Lung Nodules and Masses after CardiacTransplantation’

Linda B. Haramati, MD #{149}Larry L. Schulman, MD #{149}John H. M. Austin, MD

491

Single or multiple lung nodules ormasses were noted at chest radiogra-phy in 25 (9.7%) of 257 patients aftercardiac transplantation. Two epi-sodes occurred in each of three pa-tients, for a total of 28 (10.9%) epi-sodes in the 257 patients within thefirst 18 months after transplantation(transplantation performed betweenJuly 1987 and December 1990). Bron-choscopy, percutaneous needle bi-opsy, and open lung biopsy were per-formed as clinically warranted toestablish a diagnosis. Infection wasfound in 21 instances (8.2%) in 18 pa-tients. The most frequent pathogenswere Aspergillus (n = 9 [3.5%]) andNocardia (n = 7 [2.7%]). Aspergilluswas hospital acquired in eight (89%)of nine patients and had a right-sidedpredominance (20 [74%] of 27 le-sions). The nodules or masses ap-peared a median of 2 months aftertransplantation for Aspergillus (range,0.5-12 months) and 5 months for No-cardia (range, 1-10 months). B celllymphoma manifested as numerousnodules in two patients (0.8%). Al-though a variety of causes werefound for post-cardiac transpianta-tion nodules or masses, the majority(75%) were infectious.

Index terms: Aspergillosis, 60.2056 #{149}Heart,

transplantation, 51.459 #{149}Lung, effects of drugson, 60.469, 60.649 #{149}Lung, infection, 60.2014,

60.2056, 60.2066, 60.2075 #{149}Lung, nodule,

60.458 . Lymphoma, 60.34 #{149}Nocardia, 60.2014

Radiology 1993; 188:491-497

I From the Departments of Radiology (L.B.H.,

J.H.M.A.) and Medicine (L.L.S.), Columbia Uni-versity College of Physicians and Surgeons, Co-lumbia-Presbyterian Medical Center, New York,NY. Received December 10, 1992; revision re-

quested January 29, 1993; revision receivedMarch 10; accepted March 16. Address reprintrequests to L.B.H., Department of Radiology,Albert Einstein College of Medicine/MontefioreMedical Center, Bronx Municipal Hospital Cen-ter, Pelham Pkwy S and Eastchester Rd. NewYork, NY 10461.

.0 RSNA, 1993

C ARDIAC transplantation is now awidely accepted form of treat-

ment for end-stage heart disease. Themost common complications of car-diac transplantation are rejection ofthe donor heart and infection of thelungs and other organs (1-4). Lym-phoma and other cancers occasionallyoccur (5).

We have noted single or multiplelung nodules or masses on the chestradiographs of a number of patientsafter cardiac transplantation. In this re-port, we review the imaging findingsand causes of these nodules and masses.

MATERIALS AND METHODS

Between July 1987 and December 1990,266 consecutive patients underwent car-diac transplantation at our institution.Nine patients died in the immediate post-operative period (defined as within 48hours of surgery). The remaining 257 pa-tients form the study population. Twohundred (78%) were men, 57 (22%) werewomen. The mean age at surgery was 45years ± 17 (standard deviation [SD])(range, 28 days to 69 years). By clinical cri-teria, no patients were infected at the timeof surgery. All patients received antibioticsfor 48 hours perioperatively. The standardimmune suppression regimen includedcyclospormne, azathioprine, and predni-

sone. A small subset of patients whose

serum creatinine levels were elevated re-ceived OKT3 induction therapy post-operatively. Prophylaxis (oral trimetho-prim-sulfamethoxazole or aerosolizedpentamidine) against Pneumocystis cariniiwas administered to all patients after 1988.

Postoperative assessment included atleast three in-hospital chest radiographicexaminations per week. After initial dis-charge, physical examination and chestradiography (posteroanterior and left lat-eral) were performed at a minimum ofweekly intervals for 2 months, then bi-weekly for the next 6 months, thenmonthly for the next 6 months, and at 2-3-

month intervals thereafter. The mean fol-low-up time for all patients was 21 months± i3 (SD). No patients were lost to follow-up. Forty-nine (19%) of the 257 patientsdied during the study period.

