CVID complicated with thrombotic thrombocytopenic purpura-hemolytic uremic

syndrome
Biljana Miloevi, MD, Department of Nephrology, Institute for Child and Youth Health
Care of ojvodina, Novi !ad, !er"ia
esna !tojanovi, MD, Department of Nephrology, Institute for Child and Youth Health
Care of ojvodina, Novi !ad, !er"ia
Mar#o Ni#oli, MD, Intensi$e %nit Care, Institute for Child and Youth Health Care of
ojvodina, Novi !ad, !er"ia
&eorgios 'onstantinidis, (rof), Intensi$e %nit Care, Institute for Child and Youth Health
Care of ojvodina, Novi !ad, !er"ia
*ndrija +udi, MD, Department of Immunology and *llergology, Institute for Child and
Youth Health Care of ojvodina, Novi !ad, !er"ia
Corresponding author, esna !tojanovi, MD, Department of Nephrology, Institute for
Child and Youth Health Care of ojvodina, Novi !ad, !er"ia
-.mail, vesnasto/eunet)rs
0
Abstract
Common varia"le immunodefi$ien$y 1CID2 is a primary immunodefi$ien$y
disease $hara$teri3ed "y redu$ed serum immunoglo"ulins and heterogeneous $lini$al
features) +e$urrent pyogeni$ infe$tions of upper and lo4er respiratory tra$ts are the main
$lini$al manifestations of $ommon varia"le immunodefi$ien$y) 5hrom"oti$
throm"o$ytopeni$ purpura 6 hemolyti$ uremi$ syndrome are multisystemi$ disorders
$hara$teri3ed "y throm"o$ytopenia, mi$roangiopathi$ hemolyti$ anemia, and organ
is$hemia due to platelet agglutination in the arterial mi$rovas$ulature)
5his is one of the rare $ases of patients diagnosed 4ith CID 4hi$h 4as
$ompli$ated "y throm"oti$ throm"o$ytopeni$ purpura 6 hemolyti$ uremi$ syndrome)
Key words - Common varia"le immunodefi$ien$y7 5hrom"oti$ throm"o$ytopeni$
purpura7 Hemolyti$ uremi$ syndrome7 Child
Introduction
Common varia"le immunodefi$ien$y 1CID2 is a disorder $hara$teri3ed "y lo4
levels of serum immunoglo"ulins Ig& and Ig*, 4hile in 89: of patients the level of IgM
is lo4ered and an in$reased sus$epti"ility to infe$tion 102) It is a $ommon form of
immunodefi$ien$y 4ith varia"le $lini$al $ourse) CID $an "e hereditary autosomal
re$essive, dominant, and ;.lin#ed, 4hile a$<uired forms are also possi"le) 5he
prevalen$e of CID is appro=imately 0 $ase per 89 999.>99 999 population) +e$urrent
>
pyogeni$ infe$tions of upper and lo4er respiratory tra$ts are the main $lini$al
manifestations of $ommon varia"le immunodefi$ien$y) Bron$hie$tasis $an o$$ur from
severe and re$urrent lung infe$tions) 5hese patients 4ere more li#ely to have in$reased
fre<uen$ies of hepatosplenomegaly, irido$y$litis, autoimmune hemolyti$ anemia,
immune throm"o$ytopeni$ purpura, mala"sorption, inflammatory "o4el disease, failure
to thrive) *"out >9: of those 4ith CID develop an autoimmune disease 1>, ?2)
Diagnosis of CID is usually made "y demonstrating lo4 le4els of
immunoglo"ulins in serum) 5reatment usually $onsists of immunoglo"ulin therapy 1@2)
5he prognosis for patients 4ith $ommon varia"le immunodefi$ien$y is reasona"ly
good if they do not have "ron$hie$tasis, and $hroni$ lung damage, or severe autoimmune
disease or malignan$y 182)
5hrom"oti$ throm"o$ytopeni$ purpura 155(2 6 hemolyti$ uremi$ syndrome
1H%!2 are multisystemi$ disorders $hara$teri3ed "y throm"o$ytopenia, mi$roangiopathi$
hemolyti$ anemia, and organ is$hemia due to platelet agglutination in the arterial
mi$rovas$ulature 1A2) %ntil re$ently, the $lassifi$ation of these t4o syndromes has "een
"ased on $lini$al findings, 4ith neurologi$al dysfun$tion 4hi$h is more $ommon 4ith
55(, and renal dysfun$tion 4hi$h is predominant in H%!) Ho4ever, overlap is
su"stantial, and pre$ise distin$tion of the t4o syndromes remains some4hat ar"itrary and
$ontroversial) 55(.H%! in$iden$e in the %nited !tates is a"out ?)B 6 00 $ases per million
people 1B2)
5his paper revie4s a $ase of a $hild in 4hi$h 55(.H%! developed 4ithin CID)
?
