Fever types approach to fever PUO

1. FEVER
&
PYREXIA OF
UNKNOWN ORIGN

2. PRESENTOR
DR. GAUTHAM SUNKARAPALLI, M.B.B.S.
1ST YEAR JUNIOR RESIDENT, GM UNIT-2,
DEPARTMENT OF GENERAL MEDICINE,
MAHARAJAH’S INSTITUTE OF MEDICAL SCIENCES
2

3. MODERATORS
MODERATOR-1
PROF. DR. P. CH. MISHRA SIR, M.D.
PROFESSOR & HEAD,
DEPARTMENT OF GENERAL MEDICINE,
MAHARAJAH’S INSTITUTE OF MEDICAL SCIENCES
3
MODERATOR-2
DR. T. MOULEESWARA KUMAR SIR, M.D.
ASSOCIATE PROFESSOR, UNIT-2,
DEPARTMENT OF GENERAL MEDICINE,
MAHARAJAH’S INSTITUTE OF MEDICAL SCIENCES

4. FEVER

5. CONTENTS
▸ INTRODUCTION
▸ DEFINITION OF FEVER
▸ PHYSIOLOGY OF TEMPERATURE REGULATION
▸ AETIOLOGY OF FEVER
▸ PATHOGENESIS OF FEVER
▸ APPROACH TO THE PATIENT WITH FEVER
▸ MANAGEMENT
5

6. INTRODUCTION
▸ Fever is one of the most common presenting symptoms to clinician, which is the hallmark of the
body’s response to an infection or an inflammation.
▸ Fever is the increase in core body temperature above the daily range for an individual.
▸ The range of core body temperature is between 36.5°C - 37.5°C ( 97.7°F - 99.5°F). It is affected by
Time of the day (diurnal variation) - 0.5 °C (0.9°F) , Seasons, Ethinicity, Age, Gender, Time in menstrual
cycle, Exercise and meals. Temperature -Rectal > Oral > Axillary
6

7. TEMPERATURE REGULATION CORE BODY
TEMPERATURE REGULATIONBODY
TEMPERATURE REGULATION
CORE BODY TEMPERATURE REGULATION
▸ Control of body temperature is termed Thermoregulation.
▸ The temperature of the body depends on the balance between heat production and heat loss.
▸ Core body temperature is regulated by mechanism affecting heat generation and heat loss. These
include ANS, the endocrine system, musculoskeletal system and behavioral responses.
▸ The center of this mechanism is called the Thermoregulatorycentre, which lies in hypothalamus.
Pre optic Anterior Hypothalamus – Heat loss centre
Posterior Hypothalamus – Heat gain centre
7

8. 8

9. DEFINITION
▸ Fever is an elevation of body temperature that exceeds the normal daily variation and occurs in
conjunction with an increase in the hypothalamic set point ( From 37°C to 39°C )
▸ An A.M. temperature of >37.2 °C ( >98.9°f) or P.M. temperature of >37.7°C (>99.9°F) is considered as
fever.
▸ Causes of fever could be due to Infections, Malignancies, Connective tissue disorders, Miscellaneous,
Idiopathic.
9

10. AETIOLOGY OF FEVER
10

11. HYPOTHALAMIC FEVER
▸ It is sometimes used to describe elevated temperature caused by abnormal hypothalamic function
▸ It is due to elevated hypothalamic set point as a result of local trauma, haemorrhage,tumor or
intrinsic hypothalamic malfunction
▸ Most patients with hypothalamic damage have subnormal or supranormal body temperatures
11

12. PATHOGENESIS OF FEVER
PYROGENS INVOLVED IN PATHOGENESIS OF FEVER
a) Exogenous pyrogens
- They are derived from outside the patient like microbial products, microbial toxins or whole
microorganisms
- Examples include Lipopolysaccharide (endotoxins) of gram negative bacteria, Enterotoxins of staph
aureus and Group A and B streptococcal toxins also called superantigens
12

