ORIGINAL www.jpeds.

com • THE JOURNAL OF PEDIATRICS

ARTICLES
Development and Initial Validation of the Macrophage Activation
Syndrome/Primary Hemophagocytic Lymphohistiocytosis Score,
a Diagnostic Tool that Differentiates Primary Hemophagocytic
Lymphohistiocytosis from Macrophage Activation Syndrome
Francesca Minoia, MD1, Francesca Bovis, PhD2, Sergio Davì, MD1, Antonella Insalaco, MD3, Kai Lehmberg, MD4,
Susan Shenoi, MD5, Sheila Weitzman, MD6, Graciela Espada, MD7, Yi-Jin Gao, MD8, Jordi Anton, MD9, Toshiyuki Kitoh, MD10,
Ozgur Kasapcopur, MD11, Helga Sanner, MD12, Rosa Merino, MD13, Itziar Astigarraga, MD14, Maria Alessio, MD15,
Michael Jeng, MD16, Vyacheslav Chasnyk, MD17, Kim E. Nichols, MD18, Zeng Huasong, MD19, Caifeng Li, MD20,
Concetta Micalizzi, MD1, Nicolino Ruperto, MD, MPH1, Alberto Martini, MD1, Randy Q. Cron, MD21, Angelo Ravelli, MD1,2,*, and
AnnaCarin Horne, MD22,*, on behalf of the Pediatric Rheumatology International Trials Organization, the Childhood Arthritis
and Rheumatology Research Alliance, the Pediatric Rheumatology Collaborative Study Group, and the Histiocyte Society†

Objective To develop and validate a diagnostic score that assists in discriminating primary hemophagocytic
lymphohistiocytosis (pHLH) from macrophage activation syndrome (MAS) related to systemic juvenile idiopathic
arthritis.
Study design The clinical, laboratory, and histopathologic features of 362 patients with MAS and 258 patients
with pHLH were collected in a multinational collaborative study. Eighty percent of the population was assessed to
develop the score and the remaining 20% constituted the validation sample. Variables that entered the best fitted
model of logistic regression were assigned a score, based on their statistical weight. The MAS/HLH (MH) score
was made up with the individual scores of selected variables. The cutoff in the MH score that discriminated pHLH
from MAS best was calculated by means of receiver operating characteristic curve analysis. Score performance
was examined in both developmental and validation samples.
Results Six variables composed the MH score: age at onset, neutrophil count, fibrinogen, splenomegaly, platelet
count, and hemoglobin. The MH score ranged from 0 to 123, and its median value was 97 (1st-3rd quartile 75-
123) and 12 (1st-3rd quartile 11-34) in pHLH and MAS, respectively. The probability of a diagnosis of pHLH ranged
from <1% for a score of <11 to >99% for a score of ≥123. A cutoff value of ≥60 revealed the best performance in
discriminating pHLH from MAS.
Conclusion The MH score is a powerful tool that may aid practitioners to identify patients who are more likely to
have pHLH and, thus, could be prioritized for functional and genetic testing. (J Pediatr 2017;189:72-8).

See editorial, p 19 From the 1G. Gaslini Institute; 2University of Genova,

Genoa; 3Pediatric Hospital of Bambino Gesù, Rome, Italy;
4
University Medical Center, Hamburg, Germany; 5Seattle
Children’s Hospital and University of Washington, Seattle,
WA; 6The Hospital for Sick Children, Toronto, Ontario,

H
emophagocytic lymphohistiocytosis (HLH) is a life-threatening Canada; 7Ricardo Gutierrez Children’s Hospital, Buenos
Aires, Argentina; 8Children’s Hospital of Fudan University,
hyperinflammatory syndrome caused by a severely dysregulated immune Shanghai, China; 9Hospital Saint Joan de Déu,
response.1 It is characterized by highly activated lymphocytes and mac- Barcelona, Spain; 10Aichi Medical University, Nagakute,
Japan; 11Istanbul University, Cerrahpasa Medical School,
rophages that infiltrate tissues and produce large amounts of proinflammatory Istanbul, Turkey; 12Oslo University Hospital,
Rikshospitalet, Oslo, Norway; 13La Paz University
cytokines.2,3 A set of clinical, laboratory, and histopathologic features define the Hospital, Madrid; 14BioCruces Health Research Institute,
Cruces University Hospital, University of the Basque
acute syndrome, including unremitting fever, hepatosplenomegaly, cytopenia, Country, Barakaldo, Spain; 15University of Naples
hypofibrinogenemia, elevated ferritin, liver enzymes, triglycerides, and soluble Federico II, Naples, Italy; 16Stanford School of Medicine,
Palo Alto, CA; 17Saint Petersburg State Pediatric Medical
CD25 (or soluble interleukin-2 receptor a chain), and hemophagocytosis (the en- University, Saint Petersburg, Russia; 18St. Jude Children’s
Research Hospital, Memphis, TN; 19Guangzhou
gulfment of blood cells by activated macrophages) in different tissues and organs.4 Children’s Hospital, Guangzhou; 20Beijing Children’s
Hospital, Beijing, China; 21University of Alabama,
Birmingham, AL; and 22Karolinska University Hospital,
Stockholm, Sweden
*Contributed equally.
†List
of additional members available at www.jpeds.com
HLH Hemophagocytic lymphohistiocytosis
(Appendix).
MAS Macrophage activation syndrome
The authors declare no conflicts of interest.
pHLH Primary hemophagocytic lymphohistiocytosis
ROC Receiver operator characteristic 0022-3476/$ - see front matter. © 2017 Elsevier Inc. All rights
sJIA Systemic juvenile idiopathic arthritis reserved.
http://dx.doi.org10.1016/j.jpeds.2017.06.005

