Japanese

Joumalof

Tropical Medicinc

and Hygiene

第5巻第3，4号

昭和52年12月15日

内
原

容

著
某社来訪外国人の罹病に関する研究（英文）奥村 悦之，中井 益代，三好
マラリアのプリマキン療法・・…・一

博文，吉田

康久，豊田

一…海老沢

功，武藤

秀三17i−181

達吉183−189

コレラ初期変化の病理学的研究

一21剖検例をもとに一（英文）……一

会

・・関根

一郎191−246

報

幹事選挙経過と結果………

247−248

昭和52年度第2回幹事会記録一・……一・

248−249

昭和52年度評議員会記録・・……………・……：

249−250

第19回会務総会記録…・…一…・・…………

250

投稿規定

日熱医会誌
Japan．」．T．M．H．

日

本熱帯医学会Japan. J. Trop. Med. Hyg.. Vol. 5, No. 3, 4, 1977, pp. 171‑181

171

STUDIES ON THE MORBIDITY OF FOREIGN VISITORSTO A CERTAlN COMPANY IN JAPANETSUSHI OKUMURA1, MASUYO NAKA12, HIROFUMI MlYOSH12YASUHISA YOSHIDA3 AND SHUZO TOYOTA3
Received for publication I I October 1977

Abstract: Recent papers suggested that as the result of the increase of Japanese
travellers abroad, number of patients affected with imported tropical disease increased
every year. This fact also implies that foreign visitors are bringing tropical disease into
Japan. Therefore, we have conducted a survey of foreign visitors who visited Matsushita
Electric Co. Ltd. for the purpose oftechnical training for short periods from 1972 to 1976,
studying the p0 sibility ofinvasion of tropical diseases by interview and on medical records.

The results obtained were as follows :1 . Of total 532 visitors, 485 were from tropical regions and 47 from other countries,
and the morbidity rates indicated 20.2 per cent and 29.8 per cent respectively in the obser‑

vation period of one month following their arrival.

2. Fortunately no tropical diseases such as malaria, filariasis, dengue fever andcholera were found so far.

3. Two cases, a Malaysian with Tenia saginata and an lranian with orchitis following
mumps which had affected him for some time before their arrival, were cured.

4. Many visitors from tropical regions were easily affected with common cold withina few days after their arrival, especially in the fall and winter season, as compared withthose from Europe and North America.
5. A thorough check‑up routine of the Japanese returnees and foreign visitors toJapan and general practitioners' good understanding of the imported tropical diseases aremandatory for the prevention of tropical diseases in the future.

INTRODUCTION
As the number of Japanese travellers abroad increased recently, patients ofimported tropical diseases also increased in number year after year. These imported
tropical diseases are found among travellers who were affected with the native dis‑eases and felt sick after their return home. Besides the increase ofJapanese travellers
abroad, gradual increase of foreign visitors to Japan is also found as a new tendency,
as cultural exchange with foreign countries are being encouraged. What has to betaken into consideration with this tendency is that there is a big possibility for people
from tropical areas of bringing in some tropical diseases.

Actually, according to the questionaire survey of imported malaria by
Nakabayashi et al. ( 1 975), 14 out of 1 55 visitors from abroad were reported as affectedl Department of the Second Internal Medicine, 2 Department of Microbiology, 3 Departmentof Hygiene and Public Health. Osaka Medical College, Osaka 569, Japan.

172

patients. This fact should imply a number of problems of counterplan against
imported tropical diseases. The following is a report of our study on foreign visitors
in Japan, for the purpose of studying morbidity of imported tropical diseases among
alien people.

SUBJECTS AND METHODS
The subjects of the study were 532 foreign employees of overseas branch offices,
factories and sales offices of Matsushita Electric Co. Ltd., who visited Japan from
April 1972 to March 1976 from 33 different countries. The classification of regions
follows that of the report by Sassa et al. (1976) as shown in Figure I . They arebased on the imported tropical disease distribution chart, A ; Africa, B ; Asia,

C; Pacific Islands, D; Middle and South America and E; Caribbean Islands.
In addition, Africa is divided into subareas such as A1; Middle Western district,
A2 ; Middle East and neighbouring islands district, A3 ; North and Pacific Islands
district, A4; North Eastern district and A5; Southern district. Asia is also divided

mto Bl' Eastern Mediteranean Sea and Middle East Asia district, B2; India andPakistan district and B3 ; South East Asian district.

' ) '> )*

lr

o

lb

lp

s
s .

e'

a
'e

,s

B2

,

Bl

c
.

A:

f'",

Aa

>E
a

O
B,

Al
A2

D
As

¥¥ .:< ;..:v

r7

Figure 1

Classification of tropical regions.

The methods of the study were as follows ; Examined were people who came fora check‑up to the company clinic attached to Matsushita Overseas Training Center,complaining some disorder with in a month after their arrival from the above‑men‑tioned region during the above‑mentioned period. A11 1 12 patients were given as
much examination as the clinic could offer for the detection of imported tropical173

diseases. All I 1 2 patients were examined on their urine. People complaining highfever were given Giemsa staining test of their smear sampling of blood. People com‑plaining diarrhoea were offered microscopic examination for parasites and protozoa
and also offered cultural examination for pathogenous microorganisms. Matsushita
Overseas Training Center is located in Hirakata City, providing training and housing
to foreign trainees in Japan.

