PUO DIAGNOSTIC DILEMMA IN
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1 DIAGNOSTIC DILEMMA IN PUO DR.ARUN MOHAN.R 2 nd YEAR POST GRADUATE UNDER THE GUIDANCE OF PROF. DR. BHAKTHAVATCHALAM. N & DR. SRINIVASA. K. V DEPT. OF GENERAL MEDICINE DR.B.R.AMCH, BANGALORE. 1
2 HISTORY PATIENT : Ms.SB/50 yr, Home maker, HRBR Layout, Bangalore. CHIEF COMPLAINTS: Fever since 1 month, Joint pain since 2 weeks, Skin rash since 5 days. 2
3 HISTORY OF PRESENTING ILLNESS FEVER Since 1 month, High grade, Associated with chills & rigors, Relieved with medications. JOINT PAIN Since 2 weeks, B/L ankle & knee, not associated with Stiffness/ Swelling/ Redness. SKIN RASH Since 5 days, Trunk & upper limb, Maculo-papular, Non-pruritic. 3
4 HOPI contd. Associated with sore-throat. Significant weight loss present(10kg over 1 month). No h/o recent travel. No history of known food allergy. No h/o hair loss/oral ulcer/genital ulcer/malar rash/ photosensitivity/skin tightening. 4
5 HOPI contd. No significant past medical/ surgical history. No contributory family history. No h/o Drug intake/medications Personal history: Diet- Mixed Appetite- Decreased Sleep- Adequate Habits- No addictions No h/o high risk behavior. Attained menopause at 45y. 5
6 GENERAL PHYSICAL EXAMINATION Conscious & oriented Moderately built & nourished (BMI-22.3kg/m 2 ) Pulse: 110 bpm, regular, good volume, normal character, no vessel wall thickening, no RR/RF delay, all peripheral pulses felt & synchronous. BP: 130/80 mmhg(right arm, supine position) RR: 20 cpm, SpO 2 : RA Temperature:101.5 O F 6
7 GPE contd. Right superficial cervical lymph nodes, largest measuring about 2cm * 2cm, soft to firm, nontender, mobile, overlying skin normal. No pallor,icterus,cyanosis,clubbing,pedal edema. Posterior pharyngeal mucosa- congested 7
8 GPE contd. Maculo-papular skin rash over posterior aspect of right arm and right lower back. 8
9 SYSTEMIC EXAMINATION Cardiovascular system S1, S2 heard. Tachycardia + No murmurs Respiratory system B/L Normal Vesicular Breath Sounds. Per Abdomen Soft, Non Tender & No Organomegaly. No Bruit. Central nervous system Musculo-skeletal system No focal neurological deficits Normal 9
10 10 DIFFERENTIAL DIAGNOSIS Infection-Tuberculosis, Rickettsial infection, Occult abscess Connective tissue disease Malignancy Autoinflammatory diseases
11 INVESTIGATIONS PARAMETER VALUE Hb 9.8 TOTAL COUNT RBC COUNT 21000/cumm 3.49 lakhs CRP 159 ESR 60 RA NEGATIVE GRBS 212 HbA1C 7.7 SR.CREATININE 0.79mg/dl SR. ELECTROLYTES(NA/K/CL) 132/4.2/101 11
12 INVESTIGATIONS LFT PARAMETER VALUE TRANSAMINITIS(AST-98, ALT-46) PS FOR MALARIAL PARASITE TYPHIDOT PERIPHERAL BLOOD SMEAR BLOOD CULTURE URINE C/S HIV/HBSAG/HCV THYROID PROFILE SPUTUM FOR AFB BRUCELLOSIS WEIL FELIX TEST LEPTOSPIRA IGM/IGG NEGATIVE NEGATIVE NORMOCYTIC, NORMOCHROMIC NO GROWTH NO GROWTH NON- REACTIVE NORMAL NEGATIVE NEGATIVE NEGATIVE NEGATIVE 12
13 IMAGING STUDIES Chest X ray normal USG abdomen & pelvismild hepatomegaly(16.2cm) 2D-ECHO - normal FNAC of Lymph node - reactive lymphadenitis 13
14 CLINICAL EVENTS DAY 1 DAY 4 DAY 8 DAY 12 ARTHRALGIA FEVER PERSISTS SEROLOGY NEGATIVE FEVER PERSISTS RA NEGATIVE CRP NEGATIVE AMOXYCLAV CEFTRIAXONE DOXYCYCLINE FNAC LYMPH NODE BIOPSY SKIN BIOPSY CT CHEST & ABDOMEN BONE MARROW ASPIRATION 14
