HMGB1, anti-HMGB1 antibodies, and ratio of HMGB1/anti-HMGB1 antibodies as diagnosis indicator in fever of unknown origin.

To evaluate the feasibility of serum HMGB1, anti-HMGB1 antibodies, and HMGB1/anti-HMGB1 ratio as a diagnosis indicator of initial clinical classification in patients with fever of unknown origin (FUO). Ninety-four patients with classical FUO and ninety healthy controls were enrolled in this study. The subjects' clinical data and serum were collected. The serum concentration of HMGB1 was detected by a commercial HMGB1 ELISA kit, while the serum concentration of anti-HMGB1 antibodies were detected by an in-house built anti-HMGB1 antibodies ELISA kit and further confirmed by immunoblotting. According to the hospital diagnosis on discharge, ninety-four FUO patients were divided into four groups, Infectious disease subgroup, autoimmune disease subgroup, malignant tumor subgroup, and undetermined subgroup. The concentrations of HMGB1 in the infectious disease subgroup and autoimmune disease subgroup were higher than those in the malignant tumor subgroup, undetermined subgroup, and healthy control group. The concentration of anti-HMGB1 antibodies in autoimmune disease subtype group was higher than those in other subgroups as well as healthy control group. According to the distribution of HMGB1 and anti-HMGB1 in scatter plots of the patients with FUO, we found that the ratio of serum HMGB1/anti-HMGB1 is an ideal clinical indicator for differential diagnosis of different subtypes of FUO. The best cut-off was 0.75, and the sensitivity, specificity, and AUC were 66.67%, 87.32%, and 0.8, respectively. Correlation analysis showed that serum concentration of HMGB1 was moderately correlated with CRP in infectious diseases subgroup, and the serum concentration of anti-HMGB1 antibodies was strongly correlated with erythrocyte sedimentation rate in autoimmune disease subgroup. Our study had showed that serum HMGB1/anti-HMGB1 antibodies ratio can help clinicians identify FUO subtypes, thereby avoiding many unnecessary examinations and tests, and improving the effectiveness of clinical diagnosis and treatment of FUO.

Does rehabilitation pose a risk to patients suffering from haemato-oncological diseases? Results of a monocentric, retrospective analysis in Germany.

OBJECTIVE: Patients suffering from haemato-oncological diseases tend to have a weakened immune system after the end of their therapy. To avoid infections, patients are advised to limit contact with other people. This poses the question whether a stay at a rehabilitation facility can be recommended. METHODS: We report about 134 rehabilitation stays of patients. Premature discontinuation of the rehabilitation stay was selected as the criterion for a serious complication during the rehabilitation, and the underlying reasons were analysed. RESULTS: Compared to the discontinuation rates of patients suffering from solid tumours (2.4%), the percentage of haemato-oncological patients ending prematurely their rehabilitation stay (8.2%) is significantly increased. This rises to 17.1% for patients who have undergone an allogeneic stem cell transplantation. The analysis of the discontinuation reasons revealed that they were not directly connected to the rehabilitation. Apart from the already known risk factors for premature termination of the rehabilitation stay, we have identified the period (days) between the last therapy and the beginning of the rehabilitation stay as a risk factor. CONCLUSIONS: We show for the first time that a rehabilitation stay does not pose additional risks for patients suffering from haemato-oncological diseases.

Diagnostic utility of bone marrow examination in evaluation of fever: a descriptive study on 98 immunocompetent adults from a tertiary care institute in south India.

Five-year clinico-laboratory data from 99 (one HIV seropositive) adults (mean age = 41.3 ± 20.4 years) who underwent bone marrow examination for fever persisting for ≥ 1 week were analysed and correlated with microbiological characteristics. Infections, reactive marrow changes and haematolymphoid malignancies were most commonly associated with fever. A high concordance rate of 71% was noted between aspiration and trephine biopsies. Bone marrow granulomas (BMG) were seen exclusively on sections and were most commonly of tubercular and typhoidal in origin (two Salmonella Typhi, one Salmonella Paratyphi A). The common aetiologies associated with fever and cytopenia(s) were BMG, acute leukaemia and haemophagocytic lymphohistiocytosis (HLH; n = 3). The yield from bone marrow culture was inferior compared to other body fluids. In conclusion, bone marrow histology is superior to smears in the evaluation of prolonged fever. Marrow culture may not be useful in immunocompetent individuals other than if Salmonellosis is suspected.

