"The Fever Is Still There!": Workup and Management of Prolonged Fever.

Fever is one of the most common chief complaints that brings pediatric patients to seek medical care. Although fever is, in most cases, a physiologic response to a pathogen that has alerted the immune system, prolonged fever can be challenging to work up for the treating pediatrician. In addition to assessing causes of fever, pediatricians must also address the fears that many caregivers may have surrounding elevations in body temperature and provide education as to when fever becomes a concern. Fever can be classified by its duration as well as the presence or absence of associated symptoms. Fever without a source is defined as a fever that has been present for 1 week without a clear cause. Fever of unknown origin is a fever that has been present daily for 8 days or more without an apparent source. This article will walk through considerations for a clinician evaluating a pediatric patient with prolonged fever. [Pediatr Ann. 2023;52(4):e124-e126.].

Pyrexia of unknown origin (PUO) and the cost of care in a tertiary care institute in Sri Lanka.

BACKGROUND: Despite advancements in diagnostic technology, pyrexia of unknown origin (PUO) remains a clinical concern. Insufficient information is available regarding the cost of care for the management of PUO in the South Asian Region. METHODS: We retrospectively analyzed data of patients with PUO from a tertiary care hospital in Sri Lanka to determine the clinical course of PUO and the burden of the cost incurred in the treatment of PUO patients. Non-parametric tests were used for statistical calculations. RESULTS: A total of 100 patients with PUO were selected for the present study. The majority were males (n = 55; 55.0%). The mean ages of male and female patients were 49.65 (SD: 15.55) and 46.87 (SD: 16.19) years, respectively. In the majority, a final diagnosis had been made (n = 65; 65%). The mean number of days of hospital stay was 15.16 (SD; 7.81). The mean of the total number of fever days among PUO patients was 44.47 (SD: 37.66). Out of 65 patients whose aetiology was determined, the majority were diagnosed with an infection (n = 47; 72.31%) followed by non-infectious inflammatory disease (n = 13; 20.0%) and malignancies (n = 5; 7.7%). Extrapulmonary tuberculosis was the most common infection detected (n = 15; 31.9%). Antibiotics had been prescribed for the majority of the PUO patients (n = 90; 90%). The mean direct cost of care per PUO patient was USD 467.79 (SD: 202.81). The mean costs of medications & equipment and, investigations per PUO patient were USD 45.33 (SD: 40.13) and USD 230.26 (SD: 114.68) respectively. The cost of investigations made up 49.31% of the direct cost of care per patient. CONCLUSION: Infections, mainly extrapulmonary tuberculosis was the most common cause of PUO while a third of patients remained undiagnosed despite a lengthy hospital stay. PUO leads to high antibiotic usage, indicating the need for proper guidelines for the management of PUO patients in Sri Lanka. The mean direct cost of care per PUO patient was USD 467.79. The cost of investigations contributed mostly to the direct cost of care for the management of PUO patients.

Fever of Unknown Origin in Adults.

Fever of unknown origin is defined as a clinically documented temperature of 101°F or higher on several occasions, coupled with an unrevealing diagnostic workup. The differential diagnosis is broad but is typically categorized as infection, malignancy, noninfectious inflammatory disease, or miscellaneous. Most cases in adults occur because of uncommon presentations of common diseases, and up to 75% of cases will resolve spontaneously without reaching a definitive diagnosis. In the absence of localizing signs and symptoms, the workup should begin with a comprehensive history and physical examination to help narrow potential etiologies. Initial testing should include an evaluation for infectious etiologies, malignancies, inflammatory diseases, and miscellaneous causes such as venous thromboembolism and thyroiditis. If erythrocyte sedimentation rate or C-reactive protein levels are elevated and a diagnosis has not been made after initial evaluation, 18F fluorodeoxyglucose positron emission tomography scan, with computed tomography, may be useful in reaching a diagnosis. If noninvasive diagnostic tests are unrevealing, then the invasive test of choice is a tissue biopsy because of the relatively high diagnostic yield. Depending on clinical indications, this may include liver, lymph node, temporal artery, skin, skin-muscle, or bone marrow biopsy. Empiric antimicrobial therapy has not been shown to be effective in the treatment of fever of unknown origin and therefore should be avoided except in patients who are neutropenic, immunocompromised, or critically ill.

Fever of unknown origin: a retrospective review of pediatric patients from an urban, tertiary care center in Washington, DC.

