Systematic review: Macrophage activation syndrome in inflammatory bowel disease

Abstract

Recently, there have been increasingly frequent reports on the occurrence of macrophage activation syndrome (MAS) in patients with inflammatory bowel disease (IBD). Clinically, MAS is characterized mainly by fever, hepatosplenomegaly, cytopenia, and elevated circulating ferritin and CD25. Mortality, even if diagnosed rapidly, is high.
To identify all reports on MAS in IBD and to establish data on triggering agents, immunosuppression leading to MAS, and mortality.
A language unrestricted search on Pubmed and Scopus relating to the past 30 years was carried out by matching the following search-terms: h(a)emophagocytic lymphohistiocytosis OR h(a)emophagocytic lymphohistiocytic syndrome OR macrophage activation syndrome OR opportunistic infections OR cytomegalovirus OR Epstein-Barr virus AND Crohn's disease OR ulcerative colitis OR inflammatory bowel disease(s).
Fifty cases were identified with an overall mortality of 30%. Virus-related MAS associated with cytomegalovirus or Epstein-Barr virus infections represents the main type of MAS, but in isolated cases bacterial infections precipitated the syndrome. In four cases (8%), a lymphoma was present at the time of MAS diagnosis or developed shortly thereafter. Thiopurine monotherapy was given before MAS onset in 56% of the patients, whereas multiple immunosuppression, including biologics, was administered to 24%.
In IBD patients, the syndrome appears to be triggered by infections, but genetic susceptibility may contribute to its development. Since immunosuppressive therapy represents the backbone of therapeutic interventions in IBD, with the risk of new, or the reactivation of latent infections, even more frequent cases of macrophage activation syndrome may be expected.

Full text

Systematic review: macrophage activation syndrome in
inflammatory bowel disease
W. Fries*, M. Cottone
†
& A. Cascio
‡
*Clinical Unit for Chronic Bowel
Disorders, Department of Internal
Medicine, IBD-unit Messina,
University of Messina, Messina, Italy.
†
Clinical Unit of Internal Medicine 2,
United Hospitals Villa Sofia-Cervello,
University of Palermo, Palermo, Italy.
‡
Tropical and Parasitological Diseases
Unit, Department of Human
Pathology, IBD-unit Messina, AILMI
(Italian Association for the Control of
Infectious Diseases), University of
Messina, Messina, Italy.
Correspondence to:
Dr W. Fries, Clinical Unit for Chronic
Bowel Disorders, Department of
Internal Medicine, Policlincio
“G. Martino”, Via Consolare Valeria,
1 98125 Messina, Italy.
E-mail: fwalter@unime.it
Publication data
Submitted 30 September 2012
First decision 19 October 2012
Resubmitted 12 March 2013
Accepted 13 March 2013
This uncommissioned systematic review
was subject to full peer-review.
SUMMARY
Background
Recently, there have been increasingly frequent reports on the occurrence
of macrophage activation syndrome (MAS) in patients with inflammatory
bowel disease (IBD). Clinically, MAS is characterized mainly by fever, he-
patosplenomegaly, cytopenia, and elevated circulating ferritin and CD25.
Mortality, even if diagnosed rapidly, is high.
Aim
To identify all reports on MAS in IBD and to establish data on triggering
agents, immunosuppression leading to MAS, and mortality.
Methods
A language unrestricted search on Pubmed and Scopus relating to the past
30 years was carried out by matching the following search-terms: h(a)emo-
phagocytic lymphohistiocytosis OR h(a)emophagocytic lymphohistiocytic
syndrome OR macrophage activation syndrome OR opportunistic infections
OR cytomegalovirus OR Epstein-Barr virus AND Crohn’s disease OR ulcer-
ative colitis OR inflammatory bowel disease(s).
Results
Fifty cases were identified with an overall mortality of 30%. Virus-related
MAS associated with cytomegalovirus or Epstein-Barr virus infections rep-
resents the main type of MAS, but in isolated cases bacterial infections pre-
cipitated the syndrome. In four cases (8%), a lymphoma was present at the
time of MAS diagnosis or developed shortly thereafter. Thiopurine mono-
therapy was given before MAS onset in 56% of the patients, whereas multi-
ple immunosuppression, including biologics, was administered to 24%.
Conclusions
In IBD patients, the syndrome appears to be triggered by infections, but
genetic susceptibility may contribute to its development. Since immunosup-
pressive therapy represents the backbone of therapeutic interventions in
IBD, with the risk of new, or the reactivation of latent infections, even
more frequent cases of macrophage activation syndrome may be expected.
Aliment Pharmacol Ther
ª2013 Blackwell Publishing Ltd 1
doi:10.1111/apt.12305
Alimentary Pharmacology and Therapeutics

INTRODUCTION
Macrophage activation syndrome (MAS) or Hemophago-
cytic lymphohistiocytosis (HLH) is a life-threatening
clinical syndrome characterised by high grade non-remit-
ting fever, cytopenias affecting at least two of three lin-
eages in peripheral blood, and hepatosplenomegaly
associated with biochemical abnormalities, such as high
circulating levels of serum ferritin, soluble interleukin-2
receptor (sCD25), and triglycerides, together with a
decrease of circulating NK activity. Liver involvement is
more frequent in pediatric cases but may be present in
adults with variable levels of transaminases up to signs
of acute liver failure and coagulopathy. Respiratory dis-
tress is frequently present and respiratory insufficiency
represents a negative prognostic sign and may need
assisted ventilation. The key feature of MAS is the pres-
ence of hemophagocytic CD163 +ve macrophages
(HPC) in bone marrow (Figure 1) or lymph-node aspi-
rates.
