Treatment as Prevention for Hepatitis C (TraP Hep C) - a nationwide elimination programme in Iceland using direct-acting antiviral agents.

A nationwide programme for the treatment of all patients infected with hepatitis C virus (HCV) was launched in Iceland in January 2016. By providing universal access to direct-acting antiviral agents to the entire patient population, the two key aims of the project were to (i) offer a cure to patients and thus reduce the long-term sequelae of chronic hepatitis C, and (ii) to reduce domestic incidence of HCV in the population by 80% prior to the WHO goal of HCV elimination by the year 2030. An important part of the programme is that vast majority of cases will be treated within 36 months from the launch of the project, during 2016-2018. Emphasis is placed on early case finding and treatment of patients at high risk for transmitting HCV, that is people who inject drugs (PWID), as well as patients with advanced liver disease. In addition to treatment scale-up, the project also entails intensification of harm reduction efforts, improved access to diagnostic tests, as well as educational campaigns to curtail spread, facilitate early detection and improve linkage to care. With these efforts, Iceland is anticipated to achieve the WHO hepatitis C elimination goals well before 2030. This article describes the background and organization of this project. Clinical trial number: NCT02647879.

Incidence of cancer and overall risk of mortality in individuals treated with raltegravir-based and non-raltegravir-based combination antiretroviral therapy regimens.

OBJECTIVES: There are currently few data on the long-term risk of cancer and death in individuals taking raltegravir (RAL). The aim of this analysis was to evaluate whether there is evidence for an association. METHODS: The EuroSIDA cohort was divided into three groups: those starting RAL-based combination antiretroviral therapy (cART) on or after 21 December 2007 (RAL); a historical cohort (HIST) of individuals adding a new antiretroviral (ARV) drug (not RAL) to their cART between 1 January 2005 and 20 December 2007, and a concurrent cohort (CONC) of individuals adding a new ARV drug (not RAL) to their cART on or after 21 December 2007. Baseline characteristics were compared using logistic regression. The incidences of newly diagnosed malignancies and death were compared using Poisson regression. RESULTS: The RAL cohort included 1470 individuals [with 4058 person-years of follow-up (PYFU)] compared with 3787 (4472 PYFU) and 4467 (10 691 PYFU) in the HIST and CONC cohorts, respectively. The prevalence of non-AIDS-related malignancies prior to baseline tended to be higher in the RAL cohort vs. the HIST cohort [adjusted odds ratio (aOR) 1.31; 95% confidence interval (CI) 0.95-1.80] and vs. the CONC cohort (aOR 1.89; 95% CI 1.37-2.61). In intention-to-treat (ITT) analysis (events: RAL, 50; HIST, 45; CONC, 127), the incidence of all new malignancies was 1.11 (95% CI 0.84-1.46) per 100 PYFU in the RAL cohort vs. 1.20 (95% CI 0.90-1.61) and 0.83 (95% CI 0.70-0.99) in the HIST and CONC cohorts, respectively. After adjustment, there was no evidence for a difference in the risk of malignancies [adjusted rate ratio (RR) 0.73; 95% CI 0.47-1.14 for RALvs. HIST; RR 0.95; 95% CI 0.65-1.39 for RALvs. CONC] or mortality (adjusted RR 0.87; 95% CI 0.53-1.43 for RALvs. HIST; RR 1.14; 95% CI 0.76-1.72 for RALvs. CONC). CONCLUSIONS: We found no evidence for an oncogenic risk or poorer survival associated with using RAL compared with control groups.

Utility of oropharyngeal real-time PCR for S. pneumoniae and H. influenzae for diagnosis of pneumonia in adults.

A lack of sensitive tests and difficulties obtaining representative samples contribute to the challenge in identifying etiology in pneumonia. Upper respiratory tract swabs can be easily collected and analyzed with real-time PCR (rtPCR). Common pathogens such as S. pneumoniae and H. influenzae can both colonize and infect the respiratory tract, complicating the interpretation of positive results. Oropharyngeal swabs were collected (n = 239) prospectively from adults admitted to hospital with pneumonia. Analysis with rtPCR targeting S. pneumoniae and H. influenzae was performed and results compared with sputum cultures, blood cultures, and urine antigen testing for S. pneumoniae. Different Ct cutoff values were applied to positive tests to discern colonization from infection. Comparing rtPCR with conventional testing for S. pneumoniae in patients with all tests available (n = 57) resulted in: sensitivity 87 %, specificity 79 %, PPV 59 % and NPV 94 %, and for H. influenzae (n = 67): sensitivity 75 %, specificity 80 %, PPV 45 % and NPV 94 %. When patients with prior antimicrobial exposure were excluded sensitivity improved: 92 % for S. pneumoniae and 80 % for H. influenzae. Receiver operating characteristic curve analysis demonstrated for S. pneumoniae: AUC = 0.65 (95 % CI 0.51-0.80) and for H. influenzae: AUC = 0.86 (95 % CI 0.72-1.00). Analysis of oropharyngeal swabs using rtPCR proved both reasonably sensitive and specific for diagnosing pneumonia caused by S. pneumoniae and H. influenzae. This method may be a useful diagnostic adjunct to other methods and of special value in patients unable to provide representative lower airway samples.