RESULTSl . Regions and countries of foreign visitors and their morbidity rate

All 1 9 visitors out of A region were from the United Republic of Tanzania from1972 to 1976. Six patients were found among them and the morbidity rate was
3 1 .6 per cent. Six visitors from C region were all Australians and none was foundsick. Of 53 visitors from D region, nine patients were sick and the rate was
1 7 per cent. The breakdown of D region is as follows ; one out of nine visitors from
Mexico was sick ( I I . I o/o)' none of two visitors from El Salvador was sick, two of I O

visitors from Costa Rica were sick (200/0)' one of two visitors from Panama was sick
(500/0)' one of four visitors from Venezuela was sick (250/0)' two of 16 visitors from
Peru were sick (12.50/0)' two of 10 visitors from Brazil were sick (200/0)' Nineteen
visitors from E region were only from Puerto Rico and three were found sick (15.80/0)(Table 1).
Table I Incidence rate in A. C, D and E regions

Group

Country

Yea r1972 1973 1974 1975 1976

Total

o/o

Group‑total

6/ 1 93 1 .60/0

6/19 (31.6"/*)

UnitedA2

Republic of

TanzaniaCDE

1/3 l/3 1/4 3/8 0/lAustralia

oio oi2 0/2 0/2 o/O 0/6 1 orr r o /.)Mexicoll3

El Salvador
Costa Rica

0/0
013
0/0

Oj3
0/0
2/6

0/2
0/0

0/0

Ojl

l 19

O/ l

O/ 1

0/2

Oo/o

O/ 1

2/10

1/1

O/ l

O f 1

l f 2

013
0/2

0/3
O!2

217

Brazil

l !5

ljl

0/0
0/0
0/0
0/0
OjO

20.00/0

O/ l

0/0
0/0
0/0
0/3

Puerto Rico

3/12 0/6 0/0 0/1 0/0

PanamaVenezuela
Peru

11.lo/ol 12

50.00/0l 1425.00/0

2116
2/10
3119

20.00/0

9/53 (17.0'/･)

12.50/015.80/03119 (15.80/0)

Following are the breakdown of B region. In Bl district, one of four visitorsfrom lran (250/0) and one visitor from the United Arab Emirates (1000/0) were
found sick. In total, two of five were sick (400/0)' In B2 district, three out of nine
visitors from India were sick (33.30/0)' In B3 district, found sick were nine out of

24 vistiors from the Republic of Korea (37.50/0)' 15 out of 100 from the Republicof China (150/0)' six out of 35 from the Philippines (17.10/0)' five out of 37 fromIndonesia (13.50/0)' two from Hong Kong (lOOo/o)' one out of nine from Vietnam(11.1010)' 13 out of 26 from Thailand (500/0)' 21 out of 104 from Malaysia (20.20/0)

174

Table 2Group

CountryBl

United Arab

B2

Emirates
India
Republic of

Incidence rate in B region
Ye ar1972 1973

lran

1974 1975 1976 Total "/*Group‑total

0/0 0/20/0 0/0

0/0 1 12 OjO
0/0 0/0 1 / 1

1/1 1000/

2/5 (40.0"/o)

0/0 1 / 1

2/6 0/2 OjO

3/9 33.30/

3/9 (33.30/.)

1/4 25.00/0

OjO 4/12 l/1 4jll

0/0

9/24

37.50/0

2/11 4/23 3/25 2/21

4/20

l 5/ I OO

15.00/0

Korea
Republic of

China
Indonesia

6135 1 7. I o/olj6 2/lO 1/7 2/10 0/2
13.50/075j (20 l"A)0/0
l/3 2jl9 l/13 l/3 0/0 51375137
135"A
75j374

Hong Kong

0/0 0/0 1 / I I / 1

lOO"/‑

0/0 Oj3 0/5 1 / 1

l 19

ll.10/0

Thailand
Malaysia

0/0
o/o
0/2

2/2

Vietnam

13/26

50.00/0

5/22 7/32 6j33 2/12

l/5

2 1 j 10420.20/0

Singa pore

2/30 0/2 1/4 OjO

Oj l

3137

8. I o/oPhilippines

B3

3/5 0/2 3/6 7111

and three out of 37 from Singapore (8.1 o/o)' Seventy‑five of all 374 visitors from
B3 district were found sick and its incidence rate was 20. I per cent (Table 2).
Forty‑seven forigners who came from other regions showed following results.
In Europe, one out of three visitors from Spain (33.30/0)' five out of 12 from West
Germany (41.7010)' one out of four from Netherland (250/0) and one out of three
from Denmark (33.30/0) were found sick. Three Belgian and three British were
healthy in the observation period. Each one who came from Sweden, Switzerland
In North America, two out of five visitors from the UnitedStates ofAmerica and one out of I l from Canada were found sick. Fourteen patientswere found out of 47 visitors from other regions (29.8 ,/o) (Table 3).
Summerizing the above results, the number of patients out of 485 visitors from22 countries in the tropical regions of A, B. C, D and E was 98, and its incidence
rate was 20.2 per cent, while that of 47 visitors from I I countries in other region wasand Poland were sick.

Table 3 Incidence rate in other region

CountryYear1972 1973

1974

1975 1976

0/0
2/3
0/0

0/0

O/ 1

l 12

l/5

1/2

l/2

0/0

O!O

Ol 1

O/ 1

O/ l

O/ 1

l/1

United Kingdom

0/0

Denmark
Sweden

0/0
0/0
0/0

0/l

1 12

Spain

West Germany
Belgium
Netherland

Switzerland

0/0
0/0

Polandl/1

United States

0/0

0/0
0/0
0/0
0/0
0/0
013

O/ l

Oj2

O/ 1

010
0/0
0/2
0/0
012
0/0

Total

o/o

ll3

33.3010

5/ 1 241.70/0

013

Oolo

l 14

25.00/0

013

Oolo

ll3

33.3010l/l

l/l

1000/0

0/0
0/0
0/2

l/l

l OOo/o

0/0
OjO

0/0
0/0
0/0
213

1/l

lOOo/o2/5

40.00/0

l/4 ̲

Oj2

0/2

l/11

9. I ololjl

of America

CanadaGroup‑total

l 4/47(29.80/0)175

14 and its incidence rate was 29.8 per cent. The total number of patients out of
all 532 visitors from 33 countries was I 12 and its incidence rate was 21.1 per cent.

