[Development and use of vaccines from the 18th century to the SARS-CoV 2 period].

This review is about the development and use of vaccines from the early smallpox vaccine in the 18th century to the forthcoming SARS-CoV 2 vaccines. Immunisations have been of paramount importance for childhood mortality and public health in general, but some obstacles have also been encountered such as vaccine failures and vaccine scepticism. This calls for continued emphasis on large phase three studies not only for demonstration of efficacy but also for safety and possible side effects. The rapid approval of SARS-CoV 2 vaccines requires special attention.

CNS infections in Greenland: A nationwide register-based cohort study.

BACKGROUND: Indigenous Arctic people suffer from high rates of infectious diseases. However, the burden of central nervous system (CNS) infections is poorly documented. This study aimed to estimate incidence rates and mortality of CNS infections among Inuits and non-Inuits in Greenland and in Denmark. METHODS: We conducted a nationwide cohort study using the populations of Greenland and Denmark 1990-2012. Information on CNS infection hospitalizations and pathogens was retrieved from national registries and laboratories. Incidence rates were estimated as cases per 100,000 person-years. Incidence rate ratios were calculated using log-linear Poisson-regression. Mortality was estimated using Kaplan-Meier curves and Log Rank test. RESULTS: The incidence rate of CNS infections was twice as high in Greenland (35.6 per 100,000 person years) as in Denmark (17.7 per 100,000 person years), but equally high among Inuits in Greenland and Denmark (38.2 and 35.4, respectively). Mortality from CNS infections was 2 fold higher among Inuits (10.5%) than among non-Inuits (4.8%) with a fivefold higher case fatality rate in Inuit toddlers. CONCLUSION: Overall, Inuits living in Greenland and Denmark suffer from twice the rate of CNS infections compared with non-Inuits, and Inuit toddlers carried the highest risk of mortality. Further studies regarding risk factors such as genetic susceptibility, life style and socioeconomic factors are warranted.

Employment and disability pension after central nervous system infections in adults.

In this nationwide population-based cohort study using national Danish registries, in the period 1980-2008, our aim was to study employment and receipt of disability pension after central nervous system infections. All patients diagnosed between 20 and 55 years of age with meningococcal (n = 451), pneumococcal (n = 553), or viral (n = 1,433) meningitis or with herpes simplex encephalitis (n = 115), who were alive 1 year after diagnosis, were identified. Comparison cohorts were drawn from the general population, and their members were individually matched on age and sex to patients. Five years after diagnosis, the differences in probability of being employed as a former patient with pneumococcal meningitis or herpes simplex encephalitis versus being a member of the comparison cohorts were -19.9% (95% confidence interval (CI): -24.7, -15.1) and -21.1% (95% CI: -33.0, -9.3), respectively, and the corresponding differences in probability of receiving disability pension were 20.2% (95% CI: 13.7, 26.7) and 16.2% (95% CI: 6.2, 26.3). The differences in probability of being employed or receiving disability pension in former meningococcal or viral meningitis patients versus members of the comparison cohorts were small. In conclusion, pneumococcal meningitis and herpes simplex encephalitis were associated with substantially decreased employment and increased need for disability pension. These associations did not seem to apply to meningococcal meningitis or viral meningitis.

Long-term mortality after Staphylococcus aureus spondylodiscitis: a Danish nationwide population-based cohort study.

OBJECTIVES: To determine the long-term mortality and the causes of death after Staphylococcus aureus spondylodiscitis. METHODS: Nationwide, population-based cohort study using national registries of adults diagnosed with non postoperative S. aureus spondylodiscitis from 1994-2009 and alive 1 year after diagnosis (n Z 313). A comparison cohort from the background population individually matched on sex and age was identified (n Z 1565). Kaplan-Meier survival curves were constructed and Poisson regression analyses used to estimate mortality rate ratios (MRR) adjusted for comorbidity. RESULTS: 88 patients (28.1%) and 267 individuals from the population-based comparison cohort (17.1%) died. Un-adjusted MRR for S. aureus spondylodiscitis patients was 1.77 (95% CI, 1.39-2.25) and 1.32 (95% CI, 1.02-1.71) after adjustment for comorbidity. We observed increased mortality due to infectious (MRR 8.57; 95% CI, 2.80-26.20), endocrine (MRR 3.57; 95%CI, 1.01-12.66), cardiovascular (MRR 1.59; 95% CI, 1.02-2.49), gastrointestinal (MRR 3.21; 95% CI, 1.178.84) and alcohol and drug abuse-related (MRR 10.71; 95% CI, 3.23-35.58) diseases. CONCLUSIONS: Patients diagnosed with S. aureus spondylodiscitis have substantially increased long-term mortality, mainly due to comorbidity. To improve survival after S. aureus spondylodiscitis these patients should be screened for comorbidity and substance abuse predisposing to the disease [corrected].

