Sequential changes in hematologic and biochemical parameters in African tick bite fever.

OBJECTIVE: To evaluate the sequential changes and to estimate the frequencies of abnormalities in some commonly measured biological variables in patients with African tick bite fever (ATBF), an emerging spotted fever group (SFG) rickettsiosis in international travelers to rural sub-Saharan Africa. METHODS: A study was done of hemoglobin, total leukocyte count, absolute lymphocyte count, blood platelet count and serum levels of C-reactive protein (S-CRP), alanine aminotransferase (S-ALAT), aspartate aminotransferase, lactic dehydrogenase, gamma-glutamyl transferase, alkaline phosphatase, bilirubin, sodium and creatinine during the first two weeks of illness and prior to the institution of antirickettsial therapy in 108 patients with travel-associated ATBF. RESULTS: There were significant falls in mean total leukocyte count, mean absolute lymphocyte count, and mean platelet count, and significant increases in mean S-CRP and S-ALAT. During the first ten days of illness, elevated S-CRP, lymphopenia and elevated S-ALAT were detected in 91.7%, 73.3% and 40.7% of patients, respectively. Most abnormalities were mild. For 55 patients who underwent both S-CRP and absolute lymphocyte count determination, at least one parameter was abnormal in 52 (94.5%) patients. CONCLUSIONS: The sequential changes in many biological parameters during the acute phase of ATBF mimic those reported in other SFG rickettsioses. Mild abnormalities are frequent, with increased S-CRP and lymphopenia being the two most consistent findings.

Left ventricular volume changes during supine exercise in young endurance athletes.

AIM: The primary objective of the study was to measure the relative left ventricular volumes and the changes in left ventricular ejection fraction during supine position from rest to exercise in young endurance athletes. The secondary objective was to examine if there were gender differences regarding the volume reply and ejection fraction with exercise. METHOD: Sixty-five (35 female and 30 males) young healthy Swedish orienteers participated in the study. Left ventricular volume and ejection fraction changes between rest and submaximal supine bicycle exercise were measured with radionuclide ventriculography. RESULTS: The mean left ventricular end-diastolic volume increased by 13% (P < 0.001) but there was no change in end-systolic volume. Stroke volume was found to increase by 21% (P < 0.001). Left ventricular ejection fraction increased significantly (>0.04 units) in 54% of the athletes from rest to exercise; 5% of the athletes showed a decrease in ejection fraction. A negative correlation was found between ejection fraction at rest and the difference in ejection fraction from rest to exercise (r = -0.38, P = 0.002). There were no gender differences in the left ventricular volume changes or ejection fraction. CONCLUSION: During submaximal supine exercise, the adjustments in cardiac volumes in endurance athletes were small. There were no gender disparities concerning the left ventricular volume reply during exercise.

Immune function in Swedish élite orienteers.

During 1979-1992 an increased frequency of sudden unexpected cardiac death (SUD) occurred among young male Swedish élite orienteers. Subacute-to-chronic myocarditis was found in 12/16 (75%) at autopsy and Chlamydia pneumoniae, or a cross-reacting agent, was suspected on the basis of diagnostic tests performed. Because myocarditis is an infrequent cause of SUD and clusters of SUD are rare, whereas Chlamydia pneumoniae infections are ubiquitous and seldom cause severe myocarditis, 119 top ranked élite orienteers (67 males and 52 females) and 36 highly trained male middle-distance runners and cross-country skiers, serving as controls, underwent immunologic screening in an effort to reveal possible immune dysfunction. Except for two orienteers and one runner/skier who showed genetic C3-deficiency or IgA-deficiency, the results showed no significant differences between the orienteers and controls with respect to immunoglobulin levels, complement activation, lymphocyte subsets, including activated T lymphocytes, and sIL-2r-alpha. IL-1 beta, IL-6, TNF-alpha, and sCD8, tested in the orienteers only, were normal. However, IFN-gamma was significantly higher in controls than in orienteers, who showed normal levels, whereas the orienteers had increased sELAM-1 and sICAM-1 levels. Finally, sIL-2 receptor-alpha was similarly elevated in orienteers and controls. We conclude that, with the tests employed, no immunologic disturbance could be revealed in the orienteers that may potentially have increased their susceptibility to myocarditis and SUD.

