DrDM Khan A 28 year old female presented in outpatient department with the complaint of Fever for last 2 months and dry cough There is no significant clinical findings on physical examination Routine Lab tests fail to illicit the cause of Fever ID: 1000350
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1. PYREXIA OF UNKNOWN ORIGIN Dr.DM Khan
2. A 28 year old female presented in outpatient department with the complaint of Fever for last 2 months and dry cough. There is no significant clinical findings on physical examination. Routine Lab tests fail to illicit the cause of Fever.What is your diagnosis?Clinical Scenario
3. Old Definition:Fever higher than 38.3oC on several occasions.Duration of fever – 3 weeksUncertain diagnosis after one week of study in hospitalNew Definition:Eliminated the in-hospital evaluation requirements → 3 outpatient visits, or 3 days in hospital. … Ambulatory as well as in hospitalTerminology
4. Epidemiology and EtiologyInfections30 - 40 %Malignancies20 – 25 %Collagen Vascular Disease10 – 20 %Miscellaneous15 – 20 %Undiagnosed10 – 15 %Categories of Illness Causing PUO
5. Children → infection is the most frequent.EBV, CMV… othersElderly → Neoplasm & CT-DisordersGiant cell arteritis } > 50 yr (30%)Polymyalgia Rheumatica }The Age
6. Careful HistoryPhysical Examination (repeated)Diagnostic TestingDiagnostic Approach
7. Verify the presence of fever:Series of 347 patients → for prolonged fever → 35% were ultimately: a. No fever b. Factitious FeverDuration of Fever:The longer the duration → the less likely to have infection and malignancy.History
8. HistoryTravel:Travel to an area known to be endemic for certain disease:Name of the area, duration of stayOnset of illness … (incubation period)1 – 10 Days10 – 21 DaysWeeks - Months MalariaMalariaKala AzarPlagueTyphoidAmoebiasisDengueBrucellaHIVSalmonellaHepatitis AHepatitis
9. Drug and Toxin History:Drug-induced fever … almost all drug can cause drug fever … Antihistamine/beta lactam/hepatrin/coumarin/anti-TB … Salicylates and other NSAID …Alcohol Intake (regular use)History
10. HistoryLocalizing Symptoms:May Indicate the source of fever:Back PainTB SpondylitisBone MetastasisHeadacheChronic Meningitis/GCARUQ PainLiver AbscessLUQ PainSplenic AbscessOral & Genital UlcerBehcet’s DiseaseJaw ClaudicationTemporal ArteritisSubtle changes in behaviorGranulomatous Meningitis
11. Family History:Scrutinized for possible infectious or hereditary disordersTuberculosisFMFPast Medical Condition:Lymphoma → may recurRheumatic Fever → may recurStill’s Disease → may recurBehcet’s Disease → may recurExposure to sexual partner … Acute HIVIllicit drug abuse (IV) … infective endocarditis, Hepatitis … HIVHistory
12. Looking for the KEY physical signsDocumentation the FeverAnalyzing the Pattern of FeverLook for LymphadenopathyPhysical Examination
13. Pattern of Fever
14. Examine the Skin:Rash:Osler’s Nodes: Painful nodule on the pads of toes & fingers → Infective EndocarditisPhysical Examination
15. Embolic Skin Lesions … Janeway LesionConjunctival petechiae in a patient with bacterial endocarditis
16. Examine for Oral UlcerExamine for ArthritisExamine the FundusPhysical Examination
17. New or Changing MurmurTemporal Artery … nodular, weakly pusatibleSinus TendernessTender ToothThyroid Enlargement or TendernessCalf TendernessNails: splinter haemorrhage, clubbingPhysical Examination
18. Complete Blood CountUrinalysis, Urine Culture, U/E, LFTESRCRP-closely associated with inflammatory processLiver Function TestsRenal Function TestsDiagnostic Testing
