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A sustained viral response (SVR) after interferon-based therapy of chronic hepatitis C virus (HCV) infection is regarded to represent a cure. Previous studies have used different markers to clarify whether an SVR truly represents a cure, but no study has combined a clinical work-up with highly sensitive HCV RNA detection, and the determination of immune responses.To determine clinical, histological, virological and immunological markers 5-20 years after SVR.In 54 patients, liver biochemistry, histology and elastography were evaluated. Liver biopsies, plasma and peripheral blood mononuclear cells (PBMCs) were tested for minute amounts of HCV RNA. HCV-specific T-cell responses were monitored by ELISpot and pentamer staining, and humoral responses by measuring HCV nonstructural (NS)3-specific antibodies and virus neutralisation.Liver disease regressed significantly in all patients, and 51 were HCV RNA-negative in all tissues tested. There was an inverse association between liver disease, HCV-specific T-cell responses and HCV antibody levels with time from SVR, supporting that the virus had been cleared. The three patients, who all lacked signs of liver disease, had HCV RNA in PBMCs 5-9 years after SVR. All three had HCV-specific T cells and NS3 antibodies, but no cross-neutralising antibodies.Our combined data confirm that a SVR corresponds to a long-term clinical cure. The waning immune responses support the disappearance of the antigenic stimulus. Transient HCV RNA traces may be detected in some patients up to 9 years after SVR, but no marker associates this with an increased risk for liver disease.

The presence of autoantibodies against C-reactive protein (anti-CRP) has been reported in association with autoimmunity and histopathology in chronic hepatitis C virus (HCV) infection. Resistin could play a role in the pathogenesis of hepatitis, although results on HCV infection are ambiguous. Here we retrospectively analyzed anti-CRP and resistin levels in the sera of 38 untreated and well-characterized HCV patients at the time of their first liver biopsy. HCV activity and general health were assessed by a physician at least yearly until follow-up ended. Anti-CRP and resistin were also measured in patients with autoimmune hepatitis (AIH) and nonalcoholic fatty liver disease (NAFLD). Anti-CRP antibodies were registered in all HCV patients, whereas only a few AIH (11%) and NAFLD (12%) sera were positive. Anti-CRP levels were related to histopathological severity and were highest in patients with cirrhosis at baseline. Resistin levels were similar in HCV, AIH, and NAFLD patients, but high levels of resistin were associated with early mortality in HCV patients. Neither anti-CRP nor resistin predicted a response to interferon-based therapy or cirrhosis development or was associated with liver-related mortality. We conclude that anti-CRP antibodies are frequently observed in chronic HCV infection and could be a useful marker of advanced fibrosis and portal inflammation. Funding Agencies|Swedish Society for Medical Research||Professor Nanna Svartz Foundation||King Gustaf V 80-Year Foundation||Sweden-America Foundation||County Council of Ostergotland||Clas Groschinsky||byggmastare Olle Engkvist||apotekare Hedberg

We successfully re-vaccinated hepatitis B virus (HBV) vaccine non-responders using a double dose of the combined hepatitis A virus (HAV) and HBV vaccine. The hope was to improve priming of hepatitis B surface antigen (HBsAg)-specific cell mediated immune response (CMI) by an increased antigen dose and a theoretical adjuvant-effect from the local presence of a HAV-specific CMI. A few non-responders had a detectable HBsAg-specific CMI before re-vaccination. An in vitro detectable HBsAg-specific CMI was primed equally effective in non-responders (58%) as in first time vaccine recipients (68%). After the third dose a weak, albeit significant, association was observed between the magnitude of HBsAg-specific proliferation and anti-HBs levels. This regimen improves the priming of HBsAg-specific CMIs and antibodies.

Hepatitis B virus causes liver disease and up to 2 billion people have been in contact with the virus world wide. It can cause both acute and chronic disease. The routes for transmission are through blood, mother to infant at time of delivery and sexually. Chronic hepatitis B infection is a risk factor for development of liver cirrhosis and hepatocellular carcinoma. Prevention of hepatitis B virus infection is highly desirable. Since the early1980s hepatitis B vaccine has been available. It can effectively prevent the disease and has been found to be safe. The World Health Organisation, WHO, has recommended all countries to implement the vaccine in their children’s vaccination programmes and many countries have followed this recommendation. In Sweden so far the recommendation is vaccination of identified risk groups for hepatitis B. Health care workers who are at risk of having blood contact in their work is one such risk group. In a large study on health care workers who were intradermally vaccinated with the hepatitis B vaccine, 960/1406 (68.3%) developed protective levels of antibodies to HBsAg (anti-HBs; defined as >10 mIU/mL) after three doses. After administering of an additional fourth dose to non-responders the response rate was 1187/1335 (88.9%). Risk factors for non-response were smoking and age above 40 years. Also, the vaccine response rates improved during the study and a risk of giving a too small dose with intradermal administration was also identified. This suggests that intradermal administration is dependent on well trained personnel. A genetic factor which has been proposed to be associated with a non-responder status to HBV vaccination is the HLA haplotype of the host. In a study in on 69 responders and 53 non-responders the haplotypes were therefore determined. It was found that [DQB1*0602; DQA1*0102; DR15] and [DQB1*0603; DQA1*0103; DRB1*1301] were more likely to be found in responders (p

A total of 172 Swedish patients treated with interferon-alpha for at least 24 weeks and followed-upor =24 weeks after treatment was stopped were analysed for pre-treatment factors of importance for achieving a virological sustained response (SR). Furthermore, the predictive value for a virological SR of a positive or negative HCV RNA test at week 12 of treatment was evaluated. A low baseline viral load and genotype non-1b were pre-treatment factors indicating a favourable response. Thus, 44% (38/86) of patients with a low baseline viral load vs. only 16% (14/86) of those with a high viral load had a virological SR (p0.0001). Of patients with a negative qualitative HCV RNA test after 12 weeks of interferon treatment, 46% (44/95) had virological SR, whereas only 5.9% (4/68) of those with a positive test had (p0.0001). Prolonged (6 months) treatment with interferon-alpha tended to increase the chance of virological SR (p0.052).