Prevalence of scrub typhus in pyrexia of unknown origin and assessment of interleukin-8, tumor necrosis factor-alpha, and interferon-gamma levels in scrub typhus-positive patients.

BACKGROUND: Scrub typhus is lesser known cause of fever of unknown origin in India. Even if there have been reports documenting the prevalence of scrub typhus in different parts of India, it is still an unknown entity, and clinicians usually do not consider it as differential diagnosis. The present study was performed to document the prevalence of scrub typhus among febrile patients in western part of Uttar Pradesh and to assess the clinical profile of infected patients on the one hand and knowledge, attitude, and practices among clinicians on the other. MATERIALS AND METHODS: A total of 357 adult patients with fever of more than 5-day duration were recruited. All patients underwent complete physical examination, and detailed clinical history was elicited as per predesigned pro forma. After primary screening to rule out malaria, enteric fever, and leptospirosis infection, secondary screening for scrub typhus was done by rapid screen test and IgM ELISA. RESULTS: Scrub typhus infection was positive in 91 (25.5%) cases. The most common symptoms among the patients were fever (100%), pain in abdomen (79.1%), pedal edema 56 (61.5%), rash 44 (48.3%), headache 44 (48.3%), vomiting 42 (46.1%), constipation 33 (36.2%), cough 28 (30.7%), and lymphadenopathy 20 (21.9%). The median values of interleukin-8, interferon-gamma, and tumor necrosis factor-alpha in healthy controls were 15.54 pg/ml, 7.77 pg/ml, and 54.1 pg/ml, respectively, while the median values of these cytokines in scrub typhus-positive patients were 21.04 pg/ml, 8.74 pg/ml, and 73.8 pg/ml, respectively. CONCLUSION: Our results highlight that scrub typhus infection is an important cause of pyrexia of unknown origin, and active surveillance is necessary to assess the exact magnitude and distribution of the disease.

[Autoinflammatory Diseases as a Differential Diagnosis of Fever of Unknown Origin]. / Autoinflammatorische Erkrankungen als Differenzialdiagnose des Fiebers unklarer Genese.

Fever is the most leading symptom of autoinflammatory diseases (AID). Therefore, AID have to be considered in differential diagnosis concerning fever of unknown origin. Unspecific Inflammatory manifestations may lead to misinterpretations that possibly cause irreversible organ damage. Effective treatment options are available and imply profound diagnostics.

Clinical significance of pre-transplant circulating CD3+ CD4+ CD161+ cell frequency on the occurrence of neutropenic infections after allogeneic stem cell transplantation.

BACKGROUND: Few studies have been performed to identify factors that are associated with an increased risk of infections during the neutropenic period in patients undergoing allogeneic stem cell transplantation (allo-SCT). The aim of this study was to identify the host immune cells responsible for infections before engraftment. METHODS: A total of 282 patients who underwent allo-SCT were enrolled. Peripheral blood samples were collected before conditioning therapy. Expression of CD161-expressing T cells, natural killer cells, and immature myeloid cells was analyzed by flow cytometry. Microbially and clinically defined infections and fevers of unknown origin as proposed by the Immunocompromised Host Society were included in this study. RESULTS: The median age was 45 years (range, 16-68 years). Patients had various hematologic disorders and were transplanted from human leukocyte antigen (HLA)-matched siblings, unrelated donors, and familial HLA-mismatched donors. In univariate analysis, younger age and a familial HLA-mismatched donor were risk factors for the occurrence of infections. After adjusting for potential variables in univariate analysis, multivariate analyses revealed that a lower frequency of CD3+ CD4+ CD161+ cells was significantly associated with the occurrence of neutropenic infections. An age of 35 years or younger and allografting from familial HLA-mismatched donors showed a trend toward higher infection rates. CONCLUSION: Our data indicated that a lower frequency of CD3+ CD4+ CD161+ T cells in peripheral blood before conditioning therapy was associated with a higher incidence of infection during the neutropenic period. These results suggest that recipient innate T cells with expression of C-type lectin CD161 can guard against infections before engraftment.

