A o t a Path. Jap. 27(1):

59-

74, 1977

PULMONARY CHANGES IN CONGENITAL HEART DISEASE OF CHILDHOOD

- Histometrical and histological studies Hiroshi ITOH*,Kyoichi OOAWA**, Akira TORIYAMA**, Ken KIMURA**, Wong Ki CHEONO***, Hisashi &TO***

*

Department of Pdhdogy, **Department of Surgery, *** Department of Pedialrh, Kobe childra’8 Hoepital, Kobe (Received on May 11, 1976)

One hundred and tUty lungs from the cases below 15 years of age with various congenital heart diseases and 80 controls were used for histometrical and histological studies. Cases with congenital heart disease were divided into two groups of the increased and the decreased pulmonary blood flow. In the former group, the thickness of the pulmonary arterial media was the same a s that of controls in the neonatal period, and though the wall thickness gradually decreased in a pattern seen in controls, the thickness was constantly larger than that of controls. In some cases, the media increased gradually within 6 months after birth. Pneumonia and massive pulmonary hemorrhage were seen in a higher incidence in autopsy cases. Pneumonia in younger infants was histologically characteristic and possibly more correlated to their death. In the latter group, most of the cases were with the thinner medias of the pulmonary arteries. Massive pulmonary hemorrhage was not common in the latter group. ACTA PATH. JAP. 27: 59-74, 1977.

Zntroa’udirm

At the Kobe Children’s Hospital, about 60% of the patients with congenital heart disease die within 6 months of age (Table I ) . ~ Ones ~ having severe pulmonary hypertesnsion are especially miserable in their prognosis. It was said that the pulmonary hypertension is mostly derived from the increased resistance of the sqaller pulmonary arferies. Histopathologically, HEATH and EDWARDSclassified arterial changes in the pulmonary hypertension into 6 grades and applied them clinically.1~J7J~However, their classification cannot be accepted since they have treated the constricted or dilated states of the pulmonary arteries in the same category. Furthermore, their criterion is not suitable for infanta, since the pulmonary arteries will develop and the thickness of their wall will decrease with growth. HONDAet a1.m reported that physiological medial regression of the pulmonary arteries does not take place in younger patients with ventricular septa1 defect, and that the muscular coats retained or increased in thickness. They used the histometrical method devised by SUWAand cow0rkera.4~ This method was accepted to be excellent

t-,&I4 b b %.f B,AB %&A 3 P % Presented a t the 64th Annual Meeting of the Japanem Pathological Society (1976) 69

[email protected] 4,/ J 4 1

60

A& Path. Jap.

LUNG IN CONQENITU HEART DISaASE

for studying the exact change of arterial thickness.~J4 The histometrical results by SUWA’S method showed a correlation to the clinical features and prognosis of the patients. The purpose of this study was to show the correlation between pulmonary arterial changes and pulmonary pathological findings in congential heart disease, including the development of the pulmonary arteries.

One hundred and fifty lungs (102 autopaiea and 48 biopaiea) with congenital heart diseese (Table 1) and 80 control lunge without cardiic anomaliea below 16 yeam of age were studied histometrically and hiatologically corresponding to age. The specimens were fixed in loo/, formalin solution. The macrospecimens were embedded in paraffin. The histological sections about 5 microns thick were etained by Hematoxylin-Eoein, Eleetica-Van Gieson and Gram-etainings. The with partial modification. histometrical method was the =me aa that reported by FURUYAMA,~~ About 10 exact c m sections staiined by Elastica-Van Gieeon were photographed for histometry of the emall arteriea and arterioli by the standard magnification. The internal elmtic lamina was on the depicted photograph. traced for measuring the length (L),by attaching 8 thin cotton th& Table 1. 150 Caeee with Congenital Heart &we8

Biopsy Case8 Autopsy Caws below 8 over 8 below 8 over 8 months months months months -

~~

~~

~~

VSD (Ventricular Septa1 Defect) DORV (Double Outlet Right Ventricle) TGA (Transposition of Great Arteries) Truncus Arterioaus Fallot’e Tetralogy PDA (Patent Ductus Arterioeue) ECD (Endocardia1 Cushion Defect) Interruption of Aortic Arch TAPVR (Total Anomalous Pulmonary Venom Return) Single Atrium and or Single Ventricle TA (Tricuspid Atreaia) Aortic Stenoeia ASD (Atrial Septa1 Defect) Hypoplastic Left Heart Syndrome Othera Total

