Isolation rooms for highly infectious diseases: an inventory of capabilities in European countries.

Isolation of patients with highly infectious diseases (HIDs) in hospital rooms with adequate technical facilities is essential to reduce the risk of spreading disease. The European Network for Infectious Diseases (EUNID), a project co-funded by European Commission and involving 16 European Union member states, performed an inventory of high level isolation rooms (HIRs, hospital rooms with negative pressure and anteroom). In participating countries, HIRs are available in at least 211 hospitals, with at least 1789 hospital beds. The adequacy of this number is not known and will depend on prevailing circumstances. Sporadic HID cases can be managed in the available HIRs. HIRs could also have a role in the initial phases of an influenza pandemic. However, large outbreaks due to natural or to bioterrorist events will need management strategies involving healthcare facilities other than HIRs.

The impact of HIV-1 co-infection on long-term mortality in patients with hepatitis C: a population-based cohort study.

OBJECTIVE: To investigate the impact of HIV co-infection on mortality in patients infected with hepatitis C virus (HCV). METHODS: From a nationwide Danish database of HCV-infected patients, we identified individuals diagnosed with HCV subsequent to an HIV diagnosis. For each co-infected patient, four control HCV patients without HIV were matched on age, gender and year of HCV diagnosis. Data on comorbidity, drug abuse, alcoholism and date of death were extracted from two healthcare databases. We constructed Kaplan-Meier curves and used Cox regression analyses to estimate mortality rate ratios (MRRs), controlling for comorbidity. RESULTS: We identified 483 HCV-HIV co-infected and 1932 HCV mono-infected patients, yielding 2192 and 9894 person-years of observation with 129 and 271 deaths, respectively. The 5-year probability of survival was 0.74 [95% confidence interval (CI) 0.69-0.80] for HCV-HIV co-infected patients and 0.87 (95% CI 0.85-0.89) for HCV mono-infected patients. Co-infection was associated with substantially increased mortality (MRR 2.1, 95% CI 1.7-2.6). However, prior to the first observed decrease in CD4 counts to below 300 cells/muL, HIV infection did not increase mortality in HCV-infected patients (MRR 0.9, 95% CI 0.5-1.50). CONCLUSIONS: HIV infection has a substantial impact on mortality among HCV-infected individuals, mainly because of HIV-induced immunodeficiency.

Impact of hepatitis B virus co-infection on response to highly active antiretroviral treatment and outcome in HIV-infected individuals: a nationwide cohort study.

BACKGROUND: The impact of chronic hepatitis B virus (HBV) infection on viral suppression, immune recovery and mortality in HIV-1 infected patients on highly active antiretroviral treatment (HAART) is a matter of debate. The impact of HBeAg status is unknown. METHODS: This prospective cohort study included all adult Danish HIV-1 infected patients who started HAART between 1 January 1995 and 1 December 2006 (3180 patients). Patients were classified as chronic HBV-infected (6%), HBV-negative (87%) or HBV-unknown (7%). HBV-positive patients were divided into HBeAg-positive or -negative (3.0 vs. 2.6%). Study endpoints were viral load, CD4 cell count and mortality. RESULTS: HBV co-infection had no impact on response to HAART regarding viral suppression or immune recovery. HBV co-infection was associated with several outcomes: overall mortality [mortality rate ratio (MRR) 1.5; 95% confidence interval (CI) 1.1-2.1], liver-related mortality (MRR 4.0; 95% CI 1.6-9.9) and AIDS-related deaths (MRR 1.7; 95% CI 1.0-3.0). The presence of HBeAg did not influence patients' response to HAART. CONCLUSIONS: In HIV patients, chronic HBV infection has no impact on response to HAART concerning viral load and increase in CD4 cell count. However, co-infected patients have an increased mortality compared to HIV-monoinfected patients.

A curriculum for training healthcare workers in the management of highly infectious diseases.