BACKGROUND: Fever of unknown origin (FUO) continues to challenge clinicians to determine an etiology and the need for treatment. This study explored the most common etiologies, characteristics, and average cost of hospitalization for FUO in a pediatric population at an urban, tertiary care hospital in Washington, DC. METHODS: Records from patients admitted to Children's National Health System between September 2008 and April 2014 with an admission ICD-9 code for fever (780.6) were reviewed. The charts of patients 2-18 years of age with no underlying diagnosis and a temperature greater than 38.3 ºC for 7 days or more at time of hospitalization were included. Final diagnoses, features of admission, and total hospital charges were abstracted. RESULTS: 110 patients qualified for this study. The majority of patients (n = 42, 38.2%) were discharged without a diagnosis. This was followed closely by infection, accounting for 37.2% (n = 41) of patients. Rheumatologic disease was next (n = 16, 14.5%), followed by miscellaneous (n = 6, 5.4%) and oncologic diagnoses (n = 5, 4.5%). The average cost of hospitalization was 40,295 US dollars. CONCLUSIONS: This study aligns with some of the most recent publications which report undiagnosed cases as the most common outcome in patients hospitalized with FUO. Understanding that, often no diagnosis is found may reassure patients, families, and clinicians. The cost associated with hospitalization for FUO may cause clinicians to reconsider inpatient admission for diagnostic work-up of fever, particularly given the evidence demonstrating that many patients are discharged without a diagnosis.

Fever of Unknown Origin in US Soldier: Telemedical Consultation Limitations in a Deployment to West Africa.

OBJECTIVE: Review the application of telemedicine support for managing a patient with possible sepsis, suspected malaria, and unusual musculoskeletal symptoms. Clinical Context: Regionally Aligned Forces (RAF) supporting US Army Africa/Southern European Task Force (USARAF/ SETAF) in the Africa Command area of responsibility. Care provided by a small Role I facility on the compound. Organic Medical Expertise: Five 68W combat medics (one is the patient); one SOCM trained 68W combat medic. No US provider present in country. Closest Medical Support: Organic battalion physician assistant (PA) located in the USA; USARAF PA located in Italy; French Role II located in bordering West African country; medical consultation sought via telephone, WhatsApp® (communication with French physician) or over unclassified, encrypted e-mail. Earliest Evacuation: Estimated at 12 to 24 hours with appropriate country clearances and approval to fly from three countries including French forces support approval.

Predicting the outcomes of targeted temperature management for children with seizures and/or impaired consciousness accompanied by fever without known etiology.

BACKGROUND: Seizures and/or impaired consciousness accompanied by fever without known etiology (SICF) is common in the pediatric emergency setting. No optimal strategy for the management of SICF in childhood currently exists. We previously demonstrated the effectiveness of targeted temperature management (TTM) against SICF with a high risk of morbidity; however, some patients with SICF develop neurological sequelae despite TTM, which necessitate additional neuroprotective treatment. The clinical characteristics of these severe cases have not been studied. Accordingly, the aim of this study was to identify the clinical characteristics of children with SICF who exhibit poor outcomes after TTM. METHODS: The medical records of children admitted to Kobe Children's Hospital (Kobe, Japan) between October 2002 and September 2016 were retrospectively reviewed. Patients with SICF treated using TTM were included and divided into the satisfactory and poor outcome groups. Univariate and multivariate logistic regression analyses were used to compare clinical characteristics and laboratory findings between the two groups. RESULTS: Of the 73 included children, 10 exhibited poor outcomes. Univariate logistic regression analysis revealed that acute circulatory failure before TTM initiation, the use of four or more types of anticonvulsants, methylprednisolone pulse therapy, and an aspartate aminotransferase (AST) level ≥73 IU/L were associated with poor outcomes. Multivariate logistic regression analysis identified an elevated AST level as a significant independent predictor of a poor outcome. CONCLUSIONS: An elevated AST level within 12 h of onset in children with SICF is an independent predictor of a poor outcome after TTM initiated within 24 h of onset.

Outcomes of a clinical pathway for primary outpatient management of pediatric patients with low-risk febrile neutropenia.

BACKGROUND: Fever and neutropenia is a common reason for nonelective hospitalization of pediatric oncology patients. Herein we report nearly five years of experience with a clinical pathway designed to guide outpatient management for patients who had low-risk features. PROCEDURES: Through a multidisciplinary collaboration, we implemented a clinical pathway at our institution using established low-risk criteria to guide outpatient management of pediatric oncology patients. Comprehensive chart review of all febrile neutropenia episodes was conducted to characterize outcomes of patients with low-risk febrile neutropenia following clinical pathway implementation. RESULTS: Between April 1, 2013, and October 1, 2017, there were 169 cases of febrile neutropenia managed in our Pediatric Oncology Unit. Sixty-seven (40%) of these episodes were defined as low risk and managed either entirely in the outpatient setting (41 episodes, 24%) or with a step-down strategy involving a very brief inpatient stay (26 episodes, 15%). There were no intensive care unit admissions or deaths among the low-risk patients. Of those identified as low risk, seven patients (10%) required subsequent hospitalization during the follow-up period, two for inadequate oral intake, two for persistent fevers, one for cellulitis, one for seizure unrelated to the febrile episode, and one for a positive blood culture. CONCLUSIONS: Following implementation of a clinical pathway, the majority of patients designated as low risk were managed primarily in the outpatient setting without major morbidity or mortality, suggesting that carefully selected low-risk patients can be successfully treated with outpatient management and subsequent admission if warranted.

