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Pyrexia of Unknown Origin
            PUO or FUO
            Dr.T.V.Rao MD




1/19/2013       Dr.T.V.Rao MD   1
What is the normal human body
            temperature?

A. 37.5 C
B. 98.6 F
C. Each human being is a unique individual, and
   therefore, normal temperature cannot be
   defined.



1/19/2013            Dr.T.V.Rao MD            2
What is the normal human body
                 temperature?

A. 37.6 C
B. 98.6 F
C Each human being is a unique individual, and
   therefore, normal temperature cannot be
   defined.



1/19/2013           Dr.T.V.Rao MD            3
Normal Body Temperature
• For healthy individuals 18 to 40 years of age, the
  mean oral temperature is 36.8° ± 0.4°C (98.2° ±
  0.7°F)
• Low levels occur at 6 A.M. and higher levels at 4
  to 6 P.M.
• The maximum normal oral temperature is 37.2°C
  (98.9°F) at 6 A.M. and 37.7°C (99.9°F) at 4 P.M.
• These values define the 99th percentile for
  healthy individuals.

1/19/2013              Dr.T.V.Rao MD                                  4
                                       Mackowiak, et al., JAMA 1992;268:1578
Definition
• Fever > 38.3 on
  several occasions
• Fever lasting
  more than 3
  weeks
• No diagnosis
  despite 1 week of
  inpatient workup

1/19/2013         Dr.T.V.Rao MD   5
Terminology
•   Old Definition:
    1. Fever higher than 38.3oC on several
       occasions.
    2. Duration of fever – 3 weeks
    3. Uncertain diagnosis after one week of study
       in hospital
•   New Definition:
       – Eliminated the in-hospital evaluation
          requirements → 3 outpatient visits, or 3
          days in hospital. … Ambulatory as well as in
1/19/2013 hospital          Dr.T.V.Rao MD                6
Historical Causes of FUO
• Hippocrates: excess of yellow bile
• Middle Ages: demonic possession
  (encephalitis?)
• 18th Century: Friction associated with the
  flow of blood through the vascular
  system and from fermentation and
  putrefaction occurring in the blood and
  intestines
1/19/2013          Dr.T.V.Rao MD               7
Definition Expansion
1. Classical PUO
2. Nosocomial
   PUO
3. Neutropenia
   PUO
4. HIV-Associated
5. Transplant
1/19/2013            Dr.T.V.Rao MD   8
Categories of FUO
Feature            Nosocomial            Neutropenic              HIV-associated                Classic


Patient’s       Hospitalized,        Neutrophil count    Confirmed HIV-                   All others with
situation       acute care, no       either <500/µL or positive                           fevers for ≥3
                infection when       expected to                                          weeks
                admitted             reach that level in
                                     1-2 days
Duration of     3 daysb              3 daysb                    3 daysb (or 4             3 daysb or 3+
illness while                                                   weeks as                  outpatient
investigated                                                    outpatient)               visits

Examples        Septic               Perianal infection, MAIc infection,                  Infections,
                thrombophlebitis,    aspergillosis,      TB, non-                         malignancy,
                sinusitis, C.        candidemia          Hodgkin’s                        inflammatory
                difficile colitis,                       lymphoma, drug                   diseases, drug
                drug fever                               fever                            fever
 aAllrequire temperatures of ≥38.3 C (101 F) on several occasions.
 bIncludes at least 2 days’ incubation of microbiology cultures.
 cM. avium/M. intracellulare.


 1/19/2013                       Modified Dr.T.V.Rao Durack, AC Street, in JS Remington, MN Swartz (eds): 9
                                          from DT MD
                                 Current Clinical Topics in Infectious Diseases. Cambridge, MA, Blackwell, 1991.
Pattern of Fever




1/19/2013         Dr.T.V.Rao MD   10
Etiologies of PUO
• Infection: Three
  major causes
• Abscess .. especially
  occult ..
• Intracellular
  organisms.
  (salmonella
  mycobacterium, bruc
  ella)
• Intravascular … SBE

1/19/2013             Dr.T.V.Rao MD   11
“True Fever”
• Occurs when IL-1, IL-6, TNF-ά or other cytokines are
  released from monocytes and macrophages in
  response to infection, tissue injury, drugs, and other
  inflammatory processes, increasing the body’s set
  point. The anterior hypothalamus maintains an
  inherent set point near 36ºC(98.6ºF).
• Normal circadian rhythm, which is highest(up to 2ºC,
  3ºF) ~6pm and lowest at 6am. This accounts for
  increased volume of ER visits that peaks in the
  evening. Most true fevers follow this diurnal pattern.
Infectious Causes of FUO
• Intraabdominal abscess
  (liver, splenic, psoas, etc)
• Appendicitis, cholecystitis, tubo-ovarian
  abscess, pyometra
• Intracranial abscess, sinusitis, dental abscess
• Chronic pharyngitis, tracheobronchitis, lung
  abscess
• Septic jugular phlebitis, mycotic
  aneurysm, endocarditis, intravenous catheter
  infection, vascular graft infection
• Wound infection, osteomyelitis, infected joint
  prosthesis, pyelonephritis, prostatitis
1/19/2013             Dr.T.V.Rao MD                 13
Infectious Causes of FUO
• Intraabdominal abscess (liver, splenic, psoas, etc)
• Appendicitis, Cholecystitis, tubo-ovarian
  abscess, pyometra
• Intracranial abscess, sinusitis, dental abscess
• Chronic pharyngitis, tracheobronchitis, lung abscess
• Septic jugular phlebitis, mycotic
  aneurysm, endocarditis, intravenous catheter
  infection, vascular graft infection
• Wound infection, osteomyelitis, infected
  joint
  prosthesis, pyelonephritis, prostatitis
1/19/2013               Dr.T.V.Rao MD                    14
Infectious Causes of FUO
• Intraabdominal abscess (liver, splenic, psoas, etc)
• Appendicitis, Cholecystitis, tubo-ovarian abscess,
  pyometra
• Intracranial abscess, sinusitis, dental abscess
• Chronic pharyngitis, tracheobronchitis, lung abscess
• Septic jugular phlebitis, mycotic aneurysm,
  endocarditis, intravenous catheter infection, vascular
  graft infection
• Wound infection, osteomyelitis, infected joint
  prosthesis, pyelonephritis, prostatitis