72

HLH comprises a heterogeneous spectrum of clinically
similar but etiologically diverse subtypes, affecting all ages. In
the current classification of histiocytic disorders, it is subdi-
vided into primary and secondary forms.5-7 Primary HLH
(pHLH, also called familial HLH) refers to cases associated with
several inherited monogenic disorders.8 Secondary HLH (also
known as acquired or reactive HLH) is not typically inher-
ited, but complicates various medical conditions, including in-
fections, malignancies, and rheumatic diseases. By convention,
secondary HLH seen in rheumatic disorders is termed mac-
rophage activation syndrome (MAS).9 In childhood, this con-
dition occurs most commonly in systemic juvenile idiopathic
arthritis (sJIA).10-12
Both pHLH and MAS are potentially fatal and require im-
mediate recognition to initiate prompt treatment and avoid
a deleterious outcome. However, because they bear close clini-
cal similarities, their differentiation may be challenging. Dis-
tinction may be particularly difficult when MAS is the initial
clinical presentation of sJIA and arthritis is not yet present.
Diagnostic challenges are compounded by the increasing
number of reports of patients who develop pHLH in adoles-
cence or adulthood.13 Indeed, although pHLH typically de-
velops in the first year of life, it is now understood that there
are patients with a genetic basis for this illness who remain as-
ymptomatic until a late age.14 Documentation of biallelic patho-
logic mutations in a disease-associated gene is the gold standard
diagnostic test for pHLH. However, these studies take weeks
to complete and may not be available in resource-limited areas.
In addition, although most cases of pHLH can be verified mo-
lecularly, some cases still elude molecular diagnosis.15 More-
over, interpretation of genetic studies is not always
straightforward because some genetic overlap between MAS
and pHLH has been identified.16,17 Indeed, a substantial per-
centage of patients with secondary HLH, including MAS,
possess heterozygous mutations in the same perforin-mediated
cytolytic pathway genes associated with pHLH.18-20 Recently,
some of these heterozygous mutations have been shown to con-
tribute to disease pathophysiology by acting as dominant-
negative mutants.21,22
Timely diagnosis is essential, because pHLH is often more
severe than MAS. In addition, management of the 2 condi-
tions differs. Although both are treated with intravenous cor-
ticosteroids and cyclosporine, the treatment protocols
recommended for pHLH (HLH-94) involves dexamethasone
and etoposide,23 whereas pediatric rheumatologists almost
always use in MAS higher corticosteroid equivalents of meth-
ylprednisolone and interleukin-1 blockers.10 Furthermore, pa-
tients with pHLH often require allogeneic hematopoietic stem
cell transplantation sooner than later.24 In contrast, patients
with sJIA almost never need such treatment.
Diagnostic or classification criteria are available for both
pHLH7 and MAS.25-27 However, their ability to discriminate
between the 2 syndromes has not been investigated previ-
ously. Recently, Fardet et al28 published a weighted diagnostic
score for the broader category of reactive hemophagocytic syn-
drome, called the HScore. However, because their patient sample
was only composed of adults with reactive hemophagocytic
Volume 189 • October 2017
syndrome, no information can be drawn reliably regarding the
applicability of the HScore to pediatric patients with pHLH
or MAS. Moreover, it has been argued that the use in MAS of
some individual criteria included in the HScore may be
problematic.29
The primary purpose of this international collaborative
project was to develop and validate a diagnostic score that assists
in discriminating pHLH from sJIA-associated MAS.
Methods
Data from patients with MAS were collected in the context of
the multinational collaborative effort that led to the develop-
ment of the 2016 classification criteria for MAS complicat-
ing sJIA.26,27 The design, inclusion criteria, and data collection
procedures of this project have been described in detail
elsewhere.26,27,30-32 Briefly, international pediatric rheumatologists
and pediatric hematologists were asked to collect data from
patients with sJIA-associated MAS seen at their institution after
2002. To be included in the study, patients had to have sJIA33
and to have had an episode of MAS diagnosed and treated as
such by the caring physician.
Data from patients with pHLH were retrieved from both
the HLH-9423 and HLH-20047 trials and were recorded in the
Histiocyte Society Register. The diagnosis of pHLH was based
on the HLH-94 or HLH-2004 criteria, depending on the year
of observation. All patients had their diagnosis confirmed ge-
netically. For all patients with MAS or pHLH, demographic,
clinical, laboratory, and histopathologic information was col-
lected at disease onset. The study protocol was approved by
the ethics committee at each participating center.
Statistical Analyses
The methodology used for the construction of the
MAS/HLH (MH) score shares many features with that used
by Fardet et al28 for the development of the HS score. Eighty
percent of patients enrolled in the study were assigned ran-
domly to the developmental dataset by stratifying MAS and
patients with pHLH, and the remaining 20% were assigned to
the validation dataset. The developmental and validation groups
were comparable for all clinical, laboratory, and histopatho-
logic characteristics (data not shown). The features of pa-
tients with pHLH and MAS were compared by the c2 test (for
categorical variables) and Mann-Whitney U test (for continu-
ous variables).
To enhance the feasibility of the score, before inclusion in
univariate analysis, continuous variables were dichotomized
through a receiver operator characteristic (ROC) curve analy-
sis, retaining the value at which sensitivity and specificity were
maximized. All variables listed in Table I were assessed. The
variables with the strongest association with the diagnosis of
pHLH (ie, those that achieved an OR > 5 and a P < .05) were
scrutinized further on multivariable logistic regression pro-
cedures to evaluate their independent contribution to the
outcome (ie, the diagnosis of pHLH). The characteristics of
patients with missing variables were compared with those of
73
THE JOURNAL OF PEDIATRICS • www.jpeds.com Volume 189

Table I. Comparison of demographic, clinical, laboratory, and histopathologic features at disease onset between pa-
tients with MAS and pHLH
Patients with MAS Patients with pHLH
n (n = 362) n (n = 258) P value
Demographic characteristics
Median (1st-3rd quartile) age, y 362 8.1 (4.0-13.0) 258 0.3 (0.2-1.2) <.0001
Female 362 208 (57.5) 258 128 (49.6) .05
Clinical manifestations
Fever 355 341 (96.1) 257 236 (91.8) .03
Hepatomegaly 350 245 (70.0) 254 234 (92.1) <.0001
Splenomegaly 347 201 (57.9) 248 142 (96.2) <.0001
Generalized lymphadenopathy 346 178 (51.4) 110 28 (25.5) <.0001
CNS involvement 349 122 (35.0) 253 90 (35.6) .88
Jaundice 351 49 (14.0) 99 15 (35.4) <.0001
Median (1st-3rd quartile) values of laboratory tests
Hemoglobin, g/dL 335 9.8 (8.3-11.1) 248 7.3 (6.3-8.2) <.0001
Neutrophil count, × 109/L 297 5.4 (2.3-11.5) 221 0.6 (0.3-1.1) <.0001
Platelet count, × 109/L 338 144 (86-270) 249 29 (16-52) <.0001
Aspartate aminotransferase, U/L 327 134 (58-339) 215 171 (88-376) .01
Lactate dehydrogenase, U/L 269 1230 (666-2345) 211 696 (487-1249) <.0001
Triglycerides, mg/dL 278 234 (151-320) 236 325 (221-486) <.0001
Albumin, g/dL 258 3.1 (2.6-3.5) 189 2.7 (2.3-3.1) <.0001
Bilirubin, mg/dL 230 0.7 (0.4-1.6) 216 0.5 (0.2-1.7) .05
Fibrinogen, mg/dL 294 267 (151-440) 224 98 (60-156) <.0001
Ferritin, ng/mL 308 5353 (1500-13 080) 225 2910 (1400-7270) .003
Histopathologic features
Bone marrow aspiration and/or other biopsy 348 252 (72.4) 254 251 (98.8) <.0001
Hemophagocytosis 252 159 (63.1) 247 191 (77.3) .0006

CNS, central nervous system.

Except where indicated otherwise, data are n (%).

patients included in the best fit model of multivariable analy-
sis (results not shown).
The coefficients resulting from multiple logistic regression
analysis were used to assign score points for construction of
the MH score. For each variable that entered the best fit model,
the rule was to multiply the b value for each range by 10 and
then to round off to the nearest integer. To validate this method,
a 200-cycle bootstrapped simulation sample was constructed
to generate beta coefficients. The median beta coefficients
yielded by this analysis were very similar to those obtained in
our model. The MH score was made up by the individual scores
of the selected variables. After the calculation of the score for
each case from the developmental dataset, it was used in another
logistic regression equation designed to be converted to a prob-
ability of having pHLH. The first step in the development
of the equation was to compute the logit, as follows:
logit = b0 + (b1 × MH score), after verifying that the MH score
was distributed normally. The second step was to convert this
logit to a probability of pHLH, with the following equation:
probability(y = 1/logit) = elogit/(1 + elogit).
The cutoff value in the MH score that provided the best dis-
crimination between pHLH and MAS was calculated by means
of ROC curve analysis. To evaluate the performance of the
system, the sensitivity, specificity, area under the ROC curve,
and kappa value were calculated for both the developmental
and validation samples. Hosmer-Lemeshow tests were per-
formed on both developmental and validation sets to evalu-
ate calibration, and areas under the ROC curves were used to
evaluate discrimination. Continuous variables are presented
as medians and 1st to 3rd quartiles, whereas categorical variables
74
are presented as proportions. Missing data were not imputed
or included in the analyses. All analyses were carried out using
SAS software version 9.3 (SAS Institute Inc, Cary, North
Carolina).
Results
A total of 620 patients were enrolled in the study: 362 had MAS
and 258 had pHLH. The comparison of the demographic, clini-
cal, laboratory, and histopathologic features between the 2
patient groups are presented in Table I. Patients with pHLH
had a lower median age at onset and higher frequency of hepa-
tosplenomegaly and jaundice, whereas fever and generalized
lymphadenopathy were more common in patients with MAS.
The prevalence of central nervous system involvement was com-
parable between the 2 populations. Patients with pHLH had
more profound cytopenia and hypofibrinogenemia, and higher
levels of aspartate aminotransferase and triglycerides. Con-
versely, ferritin and lactate dehydrogenase levels were greater
in the MAS group. Hemophagocytosis was detected more com-
monly in the pHLH sample.
The developmental dataset was composed of 496 patients,
290 with MAS and 206 with pHLH. As shown in Table II, age
at onset of ≤ 1.6 years, splenomegaly, hepatomegaly, platelet
count of ≤78 × 109/L, neutrophil count of ≤1.4 × 109/L, fi-
brinogen of ≤131 mg/dL, and hemoglobin of ≤8.3 g/dL re-
vealed the strongest correlations with the diagnosis of pHLH
(OR > 5; P < .05) on univariate analysis. In the best fitted model
of multivariate procedures, 6 of these 7 variables remained sig-
nificantly associated with the probability of pHLH (Table III).
Minoia et al
October 2017 ORIGINAL ARTICLES

