pyrexia of unknown origin
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The document discusses the evaluation and diagnosis of pyrexia of unknown origin (PUO). It defines PUO and provides classifications. The most common causes are infections (30-40%), neoplasms (20-30%), and non-infectious inflammatory conditions (10-20%). The initial approach involves thorough history, physical exam, and basic lab tests. Further targeted testing is based on clues from initial evaluation and may include specialized cultures, biopsies, and imaging. The goal is to methodically consider and rule out more likely causes through an intensive diagnostic process to identify the underlying condition.
pyrexia of unknown origin
- 1. Lab diagnosis of PUO GUIDE: DR. MRS. NAKATE
- 2. TODAY’S DISCUSSION AIMS: • To recognize the potential causes of PUO • To become familiar with an approach to initial diagnostic workup for PUO • To understand the further targeted diagnostic evaluation sometimes needed with PUO
- 3. TODAY’S DISCUSSION Definition Classification Causes Approach to diagnosis Lab diagnosis
- 4. Definition Defined by Petersdorf and Beeson in 1961 as (1) Temperatures > 38.3ºC (101°F) on several occasions (2) A duration of fever of > 3 weeks and (3) A failure to reach a diagnosis despite of 1 week inpatient investigation.
- 5. Classification Durack and Street’s classification: (a) Classic PUO (b) Nosocomial PUO (C) Neutropenic PUO (d) HIV- associated PUO
- 6. Classic PUO 3 outpatient visits or 3 days in the hospital without detection of a cause or 1 week of “intelligent and invasive” ambulatory investigation.
- 7. Nosocomial PUO A temperature of > 38.3ºC develops on several occasions in a hospitalized patient who is receiving acute care and in whom infection was not manifest or incubating on admission. 3 days of investigations, including at least 2 days incubation of cultures, is the minimum requirement for this diagnosis.
- 8. Neutropenic PUO A temperature of > 38.3ºC(101ºF) on several occasions in a patient whose neutrophil count is < 500/ µL or is expected to fall to that level in 1 or 2 days.
- 9. HIV -Associated PUO A temperature of > 38.3º C(101ºF) on several occasions over a period of > 4 weeks for outpatients or > 3 days for hospitalized patients with HIV infection.
- 10. POINTS TO PONDER…. The causes of PUO are usually familiar diseases with uncommon presentations rather than rarer disorders Failure to utilize findings correctly, delay in requesting appropriate tests & misinterpretation of results all contribute to missed diagnosis
- 11. Causes of PUO Five general categories Infections 30-40% Neoplasms 20-30% Non infectious inflammatory conditions 10- 20% Miscellaneous causes 15-20% Undiagnosed 5-15%.
- 12. Causes of PUO Infections: • Cholangitis/Cholecystitis • Dental abscess • Liver abscess • Osteomyelitis • Pelvic inflammatory diseases • Perinephric/intrarenal abscess • Intravascular infections- Endocarditis
- 13. PUO.. Systemic bacterial infections Mycobacterial infections Fungal infections Viral infections Rickettsial infections Parasitic infections
- 14. Neoplasms causing PUO Hodgkin’s disease Non Hodgkin’s lymphoma Leukemia Renal cell carcinoma Hepatoma Colon carcinoma
- 15. Non infectious inflammatory causes Collagen vascular diseases: • Behcet’s disease • Adult still’s disease • Giant cell arteritis • PAN , polymyalgia rheumatica • Rheumatoid arthritis • SLE • Wegener’s granulomatosis
- 16. Inflammatory conditions.. Granulomatous diseases Crohn’ s disease Sarcoidosis Granulomatous hepatitis
- 17. Miscellaneous conditions of PUO Drug fever Gout Post myocardial infarction syndrome Adrenal insufficiency FMF Thermoregulatory disorders- Brain tumor Hyperthyroidism Pheochromocytoma
- 19. Pyrexia of unknown origin Causes by age
- 20. I CAUSES Age < 6 yrs old A) Infections (65%) B) Neoplasms(8%) C) Autoimmune(8%) D) Misc(13%) E) No diagnosis(6%) III CAUSES Age >14 yrs A) Infections (36%) B) Neoplasms(19%) C) Autoimmune(13%) D) Misc(25%) E) No diagnosis(7%) II CAUSES 6-14 yrs A) Infections (38%) B) Neoplasms(4%) C) Autoimmune(23%) D) Misc(17%) E) No diagnosis(19%) IV CAUSES >65yrs A) Connective tissue disorders – TA , PMR(30%) B) Infections(25%) C) Cancer(12%) D) No diagnosis(8%)
- 21. Evaluation of the Patient with PUO Retake history Repeat examination Review results of investigation Repeat investigation if necessary Consider further investigations
- 22. The initial approach to the patient presenting with fever should include a comprehensive history, physical examination, and appropriate laboratory testing. As the underlying process develops, the history and physical assessment should be repeated. The first step should be to confirm a history of fever and document the fever pattern.