As seen above, no paticular region, district or country showed specific charac‑
teristics in its incidence rate (Table 4) .
Table 4 Incidence rate in all regions

A‑groupl country
6!19 (31.6"/o)Tropical area
22 countries
981485 (20.20/0)

B‑group
12 countries
80!388 (20.60/0)

A2‑group
1 country
6j9 (31.60/0)

B1 group
2 countries
2/5 (40.00/0)

B2‑group
l country
3/9 (33.30/0)

Total

B8‑grou p

33 countries
532 persons

9 countries
751374 (20.lo/o)l 12 patientsl 121532 (21. 10/0)

C‑groupl country
0/6 ( Oo/o)D‑group
7 countries
9/53 (17.00/0)

E‑group
1 country
3/19 (15.80/0)

Other areal I countries
14j47 (29.8*/*)Other country‑groupl I countries
14/47 (29.80/0)

2. Classification of diseases

Out of six patients from Tanzania in A2 district, A region, five were with common

cold and one with colitis. In D region, one Mexican was with gastritis, one Costa
Rican was with common cold and the other with atopic dermatitis of arms and legs,

one Brazilian, one Panaman, one Venezuelan and two Peruvian were with common
cold, and one Brazilian with colitis. All three Puerto Rican patients were with
common cold (Table 5).
A 3 1 ‑years‑old lranian from Bl district, B region, flew to Japan, already sufferingfrom remittant fever since three days before his arrival. On the arrival at Osaka
Airport, although he felt fatigue and had fever associated with left parotid swelling,
he passed the quarantine inspection, and his fever went down to 37.5 C after a reston the following day. On the next day (the 3rd day after arrival) , the fever went

176

Table 5Classlficatron of sickness in each country

A B C D E‑GroupA2 United Republic of Tanzania
Common cold 5 (26.3 )El Salvador (0/2)(6! 19)

Costa Rica (2/lO)

Common cold l (l0.0"/o)

Colitis 1

B1

Dermatitis llran (1/4)
Orchitis 1

Panama (1/2)

Common cold l (50'O"/o)

United Arab Emirates (1/1)
Common cold I (lOOo/.)
B2

Venezuela (1/4)

India (3/9)

Common cold 1 (25.00/0)

Common cold I (1 1 . I "/o)B3

Urticaria 1
Angular stomatitis 1

Peru (2/16)

Republic of Korea (9/24)

Brazil (2/lO)

Common cold 2 (12.50/.)

Common cold 5 (20.80/0)
Motion sickness 1

Common cold l (l0'Oo/o)Colitis l

Menorrhalgia 1

Aphtha 1

Neurosis lE

Puerto Rico (3113)

Common cold 3 (15.80/0)

Republic of China (15/lOO)

Common cold 12 (12.0"/o)
Colitis 3
Philippines (6j35)

Common cold 6 (17.lo/o)Indonesia (5j37)

Common cold 5 (13.50/*)

Hong Kong (2/2)
Common cold I (50.00/*)
Gastritis 1

Vietnam (1/9)

Asthma l
Thailand (13j26)
Common cold 8 (30.8*/*)
Conjunctivitis lColitis 2
Gastritis 1

Malaysia (21/l04)
Common cold 19 (18.30/0)
Gastritis 1

Tapeworm infestation 1
Singapore (3/37)

Common cold 2 (5.40/0)
Urticaria lC

Australia (0/6)

D

Mexico (1/9)
Gastritis lOther country‑Group

Spain (1/3)
Renal calculus 1

West Germany (5/12)
Urethritis 1
Otitis externa 1
Callosity 1

Trauma 2

Belgium (Oj3)
Netherland ( I j4)
Gastritis lUnited Kingdom (0/3)

Denmark (1/3)
Common cold I (33.3"/ )Sweden (1/1)
Urticaria 1
Switzerland (1/1)

Panaritium l
Poland (1/1)

Common cold I (lOO'/o)
United States of America (2/5)
Colitis 1

Otitis media l

Canada (1/ll)
Common cold I (9.1'/.)

177

up again to 39 C. An antifebrile and an ice compress of left cheek did not calm it
down and on the fourth day after arrival (the 7th sick day) , he suffered from orchitis

on both sides. Protozoa was not proved by smear sampling of blood. Exanthemaand digestive disorder were not found either. Moreover, even after detailed check‑up,
none of typhoid fever, smallpox, dengue fever, or orchitis usually following malaria

was found. Therefore, the case was diagnosed as acute orchitis following acuteparotitis, and the patient was hospitalized in Hirakata Municipal Hospital for flvedays.

One from the United Arab Emirates had cornmon cold. Three Indians from
B2 district had urticalia, angular stomatitis and common cold respectively. Among
Korean patients from B3 district, one was homesick, one with menorrhalgia, one withaphtha, one with neurosis and five others with common cold. Three Taiwanese
were with colitis, 1 2 others were with common cold, one Singaporean was withurticaria and two others had common cold. Six Philippines and five Indonesians
were with common cold. One Chinese from Hong Kong was with gastritis and theother was with common cold. One Vietnamese was with atopic asthma and theantigen was suspected as house dust according to anamnesis and intractutaneous test.
One Thai was with colitis, one with conjuctivitis, one with gastritis, and eight others

were with common cold. One Malaysian was with gastritis, 19 with common cold
and with one Tenia saginata. This patient caused by Tenia saginata was a 27‑years‑

old man and had repeated diarrhoea for one month. He had a habit of eating
raw beef. He felt uneasy around the anus 3 days after his arrival to Japan. Afterthe examination, Tenia saginata was suspected, he was administered helminthic, 10
grams of Extractum filicis and 5 grams of magnesium sulfate in hunger, and 4 metersof helminth was excreted and no diarrhoea was found after that.
In other regions, one Spanish man suffered from right nephrolith and excreted
sesame size of calculi after a drug therapy in 18 days of hospitalization. One patientfrom West Germany was with urethritis, one with right otitis externa; one with callosity

and two with trauma. One from Denmark, one from Canada and one from Poland
were with common cold, and one Dutch was with gastritis, one Swiss with panaritium,

one American with right otitis media and another American with colitis. Eightcolitis patients of one Tanzanian, one Brazilian) three Taiwanese, two Thais and one
American were consulted with a complaint of one to three times of diarrhoea a day.

