1. Objective
To present a case of a Hemophagocytic Lymphohistiocytosis (HLH)

2. General Data BM
6 year old
Male
from Bacoor, Cavite

3. Chief complaint
FEVER

4. History of Present Illness
(+) fever (Tmax: 40degrees C)
(+) occasional cough
(+) headache and joint pains
Paracetamol for the fever
5 days PTA
(+) persistence of fever
Consult done at St. Dominic Hospital
CBC: Hgb 122/ Hct 37/ WBC 7.27/ neutro 63/ lymph 24/ platelet 289
UA: normal
Dengue NS1 negative
Impression: Upper respiratory tract infection
Clarithromycin
3 days PTA

5. History of Present Illness
(+) persistence of fever
(+) abdominal pain, nausea, myalgia
Follow-up consult St. Dominic hospital
rpt CBC: Hgb 110/ Hct 35/ wbc 1.7/ neutro 36/ lymph 58/ platelet 95
Typhidot: negative
Advised admission, but opted transfer to our institution
On the day of admission
ADMISSION

6. Past Medical History no previous hospitalization (+) asthma
no known allergies

7. Family History
(-) asthma, allergies
(-) cancer
(-) DM, HPN

8. Immunization History BCG 1 dose Hepatitis B 3 doses DPT 3 doses
OPV doses
Pneumococcal none
Rotavirus none
Hepatitis A dose
Typhoid none

9. Physical exam Awake, weak-looking , not in cardiorespiratory distress
BP: 90/60mmHg CR: 98bpm RR: 24 cpm T: 39.6 C
Weight: kg Height 131 cm
pink palpebral conjunctivae, anicteric sclerae
moist oral mucosa, no tonsillopharyngeal congestion
good air entry, clear breath sounds
regular cardiac rhythm, grade 2/6 systolic murmur on left parasternal border
soft abdomen, nontender
full and equal pulses, CRT <2sec

10. Admitted as a case of Systemic Viral Illness r/o Dengue fever
CBC done:
Dengue blot negative
Admitted as a case of Systemic Viral Illness r/o Dengue fever
IV hydration, Paracetamol
Hgb
Hct
WBC
neutro
lymph
platelet 92 28 2 31 64
120

11. Course in the Wards Problems: (+) persistence of fever
occasional cough
increased effort in breathing
with episodes of abdominal pain
cardiac findings: Grade 2/6 systolic murmur on left parasternal border
respiratory: RR 30-60s, harsh breath sounds, no rales, no wheezes
abdominal findings: soft abdomen, liver edge palpable 3-4 cm below the subcostal margin

12. Course in the Wards Infectious date Hgb Hct WBC neutro lymph platelet
2/25/14 92 28
2.2 31 64
120
2/26/14
108 32 2 61 34
126
2/27/14 a 82 24
1.7 43 50
100
2/27/14 b 83 26
1.3 37 59
dengue IgM/IgM
negative
Blood CS
NG x 24 h

13. Course in the Wards Cardiac: ECG: Normal sinus rhythm, normal axis
normal values
CK tot
u/l 37
CK MB
0-24
CK MM
30-176

14. Course in the Wards Ceftriaxone 1.5g/IV OD
Respiratory: CHEST XRAY Bilateral Interstitial Pneumonitis)
Ceftriaxone 1.5g/IV OD

15. Course in the Wards
Abdomen: PLAIN ABDOMINAL XRAY: No localizing signs in the abdominal tissues
ABDOMINAL ULTRASOUND prominent sized liver, mild to moderate ascites and pleural effusion

16. Course in the Wards Sodium correction Albumin transfusion Na K
normal values
SGPT
u/l
123
SGOT
5-34 u/l
319
Total Bilirubin
mg/dl
2.43
Direct bilirubin
0-0.5 mg/dl
2.05
Indirect bilirubin
mg/dl
0.38 PT
12-14
14.2 vs 12.7
INR 1.17 %Act 0.61
PTT
28-37
44.1 vs 28.1
Total Protein
64-83 g/l 44
Albumin
35-50 g/l 24
Globulin
29-33 20
A/G
1.2
normal values Na
mmol/L
130 K
mmol/L
4.3
Sodium correction
Albumin transfusion

17. Course in the Wards REFERRALS
IDS: Cannot totally rule out Dengue fever; HLH
GI : Systemic Viral Illness, Postinfectious hepatitis
HEMATOLOGY: t/c HLH

18. Transfer to PICU t/c SEPSIS rule out HLH prolonged fever
tachypnea RR 50s and labored breathing
tachycardia HR s bpm
still with episodes of abdominal pain
Meropenem 750 mg/IV every 8h (113.6mkd)
transferred on the 4th hospital day
O2 support 2lpm NC
2d-echo: pericardial effusion, mild MR, mild TR
Carditis with diastolic dysfunction
t/c SEPSIS
rule out HLH

