Recommendations for Updating Fever and Inflammation of Unknown Origin From a Modified Delphi Consensus Panel.

Background: Fever of unknown origin (FUO) and inflammation of unknown origin (IUO) are syndromes commonly used as medical diagnoses. Since the existing literature has a mixture of diagnostic approaches, developing consensus-based recommendations would be helpful for clinicians, researchers, and patients. Methods: A modified Delphi process was performed from October 2022 to July 2023, involving 4 rounds of online surveys and 2 live video conferences. The panel comprised international experts recruited based on peer-reviewed published publications and studies. Results: Among 50 invited experts, 26 (52.0%) agreed to participate. Twenty-three panelists completed round 1 of the survey, 21 completed rounds 2 and 3, 20 completed round 4, and 7 participated in round 5 live video discussions. Of the participants, 18 (78.3%) were academic-based clinicians and researchers, 5 (21.7%) practiced in a community-based hospital, and 6 (26.1%) were female. Consensus was reached on 5 themes: (1) incorporating epidemiologic factors, such as geographic location and travel history; (2) updated criteria for classifying FUO or IUO; (3) initial evaluation approaches; (4) a classification system for diagnoses; and (5) recommendations for judicious limitation of empiric therapies. Experts strongly disagreed with using 2-deoxy-2-[18F] fluoro-D-glucose positron emission tomography/computed tomography as part of the diagnostic criteria for FUO. There were mixed opinions about the importance of the temperature measurement site, the 3-week minimum illness criterion, the need for a standard definition of relapsing fevers, and the use of similar evaluation strategies for FUO and IUO. Conclusions: These Delphi-generated consensus-based recommendations offer potential improvements compared with earlier definitions and a guide for clinical practice and future research.

Fever of unknown origin: A 12-year case series in Colombia.

BACKGROUND: Fever of unknown origin (FUO) is a diagnostic challenge with highly heterogeneous causes. Its etiology can change according to the studied regions, and the chance of reaching a diagnosis depends on available resources. The aim of this study is to describe the clinical characteristics, etiology and the usefulness of diagnostic aids in cases of FUO managed over 12 years in a Colombian reference center. METHODOLOGY: Single-institution retrospective case series. All cases of FUO between 2006 and 2017 were identified with the help of an electronic medical record search software. Cases of adults with fever for more than three weeks who remained undiagnosed after three days of hospitalization are described. RESULTS: Of 1,009 cases evaluated, 112 cases met the inclusion criteria (median age 43 years, 66% men). The etiologies identified were infectious (31.2%), inflammatory (20.5%), neoplastic (14.3%), and miscellaneous (2.7%) diseases. 31.2% remained without etiological diagnosis. The most frequent conditions were tuberculosis (17%), Hodgkin's lymphoma (7.1%), systemic lupus erythematosus (6.3%), disseminated histoplasmosis, and adult Still's disease. Contrast tomography and biopsies were the studies that most frequently supported or confirmed the final diagnosis. CONCLUSIONS: This series of contemporary Latin American cases suggests that the categories of FUO etiologies are similar to those reported in studies from developed countries, with tuberculosis being the most frequent cause in our setting. Our results highlight the importance of tomography-guided invasive studies in the diagnostic approach to FUO.

Prospective randomized trial comparing relapse rates in dogs with steroid-responsive meningitis-arteritis treated with a 6-week or 6-month prednisolone protocol.

BACKGROUND: Traditionally, 6-month courses of prednisolone are used to treat steroid-responsive meningitis-arteritis (SRMA), but this medication is associated with adverse effects that can lead to poor quality of life. HYPOTHESIS/OBJECTIVES: Resolution of clinical signs and rate of relapse of SRMA would not be significantly different between a 6-month prednisolone protocol and a 6-week protocol. ANIMALS: Forty-four hospital cases from multiple referral centers in the United Kingdom (2015-2019). Twenty of 44 were treated with the 6-month protocol and 24/44 with the 6-week protocol. METHODS: Prospective, randomized trial with 12-month follow-up. The same prednisolone protocol reinitiated in the event of relapse. Analysis of relapses with binary logistic and Poisson regression modeling. RESULTS: All cases responded to their treatment protocol. Relapses occurred in 6/20 (30%) of the 6-month protocol and 9/24 (38%) of the 6-week protocol. There was no statistical difference in the incidence risk of at least 1 relapse between the 2 groups (odds ratio = 1.40; 95% confidence interval [CI], 0.40-4.96, P = 0.60). Among the 15 dogs that relapsed, 10/15 (67%) relapsed once, 3/15 (20%) relapsed twice, and 2/15 (13%) relapsed 3 times. No statistical difference was detected in the incidence rate ratio (IRR) of total relapse events between the 2 groups (IRR = 1.46; 95% CI, 0.61-3.48; P = 0.40). CONCLUSIONS AND CLINICAL IMPORTANCE: "Short" 6-week prednisolone protocols could be used to treat SRMA, thereby presumably reducing the duration and severity of prednisolone's adverse effects.