1/19/2013                Dr.T.V.Rao MD                 15
Bacterial Pyrogens
• Lipopolysaccharide (LPS)
  endotoxin
    Endotoxin binds to LPS-binding protein
    and is transferred to CD14 on
    macrophages, which stimulates the
    release of TNFα.
• Staphylococcus aureus
  enterotoxins
1/19/2013            Dr.T.V.Rao MD           16
Infectious Causes of FUO
• Tuberculosis, Mycobacterium avium complex, syphilis, Q
  fever, Legionellosis
• Salmonellosis (including typhoid
  fever), Listeriosis, ehrlichiosis,
• Actinomycosis, nocardiosis, Whipple’s disease
• Fungal
  (candidaemia, cryptococcosis, sporotrichosis, Aspergillosi
  s, Mucormycosis, Malassezia furfur)
• Malaria, Babesiosis, toxoplasmosis, schistosomiasis, fasci
  oliasis, Toxocariasis, amoebiasis, infected hydatid
  cyst, trichinosis, trypanosomiasis
• Cytomegalovirus, HIV, Herpes simplex, Epstein-Barr
  virus, parvovirus B19
1/19/2013                 Dr.T.V.Rao MD                    17
Miscellaneous Causes of FUO
• Complex partial status
  epilepticus, cerebrovascular accident, brain
  tumor, encephalitis
• Drug fever, Sweet’s syndrome, familial
  Mediterranean fever
• Gout, pseudo gout
• Kawasaki’s syndrome, Kikuchi’s syndrome
• Crohn’s disease, ulcerative
  colitis, sarcoidosis, granulomatous hepatitis
• Deep vein thrombosis
• Atelectasis?
1/19/2013             Dr.T.V.Rao MD               18
Bacterial Pyrogens
• Staphylococcus aureus toxic shock
  syndrome toxin (TSST)
    Both Staphylococcus toxins are super antigens
    and activate T cells leading to the release of
    interleukin (IL)-1, IL-2, TNFα and TNFβ, and
    interferon (IFN)-gamma in large amounts
• Group A and B streptococcal toxins
    Exotoxins induce human mononuclear cells to
    synthesize not only TNFα but also IL1 and IL-6
1/19/2013              Dr.T.V.Rao MD             19
CAUSES CLASSIC PUO
• INFECTIVE 20-30%
• CANCER    10-20%
• AUTOIMMUNE 15-20%
• MISC         15-25%
• UNDIAGNOSED 5-10%

1/19/2013          Dr.T.V.Rao MD   20
Classic FUO
•Infection
•Malignancy
•Collagen vascular
 diseases
1/19/2013       Dr.T.V.Rao MD   21
Infectious Causes of FUO
• Intraabdominal abscess
  (liver, splenic, psoas, etc)
• Appendicitis, cholecystitis, tubo-ovarian
  abscess, pyometra
• Intracranial abscess, sinusitis, dental abscess
• Chronic pharyngitis, tracheobronchitis, lung
  abscess
• Septic jugular phlebitis, mycotic
  aneurysm, endocarditis, intravenous catheter
  infection, vascular graft infection
• Wound infection, osteomyelitis, infected joint
  prosthesis, pyelonephritis, prostatitis
1/19/2013             Dr.T.V.Rao MD                 22
Infectious Causes of FUO
• Chronic
  pharyngitis, tracheobronchitis, lung
  abscess
• Septic jugular phlebitis, mycotic
  aneurysm, endocarditis, intravenous
  catheter infection, vascular graft
  infection
• Wound
  infection, osteomyelitis, infected
  joint
1/19/2013             Dr.T.V.Rao MD      23
Infectious Causes of FUO
• Intraabdominal abscess (liver, splenic, psoas,
  etc)
• Appendicitis, cholecystitis, tubo-ovarian
  abscess, pyometra
• Intracranial abscess, sinusitis, dental abscess
• Chronic pharyngitis, tracheobronchitis, lung
  abscess
• Septic jugular phlebitis, mycotic aneurysm,
  endocarditis, intravenous catheter infection,
  vascular graft infection
• Wound infection, osteomyelitis, infected joint
  prosthesis, pyelonephritis, prostatitis
1/19/2013             Dr.T.V.Rao MD                 24
Geography
   Malaria                               Saudi (malaria area)/Africa/India
   Brucella                              Saudi/Gulf Area
   Kala-Azar                             Yemen/Jazan/Sudan/India
   Leprosy                               Yemen/Najran…
   Typhoid                               India/Pakistan/Egypt/Indonesia
   Histoplasmosis                        USA … (West Coast)
   N.B.: Ease of Travel → Infection → All parts of the world.

   Tuberculosis

   Liver Abscess                                  All over the world.
   AIDS


1/19/2013                         Dr.T.V.Rao MD                              25
1/19/2013   Dr.T.V.Rao MD   26
Pathophysiology
• Meningitis and sepsis are serious
  etiologies of fever in infants and young
  children.
• Neonates' immature immune systems
  place them at greater risk of systemic
  infection. Hematogenous spread of
  infection is most common in this age
  group or in patients who are
  immunocompromised. For these same
  reasons, infants who have a focal
  bacterial infection have a greater risk of
  developing sepsis.
1/19/2013           Dr.T.V.Rao MD              27
Bacterial Pyrogens
• Lipopolysaccharide (LPS) endotoxin
    Endotoxin binds to LPS-binding protein and is transferred to CD14 on
    macrophages, which stimulates the release of TNFα.
• Staphylococcus aureus enterotoxins
• Staphylococcus aureus toxic shock syndrome toxin
  (TSST)
    Both Staphylococcus toxins are super antigens and activate T cells leading
    to the release of interleukin (IL)-1, IL-2, TNFα and TNFβ, and interferon
    (IFN)-gamma in large amounts
• Group A and B streptococcal toxins
    Exotoxins induce human mononuclear cells to synthesize not only TNFα
    but also IL1 and IL-6


1/19/2013                          Dr.T.V.Rao MD                             28
What are common Causes
   • The following are among the most common bacterial etiologies of
                serious bacterial infection in this age group:

• Streptococcus pneumoniae
• Group B streptococci
• Neisseria meningitidis
• Haemophilus influenzae type b
• Listeria monocytogenes
• Escherichia coli
1/19/2013                      Dr.T.V.Rao MD                           29
Consequences of Fever can be
               confusing
• Approximately 2.5-3% of highly febrile
  children younger than 3 years develop
  occult bacteremia, which typically is
  caused by S pneumoniae. Viral
  infections are common in the young
  child as well; however, exclude serious
  bacterial infection prior to assuming a
  viral etiology for the fever.
1/19/2013          Dr.T.V.Rao MD            30
History Taking
• Family History:
      – Scrutinized for possible infectious or hereditary disorders
            • Tuberculosis
            • FMF
• Past Medical Condition:
      Lymphoma         →        may recur
      Rheumatic Fever →         may recur
      Still’s Disease           →      may recur
      Behcet’s Disease →        may recur
• Exposure to sexual partner … Acute HIV
• Illicit drug abuse (IV) … infective endocarditis,
                               Hepatitis … HIV
1/19/2013                       Dr.T.V.Rao MD                         31
Physical Examination
….. Looking for the KEY physical sign …. Diagnostic yield
60% in children (50%repeated)

