@ââ¬ËFc. DTPA scanning may be suggested for screening patients at high risk of ..... gallium scanning in acquired immune deficiency syndrome. Clin Nuci Med.
Early Pulmonary Involvement in Systemic Sclerosis Assessed by Technetium-99m-DTPA Clearance Rate Stefano Fanti, Arcangelo Dc Fabritiis, Daniele Aloisi, Maurizio Dondi, Mario Marengo, Gaetano Compagnone, Francesco Fallani, Alberto Cavaffi and Nino Monetti DepamnenLr ofNuclear Bologna, Ita@y
Medicine, A@zgiology,Pflewnolo@j and Health Physics, S. Orsola-Ma4ighi Policlinic Hospiti4
membrane disease (5), Pnewnocystis carinii pneumonia Systemicsderosis(SS)is frequentlyassociatedwithinterstitial lungdisease,butdinicalsymptomsandradiologicabnormalities mayoccurlatein the courseof the disease.Thisstudyinvesti gatedeadypulmonaryinvolvementby assessingthe dearance rate of inhaled @Tc-diethy1enethaminepenteacebc acid (DTPA).Methods:Sixteenpatientsw@iproved55, no dinical pulmonarysymptomsand normalchest radiogramwere pro spectWalystudied.The @rc-DTPA clearanceratewascalcu latedas the time to half clearance(r@J and comparedwith valuesobtainedin healthynonsmokers.Results: Six patients showedabnormallyincreaseddearance(i,,@< 53 mm).Rapid dearancewas not correlatedto SS diseasedurationor to ab normalpulmonaryfunctiontests.Ryeof sixpatientswithabnor mallyincreaseddearanceunderwenthigh-resolution CT,which inallfivedemonstrated pathologicfirdngs thatweresuggestive ofearlyinterstitial disease.ConclusIon:Thesefindings indicate that in 55 asymr@omatic patientsmayfrequentlypresentwith abnormal @“Tc-DTPA dearance; @rc-DWA lungsdntigra phymayalloweadydetectionof subdinicalpulmonaryinvolve mentin55.
(6), pneumoconiosis
(7) and interstitial lung disease 5cc
ondaiy to sarcoidosis (8), collagen vascular diseases (8) and allergic alveolitis (9). Most of these studies, however, investigated patients with already demonstrated pulmonary disease; one of the
main advantages of @Tc-D1PAis its high sensitivity in the detection of diffuse lung injury(10). The clearance rate of @Tc-DTPA is held to be a sensitiveandearly indicator of ongoing damagein pulmonary interstitial disease, al though its clinical usefulness has still not been fully estab lished. Because a normal rate of clearance provides strong evidence of absence of epitheial
damage (10),
@‘Fc
DTPA scanningmay be suggested for screening patients at high risk of developing interstitial lung disease (11). A disease frequently associated with interstitial pulmonary involvement is systemic sclerosis (55), the clinical symp toms and radiologicabnormalitiesof which may occur late (12). The present study was designed to determine the clearance rate of @“@Tc-DTPA in asymptomatic patients KeyWords:pulmonaryepithelialpermeability; technebum-99m- with 55 and the role of @“Fc-DTPA lung scintigraphy in DTPAdiagnosticuse;systemicsderoatsradiOnUclide ima@ng the early detection of lung involvement. J NuciMed1994;35:1933-1936 MATERIALS AND METhODS
ulrnonary epitheial permeability can be studied by mea
Patient Population Thecriteriaforinclusioninthestudywere(1)proved55, (2)no clinical symptoms and (3) normal chest radiogram. SS was diag
suring the clearance rate of inhaled @‘@Tc-diethylenetri nosed accordingto the AmericanRheumatismAssociation'spre aminepentaacetic acid (DTPA). This hydrophilicmolecule liminary criteria for the diagnosis of SS (13). Patients with pul crosses the alveolar-capillarybarrierand diffuses from the monaiy signs at physical examination,clinical symptomsor airspace into the vascular space, probablypassing through recent lower respiratorytract infection were excluded. Standard wereassessedby two radiologistsunawareof the tight epithelial intercellularjunctions (1,2). The @Tc chestradiographs DTPA clearance rate thus provides an index of barrier clinical data. A total of 16 patients were prospectively evaluated. of the population integrityand has been shown to be alteredin a wide variety Table1 summarizesthe clinicalcharacteristics studied. of lung disorders (3). Increased clearance rates have been A historyof smokingwas not considered a criterionfor exdu reportedin adultrespiratorydistress syndrome (4), hyaline sion. Because the rapid reversibility of increased @9'c-DTPA
clearance
induced
by smoking(14)
has been demonstrated,
it was
decided to ask patientswho smoked to discontinue tobacco fOr2 Received Nov. 18, 1993; reiislon a@e@ed July 14, 1994.