Whenever a chest radiograph revealed anodular or masslike area or areas of in-creased opacity (28 episodes in 25 pa-tients), evaluation then included a com-plete blood cell count and cultures ofsputum, blood, and urine. Bronchoscopy(n = 26) was performed in 22 patients withuse of bronchoalveolar lavage (n = 26)

and transbronchial biopsy (n = 25). Open

lung biopsy (n = 4) and percutaneouscomputed tomography (CT)-guided nee-dle aspiration (n = 3) were performed asclinically warranted.

Criteria for the diagnosis of pulmonaryinfection were new radiographic nod-ule(s) or mass(es) and either (a) culture,cytologic, or histopathologic evidence of aspecific organism or organisms or (b) aclinical course in which pulmonary infec-tion appeared highly likely (6). Bacterialinfection was diagnosed by means of posi-tive cultures of lavage fluid and positivecultures of blood or pleural fluid. Alterna-tively, bacterial pneumonitis was diag-nosed by means of positive bronchoscopiccultures, a compatible radiographic area ofincreased opacity, and clinical response tospecific antimicrobial therapy. Fungal in-fection (other than yeast) was diagnosedby observing the organism in lavage fluidor culture medium, a compatible radio-graphic area of increased opacity, lack ofresponse to usual antibiotic therapy, andresponse to antifungal therapy. P cariniiwas diagnosed by means of the presenceof silver-stained cysts in lavage fluid orlung tissue. Cytomegalovirus (CMV) infec-tion was diagnosed by demonstratingcharacteristic haloed “owl eye” intranu-clear inclusions in lavage fluid or lung tis-sue, combined with positive viral cultures(7). Alternatively, CMV pneumonitis wasdiagnosed in the absence of visible inclu-sion bodies if there was tissue evidence of

interstitial pneumonitis, positive culturesof bronchial aspirate, and absence of otherinfectious causes of interstitial pneumoni-tis(7).

For the purpose of this study, all chestimaging studies were subsequently re-

viewed separately by two radiologists sub-specializing in chest disease (L.B.H.,

Abbreviations: CMV = cytomegalovirus,SD = standard deviation.

Table 1

492 #{149}Radiology August 1993

Lung Nod ules or Masses after Cardiac Transp lantation: Aspergillus ( n =9)

Patient! Time toAge (y)! Radiographic Diameter Radiographic Associated Source of Follow-up

Sex Detection (mo) Location (cm)* Appearance Findings Diagnosis Results

1!43/M 0.5 RULRLLLUL

486

Lobulated, fuzzy, onecavitary

Small, bilateral pleuraleffusions

Bronchoscopy Developed diffuse areasof increased opacity,

died at 2 mo2/44/F 1.5 RUL 2 Irregular, ill defined . . . Bronchoscopy Marked decrease at 2

wk, later completeresolution

3!63/M 1.7 RULLULRML

3, 2, 12.52(2)

Ill defined . . . Bronchoscopy Cavitated at 2 wk, re-solved at 3 mo

4!59/M 2.0 RLL 6 Lobulated . . . Bronchoscopy Marked clearing at 1mo, then slow resolu-tion

5/61!M 2.0 RMLRLLLUL

53.52.5

Ill defined, cavitary . . . Bronchoscopy Decrease at 3 wk, re-solved at 5 mo

6/57/M 2.0 RULRLL

3, 1, 0.71.5 (2)

Irregular, well margin-ated

. . . Percutaneousaspiration

Cavitated and de-creased size, died at 3mo of other causes

7/46/F

8/60/M

30

6.5

RULRMLLUL

0.8 (2)0.82.5, 1 (3)

Well defined

Irregular, well margin-ated

Mediastinaladenopathy

Patchy areas of in-creased opacity inLUL and RLL

Bronchoscopy

Bronchoscopy

Improved at 6 wk, re-solved at 5 mo

Resolved at 2 mo

9/55/M 12.0 RML 3 Irregular, cavitary Diffuse areas ofin-creased opacity, smallright pleural effusion

Bronchoscopy Gradual resolution at 7mo

Note.-LLTL = left upper lobe, RLL = right lowerlobe, RML = right middle lobe, RUL = right upper lobe.* Numbers in parentheses indicate number of lesions.

a. b.

