Objective

•To present a case of a Hemophagocytic Lymphohistiocytosis (HLH)

General Data

•BM

•6 year old

•Male

•from Bacoor, Cavite

Chief complaint

FEVER

5 days PTA

3 days PTA

(+) fever (Tmax: 40degrees C)(+) occasional cough

(+) headache and joint painsParacetamol for the fever

(+) persistence of fever

Consult done at St. Dominic HospitalCBC: Hgb 122/ Hct 37/ WBC 7.27/ neutro 63/

lymph 24/ platelet 289UA: normal

Dengue NS1 negativeImpression: Upper respiratory tract infection

Clarithromycin

History of Present Illness

On the day of admission

(+) persistence of fever(+) abdominal pain, nausea, myalgia

Follow-up consult St. Dominic hospitalrpt CBC: Hgb 110/ Hct 35/ wbc 1.7/

neutro 36/ lymph 58/ platelet 95Typhidot: negative

Advised admission, but opted transfer to our institution

ADMISSION

History of Present Illness

•no previous hospitalization

•(+) asthma

•no known allergies

Past Medical History

Family History

•(-) asthma, allergies

•(-) cancer

•(-) DM, HPN

BCG 1 doseHepatitis B 3 dosesDPT 3 dosesOPV 3 dosesPneumococcal noneRotavirus noneHepatitis A 1 doseTyphoid none

Immunization History

Physical examAwake, weak-looking , not in cardiorespiratory distressBP: 90/60mmHg CR: 98bpm RR: 24 cpm T: 39.6 CWeight: 19.8 kg Height 131 cm

pink palpebral conjunctivae, anicteric scleraemoist oral mucosa, no tonsillopharyngeal congestiongood air entry, clear breath soundsregular cardiac rhythm, grade 2/6 systolic murmur on left parasternal border

soft abdomen, nontenderfull and equal pulses, CRT <2sec

• 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

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

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 92

dengue IgM/IgM

negative

Blood CS NG x 24 h

Course in the Wards

• Cardiac: ECG: Normal sinus rhythm, normal axis

normal values

CK tot 30-200 u/l 37

CK MB 0-24 37

CK MM 30-176 0

Course in the Wards• Respiratory: CHEST XRAY Bilateral Interstitial

Pneumonitis)

Ceftriaxone 1.5g/IV OD

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

Course in the Wardsnormal values

SGPT 9-68.8 u/l 123

SGOT 5-34 u/l 319

Total Bilirubin 0.2-1.19mg/dl 2.43

Direct bilirubin 0-0.5 mg/dl 2.05

Indirect bilirubin 0.2-0.70 mg/dl 0.38

PT 12-14 14.2 vs 12.7INR 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 1.21 - 1.52 1.2normal values

Na136-145 mmol/L

130

K 3.5-5.1 mmol/L 4.3

Sodium correction Albumin

transfusion

Course in the Wards

•REFERRALS

• IDS: Cannot totally rule out Dengue fever; HLH

•GI : Systemic Viral Illness, Postinfectious hepatitis

•HEMATOLOGY: t/c HLH

Transfer to PICU

• prolonged fever

• tachypnea RR 50s and labored breathing

• tachycardia HR 110-120s bpm

• still with episodes of abdominal pain

Meropenem 750 mg/IV every 8h (113.6mkd)

O2 support 2lpm NC

t/c SEPSIS rule out HLH

2d-echo: pericardial effusion, mild MR, mild

TRCarditis with diastolic

dysfunction

Transfer to PICU• anemia, leukopenia, thrombocytopenia

• electrolyte imbalance (hypokalemia, hypocalcemia)

• fluid spacing (pleural effusion, ascites)

• deranged liver function tests

nv 2/20 2/26 2/28

Na 136-145 135 130 137

K 3.5-5.1 3.4 4.3 3.4

iCal 1.12-1.32 1.34 1.10

pRBC transfusion

K correction

Furosemide

Calcium gluconate

Other laboratory results

nv

BUN 8.96 - 20.73 4.48

Creatinine 0.52 - 0.72 0.41

Uric acid 3.56-7./2 2.37

nv

D-Dimer <0.5 ug/ml 3.10

ASO 166-250 iu/ml 58.8

CRP 22.49 ng/ml 2.92

ProCal <0.5 ng/ml 22.49

nv

LDH 125-220 u/L 1.772

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.

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

At the PICU

• Triglycerides 460.20 mg/dl (nv 0-150)

• Fibrinogen 136.2 mg/dl (nv 180-350)

• Ferritin >40,000 ng/ml (nv 8.80 - 184.7)

At the PICU

•BMA: Hemagophagocyte - 1

•for flow cytometry

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;36:306-312

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-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.

HLH may be familial, associated with a number of different infections, autoimmune disorders, or coincident with a number of malignancies.

Manual of Pediatric Hematology and Oncology 4th ed . P. Lanzkowsky (Elsevier, 2005).

Primary HLH1.Familial hemophagocytic lymphohistiocytosis (FHLH) (familial or

sporadic): ◦ an autosomal recessive disease that affects immune regulation

1.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).

Palazzi D L et al. Hemophagocytic Syndrome in Children: An Important Diagnostic Consideration in Fever of Unknown Origin. Clin Infect Dis. 2003;36:306-312

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

Secondary HLH

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.

Clinical features1.Age of onset: Less than 1 year of age (70% of

cases) *no known upper age limit for the onset of disease

2.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).

• 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 OriginHemophagocytic Syndrome in Children: An Important Diagnostic Consideration in Fever of Unknown OriginDebra L. Palazzi,1 Kenneth L. McClain,2 and Sheldon L. Kaplan1Debra L. Palazzi,1 Kenneth L. McClain,2 and Sheldon L. Kaplan11Infectious Diseases Section and 2Section of Hematology and Oncology, Department of Pediatrics, Baylor College of Medicine1Infectious Diseases Section and 2Section of Hematology and Oncology, Department of Pediatrics, Baylor College of Medicineand Texas Children’s Hospital, Houston, Texas (2003)and Texas Children’s Hospital, Houston, Texas (2003)

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).

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.

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

Treatment1.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

2.Etoposide IV (150 mg/m2 IV 2-hour infusions daily) twice weekly for 2 weeks, then weekly

3.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

4.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

5.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.

TreatmentThe 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.

PrognosisWithout 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%.

•THANK YOU