• Document the Fever:
      – Significant and persistent for more than ONE occasion.
• Analyzing the Pattern:
      – Neither specific Nor sensitive enough to be considered diagnostic …
        EXCEPT

            Tertian & Quarter Pattern   →       Malaria
            Pel-Ebstein Pattern →       Lymphoma/
                                        Tuberculosis
            Pulse-Temp Dissociation     →       Typhoid/
                                                Brucellosis
1/19/2013                               Dr.T.V.Rao MD                         32
Infections
• Tuberculosis (especially
  extrapulmonary)
  Abdominal abscesses
  Pelvic abscesses
  Dental abscesses
  Endocarditis
  Osteomyelitis
 1/19/2013     Dr.T.V.Rao MD   33
Infections
• Sinusitis
  Cytomegalovirus
  Epstein-Barr virus
  Human immunodeficiency virus
  Lyme disease
  Prostatitis
  Sinusitis
1/19/2013      Dr.T.V.Rao MD     34
Etiologies of PUO
• Infection
      – Tuberculosis: .. Disseminated
            • The single most common infection in most PUO series
              except in children and elderly.
            • Usually extrapulmonary or military, or
            • Occurs in the lungs and significant pre-existing lung
              disease.
            • Pulmonary TB in AIDS is often subtle (normal chest x-
              rays → 15 – 30%).
            • PPD is (+ve) < 50% of TB with PUO.
            • Diagnosis often requires Bx of LN/Liver/Bone marrow.
            • Sputum smear (+) only 25%
1/19/2013                        Dr.T.V.Rao MD                        35
Etiologies of PUO
       – Abscess:
            • Usually located in abdomen or pelvis.
            • Secondary to appendicitis or diverticulitis.
            • Pyogenic liver abscess usually follow biliary tract
              dis./abd. Suppuration.
            • Amoebic liver abscess is similar to pyogenic →
              amoebic serology is positive > 95% of cases.
            • Splenic abscess is usually secondary to
              hematogenous seeding.
            • Perinephric or renal abscess is usually secondary to
              UTI.
1/19/2013                        Dr.T.V.Rao MD                       36
Etiologies of PUO
      – Bacterial Endocarditis
            • Culture remains negative in 5% of patient.
            • Culture negative is likely with the following organisms:
               –   Coxiella burnetii → no growth.
               –   HACEK group → incubate blood 7 – 21 days
               –   Brucella              } Special media/
               –   Legionelle             } long time
               –   Mycoplasm/Chlamydia }
               –   Fungal → usually sterile
            • Peripheral signs may not be detected.
            • Right-side Endocarditis → Lack murmurs → self
              antibiotics → growth (-ve).
1/19/2013                             Dr.T.V.Rao MD                      37
Etiologies of PUO
• Infection
      – Tuberculosis: .. Disseminated
            • The single most common infection in most PUO series
              except in children and elderly.
            • Usually extra pulmonary or military, or
            • Occurs in the lungs and significant pre-existing lung
              disease.
            • Pulmonary TB in AIDS is often subtle (normal chest x-
              rays → 15 – 30%).
            • PPD is (+ve) < 50% of TB with PUO.
            • Diagnosis often requires Bx of LN/Liver/Bone marrow.
            • Sputum smear (+) only 25%
1/19/2013                        Dr.T.V.Rao MD                        38
Geography
   Malaria                               Saudi (malaria area)/Africa/India
   Brucella                              Saudi/Gulf Area
   Kala-Azar                             Yemen/Jazan/Sudan/India
   Leprosy                               Yemen/Najran…
   Typhoid                               India/Pakistan/Egypt/Indonesia
   Histoplasmosis                        USA … (West Coast)
   N.B.: Ease of Travel → Infection → All parts of the world.

   Tuberculosis

   Liver Abscess                                  All over the world.
   AIDS


1/19/2013                         Dr.T.V.Rao MD                              39
HIV associated PUO
•   HIV alone
•   TB,M avium/intracelulare
•   Toxoplasmosis
•   CMV ,PCP ,Salmonella
•   Cryptococcus, Histoplasmosis
•   Non Hodgkins Lymphoma
•   Drug induced

1/19/2013             Dr.T.V.Rao MD   40
Malignancies
• Chronic leukemia
  Lymphoma
  Metastatic cancers
  Renal cell carcinoma
  Colon carcinoma
  Hepatoma
  Myelodysplastic syndromes
  Pancreatic carcinoma
  Sarcomas
1/19/2013      Dr.T.V.Rao MD   41
Autoimmune Conditions with Fever
• Adult Still's disease
  Polymyalgia rheumatic
  Temporal arteritis
  Rheumatoid arthritis
  Rheumatoid fever
  Inflammatory bowel disease
  Reiter's syndrome
  Systemic lupus erythematous
  Vasculitides
1/19/2013      Dr.T.V.Rao MD    42
Miscellaneous
• Drug-induced fever
  Complications from cirrhosis
  Factitious fever
  Hepatitis
  (alcoholic, granulomatous, or
  lupoid)
  Deep venous thrombosis
  Sarcoidosis
1/19/2013        Dr.T.V.Rao MD    43
Diagnosis
• A cost-effective
  individualized approach is
  essential in the evaluation
  of these patients to
  prevent performing
  inappropriate tests.
1/19/2013      Dr.T.V.Rao MD    44
Minimal Initial Diagnostic Workup For
                 FUO
• Comprehensive history
• Physical examination
• CBC + differential
• Blood film reviewed by hematopathologist
• Routine blood chemistry
• UA and microscopy
• Blood (x 3) and urine cultures
• Antinuclear antibodies, rheumatoid factor
• HIV antibody
• CMV IgM antibodies; heterophile antibody test (if c/w mono-like
  syndrome)
• Q-fever serology (if risk factors)
• Chest radiography
• Hepatitis serology (if abnormal LFTs)

