CASE PRESENTATION : PYREXIA OF UNKNOWN ORIGIN / Hemophagocytic lymphohistiocytosis /

PYREXIA OF UNKNOWN ORIGIN / Hemophagocytic lymphohistiocytosis / CASE PRESENTATION

1. Case Presentation
By :DR DarayusP. Gazder
PG-R1

2. History:
•A 71 year old married male, resident of Quetta, Ex-Chief of
education admitted on 24
th
July 2018 via the emergency
presenting with Complains of:
•Fever since 2 months
•Associated with Headaches

3. History of Presenting Complains
•My patient is an Ex-smoker, newly diagnosed Diabetic was in his usual
state of health about two months ago, when he developed Fever. It was
sudden in onset, high grade, continuous associated with rigors and
chills. It was documented at 102 to 103F and relieved by antipyretics.
According to him fever was in the morning. He was also having night
sweats.
•Fever was associated with headaches more on the temporal and
occipital areas. According to him it felt like a continuous bilateral
pressure like heaviness, he rated the pain as mild to moderate. It was
not associated with any ear discharge, rhinorrhea, visual disturbances,
jaw claudication ,neck stiffness, vomiting, nausea or LOC.

4. System Review
Respiratory System
•Cough:PRESENT(DRY)
•Sputum
•Haemoptysis
•Chest pain
•SOB/Dyspnoea
•Hoarseness
•Wheezing
Cardiovascular
•Chest pain
•Paroxysmal Nocturnal Dyspnoea
•Orthopnoea
•Short Of Breath(SOB)
•Palpitations
•Cyanosis
Gastrointestinal/Alimentary
•Appetite: Decreased
•Oral ulcers
•Nausea/vomiting
•Difficulty in swallowing
•Abdominal pain/distension
•Regurgitation/heart burn
•Haematemesis, melaena,
haematochagia
•Jaundice
Nervous System
•Visual/Smell/Taste/Hearing
Speech problem
•Head ache
•Fits/Faints/LOC
•Muscle weakness
•Abnormal sensation
•Change of behaviour
-ve
-ve
-ve
-ve

5. System Review
Urinary System
•Frequency
•Urgency
•Hesitancy
•Terminal dribbling
•Nocturia
•Back/loin pain
•Incontinence
•Character of urine
Musculoskeletal System
•Pain
•Swelling
•Back or neck pain
•Red eyes
•Deformities
•Skin rash
•Painful/ cold fingers
Endocrine System
•Swelling in neck
•Fatigue
•Thirst
•Sweating
•Tremors
-ve
-ve
-ve
HEMATALOGICAL System
•Bruises
•Epistaxis
•Lumps
•Gum bleeding
-ve

6. Past Medical History:
-Cataract in the Right eye, as a child due to trauma to the eye.
-He was diagnosed as a Diabetic recently. NO PREVIOUS ADMISSIONS.
-Developed a swelling around the nose and face that was resolved by
oral antibiotic treatment for 5days in January 2018.
Past Surgical History:
No H/o Surgery or invasive procedures. No H/o blood transfusions
Drug history:
No Known Drug Allergies / TAB METFORMIN 500MG BD
Family history:
Parents were healthy. He has 1 brother and 2 sisters all are healthy. No history
of Ischemic heart disease, tuberculosis, asthma, thyroid disorders,
autoimmune diseases or cancers in the family

7. Personal History:
Smoked on/off at least 2 cigarettes/day for about 30 years. Has
Stopped smoking since the last 5 years. No other addictions.
Sleep: Normal / Bowel: Normal / Micturition: Normal / Appetite: Dec/
Energy Levels: Low / Weight loss: Present
Travel History:
•Stayed in Thailand for 6 months as a government trainee (1988)
•3 Hajtrips in 1992, 2005, 2013 (Was vaccinated at the time)
•Multiple trips to Karachi to meet his son
Social History:
He is a resident of Quetta, affluent lives in the city center in a large
well ventilated bungalow with 6 people. Married since 45 years. He was
working in the government and was Chief of education Balochistan. Is
now retired since the last 18 years. He enjoys gardening and is always
active at home. Drinks boiled water and eats mostly meals cooked at home. He
did drink a glass of raw milk daily since many years. No contact history of
tuberculosis. No pets or birds in his house.

