A combination of interferon-gamma and interleukin-2 production by Coxiella burnetii-stimulated circulating cells discriminates between chronic Q fever and past Q fever

Infection with Coxiella burnetii may lead to life-threatening chronic Q fever endocarditis or vascular infections, which are often difficult to diagnose. The present study aims to investigate whether measurement of in-vitro interferon-gamma (IFN-γ) production, a key cytokine in the immune response against C. burnetii, differentiates chronic from a past cleared infection, and whether measurement of other cytokines would improve the discriminative power. First, C. burnetii-specific IFN-γ production was measured in whole blood of 28 definite chronic Q fever patients and compared with 135 individuals with past Q fever (seropositive controls) and 908 seronegative controls. IFN-γ production was significantly higher in chronic Q fever patients than in controls, but with overlapping values between patients and seropositives. Secondly, the production of a series of other cytokines was measured in a subset of patients and controls, which showed that interleukin (IL)-2 production was significantly lower in patients than in seropositive controls. Subsequently, measuring IL-2 in all patients and all controls with substantial IFN-γ production showed that an IFN-γ/IL-2 ratio >11 had a sensitivity and specificity of 79% and 96%, respectively, to diagnose chronic Q fever. This indicates that a high IFN-γ/IL-2 ratio is highly suggestive for chronic Q fever. In an additional group of 25 individuals with persistent high anti-Coxiella phase I IgG titres without definite chronic infection, all but six showed an IFN-γ/IL-2 ratio <11. In conclusion, these findings hold promise for the often difficult diagnostic work-up of Q fever and the IFN-γ/IL-2 ratio may be used as an additional diagnostic marker.     

Histological characteristics of the abdominal aortic wall in patients with vascular chronic Q fever

The aim of this study was to describe specific histological findings of the Coxiella burnetii‐infected aneurysmal abdominal aortic wall. Tissue samples of the aneurysmal abdominal aortic wall from seven patients with chronic Q fever and 15 patients without evidence of Q fever infection were analysed and compared. Chronic Q fever was diagnosed using serology and tissue PCR analysis. Histological sections were stained using haematoxylin and eosin staining, Elastica van Gieson staining and immunohistochemical staining for macrophages (CD68), T lymphocytes (CD3), T lymphocyte subsets (CD4 and CD8) and B lymphocytes (CD20). Samples were scored by one pathologist, blinded for Q fever status, using a standard score form. Seven tissue samples from patients with chronic Q fever and 15 tissue samples from patients without Q fever were collected. Four of seven chronic Q fever samples showed a necrotizing granulomatous response of the vascular wall, which was characterized by necrotic core of the arteriosclerotic plaque (P = 0.005) and a presence of high numbers of macrophages in the adventitia (P = 0.007) distributed in typical palisading formation (P = 0.005) and surrounded by the presence of high numbers of T lymphocytes located diffusely in media and adventitia. Necrotizing granulomas are a histological finding in the C. burnetii‐infected aneurysmal abdominal aortic wall. Chronic Q fever should be included in the list of infectious diseases with necrotizing granulomatous response, such as tuberculosis, cat scratch disease and syphilis.     

Single nucleotide polymorphism (SNP) rs3751143 in P2RX7 is associated with therapy failure in chronic Q fever while rs7125062 in MMP1 is associated with fewer complications

ObjectivesChronic Q fever is a persistent infection with the intracellular bacterium Coxiella burnetii. Development of chronic Q fever is associated with single nucleotide polymorphisms (SNPs) in genes encoding for pattern recognition receptors, for phagolysosomal pathway components and for matrix metalloproteinases (MMPs). We evaluated the association of SNPs in these innate-immunity and MMP genes with clinical outcomes.MethodsSNPs were selected from previous association studies and analysed in a cohort of patients with chronic Q fever. The primary outcome was all-cause mortality; secondary outcomes were therapy failure and chronic Q fever–related complications. Subdistribution hazard ratios (SHR) were calculated.ResultsNineteen SNPs were analysed in 134 patients with proven and 29 with probable chronic Q fever. In multivariable analysis, none of the selected SNPs was associated with all-cause mortality. However, SNP rs3751143 located in P2RX7 appeared to be associated with therapy failure (SHR 2.42; 95% confidence interval, 1.16–5.05; p 0.02), which is in line with other reports, showing that a loss of function of the P2X7 receptor leads to inefficient killing of intracellular organisms. In addition, SNP rs7125062 located in MMP1, involved in the cleavage of extracellular matrix, was associated with fewer chronic Q fever–related complications such as acute aneurysms (SHR 0.49; 95% confidence interval, 0.29–0.83; p 0.008).ConclusionsA polymorphism in P2RX7, known to lead to loss of function of the receptor and inefficient killing of intracellular organisms, and a polymorphism in MMP1 were respectively associated with more therapy failures and fewer complications such as acute aneurysms in patients with chronic Q fever.     

