update pyrexia of unknown source 2024.pptx

review pyrexia of unknown origin

1. Pyrexia of Unknown Origin Stephen Hughes MRCPCH PhD Consultant Paediatric Immunologist

2. PRE-TEST The commonest cause of PUO is: A common disease presenting in an atypical way. A rare disease presenting in atypical way. A common disease presenting typically. A rare disease presenting typically.

3. The answer is ..A ..The commonest cause of PUO IS …Common disease presenting ATYPICALLY

4. What is a PUO? 1956 Age > 14 T > 37.4 ° C x3 or 38 ° C x1 Fever - predominant symptom Insufficient symptoms / signs to localise 1961 Days > 21, T > 38.3 ° C 1/52 hospital investigation 1968 Days > 14 No clear diagnosis Reid Petersdorf & Beeson Dechovitz & Moffet

5. What is a PUO now? Now + 2 hospital visits, or Hospital investigations for 3 days Neutropenic PUO Neutrophils < 1.0 Diagnosis not clear at 3 days Nosocomial PUO Admission infection screen negative Diagnosis not clear at 3 days HIV PUO HIV infected, fever for 4 weeks Diagnosis not clear after 3 days

6. Author Brewis Dechovitz McClung Pizzo Feigin Lohr Jacobs Year 65 68 72 75 76 77 98 N 165 8 99 100 20 54 146 Days 5 14 21 14 14 35 14 Infection 77% 25% 29% 52% 35% 33% 44% CVD 5% 75% 11% 20% 15% 15% 6% IBD 0% 0% 3% 0% 5% 6% 1% Malign 2% 0% 8% 6% 5% 13% 3% Misc 11% 0% 16% 10% 10% 15% 3% No Δ 5% 0% 11% 12% 30% 19% 42% Series

7. Malignancies Are much more common in adults (40 vs. 10%). Either because of infection or cytokines Most commonly: Lymphoma Leukaemia Neuroblastoma Sarcomas and Hepatomas } 80% of malignancies with PUO

8. Who should have a BMA? Patients with suggestive blood film / count or other evidence pointing to Leukaemia / Lymphoma Culture for TB, Salmonella, Leishmania

9. Infection frequencies Infectious mononucleosis (EBV or CMV) (up to 20%) Other viruses (NB. measles, hepatitis, HIV (up to 15%) UTI (up to 15%) Pneumonia (up to 10%) Various URTIs (up to 10%) Endocarditis (Staph. Strep. HACEK, Bruce, Cox, Rick) (up to 5%) Tuberculosis (up to 5%) Streptococcosis (up to 5%) Bartonella (cat scratch disease) (up to 5%) Meningitis / para meningeal abscess (up to 5%) Enteric infection (Salmonella, Yersinia) (up to 5%) Malaria (up to 1%) Brucella (up to 1%) HSV (generalised but occult) (up to 1%)

10. Infectious mononucleosis Diagnosis is made by EBV PCR on blood (EDTA) Support is offered by Atypical lymphocytes (a late finding, in some) Heterophile antibodies (IgM binding sRBCs) IgM antibodies to EBV Other causes include CMV, Toxoplasma, HIV, Rubella, HepAB, HHV678

11. Endocarditis If the child has congenital or acquired cardiac disease, endocarditis must be excluded. If there is no pre-morbid cardiac disease, is endocarditis possible? Y In which patients: those with lines What chance of endocarditis if there are no risk factors and no signs? <5% What are the critical tests? BC, BC, BC

12. How do I get the ECHO? Is there a risk factor? Is there a new murmur? Is there a BC positive for Staph or viridans Strep? 5-10% of IE have negative BCs Because of antibiotics or Fastidious organisms (HACEK) or Aspergillus, Bart, Bruce, Cox, Rick, Mycobacteria, Noca, Chlamydia, viruses…

13. How do I get the ECHO? Is there splenomegaly, emboli, petechiae, splinters, clubbing, Osler nodes, Roth spots, Janeway lesions or haematuria What is the ESR and the RF? Remember, the sensitivity of TTE is 80%. TOE can be considered if the Duke criteria require it later in the period of assessment

14. Bart, Bruce, Rick & Cox Bartonella (5) - the cat scratch illness, usually regional adenopathy, sometimes PUO. Sometimes HSM, sometimes Haem abnormalities. Diagnosis by serology. Brucella (1) - must have exposure (farm animal contact or unpasteurised milk). LFTs rise. Diagnosis by serology. Rickettsia (0) - imported. Coxiella (0) - Q fever, cats and unpasteurised milk. Diagnosis by serology.