13. b) Pyrogenic cytokines
- Cytokines are small proteins (molecular mass, 10,000–20,000 Da) that regulate immune, inflammatory, and
hematopoietic processes. Some cytokines also cause fever, which are formerly referred to as endogenous
pyrogens, they are now called pyrogenic cytokines.
- A wide spectrum of bacterial and fungal products induce the synthesis and release of pyrogenic cytokines.
The pyrogenic cytokines include IL-1, IL-6, tumor necrosis factor (TNF), and ciliary neurotropic factor,
a member of the IL-6 family.
- However, fever can be a manifestation of disease in the absence of microbial infection. For example,
inflammatory processes such as pericarditis, trauma, stroke, and routine immunizations induce the
production of IL-1, TNF, and or IL-6.
13

14. ELEVATION OF THE HYPOTHALAMIC SET POINT BY CYTOKINES
- During fever, levels of prostaglandin E2 (PGE2 ) are elevated in hypothalamic tissue and the third
ventricle.
- The concentrations of PGE2 are highest near the circumventricular vascular organs (organum
vasculosum of lamina terminalis)—which are networks of enlarged capillaries surrounding the
hypothalamic regulatory centers. Destruction of these organs reduces the ability of pyrogens to
produce fever.
- Both exogenous pyrogens and pyrogenic cytokines interact with the endothelium of these
capillaries and this interaction is the first step in initiating fever—i.e., in raising the set point to
febrile levels.
14

15. ▸ Myeloid and endothelial cells are the primary cell types that produce pyrogenic cytokines. Pyrogenic
cytokines such as IL-1, IL-6, and TNF are released from these cells and enter the systemic circulation.
▸ Although these circulating cytokines lead to fever by inducing the synthesis of PGE2 in the
hypothalamic tissue, they also induce PGE2 in peripheral tissues which accounts for the nonspecific
myalgias and arthralgias that often accompany fever.
▸ The elevation of PGE2 in the brain that starts the process of raising the hypothalamic set point for core
temperature.
15

16. ▸ There are four receptors for PGE2 , and each signals the cell in different ways. Of the four receptors, the
third (EP-3) is essential for fever, the gene of which, when deleted in mice, no fever follows the
injection of IL-1 or endotoxin. Deletion of the other PGE2 receptor genes leaves the fever mechanism
intact.
▸ Although PGE2 is essential for fever, it is not a neurotransmitter. Rather, the release of PGE2 from the
brain side of the hypothalamic endothelium triggers the PGE2 receptor on glial cells, and this
stimulation results in the rapid release of cyclic adenosine 5′-monophosphate (cAMP), which is a neuro
transmitter.
16

17. PATHOGENESIS OF FEVER
17

18. APPROACH TO A PATIENT WITH FEVER
HISTORY OF PRESENTING COMPLAINT
1) Onset & Duration
- Acute (< 7Days) : Malaria, Viral URTI, Pyogenic infection
- Sub-Acute (7Days to <2Weeks ) : Typhoid, Intra abdominal Abscess
- Gradual onset & Chronic (>2Weeks) : TB, HIV, Malignancies, CTD, Drugs
2) Character
- High grade fever : UTI , Malaria, Adult onset Stills disease.
- Low grade fever : TB, Malignancies, CTD
3) Pattern of Fever
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19. 19
TYPE OF FEVER DESCRIPTION INFECTIVE CAUSES
CONTINOUS / SUSTAINED
Temp > 38°C, With Fluctuations less than 1°C (1.5°F)
Not touching base line in 24 hours
Lobar pneumonia
Gram Negative Pneumonia
Acute Bacterial Meningitis
Typhoid with Plateau at 103-104°F
REMITTENT
Temp > 38°C, With Fluctuations more than 2°C (3°F)
Not touching base line in 24 hours
Infective Endocarditis
Rickettsiae
Brucellosis (Undulant)
INTERMITTENT
High spikes of fever present only for few hours and rapid
resolution with falling of temperature to normal, in a day
Double Quotidian - 12 hours periodicity with 2 distinct daily
peaks
Leishmaniasis
Gonococcal Endocarditis
Adult onset Stills Disease
Quotidian – 24 hours periodicity ……………………………… P. Knowelski
Tertian - 48 hours periodicity …………………………………. P. Vivax, P. Ovale, P. Falciparum
Quartan - 72 hours periodicity………………………………… P. Malariae

