[Guidelines for the Management of Community Acquired Pneumonia in Children and Adolescents (Pediatric Community Acquired Pneumonia, pCAP) - Issued under the Responsibility of the German Society for Pediatric Infectious Diseases (DGPI) and the German Society for Pediatric Pulmonology (GPP)]. / S2k-Leitlinie Management der ambulant erworbenen Pneumonie bei Kindern und Jugendlichen (pädiatrische ambulant erworbene Pneumonie, pCAP).

The present guideline aims to improve the evidence-based management of children and adolescents with pediatric community-acquired pneumonia (pCAP). Despite a prevalence of approx. 300 cases per 100 000 children per year in Central Europe, mortality is very low. Prevention includes infection control measures and comprehensive immunization. The diagnosis can and should be established clinically by history, physical examination and pulse oximetry, with fever and tachypnea as cardinal features. Additional signs or symptoms such as severely compromised general condition, poor feeding, dehydration, altered consciousness or seizures discriminate subjects with severe pCAP from those with non-severe pCAP. Within an age-dependent spectrum of infectious agents, bacterial etiology cannot be reliably differentiated from viral or mixed infections by currently available biomarkers. Most children and adolescents with non-severe pCAP and oxygen saturation > 92 % can be managed as outpatients without laboratory/microbiology workup or imaging. Anti-infective agents are not generally indicated and can be safely withheld especially in children of young age, with wheeze or other indices suggesting a viral origin. For calculated antibiotic therapy, aminopenicillins are the preferred drug class with comparable efficacy of oral (amoxicillin) and intravenous administration (ampicillin). Follow-up evaluation after 48 - 72 hours is mandatory for the assessment of clinical course, treatment success and potential complications such as parapneumonic pleural effusion or empyema, which may necessitate alternative or add-on therapy.

HIV-1 Transmission During Recent Infection and During Treatment Interruptions as Major Drivers of New Infections in the Swiss HIV Cohort Study.

BACKGROUND: Reducing the fraction of transmissions during recent human immunodeficiency virus (HIV) infection is essential for the population-level success of "treatment as prevention". METHODS: A phylogenetic tree was constructed with 19 604 Swiss sequences and 90 994 non-Swiss background sequences. Swiss transmission pairs were identified using 104 combinations of genetic distance (1%-2.5%) and bootstrap (50%-100%) thresholds, to examine the effect of those criteria. Monophyletic pairs were classified as recent or chronic transmission based on the time interval between estimated seroconversion dates. Logistic regression with adjustment for clinical and demographic characteristics was used to identify risk factors associated with transmission during recent or chronic infection. FINDINGS: Seroconversion dates were estimated for 4079 patients on the phylogeny, and comprised between 71 (distance, 1%; bootstrap, 100%) to 378 transmission pairs (distance, 2.5%; bootstrap, 50%). We found that 43.7% (range, 41%-56%) of the transmissions occurred during the first year of infection. Stricter phylogenetic definition of transmission pairs was associated with higher recent-phase transmission fraction. Chronic-phase viral load area under the curve (adjusted odds ratio, 3; 95% confidence interval, 1.64-5.48) and time to antiretroviral therapy (ART) start (adjusted odds ratio 1.4/y; 1.11-1.77) were associated with chronic-phase transmission as opposed to recent transmission. Importantly, at least 14% of the chronic-phase transmission events occurred after the transmitter had interrupted ART. CONCLUSIONS: We demonstrate a high fraction of transmission during recent HIV infection but also chronic transmissions after interruption of ART in Switzerland. Both represent key issues for treatment as prevention and underline the importance of early diagnosis and of early and continuous treatment.

Increases in Condomless Sex in the Swiss HIV Cohort Study.

Condomless sex is a key driver of sexually transmitted diseases. In this study, we assess the long-term changes (2000-2013) of the occurrence of condomless sex among human immunodeficiency virus (HIV)-infected individuals enrolled in the Swiss HIV Cohort study. The frequencies with which HIV-infected individuals reported condomless sex were either stable or only weakly increasing for 2000-2008. For 2008-2013, these rates increased significantly for stable relationships among heterosexuals and men who have sex with men (MSM) and for occasional relationships among MSM. Our results highlight the increasing public health challenge posed by condomless sex and show that condomless sex has been increasing even in the most recent years.