15. Could it be TB? Yes

16. Full history and examination (repeatedly) Travel Pets Contact with ticks Contact with animals Drinking unpasteurised milk Cardiac disease Dental history Growth Drugs History

17. Decision to investigate fever (arrival): verify fever Urinalysis and culture unless it is on the list, Blood culture it won’t get done Throat swab FBC (and film) CRP (and ESR) (if the blood flows, take it) NPS for viruses Could it be ‘flu? Stool culture with OCP if travelled Salmonella? For consideration at 5 days - is this Kawasaki? If it is, store serum now Investigations (step 1)

18. By days 5-7, if any focal signs or symptoms appeared, follow them. Carefully record antimicrobial prescriptions Do anything missed from step 1 and organise: CXR occult pneumonia LP occult meningitis More BC yield rises ASOT Streptococcosis is common Coagulation abnormalities will direct inv Ferritin massive elevation helpful Serum to be saved acute serology Request BMA If haem abnormal US Abdomen harmless / helpful Investigations (step 2)

19. By days 10-14, if no diagnosis is reached and not already done: ANA, dsDNA, C3, C4, ENA, Cardiolipin, RF 20% risk Lupus anticoagulant (if clotting abnormal) ECG, ECHO, converse with cardiology 1-5% risk Mantoux, QFG, ESR, Gastric lavage / sputum 1-5% risk LP (if not already done) 1-5% risk CT of any suspect region Brain, Chest, Abdo, ENT Bone scan for pelvic, skeletal osteomyelitis Serology for Bartonella 5% risk Serology for HIV, other microbes and save serum Investigations (step 3)

20. By day 21, Review everything again… TFTs CT abdomen (regardless of signs) Biopsy of abnormal tissue, inc: LNs Gut Skin (Liver) Define immune status of child (call the immunologist) Stop drugs, if started Wait for clues. Investigations (step 4)

21. Endocrine causes for PUO Hyperthyroidism Occasionally cause PUO → most frequently diagnosed clinically. Often accompanied by weight loss. No local neck pain and typically enlarged non-tender thyroid. Adrenal Rare, potentially fatal, but eminently treatable cause of PUO. Consider if: nausea/vomit, ↓weight, ↓BP, ↓Na & ↑K.

22. Rheumatology and PUO 10-20% of cases in most series In the earlier series, Rheumatic fever was key More recently, SoJIA > SLE > vasculitis (PAN, Behcet, WG) & HLH > Sarcoidosis

23. A case 14 year old girl with one month history of fever and malaise … She received 10 days amoxicillin from GP but no response … On exam, T = 38.4°C … several lymph nodes in the neck … non-tender and rubbery …

24. Most likely culprits…

25. BMA CT ASOT Urinalysis Throat swab TB tests Other Tests Blood culture US Abdomen CXR Consultation Biopsy Tea You want a what? ECHO PCRs Google PubMed HIV test Bloods

26. CXR

27. Throat swab culture

28. CT

29. Serology Complement fixation tests for Mycoplasma, Chlamydia, Adenovirus, Legionella, Coxiella were all available. Convalescent specimens are awaited. Samples were sent for Toxoplasma, Bartonella, Brucella, EBV, CMV… We have a brief (two week) wait…

30. ASOT ASOT is negative.

31. Biopsy Seriously, no. Sorry, not today. There are 5 children about to breach their 20 week wait for routine surgery. Your request is noted and will be processed through the usual channels, but please don’t hesitate to make another choice.

32. Tests of immunity What on earth are we looking for? Q. is she immune suppressed? Q. What is the diagnosis? Q. Evidence for recent immune dysregulation (Igs, B and T cells)

33. Immune Function History tells you about immune suppression. Immune function is harder. T cell numbers are normal. There are no abnormalities on routine testing

34. What is the diagnosis? Tests of immunity aren’t going to help you. The serologies are all negative.

35. Immune Dysregulation She does make immunoglobulin: lots of it - IgG 18.2, IgA 1.2, IgM 4.8 She has all the right cells.

36. Consultation Good idea. With whom shall we consult? Respiratory, ENT, Endocrinology, Bone, Rheumatology, Infection, Immunology, Gastroenterology, Haematology, Cardiology, Intensive care?

37. Abdominal ultrasound Normal

38. Blood cultures Negative at 5 days

39. Urinalysis Normal urine on dipstick, no cells on microscopy and no growth

40. Haem & Biochemistry Hb 13.2 MCV 95 Plt 252 WBC 3.2 N 1.8 L 1.0 M 0.3 E 0.1 ESR 42 U&E normal Alb 32 ALT 50 LDH 378 CRP 24

41. PCRs EBV, CMV, HHV6, HHV7, HHV8 are negative Adeno is negative Hep A and B are negative

42. Additional tests Serology Immunology

43. HIV test Negative

44. TB tests Mantoux negative Quantiferon Gold negative No contact history No AAFB seen on any sample. Cultures still awaited many weeks later.

45. Haematologists will do it, but reluctantly. Suggests you arrange imaging and then a biopsy of a node Bone marrow aspirate

46. Tea You cannot have tea until you are finished the exercise.

47. ECHO Normal structure. Normal flows. No shunts or leaks. Satisfactory function. Pressures could not be determined because of anatomical integrity.

48. Biopsy Necrotising histiocytic lymphadenitis Absent neutrophils Normal histiocytes and lymphocytes

49. Diagnosis made Kikuchi Fujimoto syndrome A disease most commonly of young Asian women. Usually lymphadenitis of cervical chain Can cause PUO Mimics TB / lymphoma Diagnosis made by pathologist

50. Thanks for participating Assessment of a fever is dominated by history and examination Repeated assessment probably has more value than blind screening Uncommon presentation of common illness is the norm Involvement of colleagues is critical With longer fever the cause is either more benign or more malign