8. Examination:
•General Impression:
A 71 year old male of average built lying on bed, with cataract in
the right eye, alert, cooperative and oriented.
Vitals:
•Blood Pressure:130/90 mm/Hg
•Pulse: 76/min, regular, equal in both arms
•Temperature: A/F
•Respiratory Rate:16/min
•Oxygen saturation: 96% room air
Weight 54kg , Height: 170cm BMI: 18.6 kg/m2

9. Examination:
HEENT:
•Normocephalic, atraumatic, no bruises
•Nose, mouth,pharynx,earsWNL
•EYE: Right eye cataract, Non reactive to light (Blind), Left eye VA:6/6, reactive to light, EOMI
NECK:
•Supple, no lymphadenopathy, No JVD, swelling in neck or carotid bruit
HEART:
•Normal S1 and S2, no murmurs, rubs or gallops.
CHEST:
•No tenderness, clear breath sounds bilaterally, no rales, wheezes or ronchi, trachea central, tactile fremitus
normal.
ABDOMEN:
•Soft, non distended, non tender, +bowel sounds, no organomegaly.
NEURO:
•Mental status: alert, Cranial nerves:Intact, Motor: 5/5 upper and lower extremities. Sensory: intact to touch and
pinprick. DTRs: 2+ symmetric in upper and lower extremities, -babinski. Cerebellar: Intact
EXTREMITIES:
•No clubbing, cyanosis or edema. Pulses 2+ and symmetric. No tremors.
MUSCLOSKELETAL:
•No warmth or erythema, no tenderness, normal range of motion, motor/sensory/reflexes, pulsations
LYMPHNODES:
•Axillary, Groin were not palpable.
RASH:
•Scales were noted on ankles, No pigmentation, or jaundice noticed at the time.

10. Differentials??
•Infection: Tuberculosis / Abscess / Enteric Fever / Brucellosis
/ Leishmaniasis
•Malignancy: Lymphoma / Leukemia / Myeloma
•Collagen vasculardisease: Giant cell arteritis /
PYREXIA OF UNKNOWN ORIGIN

11. PREVIOUS INVESTIGATIONS:

12. •Had shown a Neurologist in Karachi-12 days before admission, had advised
CT and MRI Scan brain AND labs
•Age related involutionalchanges along with bilateral white matter
ischemic changes
•Labs
18/JUL
Treated as a case of Enteric Fever VS URTI and was told to start:
1)CAP CEFIXIME 400MG BD FOR 7DAYS
2) TAB CLARITHROMYCIN 500MG BD FOR 5DAYS
BLOOD CS: NO GROWTH / THROAB SWAB: NO GROWTH
12.4
37.4
2.52
N:73,L:25
284
ESR:90
CRP:23.16
HbA1c:7.3
TB:0.64
DB:0.38
SGPT:35
AST:69
GGT:104
ALKPO4:270

13. TREATMENT AND HOSPITAL
COURSE:
•He was started on:
•IV FLUIDS
•TAB METFORMIN 500mg 1+0+1 / INSULIN S/S
•InjPanadol SOS / Sponging
•Further investigations were sent:
•1) CBC,UCE,LFT,AMYLASE,LIPASE, HBsAg, Anti-HCV, MP/ICT
•2) CXR, ECG
•WORKING DIAGNOSIS: Pyrexia of Unknown origin / ENTERIC FEVER?

14. Hospital Admission
Day 1-2
S> MULTIPLE FEVER SPIKES, ASSOCIATED WITH RIGORS
O> Awake, Alert, ORIENTED
CBC UNIT RANGE
Hb 10.7 10.9 mg/dl 11.1-14.5
MCV 89 90 fL 80-100
MCH 31 32 Pg 27-34
WBC 2.3 1.9 10
9per liter 4 to 10
PLATELETS 269 280 10
9
per liter 150-450
NEUT 81 87
LYMP 17 10
UCE
Na 133 137 Meq/L 135-145
K 3.4 3.8 Meq/L 3.5-5.5
CL 97 101 Meq/L 98-107
HCO3 22 24 Meq/L 22-29
UREA 38 35 mg/dl 10 to 50
CREATININE 0.76 0.7 mg/dl 0.6-1.5
LFT
TB 1.28 mg/dl <1.3
DB 0.84 mg/dl <0.3
SGPT 83 IU/L Upto 31
ALK P 455 U/L 39-117
GGT 237 IU/L 11 to 50