Age-specific measles mortality during the late 19th-early 20th centuries.

Measles mortality fell prior to the introduction of vaccines or antibiotics. By examining historical mortality reports we sought to determine how much measles mortality was due to epidemiological factors such as isolation from major population centres or increased age at time of infection. Age-specific records were available from Aberdeen; Scotland; New Zealand and the states of Australia at the end of the 19th and beginning of the 20th centuries. Despite the relative isolation of Australia, measles mortality was concentrated in very young children similar to Aberdeen. In the more isolated states of Tasmania, Western Australia and Queensland adults made up 14-15% of measles deaths as opposed to 8-9% in Victoria, South Australia and New South Wales. Mortality in Iceland and Faroe Islands during the 1846 measles epidemic was used as an example of islands isolated from respiratory pathogens. The transition from crisis mortality across all ages to deaths concentrated in young children occurred prior to the earliest age-specific mortality data collected. Factors in addition to adult age of infection and epidemiological isolation such as nutritional status and viral virulence may have contributed to measles mortality outcomes a century ago.

Predictability in a highly stochastic system: final size of measles epidemics in small populations.

A standard assumption in the modelling of epidemic dynamics is that the population of interest is well mixed, and that no clusters of metapopulations exist. The well-known and oft-used SIR model, arguably the most important compartmental model in theoretical epidemiology, assumes that the disease being modelled is strongly immunizing, directly transmitted and has a well-defined period of infection, in addition to these population mixing assumptions. Childhood infections, such as measles, are prime examples of diseases that fit the SIR-like mechanism. These infections have been well studied for many systems with large, well-mixed populations with endemic infection. Here, we consider a setting where populations are small and isolated. The dynamics of infection are driven by stochastic extinction-recolonization events, producing large, sudden and short-lived epidemics before rapidly dying out from a lack of susceptible hosts. Using a TSIR model, we fit prevaccination measles incidence and demographic data in Bornholm, the Faroe Islands and four districts of Iceland, between 1901 and 1965. The datasets for each of these countries suffer from different levels of data heterogeneity and sparsity. We explore the potential for prediction of this model: given historical incidence data and up-to-date demographic information, and knowing that a new epidemic has just begun, can we predict how large it will be? We show that, despite a lack of significant seasonality in the incidence of measles cases, and potentially severe heterogeneity at the population level, we are able to estimate the size of upcoming epidemics, conditioned on the first time step, to within reasonable confidence. Our results have potential implications for possible control measures for the early stages of new epidemics in small populations.

Invasive infections due to Streptococcus pyogenes: seasonal variation of severity and clinical characteristics, Iceland, 1975 to 2012.

Epidemiology and clinical characteristics of invasive Group A streptococcal infections (IGASI) are highly variable. Long-term studies are needed to understand the interplay between epidemiology and virulence. In a population-based study of IGASI in Iceland from 1975 to 2012, 288 cases were identified by positive cultures from normally sterile body sites. Charts were reviewed retrospectively and emm-types of viable Streptococcus pyogenes isolates (n=226) determined. Comparing the first and last decade of the study period, IGASI incidence increased from 1.09 to 3.96 cases per 100,000 inhabitants per year. The most common were emm types 1 (25%), 28 (11%) and 89 (11%); emm1 strains were most likely to cause severe infections. Infections in adults were significantly more likely to be severe during the seasonal peak from January to April (risk ratio: 2.36, 95% confidence interval: 1.34­4.15). Significant seasonal variability in severity was noted among patients with diagnosis of sepsis, respiratory infection and cellulitis, with 38% of severe infections in January to April compared with 16% in other months (p<0.01). A seasonal increase in severity of IGASI suggested that generalised seasonal increase in host susceptibility, rather than introduction of more virulent strains may play a role in the pathogenesis of these potentially fatal infections.

Molecular epidemiology of late recurrent candidaemia--a population-based study in Iceland.