Antibodies to Chlamydia pneumoniae in young Swedish orienteers.

During 1992-93 sera from 1790 Swedish elite orienteers were tested for antibodies to Chlamydia pneumoniae. The reason for this was that a cluster of 16 cases of sudden unexpected cardiac death had occurred among Swedish orienteers and DNA from C. pneumoniae had been found in the myocarditic heart and in the lung in 1 of 2 deceased athletes in whom testing was feasible; in addition, C. pneumoniae IgG was found in all 5 cases where serum was available. Among the orienteers, the prevalence rates of IgG antibodies in males and females were 54% (n = 1194) and 50% (n = 596), respectively. The corresponding figures for 319 male and female blood donors were 60% (n = 169) and 53% (n = 150), respectively. These differences are not statistically significant. Male orienteers had a lower prevalence of IgA antibodies than male blood donors (19% and 26%, respectively; p < 0.05), while no such difference was found in females (16% and 18%). The prevalence of IgM antibodies was < 1% in all groups. Neither the performance level of the orienteers nor the place of residence affected the antibody prevalence. In conclusion, Swedish orienteers do not show a higher prevalence of antibodies to C. pneumoniae than healthy blood donors.

Subacute bartonella infection in Swedish orienteers succumbing to sudden unexpected cardiac death or having malignant arrhythmias.

During the period 1979-92, an increasing number of sudden unexpected cardiac deaths (SUCD) occurred in young, Swedish, male elite orienteers. Myocarditis was the most common diagnosis in the 16 victims, and in 4 cases was also associated with fatty infiltration mimicking arrhythmogenic right ventricular cardiomyopathy (ARVC). Tissues from autopsies of 5 orienteers were tested for Bartonella by PCR targeting the gltA (citrate-synthase) gene. The products were then sequenced. Antibodies to B. henselae, B. quintana and B. elizabethae were measured by indirect fluorescence antibody assay. Bartonella spp. DNA was detected in the hearts of 4 deceased orienteers, and in the lung of a fifth deceased case. The sequences were close to B. quintana in 2 cases and identical to B. henselae in 3. Four of these 5 cases, as well as 2 additional cases of elite orienteers with ARVC, indicated antibodies to Bartonella. It is suggested that Bartonella-induced silent subacute myocarditis, eventually leading to electric instability, caused the increased SUCD rate among the Swedish orienteers. It is further suggested that Bartonella infection may be a major pathogenetic factor in the development of ARVC-like disease. Although the mode of transmission is unknown, both zoonotic/vector-borne and parenteral person-to-person transmission may be involved.

Serological and epidemiological analysis of the prevalence of Bartonella spp. antibodies in Swedish elite orienteers 1992-93.

The emergence of the popular, physically demanding and highly nature-interactive sport of orienteering was marked in Sweden by an elevated rate of sudden unexpected cardiac deaths in young competitors during the years 1979-92, with a common underlying cause or causes suspected. Subsequently, sera were collected during 1992-93 from the elite segment of orienteers holding a nationally ranked position, and a survey compiling various epidemiological data was performed. In this study, a total of 1136 sera were analyzed by indirect-fluorescent antibody assay for the presence of IgG antibodies against 3 Bartonella spp.: B. henselae, B. elizabethae and B. quintana. In total, 31% (355/1136) were seropositive for at least 1 species of Bartonella, with titers ranging up to 1/512; 350/1136 (31%) had antibodies against B. elizabethae, 34/1136 (3.0%) against B. henselae and 16/1136 (1.4%) against B. quintana. Males and females showed equal rates of 31% seropositisity to Bartonella spp. (males 241/766; females 114/370). In comparison, 322 time-matched sera from healthy blood donors had antibodies to Bartonella spp. in 6.8% of cases (p < 0.001). The observed high prevalence of Bartonella spp. antibodies found in Swedish elite orienteers may be indicative of a connection with risk factors for the development of myocarditis and sudden unexpected cardiac death.

Thallium-201 myocardial imaging at rest in male orienteers and other endurance athletes.