4

a

a 1 1 S

80

S S 4 S 1 1

4 6 6

1

36

5

u

S 1 S

s

9

a 1

19

15 11 10 10 S

1 1

1 1 1

a

S 77

4

4 ai 16 11 10 9

9 7 6 U

S

a a a

1

4

!&

150

The medial area between the internal and external elsetic laminae was cut from the photograph and calculated from its weight. The surfaca area of the media (8) waa acquired by comparing the weight with that of control photograph paper (lox 10 m m a ) . From the calculation of L and S. mathematically idealized radius (R)and medial thickneaa (D) of the pulmonary artery could be given a t the hypothetical condition of the uncontracted state with uniformly thick well over the whole circumference (Fig. 1). The medial thickneas (D) and radiue (R) showed a distinct linear regreaaion when they were plotted by a double logarythmic system. Thie meana that the relation D and R waa expressed by a general formula, Y=bX+A, in which X=log R, Y=log D, A=log a, a and b were constants. The regmaion coefficient b was given by (XI-%)(Y1-y)+(X,-t) (Y,-y) + + (X,-%) (Y,-y)/(X,-f)~+(X,-f)~+ +(X,-%)’. The R and D were expreaaed by D=aRb, which waa after Huxley’e formula indicating the allometric growth. As the regremion figurea were different in each individual case, the medial thickness of the pulmonary artery with the idealized radius of 100 micra was gauged after the calculation of two constants, and the regreesion figurea of the individual case of the same d i m were compared.

...

. .-

27(1): 1977

61

H. ITOH e l 4.

I I

I

I

I

1

I

-R-

The artery idealized mathematically to the uncontracted state with uniformly thick wall over the whole circumference JL’+pnf3-L D=

The traced arterial media stained by Elaatica-VanGieson staining 2nDR = S

L =271 (R-

I

+)

271

D = aRb

- s_.--. JGT4Z-L

R=-

Fig. 1. Principle of Histometrical Method (Suwa and Furuyama).

Results Histmnet+l

Stua’y

The regression line in 80 control cases is given in Fig. 2, in which the medial thickness

F Neonater

micra

w I

D~=100micra

Premature

I MAS

I

5,

I

I

I

I

I

I

1

I

62

Aeta Path. Jap.

LUNQ IN OONQENITAL HIEART DISEASE

Table 2. 150 Lungs with Cangenital Heart Diseasea Cam

-VSDKG742

Remarks

sex

F

1D

dead

0 . 0 5 4 6 ~ ~ . 14.0 ~~~

M M F

4D 4D 4D

dead dead dead

0. oa87R0.307 0. 0875R0'0M 0. 0888R0"08

S-179 KG768 5-82 5-162 5-287 S-20 5-280 538 5-206 5-18 5-109 S-118 5-170 KU-3383 s-42 KG784 75-247 74-330

F M F M M F F F F F M F F M

5D 11D 16D 16D 25D 1M 1M 2M 3M 3M 4M EM 9M 1OM 1Y 1Y7M 3M 4M

dead dead dead dead dead dead dead dead dead dead dead dead dead dead dead dead alive alive

fit 0. a750R0*036 51.8 it 0. 0S61R0*mJb 10.5 0. o ~ ~ o R ~.9.1 " ~ ~ fit fit 0. O ~ O I R O J ~14.9 ~ 8.9 fit 0. ooeaRO.* fit 0. 1787R0*R98 a5.7 8.7 fit 0. oiaiRo.aw 18.4 it 0. 07%R0'u6 0. !4055R0*761 38.4 0. 0587R0*Ma 18.S 12.4 #+ 0. olisRosu 0. O B ~ ~ R11.6 ~ . ~ ~ ~ 9.s it 0. 0588R0'786 14.1 tit 0.0896R~*~~ ~ 0. l%49R0'w7 1s.a .H 0. O ~ S S R ~ . " ~ 7.7 -I0.0089R~.'~~ 5.7 t~ 0. W1Ro*M6 1a.a

74-84 74-767 76-47 71-165 75-503 76-673 74-1014 73-521 74-559 74-1429 75-342 75-493 74-361 73-471 74-113 76455 76-225 74-1460 75-769 74-238 73-825 74462 -DORVKU-3394 5-220

M M F

alive alive alive alive alive alive alive alive alive alive alive alive alive alive alive alive alive alive alive alive alive alive

0. 18~'2Ro'903 28.8 0. o401R~'""~ 14.5

M

6M 5M 9M 1Y 1Y6M lYlOM 2Y 2Y 2Y7M 2Y9M 3Y1M 3Y5M 3Y6M 3Y7M 3Y8M 4Y2M 4Y3M 4Y4M 4Y4M 4Y6M BY 6YlOM

M M

1D 2D

dead dead

15.9 0. 1480R0*"3 0. ~ & ! d l R ~ *19.4 ~

tlt

-I-

it

tlt

KU-3260 5-87 5147 S-114 5-239

M

17D 17D 18D 47D 2M

dead dead dead dead dead

0. o a 7 i ~ O ~11.4 ~

Ht

it

0 . 0 8 6 5 R ~ - ~ l9.S 0. 070QR0'7" 12:5 O . l ~ o a R ~ *16.9 ~ 0.0441Ro~6'o 15.8

