PYREXIA OF UNKNOWN ORIGIN(PUO)

Pyrexia of unknown origin (PUO) may be defined as any febrile illness (temperature greater than 38°C) lasting 3 weeks or longer, without any obvious cause and failure to reach a diagnosis despite one week of inpatient investigation.

In these conditions there is thus a special need for a lab diagnosis
to guide the choice of
appropriate therapy.
Fever ≥ 38.3°C (>101°F) on several occasions

1. PYREXIA OF UNKNOWN ORIGIN (PUO )

2. FEVER OF UNKNOWN ORIGIN

3. PATHOGENESIS exogenous (Endo pyrogens ) Fever -systemic response of body to injury.

4. DEFINITION OF P UO Pyrexia of unknown origin (PUO) may be defined as any febrile illness (temperature greater than 38°C) lasting 3 weeks or longer, without any obvious cause and failure to reach a diagnosis despite one week of inpatient investigation. In these conditions there is thus a special need for a lab diagnosis to guide the choice of appropriate therapy.

5. 1 . Fever ≥ 38.3°C (>101°F) on several occasions DEFINITION OF P UO

6. 1. Fever ≥ 38.3°C (>101°F) on several occasions 2. Duration ≥ 3 weeks DEFINITION OF P UO

7. 1. Fever ≥ 38.3°C (>101°F) on several occasions 2. Duration ≥ 3 weeks 3. Failure to reach a diagnosis despite 1 week appropriate in-hospital investigation or 3 outpatient visits DEFINITION OF P UO

8. 1 TYPES OF P UO Classic PUO Nosocomial PUO Neutropenic PUO HIV associated PUO

9. CLASSIC PUO Petersdrof & Beason (1961) Temperature > 38ºC (101ºF Occurring for more than three weeks Inspite of investigations on three OPD visits or three days of stay in hospital or one week of invasive ambulatory investigations is called classic PUO. Acute PUO : 7-10 Day Chronic PUO : > 3 weeks or longer

10. NOSOCOMIAL PUO When temperature more than 38.3ºC(> 101°F). hospitalized patient who is receiving acute care and in whom infection was not manifest or incubating on admission is called nosocomial PUO. Three days of investigations including at least two days incubation of microbiology cultures is the minimum requirement for this diagnosis Examples: Septic thrombophlebitis, sinusitis, Clostridium difficile colitis, drug fever

11. MODE OF INFECTION CAUSATIVE ORGANISMS PATHOLOGY IV Line Staph.aureus,Staph. epidermidis Septic phlebitis IV Fluids Coagulase negative Staph.,Enterobacter,Citrobacter , Serratia,Ps.cepacia , Septicemia Prosthetic devices Coagulase negative Staph., Facultative Gm-ve bacilli, Diphtheroids, Fungi Infective endocarditis, Osteomyelitis Endotracheal tubes Staph. Aureus , H. influenzae Sinusitis, Pneumonia Urinary catheters E. coli, Klebsiella, Enterococci, Proteus UTI Nosocomial PUO –infections-50%, Non-infectious-25%

12. NEUTROPENIC P UO Less than 500 neutrophils mm -3 Fever ≥ 38.3°C (>101°F) on several occasions Diagnosis uncertain after 3 days despite appropriate investigations (including at least 48-h incubation of microbiological cultures) It is also called immunodeficient PUO. Examples: Perianal infection, aspergillosis, candidemia

13. HIV-ASSOCIATED P UO Confirmed HIV infection Fever ≥ 38.3°C (>101°F) on several occasions Duration of ≥4 weeks (outpatients) or ≥4 days in hospitalized patient Diagnosis uncertain after 3 days despite appropriate investigations (including at least 48-h incubation of microbiological cultures) Examples: M. avium/M. intracellulare infection, tuberculosis, non-Hodgkin's lymphoma , drug fever

14. INFECTIONS Bacterial infections: Enteric fever ( Salmonella spp.) Urinary tract infections (Escherichia Coli) Lung abscess and other deep abcesses Septicemia associated with pneumonia, infective endocarditis . Tuberculosis( mycobacterium tuberculosis) Brucellosis ( Brucella spp.) Rheumatic fever (Streptococcus spp.) Relapsing fever ( Borrelia recurrentis ) Leptospirosis ( leptospira ) Typhus fever ( Rickettsia prowazekii ) Q fever ( Coxiella burnetii ) ETIOLOGY