Table II. Univariate analysis of the ability of variables at disease onset to discriminate patients with pHLH from pa-
tients with MAS (N = 496)
No. of patients with available data OR (95% CI) P value
Demographic characteristics
Age ≤ 1.6 y 482 46.4 (26.9-80.2) <.0001
Sex 496 1.5 (1.1-2.2) .02
Clinical features at onset
Splenomegaly 482 14.0 (7.1-27.6) <.0001
Hepatomegaly 482 5.0 (2.8-8.5) <.0001
Jaundice 356 4.0 (2.3-7.2) <.0001
Central nervous system involvement 483 1.0 (0.7-1.5) .96
Fever 488 0.4 (0.2-0.6) .03
Generalized lymphadenopathy 360 0.3 (0.2-0.6) <.0001
Laboratory values at onset
Platelet count ≤ 78, × 109/L 466 27.5 (16.3-46.5) <.0001
Neutrophil count ≤ 1.4, × 109/L 404 24.8 (14.7-42.0) <.0001
Fibrinogen ≤ 131, mg/dL 415 10.3 (6.5-16.4) <.0001
Hemoglobin ≤ 8.3, g/dL 464 9.2 (6.0-14.1) <.0001
Triglycerides > 283, mg/dL 407 3.5 (2.3-5.3) <.0001
Lactate dehydrogenase > 835, U/L 383 3.4 (2.3-5.2) <.0001
Albumin ≤ 2.9, g/dL 355 3.3 (2.1-5.1) <.0001
Ferritin ≤ 6240, ng/mL 429 2.4 (1.6-3.6) <.0001
Aspartate aminotransferase > 124, U/L 426 2.0 (1.3-3.0) <.0001
Bilirubin ≤ 0.4, mg/dL 355 1.4 (0.9-2.2) .09
Hemophagocytosis on BM aspiration and/or other biopsy 385 2.0 (1.3-3-1) .003

BM, bone marrow aspirate.

Features with strong correlations (OR > 5, P < .05) are bolded.

Hepatomegaly was excluded from the model, because it was 11-34) in patients with MAS. The probability of receiving a
not independently associated with the diagnosis. diagnosis of pHLH by the MH score is detailed in Table V
The maximum score assigned to each variable ranged from (available at www.jpeds.com). The ROC curve analysis iden-
37 points, attributed to age and neutrophil count, to 11 points, tified the score of 60 as the cutoff value that provided the best
given to platelet count and hemoglobin. Missing data were discrimination between pHLH and MAS, with a score of ≥60
scored as 0 (Table IV). The MH score resulted from the arith- being indicative of pHLH. The application of this cutoff yielded
metic sum of the individual scores of each variable, and ranged a sensitivity of 91%, specificity of 93%, area under the curve
from 0 to 123. The median value was 97 (1st-3rd quartile 75- of 0.92, and kappa value of 0.85. The statistical performance
123) in patients with pHLH and 12 (1st-3rd quartile was similar when the score was tested after the exclusion of
patients with missing values (results not shown).
In the validation sample (n = 124), the median MH score
was 108 (1st-3rd quartile 75-123) in the pHLH group and 12
Table III. Best fitted model of multivariate analysis (1st-3rd quartile 11-25) in patients with MAS. The analysis of
(n = 338) and attributions of points for the MH score this dataset confirmed the strong discriminative power of the
Points in MH score, with the above statistical properties being 88%, 93%,
OR 95% CI b MH score 0.91, and 0.82, respectively. The goodness-of-fit test per-
Age at onset ≤ 1.6 y 40.3 10.8-150.3 3.7 37 formed on the developmental dataset yielded a P value of .95.
Neutrophil count ≤ 1.4, × 109/L 39.3 10.7-144.8 3.7 37 When the MH score was applied to the validation dataset, the
Fibrinogen ≤ 131, mg/dL 4.4 1.6-12.5 1.5 15
Splenomegaly 3.3 1.0-10.9 1.2 12 P value was 0.92, suggesting that the model can be applied ac-
Platelet count ≤ 78, × 109/L 3.1 1.1-8.6 1.1 11 curately in patients other than those in whom the model was
Hemoglobin ≤ 8.3, g/dL 2.9 1.1-7.9 1.1 11 developed. The area under the ROC curve for the MH score
The area under the curve of the model is 0.98. was 0.97 both in the developmental and in the validation
dataset, indicating excellent discrimination.
The validity of the score was further scrutinized by exam-
Table IV. The MH score ining its ability to discriminate between patients with pHLH
(n = 258) and patients who developed MAS at the onset of sJIA
Points for scoring
(n = 77) and patients (n = 95) who had the diagnosis of MAS
Age at onset, y 0 (>1.6); 37 (≤1.6) confirmed by the experts who participated in the consensus
Neutrophil count, × 109/L 0 (>1.4); 37 (≤1.4)
Fibrinogen, mg/dL 0 (>131); 15 (≤131) conference that led to the development of the 2016 classifi-
Splenomegaly 0 (no); 12 (yes) cation criteria for MAS complicating sJIA.26,27 Overall, the sta-
Platelet count, × 109/L 0 (>78); 11 (≤78) tistical performance of the score in the 2 datasets was similar
Hemoglobin, g/dL 0 (>8.3); 11 (≤8.3)
to that seen in the validation sample (results not shown).
Development and Initial Validation of the Macrophage Activation Syndrome/Primary Hemophagocytic Lymphohistiocytosis Score, 75
a Diagnostic Tool that Differentiates Primary Hemophagocytic Lymphohistiocytosis from Macrophage Activation Syndrome
THE JOURNAL OF PEDIATRICS • www.jpeds.com Volume 189

aspiration or a tissue biopsy did not display hemophagocytosis.

