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brief-report2017
CPJXXX10.1177/0009922817735997Clinical PediatricsMcCarthy et al
Brief Report
Challenges in the Diagnosis
and Management of Pediatric
Hemophagocytic Lymphohistiocytosis
Clinical Pediatrics
1­–7
© The Author(s) 2017
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https://doi.org/10.1177/0009922817735997
DOI: 10.1177/0009922817735997
journals.sagepub.com/home/cpj
Laura C. McCarthy, DO1,2, Karen S. Fernandez, MD1,3,
and Reuben Antony, MD1,4
Introduction
Hemophagocytic lymphohistiocytosis (HLH) is a multiorgan syndrome resulting from defective regulation of
inflammation in which excessive activation of macrophages and CD8+ lymphocytes causes a hyperinflammatory state mediated by high circulating levels of tumor
necrosis factor–α (TNF-α), interferon-γ (IFN-γ), interleukin-10 (IL-10), IL-6, IL-8, IL-12, and IL-18.1,2 The resulting end-organ damage causes a severe, often fulminant
systemic illness. HLH is thought to be either primary
(familial), where there is a known genetic defect of lymphocyte function, or secondary in which case a trigger
event may be identified, and there is no identified HLH
causing mutation or family history of HLH. Since many of
the clinical features seen in HLH are attributable to the
underlying causative illness, HLH is often initially overlooked as a diagnosis. Minimizing delay in diagnosis is
crucial for a favorable outcome. In this article, we outline
some challenges that might be faced when evaluating
patients for HLH and describe our experience managing
nine pediatric patients with this disease.
Results/Clinical Experience
Table 1 presents the results and clinical experience of 9
patients diagnosed with HLH.
Patient 1
A 5-year-old male presented with clinical features of atypical hemolytic-uremic-syndrome. HLH workup was commenced on day 10 of admission and HLH-directed treatment
was commenced on day 12 (intrathecal hydrocortisone,
dexamethasone, etoposide, and later alemtuzumab). Despite
extracorporeal membrane oxygenation (ECMO) support,
patient succumbed to his illness 1 month after admission.
Patient 2
A 5-year-old female presented with a 1-week history of
fever, oliguria, melena, and petechial rash. She experienced
rapid neurological deterioration and developed actue respiratory distress syndrome immediately after admission.
Magnetic resonance imaging revealed profound anoxic
brain injury and she died 48 hours after admission despite
ECMO support before HLH-directed therapy could be initiated. Autopsy revealed hemophagocytosis in several
organs and Rickettsial antigens in all tissues examined.
Patient 3
A 4-month-old male was admitted with high fever and
gastroenteritis (rotavirus). On day 4 of admission, laboratory evidence of HLH was obtained and HLH-directed
therapy was commenced on day 5 with dexamethasone
and 50% dosing of etoposide. Soluble-CD25 was
reported to be elevated on day 8 and natural killer (NK)–
cell activity was reported as being absent on day 12. He
harbored a known HLH-causing mutation and underwent a matched unrelated donor (MUD) cord blood
transplant following HLH-2004 therapy. He ultimately
succumbed to transplant-related complications.
Patient 4
A 16-year-old male with systemic Epstein-Barr virus
syndrome met 4/8 HLH-2004 diagnostic criteria at
admission. Dexamethasone/Rituximab were commenced. On day 13, soluble CD25 and NK-cell activity
results confirmed the diagnosis of HLH. He was diagnosed with X-linked inhibitor of apoptosis protein
(XIAP) deficiency and went on to receive a matched
1
University of Illinois College of Medicine at Peoria, Peoria, IL, USA
Children’s Mercy Hospital, Kansas City, MO, USA
3
Valley Children’s Hospital, Madera, CA, USA
4
University of California at Davis Children’s Hospital, Sacramento,
CA, USA
2
Corresponding Author:
Reuben Antony, University of California at Davis Children’s
Hospital, 2nd Floor, TICON 2 Building, 2516 Stockton Boulevard,
Sacramento, CA 95817, USA.