Health care workers at risk for hepatitis B virus infection are recommended for vaccination. Low-dose intradermal (i.d.) administration of vaccine has been suggested as a less expensive alternative to intramuscular (i.m.) inoculation. To evaluate the i.d. vaccination route, health care workers were included in a prospective study. The subjects were vaccinated with 0.1 ml (= 2 microg) recombinant vaccine (Engerix B, SmithKline Beecham) i.d. at 0, 1 and 6 months. Two months after the third vaccination, measurement of the anti-HBs level was conducted. An anti-HBs level > or =10 IU/l was considered protective. Those with an anti-HBs level

Sera from 62 hepatitis C virus (HCV)-infected Swedish blood donors were tested by a nested polymerase chain reaction using primers targeting the 5'-noncoding region of the GB virus-C/hepatitis G (GBV-C/HGV) genome and an enzyme-linked immunosorbent assay that detects antibodies to the envelope protein E2 of GBV-C/HGV (anti-E2). Fourteen (22%) and 21 (34%) of the 62 blood donors were found to be GBV-C/HGV RNA and anti-E2 positive, respectively. None of the blood donors was positive for both GBV-C/HGV RNA and anti-E2. Thus, 35 of 62 (56%) HCV-infected donors had been exposed to GBV-C/HGV infection. At sequencing of the 14 GBV-C/HGV isolates, 12 were identified as subtype 2a and 2 as subtype 2b. One of 7 (14%) donors with mild liver disease such as steatosis and nonspecific reactive hepatitis had been exposed to GBV-C/HGV vs. 34 of 55 (62%) with chronic hepatitis with or without cirrhosis (P = 0.04). All other differences in histology were small between HCV and dual HCV GBV-C/HGV-infected donors. In conclusion, more than half of HCV-infected Swedish blood donors in this study were positive for either GBV-C/HGV RNA or anti-E2. GBV-C/HGV viremia and seropositivity were mutually exclusive.

Summary Background Pilot studies suggested that more patients with chronic hepatitis C virus (HCV) infection had a sustained virological response when treated with the combination of interferon α-2b and ribavirin than with interferon α-2b alone. We investigated the biochemical and virological responses and safety of treatment with interferon α-2b and ribavirin compared with interferon α-2b alone. Methods In this double-blind trial 100 patients were randomly assigned to treatment with interferon α-2b (3 MU three times a week) in combination with ribavirin (1000 or 1200 mg per day) or placebo for 24 weeks and then followed up for a further 24 weeks. A further follow-up was done 1 year after active treatment stopped. The primary endpoint was the sustained virological response, defined as no detectable HCV RNA by PCR at both week 24 and week 48. Retrospectively, the baseline HCV-RNA load was analysed as a predictor of a sustained virological response. Data were analysed by intention to treat. Findings 18 (36%) of the 50 patients in the interferon α-2b and ribavirin group had a sustained virological response compared with nine (18%) of the 50 patients in the interferon α-2b and placebo group (p=0·047). At the 1 year follow-up the proportion of patients with a virological response was greater in the interferon α-2b and ribavirin group than the interferon α-2b and placebo group (42 vs 20%, p=0·03), respectively. More patients with baseline HCV-RNA concentrations greater than 3×10 6 genome equivalents (Eq) per ml had a sustained response with interferon α-2b and ribavirin than with interferon α-2b and placebo (12/29 vs 1/26, p=0·009), whereas the sustained response did not differ between the two treatment groups for HCV-RNA amounts less than 3×10 6 Eq per ml (6/21 vs 8/24, p=0·67), respectively. Interpretation More patients with chronic hepatitis C have a sustained virological response with interferon α-2b and ribavirin than with only interferon α-2b treatment. We suggest that patients with high HCV-RNA loads should be treated with interferon α-2b and ribavirin.

Fourteen patients with chronic hepatitis C who had a sustained response to a 60-week interferon alfa-2b treatment course were followed, biochemically and virologically, 2 years after treatment cessation. Biopsies were repeated in 12 of 14 for histological and virological evaluation at 2-year follow-up. All 14 patients had normal serum alanine transaminase (s-ALT) levels and were negative for hepatitis C virus (HCV) RNA in serum during treatment and at short-term follow-up 6 months post-treatment. At 2-year follow-up, 13 patients still had normal ALT levels (

To evaluate the effect of prolonged interferon-α treatment on serum aminotransferase levels and hepatitis C virus RNA in serum, 40 patients with chronic hepatitis C virus infection were treated with 3 MU interferon-α2b thrice weekly for 60 wk. Before treatment all patients had elevated serum ALT levels for at least 1 yr, antibodies to HCV by second-generation tests and liver histological findings consistent with chronic hepatitis C. Before treatment hepatitis C virus RNA was found in serum in 39 of 40 (97.5) patients. Normalization of ALT levels at treatment cessation was seen in 24 of 40 (60) patients, of whom 15 of 24 (62.5) had sustained ALT responses up to 24 wk after treatment. At follow-up, 24 wk after treatment, hepatitis C virus RNA was cleared from serum in 17 of 40 (42.5) patients, including all sustained responders, one nonsustained responder and one nonresponder. We conclude that 60 wk of treatment with interferon-α2b seems to induce a high percentage of sustained response, which coincides with cessation of viral replication. (Hepatology 1994; 19:280–285).