15. CXR

16. Hospital Admission
Day 1-2
A> RESISTANT ENTERIC FEVER?
>Malignancy
>Liver Abscess
>Tuberculosis
P> INJ MEROPENEM 1G 1+1+1
> TAB AZOMAX 500MG 1+0+0
> INJ FLAGYL 1+1+1
> INJ FOLINIC ACID
> IV FLUIDS
> TAKE ALL UNIVERSAL PRECATIONS
> FURTHERMORE SEND IHA LEVELS, ESR, GET US W/ABDOMEN

17. Hospital Admission
Day 3-4
S> Developed Cough at night, Suddenly short of breath
Was unable to stand when he went to the Bathroom,
Saturation at the time was 88% on room air and was taken on 3L supplemental Oxygen.
O> Awake, Alert, Fever still was present
> Vitals: FEVER 3 SPIKES (Range was 101-102) (Early Morning) / O/E:Normal
INVESTIGATIONS
ESR>100 / PT:13.8, INR:1.22/ HEP B, C PROFILE:-VE / MP: WAS NOT APRECIATED /
Urine DR: N / IHA FOR EntameobahistolticaWAS ABSENT
US WHOLE ABDOMEN: NORMAL
CBC UNIT RANGE
Hb 11 9.4 mg/dl 11.1-14.5
WBC 2 1.7 10
9
per liter4 to 10
NEUT 85 88
LYMP 12 10

18. A> RESISTANT ENTERIC FEVER
> Malignancy
> HIV?
> Connective tissue disorder
P> Continue previous treatment
> If no improvement/Response to treatment in 48hours then get a
Bone marrow biopsy (5
TH
ADMISSION DAY BIOPSY WAS DONE)
> Send ANA levels

19. Hospital Admission
Day 5-9
S> MULTIPLE FEVER SPIKES, ASSOCIATED WITH RIGORS
O> Awake, Alert, ORIENTED
DAILY HAD FEVER SPIKES, WITH NIGHT SWEATS / O/E: B/L HVB
1MORE EPISODE OF DESATURATION WITH TACHYCARDIA ON THE 9
TH
PAD, ECG TROP-I
WERE –VE
•ANA: WEAK POSITIVE
•ANC (DAY 5): 1.3X10^9 ----------------ANC (DAY 8): 0.85X10^9
•Blood and Urine C/S: No growth
•Retic count:0.8 / Corrected:0.55
DAY 5 6 7 8 9
CBC UNIT RANGE
Hb 10.1 10.6 12 mg/dl 11.1-14.5
WBC 1.6 1.7 1.3 1.1 2.2 10
9per liter4 to 10
NEUT 85 86 77 88
LYMPH 11 11 19 10
LFT
TB 1.46 2.32 2.74 mg/dl <1.3
DB 1.19 1.99 2.29 mg/dl <0.3
SGPT 42 50 53 IU/L Upto 31
ALK P 486 533 544 U/L 39-117
GGT 275 279 279 IU/L 11 to 50

20. A> PYREXIA OF UNKNOWN ORIGIN?
P> Continue previous treatment
> INJ FILGRASTIM (8
TH
PAD)
> Send c-ANCA, p-ANCA, Serum Protein electrophoresis
>INJ VANCOMYCIN 1GM BD WAS STARTED from 9
th
PAD
> Send ENA profile, BRUCELLA ANTIBODIES
>Plan CT Scan Whole Abdomen with IV and oral contrast
>Send Sputum Gene X-pert / AFB C/S

21. CT SCAN ABDOMEN WITH IV AND ORAL CONTRAST
VISUALIZED LUNG BASES SHOW MILD BILATERAL PLEURAL EFFUSION AND A PATCH OF
CONSOLIDATION SEEN IN LEFT LOWER LOBE. MINIMAL CHOLECYSTIC FLUID IS
APPRECIATED WITH FEW SMALL LYMPH NODE IN PORTA HEPATIS WHICH IS LIKELY TO BE
NON SPECIFIC. GALLBLADDER WAS NORMAL WITHOUT CHOLELITHIASIS