The SARS epidemic, the threat of bioterrorism, and recent examples of imported highly infectious diseases (HID) in Europe have all highlighted the importance of competent clinical and public health management of infectious disease emergencies. Although the European Union of Medical Specialists in Europe and the Infectious Diseases Society of America have developed curricula for training in infectious disease medicine, neither of those mentions training in the management of HIDs. The European Network for Infectious Diseases (EUNID, http://www.eunid.com) is a European Commission co-funded network of experts in HID management, created to help improve the preparedness for HID emergencies within Europe. One of EUNID's agreed tasks is the development of a curriculum for such a training. Between April 2005 and September 2006, EUNID developed a curriculum and accompanying training course on the basis of a questionnaire that was sent to all country representatives and discussion, followed by amendment of drafts shared through the project website, and a final consensus meeting. The resulting curriculum consists of a two-module course covering the core knowledge and skills that healthcare workers need to safely treat a patient who has, or who may have, an HID. The first module introduces theoretical aspects of HID management, including disease-specific knowledge, infection control, and the public health response, through didactic teaching and class-based discussion. The second module involves a "skill station" and a clinical scenario, and equips trainees with relevant practical skills, including the use of specialised equipment and teamwork practice in patient management. Together, the curriculum and course contribute to the creation of a common framework for training healthcare professionals in Europe, and although they are designed primarily for clinicians that are directly involved in patient care, they are relevant also to public health professionals and others who may be involved in HID management and emergency response.

Increasing incidence but decreasing in-hospital mortality of adult Staphylococcus aureus bacteraemia between 1981 and 2000.

Staphylococcus aureus is a leading cause of bacteraemia. This study analysed temporal trends from 18,702 adult cases of S. aureus bacteraemia in Denmark between 1981 and 2000. After stratification for mode of acquisition, 57% of cases were hospital-acquired (HA), 28% were community-acquired (CA) and 15% were of undetermined acquisition (UA). Incidence rates increased from 18.2 to 30.5 cases/100,000 population. Annual rates increased by 6.4% for CA, by 2.2% for HA and by 3.6% for UA cases, respectively. Case-mortality associated with HA bacteraemia decreased from 36.2% to 20.7% (43% rate reduction, p 0.0001), compared with a decrease from 34.5% to 26.5% (23% rate reduction, p 0.0001) for CA bacteraemia. Following multivariate analysis, age, pneumonia, endocarditis and chronic illness were associated with increased mortality, regardless of the mode of acquisition. Overall, mortality associated with S. aureus bacteraemia declined significantly between 1981 and 2000, but incidence rates doubled, so that the total number of deaths increased. These data emphasise the public health importance of S. aureus bacteraemia and the need for further preventive measures and improved care in order to reduce incidence rates and improve outcomes.

Invasive group A, B, C and G streptococcal infections in Denmark 1999-2002: epidemiological and clinical aspects.

Group A streptococci (GAS) have been described frequently as an emerging cause of severe invasive infections in population-based surveillance studies, whereas the descriptions of group B, C and G streptococci (GBS, GCS and GGS) have been less frequent. Enhanced surveillance for invasive GAS, GBS, GCS and GGS was performed in Denmark in 1999-2002. A detailed questionnaire was completed for 1237 (98%) of 1260 invasive infections. GAS infections dominated (40%), followed by GGS (32%), GBS (23%) and GCS (6%). Most (74%) patients had predisposing factors, and there were no significant differences between the four serogroups when comparing the prevalence of cancer, diabetes mellitus, chronic heart or lung diseases, immunodeficiency or alcohol abuse. The overall case fatality rate at day 30 was 21%, increasing significantly to 59% for patients with streptococcal toxic shock syndrome (STSS). STSS was significantly more frequent in GAS patients (10%) than in GCS (4%), GBS (2%) and GGS (2%) patients. Regression analyses showed that, despite a younger median age among GAS patients, the probability of developing septic shock and mortality was significantly higher among GAS patients than among GBS and GGS patients. These analyses showed no significant differences between GAS and GCS infections. Invasive infections caused by GAS, GBS, GCS and GGS are still a major challenge for clinicians. Continued epidemiological and microbiological surveillance is important to assess the development of these infections and to improve preventative strategies.

Changing epidemiology of HBV infection in Danish children.

Hepatitis B continues to be a worldwide threat to human health, especially if infection occurs in childhood. Universal vaccination is recommended by WHO, but has not been implemented in the Scandinavian countries, Holland and UK, because of a low incidence rate. However, clinically overt infections are rare in childhood. We therefore performed a nation wide serosurvey for HBV markers in 2428 children aged primarily 6-16 years from 16 primary schools in Denmark. Anti-HBc was found in altogether 20 children (0.8%), 12 of whom were among 144 immigrant children (8.3%) compared to 8 (0.4%) in those born in Denmark. Three of the children, all immigrants, were HBsAg positive indicating chronic infection. At school level no relation of anti-HBc in Danish born children was found to schools with high number of immigrant children or schools with HBsAg positive children indicating a low risk of Hepatitis B transmission in this setting. The results do not support implementation of general vaccination, but stress the need for HBV screening in immigrants as it provides a mean for immunization of close contacts at risk and information on prevention.

