Evidence of Rickettsia spp. infection in Sweden: a clinical, ultrastructural and serological study

Sweden is an area potentially endemic for spotted fever rickettsioses. Rickettsia helvetica has been isolated from its tick vector Ixodes ricinus, and in a handful of cases linked to human disease. This study demonstrates for the first time in Sweden the transmission of rickettsial infection after a tick bite and the attack rate in an endemic area. We present three cases of documented rickettsial infection and a prospective serological study of Swedish recruits who were trained in the area where the patients lived and showed seroconversion to spotted fever rickettsiae. All patients showed a four-fold increase in antibody titer to the spotted fever rickettsia, R. helvetica, and immunohistochemical examination revealed rickettsia-like organisms in the walls of skin capillaries and veins. Electron microscopy showed organisms resembling R. helvetica and immunogold labeling with two anti-rickettsial antibodies demonstrated specific labeling of the rickettsial organisms in the skin biopsy specimens. Eight of the thirty-five recruits showed a four-fold increase in IgG titer reflecting a high rate of exposure. The results of this study demonstrate that spotted fever rickettsioses should be taken into consideration in the diagnosis of tick-transmitted infections in Sweden.     

Serological evidence of Rickettsia infections in forestry rangers in north-eastern Italy

The prevalence of antibodies to Rickettsiae and other tick-borne microrganisms in the sera of 181 forestry rangers from Friuli-Venezia-Giulia, Italy, was examined. Seven (3.9%) sera were positive for Rickettsia conorii and Rickettsia helvetica, as single or dual infections; four of these sera had been found previously to be positive for Borrelia burgdorferi. Antibodies to Coxiella burnetii were detected in five (2.8%) sera, four of which were also positive for B. burgdorferi. These findings indicate that patients in this north-eastern Italian region with fever subsequent to tick-bite should be investigated for Rickettsia and Coxiella infections.     

Characterization of a spotted fever group Rickettsia from Ixodes ricinus ticks in Sweden.

A spotted fever group rickettsia isolated from the common tick, Ixodes ricinus, was genetically characterized by PCR and genomic sequencing. This study was performed with nymphal and adult ticks collected in southern and central Sweden. I. ricinus is the only North European tick species of medical importance which is regularly collected from humans. No species of the genus Rickettsia has previously been found in Scandinavian ticks, nor has any case of domestic rickettsial infection in humans or animals been reported. According to the nucleotide sequencing, the present Rickettsia sp. belongs to the spotted fever group of rickettsiae. Ticks are the most common arthropod reservoirs and vectors of the rickettsiae of this group. Among 748 ticks investigated, 13 (1.7%) were positive for a Rickettsia sp. Borrelia burgdorferi was detected in 52 (7%) of the ticks, a prevalence similar to or somewhat lower than that previously been recorded in other Swedish studies. There was no evidence of ehrlichial or chlamydial DNA in these ticks. The Rickettsia sp. was further characterized by 16S ribosomal DNA (rDNA) sequencing and restriction fragment length polymorphism (RFLP). The 16S rDNA sequencing resulted in a sequence identical to that described for Rickettsia helvetica, but the pattern obtained with RFLP of the citrate synthetase gene diverged from previously known patterns. The rickettsial agent of one tick which was positive by PCR was confirmed by transmission electron microscopy. The morphology of this rickettsia was similar to that of the spotted fever and typhus group rickettsiae. This represents the first documented isolate of a Rickettsia sp. from Swedish ticks.     

Prevalence of spotted fever group rickettsiae in Ixodes ricinus (Acari: Ixodidae) in southern Germany

Host-seeking Ixodes ricinus (L.) (Acari: Ixodidae) ticks were collected systematically, from May to September 2006, at selected sites in southern Germany, including a large city park in Munich. Polymerase chain reactions for amplification of genes of the rickettsial citrate synthase (gltA), the outer membrane proteins A and B (ompA and ompB), and the 16S rDNA were used to investigate 2,861 specimens (adults and nymphs). GltA sequences of spotted fever group rickettsiae were detected in 151 of all samples (5.3%; 95% CI = 4.3-6.2%). Sequencing revealed Rickettsia helvetica in 91.4% of the samples and R. monacensis in 8.6%. Amplification of ompA was not possible for R. helvetica, but in all except one of the R. monacensis. The results were analyzed statistically to test the effects of season, location, developmental stage, and gender of the tick on prevalence of Rickettsia spp. Although rickettsial DNA was detected in all investigated sites, sites in natural forest areas had significantly higher prevalences than sites in landscaped city parks. Adult female and male ticks had a similar prevalence and were significantly more often infected than nymphs. Monthly differences were not statistically significant. These results clearly show that R. helvetica is widespread throughout the study region and could result in a threat to public health in areas of high prevalence.     

