PYREXIA OF UNKNOWN ORIGIN(PUO)

BY

DR. Hayam Hebah

Associate Professor of Internal Medicine

AL Maarefa College

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

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

•New Definition:

•Eliminated the in-hospital evaluation

requirements → 3 outpatient visits, or 3 days in

hospital. … Ambulatory as well as in hospital

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).

Nosocomial PUO

• Causes:

1. hospital associated factors such as, surgery,

2. use of urinary catheter,

3. intravascular devices ,

4. drugs (antibiotics induced Clostridium difficile colitis, and drug fever),

5. immobilization (decubitus ulcers).

6. deep-vein thrombophlebitis, and pulmonary embolism,

7. transfusion reactions,

8. acalculous cholecystitis,

9. thyroiditis,

10. alcohol/drug withdrawal,

11. adrenal insufficiency,

12. pancreatitis

13. sinusitis

Pyrexia in HIV patient• HIV itself.• Secondary causes:

1. Tuberculosis

2. Toxoplasmosis

3. Pnemcystiis jer.(cariini)

4. Cryptochoccosis

5. Salmonellosis

6. Histoplasmosis

7. Cmv

8. Non Hodgikin lymphoma

9. Drug induced

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

Aetiologies of puo I-INFECTIONS

SPECIFIC LOCATIONS

SPECIFIC ORGANISMS

SPECIFIC PATIENT GROUPS

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

Specific organisms

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

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

malignancies• Hematological malignancies:

• Lymphoma, leukemia and myeloma

• Solid tumors

• Renal, liver, colon, stomach, pancreas, kidney

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

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

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.

PATTERNS OF FEVER

Microbiological investigations of PUO

1. Microscopy

2. Culture

3. Antigen detection

4. Nucleic acid detection

5. Immunological tests

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 )

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

tissues)

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

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

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.

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

SPECIAL CONDITIONS

• 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.

• 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.

• 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

•.•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.

• 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.

LymphomasThe 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.

• 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.

• 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.

• 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.

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)

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.

PUO and rash:• Rheumatic fever• Vasculitis• Inflammatory bowel syndrome• SLE

ERYTHEMA NODOSUMIdiopathic (40 percent of cases)Infectious causes

Beta-hemolytic streptococci

Yersinia species

Hepatitis C virus

Mycobacterium species

Chlamydia trachomatis

Coccidioides immitis

Noninfectious causesMedications

Sulfonamides

Oral contraceptives

Systemic lupus erythematosusSarcoidosisUlcerative colitisBehçet's syndromePregnancy

Brucellosis

THANK YOU