Gudrun Lindh

A 10-Year Follow-Up Study of Tick-Borne Encephalitis in the Stockholm Area and a Review of the Literature: Need for a Vaccination Strategy

143 people treated for tick-borne encephalitis (TBE) were included in a retrospective follow-up study. Sequelae and epidemiological characteristics in 114 individuals were analysed. The case fatality rate and the prevalence of residual paresis were low, 1.4 and 2.7%, respectively. However, 40 (35.7%) individuals were found to have a postencephalitic syndrome after a median follow-up time of 47 months, and a majority (77.5%) of these were classified as moderate to severe. Various mental disorders, balance and co-ordination disorders and headache were the most frequently reported symptoms. Increasing age was correlated to a longer duration of hospital stay, longer convalescence and increased risk of permanent sequelae. Results from a neuropsychiatric questionnaire showed marked differences between the subjects with sequelae compared to controls. 57% had noticed a tick bite before admission, and 48% were aware of at least one person in their environment who previously had contracted TBE. 79% were permanent residents or visited endemic areas often and regularly. In conclusion, we have found that TBE in the Stockholm area has a low case fatality rate, but gives rise to a considerable number of different neurological and mental sequelae, which justifies vaccination of a defined risk population in endemic areas.

Brain Regions Involved in Fatigue Sensation: Reduced Acetylcarnitine Uptake into the Brain

Fatigue is an indispensable sense for ordering rest. However, the neuronal and molecular mechanisms of fatigue remain unclear. Chronic fatigue syndrome (CFS) with long-lasting fatigue sensation seems to be a good model for studying these mechanisms underlying fatigue sensation. Recently, we found that most patients with CFS showed a low level of serum acetylcarnitine, which well correlated with the rating score of fatigue, and that a considerable amount of acetyl moiety of serum acetylcarnitine is taken up into the brain. Here we show by metabolite analysis of the mouse brain that an acetyl moiety taken up into the brain through acetylcarnitine is mainly utilized for the biosynthesis of glutamate. When we studied the cerebral uptake of acetylcarnitine by using [2-(11)C]acetyl-L-carnitine in 8 patients with CFS and in 8 normal age- and sex-matched controls, a significant decrease was found in several regions of the brains of the patient group, namely, in the prefrontal (Brodmanns area 9/46d) and temporal (BA21 and 41) cortices, anterior cingulate (BA24 and 33), and cerebellum. These findings suggest that the levels of biosynthesis of neurotransmitters through acetylcarnitine might be reduced in some brain regions of chronic fatigue patients and that this abnormality might be one of the keys to unveiling the mechanisms of the chronic fatigue sensation.

Chronic fatigue syndrome and nickel allergy

50 patients with chronic fatigue syndrome (CFS) and 73 controls were patch tested with 8 metal allergens. We found an overrepresentation of allergies among the CFS patients, which was not significant. However, allergy to nickel occurred in 36% of patients in the CFS group and in 19% of subjects in the control group (p<0.05). The high frequency of nickel allergy was more noteworthy in females in the CFS group than among female controls (52% and 24%, respectively, p<0.05). Similarly, in the males the figures were 14% and 9%. We suggest that in vivo immunoactivation by ions of nickel, or metal cross‐reacting with nickel, could be an etiological factor in CFS.

HCV genotypes in Swedish blood donors as correlated to epidemiology, liver disease and hepatitis C virus antibody profile

