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Unraveling the Mystery: Understanding Fever and Fever of Unknown Origin Dr. Murad Ali Assistant Professor (Medicine)
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Learning outcomes By the end of this presentation, participants will be able to: Demonstrate knowledge of the fundamental concepts related to body temperature, including normal ranges and the pathogenesis of fever. Recognize the potential advantages and risks associated with fever. Comprehend the essential criteria used to define Fever of Unknown Origin (FUO). Identify the various etiological factors that can contribute to the development of FUO.
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Fever Pyrexia Hyperthermia
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Fever: Fever, is the elevation of an individual's core body temperature above a 'set-point' regulated by the body's thermoregulatory center in the hypothalamus. Pyrexia: A medical term, used interchangeably with fever.. Usually signifies increase in body temperature due to causes other than infections Hyperthermia: In hyperthermia, the set-point is unaltered, and the body temperature becomes elevated in an uncontrolled fashion due to exogenous heat exposure or endogenous heat production. Not controlled by hypothalamus. Balli, Swetha, and Shweta Sharan. "Physiology, Fever." (2020).
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Normal body temperature What is the normal body temperature? A "normal" core (internal) body temperature ranges from 96º F (35.6º C) to 99.9ºF (38ºC) in healthy persons. Core temperature in the afternoon is about 1ºF higher later in the day and may be a bit higher in women In healthy individuals, body temperature tends to follow a circadian rhythm, with the lowest temperatures occurring in the early morning hours and the highest temperatures occurring in the late afternoon and evening. The diurnal variation in body temperature is thought to be influenced by various factors, including the body's internal clock, physical activity, and hormone levels Speaker SL, Pfoh ER, Pappas MA, Hu B, Rothberg MB. Oral temperature of noninfected hospitalized patients. JAMA. 2021 May 11;325(18):1899-901. Merck Manual. (2021). Body temperature regulation. https://www.merckmanuals.com/professional/physiology/biochemistry_of_temperature_regulation/body_temperature_regulation
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What is Fever?
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Fever definition There is no single universally accepted standard definition of fever, as different organizations and contexts may use slightly different cutoffs or criteria CDC considers a person to have a fever when he or she has a measured temperature of at least 100.4 °F [38 °C]. The interpretation of fever should always be considered in the context of the individual's overall clinical picture. Because: The method used to measure the temperature. Axilla, oral, rectal, tympanic membrane The age of the person. Children and older adults are more likely to have a lower normal body temperature than adults. The time of day. Body temperature is typically lower in the morning and higher in the evening. The person's activity level. Exercise can raise body temperature. The person's environment. A hot environment can also raise body temperature. Centers for Disease Control and Prevention. (2021). Fever. https://www.cdc.gov/healthywater/emergency/creating-healthy-water/contaminants/fever.html
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FEVER Recall of physiology: Fever is a physiological response of the body to infection, inflammation, or other stimuli that activate the immune system. The body's normal temperature range is tightly regulated by the hypothalamus, which acts as the body's thermostat. When a fever-inducing stimulus is detected, the hypothalamus raises the body's set point, resulting in an increase in body temperature. It can help the body fight off invading pathogens by increasing the activity of immune cells and inhibiting the growth of certain microorganisms. Mackowiak, P. A. (2012). Physiology of Fever. In Baron S, et al. (Eds.). Medical Microbiology (4th ed.). University of Texas Medical Branch at Galveston.
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Pyrogens Pyrogens are substances that can cause fever by inducing the body to raise its temperature set point. Pyrogens can be either exogenous (originating from outside the body) or endogenous (produced by the body itself). Exogenous pyrogens include infectious agents such as bacteria, viruses, and fungi, as well as certain toxins and chemicals. These substances can stimulate the immune system to release cytokines, which can then activate the hypothalamus to raise the body's temperature set point. Endogenous pyrogens are produced by the body itself in response to infection or other stimuli. The most important endogenous pyrogen is interleukin-1 (IL-1), others are tumor necrosis factor (TNF), interferon-alpha (IFN-α), and prostaglandins Dinarello, C. A. (1999). Cytokines as endogenous pyrogens. The Journal of Infectious Diseases, 179(suppl_2), S294-S304. https://doi.org/10.1086/513854
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Image taken form Doconline
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Fever is a Blessing or a Curse?