Is sarcoidosis a rickettsiosis?

The pathogenesis of sarcoidosis is still largely unknown. The generally accepted theory is that genetically predisposed individuals develop the sarcoid disease reaction as a response to one or more unknown antigen(s). A single study by Nilsson et al has related the development of sarcoidosis to an infection with Rickettsia helvetica. The aim of this thesis was to investigate whether a rickettsial infection is involved in the pathogenesis of sarcoidosis. We used different microbiological methods as serology, polymerase chain reaction, and fluorescent in situ hybridization (FISH) on samples from patients with sarcoidosis and control patients. The thesis compiles the results from four separate studies: The second paper describes a serological survey in historical patient sera. None of the results from the studies supported the hypothesis of Rickettsia being involved in the pathogenesis of sarcoidosis. In conclusion, we could not find evidence to support the primary hypothesis of the study, that a rickettsial infection should be involved in the pathogenesis of sarcoidosis.     

Procalcitonin Concentrations in Patients with Neutropenic Fever

 To assess the usefulness of markers of inflammation in distinguishing bacterial infection from severe systemic nonbacterial inflammation, concentrations of procalcitonin, neopterin, endotoxin, tumor necrosis factor, and interleukin-6 were measured in 28 neutropenic patients at the onset of fever and twice thereafter at 4 h intervals. Infection was found in 11 patients, and 17 patients had fever of undetermined origin. The procalcitonin concentration increased rapidly in patients with infection; the response was detectable within 8 h of the onset of fever. Procalcitonin is a specific but not a sensitive marker of infection in patients with neutropenic fever. Its poor sensitivity was related to an absent or delayed response in patients with gram-positive infections. Considerable overlap between infected and noninfected patients was found in levels of endotoxin, tumor necrosis factor, and interleukin-6.     

Serological follow-up in patients with aorto-iliac disease and evidence of Q fever infection

The aim of this study was to provide data on the risk of developing chronic Q fever in patients with aorto-iliac disease and evidence of previous Q fever infection. Patients with an aortic and/or iliac aneurysm or aorto-iliac reconstruction (aorto-iliac disease) and evidence of previous Q fever infection were included. The presence of phase I and II Coxiella burnetii IgG antibodies was assessed periodically using immunofluorescence assay. A total of 111 patients with aorto-iliac disease were divided into three groups, based upon the serological profile [mean follow-up: 16?±?9 months (mean?±?standard deviation)]. Group 1 consisted of 30 patients with a serological trace of C. burnetii infection (negative IgG phase I, IgG phase II titer of 1:32). Of these, 36.7 % converted to serological profile matching past resolved Q fever. Group 2 included 49 patients with negative IgG phase I titer and IgG phase II titer ≥1:64. No patients developed chronic Q fever, but 14.3 % converted to a positive IgG phase I titer. Group 3 consisted of 32 patients with positive IgG phase I and positive IgG phase II titers, of which 9.4 % developed chronic Q fever (significantly different from group 2, p?=?0.039). The IgG phase I titer increased in 28.1 % of patients (from 1:64 to 1:4,096). The risk of developing chronic Q fever in patients with aorto-iliac disease and previous Q fever infection with a positive IgG phase I titer was 9.4 %. The IgG phase I titer increases or becomes positive in a substantial number of patients. A standardized serological follow-up is proposed.     

Chronic Q fever-related dual-pathogen endocarditis: case series of three patients

Following Coxiella burnetii infection, there is a 1 to 5% risk of chronic Q fever. Endocarditis, mycotic aneurysm, and vascular prosthesis infection are common manifestations. We present three patients with endocarditis by C. burnetii concomitant with another bacterial pathogen. Chronic Q fever should therefore be considered in all endocarditis patients in regions where Q fever is endemic.     