15. Non Bacterial infections: Viral infections Infectious mononucleosis (E.B. virus) Cytomegalovirus infection Hepatitis A virus infections Hepatitis B virus infections Rubella and other infectious fevers without rashes HIV infection

16. Non Bacterial infections: Parasitic infections Malaria (Plasmodium spp.) Hepatic amoebiasis ( Entamoeba histolytica ) Visceral leishmanisis ( kala azar ) Filariasis ( Woucheria bancrofti ) Toxoplasmosis Trypanosomiasis -

17. Non Bacterial infections: Fungal infections Histoplasmosis Coccidioidomycosi s 2. NEOPLASM Haematological neoplasms Non-Hodgkin lymphoma Leukemia Hodgkin’s disease Other

18. Non Bacterial infections: Fungal infections Histoplasmosis Coccidioidomycosi s 2. NEOPLASM Haematological neoplasms Solid tumors Non-Hodgkin lymphoma Renal carcinoma Leukemia Colon Hodgkin’s disease Liver Other Other

19. 3 . CONNECTIVE TISSUE DISORDER Systemic lupus erythmatus (SLE) Polyartheritis nodosa 4.GRANULOMATUS DISEASE Sarcoidosis Crohn’s Disease 5. DRUG REACTIONS Drug induced fever

20. DIFFERNTIAL DIAGNOSIS DIAGNOSTIC STRATEGIES

21. laboratory diagnostic Microbiology history Physical,laboratory examination Pattern of organ involvement epidemiology Differential diagnosis Diagnosis DIAGNOSTIC STRATEGIES Therapeutic trial

22. History Recent travel to tropics, particularly where there is malaria. Exposure to pets and other animals Sexual history Work environment Contact with other people with similar symptoms Family history Past medical history list of medications Include OTC Transfusion, vaccination, allergies Tobacco, alcohol, illegal drugs Surgery, dentist, pedicare DIAGNOSTIC STRATEGIES

23. physical findings in patients with FUO Lymphadenopathy and pallor are common in infections Splenomegaly are mainly associated with infections and neoplasms DIAGNOSTIC STRATEGIES

24. Temperature chart raises in patients with FUO Double quotidian- stills kala - azar Malaria Miliary tuberculosis Intermittent-hectic:- abscess,lymphoma Chills & rigors Bacteremia Cholangitis pyelonephritis Pneumonia Typhoid Abscess DIAGNOSTIC STRATEGIES

25. Petechiae,splinter , hemmorages , subcutaneous nodules, clubbing on skin and nails DIAGNOSTIC STRATEGIES

26. Deep venous tenderness at lower extremieties DIAGNOSTIC STRATEGIES

27. DIAGNOSTIC STRATEGIES

28. Ulceration and tender tooth of oropharynx DIAGNOSTIC STRATEGIES

29. Enlarged iliac crest, lymph nodes, splenomegaly of abdomen DIAGNOSTIC STRATEGIES

30. Nodules, enlargement, tenderness of thyroid DIAGNOSTIC STRATEGIES

31. Chancroid tubercle, petechiae , roth’s spot of fundi or conjunctiva DIAGNOSTIC STRATEGIES

32. DIAGNOSTIC STRATEGIES

33. Intensive weight loss DIAGNOSTIC STRATEGIES

34. LABORATORY DIAGNOSIS

35. BACTERIAL INFECTIONS SPECIMENS Blood : for blood cultures, peripheral blood smear, hematology, serology and other tests. Urine : for UTI Sputum : in cases of lung infections Pus : in localised abcesses

36. PATHOLOGICAL fINDINGS INITIAL TESTS Haematology tests : Hemoguobin Total leucocyte count Differential leucocyte count Erythrocyte sedimentation rate Peripehral Blood Smear(Thick/ thin)

37. BACTERIAL INFECTIONS COLLECTIONS Specimens should be collected prior to antimicrobial therapy. Blood is collected in Blood culture bottles for cultures and in a sterile vial for serology. Mid-stream urine specimen should be collected in a sterile universal container.

38. BACTERIAL INFECTIONS CULTURE Blood culture: 5 ml of blood is collected in each bottle of 50 ml glucose broth and 50 ml Sodium tourcholate broth. These broths are incubated at 37°C for 24 hours. Subculture it on blood agar(from glucose broth) and MacConkey agar (from taurcholate broth). Incubate both the plates at 37°C for 24 hours.