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Fever: A blessing or curse? Blessing: Inhibiting the growth of microorganisms: Stimulating the immune system: Enhancing tissue repair: by increasing blood flow and nutrient delivery to affected tissues. Improving drug efficacy: Some studies suggest that fever may enhance the efficacy of certain drugs, such as antibiotics, by increasing blood flow and drug delivery to infected tissues. Mackowiak, P. A. (2012). Fever: blessing or curse? A unifying hypothesis. Annals of Internal Medicine, 156(9), 677-677. https://doi.org/10.7326/0003-4819-156-9-201205010-00011
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Quotes "Fever is nature's engine which she brings into the field to remove her enemy." - Thomas Sydenham "Fever is a wise precautionary measure taken by the body against the enemies within." - Rudolf Virchow "Fever is a battle that the body wages to conquer its invaders." – Hippocrates "Fever is the fire that burns within us, fueling the fight against infection and healing." – Unknown "Fever is not an illness to be feared but a sign that the body is actively working towards recovery." - Unknown
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Curse: Dehydration: Metabolic abnormalities: acidosis, hypoglycemia, and electrolyte imbalances. Seizures: esp in children uder 5 Organ damage: such as the brain, heart, and liver. This can lead to permanent damage if not treated promptly. Death: In rare cases, high fevers can be fatal, especially in vulnerable populations such as the elderly and immunocompromised individuals. Mackowiak, P. A. (2012). Fever: blessing or curse? A unifying hypothesis. Annals of Internal Medicine, 156(9), 677-677. https://doi.org/10.7326/0003-4819-156-9-201205010-00011
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Fever classification (Grades) Ogoina D. Fever, fever patterns and diseases called ‘fever’–a review. Journal of infection and public health. 2011 Aug 1;4(3):108-24.
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Thermometer (indispensable tool)
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thermometer What is its exact and full name? Who and When was the first clinical thermometer invented? Allbutt clinical thermometer Sir Thomas Clifford Allbutt (1836–1925) was a celebrated British physician. He spent 20 years working in Leeds during which time he devised the small clinical thermometer. A local company, Harvey and Reynolds, first manufactured this special thermometer in 1867
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Fever of Unknown Origin ( FUO)
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Fever of Unknown origin (FUO) (Pyrexia of unknown origin) The definition of PUO has evolved over time, and different organizations and experts may have slightly different criteria A widely accepted definition was proposed by Petersdorf and Beeson in 1961, through a prospective analysis of 100 cases ,which included the following criteria Fever higher than 38.3ºC on several occasions Duration of fever for at least three weeks Failure to reach a diagnosis after one week of investigations in the hospital PETERSDORF RG, BEESON PB. Fever of unexplained origin: report on 100 cases. Medicine (Baltimore). 1961 Feb;40:1-30. doi: 10.1097/00005792-196102000-00001. PMID: 13734791.
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Definition Expansion
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classification Durack and Street proposed a classification system for PUO in 1991 that is still widely used today. They classified PUO into four categories based on the presence or absence of certain clinical features and laboratory findings: Classic PUO: fever of greater than 38.3°C (101°F) for at least three weeks with no diagnosis after one week of inpatient investigation or three outpatient visits. Nosocomial PUO: fever of greater than 38.3°C (101°F) in a hospitalized patient for at least three days with no diagnosis. Neutropenic PUO: fever of greater than 38.3°C (101°F) in a patient with neutropenia (less than 500 cells/mm3) with no diagnosis after one week of inpatient investigation or three outpatient visits. HIV-associated PUO: fever of greater than 38.3°C (101°F) in an HIV-positive patient with no diagnosis after one week of inpatient investigation or three outpatient visits. This classification system provides a framework for approaching the diagnostic workup of PUO and can guide the selection of appropriate diagnostic tests and consultations with specialists. Durack, D. T., & Street, A. C. (1991). Fever of unknown origin--reexamined and redefined. Current Clinical Topics in Infectious Diseases, 11, 35-51.
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Aetiology OF PUO Causes of FUO may differ geographically based on: regional exposures, economic development, and available diagnostic tools. For example, in developing countries, the baseline incidence of infection may be higher, whereas noninfectious inflammatory and malignant conditions are more common in developed countries.