it

tlt

s-85

KG776 S-148

F M F M

F F F F F F F M

F M

F M

F M F M F F

M M F F

11.5 14.8 a7.4

tlt

ttt

fit

tlt

it it

fit

tlt

*

it fit

0.,09~4~0.~ ~ 10.8 0 . 1 ~ ~ 0 - 8 7 3 13.4 i0.0415R~*~~ 11.8 + 0.0207R~~~" 1o.a it 0. 050!4R0~008 11.8 -I-I0.0889R~.~~' 11.5 0. 0656R0*700 10.6 -I0 . 0 s 1 8 ~ ~ .14.9 ~~ 7.8 0. 0108R0*1m 0. 01S5R0'BB0 7.1 0. 0746R0*7m 13,s 0.0807R~-'~~10.1 0. 0S78R0"'6 11.6 0 . 0 1 8 a ~ ~ 8.0 ~ ~ ~ 0 . 0 ( @ 7 R ~ * ~5.6 ~~ 16.8 0. 0S75R0*3" 0 . 0 0 8 a R ~ ' ~ ~ 6.8 it 0. 0M8R0*3m a9.s 0. 074!2R0*898 9.5

+

0. 0a97R0"66

1o.a

-

tlt ttt it

Massive aspiration syndrome Subdural bleeding Messive eepiration syndrome

tlt it

tlt tlt

+ ttt

itt it iit

l&trisoniy

tlt fit it fit it fit

Pulmonary fibroeis

tlt

-

-

Cytomegalic viral pneumonitis

-

-

-

-

--

+ +

tlt

Cornelia de Lange syndrome

27(1): 1977

63

H. ITOH a t al.

Table 2. (continued) Case -DORV5-2

Course D=aRb(mm) D ~ = 1 0 0Pneu- Pulmonary micra monia hemorrhage

Sex

M F F M F M M M M

Remarke

it

2M 2M 3M 3M lYlM 3Y 3Y 3Y6M 5Y 2M 5M 3Y2M 3Y4M 4Y4M

dead dead dead dead dead dead dead dead dead alive alive alive alive alive

5-168 F 1D 1D s-80 M 5-273 M 17D 28D 5-132 M 1M KU-3070 M 1M KU-3185 F 2M S-188 F 2M KC-743 M S-255 M 2M 5-121 F 2M 3Y S-182 M 4Y S-197 M 5Y KC-817 M 74-1024 M lY6M 3Y 74-1449 M 4Y 73-846 M -Truncus arteriosIUS3D 5-270 M (type 2) 4D 5-262 (type 2) 7D KU-3339 (type 2) F 15D 5-167 (type 3) 1M S-10 (type 1) 2M 5-231 (type 2) 2M T-2 (type 3) 1Y KU-3445 (type 1) 7D T-3 M (type 4) F 5-119 1M

dead dead dead dead dead dead dead dead dead dead dead dead dead alive dive alive

11.8 o . 0 a 7 1 R ~ - ~ ~10.0 ~ 0. 0170R0-s93 6.0 0. 06S6R0.686 13. 1 0. 0737R0.731 13.6 0. 08&R0'766 i8.a 0. 0s59R0*4w 11.0 0. 0378R0.'" 9.7 0. O6%Ro'"' i4.a 0. 0869R~.~'~ 14.0 0 . 0 1 a s ~ ~ . ~8.8 ~~ 0. osaaRo*16s aa.1 0.0%fJ3R0.217 ia.3

dead

0. 0180R0*604

11.9

it

ttt

dead

0. 0%fJ8R0**m

11.4

it

itt

dead

0. 1080Ro.8"

14.7

St.

+

dead

0. O%SR0.676

9.1

itt

it

dead

0. 0447R0*6w

13.9

itt

it

dead

0. 0186R0*288

9.6

it

itt

18-trhmy

dead

0. 0219R0*374

9.3

it

itt

18-trhmy

dead

0. Oa86Ro*698

8.3

it

itt

sepsis

dead

0. O ~ W R ~ .7.9 ~ ~ ~it

itt

dead

0. Oa67Ro**

6.6

dead

0. OSBSR0'*"

7.9

S-94 5-257 S-59

S-150 5-268 S-259 KU-3115 KU-3460 75-800 74-950

74-1387 76-838 76-114

M F M M

F

0. 0539R0-488 0. 0176R0*328 0. 1s59R0.78' 0. 0MR0.370 0. 0369R0*421

11.1 8.3

aa.a

17.2 13.6 0 . 0 1 6 4 R ~ * ~ ~8.7 ~ 7.7 0. 0119R0*'88 10.1 0. 073SRo.8sg 0 . 0 1 6 6 R ~ ~ ~ 8.6 0. O067R0-063 4.9 0. M85R0'60' 11.6 0. 0666R0'"' 13.1 0. 0906R0.893 9.a 0. OUIRO.~~' 7.6

itt fit itt itt

-

it

+

it iit ftt

+ + it St it

+ +

ttt it itt it

4M

11.8 18.a

ttt

6.6

fff

itt

itt it

+ +t itt it it

+ +

it

Pulmonary fibrosis Sepsis

-

-TGA-

0. 043aR0-666 0. 0116R0*B05 0. Ola6R0*282 0. O32lR0'"'

D-trisomy

+ it + itt +

Cy c1opia

it itt itt

+ +

Pulmonary thrombosis

-

Low output syndrome

itt

-

-

Cornelia de Lange syndrome

Intre-cranial bleeding Pulmonary thrombosis

64

Aeta Path. Jap.