Email: rantony@ucdavis.edu
2
Rickettsial infection
Rotavirus
gastroenteritis
Epstein-Barr virus
Asymptomatic
Histoplasmosis
Spider bite
HHV-6
Undetermined
2
3
4
5
6
7
8
9
2
1
0
1
n/a
0
4
n/a
7
0
6: A, B, C, F,
G, H
5: A, C, D,
E, G
8: A, B, C, D,
E, F, G, H
6: A, B, C, D,
G, H
5: A, B, D,
G, H
3: C, D, G
4: C, D, G, H
5: A, B, C, D, G 6: A, B, C, D,
G, H
3: A, B, G
5: A, B, F, G, H
5: A, B, D, G, H
0
4: A, B, C, G
6: A, B, C, D,
E, F
4: A, C, D, G
6: A, B, C, D,
G, H
4
2
2
3
n/a
3
5
n/a
12
n/a
Negative
Negative
Negative
Negative
BMT
BMT
BMT
n/a
Additional
HLH
Treatment
Recovered fully
Recovered fully
XIAP deficiency discovered while
undergoing HLA workup for
brother’s BMT
Underwent matched sibling
donor BMT and succumbed to
complications
Recovered fully
Patient died 1 month and 4
days after admission after
withdrawing care (had been on
ECMO for 17 days)
Patient died within 48 hours of
admission
Transferred to outside hospital
for BMT where he succumbed
to transplant-related
complications
Currently post-MUD BMT
Outcome
Dexamethasone Etoposide Recovered fully Dexamethasone
Dexamethasone
Dexamethasone
BIRC4 hemizygous Dexamethasone
Absent XIAP
expression
BIRC4 hemizygous
n/a
Absent XIAP
expression
2 STXBP2
Dexamethasone
mutations: 703cg, and etoposide
1621ga
Negative
272 C.T (A91V) Dexamethasone
variant in 1 allele and etoposide
of the PRF1 gene
Initial HLH
Treatment
Abbreviations: BMT, bone marrow transplant; ECMO, extracorporeal membrane oxygenation; FHLH, familial hemophagocytic lymphohistiocytosis; HLA, human leukocyte antigen; HLH,
hemophagocytic lymphohistiocytosis; MUD, matched unrelated donor; n/a, not available; XIAP, X-linked inhibitor of apoptosis protein.
a
Criteria: A = fever ≥38.5°C; B = splenomegaly; C = cytopenias (2/3 lineages)—hemoglobin <9 g/dL, platelets <100 000/mL, neutrophils <1000/mL; D = triglycerides >265 mg/dL and/or fibrinogen
<150 mg/dL; E = hemophagocytosis in bone marrow, spleen, lymph nodes, or liver; F = low or absent NK-cell activity; G = ferritin >500 ng/mL; H = elevated soluble CD25.
Hemolytic-uremic
syndrome
Underlying Cause
1
Case
Days to
Consult
a
Criteriaa Met Days Admitted
Criteria Met During Course
Prior to
Genetic Studies for
Prior to Therapy
of Illness
Treating
FHLH
Table 1. Nine Patients Diagnosed With HLH Based on HLH-2004 Diagnostic Criteria.
McCarthy et al
unrelated hematopoietic stem cell transplant. He is doing
well 2 years post-transplant with no complications.
Patient 5
During pretransplant workup, the healthy 13-year-old
brother of patient 4 was found to have XIAP deficiency. He underwent a matched sibling donor stem
cell transplant but died from transplant-related
complications.
Patients 6-9
Dexamethasone alone was commenced within 96 hours
of admission. Three patients responded well to dexamethasone monotherapy; In patient 9, ferritin levels
started to increase on day 6 of therapy so etoposide was
added. None have had disease recurrence after completing HLH-2004-based therapy.
Discussion
While fever occurs in 91% of patients with HLH, it is
ubiquitous in inflammatory, infectious, or rheumatological conditions and can be absent in neonates with
HLH.4 Splenomegaly, also the result of immune activation is commonly seen in systemic infections as
well as rheumatological disorders. Splenomegaly
may be missed during physical examination and may
be absent in up to 16% of children with HLH.3
Cytopenias in HLH are speculated to occur due to
elevated levels of TNF-α and IFN-γ in the bone marrow microenvironment which suppress and/or cause
apoptosis of blood cell precursors.5,6 Bone marrow
suppression is also a common feature of many infectious, inflammatory and malignant disorders.
Hypertriglyceridemia occurs in HLH because
increased TNF-α and IFN-γ suppress the activity of
lipoprotein lipase,7 and hypofibrinogenemia is
thought to occur because activated macrophages
secrete plasminogen activator, leading to hyperfibrinolysis.8 While both of these findings are fairly specific for HLH, hypertriglyceridemia is only seen in
60% to 70% of cases9 and hypofibrinogenemia in
40%.10 Hemophagocytosis resulting from macrophage activation in bone marrow, spleen, lymph nodes
and/or liver is neither sensitive nor specific for HLH.11
It is seen in approximately 50% to 60% of patients
with HLH,11 but can also be present following blood
transfusions, in infection or autoimmune diseases in
patients without HLH.12-14 NK-cell function assays
are not widely available and may be difficult to interpret in profoundly leukopenic patients and patients
3
receiving immunosuppressive therapy. There can be
considerable variability in NK-cell function between
individuals and in an individual over time. Concurrent
NK-cell quantification testing should be performed as
the test can be falsely positive if NK-cell number is
reduced. Ferritin is released during cell breakdown15
and at high levels can be specific for HLH. If HLH is
suspected, blood samples should be diluted to accurately report high ferritin values (up to 100 000 ng/
dL) so that the serum ferritin can be used to monitor
disease response to treatment. Soluble CD25 (sCD25,
the α-chain of the IL-2 receptor) reflects T-cell activation. Reference values vary significantly by age so the
diagnostic criteria of >2400 units/mL is not applicable to all age groups. Being a send-out test for most
institutions, time to result is typically 30 to 96 hours.