Diagnosis is based on the fulfillment of a series of cri-
teria established in 2004
1
(Table 1) for HLH associated
with autosomal recessive disorders (familial HLH, fHLH)
that lead to defects involving perforin,
2
a molecule impli-
cated in apoptosis induction of virus-infected cells or
tumor cells by cytolytic immune cells such as natural
killer (NK) cells or cytotoxic T lymphocytes (CTL).
Other mutations have been identified on the UNC13D
gene, that encodes for Munc13-4, a protein involved in
perforin delivery to target cells,
3
and the genes of synth-
axin 11 or Munc18-2, both proteins which regulate and
control membrane fusion.
4
Other genetically determined
disorders associated with defects of cytotoxic activities of
NK or CTL cells (Griscelli syndrome,
5
Chediak-Higashi
syndrome,
6
Hermansky-Pudlak syndrome type II,
7
and
X-linked lymphoproliferative syndrome type 1
8
and type
2
9
) are due to mutations of proteins involved in intracel-
lular trafficking of granules, sorting, transporting, dock-
ing, membrane fusion etc. (for review see ref 4). The
secondary form of HLH, also called MAS (synonyms:
reactive MAS, secondary HLH), is an acquired form of
HLH associated with chronic inflammatory diseases,
especially rheumatic disorders, and is triggered by a vari-
ety of infectious agents ranging from viruses, bacteria,
and fungi to protozoa. Moreover, MAS has been
observed in immunocompromised patients, regardless of
the cause of immunosuppression: pharmacologic, infec-
tious, or neoplastic (neoplasia/lymphoma-related HLH).
An apparent hybrid situation is present in systemic juve-
nile idiopathic arthritis (sJIA)
10
where MAS belongs to
the clinical picture of disease being present in a subclini-
cal form in 30–40% of patients, whereas the overt form
occurs in 10–20%. In sJIA, several mutations have been
reported very recently, not only in the perforin gene,
11
different from those involved in primary HLH, but also
in the IRF5 gene,
12
a factor involved in transcription of
toll-like receptor activation, especially in the virus-medi-
ated signalling pathways.
13
In at least 50% of sJIA
patients with MAS, the search for Cytomegalovirus
(CMV)- or Epstein-Barr virus (EBV)-DNA yielded posi-
tive results,
14, 15
thus emphasizing the role of additional
infectious or other co-factors precipitating MAS.
Macrophage activation syndrome (MAS) complicating
inflammatory bowel diseases (IBD) has received little
attention in literature, but the increasing frequency of
reported cases led us to systematically review this issue
in order to identify precipitating factors such as immu-
nosuppressive therapy, infectious agents, and outcome.
We use the term MAS in order to keep it distinct from
familial HLH.
METHODS
A computerized search without language restriction was
conducted on literature of the past 30 years (PubMed,
Scopus, and within reviews). Due to the variety of names
used for the syndrome, a combination of terms was used:
h(a)emophagocytic lymphohistiocytosis OR h(a)emo-
phagocytic lymphohistiocytic syndrome OR macrophage
activation syndrome OR opportunistic infections OR
cytomegalovirus OR Epstein-Barr virus AND Crohn’s
disease OR ulcerative colitis OR inflammatory bowel
disease(s).
Figure 1 | Haemophagocytosis in bone marrow
macrophages (from case report Palermo) (Giemsa
stain; original magnification 10009).
2Aliment Pharmacol Ther
ª2013 Blackwell Publishing Ltd
W. Fries et al.

A report was considered eligible for inclusion when
data on gender, age, IBD-type, treatment before MAS
onset, triggering agent, and outcome were stated. Reports
were excluded when more than two of the requested
items were not reported. Furthermore, additional data
on the methodology employed to identify the triggering
agents and therapy of MAS were collected. Case finding
strategy is represented in Figure 2.
RESULTS
We identified 50 cases of MAS associated with IBD
including two unpublished cases from our clinic and one
case from the IBD-centre of Palermo (Table 2),
16–51
. The
first report was published in 1988 followed by six isolated
reports over the following 16 years, up to 2004. Thereaf-
ter, we observed a sharp increase in published cases with
an additional 41 cases between 2005 and October 2012, 22
of them in the previous 24 months.
We excluded three cases from analysis: one case from
a series with different background pathologies because of
insufficient clinical data,
52
and two cases of EBV infec-
tion (one of them fatal) and clinical features which
resembled MAS, but diagnosis of MAS was not made by
the authors.
53, 54
Case description of yet unpublished cases
Clinic of Messina: Case 1: a 38 year-old woman was
admitted to our hospital because of high grade fever
unresponsive to antibiotics, lasting 5 days. She had been
diagnosed with ulcerative colitis 8 years before and was
in stable remission while on azathioprine at a dose of
2 mg/kg/day over the past 8 years. On admission, pancy-
topenia (leucocytes 1800/μl, hemoglobin 92 g/L, platelets
85 000/μl) and mild transaminitis were present. An
ultrasound evaluation of the abdomen revealed an
enlarged spleen and a moderate hepatomegaly; no lymph
nodes were identified. A chest film was negative. Azathi-
oprine was stopped and repeated blood cultures and
search for EBV, CMV, human Herpes Virus-6 (HHV-6),
and serology for leishmania yielded negative results. She
was treated empirically with broad-spectrum antibiotics,
methylprednisolone, and filgrastim. High serum ferritin
and triglycerides, hyponatremia, and absent activity of
NK cells were suggestive for MAS, but a bone marrow
aspirate was negative for hemophagocytosis. Her clinical
picture evolved rapidly, and death due to multiorgan
failure occurred 10 days after admission. Clinical diagno-
sis, based on clinical and blood parameters was consis-
tent with MAS. Authorization for a post-mortem
investigation was denied.