LUNG IN CONGENITAL EMART DISEASE

Table 2. (continued) Case

&ur8e ~ = a R b ( m m )D R = ~ W Pneu- Pulmonary micra monia hsmorrhage

Sex

-Fallot's tetralogyT-1 M 13D dead S-234 M 1M dead KC-083 F 1M dead KG744 F lYllM dead KU-3276 F 6Y dead M 16Y dead KU-2673 F 1Y3M alive 76-378 F 1Y4M alive 74-260 M 3Y6M alive 74-809 F 8Y alive 73-722 -PDAM 2D dead 5-169 F 4M dead 8-203 M 6M dead 5-101 F 6M dead 5-80 F 66D alive 72-836 F 74-674 2M alive F 74-1373 1Y alive F 70-169 1Y alive F 74-163 6Y alive

-ECD-

0.0546R0'7s' 0.ols4R~'~" 0.0166R~.~ o.oo69R0**OB 0.019aR0'66g

9.0 6.6 6.8 4.3 6.2

4.3 0. O S O ~ R ~ . " ~13.8 0. 0137R0*904 6.6 0 mRO.*6* 11.6 6.2 0. 0106R0'" O.O~~BRO.~~*

11.6 0.01&3R~-~'~ 8.a 1s. 1 0. iaS9Ro*O8' 8.9 0. OS69R0'6'8 0. 0787R0'"a 22.1 0. 0106R0**M 6.6 0. Oa7aRo.soB 13.4 0. O ~ E ~ R ~ -10.9 ~** 0. OIMRO-sOO 6.9

0. 0B47R0'0'0

F 5-198 1M alive 0. 0498R0"" 1o.a F 2M dead 0. oaMRo*5m S-228 8.0 M 8-186 2M dead o . o ~ ~ ~ J R ~ . ~ 11.1 F 8-271 2M dead 0.061oR~*~~' 8.6 F 8.7 5-261 6M dead 0. 01B6R0"6' F 7M dead 6. O196Ro'" 9.7 8-288 F 9M dead 0. KC-740 7.9 KU-3463 M 11M dead 0. 0114R0"a8 8.4 F 3Y6M dead o . o w a ~ ~ * 9.8 74-824 ~~~ -InterruptionKU-2841 F 3D dead 0.1468R0'"' 16.9 S-104 M 6D dead 0. O S ~ B R ~1a.i .~~ 5-286 M 7D alive 0 . 1 3 0 8 R ~ ~ ~17.4 ~~ ~~~ 5-277 M 18D dead 0 . 0 a 4 a ~ ~ . 10.9 5-166 M 1M dead 0.0664R~"~ 19.3 5-81 M 3M dead 0. 0M7R0'w6 i6.a 76-427 M 18D dead 0. 0634R0*6ss 16.3 -TAPVRM 1M dead 0.060SRo*680 1a.s S-16 F 2M dead o . o a a ~ R ~ *11.3 KG773 ~ F 3M dead 0 . 0 8 ~ 7 R ~ * ~11.1 ~' 532 F 3M alive O.O~M)R~*"* 9.2 74-7 1 M 4Y alive 0.0878R0.81s 13.6 74-879 -Single at1'ium and or single ventricleS-129 M 30D dead 0. OMBR0.720 10.4 M 3M dead o.W6Ro"" 5-176 14.9 M 3M alive 0.06MRo'"* 76-147 13.9 F 3M alive O.O1oCRo*'s* 7.7 76-689 75-744 M -Tricuspid atresiaS-131 M 5-47 M S-96

F

3M

alive

o.O1a7Ro'"'

1M 1M

dead dead dead

O . O ~ ~ R ~ * *9.6 *~ 6. 0.061SRo*m -.A0.0484R~'~" 11.3

1Y

7.6

it

+

it it

-

+ -

it

18-trieomy

tit ttt

21-trieomy

+ it

it

-

it f

it

ttt ttt ttt ttt ttt

ttt

-

+-

iii it

-

-

ttt

-

ttt

tt

+

-

ttt

+ +-

ttt

it

st ~ ~ ttt ttt

it

-

-

ttt

+it

ttt

-

+ it +

rn

m ttt it

+

+ + it + +

ttt

ttt -I-

ttt ttt

it

-

+

-

ttt

it

+

rn

m

+-

it

+

18-trhmy 21-trisomy

+

it it

rn

Sepsis

ttt

+

it

Remarks

ttt

Pulmonary abscess Cytomegalic viral pneumonitis

Subdural bleeding Pulmonary abs&

27(1): 1977

H. ITOH

61

65

rl.