20. 20
TYPE OF FEVER DESCRIPTION INFECTIVE CAUSES
Pel-Ebstein’s – Fever for 1-2 Wks & afebrile period of 1-2 Wks
Hodgkins Lymphoma
Other Non Specific Intermittent fevers ………………………….
Pyogenic Infections & Septicemia
Tuberculosis
Schistosomiasis
Juvenile Idiopathic Arthritis
RECURRENT /
PERIODICAL
Fevers that are recurrent and are separated by periods of low
grade fever or no fever
Rat bite fever
Cyclical Neutropenia (21 Days)
Drug Fever
Factitious Fever
Crohn’s Disease
Bechets Disease
Rheumatoid Arthritis
Hyper Ig D Syndrome
TNF Receptor Ass Periodic Syndrome
RELAPSING Fever followed by an afebrile period of several days Borrelia
BIPHASIC
Dengue (Saddle Back)
Leptospirosis

21. 21
TYPE OF FEVER DESCRIPTION INFECTIVE CAUSES
TYPHUS INVERSUS
Reversal of usual Diurnal Pattern of temperature
(AM > PM)
Disseminated Tuberculosis
Typhoid Fever
Hepatic Abscess
Infective Endocarditis
Polyarteritis Nodosa
FEVER WITH RELATIVE
BRADYCARDIA
Faget’s sign - Temperature Pulse Dissociation
No increase of heart rate by 8-10 BPM with every 1°F rise in
temperature (Limbermeister’s Rule)
Meningitis
Typhoid
Leptospira
Brucella
Mycoplasma, Chlamydia
Legionella
Malaria, Babesia
Dengue
Yellow Fever
Drug Fever
FEVER WITH NIGHT
SWEATS
This pattern is seen when the mild rise in temperature is added
to the normal diurnal evening rise leading to the body
temperature rising beyond the normal level and is evident only
in the evening or late at night when the patient is woken up
sweating.
Tuberculosis
Brucella
Nocardia
Liver & Lung Abscess
Sub Acute Infective Endocarditis
Polyarteritis Nodosa
Lymphomas

22. 22
TYPE OF FEVER DESCRIPTION INFECTIVE CAUSES
INFECTIONS WITHOUT
FEVER
Blunted fever response resulting in no fever despite sctive
ongoing disease
Neonates
Elderly
Immuno Compromised
Patients on Steroid therapy
ASEPTIC FEVER Fever occurring not due to any infection
Malignancies
Acute Myocardial Infarction
Collagen Vascular Disease
Chronic diseases like CKD
Sarcoidosis
Radiation Sickness
Post Surgical Patients
Drug Fever
DRUG FEVER
Gradual onset Chronic fever beginning 1-3 wks after the start of
drug and persists 2-3 days after the drug withdrawl
Associated with Bradycardia, Rash and Eosinophilia
Propylthiouracil
Procainamide
Sulphonamide
Penicillins
ATT
Iodides
Methyldopa
Anticonvulsants

23. 23

24. 4) Grading of Fever
5) Associated Symptoms Chills & rigors Bacterial , Rickettsial and Protozoal disease, Influenza,
Lymphoma, Leukemia, Drug-induced
Night Sweats TB , Hodgkin’s lymphoma
Loss of weight Malignancy, TB
Cough & Dyspnea Miliary TB, multiple pulmonary emboli
Headache Giant cell arthritis, typhoid fever, sinusitis, meningitis
Joint Pains RA, SLE, vasculitis.
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25. 5) Associated Symptoms
25

