A case presentation about a patient with pyrexia of unknown origin

1. Case Presentation
Dr. Vishwa Jayasinghe
Registrar in Medicine
Ward 21/22
THB

2. History
 Mrs. P a 30 year old house wife and a
mother of two from Mamangam
 Presented with a fever for 2 weeks duration
 It was a low grade intermittent fever which
was associated with chills but not rigors and
responded well to antipyretics
 She complained of loss of appetite and loss
of weight of about 2 -3kg over the
preceding weeks.
 She also complained of lethargy and
tiredness.

3.  No sore throat, ear ache or discharge
 No cough, sputum or shortness of breath
 No dysuria frequency or haematruia.
 No history of any contact with mud or stagnant
water.
 She denied headache, constipation, diarrhea
and abdominal pain.
 Fever was not associated with joint pain or
early morning stiffness, no alopecia,
photosensitivity or pleuritic type chest pain
 No haemoptysis, night sweats, past or contact
history of TB.
 No past history of valvular heart disease or
childhood rheumatic fever.

4.  No history of consumption of raw milk/ meat
or contact with animals or birds.
 No sexual promiscuity, blood transfusions,
tattoos or any other high risk behaviour.
 No history of foreign travels.
 No history of recurrent infections or
bleeding.
 She has not been on any long term drugs.
 She has regular menstrual periods no
history of miscarriages or abortions
 No significant surgical history
 Not known allergies for drugs, foods or
plasters
 No significant family history
 She was a house wife and her husband

5. Fever Chart

6. Examination
 Febrile
 Pale
 Not icteric
 There was palpable cervical
lymphadenopathy
 No peripheral stigmata of infective
endocarditis
 ENT examination was normal
 No rashes, alopecia or skin changes

7.  PR-88 beats /min, good volume ,regular
 BP- 100/70 mmHg both supine and
standing
 JVP –not elevated
 Apex-not deviated
 S1 S2 normal
 No audible murmurs
 RR-14 beats/min
 Lungs-vesicular breathing
 No added sounds

8.  Abdomen not distended
 Soft,Non tender
 No hepatosplenomegaly
 No ballotable masses
 No free fluid
 DRE-Normal

9.  Upper limbs –Normal
 Lower limbs – Normal
 Cranial nerves –Normal
 No cerebellar signs
 Fundus- normal

10. Summary
 30 year old female with fever and
constitutional symptoms for 2 weeks
duration.
 On examination she was febrile and
pale with cervical adenopathy, rest of
the examination was normal.

11. Investigations
1 2 3 4 5
6 7 8 9 10
11 12 13 14 15
16 17 18 19 20
21 22 23 24 25

12. Full Blood Count
WCC (109/l) 2.63 2.01 3.4 3.5
N (109/l) 1.56 1.02 2.63 2.55
L (109/l) 0.55 0.45 0.88 0.45
Hb (g/dl) 8.9 7.7 8.5 9.6
MCV (fl) 85
MCH
(pg/cell)
85
MCHC (g/dl) 27
Platelet
(109/l)
82 66 54 84

13. Renal functions and
Electrolytes
 Na+ - 132
 K+ - 4.6
 Creatinine – 0.6 mg/dl

14. ESR
mm/1st hr 63 103 115 103

15. CRP
mg/dl 2 6

16. Cultures
 Blood and urine were repeatedly
negative

17. SAT
 Negative

18. Malaria parasite
 Negative

19. Dengue IgM / IgG
 Negative

20. Clotting Profile
 PT, APTT and PT/INR were normal

21. Mantoux
 Negative

22. Thyroid functions
 TSH – 0.7
 FT4 – 0.92

23. Blood picture
 Normocytic normochromic anaemia
with leucopenia and thrombocytopenia
 No abnormal cells

24. Bone Marrow aspiration and
trephine biopsy (at NHSL) with
Bone Marrow TB PCR
(Routinely done at that ward)
 No abnormal cells in bone marrow
histology
 Bone Marrow TB PCR positive

25. 2D Echo cardiogram
 EF – 60%
 Mitral, aortic, tricuspid and pulmonary
valves normal
 No vegetations or cardiac masses