Twenty-year survey of the epidemiology of hepatitis B in Denmark: effect of immigration.

Implementation of hepatitis B virus (HBV) vaccination is being considered in Denmark. Therefore, a 20 y survey on the epidemiology of HBV infection was performed. All notified cases of acute HBV infection in Denmark from 1982 to 2002 were reviewed retrospectively and all available data from 1970 to 2001 on the prevalence of hepatitis B surface antigen (HBsAg) in different groups of the Danish population were studied. The notified annual incidence of acute HBV infection has declined from more than 200 cases to fewer than 50 cases in 2001. In the indigenous population there has been a similar decline in prevalence of HBsAg carriers, from 0.15 to 0.03%, but owing to immigration of new HBsAg carriers from developing countries the overall number of carriers has not changed. The small effect of immigration on the incidence of acute HBV infections as well as the decreasing prevalence of HBsAg carriers among Danes should be taken into account when planning new vaccination strategies in Denmark.

T-cell receptor excisional circles, telomere length, proliferation and apoptosis in peripheral blood mononuclear cells of human immunodeficiency virus-infected individuals after 18 months of treatment induced viral suppression.

This study evaluated the effect of highly active antiretroviral therapy (HAART)-induced viral suppression on T-cell receptor excisional circles (TRECs), telomere length, proliferative responses and spontaneous as well as phytohaemagglutinin (PHA)-stimulated lymphocyte apoptosis in 27 human immunodeficiency virus (HIV)-infected individuals followed for 18 months during HAART. Our results show that HAART significantly increased the level of TRECs in CD4+ cells (P = 0.003) after 18 months of almost continuously suppressed HIV-RNA levels. Lymphocyte proliferative responses and apoptosis levels in patients were significantly lower and significantly higher, respectively, compared with healthy controls. The proliferative response and apoptosis levels did not change during follow up. Changes in telomere length were observed in CD4+ and in CD8+ T cells. The study demonstrated that HAART induces normal TREC levels in the CD4+ T-cell pool. However, the other perturbed functions in T cells indicate that immune reconstitution is incomplete and may need longer viral suppression.

Virological and immunological profiles among patients with undetectable viral load followed prospectively for 24 months.

OBJECTIVE: To quantify HIV-RNA in plasma, in lymphoid tissue and proviral DNA in peripheral blood mononuclear cells and to relate these to immunological markers among patients with plasma viral load counts of /= 1 measurement with 21-200 and 25% had >/= 1 sample with plasma HIV-RNA > 200 copies/mL. Lymphoid tissue viral load was low at enrolment and declined further during follow-up. Baseline HIV-DNA and immunoglobulin (IgA) differed significantly between the plasma viral load rebound groups (P < 0.05). CONCLUSION: In this cohort, selected solely on the basis of having a plasma viral load of

A 2-dose regimen of a recombinant hepatitis B vaccine with the immune stimulant AS04 compared with the standard 3-dose regimen of Engerix-B in healthy young adults.

An open-label randomized study was undertaken to compare a 2-dose regimen (Months 0 and 6) of hepatitis B surface antigen (HBsAg) vaccine formulated with a novel adjuvant (HBsAg/AS04) with a standard 3-dose regimen (Months 0, 1 and 6) of licensed recombinant HBsAg vaccine in terms of immunogenicity and reactogenicity when administered to healthy subjects aged between 15 and 40 y. At 1 and 6 months after the full vaccination course there was a 100% seroprotection rate (anti-HBs > or = 10 mIU/ml) with the HBsAg/AS04 vaccine, compared with a 99% response rate with the licensed vaccine. The corresponding geometric mean titres were significantly higher for the novel vaccine compared to the standard vaccine: 15,468 and 2,745 mIU/ml at Months 7 and 12 vs. 6,274 and 1,883 mIU/ml, respectively. There was a higher prevalence of local symptoms with the adjuvant vaccine (90% of doses) than with the standard vaccine (48% of doses). However, these symptoms (pain, swelling and redness) were predominantly of mild-to-moderate intensity and resolved rapidly without treatment. A 2-dose regimen of the new HBsAg/AS04 adjuvant vaccine therefore compared favourably to the standard regimen in healthy young adults. It is anticipated that the simplified vaccination schedule may improve compliance and reduce costs.

Cerebral blood flow, oxidative metabolism and cerebrovascular carbon dioxide reactivity in patients with acute bacterial meningitis.