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Aetiology ……… The list of etiologic possibilities for PUO is extensive, and it is helpful to break the differential diagnoses into 4 broader categories, such as Infection, Noninfectious inflammatory conditions, Malignancies, and Miscellaneous. The percentages of different causes of PUO can vary depending on the population and the time period studied. However, here are some estimated percentages based on a systematic review of 15 studies: Infectious diseases: 38% Neoplastic diseases: 16% Non-infectious inflammatory diseases: 14% Miscellaneous causes: 18% Undiagnosed cases: 14% Mourad, O., Palda, V., & Detsky, A. S. (2021). A comprehensive evidence-based approach to fever of unknown origin. Archives of Internal Medicine, 161(10), 1190-1202. https://doi.org/10.1001/archinte.161.10.1190
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undiagnosed cases of PUO Historically, about 25-30% of cases remained undiagnosed despite extensive workup. A prospective multicenter study of cases from 2003 to 2005 in the Netherlands reported 51% of cases without a final diagnosis. The percentages of causes of this study was: Systemic rheumatic disease (eg, vasculitis, systemic lupus erythematosus, polymyalgia rheumatica) – 22 percent Infection – 16 percent Malignancy – 7 percent Miscellaneous – 4 percent No diagnosis – 51 percent A systematic review of 18 papers published from 2005 to 2015 from regions across the globe found a lack of diagnostic outcome in 23%. In light of considerable advances in diagnostics, this number seems surprisingly high and consistent. Bleeker-Rovers CP, Vos FJ, de Kleijn EMHA, Mudde AH, Dofferhoff TSM, Richter C, Smilde TJ, Krabbe PFM, Oyen WJG, van der Meer JWM. A prospective multicenter study on fever of unknown origin: the yield of a structured diagnostic protocol. Medicine (Baltimore). 2007 Jan;86(1):26-38. doi: 10.1097/MD.0b013e31802fe858. PMID: 17220753. Fusco FM, Pisapia R, Nardiello S, Cicala SD, Gaeta GB, Brancaccio G. Fever of unknown origin (FUO): which are the factors influencing the final diagnosis? A 2005–2015 systematic review. BMC infectious diseases. 2019 Dec;19:1-1.
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Adapted from: Mourad O, Palda V, Detsky AS. Arch Intern Med 2003; 163:545.
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Aetiology ( INFECTIONS) Most Common Tuberculosis (TB) Q fever (parturient animals) Brucellosis (hooved mammals, raw dairy) Less common HIV infection Abdominopelvic abscesses Cat scratch disease (CSD) Epstein-Barr virus (EBV) infection Cytomegalovirus (CMV) infection Enteric (typhoid) fever Toxoplasmosis Extrapulmonary TB
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Aetiology (Noninfectious Inflammatory Diseases) Most common Giant cell (temporal) arteritis Adult Still disease (juvenile rheumatoid arthritis) Less Common Systemic lupus erythematosus (SLE) Periarteritis nodosa/microscopic polyangiitis (PAN/MPA) Rheumatoid arthritis (RA)
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Malignant/neoplastic causes Malignant and neoplastic causes of FUO are as follows: Most common: Lymphoma, renal cell carcinoma Less common: Myeloproliferative disorder, acute myelogenous leukemia Least common: Multiple myeloma, breast/liver/pancreatic/colon cancer, atrial myxoma, metastases to brain/liver, malignant histiocytosis
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Miscellaneous Causes of PUO Most common: Cirrhosis (due to portal endotoxins), drug fever Less common: Thyroiditis, Crohn disease (regional enteritis) Least common: Pulmonary emboli, hypothalamic syndrome, familial periodic fever syndromes, cyclic neutropenia, factitious fever (especially in those experienced with the healthcare field)
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Take Home messages Everybody complaining of fever might not have fever Every fever is not PUO PUO is defined as a fever of ≥38.3°C (100.9°F) that persists for more than three weeks, with no obvious source of infection or inflammation after one week of initial investigation. PUO is a symptom that can be caused by various underlying conditions, including infections, malignancies, autoimmune diseases, and drug reactions, among others. Accurate temperature monitoring with a thermometer is essential for the diagnosis and monitoring of PUO patients
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Approach to a Patient with PUO A systematic and multidisciplinary approach is required in order to reach a diagnosis of PUO and require the following steps: Obtaining a detail medical history Comprehensive physical examination Appropriate and targeted laboratory tests Imaging studies as indicated Mulders-Manders CM, Simon A, Bleeker-Rovers CP. Fever of unknown origin. Clin Med (Lond). 2015 Dec;15(6):592-6. doi: 10.7861/clinmedicine.15-6-592. PMID: 26643525; PMCID: PMC6293329.