Incident Hepatitis C Virus Infections in the Swiss HIV Cohort Study: Changes in Treatment Uptake and Outcomes Between 1991 and 2013.

Background. The hepatitis C virus (HCV) epidemic is evolving rapidly in patients infected with human immunodeficiency virus (HIV). We aimed to describe changes in treatment uptake and outcomes of incident HCV infections before and after 2006, the time-point at which major changes in HCV epidemic became apparent. Methods. We included all adults with an incident HCV infection before June 2012 in the Swiss HIV Cohort Study, a prospective nationwide representative cohort of individuals infected with HIV. We assessed the following outcomes by time period: the proportion of patients starting an HCV therapy, the proportion of treated patients achieving a sustained virological response (SVR), and the proportion of patients with persistent HCV infection during follow-up. Results. Of 193 patients with an HCV seroconversion, 106 were diagnosed before and 87 after January 2006. The proportion of men who have sex with men increased from 24% before to 85% after 2006 (P < .001). Hepatitis C virus treatment uptake increased from 33% before 2006 to 77% after 2006 (P < .001). Treatment was started during early infection in 22% of patients before and 91% after 2006 (P < .001). An SVR was achieved in 78% and 29% (P = .01) of patients treated during early and chronic HCV infection. The probability of having a detectable viral load 5 years after diagnosis was 0.67 (95% confidence interval [CI], 0.58-0.77) in the group diagnosed before 2006 and 0.24 (95% CI, 0.16-0.35) in the other group (P < .001). Conclusions. In recent years, increased uptake and earlier initiation of HCV therapy among patients with incident infections significantly reduced the proportion of patients with replicating HCV.

Obesity Trends and Body Mass Index Changes After Starting Antiretroviral Treatment: The Swiss HIV Cohort Study.

BACKGROUND: The factors that contribute to increasing obesity rates in human immunodeficiency virus (HIV)-positive persons and to body mass index (BMI) increase that typically occurs after starting antiretroviral therapy (ART) are incompletely characterized. METHODS: We describe BMI trends in the entire Swiss HIV Cohort Study (SHCS) population and investigate the effects of demographics, HIV-related factors, and ART on BMI change in participants with data available before and 4 years after first starting ART. RESULTS: In the SHCS, overweight/obesity prevalence increased from 13% in 1990 (n = 1641) to 38% in 2012 (n = 8150). In the participants starting ART (n = 1601), mean BMI increase was 0.92 kg/m(2) per year (95% confidence interval, .83-1.0) during year 0-1 and 0.31 kg/m(2) per year (0.29-0.34) during years 1-4. In multivariable analyses, annualized BMI change during year 0-1 was associated with older age (0.15 [0.06-0.24] kg/m(2)) and CD4 nadir <199 cells/µL compared to nadir >350 (P < .001). Annualized BMI change during years 1-4 was associated with CD4 nadir <100 cells/µL compared to nadir >350 (P = .001) and black compared to white ethnicity (0.28 [0.16-0.37] kg/m(2)). Individual ART combinations differed little in their contribution to BMI change. CONCLUSIONS: Increasing obesity rates in the SHCS over time occurred at the same time as aging of the SHCS population, demographic changes, earlier ART start, and increasingly widespread ART coverage. Body mass index increase after ART start was typically biphasic, the BMI increase in year 0-1 being as large as the increase in years 1-4 combined. The effect of ART regimen on BMI change was limited.

[Interdisciplinary AWMF guideline for the treatment of primary antibody deficiencies]. / Interdisziplinäre AWMF-Leitlinie zur Therapie primärer Antikörpermangelerkrankungen.

BACKGROUND: Currently, management of antibody deficient patients differs significantly among caregivers. Evidence and consensus based (S3) guidelines for the treatment of primary antibody deficiencies were developed to improve the management of these patients. METHODS: Based on a thorough analysis of current evidence (systematic literature search in PubMed; deadline November 2011) 14 recommendations were finalized during a consensus meeting in Frankfurt in November 2011 using structured consensus methods (nominal group technique). Experts were nominated by their scientific societies/patient initiatives (Tab. 1). RESULTS: The guidelines focus on indication, practical issues and monitoring of immunoglobulin replacement therapy as well as on different routes of administration. Furthermore recommendations regarding supportive measures such as antiinfective therapy, vaccinations and physiotherapy are given. Combining literature evidence and experience of caregivers within this evidence and consensus based guidelines offers the chance to improve the quality of care for anti-body deficient patients.

