Performance of Febrile Infant Algorithms by Duration of Fever.

OBJECTIVES: To analyze the performance of commonly used blood tests in febrile infants ≤90 days of age to identify patients at low risk for invasive bacterial infection (bacterial pathogen in blood or cerebrospinal fluid) by duration of fever. METHODS: We conducted a secondary analysis of a prospective single-center registry that includes all consecutive infants ≤90 days of age with fever without a source evaluated at 1 pediatric emergency department between 2008 and 2021. We defined 3 groups based on caregiver-reported hours of fever (<2, 2-12, and ≥12) and analyzed the performance of the biomarkers and Pediatric Emergency Care Applied Research Network, American Academy of Pediatrics, and Step-by-Step clinical decision rules. RESULTS: We included 2411 infants; 76 (3.0%) were diagnosed with an invasive bacterial infection. The median duration of fever was 4 (interquartile range, 2-12) hours, with 633 (26.3%) patients with fever of <2 hours. The area under the curve was significantly lower in patients with <2 hours for absolute neutrophil count (0.562 vs 0.609 and 0.728) and C-reactive protein (0.568 vs 0.760 and 0.812), but not for procalcitonin (0.749 vs 0.780 and 0.773). Among well-appearing infants older than 21 days and negative urine dipstick with <2 hours of fever, procalcitonin ≥0.14 ng/mL showed a better sensitivity (100% with specificity 53.8%) than that of the combination of biomarkers of Step-by-Step (50.0% and 82.2%), and of the American Academy of Pediatrics and Pediatric Emergency Care Applied Research Network rules (83.3% and 58.3%), respectively. CONCLUSIONS: The performance of blood biomarkers, except for procalcitonin, in febrile young infants is lower in fever of very short duration, decreasing the accuracy of the clinical decision rules.

Diagnostic value of F-18 FDG PET/CT in fever or inflammation of unknown origin in a large single-center retrospective study.

Cause determination is challenging in fever or inflammation of unknown origin (FUO/IUO) despite today's diagnostic modalities. We evaluated the value of F-18 FDG PET/CT in an unselected patient collective. This retrospective nonrandomized single-center study enrolled 300 male and female patients with FUO/IUO. PET/CT findings were compared with final clinical outcomes to determine the sensitivity, specificity, clinical significance, etiological distribution of final diagnoses, impact on treatment, role of white-blood cell count (WBC), and C-reactive protein (CRP). In 54.0% (162/300) PET/CT was the decisive exanimation for establishing the final diagnosis, in 13.3% (40/300) the findings were equivocal and indecisive, in 3.3% (10/300) PET/CT findings were false positive, while in 29.3% (88/300) a normal F-18 FDG pattern was present. Statistical analysis showed a sensitivity of 80.2% and a specificity of 89.8% for the contribution of PET/CT to the final diagnosis. CRP levels and WBC were not associated with PET/CT outcome. PET/CT let to new treatment in 24.0% (72/300), treatment change in 18.0% (54/300), no treatment change in 49.6% (149/300), and in 8.3% (25/300) no data was available. Our study demonstrates the utility of F-18 FDG PET/CT for source finding in FUO/IUO if other diagnostic tools fail.

[Febrile syndrome in children younger than 29 days]. / Síndrome febril en niños menores de 29 días.

INTRODUCTION: Acute fever of unknown origin (FUO) in children under 29 days is a worrying situation because of the risk of serious bacterial infection (SBI). OBJECTIVE: to study the main clinical and laboratory characteristics of a group of hospitalized children under 29 days with diagnosis of FUO. PATIENTS AND METHOD: Retrospective study of children under 29 days hospitalized due to FUO. The clinical records of the patients were reviewed, recording age, sex, history of fever before consultation, temperature at admission, estimated severity at admission and discharge, discharge diagnoses, laboratory tests, and indicated treatments. Patients were classified according to the severity of the discharge diagnosis, as severe (S) and non-severe (NS). The inclusion criteria were term newborn, age less than 29 days, fe ver > 38°C registered at home or admission, and history of < 4 days. RESULTS: 468 children with FUO were admitted. Concordance between severity at admission and discharge was low (Kappa = 0.125; p = 0.0007). 26.1% of children were S and 73.9% NS. In the S group, urinary tract infection domínate (70.5%) and in the NS, FUO (67.6%). The cut-off levels for leukocytes/mm3, C-reactive protein, and neutrophils/mm3 showed negative predictive values to rule out severe bacterial infection. Conclu sions: Most of the newborns presented mild severity at admission, but 24% of them had SBI, thus hospitalization and close clinical observation are always necessary. Laboratory tests, such as CRP, white blood cell and neutrophils count are not good predictors of SBI. Early treatment with antibio tics for patients who meet the low-risk criteria is debatable.