19. Diagnostic TestingAcute Phase ProteinsProteins IncreasedProteins DecreasedFibronogenAlbuminFerritinTransferrinPlasminogenFetoproteinProtein SCeruloplasminNew England J Med. 1999, 340.448-454
20. Blood TestingAnti-nuclear AntibodiesRheumatoid FactorCMV Antibody … IgMHeterophile Antibody Test in children and young adultTuberculin Skin Test … 5 unit IDThyroid Function TestHIV ScreeningDiagnostic Testing
21. CulturesBloodSputum: For TuberculosisDiagnostic Testing
22. Serology TestBrucella TiterCMV & EBV antibody testHIV testing (Elisa screening)ANFRadionuclear ScanningBone TC-scan → osteomyelitis (skeletal)Gallium scan → occult inflammationIndium labeled WBC-scan → occult abscessesDiagnostic Testing
23. Imaging Studies: … to localize abnormalities for definite tests or treatmentChest x-ray:Miliary shadows → disseminated tuberculosisAtelectasis } 1. Liver ↑ Hemi diaphragm } Abscess 2. Spleen Pleural Effusion } 3. Pancreatic 4. SubphrenicMediastinal mass → Lymphoma/Tuberculosis/ SarcoidIf CXR is (N) → Repeat on weekly basisDiagnostic Testing
24. CT-Scan → CT scan chestMRI: spleen, lymph node and the brain Diagnostic Testing
25. Bone MarrowGranuloma ± Tubercle Bacilli → TuberculosisAplastic Cells → LeukemiaLeishmania Bodies → Kala-AzarAtypical Cells → LymphomaAtypical Plasma Cells → M. myelomaTemporal Artery → Giant Cell ArteritisDiagnostic Testing
26. 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.Therapeutic Trials
27. Antimicrobial Trials:Expected to suppress, but not cure, an infectious process such as abscess → may have false feeling of response.Failure to have quick response → does not mean wrong diagnosis:EndocarditisPelvic inflam. DiseaseTyphoid FeverTherapeutic Trials
28. Empiric Drug:TuberculosisCulture-negative EndocarditisVasculitis … Temporal ArteritisPulmonary EmboliTherapeutic Trials
29. Empiric drug trial for suspected T.B.:Presence of granuloma on Bx before culture result.Elderly or immunocompromised patient with (+ve) TB skin test and deteriorating clinical condition.No drug for stable patient without any suggestive features laboratory result.Therapeutic Trials
30. Empiric drug trial for suspected culture (-ve) Endocarditis:Patient with new or changing murmur or peripheral signs of endocarditis.Vancomycin or ampicillin + Gentamycin, may be used. Therapeutic Trials
31. Empiric drug trials for suspected Vasculitis:Elderly with weight loss and any symptoms suggestive (headache, visual disturbance, jaw claudication) and ↑ ESR > 50 mm/hr → Prednisolone 60 POPatient above 50 yrs who is c/o muscle pain and stiffness around hip and shoulder with ↑ ESR → Prednisolone 20 mg PO ODDramatic response is enough to establish the DX.Therapeutic Trials
32. It depends on:Cause of feverNature of the underlying disease(s) BUT .. Generally poor in:ElderlyNeoplasmDiagnostic delay has adverse effect in:Intra Abdominal InfectionMiliary TuberculosisRecurrent Pulmonary EmboliDisseminated Fungal InfectionTemporal ArteritisPrognosis Arnow PM. Fever of Unknown Origin. Lancet, 1997; 350:575-580
33. If the cause of fever remains elusive → repeat history and examination.5 – 15% of cases → The diagnosis remain obscure. However, most of these patients defervesce without treatment → no disease later.Outcome
34. Undiagnosed PUO patient generally have favorable outcome.Recovery in 4 weeks time … 80%Recovery in 2 years time … 90%Require NSAIDS or steroid … 10%Mortality rate 5 years after discharge 3%Prognosis
35. THANK YOU!!!