MIP-1 alpha and MIP-1 beta induction by dengue virus

Dengue virus (DV) infection can result in either a mild febrile illness known as dengue fever (DF) or a life-threatening disease called dengue hemorrhagic fever (DHF). DHF is more prevalent in patients undergoing secondary DV infection. This observation has led to the hypothesis that DHF may be the result of immune reactions to the secondary DV infection; an event termed immunopathology. Two cellular factors, MIP-1 alpha and MIP-1 beta, have been found to be induced by infection with DV. MIP-1 induction by DV infection was observed in a myelomonocytic cell line, as well as in peripheral blood mononuclear cells isolated from a dengue naive donor. MIP-1 induction was not due to factors secreted by infected cells. In fact, replication-competent virus was required to induce MIP-1. Evidence is also provided that MIP-1 genes are expressed in patients with dengue disease. It is hypothesized that these chemokines may have roles in the immunopathology of dengue infections and may contribute to fever and bone marrow suppression observed in patients with DV infections.     

Transient CD4/CD8 ratio inversion and aberrant immune activation during dengue virus infection

The immune status after dengue virus infection was studied in dengue patients from an outbreak of serotype 3 dengue virus infection in the southern part of Taiwan during November and December 1998. Consecutive blood samples from 29 dengue patients, of whom 21 had dengue fever and 8 had dengue hemorrhagic fever/dengue shock syndrome, were collected, and the immunophenotypes of the peripheral blood mononuclear cells were determined by flow cytometry. The early activation marker CD69 appeared on lymphocytes and monocytes at day 4 after the onset of fever, and declined afterward. However, a transient reverse in the CD4/CD8 ratio occurred at days 6-10 after the onset of fever. The CD4/CD8 ratio inversion was manifested in 10 of 29 dengue patients and was encountered more frequently in dengue hemorrhagic fever/dengue shock syndrome than in dengue fever patients. Analysis of the clinical blood cell count of these 10 cases showed that increase of immature neutrophils developed at fever days 5-6, CD4(dim) or CD8(dim) monocytosis at days 6-7, and atypical lymphocytosis at days 8-10 after the onset of fever. Serum IL-6 was found at either day 7 or day 9-11. The PHA-stimulated T-cell response was depressed as well. These changes in immune parameters indicate aberrant immune activation during dengue virus infection and might be involved in the pathogenesis of dengue virus infection.     

Antibiotic resistant fever associated with herpes simplex virus infection in neutropenic patients with haematological malignancy.

The incidence of mucocutaneous herpes simplex virus infection confirmed by culture and occurring during febrile neutropenic episodes was determined in 43 patients with haematological malignancy. The outcome of 72 episodes of neutropenic fever was determined and correlated with the presence or absence of herpes simplex virus (HSV) infection. Twenty four patients had mucocutaneous HSV infection during at least one episode. In 24 episodes in which HSV was isolated only 12.5% of fevers responded to antibiotics and 75% of fevers were otherwise unexplained. Conversely, in 48 episodes of neutropenic fever in which HSV was not isolated 67% of fevers responded to antibiotics and only 8.3% were unexplained. The difference in incidence of antibiotic resistant fever in the two groups was significant. There was, therefore, a strong association between mucocutaneous HSV infection and antibiotic resistant fever in immunosuppressed neutropenic patients. As most HSV infections are the result of virus reactivation, establishing the HSV serological state of patients would identify those at risk of infection and hence those in whom the prophylactic use of acyclovir would be indicated.     

Incidence of toxoplasmosis in patients with glandular fever and in healthy blood donors.

The differential diagnosis of the clinical syndrome of glandular fever may include Epstein-Barr virus, cytomegalovirus and Toxoplasma gondii infection. Some general practitioners and clinical laboratories choose to perform serological investigations for toxoplasmosis in all patients with glandular fever, who have negative Paul-Bunnell test results. The validity of this approach was assessed by a comparison of the incidence of toxoplasmosis in healthy blood donors and in a group of patients with clinically diagnosed glandular fever who had negative Paul-Bunnell tests. The results showed no significant difference in the frequency of acute or chronic toxoplasma infection between the two groups. In view of these findings, together with evidence of the lack of appropriate effective therapy for toxoplasmosis in immunocompetent individuals, and the dangers of failing to recognize concurrent severe disease of a separate aetiology, we recommend that Paul-Bunnell negative patients with clinically diagnosed glandular fever are not investigated for toxoplasmosis as a routine. However, these guidelines do not apply to patients at risk of severe sequelae from toxoplasma infection, notably pregnant women, who still require a full assessment.     

