Approach to fever in OP:

when will you investigate?

Dr. Ram Gopalakrishnan

 What I will cover

 Acute febrile illness

 Fever of unknown origin
 When to test
 What tests to do
 What tests not to do!
 Acute febrile illness

► 32 year old male presents with fever for 2

days
► You will
 Do no tests
 Do WBC count, MP, UA
 Do WBC count, MP, blood cultures
Thangarasu et al. International Journal of Emergency Medicine 2011, 4:57
 Conclusion of study
► Among preschool-age children
► a high percentage of lower respiratory tract diseases are
likely to be of viral origin
► <13% required antibiotics.

► “Most of the febrile children probably had a viral

illness and thus required neither an antimalarial
agent nor an antibiotic. Sending such children
home without antimalarial treatment or antibiotic
treatment is reasonable in the absence of severe
clinical signs”
 Apollo study on undiff. febrile illness
July 2013 - June14 (1 year) : 238 patients
(Dr Soujanya, Dr Senthur Nambi, Dr Ramasubramanian)

Chikungunya Non specific

1% 11%
Leptospirosis
Dengue fever
3%
32%

Alternate diagnosis
3%

Mixed infections
5%

Viral fever
5%

Scrub typhus
8%

Enteric fever
Malaria
20%
12%
Approach to undifferentiated fever
► Day 1 and 2:
 symptomatic treatment only
 antibiotics unnecessary
► Day 3 and 4:
 WBC count
 MP-QBC
 UA
► Day 5-7:
► Add blood cultures
► Other tests: LFT, dengue serology
 Low CRP useful in children in
differentiating bacterial from viral
 In all patients, CRP increased during first 36 hrs of fever.
 CRP declined more rapidly in those with viral infections
versus bacterial infections
 Those with fever duration >24 hours
 If CRP >11 mg/dL: 75% probability of having a bacterial
infection.
 If CRP ≤5 mg/dL : absence of bacterial infection with >95%
accuracy

So a low CRP after day 3 in a child makes bacterial infection

unlikely

Arch Dis Child 2014 May 15;

 Procalcitonin
 Elevated in bacterial infections
 Levels correlate with severity of sepsis

 Not elevated in viral infections

 Trend more useful than a single value

 May go up in non-infectious inflammatory

states
 Best studied in regard to decision to stop
antibiotics

(Lancet 2010;375:463) (Crit Care Med 2012;40;2034)

(Crit Care Med 2011; 39:2048–58)
(Lancet Infect Diseases, Early Online Publication, 1 February 2013)
 Current recommendations

 Non-critically ill patients with suspected or proven

respiratory infection.
 Procalcitonin can be safely used at a cutoff of <0.25 µg/L to
withhold antibiotics in stable, low-risk patients with suspected
respiratory infections.
 If antibiotics are given, procalcitonin can help inform early
discontinuation of antibiotics based on serial measurements.

Open Forum Infect Dis (2017) 4 (1): ofw249.

From: Using Procalcitonin to Guide Antibiotic Therapy
Open Forum Infect Dis. 2016;4(1). doi:10.1093/ofid/ofw249
 Fever of unknown origin

 Classic or community acquired FUO

 Nosocomial FUO
 HIV associated FUO
 FUO in the immune deficient host
 Community acquired FUO
 Fever defined as temp > 99F early morning or >100F at
any other time of day
 FUO defined as temperature >101F persisting >3 weeks
despite either
 2 outpatient visits or
 3 days investigation in hospital
 Etiology
 Infections
 Auto-immune disorders
 Malignancies
 Miscellaneous
 Undiagnosed
 Etiology
 Infections commonest etiology
 Etiology will differ based on setting
 Primary care outpatient practice:
 Typhoid
 Tuberculosis
 Infectious mononucleosis in children
 Tertiary care hospital:
 Tuberculosis
 Connective tissue diseases
 Adult onset Still’s disease
 Infective endocarditis
 History - details of fever
 Duration
 Fever > 6 months: auto-immune disorders
 Fever > 1 year: infectious etiology unlikely
 Associated anorexia and weight loss is the rule
 If absent, think of habitual hyperthermia
 Good appetite but weight loss: thyrotoxicosis
 Chills: pyogenic infection, malaria
 Intermittent fever:
 Malaria
 Hemolysis
 Auto-immune diseases
 Diurnal variation
 Throughout day: typhoid
 Evening rise: TB
 History- other details
 Responds to antibiotics but returns:
 focal bacterial infection eg endocarditis, prostatitis
 Long standing fever: auto-immune entities
 Treatment details so far
 Antibiotics, especially quinolones and doxycycline

