H em o p h ag o cy tic sy n d ro m e: p itfalls in its d iag n o sis
Department of Internai Medicine Faculty of Medicine
Department of Pathology, Faculty of Medicine, State University of Campinas - Campinas, Brazil
lhe hem ophagocytic syndrom e (HS) is characterized by a clinicai picture of fever, hepatosplenom egaly, Iym phadenopathy and peripheral pancytopenia. lhe m orphologic hallm ark of this syndrom e is the phagocytosis of hem atopoietic elem ents by m orphologically norm al
m acrophages. HS is considered rare and m ay be a prim ary disease or associated to viral, infection, neoplasias or autoim m une
diseases. lreatm ent is controversial and its evolution is often fatal. Anatom o-pathological evaluation shows the phenom enon of
hem ophagocytosis in several organs, especially the hem atopoietic tissues. W e describe a case of HS, discuss its possible causes, its clinicai and pathologic features, its pathophysiology and therapeutic possibilities.
UNITERM S: Hem ophagocytic Syndrom e. Lym phohistiocytosis. pancytopenia.
INTRO DUCTIO N
H
e m o P h a g O C y tic s y n d ro m e h a s b e e n d e s c rib e d a s a d is o rd e r o f m o rp h o lo g ic a lly n o rm a lm a c ro p h a g e s . T h e c lin ic a I fe a tu re s a re fe v e r,
h e p a to s p le n o m e g a ly , ly m p h o a d e n o p a th y a n d p a n c y to p e n ia ,
s e c o n d a ry to a p h e n o m e n o n o f p h a g o c y to s is o f
h e m a to lo g ic a l e le m e n ts a n d th e ir p re c u rs o rs in b o n e m a rro w
a n d p e rip h e ra lly m p h o id o rg a n s1,2 ,3 . T h is s y n d ro m e h a s
b e e n a s s o c ia te d to v ira l in fe c tio n s , e s p e c ia ll y th e E p s te in
-B a rr v iru s , c y to m e g a lo v iru s a n d a d e n o v iru s . In th is c o n te x t
it h a s b e e n c a lle d " v iru s -a s s o c ia te d h e m o p h a g o c y tic
s y n d ro m e " (V A H S ). T h e re a re re p o rts a s s o c ia tin g H S w ith
A d d re s s fo r c o rre s p o n d e n c e :
C á rm in o A n to n io d e S o u z a
C id a d e U n iv e rs itá ria . "Z e fe rin o V a z " - P .O . B o x 6 1 9 8 C a m p in a s /S P - B ra s il- C E P 1 3 0 8 1 -9 7 0
in fe c tio n s c a u s e d b y b a c te ria , m y c o b a c te ria , fu n g i a n d p a ra s ite s a s w e l1 a s c a rc in 9 m a s a n d ly m p h o m a s , m a in ly o fT
c e l1 s1
,2 ,4 ,5 . H S m a y o c c u r in y o u n g c h ild re n a s a n is o la te d
d is e a s e n a m e d h e m o p h a g o c y tic ly m p h o h is tio c y to s is2 ,6 .
H S m a y a ls o b e a s s o c ia te d w ith o th e r d is e a s e s , s u c h
a s s y s te m ic lu p u s e ry th e m a to s u s , W e b e r-C h ris tia n d is e a s e , s a rc o id o s is a n d d ru g -in d u c e d a g ra n u lo c y to s is 1 ,2 ,3 .
A lth o u g h p h a g o c y to s is o f h e m o p o ie tic p re c u rs o rs b y
m a c ro p h a g e s in b o n e m a rro w is n o t u n c o m m o n , H S is
c o n s id e re d ra re2
• Its in c id e n c e m a y b e h ig h e r in a re fe rra l
h o s p ita l a n d its d ia g n o s is re q u ire s a tte n tio n3•
T h e m a in la b o ra to ry c h a n g e s fo u n d in H S d e m o n s tra te
p ro g re s s iv e s y s te m ic in v o lv e m e n t. A c c o rd in g to th e g u id e lin e s o f th e H y s tio c y te S o c ie ty its d ia g n o s is c o m p ris e s
fe v e r, s p le n o m e g a ly , b ic y to p e n ia o r p a n c y to p e n ia (s e e n in 7 5 % o f th e p a tie n ts ) h y p e J .~ trig lic e rid e m ia a n d
h e m o p h a g o c y to s is in b o n e m a rro w . C o a g u la tio n te s ts s h o w
p ro g re s s iv e a b n o rm a litie s in c lu d in g h y p o fib rin o g e n e m ia .