22. CXR

23. Hospital Admission
Day 10-13
S> MULTIPLE FEVER SPIKES, ASSOCIATED WITH RIGORS
O> Awake, Alert, ORIENTED
> HAVING COUGH, 1 FEVER SPIKE ON DAY 11, THEN NO MORE FEVER SPIKES
> STARTED FEELING BETTER OVERALL
> From Day 10 to 13 SCLERAL ICTERUS was present
C-ANCA, P-ANCA: -VE / URIC ACID 2.18 / ENA profile and Brucella Antibodies: ABSENT
AFB SMEAR:-VE
SERUM PROTEIN ELECTROPHORESIS: REVEALS MILD DECREASE IN ALBUMIN ALONG WITH INCREASE IN ALPHA 1 AND
DIFFUSE INCREASE IN GAMMAGLOBULIN REGION RESULTING IN DECREASE A/G RATIO WHICH COULD POSSIBLY BE
SEEN IN CHRONIC CONDITIONS LIKE CHRONIC INFLAMMATORY CONDITIONS CONNECTIVE TISSUE DISORDERS.
CHRONIC DISEASE OF LIVER AND KIDNEY ETC. NO EVIDENCE OF PARAPROTEIN SEEN.
•INITIAL BONE MARROW BIOPSY:SHOWED A SUSPICION OF GRANULOMA (DAY 10)
DAY 10 11 12 13
CBC UNIT RANGE
Hb 11 10.5 10.9 10.4 mg/dl 11.1-14.5
WBC 1.4 2.4 3.1 3.2 10
9per liter4 to 10
NEUT 90 94 96 77
PLATELETS157-->118 130 115 105 10
9
per liter150-450
LFT
TB 3.43 2.32 mg/dl <1.3
DB 3.09 1.99 mg/dl <0.3
SGPT 42 50 IU/L Upto 31
ALK P 513 533 U/L 39-117
GGT 187 279 IU/L 11 to 50

24. A> TUBERCULOSIS
> Malignancy
P> ATT WAS INITIATED, WITH VIT B6 ON THE 10
TH
DAY OF
ADMISSION
> HIV WORKUP WAS ALSO SENT
> Azithromycin Course was completed
> INJ AMIKACIN WAS STARTED From day 10 onwards
> INJ Hydrocortisone 100mg,IV 8hrly from Day 11 was also
started

25. Hospital Admission
Day 14-15
S> MULTIPLE FEVER SPIKES, ASSOCIATED WITH RIGORS
O> Awake, Alert, ORIENTED, IRRITATED, O2 sat:88-94% on room air
AFB SMEAR:ABSENT / ANTI HIV (CMIA) AND HIV CORE WERE ABSENT
SGOT: 184 / PT:14.6(11 to13.5) / APTT:35.5 (30 to 45) / INR:1.33 / Albumin:1.87
Day 14: Initial biopsy showed Lymphocytic aggregates, work-up for HLH was
sent.
DAY 14 15
CBC UNIT RANGE
Hb 10 10.5 mg/dl 11.1-14.5
WBC 2.7 2.1 10
9
per liter 4 to 10
NEUT 93 94
PLATELETS 85 110 10
9
per liter 150-450
LFT
TB 3.43 mg/dl <1.3
DB 3.14 mg/dl <0.3
SGPT 88 IU/L Upto 31
ALK P 755 U/L 39-117
GGT 272 IU/L 11 to 50

26. Fever (peak temperature of>38.5°C for>7 days) PRESENT
Splenomegaly (spleen palpable>3 cm below costal
margin) ABSENT
Cytopeniainvolving>2 cell
lines
Hb<9 g/dL */-
ANC<1X10^9 0.85 PRESENT
PLT<100,000/μL 85-110 PRESENT
Hypertriglyceridemia >256mg/dl 303 PRESENT
OR Hypofibrinogenemia Fibrinogen<1.5 g/L 1.4 PRESENT
Hemophagocytosisin BM, Spleen,LN ABSENT
Low NK cells
NOT
CHECKED
Serum ferritin>500μg/L 8525 PRESENT
Elevated soluble interleukin-2 (CD25) levels
NOT
CHECKED
HLH CRITERIA:
Fiveof these8
criteriaare required
for diagnosis

27. A> HLH SECONDARY TO??
P> ATT WAS STOPPED AS LFT’S WERE GETTING
DERRANGED.
> INJ HYDROCORTISONE (HOLD)
>INJ DEXAMETHASONE 10MG IV 6HOURLY (START FROM
Day 15)
> AWAIT FINAL BIOPSY REPORT
ATTENDANTS WANTED A SECOND OPINION FROM
ANOTHER TERTIARY CARE HOSPITAL AND PATEINT
WAS DISCHARGED ON REQUEST