Candidaemia is associated with high patient mortality. Among those who survive an initial episode of candidaemia, the incidence of recurrent episodes has been incompletely defined. All patients in Iceland with candidaemia in 1980-2008 were identified, and clinical information was reviewed. Episodes of candidaemia in the same patient were considered to be separate if they occurred ≥ 1 month apart or were caused by different Candida species. The isolates were genotyped by using PCR fingerprinting, and antifungal susceptibility was determined. During the 29-year period, candidaemia was diagnosed in 307 patients in Iceland, 298 of whom (97.1%) had a single episode. Overall, 206 patients survived >1 month from the first episode and were therefore at risk of recurrence, yielding 1062 patient-years of observation in the survivors. Of those, nine (4.4%) later developed recurrent candidaemia. The median time between recurrences was 6 months (range, <1 month to 14 years). Patients with late recurrences were younger (p 0.012) and more likely to have underlying gastrointestinal diseases than patients with single episodes (55.6% vs. 18.5%, respectively; p 0.017). The recurrences were caused by identical Candida sp. genotypes in two of 13 cases (15%), but by different species or dissimilar genotypes in eight of 13 (62%); isolates were missing in three cases. In conclusion, late recurrent candidaemia was a relatively rare event, and younger patients with gastrointestinal disorders were more prone to recurrent infections. The majority of late recurrences represented re-infections with new Candida strains that were susceptible to common antifungal agents.

Evolving epidemiology of invasive Haemophilus infections in the post-vaccination era: results from a long-term population-based study.

Historically, Haemophilus influenzae (Hi) serotype b (Hib) caused most invasive Haemophilus infections worldwide, mainly in children. In 1989 routine childhood vaccination against Hib was initiated in Iceland. We conducted a population-based study of all patients in the country with Haemophilus spp. isolated from sterile sites (n = 202), from 1983 to 2008. Epidemiology, clinical characteristics of the infections and serotypes of the isolates were compared during the pre-vaccination (1983-1989) and post-vaccination era (1990-2008). Following the vaccination, the overall incidence of Hib decreased from 6.4 to 0.3/100,000 per year (p <0.05) whereas the incidence did not change significantly for infections caused by Haemophilus sensu lato not serotype b, hereafter referred to as non-type b Hi (0.9 vs 1.2, respectively). The most frequent diagnosis prior to 1990 was meningitis caused by Hib, which was subsequently replaced by pneumonia and bacteraemia caused by non-type b Hi. Most commonly, non-type b Hi were non-typeable (NTHi; 40/59), followed by Hi serotype f (14/59) and Hi serotype a (3/59). Pregnancy was associated with a markedly increased susceptibility to invasive Haemophilus infections (RR 25.7; 95% CI 8.0-95.9, p <0.0001) compared with non-pregnant women. The case fatality rate for Hib was 2.4% but 14% for non-type b Hi, highest at the extremes of age. Hib vaccination gives young children excellent protection and decreases incidence in the elderly due to herd effect in the community. Replacement with other species or serotypes has not been noted. Pregnant women are an overlooked risk group.

Severe sepsis and septic shock: a prospective population-based study in Icelandic intensive care units.

BACKGROUND: The aims of our study were to describe the nationwide epidemiology of sepsis requiring intensive care during an entire year and to evaluate compliance with treatment guidelines. METHODS: This was a prospective, observational study of all adult patients admitted to Icelandic intensive care units (ICUs), who were screened for the ACCP/SCCM criteria for severe sepsis or septic shock on admission. Data were collected from 1 April 2008 to 31 March 2009. RESULTS: One thousand five hundred and twenty-four patients were admitted to the ICUs during the study year, 115 of them because of severe sepsis or septic shock. The incidence in Iceland was 0.48/1000 inhabitants ≥18 years per year [95% confidence intervals (CI) 0.42-0.55]. The mean APACHE II score was 20.7. Mortality was 24.6% (95% CI 17.5-33.3) at 28 days and 40.4% (95% CI 31.8-49.5) at 1 year. The main sources of infections were pulmonary (37%), abdominal (28%) and urinary tract (8%). Pathogens were gram-positive (39%), gram-negative (30%) and mixed (28%). No patient had sepsis caused by methicillin-resistant Staphylococcus aureus or a monomicrobial fungal infection. Pulmonary infections were an independent predictor of death. Compliance to the resuscitation goals of the Surviving Sepsis Campaign ranged from 60% to 72% and the 6-hour Sepsis Bundle was completed in 35% of patients. CONCLUSIONS: This nationwide study showed an incidence of 0.48/1000 inhabitants for severe sepsis and septic shock requiring intensive care therapy. The 28-day mortality rate of 25 % was in the lower range of previous reports but the compliance to resuscitation goals and sepsis bundles was similar.

