a reduced short-term mortality in patients with S. aureus bloodstream infection. Future studies are required to investigate if early low-dose acetylsalicylic acid is a suitable treatment in patients with S. aureus bloodstream infection.

Background It has been hypothesized that schistosomiasis negatively influences immune reconstitution in people living with HIV starting antiretroviral therapy (ART). In this study, we investigated the effect of schistosomiasis on the course of HIV infection in patients starting ART in a rural part of Tanzania. Methodology Retrospective study including patients prospectively enrolled in a HIV cohort in Ifakara, south-central Tanzania between January 1, 2013 and April 1, 2015. Schistosomal circulating anodic antigen (CAA) was assessed in pre-ART cryopreserved plasma. Regression models were utilized to estimate the effect of CAA positivity on virological and immunological failure and a composite outcome of death/loss to follow-up (LFU). Principal findings At ART-initiation 19.1% (88/461) of patients were CAA-positive. A tendency of higher CD4 increases was seen in CAA-positive patients (+182 cells/μl, interquartile range (IQR), 87–285 cells/μl) compared to CAA-negative patients (+147 cells/μl, IQR, 55–234 cells/μl, p = 0.09) after 10 months of follow-up. After adjustment for baseline risk factors, CAA-positivity showed no association with virological or immunological failure. In CAA-positive patients, 22.7% (20/88) died or were LFU, compared to 29.5% (110/373) of CAA-negative patients (hazard ratio (HR): 0.76, 95% confidence interval (CI), 0.47–1.22, p = 0.25). After adjustment for age, sex, body mass index, educational attainment, WHO-stage, tuberculosis status, and year of ART initiation, CAA-positivity showed a trend of a decreased hazard of death/LFU (HR: 0.58, 95% CI: 0.32–1.05, p = 0.07), while CD4 count at baseline (HR: 0.86, 95% CI: 0.76–1.00, p = 0.02) and MXD (sum of eosinophils, basophils, and monocytes counts) >1,100 cells/μl (HR: 0.56, 95% CI: 0.34–0.93, p = 0.03) were identified as independently protective factors. Conclusions/Significance Schistosomiasis is prevalent in this HIV cohort and may be beneficial for immunological reconstitution, while no effect on virological failure was apparent. A positive effect of schistosomiasis-induced immunomodulation on survival and retention in care needs confirmation in future studies., Author summary Infections with HIV and blood flukes (Schistosoma) both exert chronic modulatory effects on the host’s immune system. Coinfections, meaning the host is simultaneously infected with both pathogens, are common in sub-Saharan Africa. In this situation the induced immune modulation of one pathogen may affect the course of the disease induced by the other pathogen. One study showed that coinfection with Schistosoma in people living with HIV who begin antiretroviral therapy (ART) may have deleterious effects on the reconstitution of the HIV-induced immunosuppression. In the current study, we investigated the effect of Schistosoma coinfection on the recovery of the patient’s immune system, on the efficacy of ART to suppress HIV replication, and on a combined endpoint of lost to follow-up or death. We found that schistosomiasis may have beneficial effects on immune reconstitution, while no deleterious effect was detected on HIV-suppressive efficacy of ART. Surprisingly, our data suggest that schistosomiasis-induced immunomodulatory effects might be beneficial for survival and retention in care. Future studies are warranted to confirm these findings. In the era of increasing access to ART in sub-Saharan Africa, the issue of schistosomiasis-HIV coinfection may have major consequences on the outcome of HIV treatment programs.