Table 2. (continued) Sex

Remarka

-Aortic stenoeis5-183 M 29D dead 0.0443R0.4S0 16.1 5-238 M 1Y dead 0. 0696R0*770 8.9 -Atrial septa1 defect5-62 F 4M dead 0.0S76R0.660 10.3 76-421 M 3Y3M alive 0.01S9R0.s6 6.4 -Hypoplastic left heart syndrome5-233 F 1M dead o.18t)9Ro.000 33.7 5-200 M 1M dead 0 . 1 ~ ~ 1 9 8 R ~ 31.0 *~~ -Others5-142 M ID dead 0.09S8R0.807 11.9

ttt

ttt

it

st.

+

ttt

-

-

ttt ttt

-k

-

+I-

st.

5-214

M

4M

dead

0.0S9SR0.074

8.3

+

5-182

M

4M

dead

0 . 0 3 7 8 R ~ - ~ ~9.7 ~

+

ttt

5-5 1

F

2Y1M

dead

0 . o S 7 7 R ~ ~ ~9.7 ~~

-

-

Complicated double heart Double outlet left ventricle TGA, TAPVR. VSD. PDA, PS DORV, ECD,PA, CA, AV-block

of the pulmonary artery with the idealzied radius of 100 microns exhibited 14.6 microns in prematures, 11.3 in infants below 3 months of age, 10.0 below 6 months, 9.2 below 1 year, 8.7 below 3 years, 8.0 below 6 years and 7.6 below 15 years. The regression curve plotted against ages showed the abrupt fall within 6 months after birth and decreased gradually after 1 year of age. The relation between R and D in cases with various congential cardiac anomalies is shown in Table 2. In this study, cases were divided into two groups; the increased and the decreased pulmonary blood flow. The classification described above was based on cardiac angiography and/or catheterization and, in early death cases, the difference of the pulmonary and aortic diameters or sizes of VSD (larger than 1 cm in diameter) at autopsy, and the presence or absence of pulmonary stenosis. The group of increased pulmonary blood flow included ventricular septal defect (VSD), double outlet right ventricle (DORV), transpositions of great arteries (TGA), patent ductus arteriosus (PDA), endocardia1cushion defect (ECD), total anomalous pulmonary venous return (TAPVR), atrial septal defect (ASD) and so forth. Thrity-two neonates were in this group, in which the pulmonary medial thickness was 13.1 microns in average which is the same as that of control neonates, whereas it became thicker 15.2 microns in idiopathic respiratory distress syndrome (IRDS) and 16.1 in massive aspiration syndrome (MAS), as shown in Fig. 2. In the VSD, the regression line showed slight fall within 6 months after birth, which was constantly higher than that of controls. There was no distinct difference of the medial thickness between autopsies and biopsies. The media was thinner in DORV than in VSD, but thicker than in controls. The regression line in TGA did not fall in the neonatal period and kept rising thereafter (Fig. 3). The group with decreased pulmonary blood flow included Fallot's tetralogy and tricuspid atresia with pulmonary atresia or stenosis and the 4th type of truncus arteriosus. The other types of truncus

68

micra

1

Interruption of Aortic Arck

1 k

ARiw

Fig. 6. The r e p d o n 1 hin PDA, ECD, interruption of aortia erch, TAPVR.

art.%riosua showed thicker media. The media wm fhinner in Fallot’s in neonatal period which state lasted themafter (Fig. 4). The regression line in interruption of 40 arch exhibited highar rising after birth, One in PDA showed p a d e l or alight

27(1): 1977

H. ITOH r l a l .

67

elevation. TAPVR and ECD showed also slightly elevated lines (Fig. 5).

Histolog&cal Study Histological features revealed often pneumonia and hemorrhage in autopsied cases with increased pulmonary blood flow. Pneumonia in younger infants was characterized with lymphocytic infiltration in the alveolar septum. Bacterial organisms were not always demonstrated by Gram-staining. Cytomegalic inclusion bodies could be recognized in only two cases. With the advance of age, alveolar inflammation or bronchopneumonia increased in incidence, in which histologically leucocytic infiltration was remarkable. Pneumonia in younger infants was subdivided into three categories; mild, moderate and severe types. The mild type showed lymphocytic infiltration in addition to a few polymorphonuclear leucocytes in the slightly enlarged-septa, where capillary exposure into the alveolar space was normally preserved. The alveolar space was normal (Fig. 6). The moderate type exhibited widened septa with edema and fibrin deposits, where lymphocytes and polymorphonuclear leucocytes were distributed. The capillary exposure was rarely disturbed by pneumonitis, whereas the 2nd type alveolar pneumocytes were not proliferated (Fig. 7). The severe type showed a smaller alveolar space with thicker media, where severe infiltration of polymorphonuclear leucocytes and lymphocytes was observed. The 2nd type alveolar pneumocytes were proliferated adhering to the septa1 wall. There were furthermore disturbed capillary exposure and partial fibrosis in the septum (Fig. 8). In the severe

Fig. 6. Mild pneumonia in younger infant (75-247, female, 3 months, VSD). Alveolar septa are slightly widened by lymphocytic infiltration. Alveolar structures are almost preserved in general. HE-staining, x 148.