1/19/2013                      Dr.T.V.Rao MD                                         45
                                               Mourad, et al. Arch Intern Med. 2003;163:545
Diagnostic Testing
Blind application leads to excessive false
tests …
• Complete Blood Count
      – Anemia if present → suggest a serious underlying disease
      – Leukocytosis with bands → occult bacterial infection
      – Lymphocytosis & atypical Lymphocyte → Infectious
        mononucleosis
      – Leucopenia and Lymphopenia → advanced HIV
      – Leukoerythroblastic Anemia → Disseminated TB
      – Thrombocytopenia → Malaria/Leukemia
      – Peripheral Blood → Malaria
1/19/2013                     Dr.T.V.Rao MD                        46
Diagnostic Testing
• Urinalysis, Urine Culture, U/E, LFT
• ESR
      – If elevated → significant inflammatory
        process
      – Greatest use in establishing a serious
        underlying disease, esp. if v. high → ESR >
        100 mm/h …
        Tuberculosis … m myeloma … temporal
        arteritis
1/19/2013                Dr.T.V.Rao MD                47
Diagnostic Testing
      – 58% → malignancy → Lymphoma/myeloma
      – 25%
            • Infection – Endocarditis
            • Giant cell arteritis
      – ↑ High ESR → lacks specificity:
            • Drug Reaction                       }
            • Thrombophlebitis                    } may cause very high ESR
            • Nephrotic Syndrome                  }
      – Normal ESR → significant inflammatory process is
        absent with exception.
1/19/2013                         Dr.T.V.Rao MD                               48
Diagnostic Testing
•       CRP-closely associated with inflammatory
        process
      – Not invariable components of the febrile response.
      – Usually does not go up with viral infection.
      * ESR & CRP is elevated in:
            1.   Bacterial Infection
            2.   Neoplasm
            3.   Immunological-mediated inflammatory states
            4.   Tissue infarction

1/19/2013                        Dr.T.V.Rao MD                49
Diagnostic Testing
• Acute Phase Proteins
   Proteins Increased                    Proteins Decreased
   Fibrinogen                            Albumin
   Ferritin                              Transferrin
   Plasminogen                           Alpha-
   Fetoprotein
   Protein S
   Cerruloplasmin


   New England J Med. 1999, 340.448-454

1/19/2013                       Dr.T.V.Rao MD                 50
Diagnostic Testing
• Blood Testing
      – Anti-nuclear Antibodies
      – Rheumatoid Factor
      – CMV Antibody … IgM
      – Heterophile Antibody Test in children and young
        adult
      – Tuberculin Skin Test … 5 unit ID
      – Thyroid Function Test
      – HIV Screening
1/19/2013                  Dr.T.V.Rao MD                  51
Diagnostic Testing
• Imaging Studies: … to localize abnormalities
  for definite tests or treatment
      – Chest x-ray:
            • Military shadows → disseminated tuberculosis
            • Atelectasis         }              1. Liver
              ↑ Hemi diaphragm } Abscess         2. Spleen
              Pleural Effusion    }              3. Pancreatic
                                                 4. Subphrenic
            • Mediastinal mass → Lymphoma/Tuberculosis/ Sarcoid
            • If CXR is (N) → Repeat on weekly basis
1/19/2013                      Dr.T.V.Rao MD                      52
Diagnostic Testing
      – CT-Scan → CT scan chest
            • Mediastinal mass → Tuberculosis/Lymphoma/
              Sarcoidosis
            • Dorsal Spine → Spondylitis and disc space
              disease
            • CT-Scan Abdomen → very effective to visualize
               – All types of abscesses
               – Retroperitoneal tumor, lymph node or hematoma

      – MRI: spleen, lymph node and the brain

1/19/2013                         Dr.T.V.Rao MD                  53
Diagnostic Testing
• Serology Test
      – Brucella Titer
      – CMV & EBV antibody test
      – HIV testing (Elisa screening)
      – ANF
• Radio nuclear Scanning
      – Bone TC-scan → osteomyelitis (skeletal)
      – Gallium scan → occult inflammation
      – Indium labeled WBC-scan → occult abscesses
1/19/2013                   Dr.T.V.Rao MD            54
Diagnostic Testing
      – Hepatomegaly or Abnormal LFT
            • Hepatic Granuloma
                  – Non-caseating: Tuberculosis/Sarcoidosis & Brucellosis
                  – Caseating: Tuberculosis

      – Bone Marrow
            •   Granuloma ± Tubercle Bacilli → Tuberculosis
            •   Aplastic Cells → Leukemia
            •   Leishmania Bodies → Kala-Azar
            •   Atypical Cells → Lymphoma
            •   Atypical Plasma Cells → M. myeloma
      – Temporal Artery → Giant Cell Arteritis
      – Pleural or Pericardial → Extrapulmonary Tuberculosis
1/19/2013                                   Dr.T.V.Rao MD                   55
Investigation
• Blood culture before the
  antibiotics
• Culturing of Urine
• Sputum culture
• Stool examination for Bacterial
  and Parasitic infection.
1/19/2013        Dr.T.V.Rao MD      56
Etiologies of PUO
       – Abscess:
            • Usually located in abdomen or pelvis.
            • Secondary to appendicitis or diverticulitis.
            • Pyogenic liver abscess usually follow biliary tract
              dis./abd. Suppuration.
            • Amoebic liver abscess is similar to pyogenic →
              amoebic serology is positive > 95% of cases.
            • Splenic abscess is usually secondary to
              haematogenous seeding.
            • Perinephric or renal abscess is usually secondary to
              UTI.
1/19/2013                        Dr.T.V.Rao MD                       57
Tuberculosis
• Sputum
  examination
  for AFB
• Culturing for AFB
• Monteux test
  Tuberculin test
• X ray of the chest
1/19/2013              Dr.T.V.Rao MD   58
Diagnosis
• More invasive testing, such as LP or biopsy of
  bone marrow, liver, or lymph nodes, should be
  performed only when clinical suspicion shows
  that these tests are indicated or when the
  source of the fever remains unidentified
  after extensive evaluation.
• When the definitive diagnosis remains elusive
  and the complexity of the case increases, an
  infectious disease, rheumatology, or oncology
  consultation may be helpful.


1/19/2013            Dr.T.V.Rao MD             59
Etiologies of PUO
• Factitious Fever
      Febrile PUO
      In one study … 9% of cases of PUO
      – False fever: thermometer manipulation using external heat
          or substitute thermometer. Men use this way … physician
          are rare for this disorder. Increasing somewhat in elderly …
          115 … 116 …
      – Genuine fever (self induced)
         Administration of pyrogenic substances (bacterial
          suspensions)
         Generally young women with connection to health care …
1/19/2013
          often NURSES.            Dr.T.V.Rao MD                      60
Pyrexia of Unknown Origin
            The majority of disease remaining after an
                 initial NEGATIVE work-up are:
      1.      Neoplasm
      2.      Seronegative Collagen Vascular Disease
      3.      Increasing Tuberculosis
      4.      Increasing Drug Addition
      5.      Elderly with Endocarditis
      6.      HIV with or without infection or malignancy
      7.      Implanted prosthetic devices
      8.      Travel … New Exposure
1/19/2013                         Dr.T.V.Rao MD             61
Therapeutic Trials
• Limitation and risk of empirical therapeutic
  trials:
      – Rarely specific
      – Underlying disease may remit spontaneously false
        impression of success.
      – Disease may respond partially and this may lead
        to delay in specific diagnosis.
      – Side effect of the drugs can be misleading.


1/19/2013                 Dr.T.V.Rao MD                62
Therapeutic Trials
• What is the best
  therapy for PUO
  patient?
      – To hold therapeutic trials
        in the early stage…
        except in:
            • Patient who is very sick to
              wait.
            • All tests have failed to
              uncover the etiology.