28. BM BIOPSY

30. NEW Definition
Temperatures ≥ 38.3ºC (101ºF) onseveral occasions
Fever ≥ 3weeks
Failure to reach a diagnosis despite one week of
inpatient investigations or 3 outpatientvisits.
1)Mandell's Principles and Practices of Infection Diseases6th Edition (2004) by
Gerald L. Mandell MD, MACP, John E. Bennett MD, Raphael Dolin
MD,ISBN0-443-06643-4· Hardback · 4016 Pages Churchill Livingstone
2) Harrison's Principles of Internal Medicine18th Edition

31. Classification ofPUO
Category Definition Aetiologies
Classic •Temperature >38.3°C (100.9°F);
•Duration of >3weeks
•Evaluation of at least 3outpatient
visits or 3 days inhospital
•Infection
•Malignancy
•collagen vasculardisease
•Miscellaneous
•Undiagnosed
Nosocomial •Temperature>38.3°C
•Patient hospitalized ≥ 24 hoursbut
no fever or incubating onadmission
•Evaluation of at least 3days
•Clostridium difficileenterocolitis
•drug-induced
•pulmonaryembolism
•septicthrombophlebitis,
•sinusitis
Neutropenic•Temperature>38.3°C
•Neutrophil count ≤ 500 permm3
•Evaluation of at least 3days
•Opportunistic bacterialinfections,
•aspergillosis,
•candidiasis,
•herpesvirus
HIV-
associated
•Temperature>38.3°C
•Duration of >4 weeks for
outpatients, >3 days forinpatients
•HIV infectionconfirmed
•Cytomegalovirus,
•Mycobacteriumavium-intracellulare
complex,
•Pneumocystis cariniipneumonia,
•drug-induced,
•Kaposi’s sarcoma,lymphoma
Harrison's Manual of Medicine, 19e

32. Infection(40%)
Malignancy
(25%)
Autoimmune
Disease(15%)
Others/
Miscellaneous
(10%)
CLASSIC CAUSES:
(10%)
Undiagnosed
Harrison's Manual of Medicine, 19e

33. ClassicPUO
3 common etiologies which account for the
majority of classicPUO:
Infections
Malignancies
Collagen VascularDisease
Others/Miscellaneous which includes drug-induced
fever.
Harrison's Manual of Medicine, 19e

34. Infections
Bacterial: abscesses, TB, complicated UTI,
endocarditis, osteomyelitis, sinusitis, Lyme
disease, prostatitis, cholecystitis,empyema,
biliary tract infection, brucellosis, typhoid,
leptospirosis,
Q fever,
Parasite: Malaria, toxoplamosis, leishmaniasis,
etc.
Fungal: histoplasmosis,etc.
Viral: CMV, infectious mononucleosis, HIV,etc.

35. Infections
As duration of fever increases, infectious etiology
decreases
Malignancy and factitious fevers are more common
in patients with prolongedFUO.
Harrison's Manual of Medicine, 19e
*Naproxen sodium 250 mg is given orally every 8 hours for 3 days

36. Malignancies
Haematological
Lymphoma
Chronicleukemia
Non-haematological
Renal cellcancer
Hepatocellularcarcinoma
Pancreaticcancer
Colon cancer
Hepatoma
Harrison's Manual of Medicine, 19e

37. Collagen vascular disease/
Autoimmunedisease
Polyarteritisnodosa
Giant cellarteritis
Kawasakidisease
Adult Still'sdisease
Polymyalgiarheumatica
Temporalarteritis
Rheumatoidarthritis
Rheumaticfever
Inflammatory boweldisease
Reiter'ssyndrome
Systemiclupus
erythematosus
Harrison's Manual of Medicine, 19e

38. Others/miscellaneous
Drugs: penicilin, phenytoin, captopril, allopurinol,
erythromycin, cimetidine,etc.
Hyperthyroidism
Alcoholichepatitis
Inflammatory boweldisease
Deep VenousThrombosis
Harrison's Manual of Medicine, 19e

39. Roth AR and Basello GM. Am Fam Physician. 2003 Dec1;68(11):2223-8.

40. NosocomialPUO
More than 50% of patients with nosocomial PUOare
due to infection.
Focus on sites where occult infections may be
sequestered, suchas:
-Sinusitis of patients with NG or oro-trachealtubes.
-Prostatic abscess in a man with a urinarycatheter.
25% of non-infectious causeincludes:
-Acalculouscholecystitis,
-Deep veinthrombophlebitis
-Pulmonaryembolism.
Harrison's Manual of Medicine, 19e