LUNG IN WNOENmAL HEABT DISEASE

Acta Path. Jap.

Fig. 7. Moderate pneumonia in younger infant (538, female, 2 months, VSD). Alveolar septa are widened by edema and intlemmstory cell infiltration. Proliferation of 2nd type pneumocytes is not men. HE-staining, x 148.

Fig. 8. Severe pneumonia in younger infant (5-203, female, 4 months, PDA). Predominant infiltration of leumcytea and lymphocytea can be men in widened septa. Capillary exposures into air spaces are disturbed. HE-staining, x 148.

27(1): 1977

H. ITOH r l al.

69

Fig. 9. Pulmonary fibrosis (5-268, male, 3 yrs. DORV). Diffuse fibrosis can be recognized in the enlarged septa. Adenomatoid changes of proliferated 2nd type pneumocytee are seen along the alveolar wall. This patient received longterm oxygen therapy for 3 years. HE-staining, x 296.

Fig. 10. Massive pulmonary hemorrhage (S-234, male, Imon. Fallot’s Tetralogy). Air spaces are diffusely filled with red blood cells and their debris, in addition to a few leucorytes and lymphocytes. HE-staining, x 296.

70

LUNG IN QONGIPNITAL HEART DISNASE

A& Path. Jap.

type, many alveolar macrophages were seen in the alveolar space, phagocytizing red blood cells and their debris or mme other amorphous materials in their larger cytaplasms. Severe pneumonia was frequently seen in severe pulmonary hypertensive cases. A few cases with pulmonary fibrosis could be recognzied in severe pneumonia. In those, the thicknened septa were fibrosed with inflammatory cell infiltration. The 2nd type alveolar pneumocytes exhibited active proliferation and adenomatoid change with cuboidal cytoplasms. Capillary exposure was completely blocked with the embedded capillaries in the fibrosed septa (Fig. 9). Pneumonia was far advanced and severe in autopsy cases than biopsy. Severe pneumonia was frequently accompanied with massive pulmonary hemorrhage. On the other hand, the lungs with decreased pulmonary blood flow showed mild pneumonia, but massive hemorrhage was seen in autopsy cases (Fig. 10). Venous capillary dilatation was another characteristic in this p u p .

Discus& The pulmonary arteries are classified as elastic, muscular, arteriolar and capillaries; with diameters larger than 1O00, lo00 to 100, 100 to 10 and smaller than 10 microns respectively.14 Pulmonary blood flow is principally thought to be regulated by the smaller muscular arteries and arterioli.44 HEATHand others suggested that the relative thickness of the pulmonary arterial media is closely related with clinical and physiological features. HEATHand EDWARDS~WJ~ classified pulmonary hypertension into 6 criteria by histological findings of the pulmonary arteries. In their criteria, the 1st to 3rd grades corresponded to the high resistance/high reserve condition, and the 4th to 6th grades to the high resistance/low reserve category. The 1st grade showed the stage of foetal type arteries, whereas the pulmonary arteries occasionally exhibited the 2nd or 3rd grade in premature babies with IRDS or MAS. The pulmonary arteries in increased pulmonary blood flow belonged to the 1st to 3rd grades in our cases. None of our cases were in the 4th to 6th grades, showing plexiform lesions or dilatations or hemosiderosis or angitis. The ones with decreased blood flow were apparently thin with the arterial wall. HEATHand EDWARDS’ criterion was impossible to cover the the findings in our study and complete exmaination, since they did not care about the stage of arterial constriction. In their method, the relative thickness of the arterial media was measured by the substraction of the shortest diameter in the internal lamina from the one of the external at same cross section. However, the structure of the arterial wall in autopsies and biopsies did not always represent the living state. Most of the fixed autopsy materials expressed frequently the prominent contraction of the vessel walls possibly by agonal and postmortem changes. According to Vm CITTERS,~~ the arterial medias dilate easily by influence of perfusion of acetyl choline, and constrict by epinephrine. S U W Aand ~ ~FURUYAMA~~ circumvented a new method to evaluate the effect of arterial constriction by measuring the length of the internal elastic lamina and the area of the media. Mathematically idealized radius (R) and medial thickness (D) could be calculated from them in perfectly stretched internal elastic lamina. The