The importance of strain variation in virulence of Candida dubliniensis and Candida albicans: results of a blinded histopathological study of invasive candidiasis.

The pathogenic yeast Candida dubliniensis is increasingly reported as a cause of systemic fungal infections. We compared the virulence of 9 clinical bloodstream isolates of C. dubliniensis with 3 C. albicans isolates in a murine model of invasive candidiasis. Quantification of organisms and inflammatory changes in kidneys of infected animals were evaluated in a blinded, systematic manner. Average 7-day mortality among animals infected with C. dubliniensis was 21.0% (33/157 animals; range for strains: 0-57.1%); and with C. albicans 23.2%, (23/99 animals; range for strains: 6.7-85.0%) (p 0.65). Greater strain variation was noted within species than between the two species. Both species comprised strains of either high or low virulence, and six of the nine C. dubliniensis strains showed negligible virulence. Colony counts determined on samples from liver and kidneys did not differ between species. According to histopathological analysis, C. dubliniensis produced significantly lower levels of hyphae than C. albicans (p <0.001). Candida albicans caused a greater inflammatory response in kidneys (p <0.001) and was more commonly associated with granulomatous inflammation (p 0.003) and greater mononuclear infiltrate (p <0.001). According to multivariate analysis, increasing tissue burden of both hyphal forms (p 0.032) and yeasts (p 0.016) was independently associated with death, whereas higher levels of mononuclear cells were protective (p <0.001). The results suggest a great overlap between the virulence properties of C. dubliniensis and C. albicans. Both yeast and hyphal forms are independently associated with mortality, suggesting similar virulence for both. The source of the fungal isolates may be a neglected confounding factor in virulence studies in animal models.

Nationwide study of recurrent invasive pneumococcal infections in a population with a low prevalence of human immunodeficiency virus infection.

Recurrent invasive infections caused by Streptococcus pneumoniae are rare, and often considered to be indicative of serious underlying illness. However, the prevalence of this problem, and the relevance of specific predisposing conditions, can be hard to assess, since many of the studies are based on specific risk groups. A population-based study of recurrent invasive pneumococcal disease in Iceland during the 30-year period 1975-2004 was performed. Clinical information, including mortality and vaccine use, was analysed retrospectively. Invasive pneumococcal isolates were serotyped and susceptibility testing was performed. During this period, 36 (4.4%) of 819 patients who survived an initial infection experienced recurrence, with a median time between episodes of 9.7 months. Pneumonia with bacteraemia was the most common clinical diagnosis (48% of cases), followed by bacteraemia without a clear focus (21%) and meningitis (13%). Most (94%) of the patients had identifiable predisposing conditions, most commonly, multiple myeloma in adults, and antibody deficiencies in children. Compared with children, adults were more likely to present with pneumonia (65% vs. 18%; p 0.0001). No significant change in the 30-day mortality rate was observed during the three decades of the study. Only 26% of eligible patients received pneumococcal vaccination. Patients with recurrent invasive pneumococcal disease should be investigated thoroughly for underlying diseases. Greater use of pneumococcal vaccines should be encouraged among high-risk patients. More effective preventive and therapeutic measures are needed to improve outcomes.

Fungal phospholipase activity and susceptibility to lipid preparations of amphotericin B.

It has been postulated that phospholipases of fungal origin can affect in vitro susceptibility testing of amphotericin B lipid complex (ABLC). We used specific phospholipase-deficient mutants of Candida albicans and Cryptococcus neoformans in susceptibility testing and demonstrated that extracellular fungal phospholipase activity does not influence the in vitro susceptibilities of these two fungi to ABLC.

Extracellular phospholipase activity is a virulence factor for Cryptococcus neoformans.

The human pathogenic fungus Cryptococcus neoformans secretes a phospholipase enzyme that demonstrates phospholipase B (PLB), lysophospholipase hydrolase and lysophospholipase transacylase activities. This enzyme has been postulated to be a cryptococcal virulence factor. We cloned a phospholipase-encoding gene (PLB1) from C. neoformans and constructed plb1 mutants using targeted gene disruption. All three enzyme activities were markedly reduced in the mutants compared with the wild-type parent. The plb1 strains did not have any defects in the known cryptococcal virulence phenotypes of growth at 37 degrees C, capsule formation, laccase activity and urease activity. The plb1 strains were reconstituted using the wild-type locus and this resulted in restoration of all extracellular PLB activities. In vivo testing demonstrated that the plb1 strain was significantly less virulent than the control strains in both the mouse inhalational model and the rabbit meningitis model. We also found that the plb1 strain exhibited a growth defect in a macrophage-like cell line. These data demonstrate that secretory phospholipase is a virulence factor for C. neoformans.