Relationships between Causes of Fever of Unknown Origin and Inflammatory Markers: A Multicenter Collaborative Retrospective Study.

OBJECTIVE: Although inflammatory markers, such as the white blood cell (WBC) count, erythrocyte sedimentation rate (ESR) and levels of C-reactive protein (CRP) and procalcitonin, are widely used to differentiate causes of fever of unknown origin (FUO), little is known about the usefulness of this approach. We evaluated relationships between the causes of classical FUO and the levels of inflammatory markers. METHODS: A nationwide retrospective study including 17 hospitals affiliated with the Japanese Society of Hospital General Medicine was conducted. PATIENTS: This study included 121 patients ≥18 years old diagnosed with "classical FUO" (axillary temperature ≥38.0°C at least twice over a ≥3-week period without elucidation of the cause on three outpatient visits or during three days of hospitalization) between January and December 2011. RESULTS: The causative disease was infectious diseases in 28 patients (23.1%), non-infectious inflammatory disease (NIID) in 37 patients (30.6%), malignancy in 13 patients (10.7%), other in 15 patients (12.4%) and unknown in 28 patients (23.1%). The rate of malignancy was significantly higher for a WBC count of <4,000/µL than for a WBC count of 4,000-8,000/µL (p=0.015). Among the patients with a higher WBC count, the rate of FUO due to NIID tended to be higher and the number of unknown cases tended to be lower. All FUO patients with malignancy showed an ESR of >40 mm/h. A normal ESR appeared to constitute powerful evidence for excluding a diagnosis of malignancy. In contrast, the concentrations of both serum CRP and procalcitonin appeared to be unrelated to the causative disease. CONCLUSION: The present study identified inflammatory markers that should be considered in the differential diagnosis of classical FUO, providing useful information for future diagnosis.

Autoinflammatory syndromes as causes of fever of unknown origin.

The systemic autoinflammatory syndromes often present with recurrent fevers. They have proved exceptionally informative about the innate immune system. Although extremely rare, they are important to recognise, as many can now be completely controlled by long-term drug therapies. Diagnosis relies on clinical suspicion followed by genetic testing.

Polyclonal, newly derived T cells with low expression of inhibitory molecule PD-1 in tonsils define the phenotype of lymphocytes in children with Periodic Fever, Aphtous Stomatitis, Pharyngitis and Adenitis (PFAPA) syndrome.

PURPOSE: PFAPA syndrome is a benign, recurrent inflammatory disease of childhood. Tonsillectomy is one of the therapeutic options with a yet unexplained biological mechanism. We tested whether specific lymphocyte subsets recruited from blood to human tonsils participate in PFAPA pathogenesis. METHODS: Paired tonsils/peripheral blood (PB) samples were investigated (a) from children with PFAPA that successfully resolved after tonsillectomy (n=10) (b) from children with obstructive sleep apnoea syndrome as controls (n=10). The lymphocyte profiles were analysed using 8-colour flow cytometry, immunoglobulin (IGH) and T-cell receptor (TCR) gene rearrangements via PCR and next generation sequencing; a TREC/KREC analysis was performed using qPCR. RESULTS: The PFAPA tonsils in the asymptomatic phase had a lower percentage of B-lymphocytes than controls; T-lymphocyte counts were significantly higher in PB. The percentages of cytotoxic CD8pos T-lymphocytes were approximately 2-fold higher in PFAPA tonsils; the transitional B cells and naïve stages of both the CD4pos and CD8pos T-lymphocytes with a low expression of PD-1 molecule and high numbers of TREC were also increased. With the exception of elevated plasmablasts, no other differences were significant in PB. The expression levels of CXCL10, CXCL9 and CCL19 genes were significantly higher in PFAPA tonsils. The IGH/TCR pattern showed no clonal/oligoclonal expansion. DNA from the Epstein-Barr virus, Human Herpervirus-6 or adenovirus was detected in 7 of 10 PFAPA tonsils but also in 7 of 9 controls. CONCLUSIONS: Our findings suggest that the uninhibited, polyclonal response of newly derived lymphocytes participate in the pathogenesis of PFAPA. Because most of the observed changes were restricted to tonsils and were not present in PB, they partly explain the therapeutic success of tonsillectomy in PFAPA syndrome.