26. 6) Nature of Defervescence
26
DEFERVESCENCE BY CRISIS DEFERVESCENCE BY CRISIS
Within hours Gradually over days
Effective Anti Malarial Therapy Effective Antibiotic Therapy for Typhoid

27. FAMILY HISTORY
Anyone in family has similar problem, infections like TB ,
Non-Infectious inflammatory disease can indicate a genetic predisposition like Connective tissue disorders
SOCIAL HISTORY
Recent Travel - Amoebiasis, typhoid fever, malaria, schistosomiasis
Residential area - Malaria , leptospirosis , kala azar
SEXUAL HISTORY
Unprotected sexual practices increase the risk of both sexually transmitted diseases and Blood borne
viruses.
27

28. SYSTEMATIC HISTORY
▸ Respiratory System :
URTI : Cough , Sneezing , Sore throat , Rhinorrhea
LRTI : Productive cough, Shortness of breath, Wheeze
Sinusitis : Facial pain , Headache
Otitis : Ear pain , Ear discharge , Hard of hearing
▸ Cardiovascular system:
Infective endocarditis : IV drug abuse, Poor dental Hygeine or Recent dental procedures ,
Prosthetic heart valves
Myocarditis : Shortness of breath , Chest pain , Palpitations
Vascular infection : IV Catheters ,Trauma, Sugeries
28

29. ▸ Gastro-Intestinal System :
Gastroenteritis : Abdominal pain, Vomiting, Diarrhea involving either change in frequency or
consistency of stool and presence of mucous or blood in stool
Hepatitis : Jaundice
Cholecystitis : Right upper quadrant pain , Nausea, Vomiting
▸ Genitourinary System :
LUTI : Dysuria , frequency urgency
UUTI : Loin pain, Low back ache
STD : Vaginal or urethral discharge, Dyspareunia, Anogenital ulcers
29

30. ▸ Nervous system :
Meningitis : Headache, vomiting , neck stiffness
Encephalitis : Altered level of consciousness, Headache, Seizures, Hallucinations
IC Abscess : Sinusitis , Dental infections, CSOM – Mastoidits
▸ Musculoskeletal system:
Joint infections : History of joint replacement, Monoarthralgia, Polyarthralgia
Bone infection : Local site pain, Swelling, Deformities, Sinuses with pus draining through
skin
Adult onset Stills disease : maculopapular rash ,high spiking fever , joint pain
30

31. 31

32. 32

33. Systemic examination
▸Respiratory Tract :
- Full respiratory examination should be performed.
- Look for signs of URTI - Pharyngitis, Tonsillitis, Tonsillar abscess and Otitis
LRTI -Bronchitis , Pneumonia, Pleural effusion or empyema , lung abscess or cavitation
- Palpate for tenderness over sinuses or mastoids. Check for thyroid
▸Cardiovascular system :
- In Infective endocarditis check for Splinter and Conjunctival hemorrhages, Janeway lesions and
Osler’s nodes, New valvular regurgitation murmurs in patients with risk factors.
- In a Rheumatologic or infectious disorder Pericardial rubs, suggesting Pericarditis, should be looked for.
- In Immunocompromised patients Look for infected thrombophlebitis or vasculitis secondary to
catheter insertion
33

34. ▸ Genito-urinary System :
- In UTI, examine for Supra pubic & Renal angle tenderness and Urinary Catheter
- Male genital examination – Penis, scrotum , testis, epididymis , spermatic cord and anorectum.
- Female genital examination - External examination, to look for redness or swelling of
external genitalia; vaginal, urethral or anal discharge, vesicles, ulcers,
warts or foreign bodies.
Speculum examination, to look for any discharge from OS
Proctoscopy if any anal lesions or symptoms present.
Bimanual examination done if any suspecting PID.
▸ Gastrointestinal Tract :
- Examine for any tenderness and abdomen swellings.
- Palpate for presence of hepatomegaly , splenomegaly or a distended gall bladder and tenderness
over these organs.
34