Gender-based molecular diagnostic testing and mutation analysis for HLH is offered by referral centers.
Perforin/granzyme B protein expression (which identifies PRF1 gene function), NK-cell surface CD107a
expression (marker of exocytosis/degranulation),16
Signaling lymphocyte activation molecule (SLAM)associated protein expression (mutated in XLP1), and
XIAP expression (mutated in XLP-2)16,17 serve as
screening tests and have a relatively short turnaround
time while definitive familial HLH (FHLH) genetic
testing (AP3B1, LYST, SH2D1A, UNC13D,
BLOC1S6, MAGT1, SLC7A7, CD27, PRF1, STX11,
BIRC4, ITK, RAB27A, STXBP2) takes several weeks
and does not affect acute patient management.
Hospital clinical services that could encounter
patients with HLH should be trained to recognize
HLH to reduce time to consultation. Early referral
enables the pediatric hematology service to evaluate
patients and coordinate laboratory evaluation to
obtain all required samples prior to treatment and to
have viable samples sent to outside laboratories early
and to communicate with laboratories, send-out
department, sedation services and HLH referral center if needed. Samples are best collected immediately
prior to shipping in the evening and must be sent by
overnight courier to arrive the following morning.
Once a diagnosis of HLH is confirmed, FHLH studies
can be performed which take about 4-6 weeks to
result. In some patients who have not met all HLH
diagnostic criteria, if the history and available clinical
data are compelling, dexamethasone monotherapy
can be commenced while awaiting results of the sendout tests and for central line placement. Once all diagnostic criteria are met, and depending on the patient’s
clinical and laboratory response to dexamethasone
monotherapy etoposide may be added to the treatment
regimen (Table 2).
4
••
••
••
••
••
••
••
••
••
Ethnicity
Consanguinity
Family history
Past medical history
(esp. malignancy,
immune disorder,
treatment with
immunosuppressants
or rheumatologic
condition)
Travel history
Insect bites
Unexplained fevers
Reaction to vaccination
Previous blood
transfusion
History
Pitfalls to recognize
General Studies to Consider
Clinical
•• CBC/blood smear
•• CMP / amylase / lipase
Fever ≥ 38.5° C
Commonly absent in
•• Coagulation panel (95% have
neonates with HLH (12) and
DIC)
not specific for HLH
•• Lipid panel
Splenomegaly
Not present in 16% of cases •• T&B Cell enumeration
May not always be palpated
•• Immunoglobulin levels
on exam
•• Anti-ds-DNA
Cytopenias (2/3
Not specific for HLH
•• Reticulocyte count
lineages)
•• ANA
•• Hgb <9 g/dL
•• Bone Marrow studies
•• Plts <100,000/mcL
•• Skin biopsy
•• Abs Neutrophil
•• Lymph node biopsy
Count <1,000/mcL
•• Lumbar puncture to look for
Triglycerides >265mg/ Hypertriglyceridemia absent
elevated protein, cell count,
dL and/or
in 30-40% of cases.
and/or hemophagocytosis
Fibrinogen <150 mg/dL Hypofibrinogenemia absent in
(abnormal CSF at diagnosis
up to 60% of cases.
assoc with higher mortality)
•• Flow cytometry
Diagnostic Criteria
HLH-Specific
Lab Evaluation
Table 2. Diagnosis and Management of HLH in a Tertiary, Non-HLH Referral Children’s Hospital.