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.

Pyrexia of unknown origin as clinical presentation of Renal Cell Carcinoma: Role of F18-FDG PET/CT.

The synergy of the anatomic-metabolic details provided by PET-CT plays a substantial role in the diagnostic workup of Pyrexia of Unknown Origin (PUO). Although several imaging modalities have been used in the detection of cause of PUO, PET-CT is the most sensitive and specific modality for detection of cause. RCC is a rare cause of PUO.

Fever of Unknown Origin in a Renal Transplant Recipient: Lactate Dehydrogenase as an Important Clue to Diagnosis.

Histoplasmosis is a rare disease in nonendemic areas. We report a case of a 23-year-old male patient who presented with fever of unknown origin, cytopenias, organomegaly, and allograft dysfunction 4 months after renal transplant with father as donor. Bone marrow examination showed intracellular budding yeast cells, which was confirmed as histoplasmosis by culture of bone marrow biopsy sample. The patient was treated with intravenous liposomal amphotericin and responded well.

Plasma lipid profiles discriminate bacterial from viral infection in febrile children.

Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection are often non-specific, and there is no definitive test for the accurate diagnosis of infection. The 'omics' approaches to identifying biomarkers from the host-response to bacterial infection are promising. In this study, lipidomic analysis was carried out with plasma samples obtained from febrile children with confirmed bacterial infection (n = 20) and confirmed viral infection (n = 20). We show for the first time that bacterial and viral infection produces distinct profile in the host lipidome. Some species of glycerophosphoinositol, sphingomyelin, lysophosphatidylcholine and cholesterol sulfate were higher in the confirmed virus infected group, while some species of fatty acids, glycerophosphocholine, glycerophosphoserine, lactosylceramide and bilirubin were lower in the confirmed virus infected group when compared with confirmed bacterial infected group. A combination of three lipids achieved an area under the receiver operating characteristic (ROC) curve of 0.911 (95% CI 0.81 to 0.98). This pilot study demonstrates the potential of metabolic biomarkers to assist clinicians in distinguishing bacterial from viral infection in febrile children, to facilitate effective clinical management and to the limit inappropriate use of antibiotics.

Key diagnostic characteristics of fever of unknown origin in Japanese patients: a prospective multicentre study.

OBJECTIVE: To identify the key diagnostic features and causes of fever of unknown origin (FUO) in Japanese patients. DESIGN: Multicentre prospective study. SETTING: Sixteen hospitals affiliated with the Japanese Society of Hospital General Medicine, covering the East and West regions of Japan. PARTICIPANTS: Patient aged ≥20 years diagnosed with classic FUO (axillary temperature≥38.0°C at least twice within a 3-week period, cause unknown after three outpatient visits or 3 days of hospitalisation). A total of 141 cases met the criteria and were recruited from January 2016 to December 2017. INTERVENTION: Japanese standard diagnostic examinations. OUTCOME MEASURES: Data collected include usual biochemical blood tests, inflammatory markers (erythrocyte sedimentation rate (ESR), C reactive (CRP) protein level, procalcitonin level), imaging results, autopsy findings (if performed) and final diagnosis. RESULTS: The most frequent age group was 65-79 years old (mean: 58.6±9.1 years). The most frequent cause of FUO was non-infectious inflammatory disease. After a 6-month follow-up period, 21.3% of cases remained undiagnosed. The types of diseases causing FUO were significantly correlated with age and prognosis. Between patients with and without a final diagnosis, there was no difference in CRP level between patients with and without a final diagnosis (p=0.121). A significant difference in diagnosis of a causative disease was found between patients who did or did not receive an ESR test (p=0.041). Of the 35 patients with an abnormal ESR value, 28 (80%) had causative disease identified. CONCLUSIONS: Age may be a key factor in the differential diagnosis of FUO; the ESR test may be of value in the FUO evaluation process. These results may provide clinicians with insight into the management of FUO to allow adequate treatment according to the cause of the disease.

A rapid bio-optical sensor for diagnosing Q fever in clinical specimens.