Figure 1. Patient 3. Aspergillus appearing as multiple pulmonary nodules on a radiograph in a 63-year-old man (a) 7 weeks after cardiac trans-plantation. Treatment with amphotencin B was instituted. (b) Two weeks later, several of the nodules have cavitated.

J.H.M.A.). Differences of interpretation,which were minor, were resolved by meansof consensus. Complete clinical information

was available at the time of review.In the setting of probable community-

acquired infectious illness in which all mi-crobiologic studies were unrevealing, eachpatient was treated empirically with anti-microbial therapy specific for Nocardia (8).

If radiographic abnormalities resolvedsubsequently, they were assumed to havebeen due to Nocardia.

The Fisher Exact Test was used to com-pare proportions between two groups.The Mann-Whitney test was used to com-pare median times of onset between thetwo groups. A P value of less than .05 wasaccepted as statistically significant.

RESULTS

Single or multiple lung nodules ormasses were noted at chest radiogra-

phy in 25 (9.7%) of the 257 patients

surviving the immediate posttrans-

plantation period. Two episodes oc-curred in each of three patients, for atotal of 28 (10.9%) episodes in the 257patients. The mean age of the 25 pa-tients at the time of transplantation

was 51 years ± ii (range, 30-65

years). Twenty (80%) of the 25 pa-tients were men, five (20%) werewomen. The mean duration from the

a.

Volume 188 #{149}Number 2 Radiology #{149}� -

Table 2

Lung Nodules or Masses after Cardiac Transplantation: Nocardia (n =7)

Patient!Age (y)/

Sex

Time toRadiographic

Detection (mo) LocationDiameter

(cm)*Radiographic

Appearance

AssociatedFindings

Source ofDiagnosis

Follow-upResults

5/61/M 1.0 RLL 1.5 Round, ill defined . . . Bronchoscopy Decrease at 1 wk10/30/M 1.5 LUL 1.5 Ovoid, well defined . . . Clinical Gradual resolution by 5

mo11/42/M 2.0 RUL

LUL2.55

Lobulated, possiblesmall cavitation, illdefined

. . . Bronchoscopy Decrease at 1 mo, ulti-mately resolved

12/45/M 5.0 RULRML

RLLLULLLL

0.4 (2)0.3-0.6 (3)

0.4-0.9 (5)0.8-1.5 (12)

0.4-1.2 (3)

Well defined, roundand ovoid

2-cm-diameter subcari-nal lymph node

Clinical Resolved at 1.5 mo; new3-cm-diameter nod-

ule in LLL after ther-apy stopped, re-solved after further

13/53/F 6.0 RUL 1.7 Well defined Lingular area of in-creased opacity, smallbilateral pleural effu-sions

Clinicaltherapy

Decrease at 1 wk, re-solved at 1 mo; newnodule in RUL aftertherapy stopped, re-solved after furthertherapy

14/62/M 9.0 LUL 6 Cavitary, ill defined . . . Sputum Marked decrease at 1mo, scar at 4 mo

4/60/M 10.0 RUL 5 Well defined . . . Clinical Decrease to 3 cm in di-ameter at 3 wk, fur-ther decrease at6 mo

Note.-LLL = left lowerlobe, LUL = left upperlobe, RLL = right lowerlobe, RML = right middlelobe, RUL = right upper lobe.* Numbers in parentheses indicate number of lesions.

a. b.Figure 3. Nocardia asteroides appearing as nodular disease after cardiac transplantation.(a) Patient 5. Solitary nodule, 1.5 cm in diameter, on a radiograph in a 61-year-old man I

month after transplantation. (b) Patient 12. Multiple nodules on a CT scan in a 45-year-oldman 5 months after transplantation.

b.Figure 2. Patient 9. Aspergillus appearing as

a cavitary mass in the right middle lobe in a55-year-old man 12 months after cardiac

transplantation. (a) Detail view of anteropos-tetior chest radiograph. (b) CT scan.

time of transplantation to the time ofdetection of the radiographic abnor-mality was 4.7 months ± 4.3 (range,

0.5-18 months; median, 3.0 months).

The mean follow-up time for the 25patients was 22.9 months ± 12.9

(range, 2.3-49 months) after trans-plantation. Diagnosis was definitivein 22 (79%), presumptive in five(18%), and unknown in one (4%) of

the 28 episodes.