Case 2: a 72-year-old woman was diagnosed with Cro-
hn’s ileitis which responded well to oral mesalazine and
systemic steroids. She developed steroid-dependency in a
few months and azathioprine was added 1 year after
diagnosis at 2.2 mg/kg/day in order to control symp-
toms. Six months later she was admitted to our hospital
because of high grade fever, unresponsive to antibiotic
therapy and azathioprine withdrawal. On admission, she
presented acutely ill, dyspneic (oxygen saturation at
room air 85%), malnourished (albumin, 22 g/L), with
leucopenia (2200/mL) and anemia (hemoglobin 88 g/L).
On physical examination, herpetic lesions were noted
at her lips and i.v. treatment with acyclovir together with
methylprednisolone and parenteral nutrition was started.
An ultrasound examination of the abdomen revealed a
slightly enlarged spleen and a homogeneous, hypoechoic
wall thickening (12 mm) of the ileum proximally to the
known Crohn’s localization, raising the suspect of a
small bowel lymphoma. A chest film was positive for
significant pleural effusion, which was repeatedly drained
in order to improve ventilation. The search for serum
CMV-DNA yielded positive results and i.v. ganciclovir
was commenced. High serum ferritin, together with
hypertriglyceridemia and absent NK activity led to
the diagnosis of CMV-related MAS. After improvement
Table 1 | Hemophagocytic lymphohistiocytosis (HLH)
2004, Diagnostic criteria for familial
haematophagocytosis (from ref.
1
)
The diagnosis of HLH can be established if
either 1 or 2 below is fulfilled:
1 A molecular diagnosis consistent with HLH
2 Diagnostic criteria for HLH are fulfilled (five out of the
eight criteria below):
Fever
Splenomegaly
Cytopenias (affecting 2 lineages in the peripheral
blood):
Hemoglobin <90 g/L (in infants<4 weeks: hemoglobin
<100 g/L)
Platelets <100.000/μl
Neutrophils <1000/μl
Hypertriglyceridemia and/or hypofibrinogenemia:
Fasting triglycerides 265 mg/dL
Fibrinogen 1.5 g/L
Hemophagocytosis in bone marrow or spleen or lymph
nodes
Low or absent NK-cell activity
Ferritin 500 lg/L
Soluble CD25 2400 U/L
Supportive clinical criteria include neurologic symptoms
and cerebrospinal fluid pleocytosis, conjugated
hyperbilirubinemia, and transaminitis, hypoalbuminemia
and hyponatremia
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Systematic review: macrophage activation syndrome in IBD

of the clinical picture and blood parameters, she was
transferred to our Surgery Unit and underwent resec-
tion of the distal 50 cm of the ileum. Histopathological
evaluation of the resected bowel was consistent with
intestinal B-cell lymphoma and Crohn’s disease.
After discharge, the patient was followed by hematolo-
gists, but died 3 months later, after a second chemother-
apy cycle.
Clinic of Palermo: a 54-year-old man, diagnosed with
Crohn’s disease of the ileum in 2007 by means of colo-
noscopy, histology, and magnetic resonance imaging,
was initially treated with steroids due to fever and mild
diarrhea. The patient initially responded with clinical
remission, but relapsed early with high-grade fever. A
complete screening for infection was negative, so steroids
were re-started with an initial response, followed again
Database: PubMed
[all fields], past 30 years: “h(a)emophagocytic
lymphohistiocytosis” OR “h(a)emophagocytic
lymphohistiocytic syndrome” OR “macrophage
activation syndrome” OR “opportunistic
infections”, cytomegalovirus, Epstein-Barr
virus” AND “IBD” OR “Crohn’s disease” OR
“ulcerative colitis” OR” inflammatory bowel
disease(s)”
Database: SCOPUS
[Title, Abstract, Keywords], past 30 years
“h(a)emophagocytic lymphohistiocytosis” OR
“h(a)emophagocytic lymphohistiocytic
syndrome” OR “macrophage activation
syndrome” OR “opportunistic infections”,
“cytomegalovirus, Epstein-Barr virus” AND
“IBD” OR “Crohn’s disease” OR “ulcerative
colitis” OR” inflammatory bowel disease(s)”
Articles screened on basis of title,
abstract, and (if necessary) full text
Excluded, n = 3,110
• Not case report or series
• Described patients with IBD and
infections, but not affected with MAS
• Described patients with MAS but
pathologies other than IBD
Manuscript review and application of
inclusion criteria (patients with IBD and
MAS)
Excluded, n = 3
• No detailed information about the
patients, n = 1
• information available, clinical picture
consistent with MAS, but definitive
diagnosis was not made, n = 2
Combined search results, n = 3,149
Included, n = 40
Final, n = 37
Figure 2 | Search strategy and flow of information relative to the systematic review.