Cardiac and vascular causes of persistent fever: A systematic review.

Fever of unknown origin refers to a prolonged fever with an unknown cause despite adequate medical evaluations. This condition often leads to unnecessary extensive laboratory work-ups and antimicrobial therapies. The atypical presentations often cause a delayed diagnosis and an improper treatment with an increased morbidity rate. In cardiac surgical patients, fever of unknown origin remains an intriguing problem during the diagnostic process of cardiac surgical diseases. Cardiac myxoma or aortic dissection are often misdiagnosed when patients present with fever of unknown origin as an onset symptom. Under such circumstances, medical examinations by echocardiography and chest computed tomography, particularly fluorodeoxyglucose-positron emission tomography/computed tomography, have been proved crucial for early diagnosis. A better understanding of the clinical features of cardiac surgical disorders presenting with fever of unknown origin would facilitate early diagnosis of fever of unknown origin. A further decision-making of prompt treatment of choices of a cardiac operation is important for improving patients' outcomes.

The challenge of rapid management of fever in children under 5 in Guinea.

In 2013, the Guinean health authority had to reorganise and run a national response against malaria as a priority. The review of the National Strategic Plan to fight malaria in Guinea was carried out and one of its critical components was the prevention and rapid management of fever (RMF) attributable to malaria in children. The study reports on the demographic and health determinants of this rapid management in children under 5. The participants were 4786 children from 2874 representative households. RMF was defined in terms of recourse to primary care. The recourse was defined by child's reference for the treatment of fever which led or not to treatment of malaria. We found that 1491 children (31.2%) had a bout of fever within the 2 weeks that preceded the survey. The prevalence of malaria was 45.4% among those children who have a bout of fever. The recourse to traditional healers was estimated at 9.6% and the use of health facilities was estimated at 71.5%. Overall, 74.9% of children with fever received treatment within the recommended timeliness (24 h), with regional disparity in this rapid response. The high proportion of recourse to traditional healers is still a matter of concern. New control and prevention strategies should be extended to traditional healers for their training and involvement in directing febrile children to health facilities.

Pyrexia of unknown origin.

The syndrome of pyrexia of unknown origin (PUO) was first defined in 1961 but remains a clinical challenge for many physicians. Different subgroups with PUO have been suggested, each requiring different investigative strategies: classical, nosocomial, neutropenic and HIV-related. This could be expanded to include the elderly as a fifth group. The causes are broadly divided into four groups: infective, inflammatory, neoplastic and miscellaneous. Increasing early use of positron emission tomography-computed tomography (PET-CT) and the development of new molecular and serological tests for infection have improved diagnostic capability, but up to 50% of patients still have no cause found despite adequate investigations. Reassuringly, the cohort of undiagnosed patients has a good prognosis. In this article we review the possible aetiologies of PUO and present a systematic clinical approach to investigation and management of patients, recommending potential second-line investigations when the aetiology is unclear.

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.

Performance of risk stratification criteria in the management of febrile young infants younger than three months of age.

AIM: We evaluated the diagnosis, risk stratification and management of febrile infants under three months of age who presented to an Israeli paediatric emergency room (ER). METHODS: This retrospective study enrolled all febrile infants examined in the paediatric ER of Soroka Medical Center during 2010-2013. The patients were classified into low-risk and high-risk subgroups and compared by age and ethnicity. RESULTS: Overall, 2251 febrile infants (60.5% of Bedouin and 34.4% of Jewish ethnicity) were enrolled. Hospitalisation rates were higher among Bedouin vs. Jewish infants (55 vs. 39.8%, p < 0.001). Fever without localising signs was diagnosed in 1028 (45.6%) infants and 499 (48.5%) were hospitalised; 26% were stratified as high-risk and 74% as low-risk. Bedouin infants rates were more likely to be at high-risk (p = 0.001) and hospitalised (p < 0.001) than Jewish infants. With regard to low-risk infants, the incidence rates were higher before two months than two to three months of age (73.3 vs. 59%, p < 0.001), as were the hospitalisation rates (46.3 vs. 20.1%, p < 0.001). No differences were recorded for the hospitalisation rates of Bedouin and Jewish infants between the three daily shifts. CONCLUSION: Major differences were recorded in hospitalisation rates, risk stratification and management of Bedouin and Jewish infants with fever without localising signs.