Educational achievement and economic self-sufficiency in adults after childhood bacterial meningitis.

IMPORTANCE: To our knowledge, no previous study has examined functioning in adult life among persons who had bacterial meningitis in childhood. OBJECTIVE: To study educational achievement and economic self-sufficiency in adults diagnosed as having bacterial meningitis in childhood. DESIGN, SETTING, AND PARTICIPANTS: Nationwide population-based cohort study using national registries of Danish-born children diagnosed as having meningococcal, pneumococcal, or Haemophilus influenzae meningitis in the period 1977-2007 (n=2784 patients). Comparison cohorts from the same population individually matched on age and sex were identified, as were siblings of all study participants. End of study period was 2010. MAIN OUTCOMES AND MEASURES: Cumulative incidences of completed vocational education, high school education, higher education, time to first full year of economic self-sufficiency, and receipt of disability pension and differences in these outcomes at age 35 years among meningitis patients, comparison cohorts, and siblings. RESULTS: By age 35 years, among persons who had a history of childhood meningococcal (n=1338), pneumococcal (n=455), and H. influenzae (n=991) meningitis, an estimated 11.0% (41.5% vs 52.5%; 95% CI, 7.3%-14.7%), 10.2% (42.6% vs 52.8%; 95% CI, 3.8%-16.6%), and 5.5% (47.7% vs 53.2%; 95% CI, 1.9%-9.1%) fewer persons, respectively, had completed high school and 7.9% (29.3% vs 37.2%; 95% CI, 1.6%-14.2%), 8.9% (28.1% vs 37.0%; 95% CI, 0.6%-17.2%), and 6.5% (33.5% vs 40.0%; 95% CI, 1.4%-11.6%) fewer had attained a higher education compared with individuals from the comparison cohort. Siblings of meningococcal meningitis patients also had lower educational achievements, while educational achievements of siblings of pneumococcal and H. influenzae meningitis patients did not differ substantially from those in the general population. At end of follow-up, 3.8% (90.3% vs 94.1%; 95% CI, 1.1%-6.5%), 10.6% (84.0% vs 94.6%; 95% CI, 5.1%-16.1%), and 4.3% (90.6% vs 94.9%; 95% CI, 2.0%-6.6%) fewer meningococcal, pneumococcal, and H. influenzae meningitis patients were economically self-sufficient and 1.5% (3.7% vs 2.3%; 95% CI, -0.2% to 3.2%), 8.7% (10.0% vs 1.3%; 95% CI, 5.0%-12.4%), and 3.7% (6.2% vs 2.5%; 95% CI, 1.6%-5.8%) more received disability pension compared with individuals from the comparison cohort. CONCLUSIONS AND RELEVANCE: In a Danish population, bacterial meningitis in childhood was associated with lower educational achievement and economic self-sufficiency in adult life. This association may apply particularly to pneumococcal and H. influenzae meningitis, whereas for meningococcal meningitis the lower educational achievement may be family-related.

Microbiological and therapeutic challenges in infectious spondylodiscitis: a cohort study of 100 cases, 2006-2011.

BACKGROUND: The microbiological diagnosis of infectious spondylodiscitis is often difficult to establish and the disease requires prolonged antibiotic treatment. We analyzed the medical records of 100 patients admitted for infectious spondylodiscitis from 2006 to 2011 with an emphasis on (1) the diagnostic utility of blood cultures and invasive biopsies in the microbiological diagnosis, (2) clinical features differentiating Staphylococcus aureus infections from those with other aetiologies, and (3) evaluation of the outcome of the antimicrobial therapy. METHODS: A retrospective chart review was performed. RESULTS: Patients were diagnosed a median of 32 days after symptom onset and treated for a median of 91 days; 68% had abscesses, 65% experienced sequelae, and the 1-y crude mortality was 11%. Blood cultures yielded a diagnosis in 67%. Among blood culture-positive cases, no other culture or polymerase chain reaction results yielded further diagnoses. S. aureus infections comprised 58%. These cases compared to those with other aetiologies were younger, more frequently female, had a higher C-reactive protein, and more often had neutrocytosis, bacteraemia, and abscess formation. Presumed side effects mediated a change in treatment 33 times in 23 patients. Four patients experienced relapse. CONCLUSIONS: This contemporary case-series on infectious spondylodiscitis mostly concurs with previous studies. We emphasize the importance of thorough blood culture sampling before more invasive tests are considered. S. aureus infections exhibit, in particular, prominent pyogenic characteristics. Prospective studies evaluating the choice and duration of antimicrobial treatment are needed.

