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 Guidelines 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.