PYREXIA OF UNKNOWN ORIGIN / Hemophagocytic lymphohistiocytosis / CASE PRESENTATION

1. Case Presentation
By :DR Darayus P. Gazder
PG-R1

2. History:
• A 71 year old married male, resident of Quetta, Ex-Chief of
education admitted on 24th 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 Haj trips 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,ears WNL
• 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 vascular disease: 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 involutional changes 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
• Inj Panadol 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
Day1-2
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 1.9 109 per liter 4 to 10
PLATELETS 269 280 109 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
Day1-2
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
Day3-4
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 Entameoba histoltica WAS ABSENT
US WHOLE ABDOMEN: NORMAL
CBC UNIT RANGE
Hb 11 9.4 mg/dl 11.1-14.5
WBC 2 1.7 109 per liter 4 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 (5TH ADMISSION DAY BIOPSY WAS DONE)
> Send ANA levels

19. Hospital Admission
Day5-9
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 9THPAD, 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 2.2 109 per liter 4 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 (8TH PAD)
> Send c-ANCA, p-ANCA, Serum Protein electrophoresis
>INJ VANCOMYCIN 1GM BD WAS STARTED from 9th 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. CTSCAN 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
Day10-13
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 PROTEINELECTROPHORESIS: REVEALSMILD DECREASE IN ALBUMIN ALONG WITH INCREASE IN ALPHA 1 AND
DIFFUSE INCREASE IN GAMMAGLOBULINREGIONRESULTING IN DECREASE A/G RATIO WHICH COULD POSSIBLY BE
SEEN IN CHRONIC CONDITIONS LIKE CHRONIC INFLAMMATORY CONDITIONSCONNECTIVE TISSUE DISORDERS.
CHRONIC DISEASE OF LIVERAND KIDNEY ETC. NO EVIDENCE OF PARAPROTEINSEEN.
• 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 3.2 109 per liter 4 to 10
NEUT 90 94 96 77
PLATELETS 157-->118 130 115 105 109 per liter 150-450
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 10TH 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
Day14-15
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 2.1 109 per liter 4 to 10
NEUT 93 94
PLATELETS 85 110 109 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
Cytopenia involving > 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
Hemophagocytosis in BM, Spleen,LN ABSENT
Low NK cells
NOT
CHECKED
Serum ferritin > 500 μg/L 8525 PRESENT
Elevated soluble interleukin-2 (CD25) levels
NOT
CHECKED
HLH CRITERIA:
Five of these 8
criteria are 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) on several occasions
Fever ≥ 3 weeks
Failure to reach a diagnosis despite one week of
inpatient investigations or 3 outpatient visits.
1) Mandell's Principles and Practices of Infection Diseases 6th Edition (2004) by
Gerald L. Mandell MD, MACP, John E. Bennett MD, Raphael Dolin
MD, ISBN 0-443-06643-4 · Hardback · 4016 Pages Churchill Livingstone
2) Harrison's Principles of Internal Medicine 18th Edition

31. Classification of PUO
Category Definition Aetiologies
Classic • Temperature >38.3°C (100.9°F);
• Duration of >3 weeks
• Evaluation of at least 3 outpatient
visits or 3 days in hospital
• Infection
• Malignancy
• collagen vascular disease
• Miscellaneous
• Undiagnosed
Nosocomial • Temperature >38.3°C
• Patient hospitalized ≥ 24 hoursbut
no fever or incubating on admission
• Evaluation of at least 3 days
• Clostridium difficile enterocolitis
• drug-induced
• pulmonary embolism
• septic thrombophlebitis,
• sinusitis
Neutropenic • Temperature >38.3°C
• Neutrophil count ≤ 500 per mm3
• Evaluation of at least 3 days
• Opportunistic bacterialinfections,
• aspergillosis,
• candidiasis,
• herpes virus
HIV-
associated
• Temperature >38.3°C
• Duration of >4 weeks for
outpatients, >3 days for inpatients
• HIV infection confirmed
• Cytomegalovirus,
• Mycobacterium avium-intracellulare
complex,
• Pneumocystis carinii pneumonia,
• 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. Classic PUO
3 common etiologies which account for the
majority of classic PUO:
Infections
Malignancies
Collagen Vascular Disease
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 prolonged FUO.
Harrison's Manual of Medicine, 19e
*Naproxen sodium 250 mg is given orally every 8 hours for 3 days

