1. Pyrexia of unknown origin(PUO)BY
Dr. Hayam Hebah
Associate Professor of Internal Medicine
AL Maarefa College

2. OBJECTIVES DEFINITION TYPES (SUBSETS) OF PUO CAUSES
APPROACH FOR DIAGNOSIS
SPECIAL CONDITIONS ALERT

3. Definition:
Fever of unknown origin (FUO) was defined in 1961 as the following:
(1) a temperature greater than 38.3°C (101°F) on several occasions
(2) more than 3 weeks' duration of illness .
(3) failure to reach a diagnosis despite 1 week of inpatient investigation
New Definition:
Eliminated the in-hospital evaluation requirements → 3 outpatient visits, or 3 days in hospital.

4. Epidemiology and Etiology
infections (30-40%)
neoplasms (20-30%)
collagen vascular diseases (10-20%)
miscellaneous diseases (15-20%).
undiagnosed (5-15%) despite exhaustive studies.
FUOs that persist for more than 1 year are less likely to be caused by an infection or neoplasm and are much more likely to be the result of a granulomatous disease (the most common cause in these cases).

6. Nosocomial PUO Causes: hospital associated factors such as, surgery,
use of urinary catheter,
intravascular devices ,
drugs (antibiotics induced Clostridium difficile colitis, and drug fever),
immobilization (decubitus ulcers).
deep-vein thrombophlebitis, and pulmonary embolism,
transfusion reactions,
acalculous cholecystitis,
thyroiditis,
alcohol/drug withdrawal,
adrenal insufficiency,
pancreatitis
sinusitis

7. Pyrexia in HIV patient HIV itself. Secondary causes: Tuberculosis
Toxoplasmosis
Pnemcystiis jer.(cariini)
Cryptochoccosis
Salmonellosis
Histoplasmosis
Cmv
Non Hodgikin lymphoma
Drug induced

8. PUO IN TRANSPLANT PATIENT
May be due to infections , episodes of graft rejection in solid organ transplant recipients or in GVHD in hematopoietic stem cell transplantation.
According to time following transplantation( IN SOLID ORGAN RECIPIENTS):
0-1 month------bacterial or fungal infections related to underlying condition or surgical complications
1-6 mo CMV ,opportunistic infections as PJP
>6 MO bacterial pneumonia, community acquired infections , PTLD

9. Aetiologies of puo I-INFECTIONS
SPECIFIC LOCATIONS
SPECIFIC ORGANISMS
SPECIFIC PATIENT GROUPS

10. Fever of unknown origin is more often caused by an atypical presentation of a common entity than by a rare disorder.

12. Specific locations
Abscesses: hepatobiliary, diverticular, urinary tract(including prostate), pulmonary, CNS.
Oral cavity infections(including dental)
Head and neck (including sinuses)
Bone and joints infections
Infective endocarditis

13. Specific patient groups
1-neutropenic patients: more liable to fungal infections 2-Imported infections: Malaria, dengue ,rickettsial, brucella , amoebic liver abscess, enteric fever, leishmaniasis 3-Nosocomial infections: infections related to prothetic materials and surgical procedures 4-HIV-positive individuals: -acute retroviral syndrome. -AIDS-defining infections( disseminated Mycobacterium avium complex, Pneumocystis jirovecii (carinii) pneumonia, CMV and others

14. malignancies Hematological malignancies:
Lymphoma, leukemia and myeloma
Solid tumors
Renal, liver, colon, stomach, pancreas, kidney

15. Connective tissue disorders
Older adults: giant cell arteritis and Polymyalgia Rheumatica .
Younger adults:
Still’s disease , SLE, Vasculitic disorders( including PAN, rheumatoid disease with vasculitis and granulomatosis with polyangiitis ( Wegner‘s granulomatosis)
Polymyositis
behçet‘s disease
Geographically restricted
Rheumatic fever