SummarySixty-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.Zusammenfassung62 anti-HCV und HCV-RNA-positive schwedische Blutspender (44 Männer, 18 Frauen, Alter im Median 34 Jahre) wurden untersucht. Die HCV-Genotypen wurden in Korrelation gesetzt zu parenteralen Risikofaktoren, Lebermorphologie, Serum-Alanin-Aminotransferase (ALAT)-Spiegeln und HCV-Antikörperprofil. 40% der Spender waren mit dem HCV-Genotyp 1a infiziert, 10% mit 1b, 21% mit 2b und 29% mit 3a. Bei Spendern mit Genotyp 3a bestand häufiger eine Vorgeschichte von intravenösem Drogenabusus als bei den mit Genotyp 1a Infizierten (p=0,024). Bluttransfusionen waren bei Genotyp 2b häufiger vorausgegangen als bei Typ 3a (p=0,012). Bei 38% der mit Genotyp 2b aber nur bei 8% der mit Genotyp 1a infizierten Spender fand sich eine chronisch aktive Hepatitis mit oder ohne Zirrhose (p=0,034). 40% der Spender, die Genotyp 1a aufwiesen, hatten zur Zeit der Leberbiopsie normale ALAT-Werte, bei Genotyp 3a waren es nur 11% (p=0,046). Bei fast allen Spendern waren Antikörper gegen C33c und C22-3 nachzuweisen. Reaktivität gegen C100-3 und 5-1-1 fand sich häufiger bei Spendern mit Genotyp 1a oder 1b als bei Spendern mit Genotyp 2b oder 3a. Zusammenfassend ist festzustellen, daß Genotyp 3a mit intravenösem Drogenabusus oder Tätowierung als Risikofaktoren für eine intravenöse Akquisition der Infektion assoziiert war, Genotyp 2b dagegen mit Bluttransfusionen. Spender mit Genotyp 1a hatten offensichtlich eine weniger schwere Lebererkrankung als Spender, die mit den Genotypen 2b oder 3a infiziert waren.

Second-generation hepatitis C Elisa antibody tests confirmed by the four-antigen recombinant immunoblot assay correlate well with hepatitis C viremia and chronic liver disease in Swedish blood donors

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 μkat/1) 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.

GBV-C/HGV infection in hepatitis C virus-infected deferred Swedish blood donors

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. J. Med. Virol. 54:75–79, 1998.

No Findings of Enteroviruses in Swedish Patients with Chronic Fatigue Syndrome

Enteroviruses have been proposed to cause an immune complex disease in the chronic fatigue syndrome. Altogether 34 patients with the chronic fatigue syndrome, according to criteria of the Centers for Disease Control, USA, were studied evenly over the seasons for the possible presence of a chronic enterovirus infection. In 11 patients, 1-5 faecal samples were collected at about 6 month intervals for virus isolation before and after acid treatment, followed by ultracetrifugation at pH 3 to dissolve possible enterovirus-antibody complexes. Another 14 fecal samples were subjected to routine virus isolation alone. Seven pairs of serum-cerebrospinal fluid samples were analysed for cross-reactive IgG antibody activity to enteroviruses. In 29 patients a muscle biopsy was collected for enterovirus polymerase chain reaction (PCR). We were unable to identify enteroviruses in any of these samples by any of these techniques. Our study does not confirm evidence for persistent enterovirus infection in the chronic fatigue syndrome.

Differences between patients with chronic fatigue syndrome and with chronic fatigue at an infectious disease clinic in Stockholm, Sweden

Abstract Background data were collected from patients presenting with fatigue at the clinic of infectious diseases at Huddinge University Hospital, Stockholm. The main purpose was to look for differences as to demographic and functional status for patients fulfilling criteria for chronic fatigue syndrome (CFS) and chronic fatigue (CF). A cross‐sectional questionnaire survey was performed using a variety of instruments. A thorough medical investigation was performed. No difference was found as to social situation, occupation and illness attributions for patients in the two categories. Patients with CFS reported in general a higher degree of ‘sickness’ with more self‐reported somatic symptoms, more self‐reported functional impairment and more absence from work. A higher degree of psychiatric comorbidity was observed in CF than in CFS patients. A majority of CFS patients (80%) had an acute infectious onset compared to 43% in the CF group. Presently used criteria might, according to findings presented here, define two different patient categories in a population characterized by severe, prolonged fatigue. Because CFS patients (compared to patients with CF) have more somatic symptoms, more often report an infectious, sudden onset and have less psychiatric comorbidity, and CF patients seem to have more of an emotional, burn‐out‐like component one could speculate about the existence of different pathogenetic backgrounds behind the two diagnoses.