41. NeutropenicPUO
Patients on chemotherapy or immune deficiencies
are susceptibleto:
-Opportunistic bacterialinfection
-Fungal infections such ascandidiasis
-Bacteremicinfections
-Infections involvingcatheters
-Malignancy
Examples of aetiologicalagent:
-aspergillus
-Candida
-CMV
-Herpessimplex
Harrison's Manual of Medicine, 19e

42. HIV-associatedPUO
HIV infection alone may be a cause of fever.
Common secondary causes include:
-Tuberculosis
-Toxoplasmosis
-CMV infection
-P. carinii infection
-Salmonellosis
-Cryptococcosis
-Histoplasmosis
-Non-Hodgkin's lymphoma
-Drug-induced fever
Harrison's Manual of Medicine, 19e

43. Harrison's Manual of Medicine, 19e

44. Stage 1:Laboratory
investigations
Stage 1:(screening
tests)
1.Full blood count
2.ESR & CRP
3.UCE
4.LFTs
5.Blood culture
6.Serum virology
7.Urinalysis and
culture
8.Sputum culture and
sensitivity
9.Stool culture/
occult blood
10.CXR
11.Mantoux test
Harrison's Manual of Medicine, 19e

45. Stage 2:
1.Repeat historyand
examination
2.Protein
electrophoresis
3.CT (chest,abdomen,
pelvis)
4.Autoantibody screen
(ANA, RF, ANCA,
anti-dsDNA)
5.ECG
Stage 2: Laboratoryinvestigations
6.Bone marrow
examination
7.Lumbar puncture
8.Consider PSA,
CEA
9.Temporal artery
biopsy
10.HIV testcounselling
Harrison's Manual of Medicine, 19e

46. •Stage3:
1.Echocardiography
2.Further Ixabdomen
( scan –IBD,
abscesses, local
sepsis)
3.Bariumstudies
4.IVU
5.Liverbiopsy
Stage 3: Laboratoryinvestigations
6.Exploratory
laparotomy
7.Bronchoscopy
Harrison's Manual of Medicine, 19e

47. Treat TB,
endocarditis,
vasculitis,
trial of aspirin/ steroids
Stage 4: Laboratoryinvestigations
Harrison's Manual of Medicine, 19e

48. Diagnosing
Pyrexiaof
Unknown
Origin

49. ImagingStudies
•Tuberculosis, malignancy, Pneumocystis cariniipneumoniaChestradiograph
•Abscess,malignancy
CT of abdomen or pelvis with contrast
agent
•Infection,malignancyGallium 67scan
•OccultsepticemiaIndium-labeledleukocytes
•Acute infection and inflammation of bones and softtissueTechnetium Tc99m
•Malignancy, autoimmuneconditionsMRI ofbrain
•Malignancy,inflammationPETscan
•Bacterialendocarditis
Transthoracic ortransesophageal
echocardiography
•VenousthrombosisVenous Dopplerstudy

51. Hemophagocytosis
Phagocytosis by macrophages oferythrocytes,
leukocytes, platelets, and their precursors in bone
marrow and othertissues
HemophagocyticLymphohistiocytosis
Uncommon, life-threatening hyperinflammatory syndrome caused bysevere
hypercytokinemiaduetoahighlystimulatedbutineffectiveimmuneprocess

52. Primary(Genetic)
•FamilialHLH
–Known genedefects
•PFR1
•UNC13D
•STX11
–Unknown genedefects
•Immune deficiencysyndromes
–Chediak-Higashisyndromes
Secondary(Acquired)
•Infections
•Autoimmune
•Malignantdiseases
•Immunosuppression/
Organtransplantation
JankaG.(2009).“Hemophagocyticlymphohistiocytosis:whentheimmunesystemrunsamok”KlinPadiatrSep;221(5):278-85.
•PrimaryHLH
restrictedtoyoung
age(80%-presents
in <1 yearold)
•In adults, almost all
casesare secondary

55. Source:“Verbsky,J.W.,&Grossman,W.J.(2006).Hemophagocyticlymphohistiocytosis:diagnosis,pathophysiology,treatment,and
future perspectives. Annals of medicine, 38(1),20-31.”