Discussion It is widely recognized that a lack of hemophagocytosis can
be observed in the early stages of HLH, and the diagnosis of
We have developed a score aimed to assist in timely differen-
this condition does not depend on this morphologic finding.40,41
tiation between pHLH and MAS. The construction of the tool
Likewise, the preliminary diagnostic guidelines for MAS do not
was based on a large dataset of patients with the 2 illnesses and
require tissue confirmation.25 Thus, hemophagocytosis is
comprised 6 demographic, clinical, and laboratory variables,
not a required feature of MAS or pHLH. Moreover,
weighted through a multivariable analysis on the basis of the
hemophagocytosis may represent a counterregulatory mecha-
strength of their association with the diagnosis of pHLH. The
nism rather than underlying MAS pathology.42-44
discriminative ability of the MH score was excellent in both
It is important to note that 4 of the 6 variables included in
developmental and validation datasets.
the MH score are laboratory tests. Indeed, hemophagocytic
Our study provided the opportunity to compare the char-
syndromes are most commonly suggested by detection of
acteristics of pHLH and MAS at disease presentation in a
subtle laboratory alterations, whereas clinical symptoms are
large multinational sample, which is likely representative of
often delayed and/or similar to those observed in other
patients with the 2 conditions seen by pediatric practitioners
conditions.45,46 The strongest discriminating power between
worldwide. As expected, children with pHLH were much
the 2 illnesses was the age at onset ≤1.6 years and a neutro-
younger at disease onset than those with MAS. It is well-
phil count of ≤1.4 × 109/L, which together accounted for
known that pHLH typically starts in early infancy,20,34,35
60.2% of the total score.
whereas MAS follows the distribution of sJIA, which may
There are several study limitations. Patient data were
affects children of all ages36 with peak age of onset of 2
collected through the review of clinical charts, which is
years.37
subject to missing and possibly erroneous data. We should
Our analysis confirmed the close similarity of the clinical
also recognize that the diagnosis of MAS was based on the
phenotype of the 2 illnesses. The slightly greater prevalence
clinician’s expert opinion. However, the discriminative per-
of fever in MAS is not relevant, because this symptom is usually
formance of the score was similar when the analysis was
present in nearly all patients with both conditions. Hepato-
restricted only to patients who had the diagnosis of MAS
splenomegaly was more frequent in pHLH, whereas general-
confirmed by a consensus (≥80%) of experts. Because exclu-
ized lymphoadenopathy was more common in MAS. Central
sion of pHLH through search for mutations in disease-
nervous system involvement was detected in around one-
associated genes was not required, we cannot exclude that
third of patients in both series. Unfortunately, we could not
some patients diagnosed as MAS, particularly at presenta-
compare the occurrence of hemorrhagic manifestations, because
tion of sJIA, may have pHLH. However, the diagnostic
information about these complications was not available for
power of the score for patients who had MAS at sJIA onset
the pHLH sample.
was similar to that seen in the whole sample, and it may be a
Impairment of laboratory tests was generally more severe
semantic argument as the distinction between pHLH and
in pHLH than in MAS, given the widely recognized greater
secondary HLH is becoming blurred genetically.19 The selec-
severity of the former disease. Pancytopenia and
tion of variables based on the results of univariate analysis
hypofibrinogenemia were more profound in patients with
can be debated because it does not consider covariate adjust-
pHLH. However, the average values of ferritin and lactate de-
ments. The use of other advanced variable selection methods,
hydrogenase were higher in MAS. Notably, an increase in lactate
such as Frank Harrell’s backward selection strategy,47 to
dehydrogenase out of proportion of the other laboratory mea-
select parsimonious set of variables for the prediction model
sures of MAS may herald the occurrence of thrombotic throm-
may have led to more valid results.
bocytopenic purpura, a rare but worrying complication of
In conclusion, the MH score is a powerful tool that facili-
uncontrolled MAS.38 Aspartate aminotransferase and biliru-
tates timely discrimination of pHLH from sJIA-associated MAS
bin did not discriminate well between the 2 conditions.
and helps in decision making regarding initial therapy and
Our results are similar to those reported by Lehmberg et al39
which patients need further evaluation to diagnose sus-
in a smaller sample. They found that higher neutrophil count
pected pHLH. This score is feasible and easily applicable in
and C-reactive protein and lower soluble CD25 indicated MAS
diverse practices and countries, which should result in its wide-
rather than pHLH. Although the ferritin level was also higher
spread acceptance and use. Prospective application of the score
in their patients with MAS, its discriminative power was poor.
to other patient cohorts will further assess its discriminative
In our study, we could not assess C-reactive protein and soluble
performance. Importantly, the MH score is not intended for
CD25, because they were not available for the pHLH and MAS
use in conditions other than those investigated in this study,
cohort, respectively.
particularly MAS associated with sJIA. ■
Another important feature of both disorders is
hemophagocytosis. This phenomenon was detected more fre-
quently in bone marrow or tissue biopsies in pHLH than in Submitted for publication Feb 22, 2017; last revision received May 2, 2017;
accepted Jun 2, 2017
MAS, but did not enter the best fitted multivariable model.
Reprint requests: Francesca Minoia, MD, Pediatria II-Reumatologia, Istituto G.
Notably, >20% of patients with pHLH and approximately one- Gaslini, via G. Gaslini 5, 16147 Genova, Italy. E-mail: francescaminoia@
third of patients with MAS who underwent bone marrow gaslini.org