During the period 1979 to 1992, 16 sudden unexpected cardiac deaths were known to have occurred in young Swedish orienteers. Autopsy indicated myocarditis to be the most frequent finding, most often combined with extensive myocardial fibrosis. The aim of the present investigation was to explore whether young male orienteers show a higher frequency than other young elite endurance athletes (controls) in the occurrence of Thallium-201 myocardial perfusion defects at rest, suggestive of fibrosis evoked by myocarditis. Thallium-201 perfusion abnormalities at rest were more frequently found in the controls than in the orienteers (26% vs. 12%, p=0.03). Uneven Tl-201 perfusion was associated with left ventricular mass (r=0.32, r=0.24, p<0.01, p=0.02) and body weight (r=0.30, r=0.31, p<0.01, p=0.03) in orienteers and controls, respectively. Echocardiographic left ventricular wall motion abnormalities were found in 11 athletes (9 orienteers and 2 controls) but only two displayed an abnormal Thallium-201 perfusion scan at rest. Perfusion abnormalities at rest did not occur more frequently in the orienteers but were commonly found in both groups of apparently healthy athletes making it futile to discern abnormals from normals. Thallium-201 perfusion aberrations were not associated with left ventricular wall motion abnormalities obtained by echocardiography.

Special feature for the Olympics: effects of exercise on the immune system: infections and exercise in high-performance athletes.

The elite athlete has a potentially increased sensitivity to respiratory infections, rendering protective measures particularly important. Some other infections that may appear in clusters in the sports setting, such as gastroenteritis, leptospirosis, herpes simplex and viral hepatitis, also require special precautionary attention. Strenuous exercise during ongoing infection and fever may be hazardous and should always be avoided. In addition, early symptoms of infection warrant caution until the nature and severity of the infection become apparent. Because myocarditis may or may not be accompanied by fever, malaise or catarrhal symptoms, athletes should be informed about the symptoms suggestive of this disease. Although sudden unexpected death resulting from myocarditis is rare, exercise should be avoided whenever myocarditis is suspected. Guidelines are suggested for the management and counselling of athletes suffering from infections, including recommendations on when to resume training. Acute febrile infections are associated with decreased performance resulting from muscle wasting, circulatory deregulation and impaired motor coordination, which require variable amounts of time to become normalized once the infection is over.

Trace element changes in the myocardium during coxsackievirus B3 myocarditis in the mouse.

During most infections plasma, concentrations of trace elements change, but it is unclear if this reflects changes in infected target tissues. In coxsackievirus B3 (CB3) infection, the myocardium is a target in both humans and mice. The concentrations of 12 trace elements were analyzed by inductively coupled plasma-mass spectrometry (ICP-MS) in the myocardium of sham-inoculated controls and infected A/J mice 4 and 7 d postinoculation. The size of the inflammatory lesion was positively correlated to the virus content of the heart, as estimated by histopathology and in situ hybridization, respectively. Iron, cobalt, vanadium, and selenium showed transient changes, whereas for the other elements, tendencies on d 4 were manifest on d 7. A three-fold increase in calcium on d 7 suggests prestages of calcification, whereas increases in zinc, selenium, and copper may be the result of the accumulation of immune cells. The magnesium decrease may contribute to the increased sensitivity to cardiac arrhythmias in myocarditis.

Sequence variation in the ftsZ gene of Bartonella henselae isolates and clinical samples.

In a search for methods for subtyping of Bartonella henselae in clinical samples, we amplified and sequenced a 701-bp region in the 3' end of the ftsZ gene in 15 B. henselae isolates derived from cats and humans in the United States and Europe. The ftsZ sequence variants that were discovered were designated variants Bh ftsZ 1, 2, and 3 and were compared with 16S rRNA genotypes I and II of the same isolates. There was no ftsZ gene variation in the strains of 16S rRNA type I, all of which were Bh ftsZ 1. The type II strains constituted two groups, with nucleotide sequence variation in the ftsZ gene resulting in amino acid substitutions at three positions, one of which was shared by the two groups. One 16S rRNA type II isolate had an ftsZ gene sequence identical to those of the type I strains. Variants Bh ftsZ 1 and 2 were detected in tissue specimens from seven Swedish patients with diagnoses such as chronic multifocal osteomyelitis, cardiomyopathy, and lymphadenopathy. Patients with similar clinical entities displayed either Bh ftsZ variant. The etiological role of B. henselae in these patients was supported by positive Bartonella antibody titers and/or amplification and sequencing of a part of the B. henselae gltA gene. B. henselae ftsZ gene sequence variation may be useful in providing knowledge about the epidemiology of various B. henselae strains in clinical samples, especially when isolation attempts have failed. This report also describes manifestations of atypical Bartonella infections in Sweden.

