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Transbronchial

Biopsies

in Children

After

Heart-Lung

Transplantation

John

P. Scott,

FRACP;

Tim W. Higenbottam,

BSc, MD, FRCP;

Rosalind

L. Smyth,

MA, MCRP;

Bruce

Whitehead,

MB, BS;

Peter

Helms,

MD, FRCP;

Guy Fradet,

FRCS(C);

Marc

De Leval,

MD, FRCS;

and John

Wallwork,

FRCS

From the Heart-Lung Transplant Groups, Papworth Hospital, Cambridge, and The Hospitals for Sick Children, Great Ormond Street, London, England

ABSTRACT. Sixty transbronchial biopsies have been

per-formed in eight children after heart-lung transplantation.

The selection of fiber-optic bronchoscope or a small (4

mm; 30 cm) rigid bronchoscope was made according to

the size of endotracheal tube required at surgery. If the endotracheal tube was size 7.5 or greater, a fiber-optic

bronchoscope was used, whereas if the endotracheal tube

size was below 7, a rigid bronchoscope was used. For the diagnosis of lung rejection, the histology of biopsies

re-vealed a sensitivity of 91% and specificity of 69% (similar

to the result in adults). The histology also distinguished lung infection from rejection. Complications included

three pneumothoraces and two clinically significant

epi-sodes of hemorrhage, one of which led to a cardiorespi-ratory arrest, which may have been caused by hypoxia. As a result, arterial oxygen saturation is now monitored during the procedure using a pulse oximeter. Pediatrics

1990;86:698-702; bronchoscopy, transbronchial biopsy, heart-lung transplantation.

pulmonary disease in adults,2’3 including cystic fi-brosis,4 and it has now been successfully used in children.5’6 Transbronchial biopsies obtained

through a fiber-optic bronchoscope (FOB) have

been required in adult HLT patients to distinguish acute lung rejection from opportunistic infection,7’8

reducing the incidence of chronic rejection#{176} which

had

been

common

in early

series.’0

Transbnonchial

biopsy in children poses special problems in obtain-ing adequate tissue for histology and culture, in

hemostasis, and in the maintenance of safe levels

of oxygenation while achieving adequate sedation during bronchoscopy. We report our experience

with TBB in children after HLT and describe the

clinical and physiologic features of acute lung nejec-tion and infection in these children.

PATIENTS AND METHODS

ABBREVIATIONS. TBB, transbronchial biopsy; HLT, heart and lung transplantation; FOB, fiber-optic bronchoscope (bronchos-copy); FEV,, forced expiratory volume in 1 second; ET, endotra-cheal; RB, rigid bronchoscope (bronchoscopy).

Although transbronchial biopsy (TBB) is well

established in adults for the diagnosis of diffuse

lung disease,’ its use has not been extended to

children. Heart and lung transplantation (HLT)

was initially introduced to treat end-stage

candio-Received for publication Aug 18, 1989; accepted Nov 28, 1989. Reprint requests to (J.P.S.) Heart-Lung Transplant Research Unit, Papworth Hospital, Papworth Everard, Cambridge CB3 8RE, UK.

PEDIATRICS (ISSN 0031 4005). Copyright © 1990 by the American Academy of Pediatrics.

Eight children underwent HLT between 1987 and

1989 (Table 1). Their mean age was 11.3 years

(range 3 to 15 years). Their original diagnoses in-cluded Eisenmenger syndrome (n = 2), pulmonary primary hypertension (n = 2),

and

cystic

fibrosis

(n = 4). Donor and recipient selection

and

surgical

techniques have been previously reported.’#{176}

Rejec-tion was controlled with oral cyclosponine and

aza-thiopnine, supplemented in four patients who

ex-penienced recurrent rejection with oral

predniso-lone (0.25 mg/kg).

