Bent Faber Vestergaard

Cytokines, autoantibodies and viral antibodies in premorbid and postdiagnostic sera from patients with rheumatoid arthritis: case–control study nested in a cohort of Norwegian blood donors

Objective: To assess the timing of changes in cytokines, cytokine-related markers, autoantibodies and viral antibodies in the pathogenesis of rheumatoid arthritis (RA). Methods: Case–control study nested in a prospective cohort of 31 330 blood donors in Oslo, Norway. Forty-nine donors developed RA up to 23 years after their most recent blood donation. Stored sera from these donors (case sera) and a sex- and age-matched sample of 245 healthy donors (control sera), and postdiagnostic sera from 33 of the 49 RA cases, were analysed for a panel of cytokines and cytokine-related markers, autoantibodies and antibodies against Epstein–Barr virus and parvovirus B19. Results: Cytokines and cytokine-related markers were generally negative in case sera from >5 years before the diagnosis of RA. In the 5-year interval immediately before the diagnosis of RA, more case than control sera were positive (odds ratios >2) for interleukin (IL)-1α, IL-1β, IL-1 receptor antagonist, IL-4, IL-10, tumour necrosis factor-α and soluble tumour necrosis factor receptor I. In postdiagnostic sera, however, 11 of 16 examined cytokines and cytokine-related markers were statistically significantly elevated compared with control sera. Seropositivity for IgG antibodies against cyclic citrullinated peptides and for IgM and IgA rheumatoid factors were seen in case sera from up to 18 years before the diagnosis of RA. IgG antibodies against Epstein–Barr virus and parvovirus B19 did not differ significantly between case and control sera. Conclusions: Cytokines and cytokine-related markers appear to be upregulated rather late in RA pathogenesis. In contrast, IgM rheumatoid factor and IgG anti-cyclic citrullinated peptide autoantibodies may precede the diagnosis of RA by up to two decades.

An epidemic of parvovirus B19 in a population of 3596 pregnant women: a study of sociodemographic and medical risk factors

Objectives To estimate the incidence of human parvovirus B19 among pregnant women before and during an epidemic, to elucidate possible sociodemographic and medical risk factors during pregnancy and to estimate the association between parvovirus B19 infection and negative pregnancy outcome.

Oral candidiasis and hairy leukoplakia correlate with HIV infection in Tanzania

We report a detailed study on oral lesions and their association with the WHO revised provisional case definition of AIDS as well as serologic signs of HIV infection among 186 patients in Dar Es Salaam, Tanzania. The patient material consisted of 39 hospitalized suspected AIDS patients, 44 medical nonsuspected patients, 53 dental outpatients, and 50 patients with sexually transmitted diseases. The male:female ratio was 2.1:1 on average. Oral examination was done without knowledge of the HIV status of the patients. Among 39 suspected AIDS patients 97% had WHO AIDS criteria and 90% were seropositive for HIV. Among the 147 patients not suspected of having AIDS 18 (12%) had AIDS criteria and 15% had serologic evidence of HIV infection. The presence of WHO AIDS criteria correlated significantly with the presence of HIV antibodies, but not with HIV antigen. Oral lesions were found in 54% of those with AIDS criteria and 52% of HIV-infected patients, as compared to 3% and 6% of the patients without AIDS criteria and HIV infection, respectively (p less than 0.01). Among patients with AIDS atrophic candidiasis occurred in 21%, pseudomembranous candidiasis in 23%, hairy leukoplakia in 36%, herpetic stomatitis in 2%, Kaposis sarcoma in 4%, and nonspecific ulcer in 4%. The presence of oral lesions had a high predictive value for presence of AIDS criteria as well as for presence of HIV infection in this hospital setting. All patients should have a thorough oral examination and the presence of the aforementioned oral lesions should lead to testing for HIV infection.