Diabetes Fever.

While diabetes manifests multiple clinical presentations, complications and comorbidities, most modern discourse focuses on the cardiovascular aspects of the syndrome. In this communication, we explore the vast spectrum of fever and diabetes. We highlight the bidirectional interactions between febrile illness and diabetes, as well as drug-drug interactions. These multifaceted connections must be understood by all health care professionals who manage diabetes and/or fever.

The pyrexia channel remodels egg-laying of Liriomyza huidobrensis in response to temperature change.

BACKGROUND: The pea leafminer, Liriomyza huidobrensis, is one of the most important insect pests on vegetables and ornamentals. The survival and egg-laying behavior of leafminers are markedly affected by the environment temperature. However, the mechanisms underlying the relationship between egg-laying and temperature are still largely unknown. RESULTS: Here, we find that leafminers have evolved an adaptive strategy to overcome the stress from high or low temperature by regulating oviposition-punching plasticity. We further show that this oviposition-punching plasticity is mediated by the expression of pyx in the ovipositor when subjected to disadvantageous temperature. Specifically, down-regulation of pyx expression in leafminers under low temperature stress led to a significant decrease in the swing numbers of ovipositor and puncture area of the egg spot, and consequently the lower amount of egg-laying compared to leafminers at ambient temperature. Conversely, activation of pyx expression under high temperature stress increased the swing numbers and puncture area, still resulting in a reduction of egg-laying amount. CONCLUSION: Thereby, leafminers are able to coordinate pyx channel expression level and accordingly depress the oviposition. Our study uncovers a molecular mechanism underlying the adaptive strategy in insects that can avoid disadvantageous temperature for reproducing offspring. © 2024 Society of Chemical Industry.

Pyrexia of Unknown Origin Caused by Non-Hodgkin's Lymphoma: A Diagnostic Challenge for Clinicians.

Non-Hodgkin's lymphomas (NHLs) are a group of lymphoproliferative diseases that originate from different cell types, namely B cells, T cells, or natural killer cells. Herein, we report the case of a 69-year-old male patient who presented with a gradual-onset, intermittent, low-grade fever for four months and a right-sided neck lump for two months. On examination, a right-sided enlarged lymph node sized 1 × 1 cm2 was noted, which was mobile, hard in consistency, and non-tender. No other lymphadenopathy was noted in other parts of the body. Imaging and biochemical studies done at the initial stages did not reveal features in favor of any lymphoproliferative disorders, and the two lymph node biopsies done two weeks apart were inconclusive as well. An extended panel of investigations was done in view of excluding other infective and inflammatory pathologies, which was negative, making the patient undiagnosed of any disease state despite being symptomatic for four months. Finally, the third lymph node biopsy tested positive, which paved the way for the diagnosis of NHL. This diagnosis underlines the importance of this case. Following the diagnosis, the patient was initiated on a few chemotherapeutic agents, after which a mild symptomatic improvement was achieved.

Intrapartum pyrexia, cardiotocography traces and histologic chorioamnionitis: a case-control study.

OBJECTIVES: To compare characteristics of labor, cardiotocography traces, and maternal and neonatal outcomes, in a cohort of pregnancies at term complicated by maternal intrapartum pyrexia, with or without a histologic diagnosis of chorioamnionitis. METHODS: This is a retrospective case-control study including pregnancies at term with detection of maternal intrapartum pyrexia, delivered between January 2020 and June 2021. Cardiotocography traces were entirely evaluated, since admission till delivery, and classified according to the International Federation of Obstetrics and Gynecology (FIGO) guideline. Maternal and neonatal outcomes were also recorded as secondary outcomes. Placentas have been studied according to the Amniotic Fluid Infection Nosology Committee. RESULTS: Forty four patients met the inclusion criteria and were included in the study cohort. There was a significant association between the use of oxytocin augmentation in labor and the histologic diagnosis of chorioamnionitis. A significative recurrence of loss and/or absence of accelerations at the point of pyrexia was also documented in women with histological chorioamnionitis compared to the others. CONCLUSIONS: Chorioamnionitis appears to be associated with myometrial disfunction, as suggested by the increased use of oxytocin augmentation during active labor of women at term with intrapartum pyrexia and histologic diagnosis of chorioamnionitis.

