[Post-exposure prophylaxis against HIV].
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Biomedical subjects
Publications and source records attributed to Peter Skinhøj.
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Since November 2002 an epidemic of a new severe respiratory infection has taken place primarily in South-East Asia. Severe Acute Respiratory Syndrome (SARS) is assumed caused by a recently identified corona virus, which seems to be a new pathogen in the human population. The infection is assumed transferred primarily with droplets and is highly contagious within healthcare settings and families. Respiratory and barrier precautions are necessary to contain the virus, as it is contact tracing.
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The relationship among CCR5 genotype, cytomegalovirus infection, and disease progression and death was studied among 159 human immunodeficiency virus (HIV)-infected patients with hemophilia. One patient (0.6%) had the CCR5Delta32/CCR5Delta32 genotype (which occurs in approximately 2% of the Scandinavian population) and a rapid disease course. His HIV V3 region contained genotypic features attributable to X4 virus and resembled functionally verified X4 virus and virus from patients treated with a CD4 cell-stimulating drug, tucaresol. Age-related differences in disease progression rate and survival time were seen for CCR5/CCR5 patients. Surprisingly, no protective effect of the CCR5/CCR5Delta32 genotype on disease progression or survival was seen for children but was evident for adults. Age group-related immunologic differences might explain this variation, and transmission route and/or viral phenotype variation within donor virus may be related to the limited protection of the CCR5Delta32/CCR5Delta32 genotype. Sequence comparisons indicate that X4 virus can be selected in vivo due to either absence of CCR5 receptors or relative increase of CXCR4 receptors.
The incidence and sequelae of chronic hepatitis B (HBV) infection appear to have been overestimated previously, especially in areas outside Asia where neonatal infection predominates. A high rate of spontaneous HBeAg seroconversion is found in children as well as adults, and 40 to 50 y of replicative infection seems to be the most important risk factor for cirrhosis and hepatocellular carcinoma necessitating a cautious attitude towards antiviral treatment. Of concern, however, HBeAg seroconversion, which usually predicts a good outcome, is not always an irreversible event. Low grade replication of HBV may continue in anti-HBe positive individuals and shift in HBe status does occur in up to 10% of viral carriers with evidence of an increased risk of complications. Viral replication (HBV DNA positivity) is also found in HBeAg negative mutant infection and is an important parameter to note. To date, the data do not suggest any different prognosis for patients with this kind of infection. Also the various viral genotypes might have different prognoses partly due to the association with precore mutations, but the present knowledge does not allow different therapeutic management as in the case of hepatitis C. Treatment is available with a number of safe antiviral agents. However, all of them are mainly suppressive with low cure rates after 1 y. Initiation of therapy should therefore mainly be considered in symptomatic chronic infection and in cases with high risk of complications i.e. patients with ongoing viral replication and age above 40 y or bridging necroses verified by liver biopsy.
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The natural resistance-associated macrophage protein 1 (NRAMP1) is implicated in the pathophysiology of mycobacterial infections. We investigated by polymerase chain reaction previously published Nramp1 genotypes at 4 loci-INT4, N543D, 3'UTR, and 5'(CA)(n) microsatellite markers-in 104 human immunodeficiency virus-negative patients with tuberculosis and 176 healthy control subjects living in Denmark. No significant difference in genotype frequency was found between white patients with tuberculosis and control subjects (P>.16), but carriage of Nramp1 variant alleles at loci INT4 and 5'(CA)(n) conferred a significantly increased risk of having microscopy-positive compared with microscopy-negative tuberculosis (65% vs. 35% [P=.0004] and 63% vs. 38% [P=.047], respectively). The Nramp1 alleles were not associated with increased risk for the development of cavities seen on chest radiographs, or with extrapulmonary tuberculosis. These results indicate that variant alleles in the Nramp1 gene are associated with increased mycobacterial replication rather than susceptibility for tuberculosis and may thus confer increased risk of severe disease.
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Invasive pneumococcal disease is a serious infection that primarily affects very young children and elderly or immunocompromised individuals but also affects previously healthy people. Variant mannose-binding lectin (MBL) alleles are associated with recurrent infections and may be a risk factor for pneumococcal infections. To assess the influence of MBL genotypes on the course and outcome of invasive pneumococcal disease, clinical data for 141 adult patients were collected prospectively and their genotypes were determined. All patients included had positive blood cultures for Streptococcus pneumoniae. The distribution of variant MBL alleles related to low MBL serum concentrations was similar among the patients and healthy individuals, and MBL genotype was not associated with infection outcome. Thus, in a random adult population with invasive pneumococcal infection, MBL does not seem to play a role in the pathophysiology, in contrast to earlier observations in patients with other concomitant immune abnormalities.