Clinical course, serological response and effect of antibiotic treatment were evaluated in 34 patients with uncomplicated enterocolitis and in 27 patients with reactive arthritis (ReA) due to Yersinia enterocolitica. Patients participating in this prospective multicentre trial were randomised to treatment or no treatment with antibiotics. Only 3 (11%) of the patients who later developed ReA asked for medical care because of intestinal symptoms and fever and they all developed arthritis within 2 days after admission to hospital, i.e. before an etiological diagnosis was obtained. Patients with ReA had a history of milder intestinal symptoms than patients with uncomplicated enterocolitis. The peak IgA titer to Y. enterocolitica, as measured by enzyme linked immunosorbent assay, was higher in ReA patients and it was not affected by the presence of HLA-B27 antigen. On the other hand, untreated patients with uncomplicated enterocolitis had the longest duration of IgG antibodies. The duration of IgG antibody response was shortened in uncomplicated enterocolitis patients treated with antibiotics, but not in ReA patients. Treatment did not influence intestinal or ReA symptoms. It is concluded, that patients with uncomplicated enterocolitis due to Y. enterocolitica differ in intestinal symptoms and serological response, compared with patients who develop ReA. These parameters could however not be used to predict the development of arthritis in individual patients.

Staphylococcus aureus septicaemia is still a serious disease with a high mortality. The absence of leukocytosis in serious bacterial infections is generally considered as an unfavourable prognostic sign. The leukocyte pattern in 75 patients with S. aureus septicaemia was reviewed retrospectively. In the 66 patients where leukocyte determinations were done within 2 days of positive blood culture, 21 presented without leukocytosis which contrasts to only 1/35 patients with Escherichia coli septicaemia studied as controls (p less than 0.001). During follow up of S. aureus septicaemia only 5 of the patients developed leukocytosis greater than 10 x 10(9)/l and 2 leukopenia. There was no significant difference in mortality in patients without initial leukocytosis (14%) compared to patients with initial leukocytosis (24%). Except for septic arthritis, which was associated significantly more often with leukocytosis, complications were found with about the same frequency in both groups. Thus absence of leukocytosis seems not be an unfavourable prognostic sign in S. aureus septicaemia.

A recent nonrandomized pilot trial showed that hepatitis C virus (HCV) patients with genotype 2/3 and rapid virological response (RVR) had a 90% sustained virological response (SVR) rate after 14 weeks of treatment. We aimed to assess this concept in a randomized controlled trial. In the trial, 428 treatment-naive HCV RNA–positive patients with genotype 2 or 3 were enrolled. Patients with RVR were randomized to 14 (group A) or 24 (group B) weeks of treatment. Patients were treated with pegylated interferon α-2b (1.5 μg/kg) subcutaneously weekly and ribavirin (800-1400 mg) orally daily. The noninferiority margin was set to be 10% between the two groups with a one-sided 2.5% significance level. RVR was obtained in 302 of 428 (71%), and 298 of these were randomized to group A (n = 148) or group B (n = 150). In the intention-to-treat analysis, SVR rates were 120 of 148 (81.1%) in group A and 136 of 150 (90.7%) in group B (difference, 9.6%; 95% confidence interval, 1.7-17.7). Among patients with an HCV RNA test 24 weeks after the end of treatment, 120 of 139 (86.3%) patients in group A achieved SVR compared with 136 of 146 (93.2%) in group B (difference, 6.9%; 95% confidence interval, −0.1 to +13.9). Conclusion: We cannot formally claim that 14 weeks of treatment is noninferior to 24 weeks of treatment. However, the SVR rate after 14 weeks of treatment is high, and although longer treatment may give slightly better SVR, we believe economical savings and fewer side effects make it rational to treat patients with genotype 2 or 3 and RVR for only 14 weeks.

High serum levels of hepatocyte growth factor (HGF) may reflect the regenerative effect and enhanced local and systemic production of this cytokine after organ injuries. The possibility of using serial serum HGF values in order to predict the results of therapy for pneumonia was investigated in this study. In a prospective multicenter study we investigated the serum levels of HGF and CRP before and within 48 h after treatment in 70 patients with pneumonia. Serum levels of HGF before treatment were significantly higher than the HGF levels of a normal population (p < 0.0001). Within 48 h serum HGF levels had decreased significantly in those patients who ultimately responded to the initial antibiotic therapy (p < 0.0001). Serum HGF levels at 48 h were unchanged or increased in cases in whom the initial therapy was ineffective and had to be changed. CRP and HGF levels were significantly correlated. Using multivariate logistic regression analysis it was found that individual changes in acute serum HGF levels and serum HGF levels obtained within 48 h could predict the results of therapy at least as significantly (p < 0.003) as CRP (p = 0.05), although CRP levels were known and used by the physician to decide whether or not to change the initial therapy. We conclude that serial control of serum HGF levels can be used as an early indicator to predict the results of therapy during treatment of pneumonia.

Acute serum levels of hepatocyte growth factor (HGF) were studied in 6 clinical groups with (i) gastroenteritis, (ii) skin and soft tissue infection, (iii) urinary tract infection, (iv) septicemia, (v) influenza, and (vi) chronic hepatitis C in comparison with a normal control group using an enzyme-linked immunosorbent assay method. We found that serum HGF levels were significantly higher in patients with acute infectious diseases (p < 0.0001) compared to patients with chronic viral hepatitis and healthy controls. Serum HGF and CRP levels were correlated significantly (r = 0.65, p < 10-7). We conclude that serum HGF levels are elevated in patients with acute infectious diseases.