•• Blood culture
•• Viral Studies: EBV, CMV,
HSV, HHV-6, Parvovirus,
HIV, Influenza, VZV,
adenovirus, measles
•• Hepatitis panel
•• Mycoplasma
•• Rickettsia
•• Malaria
•• Leishmaniasis
•• Mycobacterial infection
•• Fungal studies: candida,
aspergillus, histoplasma
•• Dengue
•• Leptospirosis
•• Urine culture
•• CSF culture
•• TB test
Infectious Studies to
Consider
(continued)
•• CT neck, chest,
abdomen, pelvis
•• MRI brain
•• Chest X-ray
•• Echocardiogram
•• Abdominal US
to evaluate
hepatosplenomegaly
Radiology at admission
(tailor to symptoms)
5
••
••
••
••
••
••
••
••
••
Lab Evaluation
••
••
••
••
••
Perforin/granzyme B •• First 4 should be sent
CD107a
together once HLH
XIAP
suspected to prevent delay
SAP
in diagnosis
FHLH genetic
•• Sequencing panel, due to
sequencing panel
cost, should be saved until
HLH diagnosis is made
Molecular
Steroids &
immunosuppressants may
affect NK cell function
There can be considerable
variability in NK cell
function between individuals
and within an individual over
time.
Send out lab sent MondayThursday only
Lab technique is important to
get accurate value
Cut off value of 500ng/mL is
84% sensitive for HLH, but
no data of specificity (13)
Send-out lab sent MondayThursday only
Reference ranges vary
significantly by age (12)
••
••
••
••
••
••
••
Early Line placement
Antipyretics
Proton Pump Inhibitor
PCP prophylaxis
Voriconazole
Blood product support
IVIG
Hemophagocytosis in Is neither sensitive nor
bone marrow, spleen, specific for HLH (12).
lymph nodes and/or Commonly seen with blood Supportive Care
liver
transfusions, infection and
autoimmune disease (12).
Invasive procedures by
experienced physicians
May require sedation, utilizes
more personnel and
resources
Pallor
Low or absent NK Cell
Scleral icterus
Activity
Lymphadenopathy
Rashes / petechiae / skin
findings
Pulmonary exam
(worsening pulmonary
function is an ominous
sign and should suggest
poor HLH control)
Hepatosplenomegaly
Ferritin >500 ng/mL
Neurologic exam
Joint Exam
Peripheral neuropathy
(occurs secondary to
myelin destruction by
Elevated s-CD25
macrophages
(>2400 units/mL)
Exam
History
Table 2. (continued)
•• To treat any underlying
infection:
-Rituximab for EBV
-Antibiotics
-Antifungals
-Antivirals
Anti-Infective
Treatment
(continued)
•• Consults:
-Infectious Disease
-Hematology/
Oncology
-Surgery
•• Know when to
transfer:
- No response to
treatment
- Clinical
deterioration
•• Know when to refer:
-Genetic studies
indicate Familial
HLH and BMT
warranted
-Search for
potential BMT
donor needed
Consults/Transfers
6
HLH-Directed Treatment
•• Patient meets some diagnostic criteria but not
all, and is hemodynamically stable
•• Central line not immediately available
•• Patient responds within 24 hours to
Dexamethasone monotherapy (evidenced by
decreased fever and ferritin level) and continues
to improve
•• Parents of hemodynamically stable patients
decline Etoposide
Criteria to Add Etoposide in a Patient
Commenced on Dexamethasone Alone
•• Patient continues to be febrile and/or ferritin
continues to increase within 24 hours of starting
Dex alone
•• Any deterioration in overall clinical status
Criteria to Start Etoposide and
Dexamethasone Together
•• Patient systemically unwell, has CNS
involvement or hemodynamic instability
Criteria to Treat With Dexamethasone
Alone
History
Table 2. (continued)
PICU Staff
NICU Staff
Nursing
ER Team
Hospitalist Team
Community Physicians
Infectious Disease
Clinicians
Team initiates work up to
establish diagnosis
Usually the first to see sick
patients
To know importance of timely
labs
For those with FHLH that
present in neonatal period
Because care is often escalated
Due to infection often being
underlying cause of 2° HLH
These are our referring
physicians
Anticipation
•• Preparation of samples for •• It is important
accurate value reporting
to have printed
•• Communication with
guidelines for:
pathologists
- initial labs
•• Provide list of HLH
- initial radiology
referral labs
- clinical diagnosis
•• Knowledge of appropriate •• Appropriate and
send-out forms
timely consultations
•• Specimen storage
•• Know when to
•• Specimen processing
transfer to PICU
protocols
or to higher level
treatment center
Laboratory
Anticipated Education for Hospital and Community to Increase Awareness of HLH
Lab Evaluation
McCarthy et al
Acknowledgments
The authors would like to thank Dr Rebecca Marsh for assistance in preparing this article.
Author Contributions
LCM: concept, data collection, manuscript preparation,
table preparation. KSF: concept, manuscript preparation,
table preparation. RA: concept, manuscript preparation, table
preparation.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
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