19. Transfer to PICU anemia, leukopenia, thrombocytopenia
electrolyte imbalance (hypokalemia, hypocalcemia)
fluid spacing (pleural effusion, ascites)
deranged liver function tests
pRBC transfusion
10% Calcium gluconate 1 g + equal amounts of nSS
furosemide 20mg/iv
K correction
Calcium gluconate nv
2/20
2/26
2/28 Na
135
130
137 K
3.4
4.3
iCal
1.34
1.10
Furosemide

20. Other laboratory resultsnv
LDH
u/L
1.772
transferred on the 4th hospital day nv
BUN
4.48
Creatinine
0.41
Uric acid /2
2.37 nv
D-Dimer
<0.5 ug/ml
3.10
ASO
iu/ml
58.8
CRP
22.49 ng/ml
2.92
ProCal
<0.5 ng/ml
22.49

21. Diagnostic Criteria for HLH
Text
Treatment Protocol of the 2nd International HLH Study, 2004.) From Verbsky JW, Grossman WJ: Hemophagocytic lymphohistiocytosis: diagnosis, pathophysiology, treatment, and future perspectives, Ann Med 38:20–31, 2006, p 21, Table 1
Retrieved from Nelsons Pediatrics 19th ed.

22. At the PICU CT Abdomen with Contrast: Prominent sized liver and spleen
Liver 13.5 cm right midclavicular line
Spleen 8.2 x 8.8 x 4.3 cm
Ascites
Bilateral pleural effusion, right more than left

23. At the PICU Triglycerides 460.20 mg/dl (nv 0-150)
Fibrinogen mg/dl (nv )
Ferritin >40,000 ng/ml (nv )

24. At the PICU
BMA: Hemagophagocyte - 1
for flow cytometry

25. Hemophagocytic Lymphohistiocytosis
also called “hemophagocytic syndrome (HPS)
a nonmalignant proliferative disorder that affects the antigen-processing macrophages and that results in uncontrolled hemophagocytosis and upregulation of inflammatory cytokines impaired natural killer (NK) cell function and other defects 
Palazzi D L et al. Hemophagocytic Syndrome in Children: An Important Diagnostic Consideration in Fever of Unknown Origin. Clin Infect Dis. 2003;36:

26. Hemophagocytic Lymphohistiocytosis
A potentially fatal disorder of children and adults due to cytokine dysfunction, resulting in uncontrolled accumulation of activated T-lymphocytes and activated histiocytes (macrophages) in many organs.
HLH may be familial, associated with a number of different infections, autoimmune disorders, or coincident with a number of malignancies.
HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis.AU Henter JI, Horne A, AricóM, Egeler RM, Filipovich AH, Imashuku S, Ladisch S, McClain K, Webb D, Winiarski J, Janka G SO. Pediatr Blood Cancer. 2007;48(2):124.

27. Primary HLH
Familial hemophagocytic lymphohistiocytosis (FHLH) (familial or sporadic):
an autosomal recessive disease that affects immune regulation
Nonfamilial HLH:
develop from marked immunological activation during viral, bacterial, and parasitic infections
may also be associated with malignancies, prolonged administration of lipids, rheumatoid arthritis (macrophage activation syndrome), immune deficiencies associated with cytotoxic T- and/or Nkcell dysfunction such as DiGeorge syndrome (del 22q11.2), Chédiak–Higashi syndrome, Griscelli syndrome,* X-linked lymphoproliferative disease (XLP), and lysinuric protein intolerance (LPI).
Although it is commonly termed familial HLH, because the disease has an autosomal recessive
Inheritance, sporadic cases with no obvious family inheritance occur.
FHLH may be triggered by infections.
A lymphohistiocytic proliferation with hemophagocytosis may also develop from marked immunological activation during viral, bacterial, and parasitic infections may also be associated with malignancies, prolonged administration of lipids, rheumatoid arthritis (macrophage activation
syndrome), immune deficiencies associated with cytotoxic T- and/or Nkcell dysfunction such as DiGeorge syndrome (del 22q11.2), Chédiak–Higashi syndrome, Griscelli syndrome,* X-linked lymphoproliferative disease (XLP), and lysinuric protein intolerance (LPI).
Manual of Pediatric Hematology and Oncology 4th ed . P. Lanzkowsky (Elsevier, 2005).

28. Secondary HLH
A reactive disorder causing strong immunologic activation often resulting from severe bacterial or parasitic infection
Infection-associated HPS IAHS]
Viral infection (VAHS)
Malignancy (MAHS)
Use of drugs (phenytoin)
Prolonged administration of parenteral nutrition involving soluble lipids
Palazzi D L et al. Hemophagocytic Syndrome in Children: An Important Diagnostic Consideration in Fever of Unknown Origin. Clin Infect Dis. 2003;36:

29. Infection-Associated Hemophagocytic Lymphohistiocytosis
NK-cell activity in IAHLH patients is reconstituted as soon as the infection is cleared
decreased or absent NK cells are found more often in FHLH
Viruses:
Epstein–Barr virus, human herpes virus 6 (HHV-6), cytomegalovirus (CMV) (most common of the viruses), adenovirus, parvovirus, varicella zoster, herpes simplex virus (HSV), Q-fever virus, and measles
Treatment
EBV–related IAHLH: etoposide and immunoglobulin treatment
Other infections: antibiotics for bacterial infections, antiviral drugs for viruses, in addition to corticosteroids and/or etoposide.
Patients with persistent HLH may require FHLH treatment and HSCT.
Patients with resolved disease may discontinue therapy at 8 weeks. If the syndrome recurs therapy should be restarted and HSCT should be employed.