Fever of unknown origin: a retrospective study of 52 cases with evaluation of the diagnostic utility of FDG-PET/CT.

OBJECTIVES: Fever of unknown origin (FUO) is dynamic in its origin and will be an ongoing challenge to the clinician because of shifting disease epidemiology. Here we present a series of patients with classical FUO admitted to an infectious diseases department during a 5-y period, with an emphasis on the diagnostic utility of ¹8F-fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT) in present-day cases of FUO. METHODS: Patient records were reviewed retrospectively. RESULTS: A final diagnosis was achieved for 31 of the 52 cases (60%). The final diagnoses of these 31 cases and their distribution in the respective diagnostic categories were: infections 32% (10/31), non-infectious inflammatory disease 55% (17/31), and malignancy 13% (4/31). In our study PET/CT successfully identified an infectious, inflammatory, or neoplastic cause of fever in 10 of the 22 patients (45%) who underwent this scan. CONCLUSIONS: During the past decade the proportion of non-infectious inflammatory diseases in FUO series has increased. Based on our findings we recommend: (1) a PET/CT scan be performed early in the diagnostic work-up of patients with FUO, and (2) restraint in performing invasive procedures in patients with FUO in whom no cause of fever has been determined during diagnostic work-up.

Long-term mortality in patients diagnosed with Listeria monocytogenes meningitis: a Danish nationwide cohort study.

OBJECTIVES: To determine the long-term mortality, the causes of death and the incidence of cancer in listeria meningitis patients. METHODS: Nationwide, population-based cohort study including all adult patients diagnosed with listeria meningitis from 1977 to 2006 and alive 1 year after diagnosis, and an age-and gender-matched, population control cohort. Kaplan-Meier tables, Cox regression analysis and cumulative incidence function were used as outcome analyses. RESULTS: We identified 114 listeria meningitis patients and 1026 population controls. The adjusted mortality rate ratio (MRR) for listeria meningitis patients the first 5 years of follow-up was 2.35(95% confidence interval (CI) 1.60-3.45) thereafter the MRR was 0.93(95% CI: 0.56-1.55). Listeria meningitis patients had an increased risk of death due to cancer the first 5 years of follow-up, and in the same period patients above 50 years of age had a 2-fold increased risk of being diagnosed with cancer, thereafter the risks declined to that of the background population. CONCLUSIONS: The long-term mortality in adult patients diagnosed with listeria meningitis was increased the first 5 years of follow-up, mainly due to death from cancer, thereafter the mortality did not differ from the background population. To improve survival this patient population should be meticulously screened for predisposing conditions, mainly underlying malignant diseases.

Long-term mortality in children diagnosed with Haemophilus influenzae meningitis: a Danish nationwide cohort study.

BACKGROUND: The long-term mortality in children diagnosed with Haemophilus influenzae meningitis is poorly documented. METHODS: We performed a nationwide, population-based cohort study including all Danish children diagnosed at the age between 0 and <5 years with H. influenzae meningitis from 1977 through 1996 and who were alive 1 year after diagnosis. Data were retrieved from medical databases in Denmark. For each H. influenzae meningitis patient, 6 age- and gender-matched population controls were indentified. We constructed Kaplan-Meier survival curves and used Cox regression analysis to estimate mortality rate ratios (MRR) and analyze causes of death. The risk of inpatient admission and of requiring hospital outpatient services during follow-up was calculated. RESULTS: We identified 1242 H. influenzae meningitis patients and 7452 population controls, with a median follow-up time of 21.3 years. The MRR for patients with H. influenzae meningitis was 1.08 (95% confidence interval, 0.57-2.05), adjusted MRR was 0.97 (95% confidence interval, 0.50-1.89). No increased mortality due to infections, respiratory diseases, or cancer was observed. The overall risk of inpatient admission and of requiring hospital outpatient services for the H. influenzae meningitis patients was increased the first 15 years of follow-up, mainly due to the nervous system diseases and ear diseases, thereafter the risk decreased to that of the population controls. CONCLUSIONS: In a developed country, children younger than 5 years surviving the acute phase of H. influenzae meningitis have no increased long-term mortality and only moderately increased morbidity.

Long-term mortality in patients diagnosed with pneumococcal meningitis: a Danish nationwide cohort study.