56. Infections
Autoimmunedisorders
Malignancy
Immunosuppression/
Organtransplant
1
2
3
4

57. 1) Infections
-Viruses –Epstein-Barr Virus, Cytomegalovirus,
Parvovirus, Herpes simplex,Varicella-zoster,
measles, HHV-8, HIVinfection
-Bacteria –Brucella, Gram neg bacteria, Tuberculosis
-Parasites –Leishmaniasis
-Fungi

58. 2) Autoimmunedisorders
AlsoknownasMacrophageActivationSyndrome(MAS)
-LupusErythematosus
-Rheumatoidarthritis
-Still’sdisease
-Polyarteritisnodosa
-Mixed connective tissuedisorders
-SystemicSclerosis

59. 2
Infections
Autoimmunedisorders
Malignancy
-Leukemias
-Lymphomas
3
1

60. 3
4
Infections
Autoimmunedisorders
Malignancy
Immunosuppression/
Organtransplant
-Post-Chemotherapy
-After Renal or livertransplant
-Immunosuppressivetreatment
1
2

61. •Commonfindings
–Prolongedfever
–Hepatosplenomegaly
–Neurologic symptoms –seizures, cranial nerve
palsies
•Less commonfindings
–Lymphadenopathy
–Rash
–Jaundice

62. 100
90
80
70
60
50
40
30
20
10
0
91%90%
84%
47%43%42%
Source:“HenterJIetalIncidenceinSwedenandclinicalfeaturesoffamilialhemophagocyticlymphohistiocytosis.
Acta Paediatr Scand1991;80:428”

63. •Cytopenias
–Anemia and thrombocytopenias are morecommon
–Mechanism–
•Suppression by TNF-α andINF-γ
•Consumption byhemophagocytosis

64. •Cytopenias
•Tissue demonstration ofHemophagocytosis
–Repeated attempts needed to identifycharacteristic
histology
–Lymphnodebiopsyorbonemarrowaspirates

65. •Cytopenias
•Tissue demonstration ofHemophagocytosis
•ElevatedFerritin
–Canincreaseoverarangeofseveral10000ug/Lwithin
several hours inHLH
–Mechanisms –multiple hypotheses
•Passive release due to celldamage
•Increasedsecretionbymacrophagesandreleaseduring
erythrophagocytosis
•Increased ferritin gene expression byTNF-α
–Ferritin >500μg/L : Sensitivity 82%, Specificity42%
–Ferritin >10,000 μg/L : Sensitivity 90%,Specificity 96%

66. •Cytopenias
•Tissue demonstration ofHemophagocytosis
•ElevatedFerritin
•Elevatedtriglycerides
–Mechanism -Increased TNF-α suppress activity of
lipoproteinlipase
-Liver enzyme levels greater than three times the upper limit have
been reported in 50 to 90 percent of patients with HLH , LDH is
elevated in 85 percent.
-Bilirubinlevels between 3 and 25 mg/dLare seen in greater than 80
percent. The GGT level is an especially sensitive number to follow
because of biliary tract infiltration by lymphocytes and
macrophages
Jordan MB, Allen CE, Weitzman S, et al.
How I treat hemophagocytic
lymphohistiocytosis. Blood 2011;
118:4041.

67. •Cytopenias
•Tissue demonstration ofHemophagocytosis
•ElevatedFerritin
•Elevatedtriglycerides
•DepressedFibrinogen
–Mechanism -Increased levels of Plasminogen activator
secreted by activatedmacrophages
Source:Henter,Jan‐Inge,AnnaCarinHorne,MauLadischetal."HLH‐2004:Diagnosticand
therape2(2006):124-131.

68. •InHLH-94,diagnosiswasbasedon5five
criteria.
•In HLH-2004, three additional criteria
added, making it total 8criteria.

69. Fever (peak temperature of>38.5°C for>7 days) PRESENT
Splenomegaly (spleen palpable>3 cm below costal
margin) ABSENT
Cytopeniainvolving>2 cell
lines
Hb<9 g/dL */-
ANC<1X10^9 0.85 PRESENT
PLT<100,000/μL 85-110 PRESENT
Hypertriglyceridemia >256mg/dl 303 PRESENT
OR Hypofibrinogenemia Fibrinogen<1.5 g/L 1.4 PRESENT
Hemophagocytosisin BM, Spleen,LN ABSENT
Low NK cells
NOT
CHECKED
Serum ferritin>500μg/L 8525 PRESENT
Elevated soluble interleukin-2 (CD25) levels
NOT
CHECKED
HLH CRITERIA:
Fiveof these8
criteriaare required
for diagnosis

70. HLH
Moleculardiagnosis
e.g PRF mutations,
SAPmutations
5 out of 8diagnostic
criteriafulfilledor
•Ifpatientmeetsonly4criteriaandclinicalsuspicionfor
HLHishigh,onemustinitiateappropriatetreatment
HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic
lymphohistiocytosis.