Trace element distribution in heart tissue sections studied by nuclear microscopy is changed in Coxsackie virus B3 myocarditis in methyl mercury-exposed mice.

Methyl mercury (MeHg) has been shown to change Coxsackie virus type B3 (CB3) myocarditis in a direction compatible with the development of chronic disease. Murine models of CB3 myocarditis closely mimic the pathogenesis in humans. There are also indications that metals, such as mercury, and trace elements may interact and adversely affect viral replication and development of inflammatory lesions. The effects of low-dose MeHg exposure on myocardial trace element distribution, as determined by means of nuclear microscopy, was studied in CB3 myocarditis. Balb/c mice were fed a MeHg-containing diet (3.9 mg/kg diet) for 12 wk prior to infection. Areas of inflammatory lesions in the myocardium were identified by traditional histologic examination, and serial tissue sections in these selected areas were used for immune histology (macrophages), in situ hybridization of virus genomes, and nuclear microscopy of tissue trace element distribution. Areas with no inflammation or virus were compared with areas of ongoing inflammation and viral replication. In the inflammatory lesions of MeHg-exposed mice as compared to nonexposed mice, the myocardial contents of calcium (Ca), manganese (Mn), and iron (Fe) were significantly increased, whereas the zinc (Zn) content was decreased. The increased Ca and decreased Zn contents in the inflamed heart may partly explain a more severe disease in MeHg-exposed individuals. Although not significant in the present study, with a limited number of mice, the inflammatory and necrotic lesions in the ventricular myocardium on d 7 of the infection was increased by 50% (from 2.2% to 3.3% of the tissue section area) in MeHg-exposed mice and, also, there was a tendency of increased persistence of virus with MeHg exposure. No increased MeHg uptake, either in the inflammatory lesions or in the areas of noninflamed heart tissue in infected mice, could be detected. The present results indicate that a "competition" exists between potentially toxic heavy metals from the environment/diet and important trace elements in the body and that a disturbed trace element balance adversely influences the development of pathophysiologic changes in inflammatory heart disease.

[Three Swedish cases of African tick-bite fever. Can our native Rickettsia species cause disease in humans?]. / Tre svenska fall av "African tick-bite fever". Kan våra inhemska rickettsier ge sjukdom hos människa?

The article consists in a report of three cases of African tick-bite fever in Swedish tourists returning from brief visits to South Africa. The clinical course included eschar, regional lymphadenopathy, fever and, in two cases, maculopapular rash. Two cases were characterised by significant increases in anti-Rickettsia conorii IgG and IgM antibody titres. However, the aetiological agent was assumed to be Rickettsia africae, based on reports by others and the widespread serological cross-reactivity among spotted fever Rickettsia spp. The third case was diagnosed on clinical grounds. During the past ten years, 50 per cent (41/80) of cases diagnosed serologically as rickettsial (R. conorii antigen) spotted fever at the Swedish Institute for Infectious Disease Control were associated with travel to South Africa. Parallels are drawn to the recent finding of R. helvetica in Swedish ticks (Ixodes ricinus), and the possibility of its pathogenicity to humans is discussed, though no such clinical cases have been reported to date.

Sudden unexpected cardiac deaths among young Swedish orienteers--morphological changes in hearts and other organs.

During the years 1979-1992 an accumulation of sudden unexpected cardiac deaths (SUD) occurred among young Swedish orienteers. A reevaluation of material saved from 16 autopsies was undertaken. Myocarditis was most frequent. It was found in different stages in the majority of cases, indicating subacute or chronic disease with ongoing reparative processes. There were severe morphological changes in all cases. All but one showed a picture of fibrosis and unspecific hypertrophy and/or degenerative changes in myocytes. The hearts were classified into three groups (A-C), based on the morphological picture of the retrieved heart tissue and the macroscopic description. Group A comprised five cases in which areas with active myocarditis combined with areas of healing or healed myocarditis widely distributed in the left ventricle were the only morphological changes found. Group B comprised four cases demonstrating foci of myocarditis in different stages in the left ventricle and changes resembling those found in arrhythmogenic right ventricular dysplasia (ARVD), including degenerative changes with fibrosis and fatty infiltration located in either ventricle. Group C comprised the remaining seven cases. In none of the cases were coronary artery or valvular anomalies present, nor significant coronary sclerosis or changes outside the heart that could cause SUD.