Case report
* "oy, aged 8, developed a $ough and "reathing diffi$ulties a month "efore
hospitalisation, and re$eived outpatient treatment 4ith anti"ioti$s, and "ron$hodilators)
5he therapy failed to provide relief) * 4ee# "efore hospitalisation, the "oy 4as s4ollen
in the fa$e, urinated less, 4as e=tremely dyspnei$, 4hile on the day of admission he 4as
anuri$) 5he "oy 4as hospitalised at our Institute, in the Intensive Care %nit)
!in$e his early infan$y, the "oy has had repeated "a$terial respiratory infe$tions
1adenoid, middle ear, o"stru$tive "ron$hitis, and pneumonia2, 4hile at the age of 0, he
4as diagnosed 4ith generalised lymphoadenopathy, and hepatosplenomegaly) During his
se$ond year of life he under4ent adenoide$tomy) Due to hepatosplenomegaly, the "oy
had "een monitored "y a hematologyst 1sin$e age > to age @)82) (revious la"oratory
findings, Imunoglo"ulines of serum Ig* 9)>@ gCl 19,@0.>,DB2, IgM 9)AB gCl 19,@.0,A2, Ig&
8)8 gCl 1A.0?2) *lfa 0 antitrypsin 4ithin referente value) 5here 4ere no indi$ations of
$onatal, and a$<uired virus infe$tions 6 1H"s*g, Herpes simple=, -pstein.Barr virus,
Cytomegalovirus, 5o=oplasmosis2, hemoglo"inopathy 1 Eetal hemoglo"in, and
haptoglo"in 4ithin referente value2) Maligne diseases 1pun$ture of "one marro4 6
myeloid hyperplasia) (athohistologi$al finding of "ioptate of peripheral lymph gland,
sho4s rea$tive lymphadenitis2) In the later $ourse, pan$ytopenia 4as diagnosed) During
the stated period, the $lini$al features 4ere dominated "y an o"stru$tive pulmonary
disease, physi$al finding sho4ed splenomegalia, and generalised lymphadenopathy
a$$ompanied "y a failure to thrive) Mental status preserved) During the ne=t A months, up
@
until admission at the Institute, the "oy 4as treated in his pla$e of residen$e, 4ith
anti"ioti$s, and "ron$hodilators)
5here 4ere no similar diseases in the family)
*t the admission, the "oy 4as in a generally diffi$ult $ondition, afe"rile, 4ith
ta$hy$ardia 1( 0@9Cmin)2, ta$hydyspnea 1+ 89Cmin)2, "lood pressure 0>9CF9 mmHg) Body
4eight 0B #g 1"elo4 ? per$entile2, height 090 $m 1"elo4 ? per$entile2) 5he s#in, and the
visi"le mu$ous mem"ranes 4ere pale, a$ro$yanoti$, and edematous) Gymph glands 4ere
s4ollen, apro=imately > $m in diameter, su"mandi"ular, and a=illary, in $lusters)
*us$ultation over the lungs revealed inspiratory $ra$#les, early and late, 4ith lo4 pit$h
4hee3ing) Heart a$tion 6 gallop rhythm, no murmur) Hea#er peripheral pulses) *"domen
a"ove $hest level) Giver is palpated A $m "elo4 the right ri" ar$ in mid$lavi$ular line, of
harder $onsisten$y, spleen F $m "elo4 left ri" ar$, of harder $onsisten$y) Neurologi$al
finding 4as normal)
Ga"oratory findings, in$reased rea$tants of a$ute phase 1sedimentation rate, C.