@
wk beforeundergoing @“Tc-DTPA scintigraphy.Thisprocedure For correspondenceor repdntscont@ StefanoFanti,MD,Dept Nuc$e@ Medicine, S.OrsoIa-M*lghi Policlinic Hospital, ViaAibertor@ 15,40138Bologna. was followedwith the only smoker(Patient4) of the group.In regardto pharmacologic therapy,no patientwas receivingcorti
Inhaled
@rc-DTPA in SystemicSclerosis• Fantiat al.
1933
TABLE 1
uled for high-resolutionCl' (HRCF) of the chest. In all patients,
Population Studied
HRCF was performedusing a Somatomscanner (Siemens,Des Plaines,IL).Scanswereperformedatfullinspiration,witha slice
Involvementno.
PatientAgeDisease Sex (yr)(yr)Skin 1
F
64
2
F
56
3 4
F F
60 47
5 6
M F
30 77
7
F
56
8
F
37
9 10
F F
21 48
11 12 13 14 15 16
F F F F F F
42 59 69 54 28 45
DurationExfrapulmonwy RPEl 3 10 8 5 12 7 5 2
thickness of 1.5 mm, and reconstructed with a high-spatial-fre quency (bone) algorithm No contrast was used. HRCF scans were assessed independently by two observers
L
+
+
whowereunawareof theclinicalandscintigraphic data.
D L
+ +
+ +
RESULTS
L L L L
:i + + +
:: — + +
patients (Patient 3 forced expiratory volume in 1 sec [FEV1J = 74% of predicted value; Patient 6 FEY1 = 57%) and normal in the remaining 14 (Table 2). Results of @Tc DTPA clearance rate are detailed in Table 2. With respect
D
+
+
to the whole group of patientswith 55, the meanTia was
D D D
+ + +
+ + +
trols (p < O.05) Of 16patients, 10showednormal (Ta> 53 mm) @‘@Tc-DTPA clearance(Fig. 1); 6 showed abnor mally increasedclearance(T1,@< 53 mm, Fig 2). Rapid
L
+
+
clearance was not correlated with abnormal PFT findings
g + +
Pulmonary function testresults were abnormal intwo
g :: : 59.8 ± 19.8 min, significantly faster than that ofthecon
21 13
9 2 10 7
present; - = absent; D = diffuse;L = Iunited.
or disease duration. HRCF was performed in 5 of the 6 subjects with increased clearance, the remaining patient (Patient 16) refused to undergo CF. In all 5 studies, patho logic HRCT findingswere reported (thickened septal lines
costeroids or cyclophosphamideat the time of the study or during
in Patients 11—13 and 15 and subpleural lines in Patients 12
RP= Raynaud's phenomenon; El = esophageal lnvolvement +=
the fourpreviousmonths.
and 14) with lower lung fields primarilyinvolved (Fig. 3) All 5 HRCT scans were considered
PulmonaryFunctionTesting interstitialdisease. Spirometricmeasurementsof lungvolumes,flowindicesand diffusing capacities were performed in all patients. The data were DISCUSSION
expressed as the percentage of the predicted values for each subject using standard tables (15) and taking into account sex, age
suggestive of early
55 is a chronic, multisystemic affection frequently corn
andweight.Theresultswereconsideredabnormaliflungvolumes plicated by interstitial lung disease, which contributes sig wereless than80%of predictedvaluesand/ordiffusingcapacity nificantly to the morbidity and mortality rate (16). Post was less than 75%. mortem examinations have shown evidence of pulmonary Technetlum-99m-DTPA Lung Scintlgraphy The @“Tc-DTPA aerosolwas producedandadministeredas describedby Coates and O'Brodovich (3). Briefly,740to 1000 MBqof @Tc-DTPA wasusedwith acommerciallyavailablejet nebulizer(Ultravent,Mallinckrodt,Petten, The Netherlands), Patient which generates an aerosol of 0.89 a mass median aerosol diam
eter. Patients in the sitting position inhaled the radioaerosol for 120 to 150 sec at normal tidal breathing. Scintigraphic data were recorded dynamically(10 sec/frame) in posterior projectionon a
no.Disease 2
3
64 x 64 matrix for a 20-mm period using a large field of view
4
gammacameraequippedwitha LEGPcollimatorandinterfaced to a computer.Countswerecorrectedforradioactivedecay;no correctionwas madeforbackgroundactivity.Regionsof interest weremanuallydrawnaroundeachlung,anddatawereprocessed to obtaintime-activitycurves.The timeto halfclearance(Tia)
5 6
was calculated using a least-squares
curve-fining routine to find
the best exponential fit for the first 7 min of data. ae@@ce rate values were compared with those previously obtained in 18
7
8
TABLE 2 Results Duration (yr) PFT Results 3 10 8 5 12 7 5 2
9
10 11
healthynonsmokers(Tia 79 ±13Iflifl)andconsideredabnor malwhentheyweremorethan2 s.d. outsidemeanvalue(i.e.,T1,@
12 13 14 15
< 53 mm).