BACKGROUND: The optimal arterial carbon dioxide tension (P(a)CO(2)) in patients with acute bacterial meningitis (ABM) is unknown and controversial. The objective of this study was to measure global cerebral blood flow (CBF), cerebrovascular CO(2) reactivity (CO(2)R), and cerebral metabolic rates (CMR) of oxygen (O(2)), glucose (glu), and lactate (lac), in patients with ABM and compare the results to those obtained in healthy volunteers. METHODS: We studied 19 patients (17 of whom were sedated) with ABM and eight healthy volunteers (controls). CBF was measured during baseline ventilation and hyperventilation with single-photon emission computed tomography (SPECT) (14 patients) and/or the Kety-Schmidt technique (KS) (11 patients and all controls). In KS studies, CMR was measured by multiplying the arterial to jugular venous concentration difference (a-v D) by CBF. RESULTS: CBF did not differ significantly among groups, although a larger variation was seen in patients than in controls. CO(2)R was not significantly different among groups. At baseline, patients had significantly lower a-v DO(2), CMR(O(2)), CMR(glu), and CMR(lac) than controls. CMR(O(2)) did not change between hyperventilation compared to baseline ventilation, whereas CMR(glu) increased. CONCLUSION: In patients with acute bacterial meningitis, we found variable levels of CBF and cerebrovascular CO(2) reactivity, a low a-v DO(2), low cerebral metabolic rates of oxygen and glucose, and a cerebral lactate efflux. In these patients, a ventilation strategy guided by jugular bulb oximetry and/or repeated CBF measurements may be more optimal in terms of cerebral oxygenation than a strategy aiming at identical levels of P(a)CO(2) for all patients.

Activated T lymphocytes disappear from circulation during endotoxemia in humans.

Seventeen volunteers received an intravenous bolus of endotoxin (2 ng/kg of body weight). Endotoxin-induced lymphopenia was constituted mainly by cells with an immature phenotype (CD45RA(+) CD45RO(-)) that were less likely to undergo apoptosis (CD28(+)), whereas cells with the highest rates of disappearance were characterized by an activated phenotype (CD45RA(-) CD45RO(+)) as well as a phenotype linked to apoptosis (CD95(+) CD28(-)). In conclusion, endotoxin-induced lymphopenia reflects the disappearance from the circulation of activated lymphocytes prone to undergo apoptosis.

Is ageing associated with a shift in the balance between Type 1 and Type 2 cytokines in humans?

The balance between Type 1 and Type 2 cytokines is important for the outcome of several infectious diseases. As elderly humans show increased morbidity and mortality from infectious diseases, this study tests if ageing is associated with a change towards Type 2 dominance in T cells. Expression of IFN-gamma, and IL-4 was measured in CD4+ and CD8+ T cells by flow cytometry in three groups: young controls (n=28), 81-year-olds (n=22), and centenarians (n=25). The major findings were that the percentage of IFN-gamma+ as well as IL-4+ T cells was increased in aged subjects. Furthermore, after adjusting for decreased lymphocyte counts in the elderly, the concentration in the blood of IFN-gamma+ and IL-4+ CD8+ T cells was still increased in the 81-year-olds. In centenarians, a shift towards a relative dominance of Type 2 cytokine expression was found within CD8+ T cells. Furthermore, the percentage of T cells with cytokine expression was closely correlated to the in vivo expression of CD95 and CD45RO. In conclusion, we found some evidence for an age-related shift towards a Type 2 cytokine profile.

Decreased natural killer cell activity is associated with atherosclerosis in elderly humans.

Well-preserved natural killer cell (NK) activity has been associated with successful aging. The aim of the present study was to perform detailed analyses of NK cell function and to investigate the clinical significance of the NK cell number and function in relationship to health in a large cohort of elderly humans. It was tested if the potential of natural cytotoxicity in the blood (evaluated as an index including cytotoxicity per NK cell and the number of circulating NK cells) was preserved in 174 81-year-old humans versus 91 young controls and if NK cell mediated immunity was associated with age-related inflammatory diseases such as atherosclerosis. Elderly people had decreased cytotoxicity per NK cell in short-term but not in long-term assays. Ca(2+) independent cytotoxicity was unaltered, and NK cells maintained their cytotoxic responses to interleukin-2 and interferon-alpha signals. The decreased cytotoxicity per NK cell was not completely counteracted by increased circulating numbers of NK cells in the blood. Elderly people with severe medical disorders had low numbers of circulating NK cells. Furthermore, elderly people with atherosclerosis had low cytotoxicity per NK cell and a high number of circulating neutrophils.