Lack of benefit of preoperative antimicrobial prophylaxis in children with acute appendicitis: a prospective cohort study.

BACKGROUND: Preoperative antimicrobial prophylaxis is widely used in pediatric patients undergoing appendectomy, but evidence showing a reduction of postoperative infectious complications is lacking. METHODS: A prospective consecutive cohort study on changing from preoperative antimicrobial prophylaxis to no prophylaxis in children undergoing urgent appendectomy was undertaken. The impact of this change in management on postoperative infectious complications was evaluated by comparing the outcome in 100 patients receiving (group A) and a subsequent 100 patients not receiving prophylaxis (group B), which consisted of a preoperative single dose of intravenous metronidazole (10 mg/kg body weight). RESULTS: Histology confirmed acute appendicitis in 92 patients of group A and 95 patients of group B. In patients with histological simple appendicitis, postoperative infectious complications were noted in 2 (3.0 %) of 69 patients from group A and in none of 70 patients from group B, and in patients with histological perforated appendicitis in 5 (22 %) of 23 and 4 (16 %) of 25 patients from groups A and B, respectively. Postoperative infectious complications were more frequent (p < 0.05) in perforated than in simple appendicitis. These infectious complications included in simple appendicitis two wound infections in group A, and in perforated appendicitis four intraabdominal abscesses and one wound infection in group A and two intraabdominal abscesses and two wound infections in group B. CONCLUSION: Postoperative infectious complications were seen more often in patients with perforated appendicitis than in those with simple appendicitis. Preoperative antimicrobial prophylaxis with metronidazole did not reduce the rates of postoperative infectious complications.

TLR9 agonists induced cell death in Burkitt's lymphoma cells is variable and influenced by TLR9 polymorphism.

Toll-like receptor 9 (TLR9) triggering is a promising novel strategy to combat cancer as it induces innate and adaptive immunity responses. B-cell lymphoma is unique in this context as tumor cells express TLR9 and may harbor latent Epstein-Barr virus (EBV), a gamma-herpesvirus with remarkable oncogenic potential when latent. Latent EBV may be promoted by TLR9 triggering via suppression of lytic EBV. Here, we elaborated an initial assessment of the impact of TLR9 triggering on EBV-positive and EBV-negative B-cell lymphoma using Burkitt's lymphoma (BL) cell lines as an in vitro model. We show that, independent of the presence of EBV, the TLR9 ligand oligodeoxynucleotide (ODN) CpG-2006 may or may not induce caspase-dependent cell death in BL cells. Moreover, ODN CpG-2006-induced cell death responses of BL cells were associated with TLR9 single-nucleotide polymorphisms (SNPs) rs5743836 or rs352140, which we detected in primary BL tumors and in peripheral blood from healthy individuals at similar frequencies. Thus, our findings suggest that the effect of TLR9 agonists on BL cells should be tested in vitro before installment of therapy and TLR9 SNPs in BL patients should be determined as potential biological markers for the therapeutic response to treatment targeting innate immunity.

Impaired antibody memory to varicella zoster virus in HIV-infected children: low antibody levels and avidity*.