The examination of parasites of stool and culture of pathogenic microorganisms
were all negative (TCBS and SS medium was applied for stool culture) (Table 5).
As mentioned above, no significant relationship was found between the country
and patient sample according to these classiflcation of region‑countries and patient

sample. Among these patients, common cold was found in 77 cases. More people
from A, B, C, D and E regions were found with common cold (74 out of485; 15.30/0)
than those from North America and Europe (3 out of 47; 6.30/0)' According to thestudy of onset of common cold in these patients, most visitors from tropical zone
were affected within a week of the arrival and the peak was the third day after theirarrival (Fig. 2). Fortunately, every patient recovered by medication, mainly
antipyretics and antihistamine, and good rest. Two out of 12 Taiwanese, threeout of 19 Malaysians, two out of eight Thais, one out of five Indonesians, one out of

178

five Tanzanians, one Venezueran who were affected with common cold had fever ofat least 37.5 C to 38.5 C. On the patients who were suspected to have had malaria,
smear sampling of blood was made, and Giemsa staining test was performed. How‑ever, there was found no malaria protozoa shwoing ringstage, segmenter and game‑tocyte. Therefore, all patients were diagnosed as common cold. Tests for albumi‑
nuria and urine urobilinogen did not reveal any significant change.
Table 6 indicates monthly statistics of onset of common cold, in which most of
the patients were found in the fall and winter. The upper row indicates the numberof patients and the lower the number of foreign visitors in each month. This shows
apparently higher morbidity rate of the visitors from tropical zone than those from

Europe and North America.

40

Tropi cal ‑ group

Other ‑ group

30
1"
1;

o
L 20
q,

tl'

a

10

o

t.t

2

3

4

5

14

,. ,

21

Days after arrival

Figure 2 Number of day to onset of common cold after the arrival.

Table 6

Number of total vrs tors and common cold patients in each month for 5 years

Group

PatientsMonthand visitors,Jan. Feb. Mar. Apr. May Jun. Jul. Aug. Sep. Oct. Nov. Dec.

A, B, C, D andcold patients

CommonE group

Other countrygroup

6 6 6 4 7 O O O 2 1 8 20

22.2 24.0 9.4 6.3 Il.3 O O O 1.2 l0.3 13.5 6.3
Total visitors 1 27 25 64 64 62 68 75 127 166 174 148 80
Common(o/o)

cold patients(o/o)

Total visitors̲ I

O O I O O O O O O 1

O O l0.0 O O O O O O 6.3 l0.0 20.0

7 5 10 5 4 2 3 3 8 16 10 5DISCUSSION

Not only sea men returning from abroad, but also people coming back fromabroad and visitors to Japan by air are increasing tremendously in number, owing
to increased overseas activities such as sightseeing, business trip, trade, academic

l 79

research and study, technical aid and enterprises; more than l0,000 people arecoming into Japan everyday through both Tokyo and Osaka airports.
These people usually do not have enough knowledge on prevention and therapy
for tropical diseases. Their information is so limited that they get easily affected

and some of them died as reported by Ebisawa et al. (1973). Imported tropicaldiseases found after the return are mainly malaria as reported by Ebisawa et al.
(1969), Tsubura et al. (1973), Ebisawa et al. (1973), Yamaguchi et al. (1973) andEbisawa et al. (1975).

Ebisawa et al. (1973) reported a detailed summerization of 73 patients found in
8 years from 1966 to 1973. According to this report, most of the patients had Pl.
vivax, Pl. falciparum and others had with Pl. ovale or Pl. malariae and were obliged toreturn home. Diseases other than malaria are also imported. They are nema‑
todiasis, as reported by Kamegai et al. ( 1 976), smallpox from Bangladesh, which

was fortunately prevented from the 2nd affection in Japan by an appropriate
protection at quarantine as reportcd by Hino et al. ( 1 973), and dengue fever reported

by lwamoto (1973). In addition to these continuous reports of imported diseases,
recent reports of cholera found in Arita city, Wakayama, and cholera patients foundin Kobe who returned from on‑board college gives us a warning that we, generalpractitioners, should be always on the alert of these facts in our day to day check‑ups.
The report of Kobari et al. (1973) on pest in Vietnam implies a possibility of otherdiseases imported and brings up problems ofinspection, early discovery and treatment

and prevention of the 2nd affection.
As we had an opportunity of examining I 1 2 foreign patients from 33 countries
visiting for job orientation at Matsushita Electric Co. Ltd. for 5 years from 1972 to

1976, we made a survey on medical records.
As shown in Table 4, visitors from A, B, C, D and E tropical regions showed
20.2 per cent of morbidity rate (98 out of 485 visitors), while visitors from the otherregions showed 29.8 per cent (14 patients out of 47 visitors). Fortunately we did
not find patients with protozoa diseases such as malaria and amebic dysentheria,bacterial diseases such as cholera, typhoid fever, and virus diseases such as dengue
fever, smallpox and yellow fever. Unusual cases were patients with Tenia saginata
and a case with orchitis due to mumps infected before coming to Japan. Exractum
filicis was prescribed for the Tenia saginata patient to excrete helminth, and the orchitis

patient was treated with antifebrile and intravenous infusion, antibiotics for pro‑tection from of the 2nd affection in the hospital, and both of them were cured.
Another significant finding of our research was the fact that many common cold
patients were found among visitors from tropical regions. According to the monthly
statistics, this shows different tendency from influenza prevalence in Japan and thevisitors get affected in fall, especially in October and November quite different fromthe peak of influenza in Japan (Table 6). Moreover, most of them became sickafter a few days of their arrival. There is an assumption that the reason for this fact
is due to the difliculty in changing clothes and living customs, and slow adjustment
to the new environment of their sweat gland to control body temperature, and fatigue
as well as the fact that they are exposed to invasion of pathogenes into the respiratory
tract on the visit to a completely different climate. Therefore, we understand that

1 80

early treatment and orientation to Japanese environment, especially to clothes, areofvital importance as the preventive means for them who have had difEculty in using
their medical facilities in their home countries. Although import of typical tropicaldiseases by foreign visitors was not found, there should be a possibility of missing somediseases, and our examinations at Health Consultation Room were not enoughbecause checking points were blood test and stool examination only once.
We are convinced that the above mentioned two examinations are integral partsof prevention of imported tropical diseases when we, general practitioners, examine
foreign patients in Japan.