 Antimalarials

 ATT

 steroids

 Social history
 Travel: typhoid, diseases endemic to that area

 Animal, recreational, water and soil exposures

 Family history, especially of TB

 Clues in the history

 Blood transfusion:
 Acute HIV infection
 Water or outdoor exposure:
 leptospirosis, melioidosis, scrub typhus
 Unboiled milk consumption:
 brucellosis, M. bovis
 Frequent eating out:
 Food borne illness
 Examination

 Skin lesions
 Oropharynx
 Lymph nodes, esp supraclavicular and
axillary
 Heart murmurs, especially diastolic
murmurs
 Splenomegaly
Eschar parade
DISTRIBUTION OF ESCHARS ON THE BODY OF SCRUB TYPHUS
PATIENTS: A PROSPECTIVE STUDY
Am J Trop Med Hyg May 2007 vol. 76 no. 5 806-809
 Investigation
 Complete blood count
 ESR or CRP
 MP-QBC
 Urine routine
 Liver function tests
 CXR
 US abdomen
 Two sets of blood cultures
 HIV ELISA
 CBC
 Anemia:
 if <6.0, think of primary hematologic disease
 Leukocyte count is crucial
 Leukopenia: typhoid, TB, HIV, SLE
 Leukocytosis: pyogenic infection, vasculitis
 Reactive lymphocytosis: EBV, CMV
 Eosinophilia: drug reactions, parasitic infections
 Eosinopenia: typhoid
 Thrombocytosis: pyogenic infection, inflammation
 Thrombocytopenia: malaria, SLE, HIV
 Pancytopenia: bone marrow infiltration, SLE
 CRP vs ESR

 ESR  CRP
 Affected by a variety of factors  acute-phase reactant rapidly
 plasma concentration of synthesized in the liver
fibrinogen  less affected by extraneous
 Immunoglobulin factors than is ESR
 concentration, size and shape  genetic variation in the genetic
of erythrocytes locus controlling CRP
 age and gender of the patient production accounts for a
 Normal ESR is re-asssuring significant portion of the
 ESR > 100: variability of basal levels of this
 Tuberculosis protein in healthy individuals
 Auto–immune disorders
 Pyogenic infections
 myeloma
 Classify LFT abnormalities

 Hepato-cellular pattern (elevated

ALT/AST)
 Viral hepatitis
 Infectious mononucleosis
 Cholestatic pattern (elevated AP & GGTP)
 Granulomatous hepatitis
 Sepsis
 cholangitis
 CXR
 May miss
 Mediastinal nodes
 Retrocardiac
infiltrates
 Pulmonary vascular
disease
 Miliary TB
 US abdomen

 Liver or splenic enlargement or abscess

 Abdominal nodes
 Abdominal abscess
 Clarifies etiology of deranged LFT
 Renal abnormalities
 Further investigations
 HRCT chest if:
 Pulmonary symptoms
 CXR abnormal
 TB strongly suspected
 CT Abdomen with
contrast: best for
identifying bowel or
retroperitoneal pathology
 Other non-invasive tests
 Urine culture: only if symptoms or pyuria
 ANA: screens for SLE Serum ferritin:
elevated in AOSD
 LDH: hemolysis, increased cell turnover
 Bone scan
 CPK
 TSH
 PET-CT in FUO
 Assesses anatomy and  Mainstream
physiology
 FUO, sarcoid,
 Very sensitive but non-specific osteomyelitis, vasculitis
 Advantage in ID but
disadvantage in oncology  Useful
 Sensitivity 91%, specificity  Intravascular device
80% infections, HIV, TB
 Negative predictive value  Can light up subcentimeter
100% nodes
FDG uptake <5 in most