Recent zoonotic outbreaks, such as Zika, Middle East respiratory syndrome and Ebola, have highlighted the need for rapid and accurate diagnostic assays that can be used to aid pathogen control. Q fever is a zoonotic disease caused by the transmission of Coxiella burnetii that can cause serious illness in humans through aerosols and is considered a potential bioterrorism agent. However, the existing assays are not suitable for the detection of this pathogen due to its low levels in real samples. We here describe a rapid bio-optical sensor for the accurate detection of Q fever and validate its clinical utility. By combining a bio-optical sensor, that transduces the presence of the target DNA based on binding-induced changes in the refractive index on the waveguide surface in a label-free and real-time manner, with isothermal DNA amplification, this new diagnostic tool offers a rapid (<20 min), 1-step DNA amplification/detection method. We confirmed the clinical sensitivity (>90%) of the bio-optical sensor by detecting C. burnetii in 11 formalin-fixed, paraffin-embedded liver biopsy samples from acute Q fever hepatitis patients and in 16 blood plasma samples from patients in which Q fever is the cause of fever of unknown origin.

Recurrent FUO due to intermittent Enterobacter cloacae bacteremias from an infected pacemaker lead diagnosed by gallium scan.

Fever of unknown origin (FUO) refers to fevers of ≥101° F that persist for ≥3 weeks and remain undiagnosed after a focused inpatient or outpatient workup. FUO may be due to infectious, malignant/neoplastic, rheumatic/inflammatory, or miscellaneous disorders. Recurrent FUOs are due to the same causes of classical FUOs. Recurrent FUOs may have continuous or intermittent fevers and are particularly difficult to diagnose. With intermittent fever, recurrent FUO diagnostic tests are best obtained during fever episodes. With recurrent FUOs, the periodicity of febrile episodes is unpredictable. We present a case of a 70-year-old male who presented with recurrent FUO. Multiple extensive FUO workups failed to determine the source of his fever. During his last two episodes of fever/chills, blood cultures were positive for Enterobacter cloacae. Episodic E. cloacae bacteremias suggested a device-related infection, and the patient had a penile implant and permanent pacemaker (PPM). Following febrile episodes, he was treated with multiple courses of appropriate antibiotics, but subsequently fever/chills recurred. Since a device-associated infection was suspected, indium and PET scans were done, but were negative. The source of his intermittent E. cloacae bacteremias was finally demonstrated by gallium scan showing enhanced uptake on a cardiac lead, but not the penile implant or PPM. Gallium scanning remains useful in workup of FUOs, particularly when false-negative indium or PET scans are suspected. The involved pacemaker lead was explanted, grew E. cloacae and the patient has since remained fever free.

Procalcitonin performance in detecting serious and invasive bacterial infections in children with fever without apparent source: a systematic review and meta-analysis.

INTRODUCTION: The management of children with fever without apparent sources (FWAS) is difficult. This study aimed to evaluate the diagnostic accuracy of procalcitonin (PCT) in detecting serious or invasive bacterial infection (SBI or IBI) in children with FWAS. Areas covered: A systematic review of literature from 2007 to 2017 was performed on Medline. Twelve studies were included, involving 7,260 children with FWAS and analyzing the diagnostic performance of PCT. Four meta-analyses were performed to calculate pooled sensitivity, specificity, diagnostic odds ratio, and summary receiver operating characteristic curve for PCT in detecting SBI and IBI, at two different thresholds. Considering IBI, PCT sensitivity and specificity at a threshold of 0.5 ng/mL were 0.82 and 0.86, respectively; at a threshold of 2 ng/mL sensitivity and specificity were 0.61 and 0.94, respectively. In detecting SBI, PCT performance was lower, with 55% sensitivity and 85% specificity at a threshold of 0.5 ng/mL, and 30% sensitivity and 95% specificity at a threshold of 2 ng/mL. Expert commentary: Considering IBI, results showed high diagnostic accuracy for PCT. Conversely, PCT performance in diagnosis of SBI was poor. These findings suggest that PCT level determination could be helpful in detecting meningitis, bacteremia and sepsis in children with FWAS.

C-reactive protein concentrations can help to determine which febrile infants under three months should receive blood cultures during influenza seasons.

AIM: We explored whether C-reactive protein (CRP) concentrations could indicate which infants with fever without source (FWS) should receive undergo blood culture tests during influenza seasons. METHODS: This retrospective study focused on patients under three months of age with FWS who had received blood culture tests at the West China Second University Hospital Paediatric Emergency Department during the influenza seasons from June 2013 to January 2015. The statistical analysis comprised specificity, sensitivity, multilevel likelihood ratios (LRs), receiver operating characteristic analysis and a multivariate logistic regression model. RESULTS: We enrolled 592 febrile patients and 7.1% had bacteraemia, with levels falling with increasing age. According to the receiver operating characteristic analysis, the optimum threshold of CRP was 30.5 mg/L, and when the CRP level was higher than 30.5 mg/L, the positive LR of bacteraemia was 2.32. In patients aged 29-90 days, when the CRP level was higher than 5 mg/L, the negative LR of bacteraemia was 0.38. In the neonatal group, a CRP level of ≥30.5 mg/L had a positive LR of bacteraemia of 3.55. CONCLUSION: We found that CRP concentrations could indicate which febrile children under three months of age should undergo blood culture tests during influenza seasons.