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Medical history for PUO
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Family history Immunization status Dental history Occupational history Travel history, especially within the prior year Nutrition and weight history (including consumption of dairy products); note changes in the fit of clothing if the patient does not monitor weight Drug history (over-the-counter medications, prescription medications, illicit substances) Sexual history Recreational habits Animal contacts (including possible exposure to ticks and other vectors) Surgery, invasive procedures, trauma
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History of Present illness S--> subjective or objective ( fever must be documented on several occasions during the day) O- onset….abrupt vs Gradual C--> characteristics ( intermittent, remittent, continuous, relasping) R  Relieving factors ( cold compression, paracetamol, analgesics) A Associated factors (rigors, chills, weight loss, fatigue, night sweats) T-timing ( duration of fever, time of the day, progress of fever) E- Exacerbating factors S- severity ( mild, moderate, high grade, hyperthermia)
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systemic Review (from head to toe) Central nervous system: headache, photophobia, seizures, confusion Eyes: dryness, itching, pain ENT: sore throat, ear discharge, nasal blockage Respiratory: cough, dyspnoea, haemoptysis Cardiovascular: chest pain, palpitations, syncopy Gastrointestinal: abdominal pain, diarrhoea, diarrhea, constipation,vomiting Hepatic: jaundice, nausea, right upper quadrant tenderness Genitourinary: dysuria, frequency, haematuria, urethral discharge Musculoskeletal: joint pain, swelling, stiffness, Dermatological: rash, erythema, skin breaks, lumps and bumps (lymph nodes)
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Past medical history Previous fevers TB HIV, HCV and HBV infections Recent surgery (possible abscess) Including dental procedures Drug history Full drug history including over-the-counter (OTC) and recreational drugs Intravenous drug use (IVDU)? Ever?! If so did they needle share? Are very aware of their last hepatitis and HIV serology? Immunisations up-to-date? Family history Any family members with contagious diseases (tuberculosis or viral illness)
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Sexual history Recent sexual practice Sexual contact with at-risk individual e.g. known HIV positive partner, male-male sexual contact, sex with those from sub-Saharan Africa, sex in exchange for money, no use of barrier protection Travel history All travel in last year Location (including villages or towns); appropriate vaccinations? Diet (including eating at roadside restaurants or local food; food hygiene) Swimming (especially in lakes and rivers) Animal contact
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Social history General Smoking; alcohol (alcoholism is a TB/HIV risk factor) Occupation Any contact with animals or the outdoors (zoonotic infections) TB risks Contact with people with TB Recent visit to, or relative visiting from, TB endemic areas Homeless; poor nutrition HIV and hepatitis risks IVDU Blood transfusion pre-1980 or in poorly developed countries Tattoos Piercings Home: waste disposal, pets, water source, sanitation,
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Historical clues towards infectious causes of PUO: Exposure to sick individuals Exposure to animals Recent travels History of sexually transmitted infections Consumption of contaminated food or water History of immunosuppressant medicine/immunodeficiency History of IV drug use Previous abdominal surgeries Living in endemic areas for certain diseases Historical clues to likely noninfectious inflammatory causes of FUO Musculoskeletal symptoms Past history of autoimmune diseases Family history of autoimmune diseases Recent vaccinations Skin Rashes with fever Skin nodules like erythema nodosum Exposure to toxins like metals/pesticides CNS disorders: central fever with disorders of thermoregulation
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Historical clues to malignant causes of PUO Unexplained weight loss Night sweats (lymphomas) Lymphadenopathy Itching after a hot bath (lymphoma) Pel-Ebstein pattern of fever Erythema nodosum (lymphoma) Previous history of cancers Smoking Symptoms consistent with specific malignancies like cough and hemoptysis with lung cancers Historical clues to miscellaneous causes of FUO Prolonged immobility, car trips, flights: Thromboembolic disease Ethanol abuse: Alcoholic hepatitis, cirrhosis (endotoxemia of portal circulation) Medication list review: Drug fever Anticoagulant use: Hematoma, occult hemorrhage Inconsistent fever readings/pt behavior: factitious fever History of mental illness Heat/cold intolerance (thyroid disorders) History of head trauma/neurosurgery/radiation ( hypothalamic syndrome)
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Physical examination of a patient with PUO Definitive documentation of fever and exclusion of factitious fever are essential early steps in the physical examination. Measure the fever more than once and in the presence of healthcare personnel to exclude manipulation of thermometers. Repeat a regular physical examination daily while the patient is hospitalized. Pay special attention to rashes, new or changing cardiac murmurs, signs of arthritis, abdominal tenderness or rigidity, lymph node enlargement, funduscopic changes, and neurologic deficits.