Assessment of the specificity of a commercial human parvovirus B19 IgM assay

BACKGROUND It is important to investigate a possible cross-reaction of anti-rubella IgM in the IDEIA Parvovirus B19 IgM test because many B19 infections are either asymptomatic or have clinical symptoms similar to those of rubella virus infections. Epstein-Barr virus (EBV) IgM, cytomegalovirus (CMV) IgM, measles IgM and rheumatoid factor (RF) IgM cross-reactions were also studied. OBJECTIVES In the period from February to September 1994 (including a parvovirus B19 epidemic) more than 10,000 serum samples were examined for parvovirus B19 IgM in Denmark. This gave an opportunity to evaluate the commercial IDEIA Parvovirus B19 ELISA kit (DAKO A/S, Glostrup, Denmark), which was used routinely at Statens Serum Institut from the beginning of 1994 and onwards. STUDY DESIGN A total of 123 parvovirus B19 IgM positive sera were tested for reactivity in rubella IgM EIA. A total of 78 rubella IgM positive sera, 60 EBV VCA-IgM positive sera, 30 CMV IgM positive sera and 24 measles virus IgM positive sera were tested for reaction in IDEIA Parvovirus B19 IgM test. Finally, 25 parvovirus IgM positive sera were tested for specific IgM against measles virus, EBV (VCA), CMV and for RF. RESULTS One anti-B19 IgM positive serum sample reacted positively in the rubella IgM test. Of rubella IgM positive serum samples 4% cross-reacted in IDEIA Parvovirus B19 IgM test, as did 17 and 20% of EBV VCA-IgM and CMV IgM positive serum samples respectively. None of measles virus IgM positive serum samples cross-reacted in the IDEIA Parvovirus B19 IgM test. Of 25 initially parvovirus B19 IgM positive sera 20% cross-reacted in EBV VCA IgM test and 8% in the CMV IgM test. None reacted positively in measles virus IgM test; 28% showed weak reactivity in RF IgM test. CONCLUSIONS Precautions must be taken when results of IgM assays are interpreted. Epidemiological and clinical observations must be considered.

Herpes simplex virus type 2 infections of the central nervous system: A retrospective study of 49 patients

Herpes simplex virus type 2 (HSV-2) infections of the central nervous system (CNS) are rare with meningitis as the most common clinical presentation. We have investigated the clinical spectrum of CNS infections in 49 adult consecutive patients with HSV-2 genome in the cerebrospinal fluid (CSF). HSV-2 in the CSF was determined by polymerase chain reaction (PCR), and patients were diagnosed as encephalitis or meningitis according to predefined clinical criteria by retrospective data information from consecutive clinical journals. The annual crude incidence rate of HSV-2 CNS disease was 0.26 per 100,000. 43 (88%) had meningitis of whom 8 (19%) had recurring lymphocytic meningitis. Six patients (12%) had encephalitis. 11 of 49 patients (22%) had sequelae recorded during follow-up. None died as a result of HSV-2 CNS disease. Thus, the clinical presentation of HSV-2 infection of the CNS is mainly meningitis but encephalitis does occur and neurological sequelae are common. Recurring lymphocytic meningitis is associated with reactivation of HSV-2 and the condition might be underdiagnosed.Herpes simplex virus type 2 (HSV-2) infections of the central nervous system (CNS) are rare with meningitis as the most common clinical presentation. We have investigated the clinical spectrum of CNS infections in 49 adult consecutive patients with HSV-2 genome in the cerebrospinal fluid (CSF). HSV-2 in the CSF was determined by polymerase chain reaction (PCR), and patients were diagnosed as encephalitis or meningitis according to predefined clinical criteria by retrospective data information from consecutive clinical journals. The annual crude incidence rate of HSV-2 CNS disease was 0.26 per 100,000. 43 (88%) had meningitis of whom 8 (19%) had recurring lymphocytic meningitis. Six patients (12%) had encephalitis. 11 of 49 patients (22%) had sequelae recorded during follow-up. None died as a result of HSV-2 CNS disease. Thus, the clinical presentation of HSV-2 infection of the CNS is mainly meningitis but encephalitis does occur and neurological sequelae are common. Recurring lymphocytic meningitis is associated with reactivation of HSV-2 and the condition might be underdiagnosed.

Routine diagnosis of herpes simplex virus (HSV) encephalitis by an internal DNA controlled HSV PCR and an IgG-capture assay for intrathecal synthesis of HSV antibodies

BACKGROUND The development of antiviral therapy increases the need for rapid, sensitive and reliable methods or combination of methods for diagnosis and monitoring herpes simplex encephalitis, HSE. OBJECTIVES Evaluation of diagnostic performance of three successively developed HSV PCR assays when combined with a new capture ELISA for HSV intrathecal antibody production (ITT). STUDY DESIGN During a 3.6 year period a total of 4.206 CSF and serum samples from about 4.140 hospitalized patients with a tentative diagnosis of HSE were analyzed by a new ELISA for ITT. 1.962 CSF samples were examined also by PCR. Clinical signs and symptoms and additional tests were obtained on all ITT and/or PCR positive patients. In 1993 the PCR was a double PCR. In 1994 the PCR was a single PCR with internal inhibition control. Positive samples were confirmed by a different confirmative PCR to increase the specificity. From 1995 the PCR was as in 1994 but samples were no longer divided in the serology routine laboratory. RESULTS A total of 33 HSE cases was found (incidence 1.8 HSE per million people). All patients were treated with aciclovir. Three patients died, 9 patients had primary infection, 2 patients had HSE previously, and 2 patients relapsed. Only 11 patients recovered satisfactory. Of all 37 positive ITT 7 were unlikely positive. False positive PCR was seen in 1993 and 1994, due to sample-to-sample contamination during division of samples, but was not seen since 1995 when this procedure was changed. The test results depended on the state of the disease. Thus, the sensitivity, specificity, PPV and NPV for ITT were highest when performed more than 1 week after debut of symptoms whereas these values were highest using PCR within the first week. CONCLUSION Routine PCR diagnosis of HSE type 1 and 2 is a highly sensitive and specific method that should be performed together with serological ITT to cover the whole time span from debut of symptoms to several weeks after hospitalization.