After surgery all patients were carefully

moni-tored using respiratory symptoms-particularly

breathlessness, physical signs, crackles and wheezes

on auscultation,” pulmonary shadows on chest

na-diognaphs,’2 or a fall in forced expinatory volume in

1 second (FEy,) and vital capacity of greater than

10%7”3-as indications for TBB. In the 3-year-old

(2)

meas-TABLE 1. Patient Age, Sex, R ecipient Dis ease, Frequen cy of Rejection, and Types of Recipient Infection*

Patient Original Age, Sex Time Since Total No. Total and Type of Infection Episodes Present Disease y Surgery,

mo

of Rejection Episodes

FEy,, % Predicted

1 PPH 11 M 18 (died) 11 CMV pneumonia

...

2 PPH 15 F 18 3 Nil 94

3 CF 11 F 14 5 CMV pneumonia, Pseudomonas pneumonia 61

4 CF 14 F 11 7 Pseudomonas pneumonia 77

5 ES 14 F 10 5 Herpes simplex pneumonia 80

6 ES 3 M 6 4 Nil

...

7 CF 14 M 5 2 Pseudomonas pneumonia 73

8 CF 13 M 3 3 Pseudomonas pneumonia 94

* FEV,, forced expiratory volume in 1 second; PPH, primary pulmonary hypertension; CF, cystic fibrosis; ES,

Eisenmenger syndrome; CMV, cytomegalovirus.

urements, including spirometry, total lung capacity,

and

gas

transfer

for

carbon

monoxide,

were

made

in the others. Routine biopsies of the lungs were

performed in five patients when well at 3 and 12

months.

The

choice

of bronchoscopic

technique

was

made

according to the endotracheal (ET) tube size used

during transplant surgery. If a size 8 or larger was

used, a FOB was performed as in adult HLT

patients7 but using a 4.6-mm instrument. Sedation

was with intravenous diazepam or midazolam.

When

a size

7 to 8 ET tube had been used, patients

were anesthetized with propofol and nitrous oxide

and

an

ET

tube

size

7 to

8 was

passed.

The

FOB

was passed through this ET tube while the patients

received assisted ventilation. In two children who

had

required

ET

tubes

of

a size

below

7, rigid

bronchoscopy (RB) (4.0 mm diameter and 30 cm

length)

was

performed

using

propofol

and

nitrous

oxide,

assisted

ventilation

being

provided

through

the scope. Throughout the procedure, arterial

oxy-gen saturation was monitored using a pulse

oxi-meter (Oximeten, Copenhagen, Denmark).

Through both the FOB and RB, “alligator”

for-ceps were positioned under fluoroscopic control in

the lung periphery. Through the FOB three biopsies

were taken from each lobe in one lung, including

the lingula on the left side, whereas just middle/

lingula

and

lower lobes were sampled with the RB.

Tnansbnonchial biopsies were fixed in 10%

neu-tral

buffered

formalin

and

were

processed

in

a

Shandon hypercenter overnight or in 2 hours

ac-cording

to

urgency.

Initial

biopsies

were

cut

at

several levels 5 m apart. Later biopsies were

seri-ally sectioned and stained with Harris’ hematoxylin

eosin. Special stains, including pyronin methyl

green and Perl’s/Miller’s elastic Van Gieson, were

performed in all cases. Periodic acid-Schiff and

Gnocott’s silver method were used to demonstrate

fungi and Pneumocystis carinii.

A histologic

diagnosis

of rejection

was

made

when

there were dense perivascular lymphocytic

infil-trates, often associated with mixed cell

inflamma-tory changes in the bronchial mucosa.79 A

histo-logic diagnosis of cytomegalovirus pneumonitis was

made by the presence of typical inclusion bodies

within epithelial or endothelial cells.’4 This was

also confirmed by the growth of the virus from lung

biopsy. The histologic appearances of herpes

sim-plex virus pneumonia were those of a viral alveolitis

associated with typical “ground-glass” intranuclear 15

Acute rejection was treated with intravenous

methylprednisolone, 20 to 25 mg/kg daily for 3 days,

andthen 1 mg/kg ofonal prednisolone in decreasing

doses for 10 days. Cytomegalovirus pneumonitis was treated with ganciclovir”6 (Syntex Pharma-ceuticals, Maidenhead, Berks). Intravenous

acyclo-yin, 5 to 10 mg every 8 hours, was used to treat

herpes simplex virus pneumonia. This was

contin-ued for 14 days, when oral acyclovin was commenced

and continued as a prophylactic dose indefinitely.