BACKGROUND: Staphylococcus aureus bacteremia is still a serious problem, and the optimal treatment is under debate. Only a few studies concerning treatment are available. METHODS: The study population was all patients with a positive blood culture result for S aureus in Copenhagen County, Denmark, from May 1994 through April 1996. Of 278 patients with S aureus bacteremia, 186 were evaluated according to outcome in a prospective, observational follow-up study. The time above the minimum inhibitory concentration was estimated for dicloxacillin sodium for each treatment regimen and evaluated by logistic regression along with other potential risk factors. RESULTS: The following variables were statistically associated with death: the presence of an uneradicated focus (odds ratio [OR], 6.7; 95% confidence interval [CI], 2.1-21.0); the presence of septic shock (OR, 3.7; 95% CI, 1.5-9.1); the total daily dose of penicillinase-stable penicillin less than 4 g (OR, 3.7; 95% CI, 1.3-11.1); and age 60 years or older (OR, 2.4; 95% CI, 1.1-5.3). The following variables were significantly associated with recurrence: the total daily dose of penicillinase-stable penicillin less than 3 g (OR, 3.9; 95% CI, 1.6-10.0) and the presence of a secondary focus (OR, 3.2; 95% CI, 1.3-7.7). Among 155 patients with observation time longer than duration of treatment, this factor (duration of treatment, <14 days) was significantly related to mortality (OR, 0.84; 95% CI, 0.76-0.94). CONCLUSIONS: Focus eradication and the dosing of penicillinase-stable penicillin are important to the outcome of S aureus bacteremia. We recommend treatment with at least 1 g of penicillinase-stable penicillins 4 times daily for longer than 14 days.
In order to assess the present epidemiology, clinical presentation and outcome of patients with tuberculous meningitis (Tm), a retrospective study was conducted including 20 Tm patients admitted to a referral department in Denmark between January 1988 and July 2000. The findings were compared to those of a similar survey conducted 12 y earlier. A total of 65% of the patients came from countries with a high endemicity of tuberculosis, compared to only 26% in the previous survey. The overall mortality rate was 20%, with elderly patients with various pre-existing diseases being particularly affected. Neurological sequelae were seen in 50% of patients and seemed to be related to the duration of symptoms and treatment delay. The neurological state on admission and a rapid progression of symptoms seemed to be related to mortality. In 85% of the patients treatment was initiated without a definitive bacteriological diagnosis having been reached. The findings indicate that Tm is a rare but still serious disease, and one that is associated with high mortality and morbidity.
The proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), has been suggested to mediate septic encephalopathy through an effect on cerebral blood flow (CBF) and metabolism. The effect of an intravenous bolus of endotoxin on global CBF, metabolism, and net flux of cytokines and catecholamines was investigated in eight healthy young volunteers. Cerebral blood flow was measured by the Kety-Schmidt technique at baseline (during normocapnia and voluntary hyperventilation for calculation of subject-specific cerebrovascular CO reactivity), and 90 minutes after an intravenous bolus of a reference endotoxin. Arterial TNF-alpha peaked at 90 minutes, coinciding with a peak in subjective symptoms. At this time, CBF and Paco were significantly reduced compared to baseline; the CBF decrease was readily explained by hypocapnia. The cerebral metabolic rate of oxygen remained unchanged, and the net cerebral flux of TNF-alpha, interleukin (IL)-1beta, and IL-6 did not differ significantly from zero. Thus, high circulating levels of TNF-alpha during human endotoxemia do not induce a direct reduction in cerebral oxidative metabolism.
Streptococcus pneumoniae infections are associated with considerable morbidity and mortality throughout the world. The immunopathology is characterized by an intense inflammatory reaction, including a strong acute-phase response and increased numbers of neutrophils in the circulation. However, little is known regarding the T-cell response during in vivo infections in humans. The purpose of this study was to test the hypothesis that activated T cells producing type 1 cytokines were engaged in the host response to pneumococcal infections. The phenotype and function of T cells were studied in 22 patients at admission to a department of infectious diseases and after antibiotic treatment for 1 week compared with an age-matched, healthy control group. Pneumococcal infections induced lymphopenia in the circulation due to the disappearance of activated T lymphocytes with a type 1 cytokine profile. In contrast, the numbers of naive T cells and interleukin-4-producing T cells did not change. Activated type 1 cytokine-producing cells reappeared in the circulation in relation to the treatment and clinical improvement. The underlying mechanisms during infection may include sequestration in the peripheral tissues and/or apoptosis. In fact, increased activation-induced apoptosis in the remaining peripheral lymphocytes and elevated levels of soluble Fas ligand were detected at admission to the hospital. In conclusion, these data suggest that activated T lymphocytes with a type 1 cytokine profile are highly engaged in the in vivo immune response to S. pneumoniae.
OBJECTIVE: To investigate the changes in epidemiology of Staphylococcus aureus (SA) bacteremia in Denmark over a 30-year period, where the population has remained stable. METHODS: Bacteriologic and clinical data were generated on 17 712 SA strains from virtually all SA bacteremia cases in Denmark from 1957 to 1990 submitted to our laboratory for phage typing. The data were related to information about population, hospital activity and blood-culturing activity during that period. RESULTS: SA bacteremia cases increased from 3 to 20/100 000 inhabitants per year, with the largest increases in incidence rates for the <1-year and >50-year age groups. While blood-culturing activity increased three-fold during the period, the rate of SA bacteremias actually decreased relative to the number of blood cultures taken. The increase in SA bacteremia cases was mainly due to increases in nosocomial infections for all age groups and was related to the increasing admission rates to Danish hospitals. Major shifts in antibiotic resistance patterns and phage types took place during the period, i.e. a marked reduction in multiresistant (including methicillin-resistant) strains, but could not explain the change in the epidemiology of the infections. CONCLUSIONS: The data indicate that increases in SA bacteremia rates correlated significantly with increasing numbers of admissions to hospitals. The main increase in SA bacteremia rates was represented by nosocomial infection, although increasing blood-culturing activity during the period may have contributed.