36. Malignancies
Haematological
Lymphoma
Chronic leukemia
Non-haematological
Renal cell cancer
Hepatocellular carcinoma
Pancreatic cancer
Colon cancer
Hepatoma
Harrison's Manual of Medicine, 19e

37. Collagen vascular disease /
Autoimmune disease
Polyarteritis nodosa
Giant cell arteritis
Kawasaki disease
 Adult Still's disease
 Polymyalgia rheumatica
 Temporal arteritis
 Rheumatoid arthritis
 Rheumatic fever
 Inflammatory bowel disease
 Reiter's syndrome
 Systemic lupus
erythematosus
Harrison's Manual of Medicine, 19e

38. Others/miscellaneous
Drugs: penicilin, phenytoin, captopril, allopurinol,
erythromycin, cimetidine, etc.
Hyperthyroidism
Alcoholic hepatitis
Inflammatory bowel disease
Deep Venous Thrombosis
Harrison's Manual of Medicine, 19e

39. Roth AR and Basello GM. Am Fam Physician. 2003Dec 1;68(11):2223-8.

40. Nosocomial PUO
More than 50% of patients with nosocomial PUO are
due to infection.
Focus on sites where occult infections may be
sequestered, such as:
- Sinusitis of patients with NG or oro-trachealtubes.
- Prostatic abscess in a man with a urinarycatheter.
25% of non-infectious cause includes:
- Acalculous cholecystitis,
- Deep vein thrombophlebitis
- Pulmonary embolism.
Harrison's Manual of Medicine, 19e

41. Neutropenic PUO
Patients on chemotherapy or immune deficiencies
are susceptible to:
- Opportunistic bacterial infection
- Fungal infections such as candidiasis
- Bacteremic infections
- Infections involving catheters
- Malignancy
Examples of aetiological agent:
- aspergillus
- Candida
- CMV
- Herpes simplex
Harrison's Manual of Medicine, 19e

42. HIV-associated PUO
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 history and
examination
2. Protein
electrophoresis
3. CT (chest, abdomen,
pelvis)
4. Autoantibody screen
(ANA, RF,ANCA,
anti-dsDNA)
5. ECG
Stage 2: Laboratory investigations
6. Bone marrow
examination
7. Lumbar puncture
8. Consider PSA,
CEA
9. Temporal artery
biopsy
10. HIV test counselling
Harrison's Manual of Medicine, 19e

46. • Stage 3:
1. Echocardiography
2. Further Ix abdomen
( scan – IBD,
abscesses, local
sepsis)
3. Barium studies
4. IVU
5. Liver biopsy
Stage 3: Laboratory investigations
6. Exploratory
laparotomy
7. Bronchoscopy
Harrison's Manual of Medicine, 19e

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

48. Diagnosing
Pyrexia of
Unknown
Origin

49. Imaging Studies
•Tuberculosis,malignancy, Pneumocystis cariniipneumoniaChest radiograph
•Abscess, malignancyCT of abdomen or pelvis with contrast
agent
•Infection, malignancyGallium 67 scan
•Occult septicemiaIndium-labeled leukocytes
•Acute infection and inflammation of bones and soft tissueTechnetium Tc 99m
•Malignancy, autoimmuneconditionsMRI of brain
•Malignancy, inflammationPET scan
•Bacterial endocarditis
Transthoracicor transesophageal
echocardiography
•Venous thrombosisVenous Doppler study