BACKGROUND/AIMS: Small, uncontrolled studies of ribavirin for patients with chronic hepatitis C have reported efficacy in chronic hepatitis C. We have evaluated the efficacy and safety of a 24-week course of oral ribavirin in patients with chronic hepatitis C, compared to placebo. METHODS: A total of 114 patients were randomised to ribavirin or placebo. Ribavirin was administered in doses of 1000 or 1200 mg/day for 24 weeks. Efficacy was determined in the intention-to-treat population: 76 received ribavirin and 38 placebo. RESULTS: Ribavirin was significantly more effective than placebo in reducing and normalising serum ALT levels: 42/76 (55%) of ribavirin-treated patients vs 2/38 (5%) placebo recipients had either normalisation of the ALT levels or a reduction from baseline of at least 50% (p < 0.001). ALT levels were normal in 22/76 (29%) of ribavirin-treated patients vs 0/38 placebo recipients (p < 0.001). Twenty-four weeks after stopping ribavirin, the majority of patients had abnormal ALT levels. There was no difference between the treatment groups in reduction or disappearance of HCV-RNA levels. HCV RNA disappeared during treatment in 3% of ribavirin-treated patients and 3% of placebo recipients. More ribavirin than placebo patients showed improvement in total Knodell score (45% vs 31%), but these differences were not statistically significant. Analysis of each component of a histology activity index revealed no statistically significant differences between treatment groups. Ribavirin patients had fewer lymphoid aggregates than did placebo recipients at the post-treatment assessment (p = 0.05). Ribavirin was associated with reversible haemolytic anaemia: a fall in haemoglobin occurred in 3% of placebo- and 32% (25/78) of ribavirin-treated patients, respectively (p < 0.001). CONCLUSIONS: These data indicate that ribavirin was no more effective than placebo in reducing or eliminating HCV-RNA levels, and was not significantly more effective than placebo in improving hepatic histology after 6 months of treatment. The role of a 6-month treatment of chronic hepatitis C with ribavirin alone, without a significant effect on HCV RNA, is therefore limited

Sixty-two anti-HCV and HCV-RNA positive Swedish blood donors (44 men, 18 women; median age 34 years) were studied. HCV genotypes were correlated to parenteral risk factors, liver morphology, serum alanine aminotransferase (ALAT) levels and HCV antibody profile. Forty percent of the donors were infected with HCV genotype 1a, 10% with 1b, 21% with 2b, and 29% with 3a. Intravenous drug use (IVDU) was more common in donors with genotype 3a than in those with genotype 1a (p = 0.024), and prior blood transfusion more common in genotype 2b than in 3a (p = 0.012). Chronic active hepatitis with and without cirrhosis was found in 38% of donors infected with genotype 2b as compared to 8% of donors infected with 1a (p = 0.034). Forty percent of donors with genotype 1a had normal ALAT at the time of liver biopsy versus 11% with genotype 3a (p = 0.046). Antibodies to C33c and C22-3 were present in nearly all donors whereas reactivity to C100-3 and 5-1-1 was detected more often in donors with genotypes 1a and 1b as compared to donors with genotypes 2b and 3a. In conclusion, genotype 3a was correlated to IVDU or tattooing as parenteral risk factors for the acquisition of HCV infection, and genotype 2b to prior blood transfusion. Donors with genotypes 1a seemed to have less severe liver disease than those infected with genotypes 2b and 3a.

Summary After travelling in subSaharan Africa, an area known for sporadic cases of Marburg virus infection, a young Swedish man presented with a classical picture of severe viral haemorrhagic fever complicated by disseminated intravascular coagulation and septicaemia. Serum samples examined by electron microscopy revealed particles of a size compatible with filovirions. Indirect fluorescent antibody tests indicated transient seroconversion to Marburg virus. In lymphocyte transformation assays of cells isolated from the patient 11 months after the onset of acute disease, Marburg viral antigen was able to stimulate lymphocyte proliferation 3.9-fold; however, exhaustive attempts to isolate virus from acute phase blood cultured in vitro or in vivo from guinea pigs and monkeys failed. Data suggest that this patient may have been infected with a filovirus. This case demonstrates the difficulties that may occur in laboratory diagnosis of viral haemorrhagic fevers.

Little is known about the long-term effects of Borrelia burgdorferi (Bb) infection in untreated patients with peripheral facial palsy. We investigated 12 patients with elevated serum Bb antibody levels, with a median follow-up time of 11 years, during which 3 of the 12 still exhibited intrathecal antibody production of antibodies against Bb flagellar antigen, and 2 of the 3 had normal serum Bb antibodies. Four of the 12 had elevated serum antibody titres at the late follow-up examination. Arthralgia, reported by 7 patients, was the single most common complaint. Four patients showed extensive oculomotor disturbances, which were not correlated to antibody titres or intrathecal antibody synthesis. In 1 of the patients with intrathecal Bb antibody production, most symptoms were eradicated by antibiotic treatment 6 years after the initial infection. We conclude that even several years after a Bb infection, intrathecal Bb antibody production can still occur in serum Bb IgG antibody negative patients with a history of facial palsy.

Introduction: The causes for peripheral facial palsy remain obscure in many patients. Evidence exists suggesting viruses, especially those belonging to the herpesvirus group, may be causative. This study was developed to evaluate this theory. Methods: One hundred forty-seven patients with acute peripheral facial palsy of primarily unknown origin were studied. All were examined within 1 week of onset. Subsequent follow-up was undertaken until the palsy had recovered or become static. Paried cerebral spinal fluid and serum samples were obtained for serological evaluation to detect herpes simplex, varicella zoster, cytomegalovirus, measles, mumps, rubella, tick-borne encephalitis, adenovirus, Epstein-Barr virus, and human immunodeficiency virus, as well as the antibodies to Borrelia burgdorferi . Results: Elevated antibiotic titers to Borrelia burgdorferi were observed in 11% of patients, whereas 9% of patients demonstrated elevated viral titers. Antibody pattern consistent with Epstein-Barr virus reactivation was present in 13%. A total of 67% were classified as idiopathic. Conclusion: Patients with reactivated Epstein-Barr virus were characterized by having a higher incidence of auricular pain and displayed diabetes mellitus in a higher frequency than in other groups. In the Borrelia group, neck/back pain was more common. Healing was less favorable in the Borrelia group despite an equal rate of palsy at onset and adequate antibiotic treatment. Corticosteroid treatment used in 44% of the patients did not significantly improve the functional outcome.