rea$tive protein2, pan$ytopenia . leu#o$yte $ount >,B=09
D
CG, throm"o$yte $ount
@9=09
D
CG7 Coom"s positive hemolyti$ anemia H" A@ gCl, +et 9,90>, la$tate
dehydrogenase B)8) Ismoti$ resisten$y of red "lood $ells . normal finding) (eripheral
"lood smear . presen$e of fragmented red "lood $ells) Creatinine 08? molCl 1estimated
$reatinine $learan$e ?9 mlCminC0)B?m
>
2, urea nitrogen 0?)9 mmolCl 19,0.B2, a$idum
uri$um >BF molCl 1B0.>?92) *$tivated partial throm"oplastin time 1a(552, prothrom"in
time 1(52, D.dimer, fi"rinogen 6 normal finding) 5otal serum proteins 88)8 gCl) Blood gas
analysis indi$ates glo"al respiratory insuffi$ien$y) Hemo$ulture, stool $ulture,
urino$ulture . negative) Co=sa$#ie virus, Cytomegalovirus, Hantan virus 1Ig& i IgM2 .
8
negative) +enal ultrasound, in "oth #idneys loss of $orti$omedullar differentiation,
hypere$hogeni$ paren$hyma) Chest =.ray indi$ates inflamation, and $ongestive $hanges
4ith enlarged heart shado4) -$ho$ardiography revealed left ventri$ular $ardiomyopathy
and pulmonary hypertension)
Immediately upon admission, me$hani$al ventilation 4ith parenteral anti"ioti$
therapy 4as administered 1imipenem.$ilastatin, $lindamy$in,
sulfametho=a3oleCtrimethoprim and flu$ona3ole2, follo4ed "y $onservative therapy for
a$ute renal failure, and a$ute pulmonary edema) !in$e the third day of hospitalisation the
"oy "e$ame $omatose 1&lasgo4 Coma !$ale. @.B2, 4ith fo$al sei3ures) Gum"ar pun$ture
4as performed to e=$lude infe$tion of $entral nervous system 1CN!2 1finding 4as
normal2, 4hile a $omputer tomography of CN! revealed hyperdense $hanges the si3e of
>=> $m 1intra$ere"ral hematoma $om"ined 4ith is$hemi$ lesions2) 5he diagnosed 55(.
H%! 4as treated 4ith repeated transfusions of fresh fro3en plasma) Blood 4or#
improved) (ulmonary fun$tion and $ons$ien$e 4ere also improving, thus, on day 00, the
"oy 4as e=tu"ated, and o=ygen therapy 4as administered "y mas#) *s the a$ute renal
insuffi$ien$y progressed 1$reatinine @A0 molCl, urea nitrogen 8A,8 mmolCl, a$idum
uri$um 0A>9 molCl, estimated $reatinine $learan$e 09,B mlCmin), oliguria2, on day 0? of
hospitalisation, $ontinuous am"ulatory peritoneal dialysis.C*(D 4as started) 5his lead to
improvement of renal fun$tion test results, and further improvement of $ons$iousness as
4ell as the general $ondition, so the "oy 4as transfered to Nephrology 4ard) In order to
arrive at final diagnosis, test 4ere $ontinued to determine immunologi$al disorders 6
immunoglo"ulin deffi$ien$y, and immunologi$al response, systemi$ disease 1due to
purpura on the trun# 6 vas$ulitis, and s$lerodermatous $hanges on the right gluteus, the
A
si3e of 8=09 $m, and the right lo4er leg, the si3e of 8=?$m 6 4hi$h 4ere not initially
present2, *ntinu$lear anti"odies 1*N*2, anti.dou"le stranded DN* , anti.+N(, anti.!m,
anti.!!*C+o, anti.!!.BCGa, anti.!$l.B9, anti.!o.0, anti.$ardiolipin anti"odies 1*C*2,
anti.neutrophil $ytoplasmi$ anti"odies 1*NC*2, anti.mito$hondrial anti"odies,
antiparietal anti"odies, anti.smooth mus$le anto"odies, anti heart anti"odies, and
antithyroid anti"odies, negative) (athohistologi$al e=amination of s#in "ioptates
e=$luded s$leroderma2) Ig* 9,0A gCl 19,@0.>,DB2, Ig& ?,? gCl 1A.0?2, IgM 9,0? gCl 19,@.