51. Hemophagocytosis
Phagocytosisbymacrophagesoferythrocytes,
leukocytes,platelets,and theirprecursorsin bone
marrowand othertissues
Hemophagocytic Lymphohistiocytosis
Uncommon, life-threateninghyperinflammatory syndrome caused bysevere
hypercytokinemia due to a highlystimulated but ineffectiveimmuneprocess

52. Primary(Genetic)
• Familial HLH
– Known genedefects
• PFR1
• UNC13D
• STX11
– Unknown genedefects
• Immune deficiencysyndromes
– Chediak-Higashi syndromes
Secondary(Acquired)
• Infections
• Autoimmune
• Malignant diseases
• Immunosuppression /
Organ transplantation
JankaG. (2009).“Hemophagocyticlymphohistiocytosis:whenthe immunesystemrunsamok”Klin PadiatrSep;221(5):278-85.
• PrimaryHLH
restrictedtoyoung
age(80% - presents
in<1 yearold)
• In adults,almost all
casesaresecondary

55. Source:“Verbsky, J.W.,& Grossman,W.J.(2006).Hemophagocyticlymphohistiocytosis:diagnosis,pathophysiology,treatment, and
futureperspectives. Annalsofmedicine,38(1), 20-31.”

56. Infections
Autoimmune disorders
Malignancy
Immunosuppression /
Organ transplant
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) Autoimmune disorders
Also known as Macrophage ActivationSyndrome(MAS)
- Lupus Erythematosus
- Rheumatoid arthritis
- Still’s disease
- Polyarteritisnodosa
- Mixed connective tissuedisorders
- SystemicSclerosis

59. 2
Infections
Autoimmune disorders
Malignancy
- Leukemias
- Lymphomas
3
1

60. 3
4
Infections
Autoimmune disorders
Malignancy
Immunosuppression /
Organ transplant
- Post-Chemotherapy
- After Renal or livertransplant
- Immunosuppressive treatment
1
2

61. • Common findings
– Prolonged fever
– 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:“Henter JIet al IncidenceinSwedenand clinical featuresoffamilial hemophagocyticlymphohistiocytosis.
Acta PaediatrScand1991;80:428”

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

64. • Cytopenias
• Tissue demonstration ofHemophagocytosis
– Repeatedattempts needed to identifycharacteristic
histology
– Lymphnode biopsy or bone marrow aspirates

65. • Cytopenias
• Tissue demonstration ofHemophagocytosis
• ElevatedFerritin
– Can increase over a range of several10000 ug/Lwithin
several hours inHLH
– Mechanisms– multiple hypotheses
• Passive release due to celldamage
• Increasedsecretion by macrophagesand release during
erythrophagocytosis
• Increasedferritin gene expression byTNF-α
– Ferritin >500μg/L :Sensitivity 82%, Specificity42%
– Ferritin >10,000 μg/L :Sensitivity 90%,Specificity 96%

66. • Cytopenias
• Tissue demonstration of Hemophagocytosis
• ElevatedFerritin
• Elevatedtriglycerides
– Mechanism- Increased TNF-α suppress activity of
lipoprotein lipase
-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.
-Bilirubin levels between 3 and 25 mg/dL are 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
• Depressed Fibrinogen
– Mechanism- Increased levels of Plasminogen activator
secretedby activatedmacrophages
Source : Henter, Jan‐Inge, AnnaCarin Horne, Mau Ladisch et al. "HLH‐2004: Diagnostic and
therape 2 (2006):124-131.

68. • In HLH-94, diagnosis was based on 5 five
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
Cytopenia involving > 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
Hemophagocytosis in BM, Spleen,LN ABSENT
Low NK cells
NOT
CHECKED
Serum ferritin > 500 μg/L 8525 PRESENT
Elevated soluble interleukin-2 (CD25) levels
NOT
CHECKED
HLH CRITERIA:
Five of these 8
criteria are required
for diagnosis

70. HLH
Moleculardiagnosis
e.gPRFmutations,
SAPmutations
5 out of 8diagnostic
criteriafulfilledor
• If patient meets only 4 criteria and clinical suspicion for
HLH is high, one must initiate appropriatetreatment
HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic
lymphohistiocytosis.