infections  Can direct site for biopsy
 Factor in radiation exposure for  Can use for decision to stop
a benign disease Rx
 Misses endocarditis
 Transthoracic echocardiogram
 Sensitivity for vegetations only 50-70%,
best in right-sided endocarditis
 Obesity, COPD cause poor visualization
 False positive results are rare
 Do only where endocarditis clinically likely,
not as a screening test in fever or with
bacteremia with an unlikely organism
 Proceed to TEE if clinical suspicion high
and TTE negative
 Trans-esophageal
echocardiogram
 Sensitivity for
vegetations is 95%
 Can repeat in 7-10
days if initial exam
negative
 Especially useful for
detecting prosthetic
valve infection,
abscess, small
vegetation
 Invasive tests
 Skin biopsy
 Lymph node FNAC/biopsy for
 HPE
 AFB culture
 Xpert Mtb
 Bone marrow
 Do if bi-cytopenia or pancytopenia
 Do aspirate, trephine biopsy, Xpert Mtb and culture
 Picked up diagnosis in 24% of which 81% was hematologic
malignancy (Arch Intern Med 2009;169:2018)
 Liver biopsy
 Reserve for patient with LFT abnormalities
 Do under US guidance into lesions if seen
 Ask for both HPE and cultures
 Misleading tests-avoid!
 Widal  Leptospirosis serology
 TB serology  Mantoux
 TB PCR  Interferon gamma
 Throat swab cultures release assay (TB
 ASO titer Feron or Quantiferon
Gold)
 Malaria card tests
 Rapid antigen tests for malaria
 Two types:
 P.falciparum based on histidine rich protein
 P.vivax / P.falciparum based on LDH
 P vivax/P falciparum based on aldolase
 Caveats:
 Can miss low level parasitemia (<10/microliter)
 Remains positive for a month after treatment
 Reasonable if practicing in a situation where
microscopy not available or lab support poor (Am J
Trop Med Hyg 2010;83:1238)

 If good lab and experienced technician available,

MP by QBC technique remains preferred
 Mantoux
 Indicates exposure to M tb, not active disease so
only supports diagnosis of TB in conjunction
with other tests
 Can be false positive due to BCG vaccine and
atypical mycobacteria
 Can be false negative due to anergy
 Once positive, remains so lifelong: do not repeat
or do the test in a patient with past h/o TB
 Interferon gamma release assay (TB Feron or
Quantiferon Gold) just a more accurate Mantoux
 May be helpful in the dd of TB vs sarcoidosis
 Not a diagnostic test for active TB
 Microscopic agglutination test
(MAT) for leptospirosis
► Reference standard serologic test, is technically
challenging and relies on the maintenance of a battery
of live test antigens including all locally common enzootic
strains.
► Laboratory confirmation generally requires
demonstration of seroconversion or a ≥4-fold MAT titer
increase between paired acute- and convalescent-phase
serum specimens.
► Need for paired specimens only allows for delayed result
► WHO recently defined MAT titer of ≥1:400 in a single
serum specimen as significant
► Sensitivity within the first 15 days only 17%
 Leptospirosis diagnosis
► IgM ELISA
► is not detectable until days 5–7 after symptom onset

► sensitivities of <25% for specimens collected during the first

week of illness
► Dark field exam picks up fibrin strands in blood and gives false
positives
► Macroscopic agglutination test highly unreliable
► Sensitivity of the qPCR 51%

► If you think of the diagnosis, start doxycycline

(Clin Infect Dis54:1249-55)

 Therapeutic trials

 Antimalarials
 Antibiotics
 Anti-tuberculous drugs
 NSAID
 Steroids
 Antimalarials

 No role!
 Do 3 successive MP-QBC if malaria
strongly suspected: if negative, malaria
ruled out
 Chloroquine is an anti-inflammatory drug
and will temporarily mask fever and
inflammation
 Antibiotic trials after drawing
blood cultures
 Anti-typhoid therapy if typhoid strongly
suspected (avoid quinolones)
 Doxycycline if scrub/ lepto/ zoonosis
suspected
 Avoid quinolones!
 May mask TB and delay diagnosis
 May not work for typhoid any more
 ATT
 Never give blindly
 Consider when
 Recent family history or close contact with TB
 Clinical or lab findings suggestive but not
confirmatory
 Biopsy not technically possible
 After starting, re-evaluate in 2 weeks: if not
better, stop and continue to look for alternative
diagnosis
 Steroids

 In general, no role
 Consider when a severe auto-immune
disease is strongly suspected but cannot
be documented or classified
 No diagnosis?

