A Retrospective Study of Radiolabeled Granulocyte Kinetics in Patients with Systemic

N.D. Jonker, A.M. Peters, G. Gaskin, C.D. Pusey, and J.P. Lavender

Departments ofDiagnostic Radiology and Medicine, Hammersmith Hospital, London

seen increased diffuse activity in the lungs, not accom Patientswith systemicvasculitis,includingWegener's gran panied by abnormal focal activity, in patients with sys ulomatosis(WG) and microscopicpolyarteritis(MP), may temic vasculitis, including microscopic polyarteritis (MP), undergowhite cell scanningfor the investigationof infective during the course of routine, clinically indicated, ‘1‘In complications and/or occult fever. In a retrospective study of granulocyte scanning, suggesting that WG and MP may 12 patientswithsystemicvasculitis(sixeachof WG and MP), both be associated with increased pulmonary granulocyte all with renal disease, we observed increaseddiffuse lung margination. Patients with WG or MP have circulating radioactivitysoonafter the injectionof 111ln-labeledgranulo antibodies to components of neutrophil cytoplasm cytes or 99rT@Tc@HMPAO@labeledleukocytes in all patients with WG and in three with MP. Lung activity was quantifiedby (ANCA) which are strongly associated with active disease comparison with the liver or . The lung:liver count rate and which activate granulocytes in vitro (4). Anti-endo ratio per pixel, 1—1.5 hr after injection,in patientswith sys thelial cell antibodies have also been demonstrated in temicvasculitiswas 0.87 (s.d. 0.25), significantlyhigher(p < systemic vasculitis (5). Activation of granulocytes in vivo 0.001) than the ratio0.38 (0.13) in patientcontrolswho had by ANCA and/or of up-regulation of pulmonary endothe normalwhitecellscans.The majorityof patientswithsystemic hal leukocyte adhesion molecules (6) might lead to in vasculitishadscintigraphicevidenceof abnormalsplenicfunc creased margination in the pulmonary vasculature in sys tion. Two had focal splenicdefects, while 7 had increased temic vasculitis. In order to investigate this possibility, we labeledcelluptake.Nineofthepatientswithvasculitisshowed have retrospectively semiquantified radiolabeled granulo cell migration into the gut, presumably as a result of vasculitis, cyte activity in the lungs ofpatients with systemic vasculitis and in 6 it was prominent.Focal nasaluptake was found in and correlated it with ANCA status. 5/7 patientswith systemicvasculitiswho had their heads imaged, and may be specific for WG. Although all patients hadrenaldisease,therewas scintigraphicevidenceof diffuse METHODS parenchymalrenaluptakeof 1111n-Iabeledgranulocytesinonly one (with MP). The presenceof anti-neutrophilcytoplasmic Patients antibodiesdidnotcorrelatewithany abnormalityor with lung The patients in this retrospective study were recruited from uptake. Systemicvasculitisis associatedwith abnormalities referrals to the Nuclear Medicine Unit for routine leukocyte of granulocytekinetics, particularlyinvolvingthe lung and scanning. The group was comprised of 12 patients with systemic spleen. vasculitis(WG 6; MP 6) and 28 control patients. All vasculitis patients in this study were diagnosed according to previously J NucIMed 1992;33:491—497 defined clinicopathological criteria (7,8). All had small-vessel vasculitis; patients with WG had evidence of granulomata and had prominent involvement of the upper respiratory tract. The clinical indications for the leukocyte scan in the patients with ncreased pulmonary granulocyte margination, as a re systemic vasculitis were generally either for the evaluation of suspected gut vasculitis or for unexplained pyrexia. Their clinical suit of activation in vivo by certain cytokines, is thought details are summarized in Table 1. All had renal disease and all to occur in several clinical settings, including extracorpo were receiving treatment at the time oftheir scan with a standard real circulation (1) and in the adult respiratory distress immunosuppressive regimen which comprised prednisolone and syndrome (ARDS) (2). Following injection 1ItIn-labeled cyclophosphamide (9). One patient with MP had abnormal liver granulocytes, abnormal focal activity has been recorded in function tests. Two patients (one with WG and one with MP) the lungs of patients with systemic vasculitis, in particular were studied twice at different stages of their disease. All of the Wegener's granulomatosis (WG) (3). We have previously control patients had unequivocally negative leukocyte scans and no evidence of inflammatory disease on follow-up to date. Twenty-two had irritable bowel syndrome, two had painful knees, Received Jul. 30, 1991 ; revision accepted Oct. 16, 1991@ For reprints contact: Dr. AM. Peters, Department of Diagnostic Radiology, one had bone pain several years after gunshot wounds, one had HammersmithHospital,Du Cane Road,London,UKwi 2 OHS. diarrhea following radiotherapy, one had pyrexia following a