71. •Until1994,HLHtherapyineffectivewith90%fatalities
•HLH-94
–First international study onHLH treatment
–Included combination of chemotherapy,immunotherapy
and steroids as well as antibiotics and antiviral drugs
followed by stem celltransplant
–Twophases–Initialphase(8weeks),Continuationphase
–Survivalrate–55%atmedianfollow-upof3.1years
•HLH-2004
–CyclosporineAstartedattheonsetoftherapyinsteadat
week9

72. Immediategoals
Long termgoals

73. Immediate
goals
Suppress the severeinflammation
•Steroids –Dexamethasone
•CyclosporineA
•Intrathecal Methotrexate, hydrocortisone (patients withpersistent
active CNSdisease)
Kill the over-stimulated Antigen-PresentingCells
•Etoposide(VP-16)
Treat the triggering agent (infection, neoplasmetc.)
•Antibiotics,Antivirals
Supportivetherapy
•Prophylactic Cotrimoxazole, oralanti-mycotic
•Gastroprotection -Ranitidine
Source:Henter,Jan‐Inge,AnnaCarinHorne,MauLadischetal."HLH‐2004:Diagnosticandtherape2
(2006):124-131.
Alemtuzumab

75. Lon
g
-
t
erm
g
oal
Replace the defective immunesystem
•Allogenic Hematopoietic Stem CellTransplantation
•Best overall cure rate inHLH
•Neededfor
•Patients with genetic mutations diagnosedor
familyhistory
•Patientswhorespondedpoorlywithinitial
eight weeks ofchemotherapy
•Patients with CNSdisease
Source:Henter,Jan‐Inge,AnnaCarinHorne,MauLadischetal."HLH‐2004:Diagnosticandtherape2
(2006):124-131.

76. rizioAricó,R. MaartenEgeler,AlexandraH.Filipovich,ShinsakuImashuku,Stephan
uticguidelinesforhemophagocyticlymphohistiocytosis."Pediatricblood&cancer48,no.
Source:Henter,Jan‐Inge,AnnaCarinHorne,Mau
Ladischetal."HLH‐2004:Diagnosticandtherape
2(2006):124-131.
Dexamethasone
10 mg/m
2
per day for first twoweeks 5
mg/m
2
per day for week 3and 4
2.5 mg/m
2
per day for week 5 and6
1.25 mg/m
2
per day for week7
Tapering to zero over the 8
th
week
Etoposide(VP-16)
150mg/m
2
i.v. twice weekly for first two weeks
150mg/m
2
i.v. once weekly for next 6weeks
CyclosporineA
•Start with 6mg/Kg daily (2 divided doses) , aimat 4
levels around 200 μg/L (Troughlevel)
IntrathecalMethotrexate
12mgonceweeklyforpt>3yroldforfourweeks
(week 3 to week6)

77. :Henter,Jan‐Inge,AnnaCarinHorne,MaurizioAricó,R.MaartenEgeler,AlexandraH.Filipovich,ShinsakuImashuku,Stephan
etal."HLH‐2004:Diagnosticandtherapeuticguidelinesforhemophagocyticlymphohistiocytosis."Pediatricblood&cancer48,no.
): 124-131.
Dexamethasone pulse every second week, 10 mg/m
2
for 3days
Etoposide 150 mg/m2 every secondweek
CyclosporineA–aimforbloodlevelsaround200μg/L,MonitorGFR
Allogenic Hematopoietic Stem CellTransplantation
Source:Henter,Jan‐Inge,AnnaCarinHorne,MauLadischetal."HLH‐2004:Diagnosticandtherape2
(2006):124-131.

78. •Other treatmentapproaches
–Antithymocyteglobulin
–IvIG
–Rituximab (EBV associatedHLH)
–HIT-HLH trial –A combined use of ATG, Etoposide,
Intrathecal methotrexate and Hydrocortisone is
currently understudy.

79. PROGNOSIS
•The prognosis is guarded with an overall mortality of 50%. Poor
prognostic factors included:
HLH associated with malignancy, with half the patients dying by 1.4
months compared to 22.8 months for non-tumourassociated HLH
patients.
•Secondary HLH in some individuals may be self-limited because
patients are able to fully recover after having received only
supportive medical treatment (IV immunoglobulin only).
•However, long-term remission without the use of cytotoxic and
immune-suppressive therapies is unlikely in the majority of adults
with HLH and in those with involvement of the CNS