T ra n s a m in a s e v a lu e s a n d in fla m m a to ry te s ts a re á ls o
a lte re d . S e ro lo g ic a n d rh e u m a to lo g ic e x a m in a tio n s a re u s e fu l fo r d is c a rd in g a s s o c ia te d d is e a s e s2
,3 ,7 .
SCHETTERT, LI.; CARDINALLI, LA.; O ZELLO , M .C.; VASSALLO , J.; LO RAND-M ETZE, 1.;
SO UZA, C.A. - Hem ophagocytic Syndrom e: pitfalls in its diagnosis
The anatom o-pathological evaluation of the m any
organs
involved
shows
the
phenom enon
of
hem ophagocytosis by m orphologicallynorm al m acrophages,
in .bone m arrow, liver, spleen and lym ph nodes. It m ay also
be found in the m eninges or the skin
2,3.The pathophysiology is quite unclear, but probably a
variety of cytokines are involved. Som e specific events
m ay start an uncontrolled activation of the cellular im m une
system . Through .the release of IFN gam m a and IL-2,
cytotoxic T-Iym phocytes and CD8
+
lym phocytes activate
the m acrophage cytokines, especially TNF, PGF2 alpha,
PGE2 and IL6. These cytokines
show specific
and
interactive functions and lead to clinicaI m anifestations of
fever, coagulopathy, lipidic changes, phagocytosis, anem ia,
leukopenia and throm bocytopenia. M acrophagic activation
.also leads to hyperferritinem ia and alterations of lipidic
enzym es.
C A S E R E P O R T
E.A.G.S., a 19-year-old white m ale, presented a
history of two m onths with ecchym osis and gingivorrhagia.
No other signs and sym ptom s were found. He had been
treated for idiopathic throm bocytopenic purpura (ITP) six
years earlier. Physical exam ination showed a young m an
in a good general condition, except for petechiae and
ecchym osis. Hem oglobin: 14,3°g/dl; M CV 83 fi; M CH
26 pg; leukocytes: 5, 1x10
9/1 ,with 62% polym orphonuclear
neutrophils,
4% eosinophils,
2% basophils,
27%
lym phocytes
and 5% m onocytes;
platelets:
5x10
9/1.
Screening coagulation tests were norm al. Bone m arrow
cytology showed unspecific alterations. Prednisone 1 m g/
kg was introduced, considering a diagnostic hypothesis of
ITP.
One week later,
the patient presented fever a~d
cellulitis
in the right lim bo .Blood counts rem ained
unchanged. The patient was hospitalized and treated with
antibiotics. Laboratory tests for renal and hepatic functions
were norm al. The serology for HIV 1 and HIV 2, hepatitis
B, hepatitis C virus, cytom egalovirus and Epstein-Barr
virus, as well as syphilis and toxoplasm osis, were negative.
LE cells, Ro(SSA), Sm , Ia(SSb),
Anti-RNP, Anti-DNA and antiphospholipid antibodies were
negative. Chest X-ray and transthoracic echocardiogram
were norm al. A slightly enlarged liver and spleen were
found by abdom inal'ultra-sound.
Bone m arrow
cytology
and histology
showed
increased
cellularity,
dyserythropoiesis
and a slight
decrease in granulocytic precursors, a slight increase in
the m egacaryocytic
series and frequent m acrophages
showing hem ophagocytosis. Im m unohistochem ical
stain
for UCHL-1, L26 and lysozym e were perform ed in order
to exclude bone m arrow involvem ent
by lym phom a.
Im m unostain by lysozym e showed clearly the large num ber
of m acrophages with hem ophagocytosis (fig.1). Cytogenetic
analysis showed a 46XY karyotype.
Ten days later, hem oglobin was 11,0 g/dl, hem atocrit
34% , leukocytes 1,lx10
9/1(35% segm ented neutrophils,
60% lym phocytes and 5% m onocytes) and platelets 2x10
9/
1.
Blood
biochem istry
rem ained
norm al.