[Fungemia and other invasive fungal infections in Icelandic children. A nationwide study.].

INTRODUCTION: Invasive fungal infections are increasing in incidence. Among those who are at increased risk of fungal blood stream infections (fungemia) and disseminated fungal infections are premature infants and immunosuppressed children. These infections are associated with high morbidity and mortality. Invasive fungal infections have not yet been studied in Iceland. MATERIAL AND METHODS: We studied all cases of fungemia and/or disseminated fungal infections in Icelandic children (16 years) during a 20 year period. Histopathology reports and autopsies were reviewed. Information on predisposing factors, symptoms, treatment and outcome was collected. All obtainable fungal blood stream isolates were subcultured and their susceptibility to common antifungals determined. RESULTS: In the 20 year period from 1980-1999, 19 episodes of invasive fungal infections were diagnosed in 18 infants and children in Iceland. Twelve episodes of fungemia occured in 11 children and the nationwide annual incidence increased from 0.28 to 1.90 cases/100,000/year (p=0.037) during the study period. Half of the children were premature infants. All patients had a central venous catheter at the time of blood culture and most had received intravenous antibiotics or corticosteroids. Candida albicans was the most commonly isolated species (nine of 12 episodes, 75%). In addition to patients with fungemia, three children were diagnosed with disseminated fungal infection by histology or autopsy. Two cases of fungal meningitis, without fungemia, were identified. Furthermore, two children had invasive infections with Aspergillus fumigatus and both patients survived. Three children (3/16; 19%) with invasive Candida-infections died. CONCLUSIONS: In this study of invasive fungal infections among Icelandic children we demonstrate that the incidence of fungemia has risen significantly in the past 20 years. Diagnosis of invasive fungal infections can be complicated and negative blood cultures do not exclude disseminated infection. Given the high attributable mortality, timely diagnosis and aggressive treatment is extremely important.

Fungal meningitis.

Fungi provide many benefits to humans. However, some of these fungi have the ability to become human pathogens. All the major fungal pathogens can produce meningitis. From the common cryptococcal meningitis to the rare fungal meningitis caused by a dimorphic or filamentous fungus, medical issues are discussed in this review on a fungus-specific basis. Both primary (Cryptococcus, Blastomyces, Histoplasma, Coccidioides, and other dimorphic fungi) and secondary (Aspergillus, Candida, and a series of molds) fungal pathogens can produce life-threatening central nervous system infections. These infections require immediate and precise diagnosis and carefully selected management strategies to optimize outcomes. In this review, we examine the epidemiology, pathogenesis, clinical manifestations, and treatment for fungal meningitis in all the major fungal groups.

Association of plasma levels of human immunodeficiency virus type 1 RNA and oropharyngeal Candida colonization.

The pathophysiology of oropharyngeal candidiasis in patients infected with human immunodeficiency virus (HIV) type 1 is poorly understood. Association between oropharyngeal yeast carriage and various clinical factors in HIV-1-infected patients was studied in 83 patients with no clinical evidence of thrush and no recent antifungal use. Of the clinical factors measured, the only correlate of yeast colonization was with plasma HIV-1 RNA levels (P=.001), whereas the correlation with CD4 cell count was poor (P=.36). By multivariable regression modeling, plasma HIV-1 RNA was the only parameter that correlated with the extent of colonization with Candida infection (P=.003). These data indicate that the presence and amount of asymptomatic oropharyngeal yeast carriage in persons with HIV-1 infection is more significantly correlated with plasma HIV-1 RNA levels than with CD4 cell count. Further studies on the effect of HIV-1 on oropharyngeal yeast colonization, infection, and local immunity are warranted.

Molecular methods for epidemiological and diagnostic studies of fungal infections.

Over the past two decades there has been a remarkable increase in the incidence of invasive fungal infections. Molecular methods, such as karyotyping, restriction analysis and polymerase chain reaction (PCR), have now been applied to improve our current understanding of the epidemiology of these fungal infections. For example, investigations on nosocomial outbreaks of fungal infections have been greatly facilitated by molecular methods. In addition, the ability to diagnose and identify deep-seated mycoses may be enhanced by the use of molecular techniques. In the near future it is possible that PCR-based methods will supplement, or perhaps even replace, traditional methods for detection of Candida albicans blood stream infections, invasive aspergillosis and Pneumocystis carinii pneumonia. This review examines the progress of molecular biology into the clinical arena of fungal epidemiology, laboratory identification and diagnosis.