体温改变对血液流变性的影响及其临床意义

对４８例确诊为上呼吸道感染具有发热症状患者进行血液流变学测定，与正常对照组比较具有显著性差异。并对感染和发热致血液流变性异常的机理作了进一步研究。临床上许多疾病具有发热症状或伴有感染，这时血液流变性异常改变，一般有微循环障碍，导致组织脏器一系列病理生理变化。因此，控制感染、降低体温有助于疾病治疗和症状缓解。     

Post-infectious fatigue syndrome in dengue infection.

BACKGROUND: Although the acute manifestations of dengue are well known, few studies have assessed the long-term consequences of dengue infection. We prospectively studied the incidence and factors associated with fatigue in a cohort of patients following dengue infection. METHODS: We included patients with serologically confirmed dengue infection admitted to the National University Hospital, Singapore, during a dengue outbreak from October-November 2005. The severity of dengue was graded as dengue fever, dengue haemorrhagic fever and dengue shock syndrome. A follow-up telephone interview was performed two months following hospital discharge, where a Fatigue Questionnaire was administered. The presence of significant fatigue was considered as the main outcome measure. Significance was assessed at P<0.05. RESULTS: One hundred twenty-seven patients, 71 (55.9%) males and 56 (44.1%) females, of mean age 36.06 years (range, 16-70; S.D., 13.722), participated in this study. Twenty-five (19.7%) patients had dengue haemorrhagic fever and the remaining 102 (80.3%) had dengue fever. In multivariate analysis, increased age, female sex, the presence of chills, and the absence of rashes were significantly associated with the development of fatigue post-dengue infection. There was no significant association between fatigue and dengue severity. CONCLUSIONS: This observation represents the first systematic evidence that dengue can result in clinical disease beyond the acute phases of infection. Host factors, such as age and sex may be important in the pathogenesis of this clinical entity.     

Elevation of soluble VCAM-1 plasma levels in children with acute dengue virus infection of varying severity

Approximately 1,000 million infections with dengue viruses are estimated to occur annually. The majority of the cases develop mild disease, whereas only small proportion of the infected individuals develop severe hemorrhagic manifestations at the end of the acute phase of illness. In this study, the value of plasma levels of vascular cell adhesion molecule 1 (VCAM-1) in the pathogenesis and prognosis of dengue illness was investigated in children with dengue infections of varying severity. The plasma levels of soluble VCAM-1 (sVCAM-1) were measured in serial plasma samples obtained from 168 children aged between 7 months and 14 years with confirmed dengue infection. Of those children, 71 were suffering from dengue fever, 30 were suffering from dengue hemorrhagic fever, and 67 were suffering from dengue shock syndrome. Plasma samples obtained from 21 patients with febrile illness other than dengue served as controls. A commercially available kit (R&D Systems, Oxon, UK) was used to measure the levels of sVCAM-1 in plasma samples. sVCAM-1 was elevated during acute dengue infection, and significantly elevated among dengue shock syndrome patients as compared to dengue fever or dengue hemorrhagic fever patients (P < 0.05). Statistical analysis revealed that sVCAM-1 was associated with dengue disease severity and the time post infection (acute vs. convalescent phase) and not with age, sex, or previous exposure of the patients to dengue infection. A significant difference was found in the plasma levels of sVCAM-1 between dengue shock syndrome and dengue fever patients, however, the prognostic value of this marker in the acute stage of dengue illness proved to be limited. These data also favor to study the further elucidation of the role of sVCAM-1 in the pathogenesis of dengue infections.     