For

the

purposes

of the

determination

of

sensi-tivity and specificity, a final diagnosis of rejection

was made if there was an improvement of

symp-toms, signs, and spirometnic measurements or chest

radiographic appearances after a course of

aug-mented immunosuppression. Similarly for

infec-tion, a response to specific treatment was regarded

as confirmation (Table 2).

Analyses of sensitivity and specificity of both

TBB

and

radiographic

changes

were

calculated

for

both rejection and infection separately. (Sensitivity

= true positives X 100%/all patients with disease;

specificity = true negatives X 100%/all patients without disease).

Analysis of the optimal number of biopsies was by the method of Gilman and Wang,17 namely the minimum number of biopsies required to achieve a

positive diagnosis.

RESULTS

A total

of 60 sets

of TBB

were

performed

in eight

patients, 49 through a FOB and 11 through a RB
(3)

pneumo-thonaces after RB and two clinically significant

hemorrhages during FOB, one requiring assisted

ventilation and the other causing a

cardiorespira-tony arrest.

There were 40 episodes of rejection (Figs 1 and

2), where in the absence of infection patients

im-proved

after

initiation

of steroid

therapy.

Of these,

36 sets of biopsies showed the characteristic

abnor-malities of rejection, giving a sensitivity of 86%. Of

the 16 occasions when patients were well, 11

biop-sies

had

normal

appearances,

giving

a specificity

of

69%. Of the remaining biopsies, 2 showed evidence

of fibrosis and 2 showed nonspecific bronchial

in-flammation. Three episodes of pneumonia, one of

cytomegalovirus, and two of herpes simplex virus

were diagnosed by histology.

In

41 of the

50

TBBs

obtained

using

FOB,

all

TABLE 2. Clinical Criteria for Diagnosing Opportun-istic Infection of the Lungs and Rejection of the Lungs*

Infection

Criteria Abnormalities

Symptoms Cough and dyspnea Physical signs Fever, basal crackles on

auscultation

Physiology Fall in FEV, and FVC, fall in DLCO Radiology Diffuse bilateral

pulmo-nary shadows Response to specific

therapy (see text) Rejection

Criteria Abnormalities Symptoms Cough and dyspnea Physical signs Fever, basal crackles on

auscultation

Physiology Fall in FEV, > FVC

Radiology Diffuse bilateral pulmo-nary shadows

Response to high-dose steroids (see text)

* FEV,, forced expiratory volume in 1 second; FVC,

forced vital capacity; DLCO, diffusing capacity for carbon

monoxide.

three lobes (lingula on left) of one lung were

sam-pled.

In

9 only

the

lower

lobe

was

biopsied.

Two

lobes were biopsied on each of the 10 occasions RB

was used. In the 24 rejection episodes where all

lobes of one lung were sampled, the characteristic

histologic abnormalities of rejection were found in

the

upper

lobe

in 89%,

middle

lobe

(or

lingula)

in

92%, and lower lobe in 91%.

A total

of

28

individual

biopsy

samples

in

6

episodes of rejection studied by RB were required

to confirm the diagnosis histologically. At least 2.7

biopsies are required to provide a 99% chance of

diagnosing rejection,’7 although this calculation is

based on only two patients. By similar calculation of 36 episodes of rejection confirmed by TBB

through FOB, some 313 individual biopsy samples

were

obtained

and

4.5

individual

biopsies

were

re-quired to confirm rejection (P < .01).