39. BACTERIAL INFECTIONS CULTURE Urine culture: Mid stream urine sample is inoculated on blood agar and MacConkey agar. These media are incubated at 37°C for 24 hours. If renal tuberculosis is suspected, culture should be inoculated into Lowenstein-Jensen medium.

40. BACTERIAL INFECTIONS CULTURE Sputum culture: sample is inoculated on blood agar and MacConkey agar. These media are incubated at 37°C for 24 hours. If Pulmonary tuberculosis is suspected, culture should be inoculated into Lowenstein-Jensen medium.and are incubated at 37°C for 6 weeks.

41. BACTERIAL INFECTIONS CULTURE Pus culture: Pus is inoculated on glucose broth, blood agar and MacConkey agar. These media are incubated at 37°C for 24 hours. If M .tuberculosis is suspected, culture should be inoculated into Lowenstein-Jensen. If anaerobic organism are suspected, sample must be collected in Robertson cooked meat medium for the site of collection and processed under anaerobic condition.

42. BACTERIAL INFECTIONS IDENTIFICATION On the basis of: Colony morphology Gram’s staining Biochemical reactions Agglutination reactions (for salmonella) For M.tuberculosis : Zeihl-Neelsen’s staining(for AFB detection) Further confirmed by culture and biochemical reactions

43. BACTERIAL INFECTIONS SEROLOGY Human immunodeficiency virus Salmonellosis ( Widal test) Brucellosis • Tularemia EBV (Paul- Bunnel test) Cytomegalic Inclusion virus Other viral infections ( Hepatitis antigens) Toxoplasmosis Fungal infections

44. PARASITIC INFECTIONS Stained peripheral blood thick and thin smears are used as diagnostics for: Malaria Leishmaniasis Filariasis Toxoplasmosis Wet mount film may show microfilaria in case of filariasis . Serology is useful in ameobiasis .

45. VIRAL INFECTIONS Viral infections can be identified by Tissue culture Serological tests. Molecular methods (NASBA, PCR) for Hepatitis virus HIV Cytomegalovirus Peripheral blood smear (infectious mononucleosis)

46. fUNGAL INFECTIONS Specimen may be cultured on Sabourd’s Dextrose Agar(SDA) and brain Heart infusion agar(BHI) . and incubated at 37°C and 25°C for 7 days. Identification: Based on colony morphology Grams Staining(for yeast) KOH mount(for hyphae and yeast )

47. Other diagnostic tests Skin test: Mantoux test ( Intradermal tuberculin test) Negative tuberculin test result still does not rule out tuberculosis Skin test for Histoplasmosis , coccidiodomycosis , sarcoidosis .

48. Other diagnostic tests Haematology : Total leucocyte count (TLC) Differential leucocyte count (DLC) (these are non specific tests) Erythrocyte sedimantation Rate (ESR)

49. Other diagnostic tests Biopsy: If with evidence of organ involvement. • Most definitive approach to investigation of neoplastic cause in PU0 • Helpful in diagnosis of tuberculosis

50. Other diagnostic tests Bone Marrow: • Recommended as an important tool for detection of occult infection and malignancy • In immuno competent children occasionally useful for diagnosis of selected infectious diseases especially brucellosis and typhoid fever

51. THERAPEUTIC TRIALS   If patient is deteriorating and is haemodynamically unstable: Institute empirical therapy (especially neutropenic , HIV) Supportive & Symptomatic therapy If patient is stable: Empiric use of antibiotics, NSAID’s & Corticosteroids may be misleading as determination of a new finding is difficult. Temp fall may be fortuitous or due to drug effect. False sense of therapeutic & diagnostic security, interfere with finding a diagnosis. Spontaneous resolution of fever Iatrogenic complications

52. CONCLUSION To reach diagnosis in PUO is long and time consuming. The investigation and management of a patient with PUO requires persistence and an informed and open mind in order to reach the correct diagnosis. Therapy should be delayed till cause is determined, so that it can be correctly treated. Non specific management is rarely curative & has the potential to delay diagnosis. Most people with PUO have a treatable disease presenting in an unusual manner . The aim in the investigation of such cases is to initiate appropriate treatment . In infections, finding the right antibiotic may be life-saving so take appropriate cultures before starting antibiotic therapy.

53. Thank you