16
21 13 9 2 10 7
High-Resolution CT PFT = pulmonary function To ascertainthe presenceof fibrosingalveolitis,patientswith anabnormallyincreased @“Tc-D1PA clearancerateweresched time to half clearance.
1934
T1,@ Left Lung(mm)Right Lung
—
97
-
85
94 78
+
90
69
-
82
73
—
74
80
+
61
76
—
70
61
-
68
55
-
59
56
—
61
48
-
54
49
—
41
49
-
40
46
-
38
44
—
32
34
—
24
27
tests; —= normal; + = abnormal; T1,@=
TheJournalofNudearMedk@ne • Vol.35 • No.12• December1994
-
It
11 at U
@
-
II
RIGHT .
..
p.
LEFT
@_@_@___@
- ..
— -
ft
at U flit 111 ft
flit
I
12@
0
SEC
b
a
C
FIGURE1. Tectmetium-99m-DTPA scanof Patient2. SerIalImages(a),time-activity curves(b)andsumof all Images+ regbnsof Interest(C).Intrapimonarydepositionof @rC-DWA Is satisfactorlyhomogeneous in bothlungs.lime-activitycurvesare normal
Cr1,2 left=85mm, right =78mm).
involvement
in 70% to 100% of cases (17, 18). Clinical
symptoms are not usually present when 55 is first diag nosed, and chest radiographic abnormalities may occur late in the course of the disease. Furthermore,pharmaco logic treatment of lung involvement is believed to be more effective when started early (19) Sensitive and noninva sive methods are therefore needed to detect subclinical pulmonary involvement in 55; different approaches, such as bronchoalveolar lavage (12) and HRCT (20), have been
manifestations
show an abnormally increased
@Fc-DTPA
clearance rate. Previous reports have already described a rapid @9@c-DTPA clearance rate in patients affected by 55 with clinical or roentgenographic evidence of interstitial
lung disease (8,21—23).The present study suggests that @Tc-DTPA may reveal pulmonary involvement at an ear lier stage. It could be argued that a rapid clearance may indicate
a nonspecific increase in epithelial permeability rather suggested to this end. than subclinical fibrosing alveolitis. Alterations detected A simple and noninvasive approach to evaluate lung by @‘@Tc-DTPA need, therefore, to be determined. injury is @Tc-DTPAclearance, which was demonstrated For this reason, the patients in this study with an abnor to have a high sensitivity in a variety of diffuse pulmonary mally increased clearance rate underwent HRCF, which diseases (10). The present study proved that a significant is considered to be the method of choice to evaluate numberof patients with 55 without clinical and radiologic parenchymal lung damage in SS (20); in all cases, the
-
ft “gI@I
RIGHT .
LEFT
at as as as As as as as
aiasaias a
12@
SE C.
b
C
FiGURE2. Technetium-99m-DTPA scanofPatient 13.Thie-actMty curves showanabnormally increased clearance rateçr@ left=40 mm,right= 46mm).
Inhaled @Tc-DTPA in SystemicSderoals• Fantiat al.
1935
-
as ii •s •i
@ @
as
RIGHT
. LEFT
@I i@S 0
FIGURE3. Technetium-99m-DTPA scanandHRCTofPatient 15.Rapidclearance of
@FC-DTPA aerosol
left= 32mm,ñght =
34 mm).HRCTshowsparenchymalabnormalities(thickenedseptallines)in the lowerlobes. @Tc-DTPA and bronchoalveolarlavagefindingsin patientswith asymp HRCF findings were consistent with early interstitial tomaticallergicalveolitis.Thomx1990;45:525—529. disease. 10. StaubNC,HydeRW,CrandallE. Workshopontechniquestoevaluatelung Therefore, it seems reasonable to suggest @‘@Tc-DTPAalveolarmicrovascularinjury.Am Rev Re@pirDic1990;141:1071-1077. clearance is an effective method to reveal fibrosingalveoli 11. WellsAU, HansellDM, HarrisonNK, et at. aearance of inhaled @Fo DTPA predicts the clinical course of fibrosingalveolitis.Eur Respir I tis at an early stage. The method is particularlyinteresting 1993;6:797—802. because it is reproducible(24), simple, relatively inexpen 12. WailaertB, HatronPY,GrOSbOiS JM,et at.Subclinicalpulmonaryinvolve sive, noninvasive and, hence, repeatable. It can be sug mentincollagenvasculardiseasesassessedbybmnchoalveolarlavageAm RevRespirLXc1986;133:574—580. gested therefore that @Tc-DTPA lung scintigraphyhas a 13. MasiAT, RodnanGP, MedsgerTA, et at. Preliminarycriteriafor the role to play in the early detection of subclinical pulmonary classificationof systemicsclerosis(scleroderma).A#hiitLcRheum 1980;23: involvement in SS. 581—590.