4Aliment Pharmacol Ther
ª2013 Blackwell Publishing Ltd
W. Fries et al.

Table 2 | Year of publication, patient’s characteristics, disease type, IBD treatment and duration before macrophage
activation syndrome (MAS) onset, infectious trigger, modality of diagnosis of infectious agent, treatment of MAS, and
outcome of the retrieved cases
Author,
year IBD Gender
Age;
years
IBD-
Therapy
Duration
in
months Pathogen Detection MAS treatment Fatal
Reiner,
1988
16
CD F 44 S 36 36 Histoplasma Culture n.a. N
Posthuma,
1995
17
CD M 19 AZA 20 20 EBV IgM-VCA Acyclovir, IV-Ig
a-interferon
Plasmapheresis
Y
Sjipkens,
1996
18
CD F 20 S-AZA n.a.–18 CMV IgM anti-CMV
IgG anti-CMV
pp65 antigenemia
Ganciclovir
Prednisone
Transfusions
N
Kanaji,
1998
19
UC M 25 S n.a. ? ? Prednisolone
IV-Ig
N
Babu,
2004
20
CD M 12 AZA 24 CMV IgM anti-CMV
IgG anti-CMV
CMV-mRNA for pp67
AZA withdrawal N
Koketsu,
2004
21
UC M 35 S-
colectomy
n.a. CMV Ab anti-CMV
pp65 antigenemia
Ganciclovir
IV-Ig, G-CSF
N
Chauveau,
2005
22
CD M 37 AZA-IFX n.a.–n.a. CMV n.a. n.a. N
Hindupur,
2005
23
CD M 26 IFX 0.5 0.5 MTB Culture post-mortem Dexamethasone
Cyclosporin A
Y
Kohara,
2006
24
CD M 22 MP-IFX n.a.–4 CMV IgM anti-CMV
IgG anti-CMV
CMV-PCR
Histology
Ganciclovir
Splenectomy
Transfusions
N
James,
2006
25
CD M 26 S-IMM-
IFX
n.a.–n.a.–
n.a.
MTB n.a. n.a. Y
Siegel,
2007
26
UC M 29 MP n.a. CMV Post-mortem IV-Ig, etoposide
Dexamethasone,
G-CSF, acyclovir
Y
Francolla,
2008
27
CD F 15 AZA-IFX 30–24 EBV IgM-VCA Acyclovir
Dexamethasone
N
Serrate,
2009
28
CD F 53 AZA 20 EBV IgG-VCA
EBV-DNA
Methylprednisolone
Rituximab
Etoposide, IV-Ig
N
Miquel,
2009
29
CD
CD
F
M
63
23
AZA
S-AZA-
IFX
48
12–12–12
CMV
CMV
pp65 antigenemia
IgM anti CMV
pp65 antigenemia
CMV-DNA
Ganciclovir, IV-Ig
Methylprednisolone
Ganciclovir
N
N
Dapena
Diaz,
2009
30
CD F Pediatric n.a. n.a. n.a. n.a. HLH-04 Y
N’Guyen,
2009
31
CD M 35 AZA 36 EBV IgM-VCA
IgG-VCA
EBV-DNA
IV-Ig, prednisone
Cyclophasphamide
Vincristine,
acyclovir, rituximab
Y
Wolschke,
2010
32
CD F 28 AZA 24 CMV Serum CMV-DNA
BAL CMV-DNA
Ganciclovir
HLH-04
N
Numakura,
2010
33
CD F 48 Ifx n.a. MTB PCR sputum Anti-TBC
IV-Ig
Steroids
N
Fox, 2010
34
UC M 50 5-ASA n.a. EBV IgG-VCA
EBV-DNA
HLH-04
IV-Ig
Y
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Systematic review: macrophage activation syndrome in IBD

Table 2 | (Continued)
Author,
year IBD Gender
Age;
years
IBD-
Therapy
Duration
in
months Pathogen Detection MAS treatment Fatal
Uslu,
2010
35
CD M 11 S-AZA 24–24 Acinetobacter Blood culture Methylprednisolone
CSA, IV-Ig
Y
Deneau,
2010
36
IBDU M 11 AZA-Ifx n.a.–12 EBV/
lymphoma
Tissue
Immunohistochemistry
Etoposide
Dexamethasone
Y
Petrache,
2010
37
CD
UC
F
M
31
27
S-AZA
AZA
n.a.–n.a.
36
CMV
CMV
CMV-DNA
CMV-DNA
Ganciclovir
n.a.
N
N
Kim,
2010
38
UC M 32 SASP 24 n.a. n.a. Steroids N
Ross,
2011
39
CD M 10 AZA 12 EBV IgM-VCA
EBV-DNA
Cyclophosphamide
Vincristine
Prednisolone
rituximab
Y
Gunson,
2011
40
CD F 14 AZA 60 EBV EBV-DNA
IgG-EBNA
Methylprednisolone
IV-Ig, acyclovir
Rituximab
N
Cot
e-
Daigneault,
2011
41
CD M 21 MP-IFX 48–48 Lymphoma IgG-EBNA G-CSF
HLH-04
N
N’Guyen,
2011
31
CD
CD
CD
CD
F
F
F
F
28
33
30
38
AZA-IFX
AZA
AZA-IFX
AZA
60–24
60
48–1
24
CMV
CMV
CMV
CMV
IGM anti-CMV
CMV-DNA
IgM anti-CMV
CMV-DNA
IgM-anti-CMV
blood CMV-DNA
BAL CMV-DNA
IgM anti-CMV
CMV-DNA
Ganciclovir, steroids
Ganciclovir, steroids
Ganciclovir, steroids,
foscarnet, IV-Ig
Ganciclovir, IV-Ig
Foscarnet, steroids
N
N
N
Y
Lo Presti,
2011
42
CD F 30 AZA 8 CMV CMV-DNA Ganciclovir, steroids N
Salado,
2011
43
CD M 24 S-IFX n.a.–4 EBV EBV-DNA HLH-04 N
Biank,
2011
44
CD
CD
CD
CD
CD
n.a.
n.a.
n.a.
n.a.
n.a.