Long-term serological follow-up after primary Coxiella burnetii infection in patients with vascular risk factors for chronic Q fever

We evaluated the long-term serological follow-up of patients with vascular risk factors for chronic Q fever that were previously Coxiella burnetii seropositive. C. burnetii phase I IgG titers were reevaluated in patients that gave informed consent or retrospectively collected in patients already deceased or lost to follow-up. Of 107 patients, 25 (23.4%) became seronegative, 77 (72.0%) retained a profile of past resolved Q fever infection, and five (4.7%) developed chronic Q fever. We urge clinicians to stay vigilant for chronic Q fever beyond two years after primary infection and perform serological testing based on clinical presentation.

     

The diagnostic value of serological studies in pediatric patients with acute Mycoplasma pneumoniae infection

BackgroundMycoplasma pneumoniae is a common pathogen of respiratory tract infections in pediatric patients. Serological studies are traditional methods for the diagnosis. However, early diagnosis of M. pneumoniae infections remains problematic. We investigate the value of early serum immunoglobulin A (IgA), in addition to immunoglobulin G (IgG), and immunoglobulin M (IgM) levels, in children infected with M. pneumoniae.MethodsFrom August 2016 to February 2017, we enrolled pediatric patients based on both clinical symptoms and chest x-ray, and confirmed by positive throat culture for M. pneumoniae. Serum titers of M. pneumoniae IgM, IgG, and IgA during the acute phase were checked. All respiratory samples were further analyzed by polymerase chain reaction (PCR). Diagnostic values of different tests were evaluated.ResultsFifty-six patients fulfilled the diagnostic criteria, with a median age of 4.84 years. Most of them (89.3%) were enrolled within 7 days of disease onset. PCR was positive in 71.4% of the study population. Early IgG samples were of limited value in diagnosing M. pneumoniae infection, of which 89.3% showed a negative result. Positive rates of early serum IgA and IgM were 48.2% and 46.4%, respectively. In combination with IgA and/or IgM, the sensitivity increased to 71.4% during their early clinical course.ConclusionsIn the pediatric population, combined serological tests of M. pneumoniae IgA and IgM, offer an accurate method of early diagnosis comparable to that of PCR, and can be an alternative choice for prompt detection of mycoplasma infections when PCR and culture are not available.     

Genetic variations in innate immunity genes affect response to Coxiella burnetii and are associated with susceptibility to chronic Q fever

ObjectivesChronic Q fever is a persistent infection, mostly of aortic aneurysms, vascular prostheses or damaged heart valves, caused by the intracellular bacterium Coxiella burnetii. Only a fraction of C. burnetii-infected individuals at risk develop chronic Q fever. In these individuals, a defective innate immune response may contribute to the development of chronic Q fever. We assessed whether genetic variations in genes involved in the killing machinery for C. burnetii by macrophages, contribute to the progression to chronic Q fever.MethodsThe prevalence of 66 single nucleotide polymorphisms (SNPs) in 31 genes pivotal in phagolysosomal maturation, bacterial killing and autophagy, was determined in 173 chronic Q fever patients and 184 controls with risk factors for chronic Q fever and serological evidence of a C. burnetii infection. Associations were detected with univariate logistic regression models. To assess the effect of these SNPs on innate responses to C. burnetii, the C. burnetii-induced cytokine production and basal reactive oxygen species production of healthy volunteers was determined.ResultsRAB7A (rs13081864) and P2RX7 loss-of-function SNP (rs3751143) were more common in chronic Q fever patients than in controls. RAB5A (rs8682), P2RX7 gain-of-function SNP (rs1718119), MAP1LC3A (rs1040747) and ATG5 (rs2245214) were more common in controls. In healthy volunteers, RAB7A (rs13081864) and MAP1LC3A (rs1040747) influenced the C. burnetii-induced cytokine production. RAB7A (rs13081864) modulated basal reactive oxygen species production.ConclusionsRAB7A (rs13081864) and P2RX7 (rs3751143) are associated with the development of chronic Q fever, whereas RAB5A (rs8682), P2RX7 (rs1718119), MAP1LC3A (rs1040747) and ATG5 (rs2245214) may have protective effects.     