A single case (patient 10) was in-cluded in a previous series from ourinstitution (2).

Aspergillus was the causative organ-

ism (Table 1) on nine occasions, occur-

ring as a single episode in each of

nine (3.5%) of the 257 patients (Figs 1,2). The radiographic changes ap-

peared at a mean of 3.5 months ± 3.4

(range, 0.5-12 months; median, 2.0months) after transplantation. Four

(44%) of the nine patients wereasymptomatic. Cough was present in

four (44%), fever in one (11%), anddyspnea and rales in one (11%).

Nocardia was the proved causative

organism on three occasions and thepresumed cause on four occasions,occurring as a single episode in eachof seven (2.7%) of the 257 patients

(Table 2) (Fig 3). The radiographic

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494 #{149}Radiology August 1993

Volume 188 #{149}Number 2 Radiology #{149}495

Figure 4. Patient 16. B cell lymphoma ap-

pearing as numerous nodules 10 months af-ter cardiac transplantation in a 60-year-oldman. (a) Posteroantenor radiograph of leftlung. (b) CT scan.

changes appeared at a mean of 4.9

months ± 3.4 (range, 1-10 months;

median, 5 months) after transplanta-tion. Six (86%) of the seven patientswere symptomatic (weakness, n = 2;

cough, n = 1; green phlegm, n = 1;sweats, n = 1; chills and fever, F? = 1).Two (29%) of the seven patientsdeveloped recurrence of their Nocar-

dia nodules when treatment wasstopped. The nodules resolved afterresumption of therapy.

Comparison of Aspergillus and No-

cardia cases revealed that Aspergillus

lesions were multiple (six [67%] ofnine patients) more frequently thanNocardia lesions (two [29%] of seven

patients), but the difference was not

statistically significant (Fisher Exact

Test) (Tables 1, 2). Although the me-

dian duration from transplantation toonset of infection was only 2 monthsfor the patients infected with Aspc’rgil-

lus and 5 months for the patients in-fected with Nocardia, the difference inmedian time of onset between thesetwo groups was not statistically sig-nificant (Mann-Whitney test).

B-cell lymphonla manifested as mul-tiple nodules in two (0.8%) of the 257patients 6 and 10 months after cardiactransplantation (Table 3) (Fig 4). Bothof these patients were asymptomatic.

Combined P carinii and CMV pneu-monia formed a nodular or masslikearea of increased opacity in two

(0.8%) of the 257 patients 3.5 and 5.5

months after transplantation (Table 3)(Fig 5). One patient was symptomatic,with fever, cough, and dyspiiea; theother was asymptomatic.

A wide variety of other processes(ii = 8) also resulted in lung nodulesor masses on a single occasion (Table3). Among these, the cause was infec-

tious in three of the patients. Actinoba-

cillus actinomyceteincomitans, an un-usual pulmonary pathogen (9),manifested as a 5-cm-diameter mass.An untyped mycobacterial infectionmanifested as a 3-cm-diameter area ofincreased opacity. It was resected andstained positive for acid-fast bacilli,but no organism grew in culture. Sep-tic emboli in a patient with Lactobacil-

lus endocarditis manifested as ill-dc-fined bilateral areas of increasedopacity, some with cavitation.

One patient had severe congestiveheart failure and pulmonary embolibefore transplantation. As the pulnto-nary edema cleared after the trans-plantation, multiple peripheral areasof increased opacity were noted with-out evidence of infection, consistentwith pulmonary infarcts.

Rounded atelectasis was anothercause of a pulmonary mass. At CT, the

bronchovascular structures converged

on the mass in the classic manner de-scribed for rounded atelectasis (10).

Pleural thickening was associatedwith the mass.

Two cases mimicked true pulmo-nary nodules. One was a pulmonaryvenous varix, which markedly en-

larged during a period of acute rejec-tion related to elevated left atrial fill-ing and waned as rejection resolved.

Another was a healing second ante-rior rib fracture. After oblique viewsdid not allow definitive localization ofthe lesion, CT was required to estab-lish the diagnosis.

A single case remained withoutdiagnosis, for which the clinical sce-

nario was not appropriate for Nocar-

dia; the lesions resolved during anti-

microbial therapy.