1/19/2013                             Dr.T.V.Rao MD   63
Prognosis
• Prognosis is determined primarily by
  the underlying disease.
• Outcome is worst for neoplasms.
• FUO patients who remain undiagnosed
  after extensive evaluation generally
  have a favorable outcome and the fever
  usually resolves after 4-5 weeks.
1/19/2013         Dr.T.V.Rao MD                              64
                                  Larson et al. Medicine 1982;61:269
Summary
• FUO is often a diagnostic dilemma
• Infections comprise ~30% of cases
• Bone marrow biopsies are of low
  diagnostic yield
• Diagnostic approach should occur in a
  step-wise fashion based on the H&P
• Patient’s that remain undiagnosed
    generally have a good prognosis
1/19/2013              Dr.T.V.Rao MD      65
• Programme Created By Dr.T.V.Rao MD
    for Medical Students in the Developing
                    World
                     • Email
            • doctortvrao@gmail.com

1/19/2013            Dr.T.V.Rao MD           66

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Pyrexia of unknown origin

  • 1. Pyrexia of Unknown Origin PUO or FUO Dr.T.V.Rao MD 1/19/2013 Dr.T.V.Rao MD 1
  • 2. What is the normal human body temperature? A. 37.5 C B. 98.6 F C. Each human being is a unique individual, and therefore, normal temperature cannot be defined. 1/19/2013 Dr.T.V.Rao MD 2
  • 3. What is the normal human body temperature? A. 37.6 C B. 98.6 F C Each human being is a unique individual, and therefore, normal temperature cannot be defined. 1/19/2013 Dr.T.V.Rao MD 3
  • 4. Normal Body Temperature • For healthy individuals 18 to 40 years of age, the mean oral temperature is 36.8° ± 0.4°C (98.2° ± 0.7°F) • Low levels occur at 6 A.M. and higher levels at 4 to 6 P.M. • The maximum normal oral temperature is 37.2°C (98.9°F) at 6 A.M. and 37.7°C (99.9°F) at 4 P.M. • These values define the 99th percentile for healthy individuals. 1/19/2013 Dr.T.V.Rao MD 4 Mackowiak, et al., JAMA 1992;268:1578
  • 5. Definition • Fever > 38.3 on several occasions • Fever lasting more than 3 weeks • No diagnosis despite 1 week of inpatient workup 1/19/2013 Dr.T.V.Rao MD 5
  • 6. Terminology • Old Definition: 1. Fever higher than 38.3oC on several occasions. 2. Duration of fever – 3 weeks 3. Uncertain diagnosis after one week of study in hospital • New Definition: – Eliminated the in-hospital evaluation requirements → 3 outpatient visits, or 3 days in hospital. … Ambulatory as well as in 1/19/2013 hospital Dr.T.V.Rao MD 6
  • 7. Historical Causes of FUO • Hippocrates: excess of yellow bile • Middle Ages: demonic possession (encephalitis?) • 18th Century: Friction associated with the flow of blood through the vascular system and from fermentation and putrefaction occurring in the blood and intestines 1/19/2013 Dr.T.V.Rao MD 7
  • 8. Definition Expansion 1. Classical PUO 2. Nosocomial PUO 3. Neutropenia PUO 4. HIV-Associated 5. Transplant 1/19/2013 Dr.T.V.Rao MD 8
  • 9. Categories of FUO Feature Nosocomial Neutropenic HIV-associated Classic Patient’s Hospitalized, Neutrophil count Confirmed HIV- All others with situation acute care, no either <500/µL or positive fevers for ≥3 infection when expected to weeks admitted reach that level in 1-2 days Duration of 3 daysb 3 daysb 3 daysb (or 4 3 daysb or 3+ illness while weeks as outpatient investigated outpatient) visits Examples Septic Perianal infection, MAIc infection, Infections, thrombophlebitis, aspergillosis, TB, non- malignancy, sinusitis, C. candidemia Hodgkin’s inflammatory difficile colitis, lymphoma, drug diseases, drug drug fever fever fever aAllrequire temperatures of ≥38.3 C (101 F) on several occasions. bIncludes at least 2 days’ incubation of microbiology cultures. cM. avium/M. intracellulare. 1/19/2013 Modified Dr.T.V.Rao Durack, AC Street, in JS Remington, MN Swartz (eds): 9 from DT MD Current Clinical Topics in Infectious Diseases. Cambridge, MA, Blackwell, 1991.
  • 10. Pattern of Fever 1/19/2013 Dr.T.V.Rao MD 10
  • 11. Etiologies of PUO • Infection: Three major causes • Abscess .. especially occult .. • Intracellular organisms. (salmonella mycobacterium, bruc ella) • Intravascular … SBE 1/19/2013 Dr.T.V.Rao MD 11
  • 12. “True Fever” • Occurs when IL-1, IL-6, TNF-ά or other cytokines are released from monocytes and macrophages in response to infection, tissue injury, drugs, and other inflammatory processes, increasing the body’s set point. The anterior hypothalamus maintains an inherent set point near 36ºC(98.6ºF). • Normal circadian rhythm, which is highest(up to 2ºC, 3ºF) ~6pm and lowest at 6am. This accounts for increased volume of ER visits that peaks in the evening. Most true fevers follow this diurnal pattern.
  • 13. Infectious Causes of FUO • Intraabdominal abscess (liver, splenic, psoas, etc) • Appendicitis, cholecystitis, tubo-ovarian abscess, pyometra • Intracranial abscess, sinusitis, dental abscess • Chronic pharyngitis, tracheobronchitis, lung abscess • Septic jugular phlebitis, mycotic aneurysm, endocarditis, intravenous catheter infection, vascular graft infection • Wound infection, osteomyelitis, infected joint prosthesis, pyelonephritis, prostatitis 1/19/2013 Dr.T.V.Rao MD 13
  • 14. Infectious Causes of FUO • Intraabdominal abscess (liver, splenic, psoas, etc) • Appendicitis, Cholecystitis, tubo-ovarian abscess, pyometra • Intracranial abscess, sinusitis, dental abscess • Chronic pharyngitis, tracheobronchitis, lung abscess • Septic jugular phlebitis, mycotic aneurysm, endocarditis, intravenous catheter infection, vascular graft infection • Wound infection, osteomyelitis, infected joint prosthesis, pyelonephritis, prostatitis 1/19/2013 Dr.T.V.Rao MD 14