16. miscellaneous
Cardiovascular: atrial myxoma, aortitis,aortic dissection
Respiratory: PE, sarcoidosis, extrinsic allergic alveolitis
Gastrointestinal IBD , granulomatous hepatitis, alcoholic liver disease, pancreatitis
Endocrine/metabolic thyrotoxicosis, thyroiditis, pheochromocytoma ,adrenal insufficiency
Hematological hemolytic anemia, PNH,TTP, myeloproliferative disorders
Inherited FMF, periodic fever syndromes
Drug reactions: Antibiotic fever, drug hypersensitivity reactions
Factitious fever
idiopathic

17. FACTITIOUS FEVER CLUES
A patient looks well
Bizarre temperature chart with absence of diurnal variation &/or temperature related changes in pulse rate
Temperature >41°C
Absence of sweating during defervescence
Normal ESR and CRP despite high fever
Evidence of self injection or self harm
Normal temperature during supervised(observed) measurement.

23. Age The causes of FUO vary dramatically with age.
In children with FUO, for example, one-third were self-limited undefined viral syndromes .
In contrast, patients with FUO over the age of 65:
*31% DUE TO MULTISYSTEM DISEASES
rheumatic diseases
vasculitis including giant cell arteritis, polymyalgia rheumatica
sarcoidosis
*Infections accounted for 25 percent
*neoplasms 12 percent

24. PATTERNS OF FEVER

27. Investigations: Cbc with differential count and blood film ESR and CRP
Urine analysis
Liver function tests ,bilirubin and LDH( hepatitis markers if LFTs are suggestive)
Blood culture (3 times) and urine culture
ANA and rheumatoid factor
HIV antibodies
The heterophile antibody test specifically refers to a rapid test for antibodies produced against EBV , the causative agent of infectious mononucleosis, especially used in children.. And CMV antibody test
CXR
CT chest and abdomen

28. ESR ESR elevations above 100 mm/h among FUO:
58 %had malignancy( lymphoma, myeloma, or metastatic colon or breast cancer)
25 % had infections such as endocarditis or inflammatory diseases like rheumatoid arthritis or giant cell arteritis
drug hypersensitivity reactions, thrombophlebitis, and renal disease, particularly the nephrotic syndrome, may be accompanied by a very high ESR in the absence of infection or malignancy
A normal ESR or CRP also suggests that a significant inflammatory process, of whatever origin, is absent. Once again, however, there are exceptions. As an example, some patients with giant cell arteritis have a normal ESR

29. Microbiological investigations of PUO: I-MICROSCOPY
Atypical lymphocytes( EBV,CMV,HIV-1, hepatitis , Toxoplasma) , trypanosomiasis, malaria
Sputum for mycobacteria and fungi
Stool for ova ,cysts and parasites
Urine for WBCs, RBCs, schistosoma ova , mycobacteria( early morning urine*3)
L/M examination of biopsy for ( bacteria, mycobacteria, fungi, leishmania and other parasites)
E/M ( viruses, protozoa( e.g microsporidia) and other fastidious organisms( e.g T.whipplei )

30. II-Culture Blood Cerebrospinal fluid Gastric aspirate for mycobacteria
Stool
Swabs
Urine ± prostatic massage in older men
Aspirates and biopsies.( joint, deep abscess, debrided tissues)
III-NUCLEIC ACID DETECTION

31. IV-IMMUNOLOGICAL TESTS
SEROLOGY for viruses, dimorphic fungi and some bacteria and protozoa
Serology for CT disorders: ANA, DNA , complement levels, immunoglobulins ,cryoglobulins
 Brucellosis, CMV infection, EBV infectious mononucleosis, HIV infection, amebiasis, toxoplasmosis, and chlamydial diseases are diagnosed with serology.
Interferon gamma release assay for diagnosis of tuberculosis
Serum protein electrophoresis (SPEP)
Serum ferritin levels are useful in cases of FUO due to malignancies, SLE flare, and adult Still disease.

32. Other tests Echocardiography Abdominal u/s Plain X-rays CT/MRI spine
Isotope bone scan
Labelled white cell scan
Positron emission tomography
Lumbar puncture:
Biopsy: Liver biopsy , Lymph node biopsy , Temporal artery for giant cell arteritis or biopsy to diagnose a vasculitic process such as PAN, pleural or pericardial
Bone marrow biopsy.