76 Minoia et al
October 2017
References
1. Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis.
Annu Rev Med 2012;63:233-46.
2. Henter JI, Elinder G, Soder O, Hansson M, Andersson B, Andersson U.
Hypercytokinemia in familial hemophagocytic lymphohistiocytosis. Blood
1991;78:2918-22.
3. Osugi Y, Hara J, Tagawa S, Takai K, Hosoi G, Matsuda Y, et al. Cytokine
production regulating Th1 and Th2 cytokines in hemophagocytic
lymphohistiocytosis. Blood 1997;89:4100-3.
4. Lehmebrg K, Ehl S. Diagnostic evaluation of patients with suspected
hemophagocytic lymphohistiocytosis. Br J Haematol 2013;160:275-
87.
5. Favara BE, Feller AC, Pauli M, Jaffe ES, Weiss LM, Arico M, et al. Con-
temporary classification of histiocytic disorders. The WHO Committee
on Histiocytic/Reticulum Cell Proliferations. Reclassification Working
Group of the Histiocyte Society. Med Pediatr Oncol 1997;29:157-
66.
6. Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How I
treat hemophagocytic lymphohistiocytosis. Blood 2011;118:4041-52.
7. Henter JI, Horne A, Aricò M, Egeler RM, Filipovich AH, Imashuku S, et al.
HLH-2004: diagnostic and therapeutic guidelines for hemaphagocytic
lymphohistiocytosis. Pediatr Blood Cancer 2007;48:124-31.
8. Emile JF, Abla O, Fraitag S, Horne A, Haroche J, Donadieu J, et al. Revised
classification of histiocytoses and neoplasms of the macrophage-
dendritic cell lineages. Blood 2016;127:2672-81.
9. Stephan JL, Zeller J, Hubert P, Herbelin C, Dayer JM, Prieur AM. Mac-
rophage activation syndrome and rheumatic disease in childhood: a report
of four new cases. Clin Exp Rheumatol 1993;11:451-6.
10. Ravelli A, Grom AA, Behrens EM, Cron RQ. Macrophage activation
syndrome as part of systemic juvenile idiopathic arthritis: diagnosis,
genetics, pathophysiology and treatment. Genes Immun 2012;13:289-
98.
11. Stephan JL, Kone-Paut I, Galambrun C, Mouy R, Bader-Meunier B, Prieur
AM. Reactive hemophagocytic syndrome in children with inflamma-
tory disorders: a retrospective study of 24 patients. Rheumatology (Oxford)
2001;40:1285-92.
12. Sawhney S, Woo P, Murray K. Macrophage activation syndrome: a po-
tentially fatal complication of rheumatic disorders. Arch Dis Child
2001;85:421-6.
13. Hayden A, Park S, Giustini D, Lee AY, Chen LY. Hemophagocytic syn-
dromes (HPSs) including hemophagocytic lymphohistiocytosis (HLH)
in adults: a systematic scoping review. Blood Rev 2016;30:411-20.
14. Wang Y, Wang Z, Zhang J, Wei Q, Tang R, Qi J, et al. Genetic features of
late onset primary hemophagocytic lymphohistiocytosis in adolescence
or adulthood. PLoS ONE 2014;9:e107386.
15. Degar B. Familial hemophagocytic lymphohistiocytosis. Hematol Oncol
Clin North Am 2015;29:903-13.
16. Vastert SJ, van Wijk R, D’Urbano LE, de Vooght KM, de Jager W, Ravelli
A, et al. Mutations in the perforin gene can be linked to macrophage ac-
tivation syndrome in patients with systemic onset juvenile idiopathic ar-
thritis. Rheumatology (Oxford) 2010;49:441-9.
17. Kaufman KM, Linghu B, Szustakowski JD, Husami A, Yang F, Zhang K,
et al. Whole-exome sequencing reveals overlap between macrophage ac-
tivation syndrome in systemic juvenile idiopathic arthritis and familial
hemophagocytic lymphohistiocytosis. Arthritis Rheumatol 2014;66:3486-
95.
18. Schulert GS, Zhang M, Fall N, Husami A, Kissell D, Hanosh A, et al. Whole-
exome sequencing reveals mutations in genes linked to hemophagocytic
lymphohistiocytosis and macrophage activation syndrome in fatal cases
of H1N1 influenza. J Infect Dis 2016;213:1180-8.
19. Zhang M, Behrens EM, Atkinson TP, Shakoory B, Grom AA, Cron RQ.
Genetic defects in cytolysis in macrophage activation syndrome. Curr
Rheumatol Rep 2014;16:439.
20. Zhang K, Jordan MB, Marsh RA, Johnson JA, Kissell D, Meller J, et al.
Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are asso-
ciated with adult-onset familial HLH. Blood 2011;118:5794-8.
Development and Initial Validation of the Macrophage Activation Syndrome/Primary Hemophagocytic Lymphohistiocytosis Score,
a Diagnostic Tool that Differentiates Primary Hemophagocytic Lymphohistiocytosis from Macrophage Activation Syndrome
ORIGINAL ARTICLES
21. Zhang M, Bracaglia C, Prencipe G, Bemrich-Stolz CJ, Beukelman T,
Dimmitt RA, et al. A heterozygous RAB27A mutation associated with
delayed cytolytic granule polarization and hemophagocytic
lymphohistiocytosis. J Immunol 2016;196:2492-503.
22. Spessott WA, Sanmillan ML1, McCormick ME, Patel N, Villanueva J, Zhang
K, et al. Hemophagocytic lymphohistiocytosis caused by dominant-
negative mutations in STXBP2 that inhibit SNARE-mediated mem-
brane fusion. Blood 2015;125:1566-77.
23. Henter JI, Aricò M, Egeler RM, Elinder G, Favara BE, Filipovich AH, et al.
HLH-94: a treatment protocol for hemophagocytic lymphohistiocytosis.
HLH study Group of the Histiocyte Society. Med Pediatr Oncol
1997;28:342-7.
24. Cetica V, Sieni E, Pende D, Danesino C, De Fusco C, Locatelli F, et al.
Genetic predisposition to hemophagocytic lymphohistiocytosis: report
on 500 patients from the Italian registry. J Allergy Clin Immunol
2016;137:188-96.
25. Ravelli A, Magni-Manzoni S, Pistorio A, Besana C, Foti T, Ruperto N, et al.
Preliminary diagnostic guidelines for macrophage activation syndrome
complicating systemic juvenile idiopathic arthritis. J Pediatr 2005;146:598-
604.
26. Ravelli A, Minoia F, Davì S, Horne A, Bovis F, Pistorio A, et al. 2016 Clas-
sification criteria for macrophage activation syndrome complicating sys-
temic juvenile idiopathic arthritis: a European League against Rheumatism/
American College of Rheumatology/Paediatric Rheumatology International
Trials Organisation Collaborative Initiative. Ann Rheum Dis 2016;75:481-
9.
27. Ravelli A, Minoia F, Davì S, Horne A, Bovis F, Pistorio A, et al. 2016 Clas-
sification criteria for macrophage activation syndrome complicating sys-
temic juvenile idiopathic arthritis: a European League against Rheumatism/
American College of Rheumatology/Paediatric Rheumatology International
Trials Organisation Collaborative Initiative. Arthritis Rheumatol
2016;68:566-76.
28. Fardet L, Galicier L, Lambotte O, Marzac C, Aumont C, Chahwan D, et al.
Development and validation of the HScore, a score for the diagnosis of
reactive hemophagocytic syndrome. Arthritis Rheumatol 2014;66:2613-
20.
29. Cron RQ, Davi S, Minoia F, Ravelli A. Clinical features and correct di-
agnosis of macrophage activation syndrome. Expert Rev Clin Immunol
2015;11:1043-53.
30. Minoia F, Davì S, Horne A, Demirkaya E, Bovis F, Li C, et al. Clinical fea-
tures, treatment, and outcome of macrophage activation syndrome com-
plicating systemic juvenile idiopathic arthritis: a multinational, multicenter
study of 362 patients. Arthritis Rheumatol 2014;66:3160-9.
31. Minoia F, Davì S, Horne A, Bovis F, Demirkaya E, Akikusa J, et al.
Dissecting the heterogeneity of macrophage activation syndrome com-
plicating systemic juvenile idiopathic arthritis. J Rheumatol 2015;42:994-
1001.
32. Davì S, Minoia F, Pistorio A, Horne A, Consolaro A, Rosina S, et al. Per-
formance of current guidelines for diagnosis of macrophage activation
syndrome complicating systemic juvenile idiopathic arthritis. Arthritis
Rheumatol 2014;66:2871-80.
33. Petty RE, Southwood TR, Manners P, Baum J, Glass DN, Goldenberg J,
et al. International League of Associations for Rheumatology classifica-
tion of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J
Rheumatol 2004;31:390-2.
34. Chandrakasan S, Filipovich AH. Hemophagocytic lymphohistiocytosis:
advances in pathophysiology, diagnosis, and treatment. J Pediatr
2013;163:1253-9.
35. Janka GE, Lehmberg K. Hemophagocytic syndromes–an update. Blood
Rev 2014;28:135-42.
36. De Benedetti F, Schneider R. Systemic juvenile idiopathic arthritis. In:
Petty RE, Laxer RM, Lindsley CB, Wedderburn LR, eds. Textbook of
pediatric rheumatology. 7th ed. Philadelphia: Elsevier; 2016. p. 205-
16.
37. Behrens EM, Beukelman T, Gallo L, Spangler J, Rosenkranz M, Arkachaisri
T, et al. Evaluation of the presentation of systemic onset juvenile rheu-
matoid arthritis: data from the Pennsylvania Systemic Onset Juvenile Ar-
thritis Registry (PASOJAR). J Rheumatol 2008;35:343-8.
77
THE JOURNAL OF PEDIATRICS • www.jpeds.com
38. Efthimiou P, Kadavath S, Mehta B. Life-threatening complications of adult-
onset Still’s disease. Clin Rheumatol 2014;33:305-14.
39. Lehmberg K, Pink I, Eulenburg C, Beutel K, Maul-Pavicic A, Janka G. Dis-
criminating macrophage activation syndrome in systemic juvenile idio-
pathic arthritis from other forms of hemophagocytic lymphohistiocytosis.
J Pediatr 2013;162:1245-51.
40. Bode SF, Lehmberg K, Maul-Pavicic A, Vraetz T, Janka G, Stadt UZ, et al.
Recent advances in the diagnosis and treatment of hemophagocytic
lymphohistiocytosis. Arthritis Res Ther 2012;14:213.
41. Aricò M, Janka G, Fischer A, Henter JI, Blanche S, Elinder G, et al. He-
mophagocytic lymphohistiocytosis. Report of 122 children from the In-
ternational Registry. FHL Study Group of the Histiocyte Society. Leukemia
1996;10:197-203.
42. Behrens EM, Canna SW, Slade K, Rao S, Kreiger PA, Paessler M,
et al. Repeated TLR9 stimulation results in macrophage activa-
tion syndrome-like disease in mice. J Clin Invest 2011;121:2264-
77.
78
Volume 189
43. Canna SW, Costa-Reis P, Bernal WE, Chu N, Sullivan KE, Paessler ME,
et al. Brief report: alternative activation of laser-captured murine
hemophagocytes. Arthritis Rheumatol 2014;66:1666-71.
44. Weaver LK, Behrens EM. Hyperinflammation, rather than
hemophagocytosis, is the common link between macrophage activation
syndrome and hemophagocytic lymphohistiocytosis. Curr Opin Rheumatol
2014;26:562-9.
45. Kelly A, Ramanan AV. Recognition and management of macrophage ac-
tivation syndrome in juvenile arthritis. Curr Opin Rheumatol 2007;19:477-
81.
46. Ravelli A, Minoia F, Davì S, Horne A, Bovis F, Pistorio A, et al. Expert
consensus on dynamics of laboratory tests for diagnosis of macrophage
activation syndrome complicating systemic juvenile idiopathic arthritis.
RMD Open 2016;2:e000161.
47. Harrell FE. Regression modeling strategies: with applications to linear
models, logistic regression, and survival analysis. New York: Springer-
Verlag; 2001.
Minoia et al
October 2017
Appendix
Additional members of the Pediatric Rheumatology Interna-
tional Trials Organization, the Childhood Arthritis and Rheu-
matology Research Alliance, the Pediatric Rheumatology
Collaborative Study Group, and the Histiocyte Society include:
Mario Abinun, MD, Great North Children’s Hospital, New-
castle, UK
Amita Aggarwal, MD, Sanjay Gandhi Postgraduate Insti-
tute of Medical Sciences, Lucknow, India
Jonathan Akikusa, MD, Royal Children’s Hospital, Mel-
bourne, Australia
Sulaiman Al-Mayouf, MD, King Faisal Specialist Hospital
and Research Center, Riyadh, Saudi Arabia
Maria Alessio, MD, University of Napoli Federico II, Naples,
Italy
Jordi Anton, MD, Hospital Sant Joan de Déu, Barcelona,
Spain
Maria Teresa Apaz, MD, Catholic University of Cordoba,
Cordoba, Argentina
Maurizio Arico, MD, Universitaria A. Meyer, Florence, Italy
Itziar Astigarraga, MD, BioCruces Health Reasearch Insti-
tute, Hospital at the University of Cruces, University of the
Basque Country, Barakaldo, Bizkaia, Spain
Tadej Avcin, MD, University Children’s Hospital, Lju-
bljana, Slovenia
Nuray Aktay Ayaz, MD, Bakırkoy Maternity and Children
Education and Research Hospital, Istanbul, Turkey
Patrizia Barone, MD, Policlinic of the University of Catania,
Catania, Italy
Bianca Bica, MD, Clementino Fraga Filho University
Hospital, Rio de Janeiro, Brazil
Isabel Bolt, MD, University Hospital Pediatrics Clinic, Berne
University Hospital, Berne, Switzerland
Francesca Bovis, PhD, University of Genova, Genoa, Italy
Luciana Breda, MD, Hospital Clinic, Chieti, Italy
Vyacheslav Chasnyk, MD, Saint Petersburg State Pediatric
Medical University, Saint Petersburg, Russian Federation
Rolando Cimaz, MD, Pediatrico A. Meyer Hospital, Flor-
ence, Italy
Fabrizia Corona, MD, Ca’ Granda Italian Research
Hospital Foundation, Maggiore Hospital, Milan, Italy
Randy Q Cron, MD, University of Alabama, Birmingham,
AL, USA
Ruben Cuttica, MD, Pedro de Elizalde Children’s’ Hospi-
tal, Buenos Aires, Argentina Gianfranco D’Angelo, MD, G. Salesi
Children’s Hospital, Ancona, Italy
Sergio Davì, MD, G. Gaslini Institute, Genoa, Italy
Zane Davidsone, MD, Children’s University Hospital, Riga,
Latvia
Carmen De Cunto, MD, Italian Hospital in Buenos Aires,
Buenos Aires, Argentina
Jaime De Inocencio, MD, 12 de Octubre University Hospi-
tal, Madrid, Spain
Erkan Demirkaya, MD, Gulhane Military Medical Faculty,
Ankara, Turkey
Development and Initial Validation of the Macrophage Activation Syndrome/Primary Hemophagocytic Lymphohistiocytosis Score,
a Diagnostic Tool that Differentiates Primary Hemophagocytic Lymphohistiocytosis from Macrophage Activation Syndrome
ORIGINAL ARTICLES
R. Maarten Egeler, MD, Leiden University Medical Center,
Leiden, The Netherlands
Eli M. Eisenstein, MD, Hadassah–Hebrew University Medical
Center, Jerusalem, Israel
Sandra Enciso, MD, Federico Gomez Children’s Hospital of
Mexico, Mexico City, Mexico
Graciela Espada, MD, Ricardo Gutierrez Children’s Hospi-
tal, Buenos Aires, Argentina
Alexandra H. Filipovich, MD, Children’s Hospital Medical
Center, Cincinnati, OH, USA
Michel Fischbach, MD, Hautepierre University Hospital,
Strasbourg, France
Michael Frosch, MD, University Children’s Hospital, Munster,
Germany
Helmut Gadner, MD, FRCP, St. Anna Children’s Hospital,
Vienna, Austria
Romina Gallizzi, MD, University of Messina, Messina, Italy
Maria Luz Gamir, MD, Hospital Ramon and Cajal, Madrid,
Spain
Yi-Jin Gao, MD, Children’s Hospital of Fudan University,
Shanghai, China
Thomas Griffin, MD, Carolinas HealthCare System, Char-
lotte, NC, USA
Alexei Grom, MD, Cincinnati Children’s Hospital Medical
Center, Cincinnati, OH, USA
Soad Hashad, MD, Tripoli Children’s Hospital, Tripoli, Libya
Teresa Hennon, MD, Women and Children’s Hospital,
Buffalo, NY, USA
Jan-Inge Henter, MD, PhD, Karolinska Instiututet, Stock-
holm, Sweden
AnnaCarin Horne, MD, PhD, Karolinska Instiututet, Stock-
holm, Sweden
Gerd Horneff, MD, Center for General Pediatrics and Neo-
natology, St. Agustin, Germany
Zeng Huasong, MD, Guangzhou Children’s Hospital, Gua-
ngzhou, China
Adam Huber, MD, IWK Health Center, Halifax, Canada
Norman Ilowite, MD, Albert Einstein College of
Medicine and Children’s Hospital at Montefiore, New York,
NY, USA
Shinsaku Imashuku, MD, Kyoto City Institute of Health and
Environmental Sciences, Kyoto, Japan
Antonella Insalaco, MD, Pediatric Hospital of the Baby Jesus,
Rome, Italy
Maka Ioseliani, MD, M. Iashvili Children’s Central Clinic,
Tbilisi, Georgia
Gritta Janka, MD, PhD, Department of Hematology and On-
cology, Children’s University Hospital, Hamburg, Germany
Michael Jeng, MD, Stanford School of Medicine, Palo Alto,
CA, USA
Agneza Marija Kapović, MD, Department for Immunol-
ogy and Rheumatology, Children’s Hospital of Zagreb, Zagreb,
Croatia
Ozgur Kasapcopur, MD, Istanbul University, Cerrahpasa
Medical School, Istanbul, Turkey
Raju Khubchandani, MD, Jaslok Hospital and Research
Center, Mumbai, India
78.e1
THE JOURNAL OF PEDIATRICS • www.jpeds.com Volume 189