35. 35
Nervous System :
- Global examination of the nervous system include cognitive & physical examination.
- Look for signs of meningitis - Nuchal rigidity, Kernig's sign, Brudzinski's sign.
- Check for focal neurological signs - Brain abscess.
Skin & Musculo skeletal system:
- The skin is thoroughly inspected for focal erythema (suggesting a site of infection) and rash
(malar rash of systemic lupus erythematosus).
- Check for areas of tenderness & swelling over the spine, bones, joints.

36. INVESTIGAIONS & WORKUP
For infectious causes of fever include both laboratory and radiological investigations.
Complete Haemogram with Peripheral smear examination
Complete Urine examination with Microscopy
Inflammatory markers- APR
▸ CRP- most sensitive marker of inflammation
▸ ESR- low sensitivity for infection
▸ Procalcitonin –more sensitive marker of bacterial infection
Renal functions tests
Liver functions tests
36

37. Microbiological tests
1) Microscopy, Culture & Sensitivity
▸ Blood cultures- 2 sets taken prior to antibiotic therapy.
▸ Bone marrow cultures- For intracellular pathogens
▸ Urine culture - For urogenital infections.
▸ Urethral vaginal and cervical swabs - For genital infections.
▸ Cerebrospinal , peritoneal, joint and pleural fluid, biopsy tissue, sputum and bronchoalveolar lavage.
▸ Pus and tissue samples from abscesses, surgical debridement, biopsies and wound infection.
▸ Sample any fluid that represents the possible site of infection.
▸ Stool- culture and sensitivity for bacterial infections and Microscopy for parasites
37

38. 2) Serology
Used in diagnosis of viral infections
Positive Ig M- current or recent infection
Postive Ig G- previous infection or vaccinations
3) Molecular diagnosis
Rapid sensitive technique and not affected by previous antibiotic treatment.
Common bacterial infections diagnosed are Pertussis, meningococcal disease and TB.
Viral infections can be diagnosed with molecular tecniques like PCR
38

39. Immunological Tests
▸ SLE defined by the presence of autoantibodies .
▸ ANA and ds antibodies, antibodies to extractable nuclear antigens and complement 3 and 4 need to
the tested.
Histopathology
▸ Biopsy and staining of lymph nodes, tissue, fluid or bone marrow done to diagnose caseating
granuloma, acid fast bacilli, protozoal cysts, fungal hyphae and spores.
Radiology
▸ X-ray, USG, CT scan , MRI , PET scan are done depending on the site of infection being investigated.
39

40. PYREXIA OF
UNKNOWN
ORIGN

41. ▸ INTRODUCTION
▸ DEFINITION
▸ CATEGORIES OF FUO
▸ AETIOLOGIES OF FUO
▸ APPROACH TO THE PATIENT OF FUO
▸ TREATMENT OF FUO
▸ STRUCTURED APPROACH TO FUO
41

42. INTRODUCTION
▸ Clinicians commonly refer to any febrile illness without an initially obvious etiology asfever of
unknown origin (FUO).
▸ Most febrile illnesses either resolve before a diagnosis can be made or develop distinguishing
characteristics that lead to a diagnosis.
▸ The term FUO should be reserved for prolonged febrile illnesses without an established etiology
despite intensive evaluation and diagnostic testing
42

43. DEFINITION
FUO is now defined as follows:
1. Fever ≥38.3°C (≥101°F) on at least two occasions
2. Illness duration of ≥3 weeks
3. No known immunocompromised state
4. Diagnosis that remains uncertain after a thorough history-taking, physical examination, and the
certain obligatory investigations:
43

