4History of Present Illness (+) fever (Tmax: 40degrees C)(+) occasional cough(+) headache and joint painsParacetamol for the fever5 days PTA(+) persistence of feverConsult done at St. Dominic HospitalCBC: Hgb 122/ Hct 37/ WBC 7.27/ neutro 63/ lymph 24/ platelet 289UA: normalDengue NS1 negativeImpression: Upper respiratory tract infectionClarithromycin3 days PTA
5History of Present Illness (+) persistence of fever(+) abdominal pain, nausea, myalgiaFollow-up consult St. Dominic hospitalrpt CBC: Hgb 110/ Hct 35/ wbc 1.7/ neutro 36/ lymph 58/ platelet 95Typhidot: negativeAdvised admission, but opted transfer to our institutionOn the day of admissionADMISSION
6Past Medical History no previous hospitalization (+) asthma no known allergies
8Immunization History BCG 1 dose Hepatitis B 3 doses DPT 3 doses OPV dosesPneumococcal noneRotavirus noneHepatitis A doseTyphoid none
9Physical exam Awake, weak-looking , not in cardiorespiratory distress BP: 90/60mmHg CR: 98bpm RR: 24 cpm T: 39.6 CWeight: kg Height 131 cmpink palpebral conjunctivae, anicteric scleraemoist oral mucosa, no tonsillopharyngeal congestiongood air entry, clear breath soundsregular cardiac rhythm, grade 2/6 systolic murmur on left parasternal bordersoft abdomen, nontenderfull and equal pulses, CRT <2sec
10Admitted as a case of Systemic Viral Illness r/o Dengue fever CBC done:Dengue blot negativeAdmitted as a case of Systemic Viral Illness r/o Dengue feverIV hydration, ParacetamolHgbHctWBCneutrolymphplatelet922823164120
11Course in the Wards Problems: (+) persistence of fever occasional coughincreased effort in breathingwith episodes of abdominal paincardiac findings: Grade 2/6 systolic murmur on left parasternal borderrespiratory: RR 30-60s, harsh breath sounds, no rales, no wheezesabdominal findings: soft abdomen, liver edge palpable 3-4 cm below the subcostal margin
12Course in the Wards Infectious date Hgb Hct WBC neutro lymph platelet 2/25/1492282.231641202/26/1410832261341262/27/14 a82241.743501002/27/14 b83261.33759dengue IgM/IgMnegativeBlood CSNG x 24 h
13Course in the Wards Cardiac: ECG: Normal sinus rhythm, normal axis normal valuesCK totu/l37CK MB0-24CK MM30-176
14Course in the Wards Ceftriaxone 1.5g/IV OD Respiratory: CHEST XRAY Bilateral Interstitial Pneumonitis)Ceftriaxone 1.5g/IV OD
15Course in the WardsAbdomen: PLAIN ABDOMINAL XRAY: No localizing signs in the abdominal tissuesABDOMINAL ULTRASOUND prominent sized liver, mild to moderate ascites and pleural effusion
16Course in the Wards Sodium correction Albumin transfusion Na K normal valuesSGPTu/l123SGOT5-34 u/l319Total Bilirubinmg/dl2.43Direct bilirubin0-0.5 mg/dl2.05Indirect bilirubinmg/dl0.38PT12-1414.2 vs 12.7INR 1.17 %Act 0.61PTT28-3744.1 vs 28.1Total Protein64-83 g/l44Albumin35-50 g/l24Globulin29-3320A/G1.2normal valuesNammol/L130Kmmol/L4.3Sodium correctionAlbumin transfusion
17Course in the Wards REFERRALS IDS: Cannot totally rule out Dengue fever; HLHGI : Systemic Viral Illness, Postinfectious hepatitisHEMATOLOGY: t/c HLH
18Transfer to PICU t/c SEPSIS rule out HLH prolonged fever tachypnea RR 50s and labored breathingtachycardia HR s bpmstill with episodes of abdominal painMeropenem 750 mg/IV every 8h (113.6mkd)transferred on the 4th hospital dayO2 support 2lpm NC2d-echo: pericardial effusion, mild MR, mild TRCarditis with diastolic dysfunctiont/c SEPSISrule out HLH
19Transfer to PICU anemia, leukopenia, thrombocytopenia electrolyte imbalance (hypokalemia, hypocalcemia)fluid spacing (pleural effusion, ascites)deranged liver function testspRBC transfusion10% Calcium gluconate 1 g + equal amounts of nSSfurosemide 20mg/ivK correctionCalcium gluconatenv2/202/262/28Na135130137K3.44.3iCal1.341.10Furosemide
20Other laboratory results nvLDHu/L1.772transferred on the 4th hospital daynvBUN4.48Creatinine0.41Uric acid/22.37nvD-Dimer<0.5 ug/ml3.10ASOiu/ml58.8CRP22.49 ng/ml2.92ProCal<0.5 ng/ml22.49
21Diagnostic Criteria for HLH TextTreatment 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 1Retrieved from Nelsons Pediatrics 19th ed.
22At the PICU CT Abdomen with Contrast: Prominent sized liver and spleen Liver 13.5 cm right midclavicular lineSpleen 8.2 x 8.8 x 4.3 cmAscitesBilateral pleural effusion, right more than left
24At the PICUBMA: Hemagophagocyte - 1for flow cytometry
25Hemophagocytic 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:
26Hemophagocytic 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.
27Primary HLHFamilial hemophagocytic lymphohistiocytosis (FHLH) (familial or sporadic):an autosomal recessive disease that affects immune regulationNonfamilial HLH:develop from marked immunological activation during viral, bacterial, and parasitic infectionsmay 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 recessiveInheritance, 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 activationsyndrome), 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).
28Secondary HLHA reactive disorder causing strong immunologic activation often resulting from severe bacterial or parasitic infectionInfection-associated HPS IAHS]Viral infection (VAHS)Malignancy (MAHS)Use of drugs (phenytoin)Prolonged administration of parenteral nutrition involving soluble lipidsPalazzi D L et al. Hemophagocytic Syndrome in Children: An Important Diagnostic Consideration in Fever of Unknown Origin. Clin Infect Dis. 2003;36:
29Infection-Associated Hemophagocytic Lymphohistiocytosis NK-cell activity in IAHLH patients is reconstituted as soon as the infection is cleareddecreased or absent NK cells are found more often in FHLHViruses: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 measlesTreatmentEBV–related IAHLH: etoposide and immunoglobulin treatmentOther 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.
30Clinical featuresAge of onset: Less than 1 year of age (70% of cases) *no known upper age limit for the onset of diseaseSigns and symptoms of FHLHMost common early findings:a. Fever (91%)b. Splenomegaly (98%)c. Hepatomegaly (94%)Manual of Pediatric Hematology and Oncology 4th ed . P. Lanzkowsky (Elsevier, 2005).
31The 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)
32Clinical 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 unconsciousnessd. Multisystem involvement: lungs, bone marrow, andleptomeninges.Occasionally: ocular, heart, skeletal muscles, and kidneyManual of Pediatric Hematology and Oncology 4th ed . P. Lanzkowsky (Elsevier, 2005).
33Diagnostic Criteria for HLH TextTreatment 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 1Retrieved from Nelsons Pediatrics 19th ed.
34Pathologic 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
35TreatmentDexamethasone 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 weeksEtoposide IV (150 mg/m2 IV 2-hour infusions daily) twice weekly for 2 weeks, then weeklyCyclosporine 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 dosesIntrathecal 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 CSFAllogeneic 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.
36TreatmentThe 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.
37PrognosisWithout 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%.