Lyme borreliosis — an overdiagnosed disease?

SummaryNinety-nine patients who were referred to a clinic for infectious diseases on suspicion of Lyme borreliosis and whose major symptoms were fatigue, headache, myalgia and arthralgia were studied retrospectively to find out if there was any difference in symptomatology between patients who were seropositive or seronegative toBorrelia burgdorferi. 64/82 (78%) patients remembered one or more tick bites during previous years and 32/74 (43%) patients had a history of erythema migrans. Fatigue, headache, myalgia and arthralgia occurred in 84%, 72%, 54%, and 63% of the patients, respectively. 62/99 (63%) patients had an elevated IgM and/or IgG antibody titer toB. burgdorferi. There was no difference in frequency of symptoms between seropositive and seronegative individuals. 48/99 (49%) patients were treated with antibiotics, mostly oral doxycycline. Only 50% were improved after treatment. On follow-up 2 to 4 years after the first visit, 40% of the patients had recovered completely, 31% were improved, 24% reported unaltered symptoms and four patients were impaired. There was no difference in symptoms on follow-up between seropositive or seronegative patients. It is concluded that there probably is an overdiagnosis of Lyme borreliosis and that better microbiological methods are needed to confirm active disease.Ninety-nine patients who were referred to a clinic for infectious diseases on suspicion of Lyme borreliosis and whose major symptoms were fatigue, headache, myalgia and arthralgia were studied retrospectively to find out if there was any difference in symptomatology between patients who were seropositive or seronegative toBorrelia burgdorferi. 64/82 (78%) patients remembered one or more tick bites during previous years and 32/74 (43%) patients had a history of erythema migrans. Fatigue, headache, myalgia and arthralgia occurred in 84%, 72%, 54%, and 63% of the patients, respectively. 62/99 (63%) patients had an elevated IgM and/or IgG antibody titer toB. burgdorferi. There was no difference in frequency of symptoms between seropositive and seronegative individuals. 48/99 (49%) patients were treated with antibiotics, mostly oral doxycycline. Only 50% were improved after treatment. On follow-up 2 to 4 years after the first visit, 40% of the patients had recovered completely, 31% were improved, 24% reported unaltered symptoms and four patients were impaired. There was no difference in symptoms on follow-up between seropositive or seronegative patients. It is concluded that there probably is an overdiagnosis of Lyme borreliosis and that better microbiological methods are needed to confirm active disease.

Serum ALT levels as a surrogate marker for serum HBV DNA levels in HBeAg-negative pregnant women.

In Stockholm, Sweden, the majority of pregnant women positive for hepatitis B surface antigen (HBsAg) are hepatitis Be antigen (HBeAg) negative. Newborns to HBeAg positive mothers receive vaccination and hepatitis B immunoglobulin (HBIg). Newborns to HBeAg negative mothers receive vaccine and HBIg only if the mothers have elevated ALT levels. The aim of this study was to retrospectively evaluate ALT levels as a surrogate marker for HBV DNA levels in HBeAg negative carrier mothers. Altogether 8947 pregnant women were screened for HBV markers from 1999 to 2001 at the Virology Department, Karolinska Hospital. Among mothers screened 192 tested positive for HBsAg (2.2%). 13 of these samples could not be retrieved. Of the remaining 179 sera, 8 (4%) tested positive for HBeAg and 171 (95.5%) were HBeAg negative. Among the HBeAg negative mothers, 9 had HBV DNA levels >105copies/ml, and of these 7 had normal ALT levels indicating low sensitivity of an elevated ALT level as a surrogate marker for high HBV DNA level. Furthermore, no correlation was found between ALT and HBV DNA levels. Hence, it is concluded that the use of ALT as a surrogate marker for high viral replication in HBeAg negative mothers could be questioned.