Fever of unknown origin (FUO) due to miliary BCG: The diagnostic importance of morning temperature spikes and highly elevated ferritin levels.

Fever of unknown origin (FUO) is defined as prolonged fever of >101 °F for at least 3 weeks that remains undiagnosed after a focused inpatient or outpatient workup. One of the most elusive FUO diagnoses is miliary tuberculosis (TB) which typically has few/no localizing signs/symptoms. Since the introduction of intravesicular Bacille Calmette-Guerin (BCG) treatment for bladder carcinoma, miliary BCG has only rarely been reported as a cause of FUO. As with miliary TB, there are few/no clues to suspect miliary BCG. We present an interesting case of FUO due to miliary BCG without any localizing signs, i.e., no lung, liver or prostate involvement. The only clues to the diagnosis of this FUO due to disseminated BCG were morning temperature spikes and otherwise unexplained highly elevated ferritin levels.

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.

Blood Culture Testing via a Mobile App That Uses a Mobile Phone Camera: A Feasibility Study.

BACKGROUND: To evaluate patients with fever of unknown origin or those with suspected bacteremia, the precision of blood culture tests is critical. An inappropriate step in the test process or error in a parameter could lead to a false-positive result, which could then affect the direction of treatment in critical conditions. Mobile health apps can be used to resolve problems with blood culture tests, and such apps can hence ensure that point-of-care guidelines are followed and processes are monitored for blood culture tests. OBJECTIVE: In this pilot project, we aimed to investigate the feasibility of using a mobile blood culture app to manage blood culture test quality. We implemented the app at a university hospital in South Korea to assess the potential for its utilization in a clinical environment by reviewing the usage data among a small group of users and by assessing their feedback and the data related to blood culture sampling. METHODS: We used an iOS-based blood culture app that uses an embedded camera to scan the patient identification and sample number bar codes. A total of 4 medical interns working at 2 medical intensive care units (MICUs) participated in this project, which spanned 3 weeks. App usage and blood culture sampling parameters (including sampler, sampling site, sampling time, and sample volume) were analyzed. The compliance of sampling parameter entry was also measured. In addition, the participants' opinions regarding patient safety, timeliness, efficiency, and usability were recorded. RESULTS: In total, 356/644 (55.3%) of all blood culture samples obtained at the MICUs were examined using the app, including 254/356 (71.3%) with blood collection volumes of 5-7 mL and 256/356 (71.9%) with blood collection from the peripheral veins. The sampling volume differed among the participants. Sampling parameters were completely entered in 354/356 cases (99.4%). All the participants agreed that the app ensured good patient safety, disagreed on its timeliness, and did not believe that it was efficient. Although the bar code scanning speed was acceptable, the Wi-Fi environment required improvement. Moreover, the participants requested feedback regarding their sampling quality. CONCLUSIONS: Although this app could be used in the clinical setting, improvements in the app functions, environment network, and internal policy of blood culture testing are needed to ensure hospital-wide use.

Adrenomedullin predicts high risk and culture positivity in children with solid tumors suffering from neutropenic fever.

AIM OF STUDY: Neutropenic fever is a source of morbidity and mortality in children with cancer. It is not possible to detect the causative agent in cultures in most cases; the research for a marker that can show the severity of the disease is ongoing. We evaluated the role of adrenomedullin (ADM) at predicting prognosis on patients with febrile neutropenia, which has been proven to be a good prognostic marker for diseases with high morbidity and mortality, such as heart failure, ischemic ventricular dysfunction, sepsis, and systemic inflammatory response syndrome. MATERIALS AND METHODS: We recorded the 36 febrile episodes of 14 children receiving chemotherapy due to solid tumors. There were 10 events with unknown origin in the low-risk group, while in the high-risk group, there were 17 events with unknown origin, 8 events with microbiological origin and 1 event with clinically proven infection. Cultures were positive only in the high-risk group. However, the changes of ADM levels through time periods (first, second, third, and seventh days) were not significant. RESULTS: The first-day plasma ADM levels significantly predicted the presence of culture positivity (AUC 0.628, 95% CI 0.40-0.85, p = 0.303) and high-risk patients with neutropenic fever (AUC 0.76, 95% CI 0.56-0.97, p = 0.016). CONCLUSION: Our study showed that increased plasma ADM was correlated with high-risk neutropenic fever and culture positivity. The ADM levels in the high-risk group were clearly high at the diagnosis and continued to the end of the treatment.