Hepatosplenom egaly had increased. Bone m arrow biopsy
was repeated but findings rem ained unchanged. A new
investigation for viruses, bacteria, m ycobacteria and fungi
was perform ed but no agent was isolated. After 15 days,
the chest X - ray showed a diffuse interstitial infiltrate. The
patient presented abdom inal distention and abdom inal
ultra-sonography
and tom ography
showed a m oderate
enlargem ent
of spleenand
liver. Then,
the patient
progressed to com a, and presented clinicaI and laboratory
features of consum ption coagulopathy. CT of the skull was
norm al.
Cerebrospinal
fluid
evaluation
showed
proteinorrhachia of 81 m g/dl, with no other changes. The
electroencephalogram
was com patible
with diffuse
encephalopathy.
Despite receiving
intensive
care, the
patient died in a few days. An autopsy was perform ed.
The m ain
necroscopical
findings
were:
intensely
hypercellular
bone m arrow with m oderate increase in
erythroblasts, increase in m ore im m ature granulopoietic
precursors
and
intense'
histiocytosis
with
hem ophagocytosis (fig. 1); the liver showed slight, focal
portal lym phohistiocytic infiltration, and hyperplasia of
Kupffer cells with m oderate hem ophagocytosis
(fig. 2);
lym ph nodes showed norm al architecture
but had an
F ig u re 1 - B o n e m a rro w w ith h e m o p h a g o c y to s is (a rro w s ). A - H E , x 6 0 0 . B - Im m u n o s ta in w ith Iy s o z y m e , x 4 0 0 .
S C H E T T E R T , L T .; C A R D IN A L L I, L A .; O Z E L L O , M .C .; V A S S A L L O , J .; L O R A N D -M E T Z E , 1 .;
S O U Z A , C .A . - H e m o p h a g o c y tic S y n d ro m e : p itfa lls in its d ia g n o s is
3 ) ; s p le e n s h o w e d m y e lo id m e ta p la s ia a n d
h e m o p h a g o c y to s is . D iffu s e a lv e o la r in ju ry (in itia l p h a s e )
a n d h e m o rrh a g ic b ro n c h o p n e u m o n ia w e re fo u n d in th e
lu n g s . T h e b ra in p re s e n te d fo c a l s u b a ra c h n o id h e m o rrh a g e
a n d m e n in g e a lly m p h o h is tio c y tic in filtra tio n .
D IS C U S S IO N
H e m o p h a g o c y to s is is d e fin e d a s a c o n d itio n in w h ic h
th e p h a g o c y to s is o f h e m o p o ie tic p re c u rs o r c e lls b y
m a c ro p h a g e s o f n o rm a l a p p e a ra n c e is o b s e rv e d in b o n e
m a rro w , ly m p h n o d e s , s p le e n o r liv e r. T h is p h e n o m e n o n
m a y o c c u r in a v a rie ty o f c lin ic a I s ta te s , in c lu d in g fa m ilia l
h e m o p h a g o c y tic ly m p h o h is tio c y to s is , v ira l in fe c tio n s a n d
m a lig n a n t h is tio c y to s is , a s w e ll a s s o m e ty p e s o f m a lig n a n t
ly m p h o m a s 1 .2 .3 .5.
F ig u re 2 - L iv e r s h o w in g h y p e rp la s ia o f K u p ffe r c e lls w ith
h e m o p h a g o c y to s is (a rro w s ). H E , x 6 0 0 .
F ig u re 3 - L y m p h n o d e w ith h e m o p h a g o c y to s is (a rro w s ). H E , x 6 0 0
T h e te rm h e m o p h a g o c y tic ly m p h o h is tio c y to s is
in c lu d e s th e fa m ilia r, s p o ra d ic a n d v iru s -a s s o c ia te d
h e m o p h a g o c y tic fo rm s 2 . T h e fa m ilia r fo rm o f
h e m o p h a g o c y tic ly m p h o h is tio c y to s is p ro b a b ly h a s a
re c e s s iv e a u to s o m a l o rig in o It is a ls o k n o w n a s fa m ilia r
h e m o p h a g o c y tic re tic u lo s is , F a rq u h a r's d is e a s e , fa m ilia r
e ry th ro p h a g o c y tic ly m p h o h is tio c y to s is , ly m p h o h is tio c y tic
re tic u lo s is w ith p h a g o c y to s is , o r ly m p h o h is tio c y to s is . Its
in c id e n c e is 1 .2 c a s e s p e r m illio n c h ild re n u n d e r 1 5 y e a rs 2 .