Toshiyuki Kitoh, MD, Aichi Medical University, Nagakute, Ricardo Russo, MD, Juan P. Garrahan Pediatric Hospital,
Japan Buenos Aires, Argentina
Isabelle Koné-Paut, MD, PhD, University Hospital Center Claudia Saad Magalhães, MD, Clinical Hospital, Botucatu,
at Le Kremlin Bicêtre, Le Kremlin Bicêtre, France Brazil
Sheila Knupp Feitosa de Oliveira, MD, Federal University Helga Sanner, MD, Oslo University Hospital, Rikshospitalet,
of Rio de Janeiro, Rio de Janeiro, Brazil Oslo, Norway
Stephan Ladisch, MD, Children’s Research Institute, Wash- Wafaa Mohamed Saad Sewairi, MD, King Fahad National
ington, DC, USA Guard Hospital, Riyadh, Saudi Arabia
Bianca Lattanzi, MD, Consolidated University Hospitals, Susan Shenoi, MD, Seattle Children’s Hospital and Univer-
Ancona, Italy sity of Washington, Seattle, WA, USA
Kai Lehmberg, MD, University Medical Center, Hamburg, Clovis Artur Silva, MD, Sao Paulo University, Sao Paulo,
Germany Brazil
Loredana Lepore, MD, Burlo Garofolo Maternal and Infant Valda Stanevicha, MD, Riga Stradins University, Riga, Latvia
Italian Research Hospital Foundation, Trieste, Italy Gary Sterba, MD, Mount Sinai Medical Center, Miami Beach,
Caifeng Li, MD, Beijing Children’s Hospital, Beijing, China Miami, FL, USA
Jeffrey M. Lipton, MD, Steven and Alexandra Cohen Chil- Kimo C. Stine, MD, Arkansas Children’s Hospital, Little Rock,
dren’s Hospital of New York, New York, NY, USA AK, USA
Silvia Magni-Manzoni, MD, Pediatric Hospital of the Baby Gordana Susic, MD, Institute of Rheumatology, Belgrade,
Jesus, Rome, Italy Serbia
Despoina Maritsi, Athens Medical School, Athens, Greece Flavio Sztajnbok, MD, Pedro Ernesto University Hospital,
Alberto Martini, MD, G. Gaslini Institute, Genoa, Italy Rio de Janeiro, Brazil
Deborah McCurdy, MD, University of California, Los Angeles Syuji Takei, MD, Kagoshima University Hospital, Kagoshima
and Mattel Children’s Health Center UCLA, Orange, Los City, Japan
Angeles, CA, USA Ralf Trauzeddel, MD, Helios Clinic, Berlin, Germany
Ken L. McClain, MD, PhD, Texas Children’s Cancer Center, Elena Tsitsami, MD, Athens Medical School and Chil-
Baylor College of Medicine, Houston, TX, USA dren’s Hospital Aghia Sofia, Athens, Greece
Rosa Merino, MD, University Hospital La Paz, Madrid, Spain Erbil Unsal, MD, Dokuz Eylül University Medical School,
Concetta Micalizzi, MD, G. Gaslini Institute, Genoa, Italy Izmir, Turkey
Paivi Miettunen, MD, University of Calgary, Calgary, Canada Yosef Uziel, MD, Meir Medical Center, Kfar Saba, Israel
Francesca Minoia, MD, G. Gaslini Institute, Genoa Olga Vougiouka, MD, Kyriakou Children’s Hospital of
Velma Mulaosmanovic, MD, Children’s Hospital Univer- Athens, Athens, Greece
sity Clinical Center Sarajevo, Sarajevo, Bosnia and Herzegovina Carol A. Wallace, MD, Seattle Children’s Hospital, Seattle,
Kim E Nichols, MD, St. Jude Children’s Research Hospital, WA, USA
Memphis, TN, USA Lehn Weaver, MD, The Children’s Hospital of Philadel-
Susan Nielsen, MD, Juliane Marie Center and Rigshospitalet, phia, Philadelphia, PA, USA
Copenhagen, Denmark David Webb, MD, Great Ormond Street Hospital, London,
Seza Ozen, Hacettepe University, Ankara, Turkey UK
Priyankar Pal, Institute of Child Health, Kolkata, India Jennifer E. Weiss, MD, New Jersey Medical School and Hack-
Sampath Prahalad, MD, Emory University and Children’s ensack University Medical Center, Hackensack, NJ, USA
Healthcare of Atlanta, Atlanta, GA, USA Sheila Weitzman, MD, The Hospital for Sick Children,
Angelo Ravelli, MD, G. Gaslini Institute and University of Toronto, Ontario, Canada
Genova, Genoa, Italy Carine Wouters, MD, University Hospital Gasthuisberg,
Donato Rigante, MD, Sacred Heart Catholic University, Leuven, Belgium
Rome, Italy Nico Wulffraat, MD, Wilhelmina Children’s Hospital and
Ingrida Rumba-Rozenfelde, MD, PhD, University of Latvia, University Medical Center, Utrecht, The Netherlands
Riga, Latvia Mabruka Zletni, MD, Tripoli Children’s Hospital, Tripoli,
Nicolino Ruperto, MD, G. Gaslini Institute, Genoa, Italy Libya
3820 74 139 222 3 41 44224 5 4325
6 44779 827 94628 10 4729 11 48 3012 66 13 14 331551 34 16 35 17 3653 18 54 19
5621 5740 23 59 26 6245 31
8449 7103
32
50 70 52 7189 729037
Mario Abinun, MD , Amita Aggarwal, MD , Jonathan Akikusa, MD , Sulaiman Al-Mayouf, MD , Maria Alessio, MD , Jordi Anton, MD , Maria Teresa Apaz, MD , Itziar Astigarraga, MD , Tadej Avcin, MD , Nuray Aktay Ayaz, MD , Patrizia Barone, MD , Bianca Bica, MD , Isabel Bolt, MD , Francesca Bovis, PhD , Luciana Breda, MD , Vyacheslav Chasnyk, MD , Rolando Cimaz, MD , Fabrizia Corona, MD , Randy Q. Cron, MD , Ruben