OBJECTIVE: HIV-infected children have impaired antibody responses after exposure to certain antigens. Our aim was to determine whether HIV-infected children had lower varicella zoster virus (VZV) antibody levels compared with HIV-infected adults or healthy children and, if so, whether this was attributable to an impaired primary response, accelerated antibody loss, or failure to reactivate the memory VZV response. METHODS: In a prospective, cross-sectional and retrospective longitudinal study, we compared antibody responses, measured by enzyme-linked immunosorbent assay (ELISA), elicited by VZV infection in 97 HIV-infected children and 78 HIV-infected adults treated with antiretroviral therapy, followed over 10 years, and 97 age-matched healthy children. We also tested antibody avidity in HIV-infected and healthy children. RESULTS: Median anti-VZV immunoglobulin G (IgG) levels were lower in HIV-infected children than in adults (264 vs. 1535 IU/L; P<0.001) and levels became more frequently unprotective over time in the children [odds ratio (OR) 17.74; 95% confidence interval (CI) 4.36-72.25; P<0.001]. High HIV viral load was predictive of VZV antibody waning in HIV-infected children. Anti-VZV antibodies did not decline more rapidly in HIV-infected children than in adults. Antibody levels increased with age in healthy (P=0.004) but not in HIV-infected children. Thus, antibody levels were lower in HIV-infected than in healthy children (median 1151 IU/L; P<0.001). Antibody avidity was lower in HIV-infected than healthy children (P<0.001). A direct correlation between anti-VZV IgG level and avidity was present in HIV-infected children (P=0.001), but not in healthy children. CONCLUSION: Failure to maintain anti-VZV IgG levels in HIV-infected children results from failure to reactivate memory responses. Further studies are required to investigate long-term protection and the potential benefits of immunization.

High specificity of line-immunoassay based algorithms for recent HIV-1 infection independent of viral subtype and stage of disease.

BACKGROUND: Serologic testing algorithms for recent HIV seroconversion (STARHS) provide important information for HIV surveillance. We have shown that a patient's antibody reaction in a confirmatory line immunoassay (INNO-LIA HIV I/II Score, Innogenetics) provides information on the duration of infection. Here, we sought to further investigate the diagnostic specificity of various Inno-Lia algorithms and to identify factors affecting it. METHODS: Plasma samples of 714 selected patients of the Swiss HIV Cohort Study infected for longer than 12 months and representing all viral clades and stages of chronic HIV-1 infection were tested blindly by Inno-Lia and classified as either incident (up to 12 m) or older infection by 24 different algorithms. Of the total, 524 patients received HAART, 308 had HIV-1 RNA below 50 copies/mL, and 620 were infected by a HIV-1 non-B clade. Using logistic regression analysis we evaluated factors that might affect the specificity of these algorithms. RESULTS: HIV-1 RNA < 50 copies/mL was associated with significantly lower reactivity to all five HIV-1 antigens of the Inno-Lia and impaired specificity of most algorithms. Among 412 patients either untreated or with HIV-1 RNA ≥ 50 copies/mL despite HAART, the median specificity of the algorithms was 96.5% (range 92.0-100%). The only factor that significantly promoted false-incident results in this group was age, with false-incident results increasing by a few percent per additional year. HIV-1 clade, HIV-1 RNA, CD4 percentage, sex, disease stage, and testing modalities exhibited no significance. Results were similar among 190 untreated patients. CONCLUSIONS: The specificity of most Inno-Lia algorithms was high and not affected by HIV-1 variability, advanced disease and other factors promoting false-recent results in other STARHS. Specificity should be good in any group of untreated HIV-1 patients.

TLR9 triggering in Burkitt's lymphoma cell lines suppresses the EBV BZLF1 transcription via histone modification.

Endemic Burkitt's lymphoma (BL) is considered to preferentially develop in equatorial Africa because of chronic co-infection with Epstein-Barr virus (EBV) and the malaria pathogen Plasmodium falciparum. The interaction and contribution of both pathogens in the oncogenic process are poorly understood. Earlier, we showed that immune activation with a synthetic Toll-like receptor 9 (TLR9) ligand suppresses the initiation of EBV lytic replication in primary human B cells. In this study we investigate the mechanism involved in the suppression of EBV lytic gene expression in BL cell lines. We show that this suppression is dependent on functional TLR9 and MyD88 signaling but independent of downstream signaling elements, including phosphatidylinositol-3 kinase, mitogen-activated protein kinases and nuclear factor-kappaB. We identified TLR9 triggering resulting in histone modifications to negatively affect the activation of the promoter of EBV's master regulatory lytic gene BZLF1. Finally, we show that P. falciparum hemozoin, a natural TLR9 ligand, suppresses induction of EBV lytic gene expression in a dose-dependent manner. Thus, we provide evidence for a possible interaction between P. falciparum and EBV at the B-cell level and the mechanism involved in suppressing lytic and thereby reinforcing latent EBV that has unique oncogenic potential.

[Swiss recommendations for the management of varicella-zoster virus infections]. / Recommandations suisses pour la prise en charge des infections dues au virus de la varicelle-zoster.

