Classical fever of unknown origin in 21 countries with different economic development: an international ID-IRI study.

Fever of unknown origin (FUO) is a serious challenge for physicians. The aim of the present study was to consider epidemiology and dynamics of FUO in countries with different economic development. The data of FUO patients hospitalized/followed between 1st July 2016 and 1st July 2021 were collected retrospectively and submitted from referral centers in 21 countries through ID-IRI clinical research platform. The countries were categorized into developing (low-income (LI) and lower middle-income (LMI) economies) and developed countries (upper middle-income (UMI) and high-income (HI) economies). This research included 788 patients. FUO diagnoses were as follows: infections (51.6%; n = 407), neoplasms (11.4%, n = 90), collagen vascular disorders (9.3%, n = 73), undiagnosed (20.1%, n = 158), miscellaneous diseases (7.7%, n = 60). The most common infections were tuberculosis (n = 45, 5.7%), brucellosis (n = 39, 4.9%), rickettsiosis (n = 23, 2.9%), HIV infection (n = 20, 2.5%), and typhoid fever (n = 13, 1.6%). Cardiovascular infections (n = 56, 7.1%) were the most common infectious syndromes. Only collagen vascular disorders were reported significantly more from developed countries (RR = 2.00, 95% CI: 1.19-3.38). FUO had similar characteristics in LI/LMI and UMI/HI countries including the portion of undiagnosed cases (OR, 95% CI; 0.87 (0.65-1.15)), death attributed to FUO (RR = 0.87, 95% CI: 0.65-1.15, p-value = 0.3355), and the mean duration until diagnosis (p = 0.9663). Various aspects of FUO cannot be determined by the economic development solely. Other development indices can be considered in future analyses. Physicians in different countries should be equally prepared for FUO patients.

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.

Etiology and Resource Use of Fever of Unknown Origin in Hospitalized Children.

BACKGROUND: Fever of unknown origin (FUO) is a well-known pediatric presentation. The primary studies determining the causes of prolonged fever in children were performed 4 decades ago, before major advances in laboratory and diagnostic testing. Given that the distribution of diagnosed causes of adult FUO has changed in recent decades, we hypothesized that the etiology of FUO in children has concordantly changed and also may be impacted by a definition that includes a shorter required duration of fever. METHODS: A single-center, retrospective review of patients 6 months to 18 years of age admitted to the North Carolina Children's Hospital from January 1, 2002, to December 21, 2012, with an International Classification of Diseases, Ninth Revision diagnosis of fever, a documented fever duration >7 days before admission, and a previous physician evaluation of each patient's illness. RESULTS: A total of 1164 patients were identified, and of these, 102 met our inclusion criteria for FUO. Etiologic categories included "infectious" (42 out of 102 patients), "autoimmune" (28 out of 102 patients), "oncologic" (18 out of 102 patients), and "other" or "unknown" (14 out of 102 patients). Several clinical factors were statistically and significantly different between etiologic categories, including fever length, laboratory values, imaging performed, length of stay, and hospital costs. CONCLUSIONS: Unlike adult studies, the categorical distribution of diagnoses for pediatric FUO has marginally shifted compared to previously reported pediatric studies. Patients hospitalized with FUO undergo prolonged hospital stays and have high hospital costs. Additional study is needed to improve the recognition, treatment, and expense of diagnosis of prolonged fever in children.

Contribution of (18)F-FDG PET in the diagnostic assessment of fever of unknown origin (FUO): a stratification-based meta-analysis.

PURPOSE: The aim of this study was to quantify the contribution of FDG PET to the diagnostic assessment of fever of unknown origin (FUO), taking into account the diagnostic limitations resulting from the composite nature of this entity. METHODS: The PubMed/MEDLINE database was searched from 2000 to September 2015. Original articles fulfilling the following criteria were included: (1) FUO as the initial diagnosis, (2) no immunosuppressed or nosocomial condition, (3) final diagnosis not based on PET, (4) a follow-up period specified, (5) adult population, and (6) availability of adapted data for calculation of odds ratios (ORs). ORs were computed for each study and then pooled using a random effects model. Stratification-based sensitivity analyses were finally performed using the following prespecified criteria: (a) study design, (b) PET device, (c) geographic area, and (d) follow-up period. RESULTS: A meta-analysis of the 14 included studies showed that normal PET findings led to an increase in the absolute final diagnostic rate of 36 % abnormal PET findings to an increase of 83 %, corresponding to a pooled OR of 8.94 (95 % CI 4.18 - 19.12, Z = 5.65; p < 0.00001). The design of the studies influenced the results (OR 2.92, 95 % CI 1.00 - 8.53 for prospective studies; OR 18,57, 95 % CI 7.57 - 45.59 for retrospective studies; p = 0.01), whereas devices (dedicated or hybrid), geographic area and follow-up period did not. CONCLUSION: Abnormal PET findings are associated with a substantially increased final diagnostic rate in FUO. Consequently, FDG PET could be considered for inclusion in the first-line diagnostic work-up of FUO. Further randomized prospective studies with standardized FDG PET procedures are warranted to confirm this first-line position.

