Fever in Lupus. 21 st April 2014

Fever in Lupus 21 st April 2014

Fever in lupus Cause of fever N= 487 % SLE fever 206 42 Infection in SLE 265 54.5 Active SLE and infection 8 1.6 Tumor fever 4 0.8 Miscellaneous 4 0.8

Crucial Question Infection or SLE or both? Opposite therapy Fatal sepsis can result with use of persistent high dose steroid in infection fever

Significant fever A documented temperature > 100F or 37.5C for at least 3 days

Define SLE fever No infection identified Diagnosis of Exclusion Follow up is must Features of active SLE Suppressed with hike in steroid No evidence of infection over next 2 weeks Physical examination and Investigations Decision may take a single OPD visit to 2 weeks

Case-1 F/20 Presenting complaints Fever from 3 months Cough and multiple joint pains from 2 weeks Symptoms started with cervical lymphadenopathy 8 months back FNAC s/o tuberculosis (no report available) Started on ATT but lymphnodes increased in number

Course After 5 months started having high grade fever associated with cough Fall in hb to 4 gm/dl 4 units PRBC Multiple small and large joint pain, swelling and EMS 1 hour 2 nd episode of fall in hb 2 unit of PRBC Reddish malar rash from 2 weeks USG abdomen Hepato-splenomegaly with multiple echogenic foci Admitted in pulmonary department d/t bilateral consolidation with pleural effusion

Course CT thorax showed Bilateral lower lobe and right middle lobe consolidation with b/l pleural effusion Treated with antibiotics * 3days no response By that time, ANA 4+ homogenous 1:160, Anti-ds DNA >300 IU/ml, C3 19.9 mg/dl, C4 5.85 mg/dl, TLC 3400, PCT 0.712 ng/m, CRP 0.89 mg/dl, ESR 120 mm at 1 hr, Blood culture sterile

Transfer Started on 1 mg/kg prednisolone with antibiotic cover due to consolidation Repeat CRP 0.89 mg/dl, TLC repeated low, blood and urine culture negative Her symptoms improved, arthritis relieved, malar rash subsided, pleural effusion and chest symptoms and x-ray showed resolution in 10 days

Course Fever persisted high grade every 3 rd day As patient was taking 45 mg prednisolone (good amount!!) SLE fever unlikely Thoroughly evaluated with repeat cultures, Echo, USG abdomen hepatomegaly, Treated empirically with anti-malarial ACT orally Fever daily with increased frequency

Course Fundus showing b/l early papillo-edema, no signs of meningeal irritation CSF done normal, MRI brain normal Naprosyn 500 mg bd added, fever responded and subsided completely Likely SLE fever

Define Infection fever Clinically infection Culture, serology or clinical diagnosis Response to antibiotic therapy or reduction in Immuno-suppression No flare of lupus Next 4 months

Case-2 F/39 Diagnosed SLE 2010 minor organ At present on Azathioprine (2 mg/kg) and prednisolone 7.5 mg Presented with intermittent episodes of fever from oct 2013 Nov 2013 evaluated with admission

Nov 2013 No clinical localization for infection or disease activity CT Chest + abdomen normal Echo normal, CSF normal, Bone marrow normal dsdna high in 2010 is 61.2 C3 and C4 90 and 17 mg/dl ESR 20 and CRP 0.7, PCT no report TLC low 3200 Urine no pyuria but culture positive for pseudomonas, blood culture negative?sle fever steroid increased to 12.5 mg

Dec 2013 Non-resolving fever Gastroenterology opinion taken for liver biopsy as work-up for PUO But, then planned for a PET-CT Anti dsdna 48.6 IU/ml C3 and C4 100 and 23 mg/dl CRP 5.36 mg/dl, ESR 62 mm at 1 hour TLC low 3500 Steroid dose split to 7.5/5 mg M/E

Diagnosis PET-CT revealed abscess in lower pole right kidney Infection leading to fever

Define fever d/t both Clinical infection Culture, serology or clinical diagnosis Typical manifestations of SLE activity Response to both antibiotic therapy & increase in Immunosuppression