A Case of Pyrexia of Unknown Origin Diagnosed as Hemophagocytic Lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare disease that is even rarer in the adult population. It requires a high degree of suspicion from the treating physician, and if diagnosed early, patients might have a survival benefit from this highly fatal condition. HLH is a disorder of immune regulation where the hyperactivity of cytokines attacks different cells, which leads to multiple organ dysfunctions. Varying presentations and similarities with other diseases make diagnosis difficult. Familial HLH is commonly seen in the pediatric population, while acquired or secondary HLH is seen in adults. Secondary HLH is commonly triggered by neoplasms, infections, rheumatological diseases, and other autoimmune diseases. Here is a case of HLH that presented as chronic undiagnosed fever. In this case report, we have discussed in detail this disease, its presentation, investigations, treatment, and other important information that will help practicing doctors better diagnose and treat HLH patients.

Nuclear Medicine Imaging Tools in Fever of Unknown Origin: Time for a Revisit and Appropriate Use Criteria.

Fever of unknown origin (FUO) is a clinical conundrum for patients and clinicians alike, and imaging studies are often performed as part of the diagnostic workup of these patients. Recently, the Society of Nuclear Medicine and Molecular Imaging convened and approved a guideline on the use of nuclear medicine tools for FUO. The guidelines support the use of 2-18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) in adults and children with FUO. 18F-FDG PET/CT allows detection and localization of foci of hypermetabolic lesions with high sensitivity because of the 18F-FDG uptake in glycolytically active cells that may represent inflammation, infection, or neoplasia. Clinicians should consider and insurers should cover 18F-FDG PET/CT when evaluating patients with FUO, particularly when other clinical clues and preliminary studies are unrevealing.

Pyrexia of Unknown Origin: A Report of Two Cases.

Pyrexia of unknown origin (PUO) is a prolonged fever lasting several weeks without an identifiable cause despite extensive medical evaluation. Many a time, its cause remains largely unknown even after collecting a detailed medical history, conducting comprehensive physical assessments, and performing various standard laboratory tests and imaging procedures. This case series presents two cases of pyrexia of unknown origin. The first case includes a unique and uncommon presentation of non-Hodgkin's lymphoma. In the second case, the patient's fever remained unexplained after various investigations and treatments. The two documented cases of PUO presented in this report aim to contribute to the understanding of its diverse etiology and diagnostic challenges. By highlighting unique presentations and diagnostic dilemmas, the cases aim to promote awareness and facilitate timely recognition and appropriate management of PUO.

Long-term neuropeptide modulation of female sexual drive via the TRP channel in Drosophila melanogaster.

Connectomics research has made it more feasible to explore how neural circuits can generate multiple outputs. Female sexual drive provides a good model for understanding reversible, long-term functional changes in motivational circuits. After emerging, female flies avoid male courtship, but they become sexually receptive over 2 d. Mating causes females to reject further mating for several days. Here, we report that pC1 neurons, which process male courtship and regulate copulation behavior, exhibit increased CREB (cAMP response element binding protein) activity during sexual maturation and decreased CREB activity after mating. This increased CREB activity requires the neuropeptide Dh44 (Diuretic hormone 44) and its receptors. A subset of the pC1 neurons secretes Dh44, which stimulates CREB activity and increases expression of the TRP channel Pyrexia (Pyx) in more pC1 neurons. This, in turn, increases pC1 excitability and sexual drive. Mating suppresses pyx expression and pC1 excitability. Dh44 is orthologous to the conserved corticotrophin-releasing hormone family, suggesting similar roles in other species.

Antipyretic Use in Noncritically Ill Patients With Fever: A Review.

Antipyretics are one of the most frequently used agents in medicine. Numerous pharmacological agents, such as acetaminophen, non-steroidal anti-inflammatory agents (NSAIDs), salicylates, and selective cyclooxygenase 2 (COX-2) inhibitors, and nonpharmacological treatment modalities, such as tepid sponging and cooling blankets, are available for temperature reduction. There is a scarcity of definitive clinical guidelines on the choice of various agents in noncritically ill febrile patients. Our review examined the various modalities available for antipyresis and compared their safety and efficacy. The rationale for the choice of a particular pharmacological agent and route of administration were scrutinized. Our review also envisaged the perceived beneficial effects of antipyretics against the harmful side effects, including the evaluation of morbidity or mortality advantage conferred by antipyretics. The various toxicities associated with these agents were also highlighted.