M o s t c a s e s a re n o o ld e r th a n th re e . E v o lu tio n is s im ila r to
a s e p tic p ic tu re b u t w ith n o d e te c ta b le e tio lo g ic a g e n te
L a b o ra to ry te s ts fre q u e n tly re v e a l h y p e rtrig ly c e rid e m ia a n d
h y p o fib rin o g e n e m ia . C y to p a th o lo g ic e v a lu a tio n s h o w s
p h a g o c y to s is o f b lo o d e le m e n ts b y m a c ro p h a g e s a n d a n
in c re a s e d n u m b e r o f a ty p ic a lly m p h o c y te s in b o n e m a rro w ,
s p le e n , liv e r, ly m p h n o d e s , s k in a n d c e re b ro s p in a l flu id o
T h e d is e a s e s h o w s a n o n -re s p o n s iv e a n d ra p id c lin ic a I
c o u rs e a n d m a y b e tre a te d w ith c h e m o th e ra p y
(e p ip o d o p h y lo to x in s ) o r c y c lo s p o rin A , w ith a re s p o n s e in
s o m e c a s e s . N e v e rth e le s s , fre q u e n tly th e re is a re la p s e
w ith in s o m e y e a rs . B o n e m a rro w tra n s p la n ta tio n h a s b e e n
a n o th e r th e ra p e u tic a l o p tio n , b u t lo n g te rm e v a lu a tio n is
n o t a v a ila b le 2,8 ,9 .
V iru s -a s s o c ia te d h e m o p h a g o c y tic s y n d ro m e
(V .A .H .S .) w a s firs t d e s c rib e d in im m u n o d e fic ie n t p a tie n ts 7 ,
in w h o m p re v io u s ly d e s c rib e d fin d in g s w e re a s s o c ia te d to
v ira l in fe c tio n s . M o re re c e n tly it h a s b e e n o b s e rv e d in
im m u n o c o m p e te n t p a tie n ts . T h e m a in v iru s e s in v o lv e d a re
E p s te in - B a rr v iru s , c y to m e g a lo v iru s , a d e n o v iru s a n d
p a rv o v iru s B 1 9 . T h e c lin ic a I c o u rs e is o fte n fa ta l, d e s p ite
s p e c ific tre a tm e n t fo r in fe c tio n a n d fo r h e m o p h a g o c y tic
s y n d ro m e w ith im m u n o s u p p re s s iv e d ru g s . T h e
h e m o p h a g o c y tic s y n d ro m e , d e s c rib e d in H IV p o s itiv e
p a tie n ts , is g e n e ra lly a s s o c ia te d w ith o th e r v iru s e s ,
e s p e c ia lly th e E p s te in ~ B a rr v iru s , o r to o th e r in fe c tio n s 2 ,3 ,7 ,1 0 .
S e c o n d a ry h e m o p h a g o c y tic s y n d ro m e o c c u rs in
in fe c tio n s b y G ra m -n e g a tiv e b a c te ria , tu b e rc u lo s is , k a la
-a z -a r -a n d fu n g i 1 1 ,1 4 .It w a s a ls o o b s e rv e d in p a tie n ts w ith T
-c e llly m p h o m a s , in s o m e c a s e s w ith th e p re s e n c e o f th e
E p s te in -B a rr v iru s 1 1 ,1 2 ,1 3 .
H e m o p h a g o c y tic s y n d ro m e h a s b e e n d e s c rib e d in
o th e r d is e a s e s : in W e b e r-C h ris tia n 's d is e a s e (a s a h is tio c y tic
c y to p h a g ic p a n n ic u litis ) 7 ; in th e a d v a n c e d p h a s e o f C h e d ia k
-H ig a s h i's s y n d ro m e 1 ; in s y s te m ic lu p u s e ry th e m a to s u s 7 a n d
in p a tie n ts re c e iv in g p a re n te ra l fe e d in g w ith a h ig h lip id
c o n te n t2 . T h e re is a re p o rt o f a v e ry s u c c e s s fu l tre a tm e n t o f
W e b e r-C h ris tia n 's d is e a s e w ith c y c lo s p o rin A 7 .