Case-3 M/25 2006 f/up SLE in remission off Azoran 1 year and 2.5 mg prdnisolone tapered from 3 months April 2013 - Presented with fever, abdomen pain and loose stools and urine showing active sediments, complements low, ds DNA >200, PCT 2.10ng/ml, CRP <0.32 mg/dl, ESR 25 Developed Macrophage activation syndrome Treated with pulse steroid and 1 mg/kg prednisolone

After 1 month- may 2013 Fever relapse from 2 weeks with pain, swelling and redness in b/l thigh and buttock region MRI showing T2 enhancement of hamstrings, quadriceps and gluteal muscles Treated with vancomycin for 4 weeks and prednisolone reduced to 0.5 mg/kg Local symptoms improved but fever persisted with typical morning rise and decreases after morning steroid dose Steroid dose split fever subsided Complements normal, ds DNA 100, CRP/PCT not done

After 1 more month June 2013 Relapse of Fever 2 weeks with abdomen pain and right iliac fossa tenderness CECT abdomen multiple necrotic lymph node Started on ATT By 6 th day he developed multiple pockets of abscess in thigh and buttock region Aspirated pus positive for AFB

Define SLE fever No infection identified Diagnosis of Exclusion Follow up is must Features of active SLE Suppressed with hike in steroid No evidence of infection over next 2 weeks Physical examination and Investigations Decision may take a single OPD visit to 2 weeks

Suppressed with hike of steroid Two aspects Patient presents with fever and SLE diagnosis is made Follow up SLE patient presents with fever

Effect of steroid on fever in lupus Retrospective 22 patients suspected SLE fever 3 developed fatal sepsis at high dose

Effective steroid dose for SLE fever 80.6% in 1-5 days

Max ineffective steroid dose 5.3% still afebrile, 1 had MAS, 3 had lupus enceph

Fever in follow up SLE patients 92 patients (60 renal and 32 non-renal) 13.2+/-8 months f/up Prednisolone 10mg in 82% of flare visits, 3 were receiving NSAIDs Fever is not associated with flare (only 1 patient)

Fever in follow up SLE patients 28 patients had significant fever One SLE fever - 20 mg OD 10 mg twice daily 5 had unexplained and resolved 22 had infection as a cause of fever Respiratory tract most commonly involved So, while on follow up and regular treatment, infection is much more likely to cause fever

Features of active SLE Normal CRP, Anti ds DNA raised, low complements, normal or low leucocyte count But does not rule out infection particularly in cases where both can co-exist!! So, is there some investigations that can look for infections in flare??

Pro-calcitonin

Pro-calcitonin (PCT) & lupus PCT levels marker for sepsis Higher (>2 ng/ml) in sepsis & septic shock Correlate with severity of sepsis Response to antibiotics Do not rise significantly in viral infections The Question - cut-off values in localized bacterial & fungal infections?

PCT, lupus & Infection Ann Rheum Dis. 2001 Oct;60(10):988-9.

PCT to rule out infection Rule out = PCT of <0.17 ng/ml, NPV = 94% for infection Rule in = 100% specificity PCT>0.5 ng/ml and CRP>13 mg/dl poor sensitivity

CRP CRP - not elevated lupus flare Moderate rise - serositis and arthritis Levels are known to rise significantly in infections Considerable overlap But a margin to differentiate between the two

CRP to rule out infection CRP cutoff value 1.35 mg/dl 100% sensitive & 90% specific to detect infection

ROC of PCT & CRP 34 with infection and 39 with lupus flare

Markers of infection & flare

Infection and lupus

Infection morbidity & mortality

Infection & lupus

Sites and microorganisms

Summary Effective steroid dose can be > 40 mg Follow fever trends after steroid hike Follow up SLE patients infection PCT >2 ng/ml with fall on antibiotic likely infection PCT <0.17 ng/ml unlikely to be infection except viral Higher CRP infection CRP <1.35 mg/dl unlikely to be infection Features of active SLE in absence of evident infection

Take home message Infection is the most common cause SLE fever is diagnosis of exclusion Thank you