44. Obligatory Investigations:
▸ Determination of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level; platelet
count; leukocyte count and differential count
▸ Measurement of levels of haemoglobin, electrolytes, creatinine, total protein, alkaline phosphatase,
alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, creatine kinase,
ferritin, antinuclear antibodies, and rheumatoid factor; protein electrophoresis; urinalysis; blood
cultures (n = 3); urine culture; chest x-ray; abdominal ultrasonography; and tuberculin skin test (TST)
or interferon γ release assay (IGRA).
44

45. CATEGORIES OF FUO
45

46. AETIOLOGIES
• INFECTIONS are the most common cause of FUO. In patients with
HIV infection, opportunistic infections (e.g., tuberculosis; infection
by atypical mycobacteria, disseminated fungi, or cytomegalovirus)
should be sought.
• The most common MALIGNANCIES are lymphoma, leukaemia, renal
cell carcinoma, hepatocellular carcinoma, and metastatic
carcinomas. However, the incidence of neoplastic causes of FUO has
been decreasing, probably because they are being detected by
ultrasonography and CT, which are now widely used during initial
evaluation.
46

47. • CONNECTIVE TISSUE DISORDERS include systemic lupus erythematosus,
rheumatoid arthritis, giant cell arteritis, vasculitis, and juvenile
rheumatoid arthritis of adults (adult Still disease).
• Important MISCELLANEOUS causes include drug reactions, deep venous
thrombosis, recurrent pulmonary emboli, sarcoidosis, inflammatory
bowel disease, and factitious fever.
• No cause of FUO is identified in about 10% of adults, IDIOPATHIC.
47

48. INFECTIONS
▸ Three major causes Intracellular organisms(Salmonella ,Mycobacterium, Brucella) ; Intravascular SBE ;
Occult Abscess
48
BACTERIAL – NON SPECIFIC BACTERIAL - SPECIFIC FUNGAL VIRAL PARASITIC
Abdominal abscess
Appendicitis
Cholangitis
Cholecystitis
Endocarditis
Epidural abscess
Infected vascular catheter
Liver abscess,
Lung abscess
Mastoiditis
Mediastinitis
Osteomyelitis
PID
Pyelonephritis
Atypical mycobacteria
Brucellosis
Campylobacter
Meningococcaemia
Gonococcemia
Louse borne relapsing
fever
Tick borne relapsing
fever
Q fever(coxella burnetti)
Tuberculosis
Typhoid fever
Whipple’s disease
Aspergillosis
Blastomycosis
Candidiasis
Malassezia furfur
PCP
CMV
Dengue
EBV
Hepatitis - A,B,C,D,E
HHV 6,
HIV
Colarado tick fever
Amoebiasis
Babesiosis
Malaria
Schistosomiasis
Toxoplasmosis
Visceral leishmaniasis

49. MALIGNANCIES
▸ Lymphoma: Fever is a presenting feature and negative prognostic factor.
▸ Leukemia : In Multiple Myeloma, fever indicates infection.
▸ Renal cell carcinoma: Fever is rare except:
Secondary metastasis to the liver
Ductal obstruction or perforation like cholangio Ca or ampullary Ca
Lung carcinoma with obstruction and pneumonia.
▸ HCC or secondary metastasis to the liver
49

50. CONNECTIVE TISSUE DISORDERS
▸ SLE
▸ Still’s disease - young or adult } → 23-50% of FUO
▸ Giant cell arteritis } → 15% of FUO
▸ Polymyalgia Rheumatica
▸ Bechet's Disease
▸ Relapsing Polychondritis
▸ Sjogren's syndrome
▸ Sarcoidosis
▸ Takayasu arteritis
In Western world, Noninfectious inflammatory diseases (NIIDs) including
Autoimmune, Autoinflammatory, Granulomatous diseases, as well as Vasculitis, form the most common
causes of FUO
50

