hemophagocytic lymphohistiocytosis in a 21-year-old patient
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Hemophagocytic Lymphohistiocytosis in a 21-year-old Patient. Salem Assiri, MD; Richard Wang, MS; and Suma Jain, MD Department of Internal Medicine Ochsner Clinic Foundation, New Orleans, LA. HPI. 21-year-old Caucasian female - PowerPoint PPT PresentationTRANSCRIPT
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Hemophagocytic Lymphohistiocytosis
in a 21-year-old Patient
Salem Assiri, MD; Richard Wang, MS; and Suma Jain, MD
Department of Internal Medicine
Ochsner Clinic Foundation, New Orleans, LA
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HPI
21-year-old Caucasian female
Presented to her primary care provider with a weeklong history of fever, sore throat, myalgia, arthralgia and non-erythematous, papular rash to the chest and bilateral upper and lower extremities.
She was provided symptomatic measures and valacyclovir for fever blisters.
Rapid strep test returned negative.
Her symptoms worsened, and the rash progressed.
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HPI
She presented to the ED and was treated for dehydration.
Her earlier throat cultures returned positive for Group A strep, and she was started on amoxicillin
Her symptoms continued to progress, and she returned to the emergency room for further evaluation.
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History
PMHx Asthma
Obesity status post uncomplicated laparoscopic gastric sleeve
Bronchitis
Past Surgical Hx Minor cosmetic
surgery on chest
Maxillary advancement
Gastric sleeve
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History
Family Hx Mother
Diabetes
Brother Diabetes
Paternal Aunt
Breast cancer
Social Hx Smoking status
Never smoker
Alcohol use
Occassional
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Physical Exam Vitals: Temp: 101.4 °F (37.3 °C), Pulse: 97
Resp: 18, BP: 101/62 mmHg, SpO2: 91%
BMI: 37.87
Constitutional: Well-developed, well-nourished, non-distressed, not diaphoretic, obese
Neurological/Psych: AAO x 4, no gross CN deficits, no gross deficits in sensation, strength or tone throughout, no lateralizing or focal findings; normal mood and affect, normal behaviour, thought content and judgement.
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Exam HEENT: NC/AT, PERRL, EOMI, no scleral
icterus
OP: exudate with erythema noted to B tonsils
Neck: diffuse TTP. No lymphadenopathy, no tracheal deviation, no stridor
Cardiovascular: RRR, normal S1/S2, intact distant pulses, no m/r/g, no JVD
Pulmonary/Chest wall: CTAB, no Wheezing, rhonchi or crackles
GI: S/NT/ND, BS present
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Exam Musculoskeletal/Skin: Normal ROM, no
edema, no atrophy, no tenderness throughout; no c/c/e, non-tender, non-erythematous, non-raised papuled noted on LUE and RLE and anterior chest; palmar and plantar erythema
GU exam performed in ED: no retained foreign body
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Admission Labs WBC 14,500
hemoglobin 8.5
hematocrit 25
platelets 87
BUN 12;
Cr 1.0
TB 0.4
ALT 14; AST 54
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MICU Labs WBC 21,000
BUN/Cr 18/2.1
H/H 11/33
Troponin 0.263
lactic acid 1.1
BNP 968
LDH 1366
ESR 45
CRP 384.
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Investigations 12-lead ECG:
sinus tachycardia with ST elevations in the inferior and anterior leads, consistent with acute pericarditis.
2D echo:
an ejection fraction of 25% and diastolic dysfunction.
Chest CT:
bilateral, patchy consolidative opacities, bilateral small pleural effusion, and trace pericardial effusion.
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Investigations
CT of abdomen and pelvis:
Splenomegaly.
All blood cultures were no growth, and respiratory viral panel was negative.
EBV IgG positive, but IgM and PCR were negative.
CMV negative
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Hospital Course Upon admission to internal medicine for GAS
and possible acute rheumatic fever, she continued to spike fevers, desaturated to 80%, and became hypotensive.
She was transferred to the MICU for shock and ARDS and possible toxic shock syndrome.
Broad-spectrum antibiotics were started, and she was intubated.
She received IVIG for toxic shock syndrome with mild to modest improvement in the appearance of maculopapular rash.
Dermatology consulted for the maculopapular rash. Skin Biopsy revealed non-specific etiology but thought to be 2/2 drug eruption
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Hospital Course
Developed multi-organ failure (AKI, hepatic failure, DIC, congestive heart failure with elevated troponin and evidence of pericarditis/carditis)
Required renal replacement therapy, packed RBC transfusion, FFP, cryoprecipitate and NAC
pt cont to spike temperatures and leukcoytosis worsen despite of broad spectrum Antibiotics
Rheumatology consulted for Autoimmune disease vs macrophage activation syndrome
Pediatric hematology oncology consulted for possible hemophagocytic lymphohistiocytosis (HLH)
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Hospital Course
Subsquent blood work reveals the following
Ferritin 26000 ng/mL
TG 455 mg/dL
Absent NK cell activity
soluble CD25 (soluble IL-2 receptor alpha) 13630 pg/mL
Some Peripheral smears (hematophagocytosis)
Sternal BM biopsy negative for malignancy and no evidence of HLH
BM Chromosomal analysis: No clonal abnormality or HLH gene mutation. MDS FISH panel studies were normal
HLH diagnosis made based on HLH-2004 guideline criteria
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Hospital Course Patient started on daily high dose Dexamethasone
and biweekly Etoposide
Significant improvement noticed, fever subsided, leukocytosis resolved but pt develop neutropenia 2/2 etoposide.