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Examination in a sequence General : ill or not ill, weight, skin rashes Hands: stigmata of infective endocarditis, vasculitic changes, clubbing, Raynaud’s, arthropathies Pulse: Relative bradycardia (pulse-temperature deficit, Faget’s sign), unequal pulse in upper extremities (Takayasu’s arteritis)
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Arms: drug injection sites, epitrochlear and axillary lymph nodes, skin changes in the forearm Head and neck: Feel temporal arteries for tenderness and stiffness Paranasal sinuses for tenderness Eyes: iritis/conjunctivitis Fundoscopy: choroidal tubercles (miliary TB), Roth’s spots (infective endocarditis, retinal hemorrhages (leukemias) Jaundice Anemia Cervical Lymphadenopathy Seborrheic dermatitis (HIV) Parotid enlargement and tenderness Ears for otitis media Facial rash: butterfly rash Goiter
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Oral Cavity: Dental hygiene Oral ulcers Candidiasis Gingivitis and gums hypertrophy (leukemias) Dental tenderness on percussion (dental abscess) Tonsillar erythema and exhudates Pharyngitis Coated tongue Petechiae on palate and oral mucosa (infective endocarditis)
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Chest: Sternal tenderness: hematological malignancies Localized tenderness over the ribs Respiratory: signs of pneumonia, pleurisy, pleural effusions etc Cardiovascular: Murmurs Abdomen: Rose spots over abdomen Localized or generalized abdominal tenderness Splenomegaly Hepatomegaly Renal enlargement Abdominal masses Ascites Bowel sounds...abnormal bowel sounds (intestinal obstruction) Inguinal lymphadenopathy Rectal examination: mass/tenderness in rectum or pelvis ( abscess, carcinoma, prostatitis)
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Genitalia: Swelling or tenderness of testicles: epididymitis, orchitis, testicular torsion Testicular masses: seminoma Genital ulcers or rashes: syphilis, herpes simplex infection Penile discharge In females: PV examination by a lady doctor for vaginal discharge, genital ulcers and tenderness in the adnexal region or cervix to rule out PID, endometritis and cervical and uterine malignancies. Spine : tenderness to percussion over vertebrae: vertebral osteomyelitis, TB, Myeloma, Mets Lower Limbs: signs of DVT, PAD, joint swelling and tenderness, erythema nodosum, foot ulcers, localized tenderness (Paget’s, osteomyelitis)
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Investigations Pearls: Clinical examinations and investigations are rarely 100% sensitive or specific. It important to consider the case in relation to local epidemiology. Parry’s maxim ‘Why would this person, from this place, present in this way at this time?’ has wide-reaching relevance Sutton’s law ‘to go whether the money is’ provides sensible advice. It is worth referring back to evaluated diagnostic criteria such as the Duke’s criteria for endocarditis or the Yamaguchi criteria for adult onset Still’s disease. Bharucha T, Cockbain B, Brown M. Pyrexia of unknown origin in clinical practice. British Journal of Hospital Medicine. 2016 Oct 2;77(10):579-83.
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Investigations should be conducted to confirm or rule out the most likely diagnosis/diagnoses, based on the history and examination findings Investigation should proceed through at least two stages of baseline tests followed by more specific tests, after which each abnormal result should be weighed carefully – the more tests that are done, the more false leads will emerge. Early blanket testing for all possible aetiologies is inappropriate. Fernandez C, Beeching NJ. Pyrexia of unknown origin. Clin Med (Lond). 2018 Mar;18(2):170-174. doi: 10.7861/clinmedicine.18-2-170. PMID: 29626024; PMCID: PMC6303444.