The incidence of rejection in children was a mean

of 3.6 episodes per patient per 6 months. There was

a total of 3 episodes of infection. In all but 1 of the

rejection episodes, recovery followed steroid

then-apy.

Infiltrates were present on 55% of the chest

radiographs of those 40 rejection episodes

con-firmed by histology. Radiologic abnormalities were

more common during rejection episodes occurring

in the first 3 months, giving an 88% sensitivity.’5”7

In the

16 episodes

of rejection

occurring

after

the

first 3 postoperative months, only 19% of the chest

nadiognaphs showed abnormalities.5”2 The

infec-tions were associated with infiltrates on chest

ra-diographs in all cases. There was a significant fall

in FEy, in only 52% of cases of histologically

confirmed rejection episodes. A fall in FEV1 when

present remains a valuable noninvasive guide to the

timing of TBB. Mean FEy, was 77% of predicted

at

6 months

and

76%

of predicted

at

12 months

(Fig 3).

DISCUSSION

Transbronchial biopsy of the lung, through a

FOB

or

RB,

can

be

performed

in

children

after

TABLE 3. Total Biopsy Numbers for Each on Histologic Examination and Obtained by Bronchoscopy (RB)

Patient, Positi Fiber-Optic B

ye or Negative for Reje ronchoscopy (FOB) or

ction Rigid

Patient No. FOB Patient No. RB

Positive Negative

Positive Negative

1

35 49

2 12 10

3 54 11

4 46 10

5 49 10

7 22 13

6

8

24 8

22 2

(4)

0-6

2

6-12

Time in Months

Fig 1.

Incidence

of rejection

plotted

against

time

in

months.

12-18

0

-0 100 200 300 400 600

Days since Transplant

Fig 3.

Forced

expiratory

volume

in

1 second (FEy,) as recipient predicted of the six “long-term” (>4 months) survivors, 1 1 years of age or older, plotted against time.

Fig 2.

Photomicrograph

of characteristic

perivascular

lymphocytic

infiltrate

of acute

lung

rejection

using

he-matoxylin

and eosin

stain.

Magnification

is x200.

Episodes of Rejection FEVI % Predicted

1 20

HLT.

It allows

the

diagnosis

of acute

lung

rejection

and

lung

infection,

showing

a similar

sensitivity

and

specificity

to

TBB

when

used

in

adult

HLT

patients.7

Complications

appear

to

be

no

more

frequent7”8

but

can

be more

serious.

They

may

be

reduced

by

monitoring

arterial

oxygen

saturation

and careful selection of bronchoscopic method.

The

requirements

for

bronchoscopy

to

obtain

TBB

are

different

from

those

for

bronchoscopy

in

children

for

other

indications.’9’20

Flexible

FOB

al-lows

accurate

location

of the

forceps

under

fluoro-scopic

control,7

in particular

sampling

of the

upper

lobes.

Empirically

we

chose

to use

the

ET

size

at

surgery

as a means

of deciding

on the

use

of FOB

with

or without

an ET

tube

on RB.

The

size

of ET

tube

used

at operation,

although

usually

associated

with

age,20’2’

was

more

closely

linked

to height

ni

our

patients.

For

example,

a

13-year-old,

whose

growth

had

been

impaired

by cystic

fibrosis,

had

a

height

of the

50th

centile

for

a boy

aged

8.9 years,

and

he required

a 6-gauge

ET

tube

at surgery.

Clinical

distinction

between

acute

lung

rejection

and

infection

is not

possible,7’22

although

lung

func-tion,

symptoms,

physical

signs,

and

chest

nadiographs7’’3

are

useful

indications

for

under-taking

TBB.

In adults,

TBB

histology

can

not

only

diagnose

rejection,

it can

also

distinguish

rejection

from

infection.7

The

same

appears

true

in children.