Seventy-three Swedish blood donors (52 men, 21 women; median age 36 years) repeatedly reactive for hepatitis C antibodies (anti-HCV C-100-3) were tested with a second-generation (2nd-gen) anti-HCV Elisa and a 4-band recombinant immunoblot assay (RIBA 2). These results were correlated to serum alanine aminotransferase (S-ALAT), liver morphology and viremia as detected by 'nested' polymerase chain reaction (PCR) based on primers from a 5'-noncoding sequence of the HCV genome. Thirty-five of 46 (76%) donors with positive 2nd-gen Elisa tests confirmed by RIBA 2 were PCR positive whereof 27 had histological findings compatible with chronic persistent hepatitis (CPH) and 7 had chronic active hepatitis (CAH). Ten of 56 (18%) 2nd-gen Elisa-positive donors were RIBA 2 negative (or indeterminate) and none of these had chronic hepatitis nor were PCR positive. Seventeen of 73 (23%) donors were 1st-gen Elisa positive but 2nd-gen Elisa negative. All of these were PCR negative and only 1 (6%) had chronic hepatitis (CPH). An elevated S-ALAT level (reference < 0.7 mu kat/l) was found in 26 2nd-gen Elisa and RIBA 2-positive donors of which 18 had CPH and 7 had CAH and all 25 were PCR positive. A normal S-ALAT level was found in 9 of 34 (26%) donors with chronic hepatitis (all had CPH) and positive PCR. We have found that blood donors with positive 2nd-gen anti-HCV Elisa tests confirmed by RIBA-2 and especially with a concomitant elevated S-ALAT are highly likely to be viremic as demonstrated by PCR and to have chronic hepatitis.

Thirty-three patients with chronic hepatitis non-A, non-B/C were included in a randomized controlled study of recombinant alpha-2b interferon treatment 3 MU three times weekly for 36 weeks. In lysed whole blood, lymphocyte subpopulations were enumerated by flow cytometry detecting fluorescein or phycoerytrin conjugated monoclonal antibodies directed against seven different epitopes. Patients with chronic active hepatitis were significantly older than patients with chronic persistent hepatitis (p less than 0.05). Before treatment, the proportions of different subsets of lymphocytes were within the normal reference values and the CD4/CD8 ratio was also normal. No increased activation of T-cells was noticed. Patients over 50 years of age, however, had a significantly increased (p less than 0.01) proportion of HLA-DR+ lymphocytes, mainly B-cells. Treatment decreased the absolute number of peripheral blood leukocytes and lymphocytes. There was also a significant decline in the proportion of CD8+ lymphocytes and NK-cells, and a significant increase in the proportion HLA-DR+ cells and of the CD4/CD8 ratio. The increased proportion of HLA-DR+ cells, however, did not reflect peripheral T-cell activation; instead, it was due to increasing B lymphocyte numbers.

The incidence of post-transfusion hepatitis non-A, non-B (PTH-NANB) was prospectively assessed in two areas in the southeast region of Sweden. Patients undergoing hip arthroplasty were studied with blood sampling for alanine aminotransferase analysis before and at 2, 3, and 4 months after transfusion. Of the patients 97% and 82% were transfused and received a mean of 5.5 and 3.4 units in Linkoping and Oskarshamn, respectively. None of 38 patients in Oskarshamn but 4 of 144 patients (2.8%) in Linkoping contracted PTH-NANB. Two of these four patients developed antibodies against hepatitis C virus (HCV) by the first-generation anti-HCV enzyme-linked immunosorbent assay (ELISA) (C100). The other two patients remained negative by this test. HCV infection was, however, indicated in all four patients by positive second-generation anti-HCV ELISA confirmed by positive second-generation recombinant immunoblot assay (4-RIBA). Three of the patients were positive by polymerase chain reaction (PCR). Serum from one blood donor to the four hepatitis patients (altogether three donors) was found positive by first- and second-generation anti-HCV ELISA and 4-RIBA and was also PCR-positive. Three other blood donors, who did not transmit hepatitis, were anti-HCV ELISA (C100)-positive. This study shows that if anti-HCV ELISA had been available at the start of the trial, all cases of PTH would have been avoided at the expense of only 0.7% transfusion units discarded. Routine anti-HCV ELISA testing of all transfusion units will reduce the incidence of PTH-C even in low-risk areas.

SUMMARY Thirty-three patients with chronic hepatitis C/non-A. non-B were included in a randomized controlled study of interferon-alpha 2b (IFN-α2b) treatment, 3 × 106 U three times weekly for 36 weeks. Using an immunoperoxidase technique, frozen liver biopsy specimens were examined with MoAbs for the presence of T helper cells (CD4), T suppressor/cytotoxic cells (CD8), total T cells (CD2) and B cells (CD22) before and after treatment, β2-microglohulin (β2-MG) expression on hepatocytes was semiquantified using a scoring system on sections from paraffin-embedded biopsy specimens. Serum levels of β2-MG were analysed with a radioimmunoassay technique. Intralobular T helper and T suppressor/cytotoxic cells declined significantly in the treated patients but not in the controls. The portal CD4/CD8 ratio did not change. Before treatment, serum β2-MG levels and hepatocyte β2-MG expression were significantly higher in patients with chronic active hepatitis compared to patients with chronic persistent hepatitis. Serum β2-MG levels increased significantly in responders during IFN treatment, with a maximum after 12 weeks. However, in the liver, the hepatocyte β2-MG expression was significantly decreased after treatment. Thus. IFN-α treatment does not seem to induce an increased HLA class I antigen hepatocyte expression in chronic non-A, non-B hepatitis, which favours the hypothesis that its anti-viral effects are more important in modulating the disease activity.