REFERENCESl) Aihara, M., Tajimi, H., Takahashi, H., Amano, H. and Yamamoto, T. (1976) : Case of im‑ported Salmonella paratyphi A, Jap. J. Trop. Med. Hyg., 4 ( l), 622) Ebisawa, I., Kawamura, Z., Mitsuzawa, E., Komatsu, T., Nagashima, Y., Suzuki, H. andHagihara, M. ( 1975) : Critical condition of malaria, Jap. Med. .J., 2690, 43‑47

3) Ebisawa, I.) Nakamura, S., Sugimoto, H. and Takigami, T. ( 1969) : The recent malaria,
Jap. Med. J., 2372, 1 1‑17

Ebisawa, I. (1973) : Imported malaria, Diag. Treat., 61 (7), 76‑81
Ebisawa, I. (1973) : Current problems ofmalaria, Tokyo. J. Med. Science., 81 (1), 56‑67
Ebisawa, I., Muto, T., Nakamura, S., Komoriya, T. and Kimura, M. (1973) : Analysis of 73

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Malaria‑patients, J. Jap. Assocat. Infect. Dis., 47 (1 l), 425‑430

Hino, S. and Kawane, K. (1974) : A clinical case ofsmallpox, Jap. Med. J., 2566, 22‑26
8)lwamoto, I. ( 1973) : A case of imported dengue fever, Trop. Med., 15 (4), 225‑230
9)Kamegai, S. ( 1976) : The tapeworm diseases infected in the foreign countries, Jap. J. Trop.
Med. Hyg., 4 (1), 55
l O)
Kobari, K. (1973) : Imported infectious diseases, Infect. Inflamm. Imm. 4 (1), 1‑7ll) Nakabayashi, T., Ohtomo, H., Ebisawa, I. and Ishizaki, T. (1975) : The present situation ofmalaria, Inform. Pub. Hyg., 5 (9), 1‑412) Sassa, M., Ebisawa, I. and Kanda, R. (1969) : The tropical diseases, Ist ed., 1‑26, Tokyo
University International Edition, Tokyo
13) Tsubura, H., Tanaka, O., Ozaki, F., Ito, Y. and Fujii, H. (1973) : A clinical case of imported
malaria from Pl. vivax, Jap. J. Cln. Exp. Med., 50 (10), 92‑98
14) Yamaguchi, K., Harada, T., Akamine, T. and Tsuneda, K. ( 1973) : A clinical case of imported
malana from Pl falciparum, Diag. Treat., 61 (7)) 159‑162
7)

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f iC

ff 'l

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181

れている。この事実はまた，わが国を訪れ，特に一定期間滞在する外国人が熱帯病病原体を移入し，伝染源となり得る可能性を暗示するものである。我々はこの推定を検討するために1972年より1976年に至る5年間，技術訓練のため熱帯諸国ならびに欧州，北米より松下電器産業株式会社への来訪者にっいて，一定期間の罹病状況を診断または医学記録によって分析し，つぎの結果を得た。

1）総計532名の来訪者のうち485名が熱帯諸国より，また47名がその他諸国よりの来訪者で，その到着時より1カ月間の罹病率はそれぞれ20．2彩，29．8％であった。

2）今回の調査では幸いにも，マラリア，フィラリア，コレラ等の熱帯病は認められなかった。
3）母国で感染し，来日に際して発病したマレーシア人の無鉤条虫症，イラン人の続発性睾丸炎各1例が特記されるものであったほかは，感冒，胃腸炎，奪麻疹等一般的な疾患が多かった。

4） 熱帯圏よりの来訪者は，欧州，北米等よりのそれに比較して，特に秋，冬期に到着後2〜3日以内にかなり高率に感冒に罹患する傾向が認められた。
5） 以上得られた成績は，外国人による熱帯病移入の可能性の実態を明らかにするとともに，また，これら来訪者の健康管理上の資料として評価され得る。
6）

帰国邦人および外国人来訪者に対する，理解ある検診ならびに実地医家の，輸入熱帯病についての良き認識は，今後ともこれら疾患の移入を防ぐ対策として不可欠である。

日本熱帯医学会雑誌

第5巻

第3，4号

183

1977183−189頁

マラリアのフ。リマキン療法
海老沢 功・武藤 達吉
昭和52年11月7日 受付
1977年10月までに著者らがプリマキン療法を

は

じ

め

行った日本人症例は110人である。表1に示すよにうに感染原虫の種類は三日熱マラリアが最も多く

プリマキンは8一アミノキノリン剤に属する抗マラ79人で，熱帯熱マラリア18人，両者の混合感染4人，リア剤で，再発型マラリアの赤外型原虫（Coatney

卵形マラリア8人，四日熱マラリア1人である。

ら，1953；Gennisら，1954；WHO，1967，1969）

感染地域は東南アジア，インド亜大陸（スリラと熱帯熱マラリア原虫の生殖母体（WHO，1967，

ンカを含む）が併せて63人，オセアニア，パプア

1969；Rieckmannら，1968；Bermanら，1971）

ニューギニア29人，アフリカ17人，南アメリカ1の駆除剤としてその価値が認められている。

人となっている。

アフリカで感染した三日熱マラリアはエチオヒ。

ただし本剤は三日熱マラリア原虫の赤外型原虫

アおよびエジプトそれぞれ1人ずつである。

駆除には常用量で100％有効でないことも知られ性別では表2に示すように男103人，女7人でている（Ho，1965；Peters，1970；Clydeら，1977）。

男が圧倒的に多い。

日本では本剤に関する多数の症例を用いた報告

2．薬は少ない。われわれは前回（海老沢ら，1977）報剤告した例にさらに9例を加え，1977年10月までに主としてWinthrOP社製のプリマキンを用いた。

日本人110人に計132回のプリマキン療法を行った

1錠中プリマキン塩基として15mgを含む（リンのでその成績を報告する。

酸プリマキンとして26、5mg含有）。

一部の症例にはCamoprima⑳（1錠中Amodia−

研
1，症

究

方

quine150mgとプリマキン塩基15mg含有）を法用いた。いずれも1日1錠ずつ与えた。

14日間連日内服をもって1コースの治療とした。

例

Table1The

parasitemalaria
Species ofSoutheast

malaria

ancl

Total

and

Papua−
New

63

the

Af士icaGuinea

2

area

of

infヒction

of

29

South
America

Total

1

110

蒋

17

ワJl

P．m．

Oceaniaor

primaquine

Q﹂84只uーP．o．

continent

10000

P．び．＋P≠5

then∠竹ノ080ハ∫

subcontinentandtreated with

63000

P．∂．

Asia

Indian08401

parasites＊

speciespatients＊P≠一E批ψ礁観，丑規・一P・副α吻8，P…一P・・励and丑・・一R吻x・＃One case each ofP．∂伽κin艶ction