GranulocyteKineticsandSystemicVasculitis•Jonkeret al 491 TABLE I ClinicalSummary(At Presentation)

forFocalPatient ENTChestGutInterval: presentationtoIndication DiagnosisANCA diseasediseaseHemorrhage Other symptoms LFT scan(days)scan DDMP+No—+NoN79pyrexiaNJMPNANo——COADYesN1 diseaseGCMPNANo——YesN27gut 6gut diseaseVB 9pyrexiaVB(1)MP+No—+YesN1 abscessCOMP+No——YesN14pyrexia,?ENTDCMP+No——basalYesAbnormal1(2)MP26pelvic

5pyrexiaatelectasisHS

9pyrexia,?gutHS(1)WG+No++YesN1 (2)WG64pyrexiaEFWG+No+—NoN1 kneeGJWG+Yes——pleural 7septic (left)NoN76pyrexiaMAWG+Yes++YesN63gut effusion diseaseAMWG+No++NoN29evaluation of focal lungpathology DN WG + No + — No N 8 pyrexia NA= not known;MP= microscopicpolyartentis;WG= Wegener'sgranulomatosis;andCOAD= chronicobstructiveairwaydisease. + present, —absent. Allpatientshadrenaldisease.

minorgynecological procedureand in one it has not been possible standard techniques (11,12). Technetium-99m-HMPAO was to obtain a finaldiagnosis.The control groupdid not include any used in 10 of the controls and in five of the WG/MP patients patients with inflammatory bowel disease or any splenectomized (Table 2). Ofthe two patientsstudied twice, one had MP and the individuals. None of the controls was known to have underlying other had WG. In each ofthese two patients, the follow-up study liver or lung disease. Anti-neutrophil cytopiasmic antibodies was with a different radionuclide compared with the first (Table (ANCA) were detected by the internationally standardizedmdi 2). rect IF method (10). Since these were routine referrals, multiple spot views were obtained, with a wide field ofview gamma camera, over the whole Radiolabeled Neutrophil Studies body, including posterior views of the chest, between 1 and 1.5 Radiolabeled white cell studies were performed with 99mTc.. hr after injection (very early views), then between 2.5 and 4 hr HMPAO (11) or ‘‘‘Intropolonate (12). Cells were labeled using (earlyviews)and finallyat 20-24hr (lateviews).

TABLE 2 ScintigraphicFeatures Lunguptake PatientSpleenOtherDDDiagnosis Cellprep ANCA Diffuse Focal Nasaluptake Gutuptake enlargedNJMP Tc + — NA NA + hotGC MP In NA — — NA ++ uptakeVB(1)MP In NA — NA NA ++ enlargeddiffuse renal normalVB MP In ± ++ — + ++ normalCO(2) MP Tc ± ++ — + ++ hotDC MP In + ± — — + moderately normalHS MP In + + — NA ++ defectsHS(1) WG Tc + ++ — + + focal defectsEF(2) WG In — ++ — + — focal kneeGJ WG In + + — ++ ++ enlarged,hotuptake in hotMA WG Tc — ++ — — ++ enlarged, hotAM WG Tc — ++ + NA + defectsDN WG In — + + + — focal normalNA WG In + + — + — granulomatosis.++= notavailableor not imaged;MP= microscopicpolyartentis;WG= Wegener's absent.*marked, + present, —

At time of scan.

492 TheJournalof NuclearMedicine•Vol.33 •No.4 •April1992 A C

FIGURE 1. (A)Posteriorchestview,showingincreaseddiffuselungactivity(lung:liverratio,1.08) 1 hrfollowinginjectionof @“Tc HMPAOlabeledleukocytesin a patientwith Wegener'sgranulomatosis(HS,study 1). Note also the focal splenicdefects.(B) Chest x-ray, showinga right-sidedpleuraleffusionand a smallerone on the left, but clear lung fields. Note the presenceof a nasogastric tube.(C)A patientfrom the controlgroupgiven @“Tc-labeledcells:samegammacameraview andsametimeafter injection(lung:Iiver ratio,0.34).