26. Chest X ray

27. Ultrasound Scan of Abdomen
 Liver-normal in size & texture
 GB-Normal
 Spleen-not enlarged
 Kindney-B/L normal size ,shape &
texture
 Bladder-Normal contour with normal
wall thickness
 No free fluid
 No enlarged Para - aortic LN

28. Contrast Enhanced CT Chest
and Abdomen
 Lung parenchyma normal with no
focal lesions
 No pleural effusions
 Liver normal
 Hepatic duct and Gall bladder normal
 Spleen and kidney normal
 No enlarged para – aortic nodes
 No free fluid

29. DAT
 Negative

30. HIV
 Negative

31. Bone marrow TB PCR
 Positive

32. ANA
 Positive

33. Anti DS - DNA
 Positive ( >150)

34. Liver Function Tests
AST(u/l) 42 61 127 129 203 42
ALT (u/l) 42 63 163 124 110 36
T. Prot
(mg/dl)
68 73
Alb
(mg/dl)
47 26
Glo
(mg/dl)
41
T. Bil
(µmol/l)
5.5 2.6
D. Bil
(µmol/l)
1.5 1.9
GGT 25

35. Lymphnode biopsy
 The lymph node architecture is effaced.
There are areas of necrosis surrounded by
histiocytes.
 Multinucleated giant cells and well – formed
granulomas are not present.
 The back ground contains a polymorphous
lymphoid infiltrate.
 There is no evidence of apoptotic debris
suppuration or lymph node malignancy
 Conclusion – Necrotizing lymphadenitis
with histiocytes. Possibilities include
SLE

36. Complement Levels
 C 3 – 24.7 mg/dl (90 – 180 mg/dl)
 C 4 – 6.0 mg/dl (10 – 40 mg/dl)

37. Chronology of events
 Patient was first admitted in early December with
fever and investigated for pancytopenia
 Transferred to NHSL for haematology opinion
 Lymph node biopsy, BM biopsy done at NHSL
 Retransferred back to THB
 Respiratory Referral done
 ATT started for extrapulmonary tuberculosis
 Patient developed acute hepatitis following the
start of ATT
 ATT were withdrawn and LFT returned back to
normal

38. Diagnostic and therapeutic
dilemma
 ? TB PCR false positive
 ? Diagnosis of SLE – criteria to fulfill
 ? Will treating SLE will worsen TB

39. Discussion

40. SLE Diagnostic Criteria
(ACR)
 Serositis
 Oral ulcers
 Arthritis
 Photo sensitivity
 Haematological manifestations
 Renal manifestations
 ANA
 Immunological phenomenon – Eg. anti DS
DNA
 Neurological manifestations
 Malar rash
 Discoid Rash

41. Problems with ACR criteria
 Patients classified in to
◦ Classic SLE – Has many of ACR criteria
◦ Definite SLE – 4 of ACR criteria
◦ Possible SLE – Less than four of ACR criteria
◦ Undifferentiated Connective tissue disorder
 Patient may have SLE but may not meet all the
criteria. Eg. – Patient with lupus nephritis on
renal biopsy while being investigated for
proteinuria but may not have other criteria
 Hence, new criteria is suggested by Systemic
Lupus International Collaborating Clinics -
SLICC criteria

42. ACR Criteria SLICC criteria
Serositis Acute cutaneous lupus
Oral ulcers Chronic cutaneous lupus
Arthritis Non scarring alopecia
Photosensitivity Oral or nasal ulcers
Blood disorders Joint disease
Renal involvement Serositis
Neurologic disorder Renal involvement
Malar rash Neurologic involvement
Discoid rash Haemolytic anaemia
ANA Leucopenia/lymphopenia
Anti DS DNA thrombocytopenia
ANA
Anti DS DNA
Antiphopholipid Ab
Low compliments
DAT

43. Autoantibodies
 ANA
◦ Best diagnostic test for SLE
◦ 93% Sensitivity
◦ Other conditions with positive ANA
 Scleroderma – 85%
 Mixed connective tissue disorders – 93%
 PM/DM – 61%
 Rheumatoid arthritis – 41%
 Drug induced Lupus – almost 100%
 Discoid lupus – 15%

44.  Anti dsDNA
◦ Highly specific for SLE and associated with
disease activity
◦ Titers of anti dsDNA antibodies fluctuate with
disease activity, therefore useful in the
management
◦ Other conditions with anti – dsDNA antibodies
 Rheumatoid arthritis
 Scleroderma
 Raynaud’s phenomenon
 Mixed connective tissue disease
 TB and other infections
 Malignancies