Utility of bone marrow examination for workup of fever of unknown origin in patients with HIV/AIDS.

AIMS: The utility of bone marrow aspiration and biopsy (BMAB) as a diagnostic tool in patients with HIV/AIDS and fever of unknown origin (FUO) is a subject of debate. Because highly active antiretroviral therapy has reduced incidence of opportunistic infections, it is important to reassess the efficacy of BMAB for this diagnostic purpose. To our knowledge, no such studies have been performed in Harris County which has the highest incidence of HIV in the state of Texas. METHODS: We reviewed all BMABs from patients with HIV/AIDS and FUO or persistent cytopenia(s) from 2007 to 2011. RESULTS: Of 57 evaluable patients, BMAB was positive in 24 samples by acid fast bacilli (AFB) or Gomori methenamine silver (GMS) stains (17.5%), presence of granuloma and/or lymphohistiocytic aggregates (31.6%), culture (21.0%) or a combination. Cultures demonstrated Mycobacterium avium/intracellulare (4), M tuberculosis (2), M gordonae (1), Histoplasma capsulatum (3) and Cryptococcus neoformans (2). There were three cases in which a pathogen was grown in culture but that had a negative of 'direct examination' on tissue sections (negative AFB and GMS special stains, no morphological evidence of granuloma/lymphohistiocytic infiltrates). CONCLUSIONS: This study supports the use of diagnostic BMAB as a rapid decision-making tool in patients with HIV and FUO in the proper clinical setting. BMAB demonstrated infection-related evidence prior to positive bone marrow culture in 75% of cases. Special stains and blood cultures had similar diagnostic yield, but BMAB offers faster results. Thus, this procedure assists in clinical decision making and the refinement of treatment in a more timely manner.

Consensus guidelines for the treatment of yeast infections in the haematology, oncology and intensive care setting, 2014.

Pathogenic yeast forms are commonly associated with invasive fungal disease in the immunocompromised host, including patients with haematological malignancies and patients of haemopoietic stem cell transplants. Yeasts include the Candida spp., Cryptococcus spp., Pneumocystis jirovecii and some lesser-known pathogens. Candida species remain the most common cause of invasive yeast infections (and the most common human pathogenic fungi). These guidelines present evidence-based recommendations for the antifungal management of established, invasive yeast infections in adult and paediatric patients in the haematology/oncology setting. Consideration is also given to the critically ill patient in intensive care units, including the neonatal intensive care unit. Evidence for 'pre-emptive' or 'diagnostic-driven antifungal therapy' is also discussed. For the purposes of this paper, invasive yeast diseases are categorised under the headings of invasive candidiasis, cryptococcosis and uncommon yeast infections. Specific recommendations for the management of Pneumocystis jirovecii are presented in an accompanying article (see consensus guidelines by Cooley et al. appearing elsewhere in this supplement).

[A 55-year-old woman with cough, fever, swelling of joints, and exanthema after a trip to Ecuador]. / 55-jährige Patientin mit Husten, Fieber, Gelenkschwellungen und Exanthem nach einem Urlaub in Ecuador.

A 55-year-old woman presented 18 months after a trip to Ecuador with night sweat, malaise, and an unclear lesion of the lung. Computed tomography of the lung showed a nodular lesion of 14 mm. Antibodies against Histoplasma capsulatum were detected in the complement fixation text (CFT) and IgG western blot. Re-examination of a formalin fixed paraffin embedded (FFPE) lung-biopsy revealed yeasts after silver staining, compatible with H. capsulatum , which was verified by extraction and amplification of DNA from FFPE. After therapy with itraconazole 400 mg/day, the patient showed an uneventful clinical recovery without regression of the lung lesion. The serological follow-up examination after 17 months showed CFT without pathological findings.