0,A2, all three $lasses of immunoglo"uline 4ere lo4ered in the three samples ta#en at
monthly intervals) *ntitetanus anti"ody titer 4as at the lo4er limit of the normal range)
Cryoglo"ulines . negative) 5he nitro"lue tetra3olium 1NB52 test, opsoni3ation,
"a$teri$idal inde= 6 normal findings) Immunophenotyping, relative, a"solute values of
total 5 lympho$ytes 1CD?2, as 4ell as CD@, and CDF su"population of 5 lympho$ytes,
4ere 4ithin physiologi$al limits, 4ith preserved ratio 1inde= CD@CCDF2) 5itre of natural
anti.B anti"odies . negative) +elative and a"solute values of B lympho$ytes 1CD0D2, as
4ell as N' $ells 1CD 8A2 4ere 4ithin physiologi$al limits) Immune $omple=es 1(-&.
0DF2, $omplement C0<, C?, C@ 6 normal values) Blasti$ transformation of lympho$ytes
in $ulture stimulated "y phytohemagglutinin 1(H*2 6 high spontaneous a$tivity)
Duodenal jui$e 4as free of &iardia lam"lia) Mi$ros$opi$ stool e=amination revealed
$ysts of non.pathogeni$ amoe"a) %rin . spe$ifi$ gravity 0999, mi$ros$opi$ hematuria,
>@h proteinuria 9,@B gCday) %rine osmolality . >A9 mIsmolC#gH>I) !4eat $hloride test .
negative) !iderophages in "ron$hial aspirate . negative) C5 s$an of $hest and a"domen,
enlarged timus, mediastinal and retroperitoneal glands)
B
Diagnosis of "asi$ disease 4as diffi$ult due to numerous $ompli$ations of "asi$
disease, and normal level of immunoglo"uline at the time of medi$al $he$#up 1the "oy
initially re$eived intravenous immunoglo"ulin 1II&2 "e$ause of the heavy respiratory
infe$tion2) *fter three months 6 "ased on repeated analyses of immunoglo"uline, and its
persistently lo4 levels, $lini$al features, as 4ell as the a"sen$e of natural anti.B
anti"odies 6 $ommon varia"le immunodefi$ien$y 4as diagnosed)
*fter CID 4as diagnosed, su"stitution therapy 4as introdu$ed, 4hi$h in$luded,
II& 1A99 mgC#g per ?.@ 4ee#s2, and $orti$osteroids, 4hile, due to anemia, 4ith normal
levels of iron, transferrin saturation 15!*52, and feritin, re$om"ination eritropoetin 4as
also administered) In the $ourse of the therapy, the "oy did not have respiratory
infe$tions, signs of $hroni$ pulmonary disease 4ere persistent, hemoglo"in, leu#o$ytes,
and throm"o$ytes 4ere normali3ed, autoimmune phenomena 4ere in $omplete
regression) Cons$ien$e and mental status 4ere $ompletely restored) Control C5 s$an of
CN! sho4ed poren$ephali$ $hanges at the pla$e of previously des$ri"ed lesions) *fter ?