The objective of the study was to determine the long-term mortality and the causes of death in patients diagnosed with pneumococcal meningitis. The authors performed a nationwide, population-based cohort study including all Danish patients diagnosed with pneumococcal meningitis from 1977 through 2006 and alive 1 year after diagnosis. Data were retrieved from medical databases in Denmark. The absolute and relative risks of all-cause and cause-specific death were analyzed by using Kaplan-Meier survival curves, Poisson regression analysis, Cox regression analysis, and cumulative incidence functions. The authors identified 2,131 pneumococcal meningitis patients and an age- and gender-matched, population-based cohort of 8,524 individuals. Compared with the background population, the pneumococcal meningitis patients had an increased long-term mortality varying from an 8-fold increased mortality in the age category 0-<20 years to a 1.5-fold increased mortality in those aged 60-<80 years. The increased risk of death stemmed from neoplasms, liver diseases, and nervous system diseases. The excess mortality due to neoplasms stemmed mainly from a 5-fold increased risk of death due to hematologic neoplasms. To improve survival in patients surviving the acute phase of pneumococcal meningitis, physicians should meticulously screen this patient population for neurologic sequelae and comorbidity predisposing to the disease.

Long-term mortality in patients diagnosed with meningococcal disease: a Danish nationwide cohort study.

BACKGROUND: In contrast to the case fatality rate of patients diagnosed with meningococcal disease (MD) the long-term mortality in these patients is poorly documented. METHODOLOGY/PRINCIPAL FINDINGS: We performed a nationwide, population-based cohort study including all Danish patients diagnosed with MD from 1977 through 2006 and alive one year after diagnosis. Data was retrieved from the Danish National Hospital Register, the Danish Civil Registration System and the Danish Register of Causes of Death. For each patient four age- and gender-matched individuals were identified from the population cohort. The siblings of the MD patients and of the individuals from the population cohort were identified. We constructed Kaplan-Meier survival curves and used Cox regression analysis, cumulative incidence function and subdistribution hazard regression to estimate mortality rate ratios (MRR) and analyze causes of death. We identified 4,909 MD patients, 19,636 individuals from the population cohort, 8,126 siblings of MD patients and 31,140 siblings of the individuals from the population cohort. The overall MRR for MD patients was 1.27 (95% confidence interval (CI), 1.12-1.45), adjusted MRR, 1.21 (95% CI, 1.06-1.37). MD was associated with increased risk of death due to nervous system diseases (MRR 3.57 (95% CI, 1.82-7.00). No increased mortality due to infections, neoplasms or cardiovascular diseases was observed. The MRR for siblings of MD patients compared with siblings of the individuals from the population cohort was 1.17 (95% CI, 0.92-1.48). CONCLUSIONS: Patients surviving the acute phase of MD have increased long-term mortality, but the excess risk of death is small and stems mainly from nervous system diseases.

[Listerial meningitis at the Department of Infectious Diseases, Copenhagen University Hospital 1983-2006]. / Listeriameningitis på Epidemiklinikken, Rigshospitalet 1983-2006.

INTRODUCTION: Listeria monocytogenes rarely causes meningitis, but when it does the course can be severe and case fatality rates high. The article describes clinical and laboratory findings as well as treatment and outcome among patients treated for listerial meningitis at the Department of Infectious diseases, Rigshospitalet from 1983-2006. MATERIAL AND METHODS: Patient records were reviewed for all adults with a diagnosis of listerial meningitis. RESULTS: A total of 40 patients with a discharge diagnosis of listerial meningitis were identified; records for 36 of these were available. 61% were men and 72% were older than 50 years. 64% had underlying, predisposing illnesses or took immunosuppressant medication. At presentation, patients had fever, neck stiffness, headache and/or change in mental status. The cerebrospinal fluid (CSF) cell count was raised in all patients, but the number and differential count of leukocytes in the CSF varied. L monocytogenes was present in blood and/or CSF from all patients. Treatment records were available for 35 patients, all of whom received ampicillin. Four patients died; they all had underlying diseases and three were older than 50 years. CONCLUSION: The present study confirms the findings of other studies showing that listerial meningitis is more common in patients with underlying conditions, immunosuppression or age above 50. The case fatality rate is lower than that found in other reports, which could be due to the selection of patients. Listeriosis is an important differential diagnosis in predisposed individuals.

Circulating levels of vasoactive peptides in patients with acute bacterial meningitis.