Analysis of active disease in the nose: uptake was seen in four Regions of interest (ROIs) were drawn over the right lung, patients with WG (of whom three had clinical disease in spleen and liver from the posterior aspect. The count rate in the the nose) and in one patient with MP. However, this right lung (per pixel) was expressed as a quotient of the count patient with MP had a nasogastric tube in situ in the rate per pixel in the liver and in the spleen. In two patients with period leading up to both ofhis studies. Two ofthe patients WG there was abnormal focal uptake in the left lung, which was with WG showing nasal uptake also had nasogastric tubes, not included in the lung ROl. Spleen:liver count ratios (per pixel) although in one of these, studied twice, only prior to the were also calculated. first study. One patient with WG and clinicopathoiogical Statistics evidence of disease in the nose had no nasal uptake. This was a retrospective study and so in some studies the One patient with rapidly progressive glomeruionephntis appropriate views were not available. Specifically, these were the and acute renal failure showed faint abnormal diffuse very early views in four studies in MP and one in WG, the early uptake of ‘‘‘In-labeledgranuiocytes in the parenchyma of views in one study in MP and one in WG, the late views in two the kidneys (Fig. 3). ‘‘‘Instudies (one MP and one WG), and views ofthe face in four All patients with MP and four with WG had abnormal MP studies and one WG study (Table 2). Patient and study numbersthereforeshowsomevariationfromone measurement! uptake in the gut, consistent with vasculitis (Fig. 4). Of observation to another. Parametric statistics have been employed, these, 5/6 patients with MP and 2/4 with WG had symp using the Student t-test for unpaired data. toms compatible with gut vasculitis and one in each group had vasculitic changes demonstrated at laparotomy. When RESULTS imaged with 99mTcHMPAO this abnormal gut activity was visible within 1 hr of cell injection (i.e., it was not the Abnormal Findings in Systemic Vasculitis result of the nonspecific bowel activity seen with this All patients with WG had visibly increased diffuse lung agent). When imaged with ‘‘‘In,it was visible within 3 hr activity on the very early and early images, which had largely cleared on the late images (Fig. 1). Diffuse lung activity was generally less impressive in MP, although in three studies (two in the same patient) it was visibly increased, again clearing by 24 hr. In two patients with WG, a single abnormal focus of activity was seen in the left lung. In each case, this was superimposed on diffusely increased activity but, in contrast to the diffusely increased FIGURE 2. In activity, became more prominent on the late views. creased nasal up In seven patients with systemic vasculitis images were take(leftlateralview) seen20 hr after in obtained of the face. Increased activity in the nasal region jection of 111In-la was seen in five, four of whom had WG (Fig. 2). Two of beledgranulocytesin the seven had repeat studies and abnormal nasal activity a patient (EF) with was again seen in both. Nasal uptake did not correspond Wegener's granulo exactly to a clinical diagnosis ofWG or to clinical evidence matosis.

Granulocyte Kinetics and Systemic Vasculitis •Jonker et al 493 B,@ !@j@P@:

FIGURE3. Posterior abdom@ew, tho@ Prigdiffuse abnormal bilateralrenal paren chymal uptake 8 hr after injectionof @ 111ln-@ FIGURE 4. (A) Anteriorabdominalview showingabnormal cytesinapatient(GC) uptakeof 111In-Iabeledgranulocytesina loopof smallboweland wfthmkrosco@icpo@y thecolonatthesplenicfiexure1 hrafterinjectionof 111ln-Iabeled arteritle. granulocytesina patient(DC)withmicroscopicpolyarteritis.(B) Anteriorabdominalviewat 24 hrshowsevidenceofdistaltransit ofsmallbowelactivity,reachingascendingandtransversecolons. (i.e., was not due to swallowed activity). One patient with WG who was ANCA-positive and had abnormal gut activ The mean lung:liver ratios per pixel in the control ity consistent with gut vasculitis (with @mTc)had no patients were 0.38 (s.d., 0. 13, n = 18), 0.32 (0. 13, n = 28) evidence of gut uptake when restudied (with ‘‘‘In)at the and 0.16 (0.06, n = 16 [‘‘‘Inonly@)on the very early, early, time she was ANCA-negative, but still had diffusely in and late views, respectively. Taking systemic vasculitis as creased lung activity. one group, the lung:liver count ratios were clearly elevated There was a high incidence of abnormal splenic uptake on the very early and early views: 0.87 (0.25, n = 9, p < in the systemic vasculitis group. Two patients with WG 0.001) and 0.75 (0.26, n = 12, p < 0.001), respectively (one studied twice) had multiple focal splenic defects on (Fig. 6). The mean ratio on the late views in this group scintigraphy (Fig. 1). In seven further studies, the spleen was 0.27 (0.06, n = 7 [‘‘‘Inonly], p < 0.002), also was either enlarged or appeared unusually “hot―(or both) significantly higher than the mean ratio in the late views (Fig. 5). The spleen looked normal in only three patients in the control patients. The mean lung:liver ratio on the (one ofwhom was studied twice). early views was significantly higher in WG as compared Quantitative Comparison of Systemic Vasculitis with with MP: 0.94 (0.23, n = 6) versus 0.57 (0.22, n = 6, p < Controls 0.01), respectively (Fig. 6). (Insufficient numbers were There was no significant difference in the lung:liver ratio available for the two other imaging times.) Nevertheless, between controls given ‘‘‘In-labeled cells and controls the ratio in MP was still significantly higher than the given 99mTc@1abeledcells. The lung:liver, lung:spleen and controls on the early views (p < 0.00 1). spleen:liver ratios for ‘‘‘Inwere therefore each pooled with Spleen:liver count ratios per pixel in the controls were the corresponding ratios based on @mTcin both groups of 4.1 (2.2, n = 17) and 4.0 (1.8, n = 24) on the very early patients. and early views, respectively. Excluding the two patients