Evaluation of human seroreactivity to Bartonella species in Sweden.

Among the species that compose the expanding genus Bartonella, thus far only B. henselae and B. quintana have reportedly been isolated from humans in Europe. To evaluate the prevalence of Bartonella infection in Sweden, we conducted a retrospective serological examination of 126 human serum samples. These samples were analyzed for antibodies to B. henselae, B. quintana, and B. elizabethae. Serum samples from 100 blood donors, who spanned the ages of 20 to 60 and had no apparent clinical signs of illness, were also studied as a control group. An immunoglobulin G indirect fluorescence antibody assay revealed 4 and 8.3% Bartonella positivity rates for the blood donor and patient group, respectively, when a cutoff titer of >/=64 was chosen. Among the blood donors, four were seropositive to B. elizabethae; one of these also had concordant positive titer to B. henselae. In the patient group, 14 serum samples were positive against Bartonella spp. These serum specimens represented nine patients. In three of these seropositive patients, paired serum samples displayed a fourfold increase in antibody titer to at least one of the three antigens. These three patients are discussed. In this report we also present a case study of a 60-year-old Swedish male with fatal myocarditis. Postmortem serological analysis revealed a high titer against B. elizabethae. PCR and nucleotide sequencing of the myocardial tissue from this patient, and of liver tissue from one of the other three patients, showed sequences similar to B. quintana. The age, geographical origin, animal contacts, and serological response pattern to the different Bartonella antigens differed among the four patients. This study substantiates the presence of Bartonella spp. in Sweden, documents the seroreactivity to three Bartonella antigens in Swedish patients, and reports the first two cases of B. quintana-like infections in Sweden.

Wall motion abnormalities in male elite orienteers are aggravated by exercise.

During the period 1979-92, 16 (15 men and one woman) sudden unexpected cardiac deaths occurred among young Swedish orienteers. This finding indicated a sharp increase in the death rate of orienteers, and necropsy demonstrated that myocarditis was a common histopathological finding. Therefore, an extensive non-invasive cardiac investigation was performed. A total of 59 male élite orienteers (mean age 23 years) and 36 cross-country skiers and middle-distance runners (mean age 22 years), serving as controls, were examined by both echocardiography at rest and radionuclide ventriculography at rest and during exercise. Wall motion abnormalities were found in eight orienteers using echocardiography. The purpose of this study was to examine whether the group of orienteers with wall motion abnormalities found using echocardiography had a smaller increase in ejection fraction from rest to exercise using radionuclide ventriculography than the rest of the orienteers and the controls, indicating an aggravation of the wall motion abnormalities during exercise. There were no significant differences in the ejection fraction at rest between the groups. In the orienteers with wall motion abnormalities (group 1), 62% (five out of eight) had less than a 0.05 unit increase in left ventricular ejection fraction compared with 27% (14 out of 51) of the remaining orienteers (group 2) and 19% (7 out of 36) of the controls (group 3). A comparison of athletes in group 1 with those in groups 2 and 3 combined revealed a statistically significant difference (P < 0.05). The divergent response in left ventricular ejection fraction during exercise suggests an aggravation of the wall motion abnormalities with exercise. Both the echocardiographic and the radionuclide ventriculographic findings indicate that the orienteers in group 1 had concealed left ventricular damage.

An echocardiographic study of right and left ventricular adaptation to physical exercise in elite female orienteers.