Development of a Consensus-Based List of Potential Quality Indicators for Fever and Inflammation of Unknown Origin.

With a growing emphasis on value-based reimbursement, developing quality indicators for infectious diseases has gained attention. Quality indicators for fever of unknown origin and inflammation of unknown origin are lacking. An assembled group of international experts developed 12 quality measures for these conditions, which could be validated with additional study.

Antimicrobial prophylaxis is not indicated for horses undergoing general anaesthesia for elective orthopaedic MRI.

BACKGROUND: Post-anaesthetic fever is a known complication of general anaesthesia, however, its incidence in horses undergoing elective magnetic resonance imaging (MRI) is unknown. OBJECTIVE: To determine the incidence of post-anaesthetic fever in horses undergoing elective orthopaedic MRI and determine whether prophylactic antimicrobial therapy would be associated with a reduction in the incidence of post-anaesthetic fever. We hypothesised that prophylactic antimicrobials would be associated with a reduction in the incidence of post-anaesthetic fever. STUDY DESIGN: Retrospective cross-sectional study. METHODS: This retrospective study included 791 elective orthopaedic MRIs in systemically healthy horses between June 2006 and March 2020 that recovered from general anaesthesia and did not undergo surgery or intensive medical therapy soon after recovery. Potential factors associated with post-anaesthetic fever were evaluated using multivariable logistic regression. Case signalment, travel time, preanaesthetic haematology and fibrinogen abnormalities, use of prophylactic antimicrobials, peri-anaesthetic nonsteroidal anti-inflammatories, anaesthesia time and recovery time were all evaluated for association with post-anaesthetic fever. RESULTS: Of 791 MRI cases, 44 (5.6%) developed a post-anaesthetic fever. Horses that received prophylactic antimicrobials were [odds ratio (OR) 3.8, 95% confidence interval (CI) 1.98-7.46; p ≤ 0.001] more likely to develop a post-anaesthetic fever than those that did not receive antimicrobials. Young horses (1-4 years of age) were (OR 2.8, 95% CI 1.26-6.17; p = 0.01) more likely to develop fever compared with adult horses (≥5 years of age). MAIN LIMITATIONS: Limitations of this study pertain to retrospective analysis including nonrandomised case selection and incomplete data records. CONCLUSIONS: While fever may indicate infection, the majority of early post-anaesthetic fevers resolved before discharge from the hospital with no identified cause. The use of prophylactic antimicrobials to reduce the risk of post-anaesthetic fever for elective MRI is not supported by this study.

CONTEXTO: Febre é uma complicação comum após anestesia geral. Contudo, a incidência de febre em cavalos submetidos à ressonância magnética (RM) é desconhecida. OBJETIVO: Determinar a incidência de febre pós­anestésica em cavalos submetidos à RM devido à lesões ortopédicas e determinar se terapia antimicrobiana é necessária para reduzir a incidência de febre pós­anestésica. Nossa hipótese é que o uso de antimicrobianos é associado com a redução da incidência de febre pós­anestésica. DELINEAMENTO DO ESTUDO: Estudo retrospectivo transversal. METODOLOGIA: Esse estudo retrospectivo incluiu 791 equinos submetidos à RM por motivos ortopédicos, entre Junho de 2006 e Março de 2020, que recuperaram de anestesia geral, e não foram submetidos à cirurgia ou terapia intensa logo após a recuperação. Fatores que potencialmente poderiam ser associados com febre pós­anestésica foram avaliados utilizando regressão logística multivariada. Informações do paciente, como sexo e idade, tempo de viagem, anormalidades nos exames de sangue (hemograma e bioquímico) pré­anestésico, uso profilático de antimicrobianos, uso de anti­inflamatório não­esteroidal no período peri­anestésico, tempo de anestesia, e tempo de recuperação foram avaliados para possível associação com febre pós­anestésica. RESULTADOS: Dos 791 casos de RM, 44 (5.6%) desenvolveram febre pós­anestésica. Cavalos que receberam terapia antimicrobiana profilática foram (OR 3.8, 95% CI 1.98­7.46; p ≤ 0.001) vezes mais prováveis de desenvolverem febre pós­anestésica do que aqueles que não receberam antimicrobianos. Cavalos jovens (1­4 anos de idade) foram OR 2.8, 95% CI 1.26­6.17; p = 0.01) vezes mais prováveis de desenvolverem febre comparado com cavalos adultos (≥5 anos de idade). PRINCIPAIS LIMITAÇÕES: As limitações deste estudo são aquelas de uma análise retrospectiva, incluindo a seleção não randomizada dos pacientes e prontuários incompletos. CONCLUSÕES: Enquanto febre pode indicar a presença de infecção, a maioria das febres no período logo após anestesia se resolveram antes da alta do hospital e não tiveram nenhuma causa identificada. O uso profilático de antimicrobianos para reduzir a possível chance de febre pós­anestésica em casos de RM eletiva não é suportada por este estudo.