XDR TB in a case of IL12Rß1 deficiency: a case report of Mendelian Susceptibility to Mycobacterial Disease from India.

Mendelian Susceptibility to Mycobacterial Disease (MSMD) is a relatively new term that describes a spectrum of inherited defects in the IL-12/23 and IFN- γ pathways that result in a selective predisposition to disease caused by poorly pathogenic mycobacteria. In contrast to previous reports of patients infected with environmental mycobacteria and BCG, this manuscript elucidates the clinical course and diagnosis of MSMD in a child harboring extensively drug resistant (XDR) Mycobacterium tuberculosis.

Autism after infection, febrile episodes, and antibiotic use during pregnancy: an exploratory study.

OBJECTIVES: Results of animal studies suggest that maternal immune activation during pregnancy causes deficiencies in fetal neurodevelopment. Infectious disease is the most common path to maternal immune activation during pregnancy. The goal of this study was to determine the occurrence of common infections, febrile episodes, and use of antibiotics reported by the mother during pregnancy and the risk for autism spectrum disorder (ASD) and infantile autism in the offspring. METHODS: We used a population-based cohort consisting of 96 736 children aged 8 to 14 years and born from 1997 to 2003 in Denmark. Information on infection, febrile episodes, and use of antibiotics was self-reported through telephone interviews during pregnancy and early postpartum. Diagnoses of ASD and infantile autism were retrieved from the Danish Psychiatric Central Register; 976 children (1%) from the cohort were diagnosed with ASD. RESULTS: Overall, we found little evidence that various types of mild common infectious diseases or febrile episodes during pregnancy were associated with ASD/infantile autism. However, our data suggest that maternal influenza infection was associated with a twofold increased risk of infantile autism, prolonged episodes of fever caused a threefold increased risk of infantile autism, and use of various antibiotics during pregnancy were potential risk factors for ASD/infantile autism. CONCLUSIONS: Our results do not suggest that mild infections, febrile episodes, or use of antibiotics during pregnancy are strong risk factors for ASD/infantile autism. The results may be due to multiple testing; the few positive findings are potential chance findings.

[Invasive mycosis, immunocompromise and fever of unknown origin]. / Micosis invasivas en pacientes inmunodeprimidos con fiebre de origen desconocido.

BACKGROUND: fungal invasive infections are frequent in patients with immunosuppression. A common clinical feature is the presence of fever of unknown origin (FUO) in any of its several presentations. The aim of this study was to know the frequency of FUO associated to invasive mycosis in hospitalized patients. METHODS: samples from 34 patients were studied by immunological and microbiological procedures in order to investigate candidiasis, cryptococcosis, aspergillosis and Pneumocystis infection. RESULTS: fungal infection diagnosis was established in 12 (35 %) from 34 patients who full criterion. The fungal species isolated were Candida albicans (six), Aspergillus fumigates (four) and Cryptococcus sp. (two). All candidiasis cases were diagnosed only by microbiological studies, aspergillosis by immunological and microbiological studies, and cryptococcosis only by immunological studies. CONCLUSIONS: we concluded that is important the searching of mycosis in immunocompromised patients with fever of unknown origin by microbiological and immunological procedures.

Fever of unknown origin from a left atrial myxoma: an immunologic basis and cytokine association.

Myxoma is the most common primary tumor of the heart. The typical presentations include a triad of embolic phenomena, intracardiac flow obstruction, and constitutional symptoms. We report a case of cardiac myxoma presenting as prolonged fever. Leukocytosis with a left shift, anemia, and elevated C-reactive protein were noted. A large left atrial myxoma was found incidentally by chest computed tomography. The fever subsided after surgical removal of the myxoma. His elevated serum interleukin-4 (IL-4), IL-6, IL-12 p70, interferon-γ, and tumor necrosis factor-α returned to undetectable levels four days after surgery. Cardiac myxomas should be included in the differential diagnosis of prolonged fever, even though no typical symptoms could be found.