The

diagnosis

of rejection,

we suspect,

can

be made

by

sampling

one

lobe

in

children,

unlike

adults

where

two

lobes

must

be sampled.23

Using

FOB

at

least

four

individual

biopsies

are

required.

Chest

radiographic

findings

are

comparable

with

those

in adults.’2

Nodular

shadows

with

septal

lines

associated with pleural effusion are common in

rejection,

but

these

changes

are

similar

to

those

seen

in infection.

As in adults,

the

radiograph

less

frequently

shows

abnormalities

in

rejection

epi-sodes 3 months on more after surgery. The FEy, is

of value,

as in adults,”3

but

requires

a consistent

technique

which

children

may

require

longer

to

master.

The

incidence

of complications

of this

procedure

is

comparable

with

that

in adults.7”8

However,

one

death

can

be directly

attributed

to hemorrhage

after

TBB.

This

patient’s

arterial

oxygen

saturation

was

not

monitored

and

we suspect

that

severe

hypoxia

occurred

during

the

procedure,

leading

to candiores

piratory

arrest.

As a result

of this

early

experience,

all patients,

irrespective

of the

use

of assisted

yen-tilation,

are

now

routinely

monitored

by pulse

ox-imetry

and

supplementary

oxygen

is given.

We have

found

pulse

oximetry

to be a sensitive

measurement

and

if a fall

occurs,

this

may

be

associated

with

bleeding

on with

the

position

of the

bronchoscope

on

a pneumothonax.

Practical

considerations

in-dude

fluonoscopic

screening

for

a pneumothorax,

aspiration

of bleeding

with

wedging

of the

broncho-scope

in the

affected

segment,

avoidance

of airway

obstruction,

and

early

assisted

ventilation.

(5)

repro-ducible

in children.

In these

HLT

patients

it is both

a specific

and

sensitive

means

of diagnosing

acute

rejection

of the

lung.

Transbronchial

biopsy

may

prove

valuable

in the

diagnosis

of diffuse

lung

dis-ease

in children,

for

example,

nonbactenial

pneu-monias,

lymphomas,

and

leukemic

infiltrates.

It

may

also

be

useful

in

opportunistic

infection

in

immunocompnomised

patients.

Acknowledgments

We thank

Dr Malone

(Department

of Histopathology,

The

Hospitals

for Sick Children),

Dr C. Clelland,

and Dr

S. Stewart (Department of Histopathology, Papworth

Hospital)

for

reviewing

the

pathology

of the

biopsies.

Also we thank

Mr Ben

Milstein

for his editorial

advice.

REFERENCES

1. Hanson RR, Zavala DC, Rhodes ML, Keim LW, Smith JD. Transbronchial biopsy via flexible fibreoptic bronchoscope: results in 154 patients. Am Rev Respir Dis. 1976;114:67-72 2. Reitz BA, Wallwork J, Hunt SA, et al. Heart-lung

trans-plantation: successful therapy for patients with pulmonary vascular disease. N Engl J Med. 1982;306:557-564

3. Penketh A, Higenbottam TW, Wallwork J. Heart-lung transplantation for chronic lung disease. Br Med J.

1987;295:311-314

4. Scott J, Higenbottam T, Hutter J, et al. Heart-lung trans-plantation for cystic fibrosis. Lancet. 1988;2:192-194 5. Smyth RL, Higenbottam TW, Scott JP, et al. Early

experi-ence of heart-lung transplantation. Arch Dis Child.

