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 by Petersdorf and Beeson 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

4. New Definition:
Eliminated the in-hospital evaluation requirements → 3 outpatient visits, or 3 days in hospital. … Ambulatory as well as in hospital

5. 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).

7. 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

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

9. 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

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

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 organisms Tuberculosis(particularly extrapulmonary)
HIV-1 infection
Viral infections: CMV-EBV
Fungal infections: Aspergillus spp, Candida spp.
Bartonella spp

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

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

16. 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

17. 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 ,others
Inherited FMF, periodic fever syndromes
Drug reactions: Antibiotic fever, drug hypersensitivity reactions
Factitious fever
idiopathic

18. 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.

25. PATTERNS OF FEVER

29. Microbiological investigations of PUO
Microscopy
Culture
Antigen detection
Nucleic acid detection
Immunological tests

30. 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 )

31. culture Blood Cerebrospinal fluid Gastric aspirate for mycobacteria
Stool
Swabs
Urine ± prostatic massage in older men
Aspirates and biopsies.( joint, deep abscess, debrided tissues)

32. Antigen detection
Blood , e.g HIV p24 antigen , cryptococcal antigen, histoplasma antigen, aspergillus galactomannan ELISA.
CSF for cryptococcal antigen
BAL for aspergillus galactomannan
Nasopharyngeal aspirate/ throat swab for respiratory viruses
Urine for Legionella antigen

33. Nucleic acid detection
Blood for Bartonella spp and viruses
Csf for viruses and bacteria( meningococcus, pneumococcus)
Nasopharyngeal aspirate or throat swab for respiratory viruses
BAL for respiratory viruses
Tissue specimens
Urine for chlamydia and Neisseria gonorrhea
Stool for norovirus, rotavirus

34. IMMUNOLOGICAL TESTS
SEROLOGY for viruses, dimorphic fungi and some bacteria and protozoa
Serology for CT disorders: autoantibody screen, 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) is useful in diagnosing atrial myxoma, SLE flares, and lymphomas.
Serum ferritin levels are useful in cases of FUO due to malignancies, SLE flare, and adult Still disease.

35. Other tests Echocardiography Abdominal u/s Plain X-rays CT/MRI spine
Isotope bone scan
Labelled white cell scan
Positron emission tomography
Biopsy

36. Special conditions

37. Endocarditis
Culture-negative endocarditis (in 5-10% of endocarditis cases). Prior antibiotic therapy is the most common reason for negative blood cultures
Hepatobiliary infections
Cholangitis can occur without local signs and with only mildly elevated or normal findings on liver function tests
Osteomyelitis
In osteomyelitis, radiographs may not show changes for weeks after the development of symptoms. Radionucleotide studies (technetium Tc 99m [99m Tc] bone scanning) are more sensitive than plain radiography, and MRI is also an extremely useful test for the diagnosis of osteomyelitis.

38. Rickettsia
Chronic infections with Coxiella burnetii, chronic Q fever, and Q fever endocarditis have been identified in patients with FUO. Signs of hepatic involvement are common, and the infection is transmitted from cattle and sheep. Perform serologic tests in suspected cases.
Chlamydia
Chlamydia psittaci infection and, on rare occasions, Lymphogranuloma venereum infection can manifest as FUO. Serology is essential in the diagnosis of these chlamydial infections.

39. Systemic bacterial illnesses
Some systemic bacterial illnesses can manifest as FUOs. Brucellosis, still prevalent in Latin America and the Mediterranean, is very important. Researchers have also described systemic infection with Salmonella species,
 Neisseria meningitidis, and Neisseria gonorrhoeae as causes of FUO. Cultures and serologic tests establish the diagnosis of these infections
Fungal infections
Candida albicans is the main culprit in disseminated fungal infections. Systemic infection in a patient may remain undiscovered, because blood cultures are negative in approximately 50% of the cases

40. .
Herpes viruses
Serologic testing can confirm the diagnosis of CMV or EBV when the patient presents with lymphocytosis with atypical lymphocytes. The results of these tests may initially be negative; therefore, repeat them in suspected cases 2-3 weeks after the onset of illness.

41. Fungal infections
Candida albicans is the main culprit in disseminated fungal infections. Systemic infection in a patient may remain undiscovered, because blood cultures are negative in approximately 50% of the cases.
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.

42. Lymphomas
The correct diagnosis of Hodgkin or non-Hodgkin lymphoma can be delayed if the tumor is difficult to detect (e g, when the disease is confined to the retroperitoneal lymph nodes).
Anemia may be the most prominent laboratory abnormality in these 2 forms of lymphoma.

43. Leukemias
Acute leukemias are another important neoplastic group that can cause FUO. In preleukemic states, the peripheral blood smear and bone marrow aspirate may not reveal the correct diagnosis; therefore, perform a bone marrow biopsy.
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. Hematuria may be absent in approximately 40% of cases, whereas anemia and a highly elevated sedimentation rate are common.

44. Regional enteritis
Crohn disease is the most common gastrointestinal cause of FUO. Diarrhea and other abdominal symptoms are occasionally absent, particularly in young adults. The 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.

45. Collagen-vascular and autoimmune diseases
SLE is readily diagnosed in most cases by the demonstration of antinuclear antibodies.
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. Pathologic review shows vasculitis and a mononuclear cell infiltrate.

46. Polyarteritis nodosa
Any 3 of the following 10 findings is sufficient for the diagnosis of PAN (sensitivity 82%, specificity 86%):
Mononeuritis multiplex
Myalgias with muscle tenderness
Livedo reticularis
Testicular pain or tenderness
Renal impairment (elevated BUN and creatinine levels)
Weight loss of 4 kg or more
Diastolic blood pressure greater than 90 mm Hg
Hepatitis B positive
Arteriography showing small and large aneurysms and focal constrictions between dilated segments
Biopsy of small- or medium-sized arteries containing white blood cell infiltrate
Peripheral eosinophilia (common and an important clue to PAN)

47. MANAGEMENT OF PUO ACCORDING TO THE CAUSE
Antipyretics are mandatory in children 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.

49. PUO and rash: Rheumatic fever Vasculitis Inflammatory bowel syndrome
SLE

50. 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

51. Brucellosis

55. THANK YOU