Association between serological evidence of past Coxiella burnetii infection and atherosclerotic cardiovascular disease in elderly patients

Q fever, caused by Coxiella burnetii, may cause vascular complications, but the role that this infection may play in the development of atherosclerotic cardiovascular disease remains unknown. This study examined the association between Q fever serology and cardiovascular disease in a region where Q fever is endemic. A case-control study was conducted in the Hospital Universitario de Burgos (Spain) between February 2011 and June 2012. A total of 513 samples were tested, from 454 hospitalized patients ≥65 years old, of whom 164 were cases (patients with prevalent or incident coronary heart, cerebrovascular or peripheral artery, disease) and 290 controls (patients without cardiovascular disease). Serum IgG antibody phase II titres against Q fever were determined by immunofluorescence assay. Seropositivity (titres ≥1:256) was detected in 84/164 (51.2%) cases and in 109/290 (37.6%) controls (p = 0.005; OR, 1.7; 95% CI, 1.1–2.5). This ratio increases when adjusted for sex, hypertension, dyslipidaemia, smoking, diabetes and atrial fibrillation (OR, 2.6; 95% CI, 1.5–4.7). The geometric mean titre (GMT) for C. burnetii phase II assay was higher in cases than in controls (p = 0.004). We found no significant relationship between cardiovascular disease and C. pneumoniae, and Cytomegalovirus seropositivity (both determined by the IgG ELISA method). In conclusion, serological evidence of past Q fever is associated with atherosclerotic cardiovascular disease in elderly patients in an endemic region.     

Changes in circulating immune complex concentrations and antibody titres during treatment of Q fever endocarditis.

Serum samples from 20 patients with Q fever endocarditis were tested for the presence of circulating immune complexes to see whether their concentrations correlated with antibody titres during treatment and whether they could be used to monitor the response to antimicrobial treatment. Circulating immune complexes were found in all 20 patients. The concentrations in 15 patients correlated with either or both of the Q fever phase 1 and phase 2 antibody titres obtained during treatment. In the other five patients no correlation with the antibody titres was found. There was no association between circulating immune complex concentrations and clinical response to treatment.     

Circulating cytokine balance and activation markers of leucocytes in Q fever

As Q fever is associated with an inflammatory syndrome, we determined circulating levels of inflammatory cytokines, cytokine antagonists, and activation markers of leucocytes in patients with acute Q fever and Q fever endocarditis. Tumour necrosis factor (TNF) and IL-6, but not IL-1β, were markedly increased compared with controls. Cytokine antagonists and activation markers of leucocytes were profoundly different in acute and chronic Q fever. IL-1 receptor antagonist and TNF receptor type II were significantly increased in patients with acute Q fever, suggesting a shift of cytokine balance towards cytokine antagonists. The activation marker of B cells, sCD23, was significantly increased in Q fever endocarditis compared with controls and patients with acute Q fever. In a 2-year follow-up study of patients with Q fever endocarditis, sCD23 and specific IgG levels slowly decreased in patients whose symptoms resolved, but remained high in those who required prolonged treatment.     

Characteristics of scrub typhus,murine typhus,and Q fever among elderly patients: Prolonged prothrombin time as a predictor for severity

Background/purpose

The clinical manifestations of scrub typhus, murine typhus and acute Q fever in the elderly are not clear.

Diagnostic and prognostic value of Ischemia‐modified albumin in patients with Crimean‐Congo hemorrhagic fever

The aim of this study was to determine the diagnostic and prognostic significance of ischemia modified albumin (IMA) levels in patients with Crimean‐Congo hemorrhagic fever (CCHF). This retrospective study was conducted with patients with CCHF. IMA levels in patients with CCHF were determined using the rapid colorimetric method. IMA levels of CCHF patients were significantly higher compared with the control group (P = 0.0001). At an IMA cut‐off point of 0.555 ABSU (absorbance units), sensitivity was 65.1%, specificity 82.5%, positive predictive values (PPV) 82.5%, and negative predictive values (NPV) 65.1%. IMA levels of patients with hemorrhage were significantly higher compared with patients without hemorrhage (P = 0.005). IMA has been validated as both a new and sensitive ischemia and oxidative stress biomarker. In addition to its diagnostic significance, IMA investigated in CCHF patients at time of arrival may be an important marker with its prognostic role in determining in the early stage whether the disease will follow a hemorrhagic course. J. Med. Virol. 85:684–688, 2013. © 2013 Wiley Periodicals, Inc.     