- 23. Repeat history taking & physical examination Most important step to establish diagnosis includes independent history of current symptoms, their onset, duration, pattern of fever, recent travel, past & personal history Onset – sudden in pneumonia, pyelitis, influenza gradual in typhoid, typhus, TB subacute in SABE , brucellosis Rigors – malaria, filaria, UTI, septicemia, cholangitis Headache – meningitis, typhoid at onset, ICSOL, encephalitis
- 24. History taking & physical examination … . . Bodyache – dengue, viral fever, secondary syphilis Sweating – malaria, miliary TB, rheumatic fever, hepatic abscess Derilium – typhoid, septicaemia, meningitis, pneumonia Weight loss – TB, thyrotoxicosis, lung abscess
- 25. PAST HISTORY H/O rheumatic fever or valvular disease,TB of any form, syphilis,filariasis,previous illnesses PERSONAL HISTORY Residence in endemic areas – kalazar, mediteranean fever, trypanosomiasis Occupation – weil’s disease Contact with domestic or wild animals/birds brucellosis – cattle Psittacosis – birds Leptospirosis – cats and dogs Q fever – cattle & sheep Contact with persons with TB or other family members having infection
- 26. History ….. FAMILY HISTORY Hereditary causes of FMF MEDICAL HISTORY Conditions like lymphoma, rheumatic fever, IBD, reactivation of which may cause PUO DRUG HISTORY Over the counter medications NUTRITION HISTORY including consumption of dairy products SEXUAL HISTORY STDS, HIV
- 27. PHYSICAL EXAMINATION Definitive documentation of fever and exclusion of factitious fever are essential early steps in the physical examination. Measure the fever more than once and in the presence of a nurse to exclude manipulation of thermometers. Repeat a regular physical examination daily while the patient is hospitalized.
- 28. PHYSICAL EXAMINATION Temperature Type of fever Intermittant with high peaks : malaria , acute pyelonephritis, septicaemia, filariasis Continuous within range of 2°F : typhoid, miliary TB, SABE, pneumonia Periodic/undulating: hodgkin’s, relapsed typhoid, brucellosis Double rise: kala azar, malaria,SABE Pulse rate Relative bradycardia: typhoid, dengue, meningitis, Weil’s disease
- 29. PHYSICAL EXAMINATION… Anaemia Malaria ,kala azar, SABE,chronic sepsis Nails Transverse white bands: undulant fever Lymph nodes Generalised : Hodgkin’s disease,TB,secondary syphilis , lymphocytic leukemia Localised : plague ,glandular fever, rat bite fever, lymphogranuloma inguinale
- 30. • Jaundice – Inf. Hepatitis, weils ds, malaria, IM, liver abscess • Skin rash - typhoid , meningoococcal meningitis, rat bite fever • Petechial hemorrhage – weil ds, SABE • Clubbing – lung abscess, bronchiectasis, SABE • Skin nodules – RF, RA, Erytheme nodosum • Arthritis – RA, RF, gout
- 32. Tests should first be done for more likely infections and then if these are negative, tests for less likely should be done
- 34. CBC count and microscopic examination Hb- to r/o Anemia is an important finding and suggests a serious underlying disease. TLC DLC - Ensure that leukemias are not missed in aleukemic or preleukemic cases. Suspect herpesvirus infection if the patient has lymphocytosis with atypical cells. Atypical lymphocytes suggestive of IM
- 35. A leukocytosis with an increase in bands suggests an occult bacterial infection. Eosinophilia suggests helminthiasis Diagnose malaria with the aid of direct examination of the peripheral blood Thick and thin films should be examined for malaria, leishmaniasis,trypanosomiasis, & filariasis in travellers returned from countries in which these infections are present. CBC count and microscopic examination
- 36. ESR and other acute phase reactants Normal ESR rules out active TB, rheumatic fever & suppurative disease Striking elevation of ESR & anaemia of chronic disease frequently seen in association with GCA , and PMR C- reactive protein may be a useful cross-reference for ESR & is a more specific and sensitive indicator of an acute phase inflammatory response Measurement of another acute-phase protein, the cytokine interleukin-6 (IL-6), has been suggested as a more sensitive marker of infection, particularly for those caused by Gram-negative bacteria
- 37. Urinalysis: Exclude UTIs and malignant tumors of the urinary tract; however, not all of them consistently are associated with pathologic findings in the urine M/E for pus cells , RBCs Casts – pyelonephritis , UTI Cystitis Renal TB C/S for UTI
- 38. Stool examination Obscure pyrexia may reveal typhoid Cysts of E. Histolytica or bacillary dysentery Occult blood
- 39. BLOOD CULTURE Blood culture should always be attempted. collected before antibiotics several specimens collected on separate occasions should be examined before a negative result is accepted for both aerobic and anaerobic pathogens are essential in the evaluation Multiple blood samples (no fewer than 3 & rarely more than 6 including samples for anaerobic cultures ) should be cultured for atleast 2 weeks to ensure than any HACEK group of organisms that may be present have ample time to grow
- 40. BLOOD CULTURE…. Lysis-centrifugation blood culture should be employed in cases where prior antimicrobial therapy, or fungal or atypical mycobacterium infection is suspected Typhoid , paratyphoid, SABE, septicaemia, brucellosis