months, peritoneal dialysis 4as a"orted, $hroni$ renal insuffi$ien$y persisted 1estimated
$reatinine $learan$e ?8)9 mlCminC0)B?m
>
2 1parents did not agree to previously suggested
per$utaneous #idney "iopsy2) *fter 0 year, due to irregular su"stitution therapy "y
immunoglo"ulin 1the "oy 4as not ta#en to regular $he$#ups2, fe"rile respiratory
infe$tions re$urred) *s the $hroni$ pulmonary disease progressed, the "oy 4as on home
o=ygen therapy) * year and a half after the "asi$ disease had "een diagnosed, during a
"i$y$le ride 14ith no signifi$ant $hanges $ompared to previous days2 the "oy suddenly
died, most pro"a"ly due to $ardiorespiratory insuffi$ien$y 1the parents did not allo4
autopsy2)
F
Discussion
CID is one of the most prevalent primary immunodefi$ien$y diseases) 5he
e=pe$ted survival rate is D>.D@:) (ea# of onset o$$urs in $hildren aged 0.8 years and
persons aged 0A.>9 years) More than t4o thirds of patients are aged >0 years or older
4hen CID diagnosed 1F2)
Diagnosis is "ased on e=$lusion of #no4n $auses of humoral immune system
defe$ts) -tiology is un#no4n) CID $an "e inherited in an autosomal re$essive,
dominant, or ;.lin# pattern, and $an also "e a$<uired) In patients 4ith CID, numerous
immune.system a"normalities are reported, the most $ommon of 4hi$h is defe$tive
anti"ody formation) Conse<uently, "oth humoral and $ell.mediated lympho$yti$
responses are affe$ted) !ome CID patients may have a defe$t in the 5.$ell a"ility to
help B $ells, andCor B.$ell response to 5.$ell help 1D, 092)
Ine third of these patients develop diffuse or lo$ali3ed lymphadenopathy,
intestinal nodular hyperplasia, or lymphoid infiltrates in the lung) Histologi$ally, these
infiltrates resem"le the rea$tive lymphoid hyperplasia) &ranulomatous $hanges are the
sign of hepatosplenomegaly) Differential diagnosis 6 Bruton. ;.lin#ed
agammaglo"ulinemia 1;G*2, immunodefi$ien$y 4ithin Hyper IgM syndrome, protein
losing enteropathy, malignities 1neuro"lastoma, a$ute lympho"lasti$ leu#emia2, transitory
IgM hypogammaglo"ulinemia of infan$y, severe $om"ined immunodefi$ien$ies 1!CID2
1002)
D
Disease symptoms are non.spe$ifi$ and very often $ause "elated diagnosis, as in the $ase
of our patient) *t the moment of admission, the "oy 4as already 4ith $ompli$ations 6
$hroni$ pulmonary disease 4ith pulmonary hypertension, and $onse<uential
$ardiomyopathy, hepatosplenomegaly, limphadenopathy, autoimmune phenomena,
mala"sorption 1 retarded gro4th, and development2) %nderdiagnosis, diagnosti$ delay,
and management 4ith a variety of methods $ontri"ute to mor"idity and early mortality)
5here is an average diagnosti$ delay of >)8 years in $hildren and 8)8 years in adults 10>2)
'idney pro"lems are not $ommonly asso$iated 4ith CID) 5here have "een
des$ri"ed a$ute renal failure from II& therapy, nephroti$ syndrome from se$ondary
amyloidosis, steroid.responsive nephroti$ syndrome, and #idney dysfun$tion from
granulomatous interstitial nephritis 10?2)
!o far, in the availa"le literature, des$riptions of 55(.H%! $ompli$ations 4ithin
CID, as in the $ase of our patient, have "een e=tremely rare) Beside the triad of
symptoms $hara$teristi$ of 55(.H%! 1throm"o$ytopenia, mi$roangiopathi$ hemolyti$
anemia, and organ is$hemia2, our patient initially had a more distin$tive renal disorder
1a$ute #idney insuffi$ien$y2, follo4ed "y neurologi$al symptomatology) Differential
diagnosis e=$ludes sepsis, disseminated intravas$ular $oagulation, malignant
hypertension, and vas$ulitis) 5herapy of $hoi$e 4as plasma e=$hange) Ho4ever, due to
ina"ility to perform the same, our patient re$eived an alternative therapy of repeated
infusion of fresh fro3en plasma 4hi$h gave good results) Current out$omes of 55( and
H%! have improved signifi$antly 4ith the use of plasma e=$hange, "ut mortality remains
una$$epta"ly high at 09: to >9: 10@2) Chroni$ renal failure, 4hi$h 4as diagnosed in our
09
patient due to #idney damage, may o$$ur in >8: of patients 4ho have renal failure as a
$omponent of their initial 55(.H%! 1B2)
5his is one of the rare $ases of patients diagnosed 4ith CID 4hi$h 4as
$ompli$ated "y 55(.H%!) 5he reason for the fatal out$ome in our patientJs $ase 4as the
"elated CID diagnosis, 4ith numerous $ompli$ations . first of all, the signs of advan$ed
$hroni$ pulmonary disease and pulmonary hypertension 4ith $onse$utive
$ardiomyopathy)
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0>