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relation between the vascular pressure (P) and the tension of the wall (T) is expressed as T=PR and D=KT, in which K is constant. As the medial area (S) was shown by 2nRD=2nKPR2, in which the size of the radius was more important than P. The formula D=aRb was known as Huxley's allomtric growth, showing the most familiar biological function. The smaller the pulmonary arteries are, the more resistant, since D/R is the morphological property of the vascular wall to pressure, and is given by aRb-l=a/R1-b. This excellent method is practically used at present, and actually coincides with the clinical f e a t ~ r e s . ~ ~ ~ ~ ~ J 0 ~ ~ ~ . J ' . " ' Both pulmonary and systemic blood pressure are the same at birth, but the pulmonary arterial pressure decreases and the systemic increases thereafter. The decrease of postnatal pulmonary arterial resistance results from the rapid growth of the pulmonary vascular beds and the smooth muscle content of the small pulmonary artery decreases. So the symptom of pulmonary hypertension is usually not prominent within 1 month after birth. The reason may be documented by the fact that the pulmonary arterial media declines in increased pulmonary blood flow cases, as shown in Figs. 3 and 5. As there are generally no distinct differences in thickness of the pulmonary arterial media between survival and autopsied cases, it is estimated that the arterial change is not related with the direct cause of death. Though it is clinically known that death due to Fallot's diesease is not so frequent in early life, the autopsy cases revealed the thin media of the pulmonary artery and occasionally massive pulmonary hemorrhage. The 4th type of truncus arteriosus also showed the thinner media. COLLET and EDWARDShad classified truncus arteriosus into four types.m. Some authors considered the 4th type to be of the same category as that of Fallot with main pulmonary arterial atresia (pseudo-truncus), though these two anomalies were different embryologically and anatomically. Histologically, the most characteristic features in the autopsy lungs were pneumonia and hemorrhage, which were rarely predominant in biopsies. Lobar emphysema was not recognzied in our cases are reported by JONES et d.24

The pneumonia in younger infants affects chiefly the alveolar septa, which is histologically similar to bronchiolitis or oxygen pneumonitis. Although staphylococcal p n e u r n ~ n i is a ~often ~ ~ ~encountered ~~ in younger infants, certain noxious organisms could not always be proved in many of our cases. It was thought that the mild pneumonia could reversibly transform into the moderate or severe ones corresponding to the pat.ient's condition. On the other hand, it was possible that our three categories of pneumonia in younger infants are essentially different in origin or course. Therefore, its pathogenesis should be studied widely from the oxygen effects and arteriolar constriction, not only from immunologic aspects or hepatic function, but also from infectious agents.1.4.6,8,9,27.3s.36,46 Bronchiolitis was reproted to cause acute respiratory failure and its mortality is about 5% of hosptialzied c h i l d r e n . ~ 0 1 ~ ~ ~ ~ 0 1Surveys 2 ~ ~ 2 e ~ 4of0 1winter 4~ and spring epidemics of the disease demonstrated a signfiicantly large number of cases to be associated with respiratory viral infection, most commonly by respiratory syncytial

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virus but in a small number of cases by intIuenza B or para-influenza virus. As bronchiolar spaces are narrow and equipped with a thin wall, where they are lined by poorly ciliated epithelium with few secretory glands, the infectious process disperses easily to the diffise septa with edema and fibrin deposits, subsequently causes bronchiolar stenosis or obstruction. The disease is spread once infected, because younger infants have small number of bronchioli, alveoli and more resistant vascular beds in the lungs. Pulmonary oxygen toxicity is also known to produce various stages of pneumonitis. KAPANCI and G o u L D concluded ~ ~ ~ ~ ~ that the diffision capacity of the air blood barrier is k h l y reduced in patients treated with 100% oxygen for a period longer than 3 days. During 14 hours to 3 days with oxygen exposure, histologically, swelling of the membranous pneumocytes and polypous protruding of the granular pneumocytes could be seen with the cytoplasmic blebs of the endothelial cells in the edematous alveolar septa. In 3 to 6 days, the alveolar septa were more enlarged by diffise edema and interstitial cell infiltration. The basal membranes were frequently denuded and covered by hyaline membrane. Endothelial injury was more prominent with intracapillary fibrin thrombi. After 6 to 10 days oxygen inhalation, septa1 fibrosis and increase of elastic fibers were found associated with marked proliferation of the 2nd type pneumocytes with scanty lamellated inclusions, which seemed as irreversible changes. This pathologic process was also observed in several non-human primates.a O G A W A ~ ~ emphasized that post-operative inveterate pneumonia was closely related to long-term respiratory care. On the other hand, atelectasis or bronchopulmonary dysplasia'l has to be differentiated from pneumonia. In order to clarify this relationship, the study should be performed after the lung specimen was reexpanded by blowing air or iixingsolution to produce premortem status and to rule out postmortem changes. Massive pulmonary hemorrhage was seen in accordance with severe pneumonitis in the increased pulmonary blood flow group, but without pneumonitis in the decreased group. WILSON et d . 4 6 described that the precapillary constriction occurs early in shock followed by stasis and often reverse blood flow, observed by pulmonary microcirculation in cats during hemorrhagic shock. The capillaries and venules closed and remained empty during the shock period. At the recovery of shock, reestablishment of normal blood flow in the ischemic alveolar walls invited hemorrhage in the lung. The oxygen toxicity gave rise to endothelial damages and pulmonary hemorrhages in the newborn.' REEVESet d.87 reported that the chronic hypoxia probably sustains the retarded growth of pulmonary arteries and the increased circulation of bronchial arteries. Though the pulmobronchial arteries are specifically seen in the late foetal and neonatal lungs, some reported that the pulmobronchial arteries persist over the age of 2 months. However, the correlation between pulmobronchial arteries and hemorrhage in the lung is not yet certain a t [email protected] Acknowledgement: The authore w k h a to expreee their grateful thanks to Dr. M. FUEUYAMA, Prof. M. KYWKU and Prof. T. SUGIYABU for their kind advicea, and Mr. M. T s n z w ~and Mre. 5. BIROHfor their excellent technioal aeebtgncss in thk study.