15 Lymph node biopsy- sinus histocytosis with reactive lymphadenitis features and no evidence of granuloma or malignancy seen Skin biopsy of rash- mild non-specific perivascular inflammation CECT Chest & Abdomen multiple right cervical lymph nodes, largest 2.6cm Bone marrow aspiration - reactive marrow with no granuloma 15
16 INVESTIGATIONS PARAMETER RESULT SR PROTEIN ELECTROPHORESIS IRON PROFILE COAGULATION PROFILE ASLO TITRE ANA ANTI-CCP ANCA PRO CALCITONIN (Normal values ng/ml) NORMAL SR FERRITIN NORMAL 150IU NEGATIVE NEGATIVE NEGATIVE 4.85ng/ml 16
17 Degree Celsius TEMPERATURE CHARTING 40 Body temperature Hospital Days 17
18 10^9/L 18 White cell count Hospital Days
19 19
20 CLINICAL EVENTS, TREATMENT DECISIONS AND TREND OF HAEMATOLOGICAL PARAMETERS IN HOSPITAL 20 Parameters D1 D4 D8 D12 D16 D20 D24 D30 (F/U) TEMP TOTAL COUNT D36 (F/U) PLATELETS LFT(AST/ALT) 98/70 SR FERRITIN 1650 Sr FIBRINOGEN 260mg/dl Sr TRIGLYCERIDES 180mg/dl
21 FEVER RASH ARTHRALGIA LYMPHADENOPATHY HEPATOMEGALY TRANSAMINITIS LEUCOCYTOSIS HYPERFERRITENEMIA EXCLUSION OF MIMICKERS INFECTIONS AUTOIMMUNE MALIGNANCY AUTOINFLAMMATORY LEUCOPENIA THROMBOCYTOPENIA DIAGNOSIS??? 21
22 FINAL DIAGNOSIS ADULT ONSET STILL S DISEASE MACROPHAGE ACTIVATION SYNDROME 22
23 THE YAMAGUCHI CRITERIA FOR THE CLASSIFICATION OF ADULT- ONSET STILL S DISEASE Major criteria: Fever 39 C, lasting one week or longer Arthralgia lasting two weeks or longer Typical rash (Non-pruritic macular or maculopapular skin rash, usually found over the trunk or extremities during febrile episodes Leukocytosis ( 10,000/cumm) including 80% more of granulocytes Minor criteria: Sore throat Lymphadenopathy and/or splenomegaly Liver dysfunction Negative rheumatoid factor and negative antinuclear antibodies 23
24 THE YAMAGUCHI CRITERIA FOR THE CLASSIFICATION OF ADULT- ONSET STILL S DISEASE Exclusion criteria: Infections (especially sepsis and infectious mononucleosis) Malignancies (especially malignant lymphoma) Rheumatic diseases (especially polyarteritis nodosa and rheumatoid vasculitis with extraarticular features For a diagnosis of adult-onset Still disease, 5 criteria (including at least 2 major criteria) should be present 24
25 MAJOR CRITERIA: FAUTREL CRITERIA(2002) - Spiking fever>39 0 C - Arthralgia - Transient erythema - Pharyngitis - Neutrophilic polymorphonuclear count>80% - Glycosylated ferritin fraction<20% MINOR CRITERIA: - Typical Still s rash - Leukocytosis(10,000/mm3) Diagnosis of AOSD 4 or more major criteria or 3major and 2 minor criteria 25
26 2016 AMERICAN COLLEGE OF RHEUMATOLOGY CLASSIFICATION CRITERIA FOR MACROPHAGE ACTIVATION SYNDROME COMPLICATING AOSD (RAVELLI) MODIFIED A febrile patient with known or Acute Onset Still s Disease is classified as having macrophage activation syndrome if the following criteria are met: Serum ferritin > 684 ng/ml Plus any two of the following: Platelet count 181X10⁹ /L Aspartate aminotransferase > 48 U/L Triglycerides > 156 mg/dl Fibrinogen 360 mg/dl 26
27 CLINICAL EVENTS DAY 16 DAY20 DAY 24 DAY30 DAY 36(F/W) ACUTE ONSET CYTOPENIAS COUNTS IMPROVED FEVER HB DECLINE PERSISTENT DISCHARGED AFEBRILE, ARTHRITIS REDUCED, DISCHARGED DEXAMETHASONE STARTED PULSE METHYL PREDNISOLONE CYCLOSPORINE CYCLOSPORINE & PREDNISOLONE METHOTREXATE & LOW DOSE PREDNISOLONE 27