Among the three patients in whomnodules or masses were seen on twooccasions, Aspcrgillus was a causative

organism in each patient on one of

the occasions. The other episode wascaused by Nocardia in two of the pa-tients and by combined P carinii and

CMV in the remaining instance.

DISCUSSION

The main finding of the presentstudy is that nodular or mass lesions

are not uncommon (25 [9.7% ] of 257patients) plain chest radiographic ab-

normalities in recipients of a cardiactransplant. To our knowledge, no pre-vious series of major organ (heart,

lung, liver, or kidney) transplant re-cipients has addressed this specific

question. Infection was the leadingcause of the radiographic abnormali-

ties (21 [75%] of 28 episodes), whereas

pulmonary lymphoma developed in

two subjects (0.8% of 257 patients)

and one each of various miscella-neous causes accounted for the re-

maining five episodes (Tables 1-3). Inall but one patient, the initial radio-graphic abnormality became evidentduring the 1st year after transplanta-tion, which is generally the period ofgreatest iatrogenic postoperative im-

n�une suppression (11).

The leading pathogens causing thenodular or masslike changes wereAspergillus (nine [32% J of 28 episodes)(Table 1) and Nocardia (seven [25%] of

28 episodes) (Table 2).

Aspcrgillus is ubiquitous in water

and soil and has been reported innosoconlial outbreaks contaminating

respirators, as well as in parenteral

medication (12). Eight (89%) of thenine episodes of Aspergillus in the pre-sent series are believed to have beenacquired in the hospital. rhe radio-

logic abnormalities developed within

at most 6 weeks after discharge fromthe hospital. A clustering of three of

the Aspcrgillus cases was related to

transient contamination of two inten-

sive care unit rooms. One patient ac-quired Aspergillus 12 months aftertransplantation. He had been in thehospital 1 month prior; his infectionis believed to be related to that hos-

pitalization. Only one episode ofAspergillus developed remote from

hospitalization (6.5 months after

transplantation). This patient had

been doing construction in his home,

and that is the presumed source of hisinfection.

496 #{149}Radiology August 1993

a. b. c.Figure 5. Patient 17. Combined infection with P carinii and CMV appearing as an ill-defined mass in a 56-year-old man 3.5 months after trans-

plantation. (a) Posteroanterior radiograph. There is a mass in the left midlung area plus mild, diffuse haziness in the right lung. (b) Lateral ra-

diograph. The mass is in the superior segment of the left lower lobe. (c) Nine days later, radiograph shows the mass has decreased in size and

cavitated.

Nocardia is a soil inhabitant. Cardiac

transplantation recipients have been

shown to be susceptible to infection

with Nocardia (2,3,13,14). However,

epidemiologic evidence does not sup-

port an in-hospital point source of

nocardial contamination (3,13). The

present series confirms the results of

prior studies in that a clustering of

nocardial infection did not occur.

Aspcrgillus pulmonary infection in

the present series was characterized

by findings both of timing and of lo-

cation. Nodules or masses caused by

Aspergillus tended to develop earlier(a median of 2 months after trans-plantation) than those caused by No-

cardia (a median of 5 months aftertransplantation), but the time of onsetfor each organism’s radiographic

changes covered virtually the entire1st year. The difference was not statis-tically significant. However, we be-

lieve that the trend toward Aspergillus

occurring earlier than Nocardia relatesto more frequent in-hospital acquisi-tion of Aspergillus compared with No-

cardia.An unanticipated finding in the

present series was that the locationsof the Aspergillus pulmonary lesionswere strikingly right sided: 20 (74%)of 27 lesions (Table 1). Moreover, the

left upper lobe accounted for all sevenleft-sided Aspcrgillus lesions. An up-

per lobe predilection was noted in an

earlier series from our institution (2),

but to our knowledge, predominance

of Aspergillus infection in the rightlung after cardiac transplantation hasnot been previously described (3). The

Nocardia lesions had an upper lobe

location in six (86%) of the seven in-

volved patients (Table 2). No right- orleft-sided predilection was present.

An upper lobe predominance for no-cardial lesions has not been noted

previously, to our knowledge (8,13).