PURPOSE: The underlying mechanisms for cerebral blood flow (CBF) abnormalities in acute bacterial meningitis (ABM) are largely unknown. Putative mediators include vasoactive peptides, e.g. calcitonin-gene related peptide (CGRP), vasoactive intestinal peptide (VIP), and endothelin-1 (ET-1), all of which may be affected by therapeutic interventions used in the intensive care unit. We measured arterial levels as well as the net cerebral flux of these peptides in patients with ABM, and in healthy volunteers undergoing interventions relevant to intensive care. METHODS: Seven patients with severe ABM and sepsis and fifteen healthy volunteers were included after informed consent. The net cerebral fluxes of vasoactive peptides were measured by the Kety-Schmidt technique in ABM patients (baseline study only), as well as in volunteers at baseline, during voluntary hyperventilation, after an intravenous injection of lipopolysaccharide (LPS), and during norepinephrine infusion. RESULTS: The arterial levels of CGRP, but not of VIP or ET-1, were elevated in patients with ABM, but no net cerebral flux was present. CGRP levels decreased during hyperventilation and after LPS injection. No net cerebral flux of VIP occurred in any group at any time. A cerebral efflux of ET-1, which occurred in volunteers at baseline, was neither present in volunteers after LPS injection nor in patients with ABM. CONCLUSION: The arterial concentration of the vasodilatory peptide, CGRP, but of neither VIP nor the vasoconstrictor ET-1, is elevated in patients with ABM and sepsis. A constitutive cerebral output of ET-1 appears to be present in healthy humans, but is abolished after LPS injection.

Infection control in the management of highly pathogenic infectious diseases: consensus of the European Network of Infectious Disease.

The European Network for Infectious Diseases (EUNID) is a network of clinicians, public health epidemiologists, microbiologists, infection control, and critical-care doctors from the European member states, who are experienced in the management of patients with highly infectious diseases. We aim to develop a consensus recommendation for infection control during clinical management and invasive procedures in such patients. After an extensive literature review, draft recommendations were amended jointly by 27 partners from 15 European countries. Recommendations include repetitive training of staff to ascertain infection control, systematic use of cough and respiratory etiquette at admission to the emergency department, fluid sampling in the isolation room, and analyses in biosafety level 3/4 laboratories, and preference for point-of-care bedside laboratory tests. Children should be cared for by paediatricians and intensive-care patients should be cared for by critical-care doctors in high-level isolation units (HLIU). Invasive procedures should be avoided if unnecessary or done in the HLIU, as should chest radiography, ultrasonography, and renal dialysis. Procedures that require transport of patients out of the HLIU should be done during designated sessions or hours in secure transport. Picture archiving and communication systems should be used. Post-mortem examination should be avoided; biopsy or blood collection is preferred.

Functional characteristics of HIV-1 subtype C compatible with increased heterosexual transmissibility.

BACKGROUND: Despite the existence of over 50 subtypes and circulating recombinant forms of HIV-1, subtype C dominates the heterosexual pandemic causing approximately 56% of all infections. OBJECTIVE: To evaluate whether viral genetic factors may contribute to the observed subtype-C predominance. METHODS: Chimeric viruses were generated using V1-V3 envelope fragments from a subtype-A/C dually infected woman with preferential genital replication of subtype C. Viral adaptation, spread and cell fusion ability were evaluated in vitro using peripheral blood mononuclear cells and HeLa-CD4-CCR5 cell lines, sequencing and cloning. Structural modeling was performed using a crystal structure of gp120-CD4-X5. Phylogenetic analysis was done using subtype-A, subtype-B and subtype-C sequences from blood and cervix of 37 infected women and database sequences. RESULTS: We identified two envelope motifs, compact V1-V2 loops and V3-316T, which are found at high frequency throughout subtype-C evolution and affect gp120 interactions with CD4 and CCR5, respectively. When a V1-Delta5 deletion or V3-A316T was incorporated into subtype A, each increased viral fusion and spread several fold in peripheral blood mononuclear cell and cell lines with low CCR5 expression. Structural modeling suggested the formation of an additional hydrogen bond between V3 and CCR5. Moreover, we found preferential selection of HIV with 316T and/or extremely short V1-V2 loops in cervices of three women infected with subtypes A/C, B or C. CONCLUSION: As CD4-CCR5-T cells are key targets for genital HIV infection and cervical selection can favor compact V1-V2 loops and 316T, which increase viral infectivity, we propose that these conserved subtype-C motifs may contribute to transmission and spread of this subtype.

[Kawasaki syndrome in adults]. / Kawasakis syndrom hos voksne.

Kawasaki syndrome (KS), which is febrile systemic vasculitis complicated by coronary aneurysms, was initially described in children, but an increasing number of case-reports address adult-KS. The disease seems to be infectious of origin, but the causative agent has not been established. The debut of the disease is abrupt onset of high fever, followed by conjunctivitis, lymphadenopathy, rash, oral mucosal erythema and erythema of palms and soles. The diagnosis of KS is based on the presence of fever of at least four-five days' duration, plus four of the remaining criteria.