Non-Hodgkin lymphoma in HIV-infected patients in the era of highly active antiretroviral therapy.

This study was designed to assess the influence of highly active antiretroviral therapy (HAART) on non-Hodgkin lymphoma (NHL) among patients infected with human immunodeficiency virus (HIV). Within EuroSIDA, a multicenter observational cohort of more than 8500 patients from across Europe, the incidences of NHL and subtypes (Burkitt, immunoblastic, primary brain lymphoma [PBL], and other/unknown histology) were determined according to calendar time of follow-up, and for those who initiated HAART (> or =3 drugs) also time on HAART. Potential predictive factors of NHL were evaluated in Cox proportional hazard models. Over 26 764 person-years of prospective follow-up (PYF) from May 1994 to December 2000, the incidence of NHL decreased from 1.99 (95% confidence interval, 1.51-2.47) before September 1995 to 0.30 (0.19-0.42) cases/100 (PYF) after March 1999 (P <.001). The incidence of all subtypes of NHL decreased significantly and most pronouncedly for PBL. Among patients who started HAART, the incidence of NHL decreased from 0.88 (0.60-1.16) within the first 12 months after starting HAART to 0.45 (0.31-0.60) cases/100 PYF after more than 24 months (P =.004). In an adjusted Cox model for patients on HAART, the latest CD4 cell count and plasma viral load were both significantly associated with diagnosis of NHL; the relative hazard was 1.39 (range, 1.14-1.69) per 50% lower CD4 cell count, and 1.51 (range, 1.21-1.88) per 1 log higher plasma viral load. In conclusion, the incidence of NHL among HIV-infected patients has decreased significantly after the introduction of HAART, and the decline was most pronounced for PBL. After starting HAART, patients with insufficient immunologic and virologic responses were at highest risk of NHL.

T-cell mean telomere lengths changes in treatment naïve HIV-infected patients randomized to G-CSF or placebo simultaneously with initiation of HAART.

The effect of highly active antiretroviral therapy (HAART) and granulocyte colony stimulating factor (G-CSF) on mean telomere restriction fragment (TRF) length of peripheral blood mononuclear cells (PBMC) was examined in 11 treatment naïve human immunodeficiency virus (HIV)-infected individuals with a CD4+ T-cell count < 350 cells/mm3. Patients were randomized to HAART combined with G-CSF thrice weekly for 12 weeks (n = 6) or placebo (n = 5). An increase in the mean TRF lengths was observed in PBMC of patients on HAART after 24 weeks of treatment mainly owing to increased mean CD8+ T-cell TRF lengths. However, in the group of patients on HAART combined with G-CSF no changes of PBMC mean TRF length was observed during treatment or during 12 weeks of follow-up. The mean CD4+ T-cell TRF length did not change in any of the two groups. These results confirm that HAART induces mainly the lengthening of the mean CD8+ T-cell TRF length. However, G-CSF given simultaneously with HAART induces an inhibition of the expected lengthening in mean TRF length. These results do therefore not support the use of adjuvant G-CSF treatment simultaneously when initiating HAART and should further be evaluated before use in non-neutropenic HIV-infected patients.

Hypotension during endotoxemia in aged humans.

BACKGROUND: and objective The aim of this study was to determine possible age-associated differences in human blood pressure regulation during an immunological challenge in healthy subjects. METHODS: Eight healthy young volunteers (median age 24 yr) and nine healthy elderly volunteers (median age 66 yr) received an intravenous bolus injection of Escherichia coli endotoxin (2 ng kg(-1)). Blood pressure, heart rate and core temperature were monitored during the first 7 h. Plasma catecholamine concentrations were measured at hourly intervals. RESULTS: The elderly showed a significantly more pronounced decrease in mean arterial pressure 4-7 h after endotoxin administration compared with the young controls (ANOVA; age x time; P < 0.0005). This mainly reflected a decrease in the systolic blood pressure in the elderly. The heart rate of both groups increased without difference between groups. Increased plasma epinephrine concentrations were found 2-3 h after endotoxin administration in both groups. Five hours after the endotoxin challenge, the epinephrine concentration had returned to control values in the elderly group only, in spite of decreased blood pressure. CONCLUSION: In conclusion, healthy elderly subjects fail to maintain a constant mean arterial pressure in response to the immunological challenge of endotoxemia.