FIGURE5. Intenseuptake of @Tc-HMPAO-IabeIedIeu kocytes in a normal-sized spleen (spleen:Iiverratio, 9.3) I .5hrafterinjectionina patient (MA)withWegener'sgranulo matosis. Note the intensityon A B C the anterior view (A), in which thespleen,becauseofitspos

tailor location, is not normally @1 soprominent.Thereisalsoan area of focal uptake in the left apex (arrowed),visbie on the antenorandposterior(B)views and superimposedon abnor mallyIncreaseddiffuselungac tivity (Iung:liverratio, 1.08).An anterior view in a patient from the control group given @‘Tc labeledcells(C)is shownfor comparisonwith (A).

494 The Journalof NuclearMedicine•Vol. 33 •No. 4 •April1992 uptake must be distinguished from the immediate lung 1.41.2•0 signal which is observed when granulocytes have become

. activated as a result of manipulation in vitro during label S •@ •° 0.8 • ing (15). A characteristic feature of this “artifactual―lung > a .@ 0.6 fl sequestration is that the lungs become clear by about 40 • @0 0@

.@10 mm, as the labeled neutrophils move from the lung into ::•@Li.•. the reticuloendothelial system, particularly the liver. As a U@I:1 result, by 1 hr, the lung:liver ratio is very low (15). The recovery of labeled cells in blood (i.e., the percentage of -1 .52.5-420-24Timefrom injected labeled granulocytes still circulating in blood 30 injection (hr) mm after injection) is also low and radioactivity fails to localize in sites of inflammation. This artifactual lung FIGURE 6. ComparisonofIung:livercountrateratio(parpixel) betweensystemicvasculitisandcontrolpatients,and,withinthe sequestration is almost completely abolished when granu systemic vasculitis group, between Wegener's granulomatosis locytes are isolated on density gradient columns made up (closed symbols)and microscopicpolyarteritis (open symbols). with autologous plasma or when “mixed―leukocytes are Values based on 1111nare shown as circles and on @mTcas isolated and labeled in plasma (15). We have previously squares.The 95% confidenceintervalsfor the control patients shown similar early patterns of biodistribution for “In areshownas stippledbars. tropolonate-labeled granulocytes and 99mTcHMPAO4a beled ieukocytes (both preparations labeled in plasma), in with splenic defects, the sleen:liver ratios in systemic vas particular similar initial rapid lung transit and minimal culitis were significantly higher at both these imaging localization in the liver (22). The characteristic feature of times: 6.8 (4.1, n = 6, p = 0.05) and 7.2 (2.8, n = 8, p < genuine pathophysiological margination in the lung is an 0.001). intensity of uptake which is broadly proportional to the Lung:spleen count ratios per pixel in the controls were level ofcirculating granulocyte activity and, unlike artifac 0. 11 (0.045, n = 17) and 0.08 1 (0.024, n = 24) on very tual lung hold up, is not associated with a high liver uptake. early and early views. After excluding the two patients Increased pulmonary granulocyte margination could with focal spienic defects, lung:spleen count ratios in sys result from granulocyte activation in vivo, resulting in temic vasculitis were also higher than those in controls in increased “stiffness―or “stickiness,―or “up-regulation―of the very early and early views: 0. 16 (0.077, n = 6, 0. 1 > p leukocyte adhesion receptors on the pulmonary endothe > 0.05) and 0.12 (0.067, n = 8, p < 0.05), respectively. hum (6). Granulocytes could become activated in vivo as Lung:spleen ratios were considerably more variable than a result of exposure to ANCA. However, this appears the lung:liver ratios. There were insufficient numbers to unlikely since an increased lung radioactivity signal was compare lung:spleen ratios in WG with controls. still present in patients who were ANCA-negative at the Presence or absence ofANCA at the time of scintigraphy time of scintigraphy. Exposure to cytokines at a site of did not appear to correlate with any of the above ratios, inflammation is another possible cause of granulocyte Or with the presence or severity of gut involvement or activation in vivo since cytokines increase the stiffness of splenic abnormalities. granulocytes and prolong their passage through the lungs (23). This mechanism has been proposed in Crohn's dis DISCUSSION ease (24) where granulocytes may be exposed to cytokines It is widely believed that most ofthe MGP is in the lung as they pass through inflamed gut without leaving the (13,14), although this has not been borne out with the intravascular space. Granulocytes from patients with advent of clinical white cell scanning for the diagnosis of Crohn's disease show increased adherence in vitro (24) inflammatory disease (15). Our own estimate of the lung and this fits with the increase in lung:liver ratio that we MOP, based on kinetic studies and a comparison of “In have previously recorded in inflammatory bowel disease labeled neutrophils with radiolabeled red cells (16,1 7), is (IBD) (25). However, although most of the patients with that it represents only about 10% ofthe whole-body MOP; systemic vasculitis in this study had clinical evidence of i.e., neutrophils normally show no more tendency to mar gut vasculitis with migration of labeled granulocytes into ginate in the lungs than the overall average for the whole the gut wall and bowel lumen, as in IBD (26), it is unlikely body (18,19). This estimate is consistent with the changes that the increased pulmonary granulocyte margination of observed in the lung ‘‘‘Ingranuiocyte signal following systemic vasculitis is secondary to gut vasculitis. Hence exercise, which in our hands did not produce any pulmo the lung:liver ratio did not correlate with the intensity of nary demargination (but did result in marked splenic gut uptake and was generally much higher than those çlemargination) (20), and inhalation of platelet activating recorded in severe IBD (25). This, however, does not factor (PAF), which resulted in an acute doubling of the exclude other, as yet unrecognized, causes of granulocyte lung' ‘‘Ingranulocyte signal (21). stiffness or stickiness in systemic vasculitis. Increased, pathophysiological, pulmonary granulocyte Increased margination may be due to properties of the