An upper lobe predilection for pul-monary infection can be hypothe-sized to relate to the relative lymph

stasis, hyperoxia, or hypocarbia of

upper compared with lower lung

zones (15), but the right-sided pre-dominance of Aspergillus lesions in

the present series is an observationfor which we are unable to offer a

plausible explanation, beyond the

comparison with the modest right-

sided predominance of pulmonary

tuberculosis in the immune-compe-tent general population (16) and the

fact that inhalation of the organism is

the accepted route of entry for most

cases of infection with Aspergillus andNocardia (1). Deposition of inhaledparticles preferentially occurs in the

upper lobes, and more in the rightupper lung than in the left, a phe-nomenon possibly related to theshort, straight right main bronchus

compared with the long, curved left

main bronchus (17).Cavitation developed in five (56%)

of the nine cases of Aspergillus lesionsand in two (29%) of the seven cases of

Nocardia lesions. Each of these organ-isms has been reported previously in

association with cavitary lung lesions

(2,12,18), and this feature is not ahelpful point in differentiating thesetwo causes of pulmonary infection.Similarly, diameters of the individual

lesions did not appear to be a differ-

entiating feature (Aspergillus lesions

ranged up to 8 cm in diameter, Nocar-

dia lesions up to 6 cm in diameter).

Cavitation also occurred in one pa-

tient with combined P carinii andCMV pneumonitis and in another

with septic emboli from Lactohacillus

endocarditis (Table 3). Cavitation inthe present series was thereforefound in nine (36%) of the 25 pa-tients, and only in association with

pulmonary infection.Non-Hodgkin lymphoma is in-

creased in frequency after cardiac

transplantation, especially in patientsreceiving cyclosporine immunosup-

pression (5,19). The frequency varies

depending on the time after trans-plantation, from a low of 0.7% in oneseries (5) to a high of nearly 12% 2years after transplantation (4). Starzl

et al reported a 6% frequency of non-Hodgkin lymphoma after heart trans-

plantation in a series of patients withheart, kidney, or liver transplants (19).

Among patients who receive solidorgan transplants, patients with hearttransplants have a relatively high fre-quency of lymphoproliferative disor-ders, probably related to their highdegree of immunosuppression (19).Treatment remains controversial, al-

though reduced immunosuppressionis frequently helpful (5,18,20,21). In

the present series, one patient re-sponded to reduced immunosuppres-sion and one responded to combina-

tion chemotherapy.There is strong evidence that trans-

plantation-associated lymphoma is

frequently related to uninhibited pro-liferation of B lymphocytes that areinfected with the Epstein-Barr virus(19,20). The main immunosuppressivetarget of cyclosporine is the T lym-

phocyte, and the cell-mediated T cell

response to viral infection is corre-spondingly diminished (19,20). Two

patients in the present series devel-oped pulmonary B cell lymphoma(Table 3). The radiographic features

Volume 188 #{149}Number 2 Radiology #{149}497

were typical in that there was exten-sive extranodal parenchymal diseasein addition to less dramatic hilar andmediastinal adenopathy (21,22).

Among the miscellaneous causes ofpulmonary nodules or masses in thepresent series (Table 3), it is of interestthat carcinoma of the lung was notrepresented, despite the fact thatmany of the patients with ischemiccardiomyopathy were cigarette smok-ers who then became immunosup-pressed. However, lung carcinomaafter heart transplantation has beendescribed by others (two patients[0.7%1 in two series comprising a totalof 303 patients) (5). U

Acknowledgment: We thank MordecaiKoenigsberg, MD, for his valuable assistance.

References1. Hofflin JM, Potasman I, Baldwin JC, Oyer

PE, Stinson EB, Remington JS. Infectiouscomplications in heart transplant recipientsreceiving cyclosporine and corticosteroids.

Ann Intern Med 1987; 106:209-216.2. Austin JHM, Schulman LL, Mastrobattista

JD. Pulmonary infection after cardiactransplantation: clinical and radiologic cor-relations. Radiology 1989; 172:259-265.

3. Ettinger NA, Trulock EP. Pulmonary con-siderations of organ transplantation: part 3.Am Rev Respir Dis 1991; 144:443-451.

4. Kriett JM, Kaye MP. The registry of theInternational Society for Heart and Lung

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