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First line Investigations for All While a workup of FUO should emphasize clinical clues, the following, if not already performed, are essential laboratory and imaging tests that are of value in eliciting further diagnostic direction: Complete blood cell (CBC) count with white blood cell (WBC) differential Peripheral blood smear Complete metabolic panel (CMP; provides data on electrolytes, glucose, acid-base, renal, liver, protein status) C-reactive protein (CRP) Erythrocyte sedimentation rate (ESR) Urinalysis (used to detect glomerulonephritis, occult hematuria; pyuria) Blood cultures, preferably 3 blood draws from separate sites, performed at different times without administering antibiotics HIV serology Hepatitis A and B serology, and if epidemiologically applicable, Hepatitis E serology Tuberculosis screening tests – Purified protein derivative (PPD, or Mantoux test); interferon gamma release assays (IGRA) Posteroanterior and lateral chest radiography Beyond the above essentials in early screening, some would add antinuclear antibody titers, rheumatoid factor, and thyroid stimulating hormone (TSH) and thyroxine level in diagnosing certain conditions (lupus, RA, thyroiditis, hyperthyroidism). Their diagnostic accuracy is limited in other autoimmune and collagen vascular diseases. https://www.medscape.com/
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Second line investigations Simple clues found during initial testing often will guide the clinician toward one of the major subgroups of FUO. Further studies should be problem-focused and based on repeated clinical examinations or as a follow-up to abnormal basic test results to get potential diagnostic clues (PDC’s) The haphazard use of costly or invasive modalities of investigations should be avoided. The depth and aggressiveness of the evaluation should be guided by the severity of the patient’s illness. The diagnostic approach may be slower in generally well patients because fever often resolves during the evaluation process. Early involvement of other appropriate clinical specialties in the care of patients with PUO is important Roth AR, Basello GM. Approach to the adult patient with fever of unknown origin. American Family Physician. 2003 Dec 1;68(11):2223-8.
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List of potential second line investigations Fernandez C, Beeching NJ. Pyrexia of unknown origin. Clinical medicine. 2018 Apr;18(2):170.
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Traditionally, CT scanning of the chest, abdomen and pelvis, with the administration of intravenous contrast, has been the imaging modality of choice as the second line investigation. Recent evidence suggests a higher sensitivity with the combination of CT with fludeoxyglucose positron emission tomography (FDG-PET/CT) in which radiolabeled glucose marks foci of increased glucose metabolism, has been used successfully in oncology diagnostics and can also be used to diagnose infectious and noninfectious inflammatory foci. Recent studies recommend using FDG-PET early in the workup of FUO and suggest that including FDG-PET/CT yields a correct diagnosis in 60% to more than 80% of cases. Furthermore, the time to diagnosis may be shortened and invasive procedures reduced, potentially leading to reduced costs and morbidity. Nonetheless, the possibility of false-positive results should be kept in mind. Beresford RW, Gosbell IB. Pyrexia of unknown origin: causes, investigation and management. Internal Medicine Journal. 2016 Sep;46(9):1011-6.
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Take home message The workup of PUO can be challenging and requires a systematic approach that takes into account the patient's history, physical examination, laboratory investigations, and imaging studies.. Return to the patient’s history and examination at regular intervals. Sutton’s law ‘to go whether the money is’ provides sensible advice Consider non-infectious causes of a fever early on in the patient’s journey. All patients with PUO should have an HIV test. Do not give empirical antimicrobial or steroid trials. Be cautious with the interpretation of some serological tests as some perform poorly with high false positive and false negative rates. Perform PET-CT testing early in the patient’s diagnostic journey when there are no localising clues in the history or examination. Ensure that the patient is aware of the strong possibility of no diagnosis being made.
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Learning outcomes At the end of this presentation, the audience will be able to: Gain an insight to the general principles of management of a patient with PUO Understand the role of therapeutic trails in PUO management Know the principles of inpatient/outpatient management of PUO Know patient education and involvement in management of PUO Understand the prognosis/outcome of a patient with PUO
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Management of PUO General Principles of Management of PUO The management of PUO should be supportive until the cause has been determined. Individualized treatment decisions should be made based on the patient's specific clinical presentation, underlying conditions, and consultation with relevant specialists. The management of PUO often requires a multidisciplinary approach involving specialists from different fields such as infectious diseases, rheumatology, and hematology-oncology. Fernandez C, Beeching NJ. Pyrexia of unknown origin. Clin Med (Lond). 2018 Mar;18(2):170-174. doi: 10.7861/clinmedicine.18-2-170. PMID: 29626024; PMCID: PMC6303444.