GranulocyteKineticsandSystemicVasculitis•Jonkeret al 495 endothelium, for example, up-regulation of adhesion mol mal pulmonary granulocyte signal. With the increasing ecules (6). This could also be induced by cytokines. Inter interest in the role of neutrophils in lung injury and leukin-l, for instance, induces marked granulocyte accu systemic organ failure (27,31), the observation of diffusely mulation in the lungs ofexperimental animals (27), while increased lung granulocyte accumulation, consistent with in man we have shown that inhalation of PAF causes an increased pulmonary margination, is also important. immediate increase in pulmonary granulocyte margina In conclusion, we have presented evidence of increased tion (21). Alternatively, margination may be increased by granulocyte margination in the lungs in systemic vasculitis, an, as yet undefined, effect ofthe anti-endothelial antibod especially WG. It will now be important to: (1) strengthen ies which have been detected in the sera of some patients these observations with a more rigorous quantification of with systemic vasculitis (5). pulmonary margination in vivo, such as the simultaneous Immunosuppressive therapy administered to these pa use of radiolabeled red cells as a marker for the circulating tients seems an unlikely cause ofthe increased granulocyte component of the lung granulocyte signal and against margination. Steroids would, if anything, reduce it (28), which the transit time of the labeled granulocyte could be and although WG and MP were treated essentially the compared (1 7); and (2) identify whether the granulocyte same, there was a significantly higher lung signal in WG. or pulmonary endothelium is primarily activated. Fur Although the lungs appeared largely to clear by 24 hr in thermore, patients with systemic vasculitis sometimes have all patients with a diffusely increased uptake in the early abnormalities of the spleen, which may collectively be views, the lung:liver ratio remained significantly elevated expressed as splenic “vasculitis.― in the patients with systemic vasculitis. In addition to increased focal lung activity, which was seen in only two ACKNOWLEDGMENTS patients, there could be some degree of diffuse migration oc;m@aMedicalResearchCounciltrainingfellow. of granulocytes in the lungs in systemic vasculitis in addi tion to, and possibly resulting from, the increased margin REFERENCES ation. In general, it is not clear from granulocyte kinetic 1. Craddock PR, Fehri, Dalmasso AP, Brigham KL, Jacob H5. Hemodialysis leukopenia: a pulmonary vascular resulting from complement studies if a stimulus to increased margination invariably activation by dialyzer cell membranes. 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Granulocyte Kinetics and Systemic Vasculitis •Jonker et al 497