  • 15. Infectious Causes of FUO • Intraabdominal abscess (liver, splenic, psoas, etc) • Appendicitis, Cholecystitis, tubo-ovarian abscess, pyometra • Intracranial abscess, sinusitis, dental abscess • Chronic pharyngitis, tracheobronchitis, lung abscess • Septic jugular phlebitis, mycotic aneurysm, endocarditis, intravenous catheter infection, vascular graft infection • Wound infection, osteomyelitis, infected joint prosthesis, pyelonephritis, prostatitis 1/19/2013 Dr.T.V.Rao MD 15
  • 16. Bacterial Pyrogens • Lipopolysaccharide (LPS) endotoxin Endotoxin binds to LPS-binding protein and is transferred to CD14 on macrophages, which stimulates the release of TNFα. • Staphylococcus aureus enterotoxins 1/19/2013 Dr.T.V.Rao MD 16
  • 17. Infectious Causes of FUO • Tuberculosis, Mycobacterium avium complex, syphilis, Q fever, Legionellosis • Salmonellosis (including typhoid fever), Listeriosis, ehrlichiosis, • Actinomycosis, nocardiosis, Whipple’s disease • Fungal (candidaemia, cryptococcosis, sporotrichosis, Aspergillosi s, Mucormycosis, Malassezia furfur) • Malaria, Babesiosis, toxoplasmosis, schistosomiasis, fasci oliasis, Toxocariasis, amoebiasis, infected hydatid cyst, trichinosis, trypanosomiasis • Cytomegalovirus, HIV, Herpes simplex, Epstein-Barr virus, parvovirus B19 1/19/2013 Dr.T.V.Rao MD 17
  • 18. Miscellaneous Causes of FUO • Complex partial status epilepticus, cerebrovascular accident, brain tumor, encephalitis • Drug fever, Sweet’s syndrome, familial Mediterranean fever • Gout, pseudo gout • Kawasaki’s syndrome, Kikuchi’s syndrome • Crohn’s disease, ulcerative colitis, sarcoidosis, granulomatous hepatitis • Deep vein thrombosis • Atelectasis? 1/19/2013 Dr.T.V.Rao MD 18
  • 19. Bacterial Pyrogens • Staphylococcus aureus toxic shock syndrome toxin (TSST) Both Staphylococcus toxins are super antigens and activate T cells leading to the release of interleukin (IL)-1, IL-2, TNFα and TNFβ, and interferon (IFN)-gamma in large amounts • Group A and B streptococcal toxins Exotoxins induce human mononuclear cells to synthesize not only TNFα but also IL1 and IL-6 1/19/2013 Dr.T.V.Rao MD 19
  • 20. CAUSES CLASSIC PUO • INFECTIVE 20-30% • CANCER 10-20% • AUTOIMMUNE 15-20% • MISC 15-25% • UNDIAGNOSED 5-10% 1/19/2013 Dr.T.V.Rao MD 20
  • 21. Classic FUO •Infection •Malignancy •Collagen vascular diseases 1/19/2013 Dr.T.V.Rao MD 21
  • 22. Infectious Causes of FUO • Intraabdominal abscess (liver, splenic, psoas, etc) • Appendicitis, cholecystitis, tubo-ovarian abscess, pyometra • Intracranial abscess, sinusitis, dental abscess • Chronic pharyngitis, tracheobronchitis, lung abscess • Septic jugular phlebitis, mycotic aneurysm, endocarditis, intravenous catheter infection, vascular graft infection • Wound infection, osteomyelitis, infected joint prosthesis, pyelonephritis, prostatitis 1/19/2013 Dr.T.V.Rao MD 22
  • 23. Infectious Causes of FUO • Chronic pharyngitis, tracheobronchitis, lung abscess • Septic jugular phlebitis, mycotic aneurysm, endocarditis, intravenous catheter infection, vascular graft infection • Wound infection, osteomyelitis, infected joint 1/19/2013 Dr.T.V.Rao MD 23
  • 24. Infectious Causes of FUO • Intraabdominal abscess (liver, splenic, psoas, etc) • Appendicitis, cholecystitis, tubo-ovarian abscess, pyometra • Intracranial abscess, sinusitis, dental abscess • Chronic pharyngitis, tracheobronchitis, lung abscess • Septic jugular phlebitis, mycotic aneurysm, endocarditis, intravenous catheter infection, vascular graft infection • Wound infection, osteomyelitis, infected joint prosthesis, pyelonephritis, prostatitis 1/19/2013 Dr.T.V.Rao MD 24
  • 25. Geography Malaria Saudi (malaria area)/Africa/India Brucella Saudi/Gulf Area Kala-Azar Yemen/Jazan/Sudan/India Leprosy Yemen/Najran… Typhoid India/Pakistan/Egypt/Indonesia Histoplasmosis USA … (West Coast) N.B.: Ease of Travel → Infection → All parts of the world. Tuberculosis Liver Abscess All over the world. AIDS 1/19/2013 Dr.T.V.Rao MD 25
  • 26. 1/19/2013 Dr.T.V.Rao MD 26
  • 27. Pathophysiology • Meningitis and sepsis are serious etiologies of fever in infants and young children. • Neonates' immature immune systems place them at greater risk of systemic infection. Hematogenous spread of infection is most common in this age group or in patients who are immunocompromised. For these same reasons, infants who have a focal bacterial infection have a greater risk of developing sepsis. 1/19/2013 Dr.T.V.Rao MD 27
  • 28. Bacterial Pyrogens • Lipopolysaccharide (LPS) endotoxin Endotoxin binds to LPS-binding protein and is transferred to CD14 on macrophages, which stimulates the release of TNFα. • Staphylococcus aureus enterotoxins • Staphylococcus aureus toxic shock syndrome toxin (TSST) Both Staphylococcus toxins are super antigens and activate T cells leading to the release of interleukin (IL)-1, IL-2, TNFα and TNFβ, and interferon (IFN)-gamma in large amounts • Group A and B streptococcal toxins Exotoxins induce human mononuclear cells to synthesize not only TNFα but also IL1 and IL-6 1/19/2013 Dr.T.V.Rao MD 28
  • 29. What are common Causes • The following are among the most common bacterial etiologies of serious bacterial infection in this age group: • Streptococcus pneumoniae • Group B streptococci • Neisseria meningitidis • Haemophilus influenzae type b • Listeria monocytogenes • Escherichia coli 1/19/2013 Dr.T.V.Rao MD 29
  • 30. Consequences of Fever can be confusing • Approximately 2.5-3% of highly febrile children younger than 3 years develop occult bacteremia, which typically is caused by S pneumoniae. Viral infections are common in the young child as well; however, exclude serious bacterial infection prior to assuming a viral etiology for the fever. 1/19/2013 Dr.T.V.Rao MD 30
  • 31. History Taking • Family History: – Scrutinized for possible infectious or hereditary disorders • Tuberculosis • FMF • Past Medical Condition: Lymphoma → may recur Rheumatic Fever → may recur Still’s Disease → may recur Behcet’s Disease → may recur • Exposure to sexual partner … Acute HIV • Illicit drug abuse (IV) … infective endocarditis, Hepatitis … HIV 1/19/2013 Dr.T.V.Rao MD 31