A Quasi-Experimental Study Analyzing the Effectiveness of Portable High-Efficiency Particulate Absorption Filters in Preventing Infections in Hematology Patients during Construction.

OBJECTIVE: The increased risk of infection for patients caused by construction and renovation near hematology inpatient clinics is a major concern. The use of high-efficiency particulate absorption (HEPA) filters can reduce the risk of infection. However, there is no standard protocol indicating the use of HEPA filters for patients with hematological malignancies, except for those who have undergone allogeneic hematopoietic stem cell transplantation. This quasi-experimental study was designed to measure the efficacy of HEPA filters in preventing infections during construction. MATERIALS AND METHODS: Portable HEPA filters were placed in the rooms of patients undergoing treatment for hematological malignancies because of large-scale construction taking place near the hematology clinic. The rates of infection during the 6 months before and after the installation of the portable HEPA filters were compared. A total of 413 patients were treated during this 1-year period. RESULTS: There were no significant differences in the antifungal prophylaxis and treatment regimens between the groups. The rates of infections, clinically documented infections, and invasive fungal infections decreased in all of the patients following the installation of the HEPA filters. When analyzed separately, the rates of invasive fungal infections were similar before and after the installation of HEPA filters in patients who had no neutropenia or long neutropenia duration. HEPA filters were significantly protective against infection when installed in the rooms of patients with acute lymphocytic leukemia, patients who were undergoing consolidation treatment, and patients who were neutropenic for 1-14 days. CONCLUSION: Despite the advent of construction and the summer season, during which environmental Aspergillus contamination is more prevalent, no patient or patient subgroup experienced an increase in fungal infections following the installation of HEPA filters. The protective effect of HEPA filters against infection was more pronounced in patients with acute lymphocytic leukemia, patients undergoing consolidation therapy, and patients with moderate neutropenia.

Modeling the hospital burden of common infectious diseases with application to northeastern Thailand.

UNLABELLED: This study aims to identify the incidence patterns of the most common infectious diseases, including acute diarrhea, pyrexia of unknown origin, hemorrhagic conjunctivitis, and pneumonia, in the 7 provinces of northeastern Thailand, based on individual hospital case records of infectious disease routinely reported from 1999 to 2004. Log-linear regression analysis with age-group, season, and district as factors was used, with data from all 4 diseases as outcomes combined into 1 model. RESULTS: confirmed that the highest incidence of each infectious disease occurred in children aged less than 5 years of age, with particularly high rates for diarrhea. In addition, the burden of pyrexia of unknown origin was found to be lower in districts bordering Laos, and the incidence rates were higher from April to June in 1999-2001 and 2004 and from July to September in 2002-2003. Higher incidence rates also occurred in most rural districts of Loei and Udon Thani provinces.

[Evaluation of impact of CRP rapid test in management of febrile children in ambulatory pediatric practice]. / Evaluation de l'impact du test rapide de la CRP en microméthode par des pédiatres de ville prenant en charge des enfants de plus de trois mois avec fièvre isolée.

OBJECTIVE: Fever without source (FWS) is a common cause of children visits to pediatric practices. Clinical evaluation does not always rule out efficiently an invasive bacterial infection. Among blood markers, several publications have suggested the value of C-reactive protein (CRP). This study was performed to assess, in private practices, the impact of rapid CRP test compared to usual technique at the laboratory for the management of children with FWO. MATERIAL AND METHODS: The study was undertaken in 2006-2007, in 14 pediatric practices. Pediatricians had to enroll all children, older than three months, consulting for FWS, for whom CRP was prescribed. The pediatric practices were distributed in two groups: in the first one, pediatricians had rapid CRP tests (NycoCard) CRP test, Progen Biotechnique) and in the second one, they sent children to laboratory for the dosage of CRP as usually. RESULTS: Between October 2006 and June 2007, 227 children were enrolled by 17 pediatricians: 159 in the group with rapid CRP test (group 1), 68 in the group without (group 2). The cost of routine biological tests (micro or macro CRP, blood cell count and urine cultures) was on average lower for group 1 compared to the group 2: respectively 7.7 versus 39.3 euro (P<0.0001), a reduction from approximately 80% of cost. In group 1, more dipstick urine tests (22.6 versus 4.4, P=0.0009), less urine cultures (19.5% versus 67.6% P<0.0001) and blood prescriptions were prescribed (3.8% versus 100%, P<0.0001), pulmonary X-rays were not different (23.9% versus 19.1%, P=0.4). It was not observed difference in antibiotic prescription between the two groups (15.7% group 1 versus 19.1% group 2, p=0.5). The average time to obtain the results examinations in laboratory was approximately 11h (median 4.5h, extremes 45 min to two days), for five min in group 1. In group 1, children management was different according to the CRP levels. During the follow-up, no difference was observed between the two groups except less hospitalizations in group 1 (2.9% versus 15.3%, P=0.0015). CONCLUSION: This study suggests the interest of rapid CRP test for febrile children in ambulatory pediatric practice by reducing number and cost of laboratory examinations and timesaving for patients and practitioners.