Pediatric
Pediatric
Pediatric
Pediatric
Pediatric
MP
AZA
AZA
AZA
MP
13
4
78
52
6
EBV
EBV
EBV
EBV
n.a.
EBV-DNA
EBV-DNA
EBV-DNA
EBV-DNA
n.a.
HLH-04
HLH-04
HLH-04
HLH-04
Infliximab
N
N
Y
N
N
van
Langenberg,
2011
45
UC
CD
F
M
32
22
AZA
AZA
24
24
CMV
CMV
IgM anti-CMV
PCR blood/BAL
IgM anti-CMV
PCR blood/BAL
Ganciclovir
Ganciclovir
N
N
Duque,
2011
46
UC M 19 AZA 36 EBV IgM-VCA
EBV on LN histology
Prednisolone,
Transfusions
IV-Ig, G-CSF
N
Ingvardsen,
2012
47
UC M 22 AZA n.a. EBV n.a. n.a. Y
Munoz,
2012
48
CD F 24 MP 24 CMV IgM-anti-CMV
CMV-DNA
HLH-04
IV-Ig, ganciclovir
N
Altaf,
2012
49
CD F 15 MP n.a. EBV/
lymphoma
IgG-EBNA
EBV-DNA
Rituximab, IV-Ig
HLH-04
N
Fitzgerald,
2012
50
CD F 14 AZA 48 EBV EBV-DNA Rituximab N
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by early relapse with fever and arthralgias. Azathioprine
was added and the patient went into remission for
2 years, but in December 2009 he relapsed with high
fever unresponsive to steroids. Infliximab was initiated
followed by complete remission until October 2011 when
he relapsed again with high fever and arthralgias. At
admission, splenomegaly and an increase in size of
abdominal lymph-nodes were observed; a complete
screening of infectious diseases through blood and urine
cultures for bacterial, viral and fungal infections was per-
formed. HSV-1, with typical labial lesions, was present
and i.v. acyclovir was started. Despite negative bacterial
cultures, an empiric broad-spectrum antibiotic treatment
was started. At this moment, red blood cell, platelet and
leucocyte counts were normal and a bone marrow aspi-
rate was negative. Subsequently, red blood cell, platelet
and leucocyte counts decreased gradually and serum fer-
ritin increased to more than 10000 g/dL while serum tri-
glycerides rose to 800 mg/dL. Bone marrow aspirate was
repeated and haemophagocytosis was identified (Fig-
ure 1). A treatment regimen according to the treatment
protocol HLH-04 was established with dexamethasone,
etoposide and cyclosporine A, but the patient’s condi-
tions deteriorated and he died 10 days later.
In the retrieved cases, gender distribution was equal
(21 females, 24 males, five not reported) in the whole
series and 36/50 (72%) were adults, aged from 19 to
72 years; the median age in adults was 28.5 years. The
underlying bowel diseases in adults were Crohn’s disease
(CD) in 26/36 (72%), and ulcerative colitis (UC) in 10
patients (28%). In the 14 pediatric patients, 13 (92.8%)
were diagnosed with CD and one with inflammatory
bowel disease unclassified (IBDU) (6%).
Overall mortality was 30%. In adults, death occurred
in 10/36 (28%), whereas fatal outcome was observed in
5/14 pediatric patients (38%). Where indicated, the final
cause of death was multiorgan failure in six patients;
hepatic failure, respiratory failure, gastrointestinal bleed-
ing, or intracerebral hemorrhage were reported in other
patients. One patient died during emergency surgery due
to a perforated gastric ulcer. Two adult patients with
lymphoma died during the follow-up after MAS had
been successfully treated (our clinic,
41
).
Treatment before MAS onset. Treatment with thiopu-
rines was reported in 39/50 patients with a duration that
ranged from 4 months to 8 years. Thiopurine monother-
apy was administered in 28/37 patients, whereas in the
remaining cases thiopurines were associated with steroids
(three cases), with infliximab (seven patients) or both
(one case). In two patients, an immunosuppressor with-
out indication of the exact molecule was associated with
infliximab and steroids
25
or was used as single therapeu-
tic agent,
30
respectively. Infliximab was used as single
therapy in three patients, associated with steroids in 1
patient. All other patients were treated with a combina-
tion with thiopurines. Duration of infliximab treatment,
when reported, ranged from 0.5–60 months.
In pediatric patients, thiopurines were administered to
13/14 patients, as monotherapy in 10/13, or combined
with steroids (one patient) or with infliximab (two
patients). In one patient treatment was not indicated.
30
Table 2 | (Continued)
Author,
year IBD Gender
Age;
years
IBD-
Therapy
Duration
in
months Pathogen Detection MAS treatment Fatal
Weinkove,
2012
51
CD M 21 AZA n.a. CMV IgM anti-CMV
CMV-DNA
HLH-04
Foscarnet
Valganciclovir
N
Clinic of
Messina
UC
CD
F
F
38
72
AZA
AZA
96
6
?
CMV/
lymphoma
?