Infections with varicella zoster virus (VZV) are common viral infections associated with significant morbidity. Diagnosis and management are complex, particularly in immunocompromised patients and during pregnancy. The present recommendations have been established by a multidisciplinary panel of specialists and endorsed by numerous Swiss medical societies involved in the medical care of such patients (Appendix). The aim is to improve the care of affected patients and to reduce complications.

Swiss recommendations for the management of varicella zoster virus infections.

Infections with varicella zoster virus (VZV) are common viral infections associated with significant morbidity. Diagnosis and management are complex, particularly in immunocompromised patients and during pregnancy. The present recommendations have been established by a multidisciplinary panel of specialists and endorsed by numerous Swiss medical societies involved in the medical care of such patients (Appendix). The aim was to improve the care of affected patients and to reduce complications.

[Acute fever in infants]. / Akutes Fieber beim Kleinkind.

The body temperature is influenced among other things by time of day or age and exhibits a Gaussian inter-individual distribution. If measured orally, normal values vary between 35.6 degrees C and 38.2 degrees C. Temperature exceeding the 99th percentile (> 37.7 degrees C) can therefore be interpreted as fever. Nevertheless, an universally accepted definition of fever does not exist. Viral infection is the most frequent cause of acute fever in infants, even in the absence of a source. Bacterial infections are by far a rarer reason. Nevertheless, below the age of 3 years, acute fever is a ticklish issue because of the higher risk for rapidly evolving life-threatening invasive bacterial infections. Following introduction of vaccination against Haemophilus influenzae type b (Hib), Streptococcus pneumoniae has advanced to the most frequent cause of invasive bacterial infections in infants. Fever is rarely seen in newborns (age 1-28 days), but when present, it is more frequently serious. Around 12% of these newborns show an invasive bacterial infection. Therefore, a full workup for sepsis is strongly indicated. This includes cultures of blood,urine and cerebrospinal fluid plus a chest radiography. In addition, immediate start of an empirical intravenous antibiotic therapy and monitoring in a hospital setting are necessary. Apart from this exception, primary antibiotic therapy is rarely necessary in fever without a detectable focus and source. Also, routine prescription of antipyretics is not indicated. Though paracetamol may improve well-being and drinking behavior of infants, it does neither shorten the duration of fever duration, nor prevent febrile seizures.

Disseminated Fusarium oxysporum infection in hemophagocytic lymphohistiocytosis.

The portal of entry of disseminated Fusarium spp. infections is still not clearly defined. We report on a disseminated Fusarium oxysporum infection occurring during a long period of severe neutropenia in a child with hemophagocytic lymphohistiocytosis. A nasogastric feeding tube was the possible source of entry of the fungus.

Pulmonary and systemic bacterial co-infections in severe RSV bronchiolitis.

In 127 infants admitted to intensive care for RSV bronchiolitis, concomitant bacterial sepsis was a rare event. However, in the subgroup of intubated patients the incidence of bacterial pneumonia was 43.9% (95% CI 31.0-56.8%), half community acquired and half nosocomial. As clinical signs are not helpful in identifying these patients, tracheal aspirates have to be investigated microbiologically on a routine basis in order to start antibiotics in time.

Port-A-Cath infections in children with cancer.

Implanted subcutaneous (s.c.) central venous port accesses including Port-A-Cath (PAC) facilitate the administration of chemotherapy or blood products and are frequently used in children with cancer. The incidence of PAC-related infections was determined in 155 consecutive paediatric cancer patients with PAC followed for a total of 134,773 days (median, 738; range, 25-2080). Overall, 48 bloodstream infections occurred in 26 patients. 12 (25%) of these infections and 3 local infections at the insertion site were treatment-resistant and demanded removal of the PAC. Coagulase-negative staphylococci were involved in 12 of these 15 episodes. The rate of clearly PAC-related infections in this so far largest reported series was 0.11 episodes per 1000 PAC days, one of the lowest in the literature. Although catheter-related infections demanded PAC removal in 8% of our patients, the long periods PAC were in use and their benefits argue for continued PAC use in the paediatric cancer population.

Cerebral actinomycosis before adolescence.