From prolonged febrile illness to fever of unknown origin: the challenge continues.

BACKGROUND: Epidemiological changes and the ongoing expansion of the diagnostic armamentarium warrant a regular update of the spectrum of diseases that present as prolonged febrile illnesses. METHODS: We prospectively collected a series of 290 immunocompetent patients referred to our university hospital between 1990 and 1999 with a febrile illness (temperature >38.3 degrees C) of uncertain cause, lasting at least 3 weeks. Patients were categorized in 4 groups according to the timing of diagnosis: early diagnosis (within 3 in-hospital days or 3 outpatient visits), intermediate diagnosis (between days 4 and 7), late diagnosis (after day 7), and no diagnosis during index contact or follow-up. RESULTS: A final diagnosis was established early in 67 patients (23.1%), intermediate in 38 (13.1%), and late in 87 (30.0%). In the remaining 98 (33.8%), no diagnosis was made. The cause of the fever remained obscure in 50 (47.6%) of 105 patients with episodic fever vs 48 (25.9%) of 185 patients with continuous fever (P<.001). Among the 192 patients with a final diagnosis, noninfectious inflammatory diseases represented the most prevalent diagnostic category (35.4%), surpassing infections (29.7%), miscellaneous causes (19.8%), and malignancies (15.1%). Fourteen disorders accounted for over 59% of diagnoses, whether diagnosis was reached early, intermediate, or late. Hematological malignancies made up 11.5% of diagnoses, but were responsible for 14 (58.3%) of the 24 fatalities related to the febrile illness. Of the 80 patients discharged alive without diagnosis and for whom follow-up was available, 3 died, but the deaths were considered to be unrelated to the feverish illness. CONCLUSIONS: Prolonged febrile illnesses remain a diagnostic challenge. Despite the technological progress of the late 20th century, the origin of the fever remains elusive in many patients, especially in those with episodic fevers. Noninfectious inflammatory diseases emerge as the most prevalent diagnostic category.

The discrepancy between daily practice and the policy of a decision-analytic model: the management of fever of unknown origin.

The optimal treatment of children with fever of unknown origin is controversial, in spite of two decision analyses that advise treatment with antibiotics for all such children. The aim of this study was to analyze the differences between pediatricians' diagnostic and therapeutic decisions and the outcomes of the decision-analytic models. Thirty-six pediatricians were asked to evaluate 30 patient cases and to give their diagnostic and therapeutic judgments. In addition, the pediatricians were asked questions about the epidemiology of fever of unknown origin. Analyses showed that the differences in policy between pediatricians and the models could not be explained by the reasons mentioned in the literature, i.e., 1) differences in epidemiologic data used, 2) differences in the weighting of clinical information, and 3) differences in the evaluation of outcomes. The differences in policy might be due to a difference between the objective of the models and pediatricians' aim. In a curative setting, pediatricians are not trying to prevent meningitis (or another serious disease) by treating possible occult bacteremia, but rather aim to detect meningitis in an early stage. A decision analysis determining the most cost-effective strategy for early detection of meningitis might therefore be more easily accepted by pediatricians.

Should blood cultures be obtained in the evaluation of young febrile children without evident focus of bacterial infection? A decision analysis of diagnostic management strategies.

The technique of decision analysis was used to compare the benefits (prevention of major infectious sequelae of bacteremia) and risks (unnecessary hospitalization and intravenous antibiotic treatment of children whose bacteremia would have resolved spontaneously, discomfort of venipuncture) of alternative diagnostic management strategies in the evaluation of children 3 to 24 months of age with fever (rectal temperature greater than or equal to 39 degrees C) of acute (less than or equal to 4 days) onset and without evident focus of bacterial infection. The diagnostic strategies compared at the initial visit were blood culture in all, blood culture in none, and selective blood culture (restricted to children judged to be at high risk). Probability estimates were based on published epidemiologic studies and case series, and utilities were elicited from mothers of 3- to 24-month-old children and from pediatricians. Based on initial probabilities and utilities, the "no blood culture" strategy had the highest expected utility, followed closely by the "selective blood culture" strategy, with the "blood culture all" strategy a distant third. Sensitivity analyses based on increased risk of major infectious sequelae or of bacteremia had no effect on the ranking of the three initial management options. Eliminating the "disutility" of venipuncture or augmenting the disutility of major infectious sequelae also failed to alter the ranking. Even when an extreme relative disutility for major sequelae was assumed, the "blood culture all" strategy was not favored. Thus, the risk of unnecessary hospitalization and intravenous antibiotic treatment of the relatively large number of children whose bacteremia spontaneously resolves appears to outweigh the benefit of preventing serious infectious sequelae in the few children in whom positive blood culture results permit timely intervention. The explicitness and coherence of the decision analysis approach should help in developing a rational diagnostic approach to the young febrile child.