1989;64:1225-1230

6. Vouhe PR, Le Bidois J, Carteville PH, et al. Heart and heart-lung transplantation in children. Eur J Cardiothorac Surg. In press

7. Higenbottam TW, Stewart 5, Penketh A, Wallwork J.

Transbronchial lung biopsy for the diagnosis of rejection in heart-lung transplant patients. Transplantation. 1988;46:532-539

8. Hutter JA, Stewart S, Higenbottam T, Scott JP, Wallwork

J. Histological changes in heart-lung transplant recipients

during rejection episodes at routine biopsy. J Heart

Trans-plant. 1988;7:440-444

9. Scott JP, Higenbottam TW, Hutter J, et al. The natural history of obliterative bronchiolitis. Transplant Proc.

1989;21:2592-2593

10. Burke CM, Theodore J, Baldwin JC, et al. Twenty-eight cases of human heart-lung transplantation. Lancet.

1986;1:517-519

11. Penketh ARL, Higenbottam TW, Hutter J, Coutts C, Stew-art S, Wallwork J. Clinical experience in the management ofpulmonary opportunistic infection and rejection in heart-lung transplant recipients. Thorax. 1988;43:762-769

12. Millett B, Higenbottam TW, Flower CDR, Stewart 5, Wall-work J. The radiographic appearances of infection and acute rejection of the lung following heart-lung transplantation.

Am Rev Respir Dis. 1989;140:62-67

13. Otulana BA, Higenbottam TW, Scott JP, Clelland C, Hutter

JA, Waliwork J. Pulmonary function monitoring allows

diagnosis of rejection in heart-lung transplant recipients.

Transplant Proc. 1989;21:2583-2584

14. Myers JD, Spencer HC, Watts JC, et al. Cytomegalovirus pneumonia after human marrow transplantation. Ann

In-tern Med. 1975;82:181-188

15. Fanta CH, Pennington JE. Fever and new lung infiltrates in the immunocompromised host. Clin Chest Med.

1981;2:19-39

16. Hutter JA, Scott JP, Wreghitt T, Higenbottam TW, Wall-work J. The importance of cytomegalovirus in heart-lung transplant recipients. Chest. 1989;95:627-629

17. Gilman MJ, Wang KP. Transbronchial lung biopsy in

sar-coidosis. Am Rev Respir Dis. 1980;122:721-724

18. Falkerson W. Current concepts: fibreoptic bronchoscopy. N

Engi J Med. 1984;311:511-515

19. Sherman JM. Rigid or flexible bronchoscopy in children.

Pediatr Pulmonol. 1987;3:141-142

20. Godfrey S, Springer C, Maayan C, Arital A, Vatashky E, Belin AD. Is there a place for rigid bronchoscopy in the management of paediatric lung disease? Pediatr PulmonoL

1987;3:179-184

21. Slater HM, Sheridan CA, Ferguson RH. Endotracheal tube sizes for infants and children. Anesthesiology 1955;16:950-952

22. Hutter JA, Despins P, Higenbottam TW, Stewart S, Wall-work J. Heart-lung transplantation: better use of resources. Am J Med. 1988;85:4-11

23. Ighoaka GUA, Higenbottam TW, Scott JP, Smyth RL, Wallwork J. The distribution oflung rejection and infection

in heart-lung transplantation. Am Rev Respir Dis.

1989;139:A242

ERRATUM

In

the

article

“Cosleeping

in

a Community

Sample

of

2- and

3-Year-Old

Children”

by Madansky

and

Edelbrock

(Pediatrics

1990;86:197-203),

Figures

1

(6)

1990;86;698

Pediatrics

Guy Fradet, Marc De Leval and John Wallwork

John P. Scott, Tim W. Higenbottam, Rosalind L. Smyth, Bruce Whitehead, Peter Helms,

Transbronchial Biopsies in Children After Heart-Lung Transplantation

Services

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1990;86;698

Pediatrics

Guy Fradet, Marc De Leval and John Wallwork

John P. Scott, Tim W. Higenbottam, Rosalind L. Smyth, Bruce Whitehead, Peter Helms,

Transbronchial Biopsies in Children After Heart-Lung Transplantation

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The online version of this article, along with updated information and services, is located on

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Figure

Fig 3.Forcedsurvivors,expiratoryvolumein1 second(FEy,)asrecipientpredictedofthesix“long-term”(>4months)1 1 yearsofageorolder,plottedagainsttime.

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