71. • Until 1994, HLH therapyineffectivewith 90% fatalities
• HLH-94
– First international study onHLH treatment
– Included combination of chemotherapy,immunotherapy
and steroids as well as antibiotics and antiviraldrugs
followed by stem celltransplant
– Twophases – Initialphase (8 weeks), Continuation phase
– Survival rate – 55% at median follow-upof 3.1years
• HLH-2004
– CyclosporineA startedat the onset of therapy insteadat
week 9

72. Immediategoals
Longtermgoals

73. Immediategoals
Suppressthe severeinflammation
• Steroids – Dexamethasone
• CyclosporineA
• IntrathecalMethotrexate, hydrocortisone (patients withpersistent
active CNS disease)
Killthe over-stimulatedAntigen-Presenting Cells
• Etoposide(VP-16)
Treatthe triggeringagent (infection,neoplasmetc.)
• Antibiotics,Antivirals
Supportivetherapy
• Prophylactic Cotrimoxazole,oralanti-mycotic
• Gastroprotection - Ranitidine
Source : Henter, Jan‐Inge, AnnaCarin Horne, Mau Ladisch et al. "HLH‐2004: Diagnostic and therape 2
(2006):124-131.
Alemtuzumab

75. Long-termgoal
Replacethe defective immunesystem
• AllogenicHematopoietic StemCell Transplantation
• Best overall cure rate inHLH
• Neededfor
• Patients with geneticmutations diagnosedor
family history
• Patientswho respondedpoorly with initial
eight weeks of chemotherapy
• Patients with CNSdisease
Source : Henter, Jan‐Inge, AnnaCarin Horne, Mau Ladisch et al. "HLH‐2004: Diagnostic and therape 2
(2006):124-131.

76. rizio Aricó, R.Maarten Egeler,AlexandraH.Filipovich, ShinsakuImashuku,Stephan
utic guidelinesforhemophagocyticlymphohistiocytosis."Pediatricblood & cancer 48,no.
Source :Henter,Jan‐Inge, AnnaCarin Horne, Mau
Ladisch et al. "HLH‐2004: Diagnostic and therape
2 (2006):124-131.
Dexamethasone
10 mg/m2perdayforfirsttwoweeks 5
mg/m2perdayforweek3and 4
2.5 mg/m2per dayforweek5 and6
1.25mg/m2perdayforweek7
Tapering tozerooverthe8thweek
Etoposide(VP-16)
150mg/m2 i.v.twiceweeklyforfirst twoweeks
150mg/m2 i.v.once weeklyfornext6weeks
CyclosporineA
• Start with6mg/Kgdaily (2 divideddoses) ,aimat4
levels around 200 μg/L(Trough level)
Intrathecal Methotrexate
12mg once weekly for pt >3 yr old for four weeks
(week 3 to week6)

77. :Henter, Jan‐Inge,AnnaCarinHorne,MaurizioAricó, R.Maarten Egeler,AlexandraH.Filipovich, ShinsakuImashuku,Stephan
et al."HLH‐2004: Diagnosticandtherapeuticguidelinesforhemophagocyticlymphohistiocytosis."Pediatricblood & cancer48, no.
):124-131.
Dexamethasonepulseevery second week, 10 mg/m2 for 3days
Etoposide150 mg/m2 every secondweek
CyclosporineA– aim for blood levelsaround 200 μg/L, Monitor GFR
AllogenicHematopoieticStemCellTransplantation
Source : Henter, Jan‐Inge, AnnaCarin Horne, Mau Ladisch et al. "HLH‐2004: Diagnostic and therape 2
(2006):124-131.

78. • Other treatmentapproaches
– Antithymocyte globulin
– Iv IG
– Rituximab (EBV associatedHLH)
– HIT-HLHtrial – A combined use of ATG,Etoposide,
Intrathecalmethotrexate and Hydrocortisone is
currently under study.

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-tumour associated 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