BackgroundLittle is known about heart diseases and their treatment in rural sub-Saharan Africa. This study aimed to describe the occurrence, characteristics, and etiologies of heart diseases, and the medication taken before and prescribed after echocardiography in a rural referral Hospital in Tanzania.MethodsThis prospective descriptive cohort study included all adults and children referred for echocardiography. Clinical and echocardiographic data were collated for analysis.ResultsFrom December 2015 to October 2017, a total of 1'243 echocardiograms were performed. A total of 815 adults and 59 children ≤15 years had abnormal echocardiographic findings; in adults 537/815 (66%) had hypertension, with 230/537(43%) on antihypertensive drugs, and 506/815 (62%) were not on regular cardiac medication; 346/815 (42%) had severe eccentric or concentric left ventricular hypertrophy, and 182/815 (22%) had severe systolic heart failure. Only 44% demonstrated normal left ventricular systolic function. The most frequent heart diseases were hypertensive heart disease (41%), valvular heart disease (18%), coronary heart disease (18%), peripartum cardiomyopathy (7%), and other non-hypertensive dilated cardiomyopathies (6%) in adults, and congenital heart disease (34%) in children. Following echocardiography, 802/815 (98%) adults and 40/59 (68%) children had an indication for cardiac medication, 70/815 (9%) and 2/59 (3%) for oral anticoagulation, and 35/815 (4%) and 23/59 (39%) for cardiac surgery, respectively.ConclusionHypertension is the leading etiology of heart diseases in rural Tanzania. Most patients present with advanced stages of heart disease, and the majority are not treated before echocardiography. There is an urgent need for increased awareness, expertise and infrastructure to detect and treat hypertension and heart failure in rural Africa.

We describe a 66-year-old woman hospitalized with fever, fatigue and hepatopathy. In her medical history arterial hypertension (treated with propranolol and lisinopril), diabetes mellitus type 2 (no treatment before admission) and a gout arthropathy were noted wherefore a therapy with allopurinol 300 mg per day has been started 4 months before. Liver biopsy revealed fibrin-ring granulomas, compatible with allopurinolinduced hepatitis. Because of persistence of high fever after stopping allopurinol, steroids (1 mg/kg) were started. Under this treatment, she developed pancytopenia and fever. The bone marrow aspiration revealed Leishmania infantum. A second liver biopsy showed amastigotes and a disappearance of the granulomas. The history revealed a travel to Malta 2 years earlier. Despite adequate treatment with liposomal amphotericin B the patient deteriorated and finally died in septic shock

To what extent antiretroviral therapy (ART) reduces mother-to-child HIV transmission (MTCT) during breastfeeding remains unclear. We assessed the MTCT risk from mothers on ART to their infants during breastfeeding.Ifakara, rural Tanzania.We included infants born between January 2013 and May 2016 to mothers who initiated ART before delivery, had a negative HIV DNA polymerase chain reaction at 4-12 weeks and exclusively breastfed for ≥6 months. Mothers' plasma HIV-RNA viral loads (VLs) were measured up to 11 months postdelivery. Infants were tested for HIV following national guidelines.Among 214 women with 218 pregnancies and 228 infants (10 twins), the median age at delivery was 33 years (interquartile range 28-36 years), and the mean time on ART was 23 months (interquartile range, 4-52 months). VL was measured twice in 53% (113/218) of pregnancies. During breastfeeding, 91% of mothers (199/218) had VL of1000 copies per milliliter, and 75% (164/218) had100 copies per milliliter. To November 2017, 8% (19/228) of infants were lost to follow-up (LTFU), 2% (5/228) transferred, and 8% (18/228) died before the determination of final HIV serostatus. Among the remaining 186 infants, 2 (1%; 95% confidence interval: 0.3% to 4%) were HIV positive: 1 born from a mother with high VL 1-month postdelivery and 1 from a mother who interrupted ART. Assuming a 15% MTCT risk through breastfeeding among the 42 infants LTFU, transferred, or dead, the overall MTCT risk would be 4%.We found no MTCT from mothers who were retained in care and had suppressed VL. Breastfeeding signifies a very low risk when mothers adhere to ART. Adherence counseling, VL monitoring, and strategies to trace back those LTFU should be a priority.

Contemporary, comprehensive data on epidemiology and outcomes of invasive fungal disease (IFD) including breakthrough IFD among allogeneic hematopoietic stem cell transplantation (HSCT) recipients are scarce. We included 479 allogeneic HSCT recipients with 10 invasive candidiasis (IC) and 31 probable/proven invasive mold disease (IMD) from the Swiss Transplant Cohort Study from 01.2009 to 08.2013. Overall cumulative incidence was 2.3% for IC and 8.5% for probable/proven IMI: 6% for invasive aspergillosis (IA) and 2.5% for non-AspergillusIMI. Among 41 IFD, 46% IFD were breakthrough, with an overall incidence of 4.6%, more frequently caused by other-than-Aspergillus fumigatus molds than primary IFD (47.6% (10/21) vs 13% (3/23), P = 0.04). Twelve-week mortality among patients with IC was 20% and 58.6% for probable/proven IMD (60% IA and 54.6% non-Aspergillus). Our results reveal that breakthrough IFD represent a marked burden of probable/proven IFD postallogeneic HSCT and mortality remains above 50% in patients with probable/proven IMD, underscoring the ongoing challenges to prevent and treat IFD in these patients.