- 41. Cultures of other specimens Microscopic & cultural investigation of urine, sputum & faeces may provide clues in the presence of signs or symptoms. Obtain cultures for bacteria, mycobacteria, and fungi in all normally sterile tissues and liquids that are sampled during further workup. These tissues and fluids include CSF, pleural or peritoneal fluid, BAL and fluid from the liver, bone marrow, and lymph nodes. Culture of wounds, intravenous lines etc Examination of throat swabs, ear swabs or conjunctival swabs may be indicated
- 42. CSF when suspecting meningitis, encephalitis LE cell phenomenon Serological tests for syphilis Serum immunoglobulins – EBV & CMV IgG & IgM
- 43. Serum Chemistry LFT : At least one liver function test is usually abnormal, with an underlying disease originating in the liver or a disease that causes nonspecific alterations of the liver (eg, granulomatous hepatitis). Most other chemistry tests rarely contribute to the diagnosis, though they are frequently ordered. Eg. urea, creatinine, electrolytes, blood sugar serum iron, transferrin and albumin levels
- 44. Serologies Imp in diagnosis of viral , collagen , fungal 7 protozoal inf. First specimen should be collected as early as possible & second 2-4 weeks later Widal test- Typhoid VDRL- syphilis Weil felix test – rickettsial Paul bunnel test- IM ASO titre- strepto Ra factor- RA
- 45. • ANA – SLE & other cllagen vascular ds • ELLISA . CFT, Other – various viral , protozoal inf
- 46. Skin test for sarcoidosis , histoplasmosis Tuberculin test & chest X- ray should be done to detect tuberculosis ACE levels HIV screening
- 47. Imaging studies Routinely obtain chest radiographs- TB . Lung tumor PNS x ray - sinusitis Routine abdominal USG even in the absence of signs of intraabdominal process. CT scans If ultrasound studies fail to help reveal the diagnosis, symptoms suggesting an intraabdominal process, patients with suspected retroperitoneal tumors or infections, or in those with abnormal LFTs. Intravenous pyelography may be more sensitive than the CT scan in detecting processes involving the descending urinary tract MRI can be very useful in for whole body scanning.
- 48. Other tests Endoscopic examination upper and lower GIT for Crohn disease, Whipple disease, biliary tract disease, and GI tumors. Radionucleotide studies Perform V/Q radionucleotide studies to document pulmonary emboli. Pulmonary angiography when suspecting pulmonary emboli A technetium bone scan may be a more sensitive method for documenting skeletal involvement when suspecting osteomyelitis Consider radionucleotide studies using gallium citrate or granulocytes labeled with indium In 111 for diagnosis of occult abscesses, neoplasms, or soft tissue lymphomas. PET scanning for occult neoplasms, lymphomas, and vasculitides & deep seated infections Echocardiography: Highly sensitive in diagnosing endocarditis, particularly TEE
- 49. Procedures The final diagnosis is obtained during direct biopsy examination of involved tissue. Biopsy is required if an undiagnosed abnormality is suspected in tissue that is accessible for biopsy, such as liver, bone marrow, skin, pleura, lymph nodes, intestine, or muscle. Biopsy specimens should be evaluated by histopathologic examination and cultured for bacteria, fungi, viruses, and mycobacteria. Muscle biopsy or skin biopsy of rashes may diagnose vasculitis. B/L temporal artery biopsy may diagnose temporal arteritis in the elderly patient with an unexplained ESR elevation.
- 50. SUGGESTED WORKUP FOR PYREXIA OF UNKNOWN ORIGIN
- 51. Repeated meticulous history taking ,paying attention to sick contacts , pets, animals, sexual activities ,drug use, hobbies,& medications, discontinue nonessential medications Repeated physical examination, paying special attention to LNs,temporal artery, teeth &oral cavity, sinus tenderness, thyroid,abdominal tenderness, genitourinary & rectal exam. & cutaneous lesions
- 52. Initial studies ,CBC count, with differential ,ESR, basic chemistry profile (including liver enzymes Urine analysis ,blood & urine cultures & chest radiograph If abnormality detected, perform targeted tests to confirm
- 53. If no abnormality or clues detected ,order tests forANA,anti – DNA antibodies,comp. levels,cryoglobulins RF,ANCA,Thyrotropins, free T4,HIV,EBV,CMV,hep. A, B,C virus,serum protein electrophoresis, USG abdo,& pelvis, CT chest , abdo, pelvis If abnormality detected, perform targeted tests to confirm
- 54. If no abnormality detected specialized bld culture techniques,biopsy of liver, bone marrow & temporal artery & other serological tests
- 55. When no cause is found…… When no underlying cause of PUO is identified after prolonged observation ( >6 months) , the prognosis is generally good, however vexing the fever may be to the patient Hence an intensive and rational diagnostic evaluation usually results in the identification of the most serious diseases that initially manifest as PUOs.
- 57. REFERENCES Practical medical microbiology cruickshanks Principles of medicine – harrison Internet