CSF and serum were examined in acute and convalescence phase from 56 patients with acute idiopathic peripheral facial palsy. CSF protein analysis, viral and borrelia serology were performed. Borrelia infection was found in 9/56 cases and was often associated with inflammatory CSF findings. One patient each had serological evidence for a recent or ongoing infection with herpes simplex, varicella zoster, adeno, influenza B, echo and Epstein-Barr virus, but none had specific intrathecal antibody synthesis; 11 patients had a serological pattern compatible with a reactivated Epstein-Barr virus infection. Eleven patients displayed mononuclear CSF pleocytosis. Four of them had a borrelia infection. A disturbed blood-brain barrier was observed in 19 patients. Intrathecal immunoglobulin synthesis as indicated by elevated IgM-indices was found in 16 patients and by IgG indices in three. Nine patients had oligoclonal IgG bands in serum and CSF, three exclusively in CSF. It is concluded that patients with facial palsy often have inflammatory CSF findings, indicating a generalised central nervous system affection, and not only a mononeuritis. The importance of viral infections in the pathogenesis is still obscure. Borrelia is the most common infectious cause of facial palsy.

The biochemical and histological long-term outcome of interferon alpha-2b treatment for chronic posttransfusion non-A, non-B/C hepatitis was evaluated in a randomized study. 4/19 treated patients had a sustained response with normal serum alanine aminotransferases (s-ALAT) levels during follow-up, at present for 18-20 months after the end of interferon treatment. None of 11 responders with biochemical relapse normalized their s-ALAT levels during 1 year follow-up after treatment. Histological changes were assessed by a scoring system. The scores for portal inflammation, piecemeal necrosis and fibrosis were essentially unchanged in all treated patients between biopsies taken at the end of treatment and 1 year later. Six non-responders to 3 million units (MU) alpha-2b interferon thrice weekly (t.i.w.) were given 6 MU t.i.w. for at least 8 weeks. None normalized the s-ALAT levels during treatment with the higher dose, instead the side effects were much more pronounced, an obstacle to the usefulness of higher interferon doses. The biochemical non-responders had higher pretreatment histologic inflammation scores indicating a more severe infection. They also had a higher body weight and seemed to have prominent macrovesicular steatosis more often than responders, a finding that could contribute to raised aminotransferases, thereby in some of the non-responders, masking a positive biochemical effect of interferon treatment.

OBJECTIVE--To find out whether a 10-14 days' course of antibiotics early in the course of reactive arthritis associated with enteric infections could reduce the severity and duration of the disease and whether the antibody response in patients with reactive arthritis associated with yersinia infection differed between those treated and those not treated with the antibiotics. DESIGN--Prospective multicentre trial in which patients were randomised to treatment or no treatment with antibiotics. Patients were seen at three and six weeks and three, six, nine, 12, and 18 months after their first visit. SETTING--Departments of infectious diseases in three hospitals in Linkoping, Malmo, and Stockholm, Sweden. PATIENTS--40 Consecutive patients who had had symptoms of reactive arthritis associated with enteric infection for less than four weeks. INTERVENTIONS--20 Patients were allocated to treatment with antibiotics and 20 patients did not receive antibiotics. All patients received non-steroidal anti-inflammatory drugs, and four also received intra-articular steroid injections after at least six weeks' observation. MAIN OUTCOME MEASURES--Arthritic symptoms assessed clinically and by using Ritchies' index; blood measurements reflecting inflammatory activity; serum IgG, IgM, and IgA antibody titres; HLA tissue type. RESULTS--No difference was observed concerning duration of arthritis, grade of inflammation, and number of joints affected between patients treated and those not treated with antibiotics. Furthermore, there was no significant difference between the two groups in erythrocyte sedimentation rate and haptoglobin, IgG, and IgA concentrations. All values had returned to normal within three months. No patient developed chronic arthritis, but sustained slight arthralgia occurred in three patients. The HLA-B27 antigen was found in 23 (58%) of the patients, and its presence did not affect clinical outcome. The IgG, IgM, and IgA antibody responses were similar in patients treated with antibiotics and those not treated. CONCLUSION--Short term antibiotic treatment has no beneficial effect on the clinical outcome of reactive arthritis associated with enteric infection.

Septicemia is a rare but serious complication of infection with Yersinia enterocolitica (Y.e.). Seven cases of Y.e. septicemia are presented. Five of the patients had no underlying disease predisposing to septicemia. Five patients displayed recurrent episodes of septicemia, despite treatment with recommended doses of antibiotics to which the isolates were sensitive in vitro. One patient developed endocarditis which required surgical replacement of the aortic valve. Other clinical manifestations were arthritis, diverticulitis and pulmonary abscesses. The outcome was fatal to 3 elderly patients. The serological response to Y.e. was followed by tube agglutination and a diffusion-in-gel enzyme-linked immunosorbent assay. One patient, with a benign course of illness, had transient elevated Y.e. antibody titres, while the 3 cases with a protracted disease showed sustained antibody responses for 6-18 months. Blood isolates of Y.e. had ordinary virulence characteristics identical to fecal isolates and produced extracellular beta-lactamase. All isolates were sensitive in vitro to trimethoprim-sulfamethoxazole, mecillinam, piperacillin, cefotaxime, ceftazidime, chloramphenicol and gentamicin. The lowest MIC values were recorded for mecillinam. Full synergistic activity was demonstrated when mecillinam was combined with trimethoprim-sulfamethoxazole, cefuroxime or rifampicin.

33 patients with biopsy-proven chronic non-A, non-B posttransfusion hepatitis (NANB PTH) were randomized 2:1 to treatment with interferon alpha-2b (Introna) or to controls. The treatment group received 3 MU interferon 3 times weekly subcutaneously for 36 weeks. 22/33 (67%) patients were reactive for antibodies against hepatitis C virus (anti-HCV). 11/19 (58%) treated patients versus none of the 12 controls had a complete response with normalization of serum alanine aminotransferase levels (p less than 0.001). Another 4/29 (21%) treated patients had a partial response which was also seen in 4/12 (33%) controls; 4 treated patients were nonresponders, all with chronic active hepatitis. Nonresponders had a significantly higher mean weight than responders (p less than 0.05) and tended to have a longer duration of their disease before therapy. During the 6-month follow-up period post treatment 4/11 (36%) complete responders had a sustained response and 7/11 (64%) relapsed. All who were retreated responded again. We conclude that a majority of patients with chronic NANB PTH will respond to 9 months interferon alpha-2b treatment, but that only 1 out of 3 will have a sustained response 6 months post treatment, and that the reactivity for anti-HCV was not correlated to the outcome of therapy.