The sexual dimorphism of anticardiolipin autoantibodies in acute Q fever patients

ObjectivesQ fever is a zoonotic disease caused by Coxiella burnetii which affects men more than women (sex ratio men/women: 2.2). Acute Q fever complications are associated with elevation of anticardiolipin (aCL) antibodies. Here, we investigate the sexual dimorphism of aCL antibodies during acute C. burnetii infection.MethodsIgG aCL antibodies were evaluated at the time of Q fever serological diagnosis with enzyme-linked immunosorbent assay. Results were analysed according to sex.ResultsAmong the 1323 patients with Q fever tested for aCL, 1013 had acute Q fever (692 men/321 women) and 310 had persistent focalized infection (226 men/84 women). In cases of acute Q fever, men presented a significantly higher proportion of positive aCL antibodies (351/692, 50.7%) than women (113/321, 35.2%) (p <0.05). In addition, men had significantly higher aCL antibodies levels than women (p <0.001).ConclusionsWe highlight a relationship between sex and markers of autoimmunity during Q fever. Further investigations are necessary to better understand the mechanisms of this sexual dimorphism.     

A possible link between recurrent upper respiratory tract infections and lower cytokine production in patients with Q fever fatigue syndrome

Besides fatigue, many Q fever fatigue syndrome (QFS) patients also complain of frequently recurring upper respiratory tract infections with severe symptoms. We investigated whether immunologic dysregulation contributes to these complaints. Cytokine and chemokine production was measured after stimulating monocytes of QFS patients and age‐ and sex‐matched healthy controls with LPS and several viral ligands. The H3K4me3 mark of open chromatin was measured at the promoter regions of cytokines and chemokines that differed significantly from healthy controls. Monocytes of QFS patients produced significantly less TNF‐α (p = 0.032), IL‐1β (0.004, 0.024, and 0.008), IL‐6 (0.043), RANTES (0.033), IP‐10 (0.049), MCP‐1 (0.022), IL‐ 13 (0.029), and IL‐10 (0.026) than healthy controls when stimulated with various ligands. H3K4me3 expression was significantly lower in QFS patients than in healthy controls on the promoter regions of IL‐1β (p = 0.004), MCP‐1 (<0.001 and <0.001), IP‐10 (<0.001), IL‐10 (0.041), and IL‐13 (<0.001, <0.001, and 0.001). QFS patients showed diminished cytokine responses to various stimuli compared to age‐ and sex‐matched healthy controls, likely due to epigenetic remodeling and long‐term memory as a result from the acute Q fever infection. This might explain the upper respiratory tract ailments in QFS.     

慢性病毒性肝炎临床与病理的相关性研究

目的：研究慢性病毒性肝炎（CH）临床与病理的相关性及CH的临床诊断。方法：对973例CH患者血清生化指标、影像学检查、症状与体征等多种因素与肝组织病理损伤程度进行单因素及多因素判别分析，采用肝功能指数（AAPEA指数）分析血清生化指标在CH诊断中的应用。结果：CH患者凝血酶原活动度（PTA）、血清丙氨酸转氨酶（ALT）、总胆红毒（TBIL）、白蛋白（ALB）、白／球蛋白比值（A／G）、蛋白电泳γ球蛋白（γG）、天冬氨酸转氨酶（AST）、胆碱酯酶（CHE）等生化指标及B超脾脏厚度等，与肝组织病理损伤程度密切相关；AST反映肝脏炎症活动程度优于ALT。多因素判别分析总体误判率为28.1%，但对中、重度误判率较率。肝功能指数（AAPEA）指数与CH肝组织炎症活动程度、纤维化程度及病理分度的相关系数分别为0．559、0．545及0．529（P＜0．0001）。结论：PA、ALT、TBIL、ALB、A／G、γG、CHE、AST等生化指标以及B超脾脏厚度在判定CH程度方面有重要意义。AST反映肝脏炎症活动程度优于ALT。多因素判别分析对CH中、重度误判率较高。AAPEA指数与病理诊断符合率比单项指标判定为高。     

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.     