Diagnosis and empirical treatment of fever of unknown origin (FUO) in adult neutropenic patients: guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO).

Fever may be the only clinical symptom at the onset of infection in neutropenic cancer patients undergoing myelosuppressive chemotherapy. A prompt and evidence-based diagnostic and therapeutic approach is mandatory. A systematic search of current literature was conducted, including only full papers and excluding allogeneic hematopoietic stem cell transplant recipients. Recommendations for diagnosis and therapy were developed by an expert panel and approved after plenary discussion by the AGIHO. Randomized clinical trials were mainly available for therapeutic decisions, and new diagnostic procedures have been introduced into clinical practice in the past decade. Stratification into a high-risk versus low-risk patient population is recommended. In high-risk patients, initial empirical antimicrobial therapy should be active against pathogens most commonly involved in microbiologically documented and most threatening infections, including Pseudomonas aeruginosa, but excluding coagulase-negative staphylococci. In patients whose expected duration of neutropenia is more than 7 days and who do not respond to first-line antibacterial treatment, specifically in the absence of mold-active antifungal prophylaxis, further therapy should be directed also against fungi, in particular Aspergillus species. With regard to antimicrobial stewardship, treatment duration after defervescence in persistently neutropenic patients must be critically reconsidered and the choice of anti-infective agents adjusted to local epidemiology. This guideline updates recommendations for diagnosis and empirical therapy of fever of unknown origin in adult neutropenic cancer patients in light of the challenges of antimicrobial stewardship.

Current Evidence on the Evaluation and Management of Fever Without a Source in Infants Aged 0-90 Days: A Review.

BACKGROUND: Despite development of risk stratification tools decades ago, the best strategy for evaluation and management of young infants with fever without a clear source remains uncertain. OBJECTIVE: To describe the variability in current practice and review recently published evidence in three key areas: inflammatory markers were used as a tool for risk stratification, impact of viral testing, and optimal observation time on antibiotics. METHOD: Articles were identified using PubMed, Scopus, and Cochrane databases and via experts. Abstracts were screened and potential articles underwent full review if they focused on febrile infants 0- 90 days with fever without a source and outcomes for key topics. RESULTS: Thirty-two articles were included. Recent studies show that variability exists for most aspects of evaluation and management. C reactive protein and procalcitonin (PCT) perform poorly for identification of serious bacterial infections (SBIs). However, PCT has good diagnostic accuracy for detection of invasive bacterial infections (IBIs), such as bacteremia and meningitis. When PCT is combined with urinalysis and clinical appearance in the Step-by-Step method, the sensitivity for detection of IBI is 92% for infants > 21 days of age. Infants with lab-confirmed viral infection were found to have reduced risk for SBI. Blood culture yield for true pathogens was the highest in the first 12-36 hours after incubation. CONCLUSION: Recent studies suggest viral testing and inflammatory markers (specifically PCT) can help better stratify young febrile infants at risk for IBIs. Infants who are deemed low risk may benefit from shorter observation times and tailored or discontinued antibiotic therapy.

[A 59-year-old woman with upper abdominal pain and fever]. / 59-jährige Patientin mit Oberbauchschmerzen und Fieber.

A 59-year-old woman suffered from fever and upper abdominal pain. The computed tomography (CT) scan revealed a liver lesion. Conventional imaging techniques (CT, magnetic resonance imaging, contrast-enhanced ultrasonography) did not allow for a consistent diagnosis. Fine needle biopsy of the liver lesion was performed. Histologically, fibrotic inflammation was found and an inflammatory pseudotumor (IPT) diagnosed. Despite treatment with steroids and antibiotics, the size of the IPT increased; thus, surgical resection was necessary. In case of fever of unknown origin, IPT should be considered as a potential diagnosis.

[Febrile Urinary Tract Infections: When are they an Emergency?] / Der fieberhafte Harnwegsinfekt ­ Wann ein Notfall?

Urinary tract infections should be suspected in every febrile infant until proven otherwise. While older children and adolescents mostly present with classical features such as dysuria, flank pain and/or abdominal pain, secondary enuresis or pollakiuria, diagnosing infants or newborns, who are incapable of describing or pinpointing pain, can be much more challenging. As such, an infection with gradual and subtle onset may result in fulminant disease and emergency situations. In children with urinary tract infections and known mechanical or functional obstructions of the urinary tract, adequate drainage of the infected urinary tract may be necessary (e. g. nephrostomy, ureteral stent or transurethral catheter).