Five children aged 1/2--10 years with benign meningococcemia are reported. The clinical picture was quite uniform: good general condition, spikes of fever, skin eruptions as maculopapules--sometimes haemorrhagic, appearing in association with febrile periods, and arthralgia (big joints). The diagnosis involves either isolation of meningococci (MC) from blood, demonstration of MC with immunofluorescence in skin eruptions, or a significant elevation of MC antibody titre in connection with typical clinical signs and symptoms. Important differential diagnoses are Henoch-Schönlein syndrome, disseminated gonococcal infection, septicemia of other origins, subacute bacterial endocarditis, viral infections, hypersensitivity reactions and subsepsis allergica. By co-agglutination technique, the causative agent of meningococcemia in 4 of the 5 children was shown to be MC group B. These have some features in common with gonococci, whereby an incorrect diagnosis might be suggested as demonstrated in one of our patients. The question is raised whether MC group B is the main causative agent in benign meningococcemia.

32 patients with biopsy-proven chronic non-A, non-B posttransfusion hepatitis and raised aminotransferase levels since more than 1 year were randomized 2:1 to treatment with interferon alpha-2b, Introna, or to controls. The interferon group received 3 MU interferon 3 times weekly subcutaneously. Interim results 12 weeks after randomization showed that 14/21 (67%) patients in the treatment group had normalized their serum alanine aminotransferase levels whereas none of 11 patients in the control group had (p less than 0.001). If interferon alpha-2b is only suppressive during ongoing therapy or curative will be shown later during continued follow-up.

11 patients with bacterial meningitis, examined during the course of the disease for immunoglobulin (Ig) abnormalities in the cerebrospinal fluid (CSF), all had an increased CSF IgM index equal to (CSF/serum IgM):(CSF/serum albumin), indicating intrathecal IgM production. Seven patients had a slightly increased CSF IgG index, and 7 a slightly increased IgA index. Six of the 11 patients had an increased IgM index in the presence of normal indices for IgG and IgA. Follow-up revealed the return of these values to normal. Four patients had identical oligoclonal IgG bands in the CSF and serum, probably representing a systemic immune response, but in only one case were oligoclonal bands suggestive of intrathecal IgG production found. No oligoclonal IgA response was demonstrable in the 4 patients examined. Antigen-immunofixation or antigen-absorption studies revealed evidence of a specific, intrathecal IgG antibody response in only 2 patients, while a search for IgG antibodies against aetiologically unrelated bacterial and viral antigens was negative. With the exception of IgM production, therefore, a humoral intrathecal immune response is less common in bacterial than in aseptic meningitis.

The occurrence of viral antibodies in relation to IgG separated by thin-layer polyacrylamide gel isoelectric focusing was studied in CSF and serum from 24 patients with mumps meningitis by immunofixation with viral antigens and autoradiography. Eleven of the patients displayed on the autoradiograms evidence of locally in the central nervous system synthesized mumps virus antibodies which were related to oligoclonal IgG bands in all 5 patients who displayed this CSF abnormality, otherwise to polyclonal IgG bands. Local synthesis of mumps virus antibodies was detectable in 43% of specimens obtained 1–13 days after onset, and in 75% obtained 27–47 days after onset. Only one patient displayed local synthesis of antibodies to other viruses (measles and herpes simplex) which could then be traced to polyclonal IgG bands.

With the use of enzyme-linked immunosorbent assay (ELISA) for demonstration of specific viral antibodies in 21 patients with mumps meningitis (MM), 19 (91%) displayed evidence for synthesis within the central nervous system (CNS) of IgG antibodies and 11 (52%) of IgM antibodies. Only one MM patient did not show local antibody production, but he had high mumps IgM titers in serum. Elevated IgG and IgM indices reflecting local IgG and IgM production, were found in 4 (19%) and 17 (81%) of the patients, respectively, and frequently did not coincide with local synthesis of specific antibodies. None of 21 control patients with acute aseptic meningitis of other etiology showed evidence for a local antibody response against mumps. In one of the MM patients, local production of measles IgM antibodies was demonstrated, reflecting an IgM response within the CNS against an antigen unrelated to the disease. This study concludes that in less serious CNS infections, such as MM, highly sensitive methods as ELISA are needed to demonstrate intrathecal specific viral immune response.

Oligoclonal immunoglobulins (Ig) demonstrble as bands by agarose-gel electrophoresis of CSF were characterized in ten patients with aseptic meningitis. Oligoclonal CSF IgG was found in all patients, IgM was found in two. The oligoclonal Ig was more often of lambda light-chain type than of kappa type. In four patients, oligoclonal Ig bands contained kappa and lambda light chains simultaneously. In two patients, bands consisting of free lambda light chains were found. On repeated investigations more than one year later in three cases, the oligoclonal IgG was of the same light-chain type. The immune response within the CNS in aseptic meningitis seems to be dominated by synthesis of IgG with lambda light chains.

Virus-induced proliferation of cerebrospinal fluid (CSF) lymphocytes and blood lymphocytes was studied in patients with mump meningitis and in patients with aseptic meningitis of other etiology. In four out of five patients with mump meningitis the proliferation of CSF lymphocytes after mumps virus stimulation was higher than obtained with the corresponding number of blood lymphocytes. No proliferation was registered when lymphocytes from patients with other aseptic meningitis were stimulated with mumps virus. These data indicate the occurrence in CSF of lymphocytes specifically sensitized against mumps virus in patients with mumps meningitis.