東京大学医科学研究所熱帯疫学研究室

fヒom

Ethiopia

andEgypt．

184

Table2The

parasiteofmalaria

speciesand thepatients

表3における短期間療法とは，主として熱帯熱マ

sextreated with

ラリア患者の生殖母体の駆除の際行ったものであprimaquine

P．o．

且∫
P．∂．＋丑∫
P．o．
P．窺．

TotaI
＊See

7

103
footnote

Table3

of

The

Total

9
8481
71

Female
門D2000species＊

る。多くの場合1日1錠5日あるいは7日間与え

Male

4
648ー
ウノー

Parasite

110

Table1．

parasite

Parasite

speciesNumberand

染例で生殖母体駆除のため5日間用いたもの2例と，副作用のため12日で中止した1例である。

3．

the

durationFullcourse＃ 1Sh・rtterm＊＊

fUllcourse

means

l5mg

therapydaily

fbr14days，and30mg

daily

Tota1
﹃ノn∠481﹄18＊See footnote of Table l．

＃A

ofprimaquineQ﹂2lnumber14300

114」P．η2．

andPrimaquine therapy

lO

P、∂．十P≠

副作用

プリマキン内服中の患者は全部無熱期で大部分

9

P．o．

Tota1

説明したとおり熱帯熱と三日熱マラリアの混合感

6只∪181

P．∫

リマキンがなかったためである。その他は前報で

けノーQ﹂8481

P．ひ．

三日熱マラリアで短期間（7日）与えた例はプofpatients

species＊た。1例1日45mg頓服で与えた例がある。

132

fbr7daysin2cases ofvivax malaria．
＊＊A

short

fbr5daystermintreatment

the

case

means

daily l5mg

of塩lcipamm

は外来患者であったため副作用に関する調査は内服終了あるいはその中間の時点で行った。
4．

プリマキン内服後の再発の有無

for12daysorless．It is usuallymalaria．
線を求めた。

この直線に対してプリマキン内服後の生殖母体数の変動を比較して薬剤の効果判定に用いた。

プリマキン内服者はマラリア罹患後国内に半年以上の長期滞在者もあったが2−3カ月後には，マ結ラリア罹患後再び流行地に行く者が多かった。し果

たがって正確な失敗率は求められない。失敗例と1．

してここにあげた例は，プリマキン療法後マラリ（i） 1コースの治療後再発

ア流行地に渡航しない中に発病した者，あるいは感染地域はパプアニューギニア2人，カリマン

流行地域に戻ったが都市内にのみ滞在し，帰国後再発した例である。

5．熱帯熱マラリア原虫生殖母体に対するプリマキンの効果プリマキンを与える前後において毎日定量的にプリマキン療法後の三日熱マラリア再発

タン2人，インド1人の計5人。
この中97日後に再発した女性患者はその後流行地に入って再感染しているので，2回目のプリマキン療法で根治できたか否か不明である。173日

目に再発した1人とカリマンタンで感染した2人

流血中の原虫数を数えた。求められたμ1当たり

は，再発時に行った2回目のプリマキン療法後再の原虫数を対数変換して，経時的原虫数の消長を発していない。インドで感染した1人は2回目のRicomac

プリマキン療法後6月経ってまだ再発していない。

X−844コンピューターに入れて回帰直185

しかし第1回の再発が232日後に起きているのでを起こしていない。インドで感染した例は次回のなお観察を続ける必要がある。

14日間のプリマキン治療後4ヵ月を経て再発を起（ii）

2コースの治療後再発

こしていないが，1コースの治療後232日以上経って再発している例があるので注意を要する。

プリマキン療法を2−3カ月間隔で2回行った後12日間のプリマキン内服後再発した1例は再発再発した例が3人ある。2例はパプアニューギニ
アで，1例はフィリピンで感染している。いずれの治療後2コースのプリマキン療法を行ってなおも5ヵ月以上11ヵ月半におよぶ長い間隔で再発し再発したことは前述した。最終的には1日30mg，ている。3例とも最終回には1日30mg，7日間

7日間の治療でその後再発を見ていない。

のプリマキンで治療した。パプァニューギニァで2．卵形マラリアのプリマキン療法

プリマキンを与えなかった3例中1例は7ヵ月

感染した2例はすでに1年以上を経過して発病しの間隔をおいて確実に再発している。

ていないので根治したと思われる。フィリピンで他の2例は1例のみ健在という情報が入ってい感染した例は治療後まだ4カ月しか経っていない

るが両例とも詳細はわからない。

ので更に観察を続ける必要がある。
（iii）

プリマキンを使った8例中1例はオランダに行

不完全プリマキン療法

規定の2週間に及ばない内服期間であったので

き，1例は使用後2ヵ月以内であるので除く。残再発したとしてもやむをえない。スラウェシで感りの6人はプリマキン療法後1〜2年以上経って染した例は2回目の，14日間の内服でその後再発

いるが再発を見ていない。

Table4 Vivax malaria patients who developed relapse following
primaquine

Primaquine
therapy

therapy

NumberofAreapatients

andlnterval betwcenof infヒction

lastdayof掩ver

number ofpatients

and5courseαEast

Kalimantan（2）India（1）

Two

Short

term
α：15mg

5days
7days
12days
daily

fbr

same

246days
92days34daysd
68daysSulawesi（1）India（1）The
M

Philippines（1）cdays。

わ：Repetition ofthe：The

Papua−New Guinea（2）The Philippines（1）c3

courscsむ

relapse97andl73days
l41and142days
Over232days
172and316days

Papua−New Guinea（2）

One

the

above

person．He

regimen2to3months

had

to

stop

apart．

primaquine

therapyafter12days

becauseof psychiatric disturbance，relapsed after68days，and underwent2co皿ses
ofprimaquine unsuccess血11y，He was且nally cured by30mg ofprimaquine