PCR
Methylprednisolone
G-CSF
Methylprednisolone
Ganciclovir
Y
N
Clinic of
Palermo
CD M 54 IFX 15 ? ? HLH-04 Y
UC, ulcerative colitis; CD, Crohn’s disease; F, female; M, male; 5-ASA, mesalazine; SASP, salazopyrin; AZA, azathioprine; MP, mer-
captopurine; IMM, immunomodulator (exact molecule not stated); n.a., information not available; ?, no infectious agent identified;
CMV, cytomegalovirus; EBV, Ebstein-Barr virus; MTB, Mycobacterium tuberculosis; HSTL, hepatosplenic T-cell lymphoma; IV-Ig,
intravenous immunoglobulin; G-CSF, granulocyte colony stimulating factor; HLH-04, treatment protocol recommended in HLH
52
,
i.e. an association of steroids, etoposide and cyclosporine A; S, steroids; N, no; Y, yes.
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When indicated, thiopurine dosing ranged from 0.9 to
3.15 mg/kg/day for azathioprine and 1.4 to 1.76 mg/kg/
day for mercaptopurine. In six patients (Table 3), deter-
mination of erythrocyte concentrations of 6-thioguanine
nucleotides (6-TGN), and in four patients also those of
6-methylmercaptopurines (6-MMP), was available shortly
before onset of MAS, showing the former levels to be
within the therapeutic range and the latter below the
toxic limit.
27, 44, 50, 51
Mesalazine or sulphasalazine alone were reported in
one patient, steroids alone in two patients and steroids
followed by colectomy in one patient with UC.
Triggers associated with MAS onset. Viral infections
were causally associated in 39/50 patients (78%) with
infections due to EBV equally frequent to those due to
CMV (19 EBV, 20 CMV); one CMV/herpes simplex
virus (HSV) co-infection was seen (own observation).
Interestingly, in pediatric patients, EBV was identified
in 11/14 (79%), CMV or Acinetobacter in one case
each, and in one patient no infectious agent was indi-
cated.
Primary EBV infections were reported in 12 patients,
while the remaining were consistent with EBV reactiva-
tion. Primary CMV infections were diagnosed in 7 out
of 20 patients.
In the whole series, bacterial or fungal infections were
identified in five cases. Among these latter agents Myco-
bacterium tuberculosis was reported in three patients and
all these patients received infliximab.
In seven cases, no infectious agent was identified.
Three cases were associated with lymphomas; one hepa-
tosplenic T-cell lymphoma (HSTCL) in a 21-year old
male treated with infliximab +MP,
41
one B-cell lym-
phoma in a 72-year old woman treated with AZA for
CD (own observation), and one NK/T-cell lymphoma in
an 11-year old boy treated with infliximab +AZA for
IBDU
36
: the two former patients died due to neoplastic
disease, the latter patient died due to MAS.
Clinical presentation of MAS in IBD
With respect to the diagnostic criteria of HLH (Table 1),
and given that not all reports indicate numeric data,
clinical features included temperature ranging from 38.6
to 40°C in 92% of all cases. In four reports, no detailed
data were available. Enlargement of liver and spleen was
reported in almost half of patients. In all cases, leuco-
penia was reported with a median value of 1200/mL
(range 300–3100/mL). In roughly 30% cases, leucocytes
were above the limit set by Henter et al.
1
Median hae-
moglobin levels were 87 g/L (range 65–133 g/L), with
only 8% above the upper limit. Median platelet counts
were 80 000/mL (range 8000–187 000/mL) with 10%
above the limit indicated by diagnostic criteria. Serum
ferritin was the most frequently reported variable, with
all of the reported values above the threshold of 500 μg/
L (median value 5000 μg/L; range 583–52 397 μg/L),
whereas triglycerides were normal in 16% with a median
concentration of 339 mg/dL (range 162–1235 mg/dL).
Only seven reports included serum fibrinogen with a
range from 0.3 to 1.7 g/L (normal in 1/7) and another
seven gave circulating levels of CD25 (range 5941–
39 222 U/mL). NK activity was reported in only four
reports with values compatible with HLH.
Treatment of established MAS. Besides withdrawal of
immunosuppressive therapy, sufficient to resolve the
clinical picture in one patient,
20
and specific treatment
for recognized bacterial, fungal or viral infections, vari-
ous approaches were described including administration
of i.v. immunoglobulins, plasmapheresis, granulocyte-col-
ony stimulating factor, and foscarnet in addition to
ganciclovir. Vincristine and/or cyclophosphamide were
used in EBV-related lymphoproliferative disorders. The
full HLH-04 protocol, published in 2007,
1
an association
of dexamethasone, etoposide, and cyclosporine A, was
employed in 13 patients, starting from 2009 (eight
patients with EBV, three with CMV, and two patients
without identification of an infectious agent). Death
occurred in four of them. Four patients with EBV-related
Table 3 | Cases where erythrocyte (RBC)
concentrations of thiopurine metabolites were assessed
shortly before macrophage activation syndrome onset
showing non-toxic concentrations
Author,
year IBD
6-TGN pmol/
8910
8
RBC
6-MMP pmol/
8910
8
RBC
Francolla,
2008
27
CD 166 790
Biank,
2011
44
CD
CD
CD
72
210
171
875
4066
1952
Fitzgerald,
2012
50
CD 264 –
Weinkove,
2012
51
CD 201 –
6-TGN, 6-thioguanine nucleotides; 6-MMP, 6-methylmercap-
topurine; RBC red blood cells.
Weinkove’s case, author’s personal communication.
8Aliment Pharmacol Ther
ª2013 Blackwell Publishing Ltd
W. Fries et al.

MAS were treated successfully with one or more admin-
istrations of rituximab, an anti-CD20 antibody, whereas
one patient died despite this treatment. Interestingly, inf-
liximab was administered successfully in a pediatric
MAS virus-negative patient formerly treated with mer-
captopurine.
44
Outcome after MAS. Follow-up ranging from 6 months
to 3 years was reported in 20 of the surviving patients.