BACKGROUND: A considerable body of echocardiographic studies has described how athletic training induces morphological adaptation of the left ventricle in male endurance athletes, but only a few studies have described left ventricular adaptation in female endurance athletes. In contrast to changes in the left ventricle far less attention has been directed towards right ventricular changes due to extensive physical exercise. The purpose of this study was to obtain normal values and to determine if there are any differences in right and left ventricular cavity and wall dimensions between female orienteers and females with a mainly sedentary lifestyle. METHODS: Echocardiography was performed in 42 highly trained elite female orienteers and 32 healthy female students with a predominantly sedentary lifestyle. The 74 females had no history of cardiac disease, a normal electrocardiogram and showed no echocardiographic abnormalities. M-mode and two-dimensional measurements of the right and left ventricular cavity and wall were obtained in elite orienteers and sedentary females. For the right ventricle and wall, multiple cross-sections were used and measurements were obtained from the right ventricular inflow and outflow tract. RESULTS: The left ventricular end-diastolic cavity dimension and the left ventricular wall thickness were significantly greater in the athletes compared with the sedentary controls. The right ventricular inflow tract measurements were all significantly greater in the orienteers compared with the controls but the right ventricular outflow tract measurements were comparable in the study groups. The right ventricular wall thickness, calculated as the mean of three different wall measurements was an average of 13% greater in the athletes compared with the sedentary controls. CONCLUSION: This study suggests symmetrical cardiac enlargement with a concomitant increase in both the right and left ventricular wall, probably reflecting the increased haemodynamic loading in the female athletes.

Phylogenetic placement and characterization of a new alpha-2 proteobacterium isolated from a patient with sepsis.

An alpha-2 proteobacterium, previously unknown as determined by its phylogenetic characteristics and the DNA sequence of its 16S rRNA gene, was isolated from a patient who presented an unusual clinical picture, including high remitting fever and multiorgan involvement. The bacterium was detected in multiple plasma samples, obtained during the acute phase of the disease, after cocultivation in cell culture media. Electron microscopy of the organism showed a three-layer laminar cell wall and electron-dense granules within the cytoplasm, as well as a polar flagellum. By means of PCR followed by sequencing of amplified 16S ribosomal DNA fragments, the bacterium was found to differ from all species for which ribosomal sequence information is available. It is here provisionally named the Rasbo bacterium. At a subsequent relapse, the bacterium was identified in pericardial fluid both by PCR/sequencing and by direct electron microscopy. At a second relapse, it was again cultured from plasma. After in vitro adaptation to solid media, the MICs of various antibiotics could be determined. A transient immunoglobulin M (IgM) but no IgG response to the bacterium was found by an indirect immunofluorescence test, as well as by an immobilization test during the acute phase of the disease.

An echocardiographic study comparing male Swedish elite orienteers with other elite endurance athletes.

Between 1979 and 1992, there were 16 known cases of sudden unexpected cardiac death among young Swedish orienteers, whose autopsies showed myocarditis to be a common finding. Therefore, 96 elite orienteers and 47 controls underwent echocardiography, showing left ventricular wall motion abnormalities in 9% of the orienteers compared with 4% in the controls.

Effects of methyl mercury on cytokines, inflammation and virus clearance in a common infection (coxsackie B3 myocarditis).

A myocarditic coxsackievirus B3 (CB3) infection in Balb/c mice was used to investigate the effects of 12 weeks of methyl mercury (MeHg) exposure (3.69 mg/g diet) on inflammatory heart lesions, virus in the heart, the cytokine response, i.e. cachectin/TNF-alpha and gamma-interferon (IFN-gamma) levels in plasma, and on disease complications and mortality. This dose of MeHg did not influence mortality in this infection model. The inflammatory and necrotic lesions in the ventricular myocardium 7 days after the inoculation covered 2.2% of the tissue section area in infected control mice. This damage was increased (n.s.) by 50% (to 3.3% of the tissue section area) in MeHg-treated mice. The response pattern of lymphocyte subsets in situ in myocardial inflammatory lesions was corroborated using an immune histological technique. MeHg treatment tended to increase (2.2-fold, n.s.) the number of Mac 2+ cells (macrophages) in the heart muscle in this infection. Plasma levels of both TNF-alpha and IFN-gamma increased on day 3 of the infection in MeHg-treated as well as in non-MeHg-treated mice, but the mean IFN-gamma response was more pronounced in the MeHg-treated mice. On day 7 of the infection, when most animals still showed clinical signs of disease, cytokine levels were back to normal. MeHg-exposure in non-infected mice did not affect cytokine levels. In situ hybridization of virus RNA in myocardial tissue showed remaining virus in those mice who had the lowest plasma IFN-gamma levels. A 20% increased (P < 0.05) lymphoproliferative response to the T cell mitogen Con A was observed as a result of the MeHg treatment. Even heart tissue lesions and virus persistence tended to be influenced by MeHg in a direction compatible with the development of chronic disease.