Acyclovir and sulfamethoxazole-trimethoprim added for prophylaxis
Extubated and kidney function recovered
Subsequently developed SVT and became HD unstable
Echocardiogram revealed significant pericardial effusion and tamponade physiology
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Hospital Course
Pericardiocentesis performed and yeild > 1 L bloody pericardial fluid. Cytology negative for HLH or malignancy
Pt cont to recover
Stepped down to pediatric hematology
Subsequently developed seizure and found to be in status epilepticus
Intubated and admitted to neurocritical care
AEDs started
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Hospital Course
MRI brain revealed Extensive relatively symmetrical T2/flair signal abnormality within the parenchyma primarily within the sub cortical white matter
DDX CNS involvement of lymphohistiocytosis vs posterior reversible encephalopathy
Intrathecal methotrexate initiated
Alemtuzumab added for HLH salvage treatment
Repeated MRI showed resolving the white matter lesions
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MRI brain
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Hospital Course Subsequently pt develop maculpapular rash on
the extremities which rapidly progressed to the entire body
Skin biopsies were consistent with SJS/TEN
SJS/TEN thought to be 2/2 drug eruption
All blood cultures were negative
CSF: WBC 1, RBC 820, glucose 55, protein 50
CSF cytology negative for HLH or malignancy
Bactrim, acyclovir, keppra and Onfi (clobazam) held
Pt exhibited improvement in her mental status but skin lesions cont to get worse
Transferred to burn center
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Differential Diagnosis
Infection/sepsis
Malignancies
(leukemia, lymphoma, other solid tumors)
Drug reaction with eosinophilia and systemic symptoms (DRESS)
Autoimmune lymphoproliferative syndrome (ALPS)
Adult Still's Disease
Macrophage activating syndrome
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Diagnosis of HLH
While initially thought to be due to infection (positive strep throat culture and positive ASO titers), the diagnosis of HLH was considered.
A sternal bone marrow was obtained which was negative for malignancy (no comment on hematophagocytosis but apparently few histiocytes although some peripheral blood smears showed hematophagocytosis).
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Etiology: Hemophagocytic lymphohistiocytosis (HLH) A rare, aggressive syndrome of excessive
inflammation and tissue destruction due to abnormal immune activation
Primarily a pediatric disease
Manifests as either a familial disorder or a sporadic condition
Both forms are associated with a variety of triggers, typically an infection.
In this patient’s case, secondary to Group A strep infection.
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Guidelines set by HLH-2004:
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Diagnostic Reasoning According to the guidelines set by HLH-2004,
she fit the diagnostic criteria for HLH even without having hematophagocytosis in the bone marrow.
She fulfilled at least 5 of the criteria with
Fever
Splenomegaly
Hypertriglyceridemia
Ferritin greater than 10000 microgram/L
Soluble CD25 (soluble IL-2 receptor) greater than 2400 U/ml
Also demonstrated a sixth criteria with a platelet count less than 100 x 109 and a hemoglobin less than 10 g/dL.
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Treatment Can include a combination of chemotherapy,
immunotherapy and steroids.
Antibiotics and antiviral drugs may also be used.
Treatments may be followed by a bone-marrow or stem-cell transplant in patients with persistent or recurring HLH.
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Treatment Therapy based on the HLH-2004 protocol
consists of eight weeks of induction therapy with etoposide (VP-16) and dexamethasone, with intrathecal therapy for those with CNS involvement.
Etoposide (VP-16) is given at a dose of 150 mg/m2 for adults, and 5 mg/kg for children weighing <10 kg.
Dose is given twice weekly for the first two weeks, and once weekly for weeks three through eight.
Dexamethasone is the preferred corticosteroid because it can cross the blood-brain barrier.
Given intravenously or orally and tapered over the eight-week induction
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Treatment The major modifications of the HLH-2004
protocol (trial from 2004 to 2011) are to begin cyclosporin simultaneously with etoposide and to add hydrocortisone to the intrathecal methotrexate, but results are not yet available.
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Prognosis Without therapy, mortality of patients with HLH
is high
Those with an inherited mutation in an HLH gene have a survival of approximately two months without treatment.
Patients treated on the HLH-2004 protocol had a median survival of 54 percent at 6.2 years (249 patients, median age eight months).
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Reference
Henter, J.-I., Horne, A., Aricó, M., Egeler, R. M., Filipovich, A. H., Imashuku, S., Ladisch, S., McClain, K., Webb, D., Winiarski, J. and Janka, G. (2007), HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr. Blood Cancer, 48: 124–131. doi: 10.1002/pbc.21039
McClain, K. Treatment and prognosis of hemophagocytic lymphohistiocytosis. In: UpToDate, Post, TW (Ed), UpToDate, Waltham, MA, 2014.
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Questions ??