55
Cuttica, MD

931075 58 95 779611 360

78 97 61
, Sergio Davì, MD

80 63100
81 564 82
, Zane Davidsone, MD
6583 67 68 6987 105
, Carmen De Cunto, MD
73
, Jaime De Inocencio, MD , Erkan Demirkaya, MD , Eli M. Eisenstein, MD , Sandra Enciso, MD , Graciela Espada, MD , Michel Fischbach, MD , Michael Frosch, MD , Romina Gallizzi, MD , Maria Luz Gamir, MD , Yi-Jin Gao, MD , Thomas Griffin, MD , Alexei Grom, MD , Soad Hashad, MD , Teresa Hennon, MD , Jan-Inge Henter, MD,

2 76 19 85 86 8 1624 88 106 91
PhD , AnnaCarin Horne, MD, PhD , Gerd Horneff, MD , Zeng Huasong, MD , Adam Huber, MD , Norman Ilowite, MD , Antonella Insalaco, MD , Maka Ioseliani, MD , Michael Jeng, MD , Agneza Marija Kapović, MD , Ozgur Kasapcopur, MD , Raju Khubchandani, MD , Toshiyuki Kitoh, MD , Isabelle Koné-Paut, MD, PhD , Sheila Knupp Feitosa de Oliveira, MD , Bianca Lattanzi, MD , Kai Lehmberg, MD , Loredana Lepore,

10892 94 9812 99 13 21101 622102 14 3223 15 10433 107

MD , Caifeng Li, MD , Jeffrey M. Lipton, MD , Silvia Magni-Manzoni, MD , Despoina Maritsi , Alberto Martini, MD , Deborah McCurdy, MD , Rosa Merino, MD , Concetta Micalizzi, MD , Paivi Miettunen, MD , Francesca Minoia, MD , Velma Mulaosmanovic, MD , Kim E. Nichols, MD , Susan Nielsen, MD , Seza Ozen , Priyankar Pal , Sampath Prahalad, MD , Angelo Ravelli, MD , Donato Rigante, MD , Ingrida

181 4
Rumba-Rozenfelde, MD, PhD , Nicolino Ruperto, MD , Ricardo Russo, MD , Claudia Saad Magalhães, MD , Helga Sanner, MD , Wafaa Mohamed Saad Sewairi, MD , Susan Shenoi, MD , Clovis Artur Silva, MD , Valda Stanevicha, MD , Gary Sterba, MD , Kimo C. Stine, MD , Gordana Susic, MD , Flavio Sztajnbok, MD , Syuji Takei, MD , Ralf Trauzeddel, MD , Elena Tsitsami, MD , Erbil Unsal, MD , Yosef Uziel, MD , Olga

926
Vougiouka, MD
MD
, Carol A. Wallace, MD
From the
20
, Lehn Weaver, MD
Great North Children’s Hospital, Newcastle, UK;
, Jennifer E. Weiss, MD

34 25 17 35
, Sheila Weitzman, MD
Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India;
, Carine Wouters, MD , Nico Wulffraat, MD
Royal Children’s Hospital, Melbourne, Australia;
, Mabruka Zletni, MD , Maurizio Arico, MD
King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia;
, R. Maarten Egeler, MD , Alexandra H. Filipovich, MD
University of Napoli Federico II, Naples, Italy;
, Helmut Gadner, MD
Hospital Sant Joan de Déu, Barcelona, Spain;
, Shinsaku Imashuku, MD
Catholic University of Cordoba, Cordoba, Argentina;
, Gritta Janka, MD, PhD , Stephan Ladisch, MD , Ken L. McClain, MD, PhD , and David Webb,
BioCruces Health Reasearch Institute, Hospital at the University of Cruces, University of the Basque Country, Barakaldo, Bizkaia, Spain;