Few epidemiological studies have been carried out to assess the aetiology and antimicrobial susceptibility patterns of pathogens giving rise to skin and soft tissue infections (SSTIs) in sub-Saharan Africa. In the present study from six healthcare facilities in Bagamoyo, Tanzania, wound swabs from outpatients with SSTIs were analysed by a suite of methods, including microbiological culture techniques, matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry and resistance testing. Among 185 patients with SSTIs, 179 (96.8%) swabs showed microbiological growth. In total, 327 organisms were found, of which 285 were of potential aetiological relevance. Staphylococcus aureus was the predominant pathogen (prevalence: 71.4%), followed by the Gram-negative bacteria Enterobacter cloacae complex (14.6%), Klebsiella pneumoniae (12.4%) and Pseudomonas aeruginosa (11.8%). While one out of three isolates of S. aureus showed resistance to macrolides, tetracyclines, cotrimoxazole and clindamycin, only a single methicillin-resistant S. aureus (MRSA) strain was found. In Gram-negative bacteria, resistance to ampicillin and cotrimoxazole was common, while extended-spectrum beta-lactamases were rarely detected (

Background: We assessed the prevalence, incidence, and predictors of renal impairment among people living with HIV (PLWHIV) in rural Tanzania. Methods: In a cohort of PLWHIV aged >/=15 years enrolled from January 2013 to June 2016, we assessed the association between renal impairment (estimated glomerural filtration rate < 90 mL/min/1.73 m(2)) at enrollment and during follow-up with demographic and clinical characteristcis using logistic regression and Cox proportional hazards models. Results: Of 1093 PLWHIV, 172 (15.7%) had renal impairment at enrollment. Of 921 patients with normal renal function at baseline, 117 (12.7%) developed renal impairment during a median follow-up (interquartile range) of 6.2 (0.4-14.7) months. The incidence of renal impairment was 110 cases per 1000 person-years (95% confidence interval [CI], 92-132). At enrollment, logistic regression identified older age (adjusted odds ratio [aOR], 1.79; 95% CI, 1.52-2.11), hypertension (aOR, 1.84; 95% CI, 1.08-3.15), CD4 count

Background Differences in rural and urban settings could account for distinct characteristics in the epidemiology of tuberculosis (TB). We comparatively studied epidemiological features of TB and helminth co-infections in adult patients from rural and urban settings of Tanzania. Methods Adult patients (≥ 18 years) with microbiologically confirmed pulmonary TB were consecutively enrolled into two cohorts in Dar es Salaam, with ~ 4.4 million inhabitants (urban), and Ifakara in the sparsely populated Kilombero District with ~ 400 000 inhabitants (rural). Clinical data were obtained at recruitment. Stool and urine samples were subjected to diagnose helminthiases using Kato-Katz, Baermann, urine filtration, and circulating cathodic antigen tests. Differences between groups were assessed by χ2, Fisher’s exact, and Wilcoxon rank sum tests. Logistic regression models were used to determine associations. Results Between August 2015 and February 2017, 668 patients were enrolled, 460 (68.9%) at the urban and 208 (31.1%) at the rural site. Median patient age was 35 years (interquartile range [IQR]: 27–41.5 years), and 454 (68%) were males. Patients from the rural setting were older (median age 37 years vs. 34 years, P = 0.003), had a lower median body mass index (17.5 kg/m2 vs. 18.5 kg/m2, P