Increasing rates and clinical consequences of nalidixic acid-resistant isolates causing enteric fever in returned travellers: an 18-year experience

The purpose of this study was to examine the rate and clinical consequences of nalidixic acid-resistant (NAR) isolates in travellers with enteric fever presenting to a hospital in a developed country. We retrospectively examined microbiologically confirmed cases of enteric fever in adult returned travellers over an 18-year period presenting to two tertiary referral hospitals in Melbourne, Australia. There were 59 cases of Salmonella typhi infection, 43 cases of S. paratyphi A infection and two cases of S. paratyphi B infection. Most patients reported recent travel to India (36%) or Indonesia (29%). NAR isolates were commonly encountered (41% of all isolates), particularly from India (75%), Pakistan (80%) and Bangladesh (60%). The number of NAR isolates increased progressively after 2003. Patients with NAR isolates had prolonged mean fever clearance time (5.6 vs. 3.3 days, P = 0.03) and prolonged hospital stay (7.9 vs. 5.7 days, P = 0.02) compared to non-resistant isolates. This represents the largest report of NAR enteric fever in returned travellers. NAR isolates predominate in cases of enteric fever from South Asia and result in prolonged fever clearance time and hospital stay. Empiric therapy with alternative antibiotics such as ceftriaxone or azithromycin should be considered in patients with suspected enteric fever from this region.     

Crimean Congo hemorrhagic fever virus infects human monocyte-derived dendritic cells

For some patients infection with Crimean Congo hemorrhagic fever virus (CCHFV) causes a severe disease characterized by fever, vascular leakage and coagulopathy. Knowledge of CCHF pathogenesis is limited and today there is no information about the specific target cells of CCHFV. In this study we analyzed the permissiveness of human peripheral blood mononuclear cells (PBMCs) including monocyte-derived dendritic cells (moDCs) to CCHFV infection. Interestingly, we found that moDCs are the most permissive to CCHFV infection and this infection induced cytokine release from moDCs. Furthermore, supernatants from infected moDCs were found to activate human endothelial cells.     

WBC、CRP和PCT在急诊发热患者诊治中的应用

目的 探讨WBC、CRP和PCT在急诊发热患者诊治中的应用效果。方法 选用2015年11月~2017年11月中山市人民医院救治的119例急诊发热患者为研究对象,给予患者实施WBC、CRP和PCT检测和病因学检查,依据诊断结果中是否感染细菌分为对照组和观察组,对照组32例为非细菌感染患者,观察组87例为细菌感染患者,对比两组WBC、CRP、PCT诊断情况。结果 观察组的WBC、CRP、PCT水平高于对照组,血液WBC、CRP、PCT的指标中,敏感度、特异度等进行比较,三种联合检测的敏感度和准确度最高。结论 WBC、CRP和PCT在急诊发热患者诊治中的应用效果显著,细菌感染发热患者WBC、CRP和PCT水平明显提升,PCT的特异性更优,CRP敏感度更优,联合检测的应用价值最高。     

Bartonella henselae infection as a cause of fever of unknown origin

Fourteen of 41 patients (34%) with a serological diagnosis of Bartonella henselae infection were found to have prolonged fever or fever of unknown origin, suggesting that generalized systemic B. henselae infection is not rare in immunocompetent healthy individuals.     

Serum cytokine/chemokine profiles in patients with dengue fever (DF) and dengue hemorrhagic fever (FHD) by using protein array

BackgroundDENV infection can induce different clinical manifestations varying from mild forms to dengue fever (DF) or the severe hemorrhagic fever (DHF). Several factors are involved in the progression from DF to DHF. No marker is available to predict this progression. Such biomarker could allow a suitable medical care at the beginning of the infection, improving patient prognosis.ObjectivesThe aim of this study was to compare the serum expression levels of acute phase proteins in a well-established cohort of dengue fever (DF) and dengue hemorrhagic fever (DHF) patients, in order to individuate a prognostic marker of diseases severity.Study designThe serum levels of 36 cytokines, chemokines and acute phase proteins were determined in DF and DHF patients and compared to healthy volunteers using a multiplex protein array and near-infrared (NIR) fluorescence detection. Serum levels of IL-1ra, IL-23, MIF, sCD40 ligand, IP-10 and GRO-α were also determined by ELISA.ResultsAt the early stages of infection, GRO-α and IP-10 expression levels were different in DF compared to DHF patients. Besides, GRO-α was positively correlated with platelet counts and IP-10 was negatively correlated with total protein levels.ConclusionsThese findings suggest that high levels of GRO-α during acute DENV infection may be associated with a good prognosis, while high levels of IP-10 may be a warning sign of infection severity.