In a 10-year-old boy presenting with focal seizures and 6 months later with acute right-sided hemiparesis, the diagnosis of a cerebral abscess due to Actinomyces israelii was established. The immunocompetent child suffered from a complex congenital heart disease with pulmonary arteriovenous shunts and pulmonary hypertension causing mild cyanosis. His parents had been reluctant to agree to neuroimaging investigations resulting in a delayed diagnosis. Despite the long interval between first symptoms and commencement of treatment including neurosurgical excision of the abscess followed by a 4-week course of ceftriaxone, a complete recovery of the hemiparesis was observed. This patient is the first case with cerebral actinomycosis before adolescence reported so far.

Fosfomycin for the initial treatment of acute haematogenous osteomyelitis.

BACKGROUND AND AIMS: At our institution there has been a dichotomous antimicrobial treatment behaviour for acute haematogenous osteomyelitis (AHOM) since 1984. The surgical department favoured fosfomycin as initial choice and the medical department beta lactams. We aimed to compare the performance of both strategies. METHODS: Data from patients discharged with the diagnosis of AHOM between January 1984 and January 1998 were gathered from the charts by means of a questionnaire. Patients receiving fosfomycin treatment (FT) were compared with those receiving fosfomycin plus other antimicrobials (FT+) and those receiving no fosfomycin treatment (NFT). RESULTS: A total of 103 patients aged 0.1-15.5 years (mean 6.5, median 6.9) with AHOM received no surgical treatment initially. In 23 (22.3%) FT was instilled initially, in 47 (45.6%) FT+, and in 33 (32.0%) NFT. The pathogen was established in 30%, 36%, and 42% of FT, FT+, and NFT patients, respectively, Staphylococcus aureus being the predominant isolate. Mean C reactive protein levels and erythrocyte sedimentation rates normalised in all treatment groups after two and four weeks, respectively. The mean duration of intravenous antimicrobial treatment in FT patients was 2.5 weeks, in FT+ patients 3.1 weeks, and in NFT patients 3.8 weeks (p < 0.05), whereas the mean duration of intravenous plus oral treatment was comparable (7.1 v 6.8 v 6.5 weeks). CONCLUSIONS: The leucocyte penetrating fosfomycin performed similarly to extracellular beta lactams in the treatment of AHOM. Intravenous treatment for longer than 2.5 weeks offered no advantage.

Prospective survey of antibiotic utilization in pediatric hospitalized patients to identify targets for improvement of prescription.

BACKGROUND: The rise in the use of antibiotics has resulted in increasing health care costs and the emergence of resistant bacteria. Little is known about the general misuse of antibiotics in hospitalized children. We evaluated the utilization of antibiotics in a pediatric teaching hospital aiming to identify targets for improvement of prescription. PATIENTS AND METHODS: Clinical, radiological, laboratory and treatment data of patients hospitalized in a pediatric medical and a pediatric surgery ward were prospectively collected during a 6-week period. A subsequent review of the collected data by a pediatric infectious diseases specialist, taking into consideration existing in-house treatment guidelines, was carried out. RESULTS: A total of 125 (36%) of 349 patients was prescribed 246 antibiotics. The median length of hospital stay for children prescribed antibiotics was 5 days (range, 2-30 days) and for those not prescribed 3 days (1-32 days; p < 0.001). Of 154 patients in the medical ward, 64 (42%) received antibiotics, compared to 61 (31%) of 195 patients in the surgical ward (p < 0.05). Empirical prescriptions were more frequent than prophylactic ones, which were more frequent than therapeutic prescriptions (136 [55%] vs 94 [38%] vs 16 [7%]; p < 0.001). Overall, 85% of the prescriptions were considered justified. The rates of inappropriate prescriptions were similar in the medical and surgical ward, and higher for therapeutic (19%) or prophylactic treatment (18%) than for empirical treatment (12%). Higher inappropriate prescription rates were noted for macrolides than for co-trimoxazole and beta-lactams (50% vs 18% and 15%, respectively; p < 0.05). CONCLUSION: Efforts need to be undertaken towards continuous education of medical staff on judicious antibiotic use, as well as ensuring compliance with existing guidelines. Improvement in the availability of rapid diagnostic methods to discern viral from bacterial infections may help reduce the numbers of empiric therapies in favor of pathogen-targeted therapeutic treatments.