ACKNOWLEDGMENT TheauthorsthankMr.StephenJewkesforhiscarefultransla
14. MasonOR,UszlerJM,EffrosRM,ReidE. Rapidlyreversiblealterationsof pulmonaryepitheliatpermeabilityinducedby smoking.Chest 1983;83:6—11. 15. MorrisJF, KoskiA, JohnsonLC. Spirometricstandardsfor healthynon smoking adults. Am Rev RespirDis 1971;103:57—67.
16. MedsgerTA, MasiAT, RodnanOP. BenedekTS, RobinsonH. Survival with systemicsclerosis (scleroderma):a life-tableanalysisof clinicaland demographicfactors in 309patients.Ann Intern Med 1971;75:369—376. REFERENCES 17. WeaverAL,DivertieMB,litusiL Pulmonary scleroderma. BrIDis Chest 1968;54:490—498. 1. Oberdorster0, Utell MJ,MorrowPE, Hyde RW,WeberDA. Bronchial andalveolarabsorptionof inhaled @Fc-DTPA. Am RevReSpWDLS 1986; 18. D'AngeloWA,FriesJF, MasiAT, SchulmanLE. Pathologicobservations in systemicsclerosis(scleroderma). AmI Med 1969;46:428-440. 134:944-950. M, BurrowsB, JohnsonA. Cryptogenicfibrosingalveoli 2. SchmekelB, BoaJAH, KahnAR, WohifartB, LachmannB, WolimerP. 19. Turner-Warwick
tion.
Integrity of the alveolar-capillary barrier and alveolar surfactant system in
smokers. Thomx1992;47:603—608. 3. Coates0, O'BrodovichH. Measurementof pulmonaryepithelialperme abilitywith @Fc-DTPA aerosol.SeminNuci Med 1986;16:275-284. 4. MasonOR,EffrosRM,UszlerJM,MenaI. Smallsoluteclearancefromthe lungs in patients with cardiogenic and noncardiogenic pulmonary edema. Chest 1985;88:327-334.
5. JeifriesAL,COateSG,O'BrodovichH. Pulmonaiyepithelialpermeabiityin hyaline membrane disease. NEngIJMed
1984;311:1075—1080.
6. PinnedC, MeignanM, RossoJ, et a!.Technetium-99m-DTPA aerosoland gallium scanning in acquired immune deficiency syndrome. Clin Nuci Med 1987;12:501—506.
7. SusskindH, Rom WN. Lung inflammationin coal minersassessed by uptake of 67Ga-citrate and clearance of Inhaled
@Fc-labeledDTPA. Am
Rev RespirDis 1992;146:47—52. 8. RinderknechtJ, ShapiroL,KrauthammerM, et at.Acceleratedclearanceof smallsolutesfromthe lungsin interstitiallungdisease.Am RevRespirDis 1980;121:105—117.
9. SchmekelB, WoilmerP. VengeP, LindenM, Blom-BulowB. Transferof
1936
tis: response to corticosteroid treatment and its effect on survival. Thoiux
1980;35:593—599. 20. Wariick JH, Bhaila M, Schabel SI, Silver RM. High resolution computed
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21. HarrisonNK, GlanvilleAR, StricklandB, Ctat.Pulmonaryinvolvementin systemic sclerosis: the detection ofearly changes by thin section CF scan, bronchoalveolar lavage and @Fc-D1PAclearance. Respir Med 1989;83: 403—414. 22. Tateno M, Nakano A, Hasegawa A, et al Pulmonary clearance of @Fc
DTPA aerosol in patients with progressivesystemic scleroderma.Kaku @gaku 1992;29:585—590. 23. Schurawitzki H, Striglbauer R, Grawinger W, et at. Interstitial lung disease in progressive systemic sclerosis: high resolution CT versus radiography. Radiology 1990;176:755—759. 24. Thunberg 5, Larsson K, EkIUnd A, Blaschke E. @“Tc-DTPA clearance
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TheJournalofNuclearMedicine • Vol.35 • No.12• December1994