Apparently, no patient resumed the same immunosup-
pressor given before MAS-onset. Four patients remained
in remission on oral and topical mesalazine,
20, 41, 45, 46
in
two patients methotrexate was started successfully, one
patient is on low-dose prednisolone (10 mg/day) and one
is on low dose cyclosporine (target serum trough level
100 ng/mL, personal communication from ref 51) treatment.
Finally, one patient is on an empirical anti-MAP (Myco-
bacterium avium spp. paratuberculosis) therapy
45
and one
patient is on evaluation for stem cell transplantation.
48
DISCUSSION
In the retrieved records, most of the patients suffered
from CD and all except five patients were under immu-
nosuppressive therapy. The prevalence of CD may reflect
the more frequent use of immunomodulators in this dis-
ease compared to UC rather than a disease-related sus-
ceptibility to MAS. Roughly one out of three patients
died. Although we have no epidemiologic data on the
incidence of MAS in IBD, it is plausible that the rising
frequency is due to an improved awareness on the part
of gastroenterologists rather than to a phenomenon that
has increased over the past 5 years. Immunomodulators
such as AZA or MP have been constantly used over the
past 30 years throughout the world, and biologic thera-
pies have now been in use for almost 10 years. The main
therapeutic intervention prior to onset of MAS was with
thiopurines, while the duration of thiopurine treatment
seems not to have been significant (range 4–69 months).
Other treatments for IBD include biologics, infliximab
alone or in combination with steroids or thiopurines.
Adalimumab has not yet been reported in IBD to be
associated with MAS, but has been reported in one
patient with rheumatoid arthritis.
55
Surprisingly, salazop-
yrin and mesalazine were reported in one patient each as
the only therapy before MAS onset, pointing to genetic
factors, thus making immunosuppression as the only
causative factor unlikely.
It is possible that the occurrence of MAS in patients
with IBD is the result of a fatal combination between
persistence of, or a new infection with, a virus, the effect
of immunosuppressive therapy weakening immune sur-
veillance, and the potential presence of a genetic suscep-
tibility. Thioupurines inhibit the activity of CD4 T-
lymphocytes by inducing apoptosis through inhibition of
Rac1
56
thus weakening defence against viral infections.
Biologics, on the other hand, seem to expose patients
more to fungal or bacterial agents.
57
In systemic lupus
erythematosus (SLE) patients, a killing defect of NK cells
has been demonstrated which is ultimately accentuated
by a reduction of NK cells induced by azathioprine.
58
Likewise in kidney transplant patients
59
there is a signifi-
cant difference in NK cell activity depending on the
immunosuppressive drug used to prevent graft rejection.
Indeed, the combination of tacrolimus/mycophenolate
mofetil did significantly better in terms of less NK cell
reduction and less NK cytotoxicity reduction than the
combination with cyclosporine/azathioprine. In an exper-
imental murine model of MAS, repeated stimulation of
the toll-like receptor 9 (TLR9) with CpG DNA precipi-
tates the syndrome.
60
EBV is known to trigger TLR9,
and high loads of EBV were found in macrophages of
patients with MAS.
33
In the juvenile form of SLE, where
MAS appears to have a high clinical impact,
61
overstimu-
lation of TLR9 is believed to be induced by autoanti-
gens.
62
In sJIA-related MAS, occult MAS appears to be
present in up to 30%
9, 63
and it has been hypothesized
that an intrinsic hyperactivity of TLR/IL-1R signaling
may trigger evolution to MAS
64
. The common denomi-
nator is an inefficacious response to antigens that leads
to an overwhelming Th1/Th1-related cytokine produc-
tion and, finally, to macrophage activation in the bone
marrow, liver, and spleen leading to its principal feature
i.e. a two- to three-line cytopenia.
It is becoming apparent that compared to other im-
munomodulators or biologics, thiopurines carry a risk
for reactivation of viral infections other than CMV,
including activating warts (human papilloma virus,
HPV) with possible cervical dysplasia/cancer,
65
and Eb-
stein-Barr virus (EBV) with an increased risk of related
lymphomas.
66
Herpes viruses, after the primary infection,
enter in latency in the human organism but remain
under the control of the immune system, namely NK
cells and cytotoxic T cells. Latent varicella-zoster virus
(VZV) and HSV are harbored in neural cells, whereas
latent EBV and CMV reside in precursors of myeloid
derived monocytes and dendritic cells.
67
The figures for
seroprevalence in healthy adults for CMV, EBV, HSV,
and VZV reach 100%, 96%, >90%, and >90%, respec-
tively
68–72
, which means that nearly every patient is at
risk for reactivation. Interestingly, in the retrieved cases,
Aliment Pharmacol Ther 9
ª2013 Blackwell Publishing Ltd
Systematic review: macrophage activation syndrome in IBD

12 patients were reported to have a primary EBV infec-
tion and 7 patients were classified as primary CMV
infection. Despite these findings, no recommendation
concerning a search for antibodies against either EBV or
CMV has been advised in the most recent ECCO guide-
lines on opportunistic infections.
73
Since TNF plays a role in the inhibition of viral replica-
tion,
74
much attention has been paid to potential viral
infections in anti-TNF treated patients. In a large register
from rheumatologic patients in Spain, VZV and HSV
infections were the most frequent viral infections in
patients treated with biologics, ranking however after bac-
terial or fungal complications.