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R t ? j ~ ~ 1. ADAMS,F.H.: Functional development of the fetal lung. J. Pediatrics 68: 7-01, 1988. , SIAMMONA, S., LINDSKOG, G.E., COOKE,R.E.: Staphylococcal pneumonia 2. B L O O ~ RW.E., and empyema in infancy. J. Thorn. Surg. 30: 265-274, 1955. 3. BOOTHBY, C.B.. DESA, D.J.: Massive pulmonary hemorrhage in the newborn, a changing pattern. Archives Die. Childhood 48: 2130, 1973. 4. BOYDEN, E.A.: Notea on the development of the lung in infancy and early childhood. Am. J. h a t . 121: 749-762, 1970. 5. COOK, T.A., YATES,P.O.: A critical survey of techniques for arterial mensuration. J. Pathol. 108: 119-127, 1972. 6. DAVIDSON, F.F., GLAZIER, J.B., MURRAY, J.F.: The components of the alVeol8C-8rteri8l

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oxygen tension difference in normal subjects and in patients with pneumonia and obstructive lung diseaee. Am. J. Med. 52: 754-762, 1972. DAVIES,P.A., AHERNE, W.: Congenital pneumonia. Arch. Dis. Child. 37: 598802, 1962. DEEU~~ER, G.B.: T h e fixation of pulmonary surfactant for electron microscopy. 2. Transport of surfactant through the air-blood barrier. J. U h s t . %a. 31: 229-246, 1970. DEIWER,G.B.: The pulmonary surfactant content of the inclusion bodies found within tspe 2 S~VeO18rcells. J. uhral8t. h. 33: 306317, 1970. C.: Acute respiratory failure in D o m a , J. J., WOOD,D.W., STRIKER,T.W., HADDED, infants with bronchiolitis. Anesthesiology 29: 426434, 1988. ~ U Y A M A M.: , Histometrical investigations of arteries in reference to arterial hypertension. Tohoku J. Exp. Med. 76: 388414, 1962. G o a ~ ,V.E., Tosoo, R., WHEELIS, R., KAPANCI,Y.: Oxygen pneumonitis in man, uhastructural observations on the development of alveolar lesions. Lab. Invest. 26: 499608,

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Histometrische Befunde nach Diffusions- und nach Perfusions-fixierung von Aorta und Organarterien bei Keninchen. Exp. Path. 5: 154-162, 1971. HARAZAWA, M. : Pulmonary circulation, fundamental and clinical wpects. Tokyo, KinbaraShuppan, pp 1 3 , 1988 (in Jupaneee). HARAZAWA, M.: Concerning to infectious bronchitis, acute bronchiolitis in infants and patients with chronic respiratory d i m . Reap. Circul. 22: 44, 1974 (in J u p w e ) . HEATH,D., EDWARDS, J.E.: The pathology of hypertensive pulmonary VeSCUl8r diseaae. A description of six grades of structural changes in the pulmonary arteries with special reference to congenital cardiac septal defects. Circulation 18: 533-547, 1958. HEATH,D., HE-OLZ, H.F., JR.,BURCEELL, H.B., Du SHANE,J.W., EDWARDS, J.E.: Graded pulmonary vascular changes and hemodynamic findings in cases of atrial and ventricular septal defect and patent ductus mrteriosus. Circulation 18: 1155-1186, 1958. HEATH,D., HELMEOLZ, H.F. JR., BURCHELL, H.B., DUSEANE, J.W., KIRRKLRY, J.W., EDWARDS, J.E.: Relation between structural changes in the small pulmonary arteries and the hmediate reversibility of puhonary hypertension following closure of ventricular and atrial septal defects. Ciculation 18: 1167-1174, 1958. HEYCOCK, J.B., NOBLE,T.C.: 1230 cases of acute bronchiolitis in infancy. Brit. Med. J. 3:

879881, 1962. 20. HONDA, T., HOIUUCEI,T., ABE, T., KOYAMADA, K., ISJXITOYA. T.,ISHI~AWA, E.: Histo-

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Pulmonary changes in congenital heart disease of childhood: histometrical and histological studies.

A o t a Path. Jap. 27(1): 59- 74, 1977 PULMONARY CHANGES IN CONGENITAL HEART DISEASE OF CHILDHOOD - Histometrical and histological studies Hiroshi...
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