30. Clinical features
Age of onset: Less than 1 year of age (70% of cases) *no known upper age limit for the onset of disease
Signs and symptoms of FHLH
Most common early findings:
a. Fever (91%)
b. Splenomegaly (98%)
c. Hepatomegaly (94%)
Manual of Pediatric Hematology and Oncology 4th ed . P. Lanzkowsky (Elsevier, 2005).

31. The most common reason for hospital admission was fever with or without additional symptoms or signs.
Hemophagocytic Syndrome in Children: An Important Diagnostic Consideration in Fever of Unknown Origin Debra L. Palazzi,1 Kenneth L. McClain,2 and Sheldon L. Kaplan1 1Infectious Diseases Section and 2Section of Hematology and Oncology, Department of Pediatrics, Baylor College of Medicine and Texas Children’s Hospital, Houston, Texas (2003)

32. Clinical features Other findings: a. Lymph node enlargement (17%)
b. Skin rash (6%)
c. Neurologic abnormalities (20%)
Neurologic: irritability, bulging fontanel, neck stiffness, hypotonia, hypertonia, convulsions, cranial nerve palsies, ataxia, hemiplegia, blindness, and unconsciousness
d. Multisystem involvement: lungs, bone marrow, and
leptomeninges.
Occasionally: ocular, heart, skeletal muscles, and kidney
Manual of Pediatric Hematology and Oncology 4th ed . P. Lanzkowsky (Elsevier, 2005).

33. Diagnostic Criteria for HLH
Text
Treatment Protocol of the 2nd International HLH Study, 2004.) From Verbsky JW, Grossman WJ: Hemophagocytic lymphohistiocytosis: diagnosis, pathophysiology, treatment, and future perspectives, Ann Med 38:20–31, 2006, p 21, Table 1
Retrieved from Nelsons Pediatrics 19th ed.

34. Pathologic findings —result from the aggressive proliferation of normal histiocytes and T-lymphocytes in various tissues. Hemophagocytosis of red cells (erythrophagocytosis), other white blood cells, or platelets in the bone marrow, spleen, or lymph nodes is the key diagnostic finding.
Bone marrow from a child with hemophagocytic syndrome, secondary to Epstein-Barr virus infection. Reactive histiocytes show phagocytosis of nucleated red blood cells (red arrows) and platelets (black arrows). Wright-Giemsa stain

35. Treatment
Dexamethasone 10 mg/m2/day for 2 weeks followed by a decrease every 2 weeks to 5 mg/m2, 2.5 mg/m2, and 1.25 mg/m2 for a total of 6 weeks
Etoposide IV (150 mg/m2 IV 2-hour infusions daily) twice weekly for 2 weeks, then weekly
Cyclosporine A 3–5 mg/kg/day by continuous IV infusion starting week 8 to reach a blood trough level of 150–200 ng/mL and switching to oral administration of 6–10 mg/kg/day in two divided doses
Intrathecal methotrexate (IT MTX), age-adjusted doses of IT MTX weekly for 3–6 weeks as follows if there are progressive neurologic symptoms or if abnormalcells persist in the CSF
Allogeneic stem cell transplantation (BMT) after cytotoxic chemotherapy for all patients with familial disease or those with persistent nonfamilial disease.
Manual of Pediatric Hematology and Oncology 4th ed . P. Lanzkowsky (Elsevier, 2005).
Modern management of children with haemophagocytic lymphohistiocytosis. AU Janka GE, Schneider EM SO Br. J Haematol. 2004;124(1):4.

36. Treatment
The standard of care in 2011 for HLH patients being treated outside of a therapeutic research trial is treatment with dexamethasone and etoposide, as outlined in the HLH-94 trial. 
Cyclosporine may be added (initial dose 6mg/kg per day, divided in two daily doses; target trough levels 200 mcg/L), but the benefit of its use during the initial eight-week induction period is not yet proven and its use has been associated with posterior reversible encephalopathy syndrome (PRES)
In the HLH-2004 research protocol, cyclosporine will be started on day one.
Modern management of children with haemophagocytic lymphohistiocytosis. AU Janka GE, Schneider EM SO Br. J Haematol. 2004;124(1):4.

37. Prognosis
Without treatment, FHLH is usually rapidly fatal, with a median survival of about 2 months.
Chemotherapy and immunosuppressive therapy may prolong survival in FHLH but only stem cell transplantation may be curative.
Patients with known familial disease or severe or persistent acquired disease should receive hematopoietic stem cell transplantation (HSCT). The 3-year actuarial survival in familial HLH with this approach has been reported as 51% ± 20%.

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