Varicella zoster in Guinea-Bissau: intensity of exposure and severity of infection

Objective: To describe the epidemiology of and risk factors for severe chickenpox in Guinea- Bissau. Methods: A prospective household study in a semiurban area of the capital. Severity was assessed by number of pox, fever response and presence of pneumonia. Severity was compared for the first case in a house, that is, the index case, and the secondary cases infected at home. Result: We identified 1539 cases of chickenpox. The median age was lower for boys and secondary cases (both P < 0.03); 44.6% of children were 1–4 years of age. The likely minimum interval between index and secondary cases was 10 days; most secondary cases occurred 14–17 days after the index case. The length of the incubation period was related to the intensity of exposure (P < 0.01). The number of pox was higher for secondary cases (P < 0.01) and was related to intensity of exposure (P < 0.01). Secondary cases had higher fever and more frequently pneumonia (relative risk, 2.17; 95% confidence interval, 1.54–3.08). Children with pneumonia were younger and had more pox. Nutritional status was not related to severity. Conclusions: Age and intensity of exposure are important determinants for severity of chickenpox infection. The length of the incubation period depends on intensity of exposure, suggesting that the dose of infection might be important.

Inhibition of human immunodeficiency virus 1 (HIV-1) and herpes simplex virus 1 (HSV-1) infectivity with a broad range of lectins

Five lectins with specificity for N- and O-linked oligosaccharides were examined for inhibition of HIV-1 and HSV-1 infectivity in vitro. HIV-1 isolate HTLVIIIB was preincubated with lectin and subsequently inoculated onto MT-4 cells. Lectins specific for N-linked oligosaccharides blocked HIV infection in nanomolar-micromolar concentrations, but no anti-HIV effect was found with the lectin HPA, mainly reacting with O-linked oligosaccharides. HSV-1 infectivity was measured in a plaque reduction assay using Vero cells, and while both N- and O-linked oligosaccharide -specific lectins inhibited HSV-1 infection, the most potent inhibition was found with the lectin HPA. These results indicate that lectins may have a broad antiviral effect on enveloped viruses only limited by types of oligosaccharides present on individual viruses.

Competitive ELISA for detection of HHV-6 antibody: seroprevalence in a Danish population

A competitive HHV-6 enzyme-linked immunosorbent assay (ELISA) was established, utilizing HHV-6 rabbit polyclonal antibodies and HHV-6 cellular antigen. In total, 285 sera from Danish children aged 1-6 years were screened for HHV-6 antibodies. The lowest seropositive rate, 78% was found in the youngest age group from 1 year to 15 months. All 120 (100%) children aged 3 years and above were seropositive. The ELISA was compared with indirect immunofluorescence assay (IFA) using a group of 83 serum samples from 65 Danish patients (aged 4 weeks to 72 years). All but one of the sera (100% of patients) were positive in the ELISA, but only 71% of sera (65% of patients) were positive with both assays. The ELISA detected one seroconversion in a baby, which was not detected by IFA. The ELISA was found to be more sensitive than IFA.

Abnormal Papanicolaou Smear: A Population-based Study of Risk Factors in Greenlandic and Danish Women

Possible risk factors for abnormal Papanicolaou smear were investigated in a population‐based cross‐sectional study. From Nuuk (Greenland) and Nykebing Falster (Denmark), random samples of 800 women aged 20–39 years were drawn. Totals of 586 and 661 women were included in Greenland and Denmark, respectively. All women went through a personal interview, and had a gynecologic examination including a PAP smear and cervical swab for HPV analysis. A blood sample was taken for analysis of HSV type specific antibodies. Multiple sexual partners was the most important risk factor for abnormal cervical cytology (OR = 4.2). An infectious etiology was also indirectly supported by a relatively protective effect of barrier contraceptive methods (OR = 0.6). The simultaneous finding of HPV 16/18 as a significant risk factor (OR = 2.4) cannot be taken uncritically as support for a causal effect of this HPV type, since such a relationship between cytological changes of the cervix and HPV infection could also emerge if the positive PAP smear was not just a measure of intra‐epithelial neoplasia but also an expression of the infection itself on the cervix.