Churg-Strauss syndrome: the clinical features and long-term follow-up of 17 patients

Churg-Strauss syndrome (CSS) is a rare multi-system vasculitis; some cases have been reported in Korea. The aim of this study is to describe the clinical features, treatment outcome, and long-term follow-up of CSS from a single Korean medical center. Between 1995 and 2004, seventeen patients were diagnosed with CSS at the Department of Medicine of the Samsung Medical Center, Sungkyunkwan University School of Medicine. The diagnosis of CSS is based on the classification criteria of the American Collage of Rheumatology. All patients had asthma. As in other case series, the lung, peripheral nervous system, and skin were the most commonly involved organs. During the active stage of the disease, most of the patients exhibited peripheral blood eosinophilia and an elevated serum eosinophil cationic protein level. Ten patients were treated with pulses of methylprednisolone followed by tapering and cyclophosphamide, and the others were treated with corticosteroids alone. The outcomes after long-term follow-up were generally good. One patient who was refractory to initial treatment died of heart failure during the follow-up period. CSS was highly variable in its presentation and course. The manifestations may range from mild symptoms to life-threatening conditions. The outcome after long-term follow-up was as good as that of previous studies.     

Neurophysiological aspects and their relationship to clinical and functional impairment in patients with chronic obstructive pulmonary disease

OBJECTIVE:

The purpose was to assess functional (balance L–L and A–P displacement, sit‐to‐stand test (SST) and Tinetti scale – balance and gait) and neurophysiological aspects (patellar and Achilles reflex and strength) relating these responses to the BODE Index.

INTRODUCTION:

The neurophysiological alterations found in patients with chronic obstructive pulmonary disease (COPD) are associated with the severity of the disease. There is also involvement of peripheral muscle which, in combination with neurophysiological impairment, may further compromise the functional activity of these patients.

METHODS:

A cross‐sectional study design was used. Twenty‐two patients with moderate to very severe COPD (>60 years) and 16 age‐matched healthy volunteers served as the control group (CG). The subjects performed spirometry and several measures of static and dynamic balance, monosynaptic reflexes, peripheral muscle strength, SST and the 6‐minute walk test.

RESULTS:

The individuals with COPD had a reduced reflex response, 36.77±3.23 (p<0.05) and 43.54±6.60 (p<0.05), achieved a lower number repetitions on the SST 19.27±3.88 (p<0.05), exhibited lesser peripheral muscle strength on the femoral quadriceps muscle, 24.98±6.88 (p<0.05) and exhibited deficits in functional balance and gait on the Tinetti scale, 26.86±1.69 (p<0.05), compared with the CG. The BODE Index demonstrated correlations with balance assessment (determined by the Tinetti scale), r = 0.59 (p<0.05) and the sit‐to‐stand test, r = 0.78 (p<0.05).

CONCLUSIONS:

The individuals with COPD had functional and neurophysiological alterations in comparison with the control group. The BODE Index was correlated with the Tinetti scale and the SST. Both are functional tests, easy to administer, low cost and feasible, especially the SST. These results suggest a worse prognosis; however, more studies are needed to identify the causes of these changes and the repercussions that could result in their activities of daily living.     

Diagnostic value of neopterin during neutropenic fever and determination of disease activity in childhood leukemias

Neopterin, a pteridine group compound that is secreted from macrophages is shown to be increased in adult leukemia; however there are few studies in childhood leukemia. This study aimed to investigate neopterin levels during childhood leukemia treatment and neutropenic fever episodes for the possibility of using as a marker for disease activity and differentiation of infections. A total of 44 children with acute leukemia, 19 children with infection (control group 1) and 21 healthy children (control group 2) were studied. Median serum neopterin level before induction chemotherapy (day 0) in 25 children (patient group 1) was significantly higher (27.7 nmol/L) than those at the beginning of 30 febrile episodes in 19 children in bone marrow remission (2.2 nmol/L) (patient group 2) and in control group 2 (0.4 nmol/L) (p< 0.05). It was (27.7 nmol/L) also significantly higher in control group 1 than in patient group 2 and control group 2 (p< 0.05). Serum neopterin levels at day 15 (2.1 mmol/L) and day 33 (0.4 mmol/L) of induction were significantly lower than day 0 of ALL subgroup at patient group 1. There were no significant difference in neopterin levels between days 0, 3 and 5 of neutropenic fever as well as between patients with microbiologically and/or clinically documented infections and those with fever of unknown origin in patient group 2 (p> 0.05). Serum neopterin did not show significant correlation with absolute neutrophil count and absolute monocyte count (p> 0.05). In conclusion, elevated neopterin at diagnosis of leukemia with decrement during induction therapy suggest that it might be an indicator of leukemic process; however larger studies for its role in identifying infections are warranted.