T h e p a th o p h y s io lo g y o f th e h e m o p h a g o c y tic s y n d ro m e
is s tiU u n c le a r, a lth o u g h th e re is e v id e n c e th a t s e v e ra l
c y to k in e s (m a in ly IL 2 , P G E 2 , P G F 2a
,IF N g a n d T N F ) a re
a s s o c ia te d w ith th e p h e n o m e n o n o r its trig g e rin g . T h e fa c t
. u
S C H E T T E R T , L T .; C A R D IN A L L I, L A .; O Z E L L O , M .C .; V A S S A L L O , J .;L O R A N D -M E T Z E , 1 .;
S O U Z A , C .A . - H e m o p h a g o c y tic S y n d ro m e : p itfa lls in its d ia g n o s is
that some cases responded
to therapy with cyclosporin
A
suggests
a dysfunction
of T lymphocytes
and NK cells in
the pathogenesis
of macrophage
activation2,5,6,8.
In the present
case,
the initial
manifestation
was
pancytopenia
and the only
alterations
we found
were
dyserythropoesis
and the presence ofhemophagocytosis
in
bone marrow.
There was no evidence
of a family history.
Initially, ITP was hypothesized
but the use of corticosteroids
did not result in an increase of platelets. Instead, the disease
progressed
with
pancytopenia
and
an increase
in
hepatosplenomegaly
and fever. Serological
and molecular
tests failed to demonstrate
a bacterial
or viral infection.
Cell atypias were found in all three hemopoietic
celllines,
suggesting
the diagnosis of myelodysplastic
syndrome, but
significant
hemophagocytosis
is not usually found in this
condition ..Jmmunohistochemistry
was used to exclude bone
marrow
involvement
by lymphoma.
This technique
was
also
important
in demonstrating
the
extent
of the
macrophage
hyperplasia,
and in confirming
the diagnosis
of the hemophagocytic
syndrome.
The
patient
did
not
show
any
evidence
of a
rheumatologic
disorder,
neoplasia
or a congenital
disease.
The clinicaI
evolution
was similar
to that reported
for
"idiopathic"
hemophagocytic
syndrome2,3,
with
bone
marrow,
liver,
spleen
and lymph
node
involvement
by
hemophagocytosis.
As it has been reported,
there was no
response
to corticosteroids.
Growth
factors
(G- CSF), as
well as cytarabine in low doses were used with no response.
Reiner
and
Spivak
3evaluated
23 patients
and
performed
an extensive
review
of the literature
about
hemophagocytic
histiocytosis.
According
to these authors,
this syndrome
may not be rare. In their experience,
amo~g
2634 bone marrow
cytological
examinations,
four cases
with this syndrome
were diagnosed
per year (0,7%).
The
increase
in viral
infections
and
neoplasias,
and
the
refinement
of diagnostic
techniques,
are likely to enhance
the diagnosis
of hemophagocytic
syndrome.
As studies of
the relationships
between
immunological
mediators
progress,
a better understanding
of the pathophysiologic
mechanisms
underlying
this syndrome
may be achieved.
RESUMO
A síndrom e hem ofagocítica (SH) caracteriza-se por<>um quadro clínico de febre, hepatoesplenom egalia, linfonodom egalia e
pancitopenia periférica. A fagocitose de elem entos hem atopoiéticos por m acrófagos, m orfologicam ente norm ais, está na origem da síndrom e. A SH é considerada rara, m anifestando~se com o um a doença prim ária, ou associada a vírus, a neoplasias ou a doenças auto-im unes. O tratam ento é controverso e a sua evolução, m uitas vezes é fatal. A avaliação anátom o-patológica, apresenta o fenôm eno da hem ofagocitose em diversos órgãos, incluindo, principalm ente, os hem atopoéticos.
Apresentam os os vários contextos clínicos no qual esta síndrom e aparece, a im portância do seu diagnóstico e o estudo da
interação entre as citoquinas, as células im unorreguladoras e a terapêutica im unossupressora. Exem plificam os a síndrom e
hem ofagocítica através de um caso clínico, com seus dados com plem entares, incluindo os necroscópicos.
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SCHETTERT, LT.; CARDINALLI, LA.; O ZELLO , M .C.; VASSALLO , J.; LO RAND-M ETZE, 1.;
SO UZA, C.A. - Hem ophagocytic Syndrom e: pitfalls in its diagnosis
1 1 . C h en g A , S u I, C h en Y , U en W , W an g C . C h aracteristic
C lin ico p ath o lo g ic F eatu res o f E p stein -B arr V iru
s-A sso ciated P erip h eral T -C ell L y m p h o m ~ . C an cer
1 9 9 3 ;7 2 :9 0 9 -9 1 6 3 .
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