51. Miscellaneous
▸ Vascular Causes:
Deep vein thrombosis, Pulmonary Emboli
Hematoma in closed space like retroperitoneum or within the wall of an aneurysm or dissection of
the thoracic or abdominal aorta.
▸ Cerebrovascular accident, brain tumour, encephalitis
▸ Gout, Pseudogout
▸ Hyperthyroidism
▸ Familial Mediterranean Fever
▸ Kawasaki’s syndrome, Kikuchi’s syndrome
▸ Crohn’s disease, ulcerative colitis
▸ Sarcoidosis, Granulomatous hepatitis, Alcoholic Hepatitis
▸ Drug fever
51

52. APPROACH TO THE PATIENT
Potentially diagnostic clues (PDCs)
▸ The most important step in the diagnostic workup is the search for potentially diagnostic clues(PDCs)
through complete and repeated history taking and physical examination and the obligatory
investigations.
▸ PDCs are defined as all localizing signs , symptoms ,and abnormalities potentially pointing toward a
diagnosis.
▸ Although PDCs are often misleading, only with their help can a concise list of probable diagnoses be
made.
52

53. 53

54. 54

55. History taking
• History aims to uncover focal symptoms and facts (e.g., travel, occupation, family history, exposure to
animal vectors, dietary history) that may suggest a cause.
• History of present illness should cover all details of fever like Onset, Duration, Associated symptoms
etc . Fever patterns usually have little or no significance in the diagnosis of FUO
• Review of systems should include nonspecific symptoms, such as weight loss, anorexia, fatigue, night
sweats, and headaches. Symptoms of connective tissue disorders (eg, myalgias, arthralgias, rashes)
and gastrointestinal disorders (eg, diarrhea, steatorrhea, abdominal discomfort) should be sought.
55

56. • Past medical history should include disorders known to cause fever, such as cancer, tuberculosis,
connective tissue disorders, alcoholic cirrhosis, inflammatory bowel disease, rheumatic fever, and
hyperthyroidism.
• Clinicians should note disorders or factors that predispose to infection, such as immunocompromised
state (due to disorders such as HIV infection, cancer, diabetes, or use of immunosuppressants),
structural heart disorders, urinary tract abnormalities, operations, and insertion of devices (IV lines,
pacemakers, joint prostheses).
56

57. • Travel History - Travel to an area, known to be endemic for certain diseases is significant. Duration of
stay, possible exposure to animal or insect and tick vectors and Onset of illness (incubation period)
should be checked .
57

58. ▸ Drug history should include questions about specific drugs known to cause fever.
▸ Social history should include questions about risk factors for infection such as injection drug use,
high-risk sexual practices (unprotected sex, multiple partners), infected contacts (with tuberculosis),
Risk factors for cancer, including smoking, alcohol use, and occupational exposure to chemicals,
should also be identified.
▸ Family history should include questions about inherited causes of fever (familial Mediterranean
fever).
▸ Medical records are to be checked for previous test results, particularly those that effectively rule out
certain disorders.
58

59. INVESTIGATIONS & WORKUP
▸ Complete Haemogram
▸ Complete Urine analysis and Microscopy
▸ Chest X-ray
▸ Blood Cultures x 3
▸ Urine culture
▸ LFT, RFT
▸ Viral Markers ( HIV, Hep-B, Hep-C, VDRL)
▸ HS CRP
▸ Anti Nuclear Antibodies
▸ Rheumatoid Factor
▸ CMV IgM
▸ Mononucleosis Spot test
▸ PPD (Tuberculosis test)
59

60. • Despite the high percentage of false-positive ultrasounds and the relatively low sensitivity of chest
x-rays, the performance of these simple, low-cost diagnostic tests remains obligatory in all patients
with FUO in order to separate cases that are caused by easily diagnosed diseases from those that are
not.
• Abdominal ultrasound is preferred to abdominal CT as an obligatory test, because of relatively low
cost, lack of radiation burden, and absence of side effects.
• The diagnostic yield of echocardiography, sinus radiography, radiologic or endoscopic evaluation
of the gastrointestinal tract, and bronchoscopy is very low in the absence of PDCs. Therefore, these
tests should not be used as screening procedures.
60