45. Extrapulmonary and Miliary
Tuberculosis
 Miliary TB refers to clinical disease resulting from the
haematogenous dissemination of Mycobacterium
tuberculosis – a term used since 1700s
 Clinical manifestations
◦ Disseminated pulmonary disease
◦ Lymphatic disease
◦ Bone and joint involvement
◦ Gastrointestinal disease
◦ Genito urinary disease
◦ CNS involvement
◦ Other Organs – Adrenal, Heart, Eye, thyroid, laryngitis, otitis
media

46. Haematological manifestations
of Tuberculosis*
 Normocytic normochromic anaemia is the most
commonly observed abnormality (84% in MTB/DTB
and 86% in PTB)
 Leucopenia (25% in DTB/MTB but very rare in
PTB)
 Pancytopenia occurs only in MTB
 Thrombocytosis more common in PTB, where as
thrombocytopenia was more in DTB/MTB
 Haemophagocytic syndromes also are described
 MTB – Milliary Tuberculosis
 DTB – Disseminated Tuberculosis
 PTB – Pulmonary Tuberculosis
 * Singh KJ, et al 2001 J. of associated Physicians India2001
Aug;49:788

47. TB PCR in Bone marrow in patients
presenting with PUO*
 PCR appears to be valuable in establishing
the diagnosis of tuberculosis in patients
presenting with PUO
*Singh UB at el American J of Tropical Medicine 75(5), 2006, pp960-963

48. Problems with Bone Marrow TB
PCR
 High rate of false positives, due to
macrophages in bone marrow which
contain dead TB bacilli will give a positive
PCR result.
 In this patient with
◦ Negative Mantoux
◦ Normal CRP
◦ Normal CXR
◦ Normal CECT chest and abdomen
◦ LN biopsy not suggestive of TB
 Diagnosis of TB is less likely

49. Side effects of ATT
Drug Common Side Effects Rare Side Effects
1. Isoniazid • Nausea and vomiting
• Peripheral neuropathy
• Hepatitis
• Histamine reaction
• Skin rashes
• Convulsions
• Psychosis
• Optic neuritis
• Hematological
• SLE like syndrome
2. Rifampicin • Hepatitis
• Potent hepatic enzyme
induction
• Rashes
• ARF
• Hemolytic anemia
3. Pyrazinamide • Skin rashes
• Joint pain
• Hepatitis
• Sideroblastic
anemia
4. Streptomycin • Renal damage
• Auditary / vestibular
damage
• Imparied
neuromuscular
transmission
5. Ethambutol • Optic neuritis

50. ATT induced acute Hepatitis
 Most commonly by Isoniazid, Pyrazinamide
and rifampicin.
 A transaminase rise of 2 -3 folds is normal,
elevated AST ALT is not an indication to
stop ATT provided that bilirubin is normal
 LFTs should be performed if the patient is
having symptoms of acute hepatitis.
 If drug induced hepatitis is suspected all
ATTs should be stopped
 ATT should be re – introduced once LFTs
are normal in sequential order Rifampicin,
Isoniazid and Pyrazinamide

51. Bridge Therapy in ATT induced
Hepatitis
 In some patients we may not be able to
completely withdraw ATT in acute hepatitis.
 Streptomycin, Ethambutol and a quinolone
(Levofloxacin) when both serum bilirubin
and transaminases are high used in such
patients.
 Once LFTs return to normal the original
drugs reintroduced in sequential order
Isoniazid, Rifampicin and Pyrazinamide.
 Do not do it by your self – Get the help of a
Respiratory Physician.

52. Coming back to our patient Mrs.
P
 Plan of management
◦ Do a Quantiferon gold test to rule out TB
– awaiting the report
 To start managing SLE with Isoniazid
cover

53. Management of Mrs. P
 Prednisolone 30mg/d
 HCQ 200mg/d
 Enalapril 2.5mg/d
 Vitamin D and Calcium
supplementation
 Alandronate 75mg/ week
 Isoniazid 300mg/d (until Quantiferon
report available)
 Eye screening
 DEXA scan planned via clinic follow
up

54. Response to Treatment

55. Thank you