FDG-PET/CT for investigation of pyrexia of unknown origin: a cost of illness analysis.

BACKGROUND: Our study aims to explore the current utilisation of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in the diagnostic pathway of pyrexia of unknown origin (PUO) and associated cost of illness in a large tertiary teaching hospital in Australia. METHOD: 1257 febrile patients between June 2016 and September 2022 were retrospectively reviewed. There were 57 patients who met the inclusion criteria of "classical PUO", of which FDG-PET/CT was performed in 31 inpatients, 15 outpatients and 11 inpatients did not have an FDG-PET/CT scan. The patient demographics, clinical characteristics and inpatient cost were analysed, together with the diagnostic performance of FDG-PET/CT and impact on clinical management. RESULT: The mean age, length of stay and total cost of admission were higher for inpatients who received FDG-PET/CT versus those who did not. The median cost per patient-bed-day did not differ between the two groups. Inpatients who received earlier FDG-PET/CTs (≤ 7 days from admission) had shorter length of stays and lower total cost compared to those who received a later scan. A negative FDG-PET/CT scan, demonstrating no serious or life-threatening abnormalities resulted in subsequent discharge from hospital or outpatient clinic in 7/10 (70%) patients. There were 11/40 (28%) scans where ancillary abnormalities were identified, requiring further evaluation. CONCLUSION: FDG-PET/CT showed high diagnostic accuracy and significant impact on patient management in patients with PUO. FDG-PET/CT performed earlier in admission for PUO was associated with shorter length of stay and lower total cost.

2-Hydroxybenzohydrazide as a novel potential candidate against nociception, inflammation, and pyrexia: in vitro, in vivo, and computational approaches.

The current study was designed to evaluate the 2-hydroxybenzohydrazide (HBH) as a drug having efficacy against pyrexia, inflammation, and nociception. Besides, the therapeutic effects of HBH on oxidative stress and C-reactive proteins were also evaluated. The pharmacological studies on HBH (20-60 mg/kg) were conducted using nociception, inflammation, and pyrexia standard models. Naloxone antagonism was performed to assess the possible involvement of opioidergic mechanisms. The antioxidant study was conducted on ABTS and DPPH assays using gallic acid as a standard. Moreover, the binding capability of HBH with enzymes cyclooxygenase-I/II (COX-I/II) was determined using molecular modeling analysis. The findings indicated that the HBH dose-dependently inhibited pain, inflammation, and pyrexia. The HBH has significant anti-nociceptive and anti-inflammatory activities at 60 mg/kg (***p < 0.001), similar to the lower doses of diclofenac sodium (50 mg/kg) and tramadol (30 mg/kg). The HBH at 60 mg/kg reduced pyrexia as paracetamol (150 mg/kg). The HBH at 20-60 mg/kg doses declined the plasma C-reactive protein concentration. The mechanistic studies showed that the anti-nociceptive effect of HBH was antagonized by naloxone, indicating that the opioidergic mechanisms are involved. Furthermore, computational studies showed that the HBH exhibited an affinity for COX-I/II target receptors. The HBH significantly inhibited ABTS and DPPH radicals (IC50 = 33.81 and 26.74 µg/ml). These results proposed that the HBH has significant antipyretic, anti-inflammatory, and anti-nociceptive activities involving opioidergic mechanism.

Subacute Thyroiditis Causing Fever of Unknown Origin: A Reminder of the Uncommon Cause.