In vivo T-cell depletion with anti-thymocyte globulin (ATG) can attenuate GvHD but may increase infection and relapse risks. ATG-Fresenius (ATG-F) at a dose of 60 mg/kg was standard GvHD prophylaxis in unrelated donor hematopoietic stem cell transplantation (HSCT) at our institution. We changed to an incremental reduced dose regimen of 35 mg/kg and extended ATG prophylaxis to include older matched-related donor transplants considered to be at higher risk of GvHD. A total of 265 adults with hematological malignancies receiving a first allogeneic HSCT after myeloablative conditioning between 2009 and 2014 were analyzed in this cohort study. Patients had either received higher dose (n=32) or lower dose ATG-F (n=88) or no ATG (n=145). ATG-F was associated with slower engraftment and less chronic GvHD, whereas no effect was noted on acute grade II-IV GvHD and relapse incidence. Transplant-related mortality (TRM) was lower and survival higher with lower dose, but not with higher dose ATG-F. Both ATG-F groups were associated with more viral reactivation, viral disease and bacterial blood stream infection, but not invasive fungal infection, and with slower immune reconstitution. The recently adopted strategy of using lower doses of ATG-F in unrelated and older age-related donor HSCT appears to reduce TRM without increasing disease relapse, leading to slightly enhanced survival.

Introduction In immunosuppressed hosts, rapid identification of microorganisms of bloodstream infections is crucial to ensuring effective antimicrobial therapy. Conventional culture requires up to 72 h from sample collection to pathogen identification. Methods We used the SepsiTyper Kit and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF; Microflex, Bruker) directly from positive blood culture (BacT/ALERT 3D, FN/FA vials; bioMerieux) in comparison to standard culture methodology (VITEK 2; bioMerieux) for species identification. Results A total of 62 consecutive positive blood cultures from immunosuppressed patients (solid organ or hematopoietic transplant recipients, or with febrile neutropenia) were analyzed. Culture yielded gram-negative bacteria (GNB) in 27/62 (43.5%) and gram-positive (GPB) in 35/62 (56.5%) vials. For GNB, the predominant species identified by MALDI-TOF and confirmed by VITEK were Escherichia coli (16/16 correctly identified) and Enterobacter cloacae (4/4), with a sensitivity and specificity of 92.6% and 100%, respectively. For GPB, predominant species were Staphylococcus aureus (3/3), coagulase-negative staphylococci (12/24), and Enterococcus faecium (6/6) with a sensitivity of 100%, 60%, and 100%, respectively. The median time from blood collection to species identification was 27.4 h with MALDI-TOF identification and 46.6 h with conventional methodology. Conclusion Using MALDI-TOF directly from positive blood cultures allowed a shorter time to identification with high sensitivity and specificity in immunosuppressed patients.

© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. Background. Polymorphisms in IFNL3 and IFNL4 the genes encoding interferon ?3 and interferon ?4 respectively have been associated with reduced hepatitis C virus clearance. We explored the role of such polymorphisms on the incidence of cytomegalovirus (CMV) infection in solid organ transplant recipients. Methods. White patients participating in the Swiss Transplant Cohort Study in 2008 2011 were included. A novel functional TT/ G polymorphism (rs368234815) in the CpG region upstream of IFNL3 was investigated. Results. A total of 840 solid organ transplant recipients at risk for CMV infection were included among whom 373 (44) received antiviral prophylaxis. The 12 month cumulative incidence of CMV replication and disease were 0.44 and 0.08 cases respectively. Patient homozygous for the minor rs368234815 allele ( G/ G) tended to have a higher cumulative incidence of CMV replication (subdistribution hazard ratio [SHR] 1.30 [95 confidence interval {CI}. 97 1.74]; P =. 07) compared with other patients (TT/TT or TT/ G). The association was significant among patients followed by a preemptive approach (SHR 1.46 [95 CI 1.01 2.12]; P =. 047) especially in patients receiving an organ from a seropositive donor (SHR 1.92 [95 CI 1.30 2.85]; P =. 001) but not among those who received antiviral prophylaxis (SHR 1.13 [95 CI. 70 1.83]; P =. 6). These associations remained significant in multivariate competing risk regression models. Conclusions. Polymorphisms in the IFNL3/4 region influence susceptibility to CMV replication in solid organ transplant recipients particularly in patients not receiving antiviral prophylaxis.