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General principles…. Therapeutic trials of antimicrobials or steroids are not recommended because they can mask symptoms and signs of the underlying disease process. Thus an approach to PUO of awaiting diagnosis before considering treatment is suggested as the mortality of PUO is low, and early use of antipyretics or antimicrobials may delay diagnosis. Stop or change all the previous medicines which the patient is taking to exclude drug fever. Stopping the causative drug generally leads to defervescence within 2 days. Close follow-up and monitoring of patients with PUO are essential to evaluate the response to treatment and make adjustments as necessary. Fernandez C, Beeching NJ. Pyrexia of unknown origin. Clin Med (Lond). 2018 Mar;18(2):170-174. doi: 10.7861/clinmedicine.18-2-170. PMID: 29626024; PMCID: PMC6303444.
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Therapeutic Trails Therapeutic trials of antimicrobials or glucocorticoids, while tempting in the effort to "do something," rarely establish a diagnosis. The diagnostic yield of blood cultures and cultures of biopsy material will be reduced following the initiation of antibiotics. Antimicrobial agents could be expected to suppress, but not cure, many infectious processes such as an occult abscess since adjunctive drainage would usually be required. Antibiotics can have effects on other infections than the ones to which therapy is directed. Rifampin, for example, used in a therapeutic trial for tuberculosis may suppress staphylococcal osteomyelitis or diminish the ability to detect difficult-to-isolate organisms causing endocarditis. The appropriate duration of a therapeutic trial is also unclear since a number of infections such as endocarditis or pelvic inflammatory disease can take as much as one week for fever to abate, even with appropriate therapy. Empiric antibiotics should never be started solely to treat fever. http://www.uptodate.com. (Accessed on May 10, 2023)
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therapeutic Trails…. A therapeutic trial of glucocorticoids for inflammatory disease processes should only be considered when malignancies are ruled out. Moreover, a response to steroid therapy must not halt the diagnosis work up for steroid responsive diseases like sarcoidosis, vasculitis, autoimmune diseases Antipyretics improve patients' comfort, reducing headache, myalgias, arthralgias, and fatigue. However, drugs with antipyretic effects may delay or obscure early symptoms and signs of specific diseases http://www.uptodate.com. (Accessed on May 10, 2023)
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Urgent Therapy for PUO Some studies suggest the following 4 diseases as exceptions to this general approach, in which empirical therapy is appropriate: Cases that meet criteria for culture-negative endocarditis Cases in which findings or the clinical setting suggests cryptic disseminated TB Cases in which temporal arteritis with vision loss is suspected https://www.medscape.com( Assed on May 10,2023) Fernandez C, Beeching NJ. Pyrexia of unknown origin. Clin Med (Lond). 2018 Mar;18(2):170-174. doi: 10.7861/clinmedicine.18-2-170. PMID: 29626024; PMCID: PMC6303444.
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Empirical treatment for TB should always be discussed with a specialist, as the risk of drug resistance needs to be evaluated for each patient, together with the need for early adjunctive steroid therapy for CNS and pericardial TB (at differing dosing regimens). Patients with giant cell arteritis should be treated with high doses of steroids, and intravenous steroids should be administered if the patient is very ill or has significant ocular compromise in order to prevent vision loss. Carefully monitor the patient, since inadequate treatment and steroid toxicities (eg, hypertension, diabetes, dyspepsia, bone loss, psychosis, cataracts) can cause significant morbidity. If infective endocarditis is suspected, then the patient should be admitted to a hospital, and empiric intravenous antibiotics should be commenced after three sets of blood cultures have been collected. Beresford RW, Gosbell IB. Pyrexia of unknown origin: causes, investigation and management. Internal Medicine Journal. 2016 Sep;46(9):1011-6.