75
Atypical varicella and
VZV reactivation have been reported
76
and severe infec-
tions due to VZV are reported among the most frequent
viral complications of anti-TNF therapy in the French
RATIO registry, followed by HSV. However, the overall
risk of reactivation of latent herpes viruses in patients on
biologics appears to be low; at least after 3 months of ther-
apy in IBD
77
and after 6 weeks in rheumatoid arthritis.
78
Concerning CMV, T-cell response to CMV was investi-
gated in 25 patients on anti-TNF therapy, showing that
the interferon-cresponse of CD4 +ve cells and the prolif-
erative response were maintained upon CMV antigen
stimulation
79
. Indeed, in most of the retrieved cases, and
other reports on CMV infections
80
, patients were on con-
comitant thiopurine treatment. EBV is a virus with the
potential of inducing malignant lymphomas, and many
studies deal with this topic.
81
Investigating reactivation of
EBV on anti-TNF therapy, however, yielded negative
results in rheumatologic
78, 82
as well as in IBD patients.
77
Despite these considerations, in the past few years a
growing number of reports have been published on IBD
patients with opportunistic infections complicated by a
syndrome of macrophage and T-cell activation, accom-
panied by a potentially fatal cytokine storm and over-
whelming inflammatory reaction, the MAS syndrome,
which, in the present review, reaches a mortality rate of
30%. For comparison, over the past 5 years, one of the
major concerns regarding therapeutic interventions in
IBD has been represented by HSTCL, a highly lethal
lymphoma affecting mostly young males treated with thi-
opurine monotherapy or with combined therapies (thi-
opurines plus biologics). Altogether, 38 cases of HSTCL
are reported, 23 of them on thiopurine monotherapy
83
with a range of therapy duration between three and
17 years. In the present series of MAS, a 21-year old
male patient was diagnosed with HSTCL after MAS
onset and died somewhat later due to sepsis.
40
It appears that one of the major problems is to recog-
nize the syndrome, which may present with a variety of
symptoms, ranging from neurologic-predominant signs
to acute liver failure. In fact, two of the retrieved reports
were excluded as MAS was not diagnosed despite a com-
patible clinical picture.
53, 54
Misinterpretation of clinical/
biochemical signs leads to diagnostic delays, since fever
and cytopenia may represent side effects of thiopurine
therapy, whereas cytopenia may be present in patients on
biologics. The presence of hemophagocytic CD163 +ve
macrophages in bone marrow or lymph-node aspirates,
may be missed, at least in initial stages, and negative his-
tology should not rule out MAS,
84
whereas repeated aspi-
rates retard diagnosis. The clinical picture, together with
the infiltration of bone marrow or liver by activated mac-
rophages, may lead to the correct diagnosis. Additional
features such as the reduction/absence of peripheral
CD8 +ve NK cells,
85
are present in early stages in nearly
all patients.
86
Other biochemical signs, e.g. a highly ele-
vated serum ferritin, most likely expression of the acute
phase response, are almost always present and an early
decrease after therapy start may be used as prognostic
marker for a more favourable outcome in HLH.
87
Other
immunologic markers are raised in MAS, such as sCD25
and the receptor for haemoglobin/haptoglobin complexes
CD163. CD25 is believed to have an immunosuppressive
action as it binds circulating IL-2, but may reflect in
MAS only the complete dysregulation of the immune sys-
tem.
88
A proinflammatory action of CD25, by enhancing
the IL-17 immune response, has been shown recently in
an animal model of autoimmune disease.
89
CD163 is
involved in clearance and endocytosis of haemoglobin/
haptoglobin complexes by macrophages and may protect
tissues from free haemoglobin-mediated oxidative
damage. In sJIA, high circulating levels of sCD25 and
sCD163 are promising diagnostic markers for early diag-
nosis of MAS together with serum ferritin
90
and should
be investigated in IBD patients with suspected MAS.
With regard to therapy, treatment of the underlying
infection is mandatory and may require empirical treat-
ment in the first 24–48 h. If MAS is suspected, a broad
search for infectious agents with appropriate techniques
is necessary, including determination of EBV-, CMV-,
human herpes virus-6 (HHV-6)-DNA, search for Myco-
bacterium tuberculosis, histoplasmosis (urines), repeated
blood and urinary cultures, etc. In hyperacute situations,
additional immunosuppression with steroids, cyclospor-
ine A, or etoposide may be required (see Henter, ref 1).
Other treatment options, e.g. rituximab, immunoglobulins,
10 Aliment Pharmacol Ther
ª2013 Blackwell Publishing Ltd
W. Fries et al.

or intrathecal dexamethasone are extensively reviewed in
Jordan et al
91
.
In conclusion, in IBD patients, thiopurine treatment
in particular is associated with MAS, most likely by pro-
moting viral reactivation through inhibition of NK and
cytotoxic T cells. However, although less frequent, almost
every treatment and a variety of infectious agents may
lead to this syndrome. Overall, mortality is high, espe-
cially in pediatric patients. It is possible that genetic sus-
ceptibility, together with reactivated latent or primary
viral infections, contributes to the occurrence of MAS.
Genetic determinants should be investigated in IBD
patients with MAS.
AUTHORSHIP
Guarantor of the article: Walter Fries.
Author contributions: WF and AC designed the research
study, performed and analyzed the literature search, and
drafted the paper. MC contributed the case from Palermo
and critically reviewed the manuscript. All authors
approved the final version of the manuscript.
ACKNOWLEDGEMENT
Declaration of personal interests: WF served as an advisory
board member for MSD and Abbvie. The authors wish
to thank Trays Ricciardi for language assistance.
Declaration of funding interests: None.
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Systematic review: macrophage activation syndrome in IBD