fbr7days．
4：This patient s且rst

primaquine

which

was

illnesswastreatedwithsuspended

hal飾aybecause3．副作用（i）

消化器系症状多少の不快感ないし軟便を訴えるものが2−3人あったが，ほとんどの例はプリマキンを14日間内服し得た。途中で中止した例は1例もなかった。

clindamycin

fbllowed

ofshortage

ofthe

by7daysofdrug．

Camoprima⑬を内服した例では軟便その他の消化器症状が強く，中止せざるをえない例があった。
（ii）

溶血性貧血

日本人には赤血球の先天性酵素欠損症である
G−6−PD欠亡症は極めて稀である（Miwa8力認，1861965）ので各例にっいてその検査をしなかった。

本例はその後三日熱マラリア再発のためプリマ

臨床的に溶血性貧血の症状を呈する者はなかった。
（iii）

キン療法をさらに3回繰り返した。すなわち10月

精神，神経系の異常

25日より14日間，1977年3月中旬より14日間，7次にのべる例は上記所見を呈していたとき入院

月4日より1日30mg7日間。とくに10月25日よ中で，流血中にマラリアの原虫はいなかったがプりの内服は入院中に行ったが精神，神経の異常はリマキン内服開始後7日目より37C台の微熱が認められなかった。

あり，12錠内服した日から異常を呈しはじめた。

症例

したがって本例における1976年8月17と18日のF．H．44歳男，熱帯熱マラリアと三日熱

初回プリマキン療法時に見られた精神，神経症状

マラリアの混合感染が何に由来するものかは不明である。

フィリピンで感染。発病1976年7月20日

入院

4．プリマキンの熱帯熱マラリア原虫生殖母体

7月26日。当日の流血中マラリア原虫数は熱帯熱に対する効果マラリア原虫49，200／μ1，三日熱マラリア原虫230／（i）無処置例

μ1。7月29日と30日にMP錠（1錠中スルファモ

発病後早期に発熱発作の治療を行った例では，

ノメトキシン500mg，ヒ。リメサミン25mg含有）

生殖母体数も少なく，1〜2週間で消失した例がを2錠と1錠内服した。

ある。またかなり多数の幼若生殖母体が出現した

8月2日より無熱，8月5日よりプリマキン内にも拘らず，比較的早期に陰性化した例もあった。

服開始。8月11日より微熱。37C台。

治療が不完全のため発熱発作の治癒が長びき，成精神，神経症状の出現。

熟した生殖母体が多数出現した例において，連日

8月17日，手のふるえ，異常行動を認められる。 定性的観察を続けた例では，濃塗標本で陰性化す
8月18日，時と場所の指南力消失。娘の生年月るまで40日以上かかった例がある。

日失念，問いに対して応答がおそく，しぱらく考

図1では横軸にプリマキン療法開始前後の日数，

えてから返事する。

縦軸に血液1μ1中の生殖母体数を対数で示してあ

指一指，指一鼻テストはよくできない。左足クる。治療開始前に，曲線cの症例では最高25，200／

ローヌス陽性。直進，片足起立不能。

μ1，曲線dの症例では最高5，100／μ」の値を示した。

8月19日には左足のクローヌス陰性，精神症状

それぞれ12と10日間プリマキンを与えないで観察改善す。なお微熱は18日まで続き最高38Cでを続けた。

あったがこの間流血中マラリア原虫は陰性であっコンピューターから得られた回帰直線はた。溶血性貧血の徴候なし。

c…lo9ツ＝一〇，1366広＋4．3870となりEf〒ocfof primoquino on P．fo c

ραrumgome†ocyfo

6
5

一蔓﹂OO

5

3

一こコOO

4

C

一・、、

一・：：二：二4．

．

幅−「 2 、＼ 、＼課、
＼ ミN＼

γ

0

OO一

︐︐

1

e／1
／

b〆
／

2

OピのO﹄Oこ、一

一Aヤ》

噛隠4＝《〜

．！へ慧

・一

｝．へ、
d

d＼・・ ギ0￥＼ 、、
一12一睾1

一監0

−9

−8

一

7

−6

−5

−4

−3 −2

1 Day一甘eat㎡ent
Figurel

EHヒct ofprimaquine

−1

0

1

2

3

、

4

1

5

6

、

7

i肋幽惚at…t−don

P．ノ乙Jo御耀η〜gametocyte．

8

9

10

187

ッ＝1のとき灘二32となった。

曲線dでは

考

d…109ツ＝一〇．0869∬＋3．6497と：なり』y＝1のときヱニ42となった。

察

1．再発型マラリアにおけるプリマキン療法のすなわち流血中の生殖母体数が0に近づくには，

失敗

観察初期から数えて1ヵ月以上かかるということ

プリマキン療法を受けた者の中で根治療法が不である。1μZ中1コ以下とは例えぱ白血球数が成功に終った者が何パーセントぐらいあるかは大5，000／μ」であるときは，濃塗標本で5，000コの白切な問題であるが，われわれの症例の多くは発熱

血球を数えるぐらい視野を移動しても1つも生殖発作治療後2−3ヵ月以内にマラリア流行地に行く

母体が見つからないという数である。

ものがありその答えは得られなかった。

生殖母体が出現しはじめてから次第に増加してただし引き続き国内に留っていた例では，再感ゆく例（b，eなど）では103あるいは104／μ」以上

染のない国内での発病であるから，直ちにこれをに増加してゆくことがわかる。

再発と見なしうる便利さがある。

（ii） プリマキン療法

1日15mgずつのプリマキンを与えても治療開パプァニューギニアの三日熱マラリアがプリマキンで根治しにくいことはよく知られている

始後2−3日間は原虫数にほとんど影響がなく，b（Peters，1970）。しかしながらわれわれの症例は1

例ではむしろ増加してゆく傾向が見える。

日30mg7日間の内服で根治しているので，Ches−

しかしながらc，d例においてはいずれも5日 son株のように1日30mg14日間あるいは1日60mg7日間の内服を必要とするほど（Clydeら，

後には陰性となっている。前述の計算では1ヵ月以上かかることが計算されたので，製上の所見はプリマキンの効力を如実に示すものであろう。
（Hi）

無性原虫のクロロキン感受性とクロロキ

1977）プリマキン低感受性でなかったのは幸である。

プリマキンの1ないし2コースの治療で根治でン耐性例におけるプリマキンの反復療法

きない三日熱マラリアがさらにフィリピン，カリ

一般的に言ってプリマキンは，その患者の無性

マンタン，インドなどにもあることは今後これら原虫がクロロキン感受性，耐性の如何に拘らず生の地域からの帰国者の治療に際して注目すべきこ

殖母体に対して効力を示した。プリマキン使用開とであろう。1コースのプリマキンで不成功例が始後生殖母体消失までの日数は流血中の原虫数のあることは中国でもすでに報告されている（Ho，多少にも関係する所見がえられた。