  • 32. Physical Examination ….. Looking for the KEY physical sign …. Diagnostic yield 60% in children (50%repeated) • Document the Fever: – Significant and persistent for more than ONE occasion. • Analyzing the Pattern: – Neither specific Nor sensitive enough to be considered diagnostic … EXCEPT Tertian & Quarter Pattern → Malaria Pel-Ebstein Pattern → Lymphoma/ Tuberculosis Pulse-Temp Dissociation → Typhoid/ Brucellosis 1/19/2013 Dr.T.V.Rao MD 32
  • 33. Infections • Tuberculosis (especially extrapulmonary) Abdominal abscesses Pelvic abscesses Dental abscesses Endocarditis Osteomyelitis 1/19/2013 Dr.T.V.Rao MD 33
  • 34. Infections • Sinusitis Cytomegalovirus Epstein-Barr virus Human immunodeficiency virus Lyme disease Prostatitis Sinusitis 1/19/2013 Dr.T.V.Rao MD 34
  • 35. Etiologies of PUO • Infection – Tuberculosis: .. Disseminated • The single most common infection in most PUO series except in children and elderly. • Usually extrapulmonary or military, or • Occurs in the lungs and significant pre-existing lung disease. • Pulmonary TB in AIDS is often subtle (normal chest x- rays → 15 – 30%). • PPD is (+ve) < 50% of TB with PUO. • Diagnosis often requires Bx of LN/Liver/Bone marrow. • Sputum smear (+) only 25% 1/19/2013 Dr.T.V.Rao MD 35
  • 36. Etiologies of PUO – Abscess: • Usually located in abdomen or pelvis. • Secondary to appendicitis or diverticulitis. • Pyogenic liver abscess usually follow biliary tract dis./abd. Suppuration. • Amoebic liver abscess is similar to pyogenic → amoebic serology is positive > 95% of cases. • Splenic abscess is usually secondary to hematogenous seeding. • Perinephric or renal abscess is usually secondary to UTI. 1/19/2013 Dr.T.V.Rao MD 36
  • 37. Etiologies of PUO – Bacterial Endocarditis • Culture remains negative in 5% of patient. • Culture negative is likely with the following organisms: – Coxiella burnetii → no growth. – HACEK group → incubate blood 7 – 21 days – Brucella } Special media/ – Legionelle } long time – Mycoplasm/Chlamydia } – Fungal → usually sterile • Peripheral signs may not be detected. • Right-side Endocarditis → Lack murmurs → self antibiotics → growth (-ve). 1/19/2013 Dr.T.V.Rao MD 37
  • 38. Etiologies of PUO • Infection – Tuberculosis: .. Disseminated • The single most common infection in most PUO series except in children and elderly. • Usually extra pulmonary or military, or • Occurs in the lungs and significant pre-existing lung disease. • Pulmonary TB in AIDS is often subtle (normal chest x- rays → 15 – 30%). • PPD is (+ve) < 50% of TB with PUO. • Diagnosis often requires Bx of LN/Liver/Bone marrow. • Sputum smear (+) only 25% 1/19/2013 Dr.T.V.Rao MD 38
  • 39. Geography Malaria Saudi (malaria area)/Africa/India Brucella Saudi/Gulf Area Kala-Azar Yemen/Jazan/Sudan/India Leprosy Yemen/Najran… Typhoid India/Pakistan/Egypt/Indonesia Histoplasmosis USA … (West Coast) N.B.: Ease of Travel → Infection → All parts of the world. Tuberculosis Liver Abscess All over the world. AIDS 1/19/2013 Dr.T.V.Rao MD 39
  • 40. HIV associated PUO • HIV alone • TB,M avium/intracelulare • Toxoplasmosis • CMV ,PCP ,Salmonella • Cryptococcus, Histoplasmosis • Non Hodgkins Lymphoma • Drug induced 1/19/2013 Dr.T.V.Rao MD 40
  • 41. Malignancies • Chronic leukemia Lymphoma Metastatic cancers Renal cell carcinoma Colon carcinoma Hepatoma Myelodysplastic syndromes Pancreatic carcinoma Sarcomas 1/19/2013 Dr.T.V.Rao MD 41
  • 42. Autoimmune Conditions with Fever • Adult Still's disease Polymyalgia rheumatic Temporal arteritis Rheumatoid arthritis Rheumatoid fever Inflammatory bowel disease Reiter's syndrome Systemic lupus erythematous Vasculitides 1/19/2013 Dr.T.V.Rao MD 42
  • 43. Miscellaneous • Drug-induced fever Complications from cirrhosis Factitious fever Hepatitis (alcoholic, granulomatous, or lupoid) Deep venous thrombosis Sarcoidosis 1/19/2013 Dr.T.V.Rao MD 43
  • 44. Diagnosis • A cost-effective individualized approach is essential in the evaluation of these patients to prevent performing inappropriate tests. 1/19/2013 Dr.T.V.Rao MD 44
  • 45. Minimal Initial Diagnostic Workup For FUO • Comprehensive history • Physical examination • CBC + differential • Blood film reviewed by hematopathologist • Routine blood chemistry • UA and microscopy • Blood (x 3) and urine cultures • Antinuclear antibodies, rheumatoid factor • HIV antibody • CMV IgM antibodies; heterophile antibody test (if c/w mono-like syndrome) • Q-fever serology (if risk factors) • Chest radiography • Hepatitis serology (if abnormal LFTs) 1/19/2013 Dr.T.V.Rao MD 45 Mourad, et al. Arch Intern Med. 2003;163:545
  • 46. Diagnostic Testing Blind application leads to excessive false tests … • Complete Blood Count – Anemia if present → suggest a serious underlying disease – Leukocytosis with bands → occult bacterial infection – Lymphocytosis & atypical Lymphocyte → Infectious mononucleosis – Leucopenia and Lymphopenia → advanced HIV – Leukoerythroblastic Anemia → Disseminated TB – Thrombocytopenia → Malaria/Leukemia – Peripheral Blood → Malaria 1/19/2013 Dr.T.V.Rao MD 46
  • 47. Diagnostic Testing • Urinalysis, Urine Culture, U/E, LFT • ESR – If elevated → significant inflammatory process – Greatest use in establishing a serious underlying disease, esp. if v. high → ESR > 100 mm/h … Tuberculosis … m myeloma … temporal arteritis 1/19/2013 Dr.T.V.Rao MD 47
  • 48. Diagnostic Testing – 58% → malignancy → Lymphoma/myeloma – 25% • Infection – Endocarditis • Giant cell arteritis – ↑ High ESR → lacks specificity: • Drug Reaction } • Thrombophlebitis } may cause very high ESR • Nephrotic Syndrome } – Normal ESR → significant inflammatory process is absent with exception. 1/19/2013 Dr.T.V.Rao MD 48