61. • In patients without PDCs or with only misleading PDCs, fundoscopy by an ophthalmologist may be
useful in the early stage of the diagnostic workup to exclude retinal vasculitis.
• When the first-stage diagnostic tests do not lead to a diagnosis, 18F-fluorodeoxyglucose (18F-FDG)
positron emission tomography combined with computed tomography (PET/CT) or, If the former is
not available, radiolabeled leukocyte scintigraphy should be performed, especially when the ESR or
the CRP level is elevated.
61

62. PET CT
62

63. radiolabeled
leukocyte
scintigraphy
63
radiolabeled leukocyte scintigraphy

64. TREATMENT
Empirical therapeutic trials with Antibiotics, glucocorticoids, or Anti tuberculous agents should be
avoided in FUO except, when a patient’s condition is rapidly deteriorating after the aforementioned
diagnostic tests have failed to provide a definite diagnosis. Antibiotic or antituberculous therapy may
diminish the ability to culture fastidious bacteria or mycobacteria.
If the TST or IGRA is positive or if granulomatous disease is present with anergy and sarcoidosis seems
unlikely, a trial of therapy for tuberculosis should be started. If the fever does not respond after 6 weeks
of empirical anti tuberculous treatment, another diagnosis should be considered.
Colchicine is highly effective in preventing attacks of familial Mediterranean fever (FMF) but is not
always effective once an attack is well under way
64

65. If the fever persists and the source remains difficult to find after completion of investigations, supportive
treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) can be helpful. The response of adult-
onset Still’s disease to NSAIDs is dramatic in some cases.
The effects of glucocorticoids on giant cell arteritis and polymyalgia rheumatica are equally impressive
Interleukin (IL) 1 is a key cytokine in local and systemic inflammation and the febrile response.
Anakinra, a recombinant form of the naturally occurring IL-1 receptor antagonist (IL-1Ra), blocks the
activity of both IL-1α and IL-1β.
It is extremely effective in the treatment of many autoinflammatory syndromes, such as FMF, tumor
necrosis factor receptor–associated periodic syndrome, mevalonate kinase deficiency (hyper IgD
syndrome), Schnitzler syndrome, and adult onset Still’s disease. A therapeutic trial with anakinra can be
considered in patients whose FUO has not been diagnosed after later-stage diagnostic tests.
65

66. summary
▸ Fever is an elevation of body temperature that exceeds the normal daily variation and occurs in
conjunction with an increase in the hypothalamic set point . An A.M. temperature of >37.2 °C ( >98.9°f)
or P.M. temperature of >37.7°C (>99.9°F) is considered as fever.
▸ Causes of fever could be due to Infections, Malignancies, Connective tissue disorders, Miscellaneous,
Idiopathic
▸ Hyperthermia is uncontrolled increase in the body temp that exceeds the body's ability to lose heat.
Hypothalamic thermoregulatory center is unchanged. Heat stroke, Malignant hyperthermia,
neuroleptic malignant syndrome, serotonin syndrome.
▸ Investigations should be done to figure out the cause of fever and treatment should be giver
accordingly with acetaminophen, Aspirin, Nsaids, antibiotics.
▸ If the cause of fever is not identified after history taking, physicalexamination,investigations then it is
PUO.
66

67. STRUCTURED APPROACH TO PUO
67

68. 68

69. REFERENCE - 1
Harrison’s Principles Of
Internal Medicine, 21st
Edition
69

70. REFERENCE - 2
The Washington Manual
of Medical Therapeutics
South Asian Edition
70

71. REFERENCE - 3
Hutchison's Clinical
Methods: An Integrated
Approach to Clinical
Practice, International
Edition, 25e
71

72. REFERENCE - 3
An Insider’s Guide To
Clinical Medicine (2022)
By Archith Boloor
72

73. THANK
YOU
73