The cell responses to different polyclonal lymphocyte activating substances were studied in 15 patients with aseptic meningitis by analysis of lymphocyte proliferation. the in vitro response to phytohaemagglutinin (PHA), concanavalin A (Con A) and poke weed mitogen (PWM) was investigated in blood and CSF lymphocytes simultaneously. the blood lymphocytes responded stronger than the corresponding number of CSF lymphocytes. These cells were, however, always capable of a response, suggesting that they were immunologically competent. No predominance of either PHA or Con A populations of T lymphocytes could be demonstrated in CSF compared to blood by this technique. When culture conditions were changed from the optimal cell or mitogen concentrations, the decrease in proliferation of the CSF lymphocytes was more pronounced than that of blood lymphocytes.

Cerebrospinal fluid (CSF) lymphocytes from two patients with tuberculous meningitis proliferated stronger than the corresponding peripheral blood lymphocytes (PBL) when stimulated with tuberculin purified protein derivative (PPD) in the lymphocyte transformation test after 3 days of culture. This might indicate an accumulation of specifically primed lymphocytes within the central nervous system. CSF lymphocytes and PBL from nine of ten patients with acute aseptic meningitis investigated as controls showed no or low responses when stimulated with. PPD, whereas the remaining patient displayed a significant proliferation of CSF lymphocytes, which was more pronounced than that of PBL. Stimulation with the mitogens phytohaemagglutinin, concanavalin A, and pokeweed mitogen gave lower proliferation of CSF lymphocytes compared with PBL in tuberculous and aseptic meningitis. Evaluation of the proliferative response of CSF lymphocytes compared with PBL on stimulation with PPD might be a useful complement in the diagnosis of tuberculous meningitis.

At our hospital 15 cases of leukaemic reticuloendotheliosis and 4 cases of legionnaires' disease have been diagnosed. 3 patients had both diseases. The clinical findings are reported. It is probable that patients with leukaemic reticuloendotheliosis have an increased susceptibility to Legionnaires' disease. Possible reasons for the decreased resistance are discussed.

B and T cells were defined in cerebrospinal fluid (CSF) and blood of 18 multiple sclerosis (MS), five optic neuritis, and 17 mumps meningitis patients by counting immunoglobulin-bearing lymphocytes for B cells, and the capacity of rosette formation with sheep erythrocytes of T-cell determination. Patients with MS and mumps meningitis had significantly higher T-cell values in CSF compared to blood, while the B cell value was significantly lower in CSF in mumps meningitis only. MS patients also displayed significantly lower B-cell values in blood compared to mumps meningitis patients and blood donors. No significant differences were observed between MS patients in exacerbation and in remission.

By means of a microculture technique and calculation of incorporation of 14C-thymidine, cerebrospinal fluid (CSF) lymphocytes from multiple sclerosis (MS) patients showed low or absent proliferation when stimulated with phytohaemagglutinin, concanavalin A, or pokeweed mitogen, in contrast to peripheral blood lymphocytes (PBL) obtained simultaneously and investigated in parallel. A lower proliferation of CSF lymphocytes compared with PBL was also found in acute aseptic meningitis, although it has been reported that CSF lymphocytes show greater proliferation than PBL when specifically stimulated. The low proliferation of MS CSF lymphocytes on mitogen stimulation may be a consequence of prolonged sensitization to an as yet unidentified antigen. The proliferation of MS CSF lymphocytes was not improved by adding irradiated PBL, making helper cell insufficiency less likely. MS CSF had no inhibitory effect on proliferation of PBL, arguing against an inhibitory effect of soluble factors in the CSF as an explanation for the depressed response of CSF lymphocytes.

Ornithosis is a notifiable disease in Sweden since 1954. In 1981 and 1982 a sharp increase in the number of notifications occurred. Since then the number has declined but is still high. A changed epidemiology characterized by no history of bird contact and no common source, raised the suspicion of a new agent. Serological data now suggest that the epidemic was to a substantial part due to Chlamydia pneumoniae (strain TWAR) (48% of the patients during 1981-1982 compared to 9% during 1984-1987). During recent years TWAR infections have thus become uncommon but reappearance can be expected in the near future. The clinical picture as well as the complications appear to be very similar in infections caused by C. pneumoniae and C. psittaci.

The phytohaemagglutinin (PHA) response of lymphocytes from seven patients with natural rubella infection was investigated during the acute, early and late convalescence stages of the disease. When the lymphocytes were cultured in autologous serum, a moderate depression of the response, following stimulation with PHA in both optimal and suboptimal concentrations was obtained two weeks after the onset of exanthema (early convalescence). Two months later (late convalescence), the lymphocyte stimulation response had returned to almost normal values. On the other hand, lymphocytes incubated in pooled homologous serum reacted normally to PHA in optimal concentrations at all three stages. Determination of T- and B-lymphocytes did not reveal any change in the relative proportion of T-lymphocytes during the course of the disease. However, in late convalescence, a significant decrease in the relative number of B-lymphocytes was recorded.

The frequencies of the HLA antigens A3, B7, and Dw2, previously related with multiple sclerosis, were investigated in 26 patients with acute aseptic meningitis and oligoclonal immunoglobulins in cerebrospinal fluid (CSF), but not in serum when investigated by agarose gel electrophoresis. HLA antigen frequencies were similar in patients with aseptic meningitis and controls. The oligoclonal immune response within the central nervous system in aseptic meningitis is not associated with the same HLA antigens found in patients with multiple sclerosis.

Two cases of infection of the central nervous system (CNS) with Haemophilus parainfluenzae — a 12-month-old girl with meningitis and a 17-month-old girl with brain abscess—are reported. Both infants had long-standing upper respiratory infection before CNS disease. Both recovered after treatment.