28 TREATMENT Antipyretics Antihistamines Antibiotics- AMOXYCLAV 625mg BD for 5days followed by IV CEFTRIAXONE 1GM BD FOR 7days with Oral DOXYCYCLINE INTRAVENOUS DEXAMETHASONE(8mg/day/TID) Pulse METHYLPREDNISOLONE(1g/day) CYCLOSPORINE(6mg/kg) NSAIDS METHOTREXATE(7.5mg/wk) & LOW DOSE PREDNISOLONGE(10mg/kg/day) - Followup and doing well 28
29 26
30 30
31 ADULT ONSET STILL S DISEASE Rare systemic inflammatory disease of unknown etiology Described- BYWATERS 1971 Prevalence- 1.5 cases per 100,000people Bimodal age with 2peaks Pathogenesis-unknown factors- genetics, infectious agents, environmental TNF-alpha,IL-1,IL-6,IL-18 31
32 MACROPHAGE ACTIVATION SYNDROME An acute overwhelming inflammation caused by a cytokine storm Prevalence-9.5%-22% Overproduction of proinflammatory cytokine resulting in uncontrolled accumulation of activated T-lymphocytes and macrophages 32
33 33
34 NEWER THERAPIES DMARDS- Methotrexate Anti-inflammatory and Antineoplastic agents- Azathioprine,cyclosporine, cyclophosphamide Anti-TNF agents- Infliximab,etanercept,adalimumab Il-1 antagonists- canakinumab,rilonacept,anakinra Il-6 antagonists- Tocilizumab Biologicals- Abatacept Plasma exchange and intravenous immunoglobulins 34
35 THE CASE IS PRESENTED IN THIS FORUM OWING TO. Rarity Of Macrophage Activation Syndrome Barrier To Successful Outcome- Delay In Diagnosis Variable Clinical Presentation And Lack Of Specificity Of Clinical And Laboratory Findings 35
36 TAKE HOME MESSAGE AOSD still remain as diagnostic dilemma for physicians as it presents with combination of nonspecific symptoms MAS is a life-threatening condition that can complicate AOSD and not infrequently, the boundary between MAS and AOSD may be blurred due to their overlapping clinical and laboratory characteristics. Timely diagnosis and treatment of the disease can prevent complications and lead to a favourable prognosis with improved quality of life. 36
37 LET S PUT THE DRAGON TO SLEEP!! Still.., a not so simple fever 37
38 REFERENCES Sobha V V, Gopalakrishnan M, Shamanna. Macrophage Activation Syndrome Complicating Adult-Onset Still s Disease: A Diagnostic Challenge, Int. J of Advanced Medical and Health Research;2018;5; Giacomelli R, Ruscitti P, Shoenfeld Y. A Comprehensive review on adult onset Still s disease; J of Autoimmunity;2018;1-9. Gopalarathinam R, Orlowsky E, Kesavalu R, et al. Adult Onset Still s Disease: A Review on Diagnostic Workup and Treatment Options; Case Reports in Rheumatology; 2016;
39 REFERENCES Ravelli A, Minoia F, Davi S, Horne A, Bovis F, Pistorio A,et al.2016 classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: A European League Against Rheumatism/ American College of rheumatology/paediatric Rheumatology International Trials Organisation Collaborative Initiative. Arthritis Rheumatol 2016;68; Ravelli A, Minoia F, Davi S, Horne A, Bovis F, Pistorio A,et al. Expert conscnsus on dynamics of laboratory tests for diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. RMD Open 2016;e Machaczka M, Klimkowska M. Bone marrow assessment in the diagnosis of acquired hemophagocytic lymphohistiocytosis in adults.am J Clin Pathol; 2015;143;308-10; 39
40 40
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