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Inpatient Treatment If extensive work up for PUO has done and still the diagnosis is not made, then the patient can be discharged as work up or management can be carried out as outpatient. This is because the prognosis is good and most fevers resolve by itself. No evidence supports prolonged hospitalization of patients who are clinically stable and whose workup findings are unrevealing. https://www.medscape.com( Assed on May 10,2023) Cunha BA. Fever of unknown origin: clinical overview of classic and current concepts. Infect Dis Clin North Am. 2007;21(4):867-915.
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Outpatient care According to the guidelines based on general principles of outpatient care, clinical experience, and expert consensus in managing patients with undiagnosed fevers, the outpatient care of a patient with PUO should comprise of: Regular Follow-up:The frequency of follow-up visits may vary based on the severity of symptoms, the underlying cause of PUO, and the specific treatment plan. Symptom Management: Focus on alleviating symptoms such as fever, pain, or other accompanying complaints. Diagnostic Workup: Continue the diagnostic workup initiated during the inpatient evaluation as deemed necessary. Specialist Referrals: If the initial workup does not provide a definitive diagnosis or if the clinical picture becomes complex, consider involving specialists from various disciplines, such as infectious diseases, rheumatology, or oncology, to provide specialized expertise and guide further evaluation and treatment. https://www.medscape.com( Assed on May 10,2023)
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outpatient care…. Communication and Collaboration: Regular updates, sharing of information, and multidisciplinary discussions are essential to ensure coordinated and comprehensive management. Patient Education: Educate the patient about the nature of PUO and the ongoing diagnostic process. Empower patients to actively participate in their care, report any new symptoms or changes, and adhere to prescribed medications or lifestyle modifications. Psychological Support: Recognize the potential psychological impact of prolonged fever and diagnostic uncertainty on patients and provide appropriate support and counseling. Address their concerns, provide reassurance, and offer resources for additional psychological support if needed. https://www.medscape.com( Assed on May 10,2023)
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outcome/prognosis The outcome of patients with an FUO depends upon the underlying diagnosis and any comorbid conditions. The rate of no diagnosis in studies of FUO published since 1990 has varied from 9 to 51 percent. Among children with FUO, 88 percent of those caused by infections have no sequelae. Most adults who remain undiagnosed after an extensive evaluation have a good prognosis. This was illustrated in a study of 199 patients with FUO, 61 of whom (30 percent) were discharged from the hospital without a diagnosis: A definite diagnosis was established in 12 (20 percent), usually within two months after discharge. Thirty-one (51 percent) became symptom-free during hospitalization or shortly following discharge. Eighteen (30 percent) had persisting or recurring fever for several months or even years after discharge, 10 of whom were considered to be finally cured. Four were treated with glucocorticoids and six required intermittent therapy with nonsteroidal anti-inflammatory drugs. Six died, but the cause of death was considered to be related to the disease that caused FUO in only two cases. Knockaert DC, Dujardin KS, Bobbaers HJ. Long-term follow-up of patients with undiagnosed fever of unknown origin. Archives of internal medicine. 1996 Mar 25;156(6):618-20.
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Similar findings were noted in the Netherlands series of 73 patients. Among the 37 patients with no diagnosis who were followed for at least six months 16 spontaneously recovered 5 recovered with nonsteroidal anti-inflammatory drugs or glucocorticoids, 15 had persistent fever, and 1 died. de Kleijn EM, van den Broucke JP, van der Meer JW. Fever of unknown origin (FUO): I. A prospective multicenter study of 167 patients with FUO, using fixed epidemiologic entry criteria.
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Summery/take home messages PUO requires a comprehensive diagnostic workup to identify the underlying cause, as the treatment approach depends on the specific etiology. The complexity and variability of PUO cases necessitate a tailored approach to treatment, with a focus on personalized medicine and evidence-based practices. Antimicrobial therapy, when needed, plays a crucial role in managing infectious causes of PUO, and treatment should be guided by microbiological investigations and adjusted based on culture and sensitivity results. A multidisciplinary approach involving specialists from different fields, such as infectious diseases, rheumatology, and oncology, is often required to provide comprehensive care for patients with PUO. Close follow-up and monitoring are essential to assess treatment response, adjust therapy if necessary, and detect any complications or disease progression. Patient education and involvement are crucial in understanding the diagnostic and treatment process, managing expectations, and ensuring adherence to prescribed medications and follow-up appointments.
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