  • 49. Diagnostic Testing • CRP-closely associated with inflammatory process – Not invariable components of the febrile response. – Usually does not go up with viral infection. * ESR & CRP is elevated in: 1. Bacterial Infection 2. Neoplasm 3. Immunological-mediated inflammatory states 4. Tissue infarction 1/19/2013 Dr.T.V.Rao MD 49
  • 50. Diagnostic Testing • Acute Phase Proteins Proteins Increased Proteins Decreased Fibrinogen Albumin Ferritin Transferrin Plasminogen Alpha- Fetoprotein Protein S Cerruloplasmin New England J Med. 1999, 340.448-454 1/19/2013 Dr.T.V.Rao MD 50
  • 51. Diagnostic Testing • Blood Testing – Anti-nuclear Antibodies – Rheumatoid Factor – CMV Antibody … IgM – Heterophile Antibody Test in children and young adult – Tuberculin Skin Test … 5 unit ID – Thyroid Function Test – HIV Screening 1/19/2013 Dr.T.V.Rao MD 51
  • 52. Diagnostic Testing • Imaging Studies: … to localize abnormalities for definite tests or treatment – Chest x-ray: • Military shadows → disseminated tuberculosis • Atelectasis } 1. Liver ↑ Hemi diaphragm } Abscess 2. Spleen Pleural Effusion } 3. Pancreatic 4. Subphrenic • Mediastinal mass → Lymphoma/Tuberculosis/ Sarcoid • If CXR is (N) → Repeat on weekly basis 1/19/2013 Dr.T.V.Rao MD 52
  • 53. Diagnostic Testing – CT-Scan → CT scan chest • Mediastinal mass → Tuberculosis/Lymphoma/ Sarcoidosis • Dorsal Spine → Spondylitis and disc space disease • CT-Scan Abdomen → very effective to visualize – All types of abscesses – Retroperitoneal tumor, lymph node or hematoma – MRI: spleen, lymph node and the brain 1/19/2013 Dr.T.V.Rao MD 53
  • 54. Diagnostic Testing • Serology Test – Brucella Titer – CMV & EBV antibody test – HIV testing (Elisa screening) – ANF • Radio nuclear Scanning – Bone TC-scan → osteomyelitis (skeletal) – Gallium scan → occult inflammation – Indium labeled WBC-scan → occult abscesses 1/19/2013 Dr.T.V.Rao MD 54
  • 55. Diagnostic Testing – Hepatomegaly or Abnormal LFT • Hepatic Granuloma – Non-caseating: Tuberculosis/Sarcoidosis & Brucellosis – Caseating: Tuberculosis – Bone Marrow • Granuloma ± Tubercle Bacilli → Tuberculosis • Aplastic Cells → Leukemia • Leishmania Bodies → Kala-Azar • Atypical Cells → Lymphoma • Atypical Plasma Cells → M. myeloma – Temporal Artery → Giant Cell Arteritis – Pleural or Pericardial → Extrapulmonary Tuberculosis 1/19/2013 Dr.T.V.Rao MD 55
  • 56. Investigation • Blood culture before the antibiotics • Culturing of Urine • Sputum culture • Stool examination for Bacterial and Parasitic infection. 1/19/2013 Dr.T.V.Rao MD 56
  • 57. Etiologies of PUO – Abscess: • Usually located in abdomen or pelvis. • Secondary to appendicitis or diverticulitis. • Pyogenic liver abscess usually follow biliary tract dis./abd. Suppuration. • Amoebic liver abscess is similar to pyogenic → amoebic serology is positive > 95% of cases. • Splenic abscess is usually secondary to haematogenous seeding. • Perinephric or renal abscess is usually secondary to UTI. 1/19/2013 Dr.T.V.Rao MD 57
  • 58. Tuberculosis • Sputum examination for AFB • Culturing for AFB • Monteux test Tuberculin test • X ray of the chest 1/19/2013 Dr.T.V.Rao MD 58
  • 59. Diagnosis • More invasive testing, such as LP or biopsy of bone marrow, liver, or lymph nodes, should be performed only when clinical suspicion shows that these tests are indicated or when the source of the fever remains unidentified after extensive evaluation. • When the definitive diagnosis remains elusive and the complexity of the case increases, an infectious disease, rheumatology, or oncology consultation may be helpful. 1/19/2013 Dr.T.V.Rao MD 59
  • 60. Etiologies of PUO • Factitious Fever Febrile PUO In one study … 9% of cases of PUO – False fever: thermometer manipulation using external heat or substitute thermometer. Men use this way … physician are rare for this disorder. Increasing somewhat in elderly … 115 … 116 … – Genuine fever (self induced) Administration of pyrogenic substances (bacterial suspensions) Generally young women with connection to health care … 1/19/2013 often NURSES. Dr.T.V.Rao MD 60
  • 61. Pyrexia of Unknown Origin The majority of disease remaining after an initial NEGATIVE work-up are: 1. Neoplasm 2. Seronegative Collagen Vascular Disease 3. Increasing Tuberculosis 4. Increasing Drug Addition 5. Elderly with Endocarditis 6. HIV with or without infection or malignancy 7. Implanted prosthetic devices 8. Travel … New Exposure 1/19/2013 Dr.T.V.Rao MD 61
  • 62. Therapeutic Trials • Limitation and risk of empirical therapeutic trials: – Rarely specific – Underlying disease may remit spontaneously false impression of success. – Disease may respond partially and this may lead to delay in specific diagnosis. – Side effect of the drugs can be misleading. 1/19/2013 Dr.T.V.Rao MD 62
  • 63. Therapeutic Trials • What is the best therapy for PUO patient? – To hold therapeutic trials in the early stage… except in: • Patient who is very sick to wait. • All tests have failed to uncover the etiology. 1/19/2013 Dr.T.V.Rao MD 63
  • 64. Prognosis • Prognosis is determined primarily by the underlying disease. • Outcome is worst for neoplasms. • FUO patients who remain undiagnosed after extensive evaluation generally have a favorable outcome and the fever usually resolves after 4-5 weeks. 1/19/2013 Dr.T.V.Rao MD 64 Larson et al. Medicine 1982;61:269
  • 65. Summary • FUO is often a diagnostic dilemma • Infections comprise ~30% of cases • Bone marrow biopsies are of low diagnostic yield • Diagnostic approach should occur in a step-wise fashion based on the H&P • Patient’s that remain undiagnosed generally have a good prognosis 1/19/2013 Dr.T.V.Rao MD 65
  • 66. • Programme Created By Dr.T.V.Rao MD for Medical Students in the Developing World • Email • doctortvrao@gmail.com 1/19/2013 Dr.T.V.Rao MD 66