33. MANAGEMENT OF PUO ACCORDING TO THE CAUSE
In children :Antipyretics are mandatory to avoid development of febrile convulsions.
In adults, mandatory in bad general condition or if there is associated cardiovascular or respiratory problems
Aspirin, NSAIDs or corticosteroids are options but acetaminophen remain the best due to paucity of side effects.

34. Therapeutic trials
patients with FUO should not have empiric antibiotics started solely to treat fever.

35. Special conditions

36. Endocarditis
In the current era, when endocarditis appears as an FUO, it is more likely to be culture-negative or caused by difficult-to-isolate organisms, such as Bartonella quintana.
Hepatobiliary infections
Cholangitis can occur without local signs and with only mildly elevated or normal findings on liver function tests
Osteomyelitis: (technetium Tc 99m [99m Tc] bone scanning) are more sensitive than plain X ray. MRI is also an extremely useful test for the diagnosis of osteomyelitis.

37. Systemic bacterial illnesses
Some systemic bacterial illnesses can manifest as FUOs. Brucellosis, systemic infection with Salmonella species,
 Neisseria meningitidis, and Neisseria gonorrhoeae  . Cultures and serologic tests establish the diagnosis of these infections
Fungal infections
Candida albicans is the main culprit in disseminated fungal infections.
Herpes viruses
Serologic testing can confirm the diagnosis of CMV or EBV when the patient presents with lymphocytosis with atypical lymphocytes. Repeat them in suspected cases , if originally negative,2-3 weeks after the onset of illness.

38. Parasitic infections
Consider toxoplasmosis in patients who are febrile with lymph node enlargement; however, the diagnosis may be difficult to establish because the lymph nodes may be small. Rising antibody titers and immunoglobulin M (IgM) antibodies confirm the diagnosis.
Lymphomas
Diagnosis of lymphomas can be delayed if the tumor is difficult to detect (e g, when confined to the retroperitoneal lymph nodes).Here,anemia may be the most prominent laboratory abnormality in these 2 forms of lymphoma.
Leukemias
In preleukemic states, the peripheral blood smear and BM aspirate may not reveal the correct diagnosis; therefore, perform a bone marrow biopsy.

39. Solid tumors
Among solid tumors, renal cell carcinoma is most commonly associated with FUO, with fever being the only presenting symptom in 10% of cases.
Regional enteritis
Crohn disease is the most common gastrointestinal cause of FUO. Diagnosis is established with endoscopy and biopsy.
Granulomatous hepatitis
In some patients with hepatic granulomas, none of the diseases usually associated with FUO (eg, TB, syphilis, brucellosis, sarcoidosis, Crohn disease, Hodgkin disease) are found. An elevated alkaline phosphatase level is the most consistent laboratory abnormality.

40. Collagen-vascular and autoimmune diseases
Systemic-onset JRA is often difficult to diagnose. Laboratory abnormalities include pronounced leukocytosis, an elevated erythrocyte sedimentation rate (ESR), anemia, and abnormal liver function tests. These findings usually trigger a search for an infectious cause; thus, they delay the correct diagnosis.
Giant cell arteritis
Laboratory findings in GCA include an elevated ESR, mild to moderate normochromic normocytic anemia, elevated platelet counts, and abnormal liver function tests (25% of cases). Perform a biopsy of a temporal artery to obtain a definitive diagnosis.

41. ERYTHEMA NODOSUM Idiopathic (40 percent of cases) Infectious causes
Beta-hemolytic streptococci
Yersinia species
Hepatitis C virus
Mycobacterium species
Chlamydia trachomatis
Coccidioides immitis
Noninfectious causes
Medications
Sulfonamides
Oral contraceptives
Systemic lupus erythematosus
Sarcoidosis
Ulcerative colitis
Behçet's syndrome
Pregnancy

42. THANK YOU