4627 63 375547 64 28 38 39 29 30 31 50 42
University Children’s Hospital, Ljubljana, Slovenia; Bakırkoy Maternity and Children Education and Research Hospital, Istanbul, Turkey; Policlinic of the University of Catania, Catania, Italy; Clementino Fraga Filho University Hospital, Rio de Janeiro, Brazil; University Hospital Pediatrics Clinic, Berne University Hospital, Berne, Switzerland; University of Genova, Genoa; Hospital Clinic, Chieti, Italy; Saint Petersburg State Pediatric Medical University, Saint Petersburg, Russian Federation; Pediatrico A. Meyer

45
53 36
Hospital, Florence;

54 56664840 7657
Hadassah–Hebrew University Medical Center, Jerusalem, Israel;
Children’s Hospital Medical Center, Cincinnati, OH, USA;
49 4167 58 78 68 5143
Ca’ Granda Italian Research Hospital Foundation, Maggiore Hospital, Milan, Italy;

59 60
Tripoli Children’s Hospital, Tripoli, Libya;
5261 44 University of Alabama, Birmingham, AL, USA;
Federico Gomez Children’s Hospital of Mexico, Mexico City, Mexico;
Women and Children’s Hospital, Buffalo, NY, USA;
Pedro de Elizalde Children’s’ Hospital, Buenos Aires, Argentina Gianfranco D’Angelo, MD, G. Salesi Children’s Hospital, Ancona;
Ricardo Gutierrez Children’s Hospital, Buenos Aires, Argentina;
; Karolinska Instiututet, Stockholm, Sweden;
Hautepierre University Hospital, Strasbourg, France;
G. Gaslini Institute, Genoa, Italy;
University Children’s Hospital, Munster, Germany;
Center for General Pediatrics and Neonatology, St. Agustin, Germany;
Children’s University Hospital, Riga, Latvia;
University of Messina, Messina, Italy;
Guangzhou Children’s Hospital, Guangzhou, China;
Italian Hospital in Buenos Aires, Buenos Aires, Argentina;
Hospital Ramon and Cajal, Madrid, Spain;
IWK Health Center, Halifax, Canada;
12 de Octubre University Hospital, Madrid, Spain;
Children’s Hospital of Fudan University, Shanghai, China;
Albert Einstein College of Medicine and Children’s Hospital at Montefiore, New York, NY, USA;
Gulhane Military Medical Faculty, Ankara, Turkey;
Carolinas HealthCare System, Charlotte, NC; Cincinnati
Pediatric Hospital of the Baby Jesus, Rome, Italy;

81 62 82
72 83 73
UCLA, Orange, Los Angeles, CA, USA;
8474 65
M. Iashvili Children’s Central Clinic, Tbilisi, Georgia;

75
Consolidated University Hospitals, Ancona, Italy;

85 86 77 87
University Hospital La Paz, Madrid, Spain;
88 79 89 69
University Medical Center, Hamburg, Germany;
8070 90 71
Stanford School of Medicine, Palo Alto, CA, USA;
G. Gaslini Institute, Genoa, Italy;
Department for Immunology and Rheumatology, Children’s Hospital of Zagreb, Zagreb, Croatia;
Burlo Garofolo Maternal and Infant Italian Research Hospital Foundation, Trieste, Italy;
University of Calgary, Calgary, Canada; G. Gaslini Institute, Genoa;
Istanbul University, Cerrahpasa Medical School, Istanbul, Turkey;
Beijing Children’s Hospital, Beijing, China;
Jaslok Hospital and Research Center, Mumbai, India;
Steven and Alexandra Cohen Children’s Hospital of New York, New York, NY, USA;
Children’s Hospital University Clinical Center Sarajevo, Sarajevo, Bosnia and Herzegovina;
Aichi Medical University, Nagakute, Japan;
Pediatric Hospital of the Baby Jesus, Rome, Italy;
St. Jude Children’s Research Hospital, Memphis, TN, USA;
University Hospital Center at Le Kremlin Bicêtre, Le Kremlin Bicêtre, France;
Athens Medical School, Athens, Greece;
Juliane Marie Center and Rigshospitalet, Copenhagen, Denmark;
G. Gaslini Institute, Genoa, Italy;
Hacettepe University, Ankara, Turkey;
Federal University of Rio de Janeiro, Rio de Janeiro, Brazil;
University of California, Los Angeles and Mattel Children’s Health Center
Institute of Child Health, Kolkata, India; Emory University and

9991 92 101 93 94 95 104 96 10597 98

Children’s Healthcare of Atlanta, Atlanta, GA, USA; G. Gaslini Institute and University of Genova, Genoa; Sacred Heart Catholic University, Rome, Italy; University of Latvia, Riga, Latvia; G. Gaslini Institute, Genoa, Italy; Juan P. Garrahan Pediatric Hospital, Buenos Aires, Argentina; Clinical Hospital, Botucatu, Brazil; Oslo University Hospital, Rikshospitalet, Oslo, Norway; King Fahad National Guard Hospital, Riyadh, Saudi Arabia; Seattle Children’s Hospital and University of Washington, Seattle, WA, USA;

107
Turkey;
100 108 102
Sao Paulo University, Sao Paulo, Brazil;
Meir Medical Center, Kfar Saba, Israel;
Tripoli Children’s Hospital, Tripoli, Libya; 103 Riga Stradins University, Riga, Latvia;
106
Mount Sinai Medical Center, Miami Beach, Miami, FL;
Kyriakou Children’s Hospital of Athens, Athens, Greece;
Universitaria A. Meyer, Florence, Italy;
Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX, USA; and
Arkansas Children’s Hospital, Little Rock, AK, USA;
Seattle Children’s Hospital, Seattle, WA, USA;
Leiden University Medical Center, Leiden, The Netherlands;
Great Ormond Street Hospital, London, UK
Institute of Rheumatology, Belgrade, Serbia;
The Children’s Hospital of Philadelphia, Philadelphia, PA, USA;
Children’s Hospital Medical Center, Cincinnati, OH, USA;
Pedro Ernesto University Hospital, Rio de Janeiro, Brazil;
New Jersey Medical School and Hackensack University Medical Center, Hackensack, NJ, USA;
FRCP, St. Anna Children’s Hospital, Vienna, Austria;
Kagoshima University Hospital, Kagoshima City, Japan;
The Hospital for Sick Children, Toronto, Ontario, Canada;
Kyoto City Institute of Health and Environmental Sciences, Kyoto, Japan;
Helios Clinic, Berlin, Germany; Athens Medical School and Children’s Hospital Aghia Sofia, Athens, Greece;
University Hospital Gasthuisberg, Leuven, Belgium;
Dokuz Eylül University Medical School, Izmir,
Wilhelmina Children’s Hospital and University Medical Center, Utrecht, The Netherlands;
Department of Hematology and Oncology, Children’s University Hospital, Hamburg, Germany; Children’s Research Institute, Washington, DC;

78.e2 Minoia et al
October 2017 ORIGINAL ARTICLES

Table V. Probability of pHLH according to the MH score

MH scores Probability of pHLH (%)
0 <1
11 1.3
12 1.4
15 1.9
22 3.5
23 3.8
26 5.0
27 5.4
34 9.6
37 12.4
38 13.5
48 28.1
49 29.9
52 36.0
59 51.6
60 53.9
64 62.8
71 76.2
74 80.8
75 82.2
85 92.0
86 92.7
97 97.2
100 97.9
108 99.0
111 99.2
112 99.3
123 99.7

The best cutoff value for the MH score was ≥ 60, with a sensitivity of 91% and a specificity of
93% in discriminating pHLH from MAS.

Development and Initial Validation of the Macrophage Activation Syndrome/Primary Hemophagocytic Lymphohistiocytosis Score, 78.e3
a Diagnostic Tool that Differentiates Primary Hemophagocytic Lymphohistiocytosis from Macrophage Activation Syndrome