Subacute thyroiditis (SAT) is a transient inflammation of the thyroid gland that often occurs following a viral infection. It is an infrequent cause of fever of unknown origin (FUO). We present a 46-year-old gentleman who presented with two weeks of fever and some non-specific left-sided neck pain. His initial investigations and microbiological workup were unremarkable. He did not report any hyperthyroid symptoms. A computed tomography of the neck, chest, abdomen, and pelvis showed a heterogeneous appearance of his thyroid gland. Thyroid function was then performed, and it showed primary hyperthyroidism. His thyroid autoantibodies were negative. Ultrasonography of his thyroid showed features consistent with thyroiditis. He was treated with a course of oral steroids. His fever lysed. His thyroid function turned from a primary hyperthyroid pattern to subclinical hypothyroidism. His anti-thyroglobulin antibody level remained elevated after the steroid treatment. Our case highlights that SAT is an uncommon cause of FUO in patients without specific localizing symptoms. It can present without overt hyperthyroid clinical features. Steroid treatment is useful. There may be value in monitoring the anti-thyroid antibodies in SAT's management.

Management of Nasya-induced pyrexia in a patient with refractive error and migraine: a case report.

A 23 year old young lady was admitted for Ayurveda treatments of her refractive error coupled with migraine. She was put on Shadbindu Taila Nasya, 24 drops in both her nostrils immediately the next day. Within 6 h of performing Nasya, the patient started developing pyrexia which was initially of low grade, and later, within 6 h, went on to high-grade. Nasya was suspended, and rescue Ayurveda medicines were started but had no improvement. The patient later self-medicated an antipyretic drug, and with a single dose, the high-grade pyrexia came down to normal. Naranjo adverse drug reaction probability scale recording gave a score of six, which shows that the AE could be probably due to Nasya with Shadbindu Taila. This case report adds evidence to the medical database of under-reported/poorly reported adverse effects (AE) cases of Nasya therapy. It shows that Nasya is not a 100 % complication and adverse effect free treatment, but rather has to be done with extreme caution. This case report highlights that effective Ayurveda principle based preparatory treatments are also to be done before initiating Nasya to minimize the chances of adverse effects. This case report also suggests practicing a test dose of Nasya, before initiating a high dose, so as to detect adverse events and prevent severe complications.

Current State of Knowledge on the Definition, Pathophysiology, Etiology, Outcomes, and Management of Fever in the Intensive Care Unit.

Fever-an elevated body temperature-is a prominent feature of a wide range of disease conditions and is a common finding in intensive care, affecting up to 70% of patients in the intensive care unit (ICU). The causes of fever in the ICU are multifactorial, and it can be due to a number of infective and noninfective etiologies. The production of fever represents a complex physiological, adaptive host response that is beneficial for host defense and survival but can be maladaptive and harmful if left unabated. Despite any cause, fever is associated with a wide range of cellular, local, and systemic effects, including multiorgan dysfunction, systemic inflammation, poor neurological recovery, and an increased risk of mortality. This narrative review presents the current state-of-the-art knowledge on the definition, pathophysiology, etiology, and outcomes of fever in the ICU and highlights evidence-based findings regarding the management of fever in the intensive care setting.

Review on Scrub Typhus: An Important Etiology of Acute Undifferentiated Fever Illness.

One of India's predominant public health issues is acute undifferentiated fever illness (AUFI), a typical response to an infectious agent. Diagnosis becomes challenging when the disease has been reported with fever as the primary symptom. Among the cases presenting at a tertiary care hospital in central India, 88% had an acute undifferentiated fever, the most common being dengue infection. In India, rural communities are at more risk from AUFI than cities. Most of those in danger are those who reside in remote areas, and one of the most significant risks is for those who reside close to forests. AUFI is a complex condition for physicians to deal with and is one of the most frequent clinical conditions for which empirical treatment is required. Nowadays, AUFI can be managed by a syndromic approach with the judicial use of antibiotics. Symptoms of AUFI, along with myalgia, headache, and anorexia, can be caused by various illnesses. Patients are recommended to undertake a battery of investigations, which may delay the therapy and increase expenses because many diseases may present with the same symptoms. In the developed world, viral illness is the primary cause of AUFI. However, in developing countries like India, it can also be brought on by potentially curable but life-threatening conditions such as malaria, leptospirosis, hantavirus infection, and Japanese encephalitis. Lack of knowledge of the locally prevalent illnesses, which might be the cause of AUFI, and lack of preliminary screening and diagnostics at the point of care to identify the etiologies make it difficult to control these generally curable causes of the burden of AUFI, especially in tropical and subtropical countries. A deeper understanding of AUFI is required to develop better diagnostics and cures for various etiologies, especially scrub typhus.