 Continue to observe temp chart and

maintain weekly weight record
 Longer the fever
 Diagnosis less likely to be made
 Unlikely to have a serious etiology
 Long term prognosis good
 Case 1
 66/m with fever for 2 mths
 Responds to antibiotics but relapses on stoppage
 Spleen tip palpable
 WBC= 14,000
 UA: 4-6 RBC
 LFT normal
 Echo normal
 Blood & urine cultures: no growth
 What next?

 CT chest
 Bone marrow
 Serum ferritin
 Trans-esophageal echo
 Trial of IV antibiotics
 Case 2

 26/f with fever for 3 weeks

 Recently engaged
 Small lymph nodes in neck, axilla
 WBC=4000 (P34, L55, E4, M7)
 ALT= 128
 HIV negative
 What next?

 Lymph node biopsy

 Bone marrow examination
 ANA
 Trial of therapy for typhoid
 EBV VCA IgM
 Case 3

 22/f with intermittent fever for 6 mths

 Occasional arthralgia in fingers and wrists
 Occasional oral ulcers
 Pain in left chest on deep breathing
 CXR normal
 WBC=4000
 Significant neck nodes bilaterally
 What next?

 Biopsy the node

 CT chest
 RA factor
 ANA
 Trial of ATT
 Case 4

 40/m with fever, wt loss of 6 kg and

increased bowel movements for 2 mths
 Appetite good
 Mantoux 14 mm
 CBC and LFT normal
 CT chest and abdomen normal
 What next?

 ATT trial
 Echo
 PET scan
 Course of antibiotics for typhoid
 TSH
 14 year old girl
 Fever for 10 days, high  WBC=15,000
grade, continuous  Platelets=95,000
 Myalgia, headache,  ALT=78, AP=800,
vomiting Bilirubin=3.8 (d=3.0)
 Had gone to visit family  MP negative
in rural AP 3 weeks  Blood and urine
ago, was playing cultures negative
outdoors with relations
 No response to cefixime  CXR/US normal
for presumed typhoid
 Exam: rash, icteric
Eschar of scrub typhus
 15 year old boy
 Fever for 6 weeks  Hb=9.8, WBC=4500
 Low grade, increased in  ESR=77
evening, wt loss  Mantoux negative
 Slight cough  CXR twice/US normal
 Improved on ofloxacin  ALT normal, AP=900,
for possible typhoid but bili normal
again febrile  Sputum AFB negative
 Travelled to Gujarat for  Widal O titer positive 1:
2 weeks before onset of 160
illness
 Exam: normal
Miliary TB
 35 year old male
 Fever for 4 weeks,  Hb=9.2
intermittent, upto 104  WBC count=17,000
 Transient rash at time  ALT=80, ESR=96
of fever  MP negative
 Well in between  CXR/US normal
episodes of fever
 Widal positive H titer
 Arthralgia 1:80
 Exam normal except  Blood cultures: no
for pallor growth
 Diagnosis?

 Serum ferritin=6082

 Adult onset Still’s disease

 In summary

 Fever < 3 days requires minimal or no

testing and no antibiotics
 CBC and LFT very useful in directing
investigation in FUO
 Avoid empiric antibiotics unless typhoid
strongly suspected
 Avoid empric antimalarials and steroids
 TB remains the commonest cause of FUO
Are you an MD/DNB (Internal Med)
interested in an ID career?
 DM (Infectious Diseases)
 CMC, Vellore and AIIMS, New Delhi
 FNB (National Board of Examinations):
◦ Two year fellowship

◦ Apollo Hospitals, Chennai

◦ For details go to NBE website

 Tamil Nadu Dr. MGR Medical University:

◦ Two year fellowship

◦ Apollo Hospitals, Chennai and CMC, Vellore

◦ Contact institutions for details