1965）。

図1において曲線a，bであらわした例はクロ2．副作用

ロキン耐性の同一患者の第1回（a）と再燃後のプリマキン内服にもとづく溶血性貧血の危険性

第2回目（b）のプリマキン療法時における生殖は常に念頭におくべきであるが，幸にも日本人に

母体の消長を示す。第2回目の治療時にはプリマ

はG−6−PD欠亡症が少ないので本剤は安心してキンに対する反応が遅く，消失までに3日多くか使える。

かっている。

症例

F．H．における精神，神経症状がプリマ以上の所見は同一患者に反復してプリマキンをキン内服によって起こったものか，たまたま同じ使用することにより，プリマキン耐性が出現する頃感染した中枢神経系の感染（臼本脳炎あるいは可能性を示すものか否か，注意を要する所見であECHOウィルス感染症）によるものか不明のまろう。

まで終わった。後で3回プリマキン療法を行い，3回とも異常を認めなかったので，おそらくはプ
リマキンによるものではないであろう。

3．熱帯熱マラリア原虫生殖母体に対する効果

188

生殖母体が大部分成熟しておりその数値がほぼた。

2． 1日15mg内服で2週間治療しても大部分一定した，あるいは少しずつ減少しかけて来たとの患者は特別な副作用がなく耐えられた。

き5−7日間無処置のままで観察すると，対数グラ3．

フできれいな回帰直線が求められることがわかっ

三日熱マラリアではプリマキン1コースなた。この式を求めておくと，プリマキンその他の

いし2コースの治療で根治できない例がパプア

薬剤を用いたとき，その効果判定に役立つであろニューギニア，カリマンタン，フィリヒ。ン，インう。

ドから輸入されている。2コースの治療で根治で現在までのところ，無性原虫のクロロキン感受きない例は1日30mg，7日間内服で根治できた。

性，耐性の如何に拘らずプリマキンが有性原虫に4．卵形マラリアは1コースの治療で根治でき対して有効であったことは幸である。しかしながたと考えられる。

ら反復使用により感受性低下の傾向も見られるの

5．熱帯熱マラリア原虫生殖母体はその無性原で，再燃を起こさぬよう発熱発作の完全な治療を虫のクロロキン耐性の有無に拘らず，プリマキンで駆除される。反復治療で反応がやや低下した1

心がける必要がある。

4．卵形マラリアのプリマキン療法例があった。

観察期間が1年以上に及ぶ6人ではすべて再発が起きていないので卵形マラリアに関する限り問辞謝

題はないであろう。

この研究に用いたPrimaquineの一部は石崎達
結1．

教授（当時国立予防衛生研究所寄生虫部長）の努論力によりWinthrOP社から供与されたものである。

プリマキン療法を日本人110人に132回行っ

関係者一同に感謝する。

文1）Berman，S
tion

J．and

man

Holmes，K，H．（1971）：Gametocytemia in falcipamm malaria．Eradica−ofgametocytemia2）Clyde，DF。and

献with primaquine，J．AmeL Med．Assoc．，215，291−292

McCarthy，V．C．（1977）：Radical

by7，not14，daysoftreatment

with

cure

of

Chessonprimaquine，AmeL

strainvivax

malariain

J．Trop．Med．Hyg、，26，562−563

3） Coatney，G．R．，Alving，A．S．，Jones，R．，JL，Hankey，D．D．，Robinson，D．H．，Garrison，P・L．，

Coker，W．G．，Donovan，W．N．，Lorenzo，IA．Di．，Max，R、L．and
rean

vivax

malaria．V．Cure

of

the

infectionbyprimaquine

Simmons，1．H．（1953）：Ko−

administeredduringlong−term

latency，Amer．J．TroP．Med．Hyg．，2，985−988

4）海老沢功，武藤達吉（1977）：輸入マラリアII，再発型マラリアのプリマキン療法，感染，炎症，免疫，7，65−70

5）Gennis，J．，Straus，B．，Kenney，M．and
treatment

6）Ho Chofmalariain

i（1965）：Studies

Klein，B．（1954）：Theonmalariainnew

China，Chinese

7）Miwa，S．，Momma，K．，Ise，T．，Irisawa，K．andhydrogenase（G−6−PD）deficiency．II．Incidencehaematologica

ofofprimaquine

for

the

of

Med．，J．，84，491−497

Oyama，H．（1965）：Glucose−6−phosphatede−G−6−PDde五ciency

intheJapanese，Actajaponica，28，590−5928）Peters，W，（1970）：Chemotherapy

9）Report

use

Korean veterans，Amer．J．Med．，17，223−228

and drug

resistance in malaria，Academic Press，London

aWHOScientincGroup（1967）：Chemotherapyofmalaria，WHO

Technical

Re一

1 89

port Series No. 375, Geneva

10) Report of a WHO Scientific Group (1969) : Parasitology of malaria, WHO Technical Report
Series No. 433. Geneva
11) Rieckmann, K. H., McNamara. J. V., Frisher, H., Stockert, Th. A., Carson, P. E. and Powell,

R. D. (1968) : Gametocytocidal and sporontocidal effects of primaquine and sulfadiazine
with pyrimethamine in a chloroquine‑resistant strain of Plasmodium falciparum, Bull. Wld.
Hlth. Org. 38, 625‑626

PRIMAQUINE TREATMENT OF MALARIAISAO EBISAWA AND TATSUKICHI MUTO
Received for publication 7 November 1977

Primaquine was given to 1 10 Japanese malaria patients 132 times for the eradication of P.falciparum

gametocytes or for the treatment of relapsing malarias.

I) Primaquine was tolerated well by the patients despite minor gastrointestinal discomforts. No
hemolytic anemia developed reflecting the extreme rarity of C 6‑PD deficiency among the Japanese.
2) The exact failure rate ofradical treatment of vivax malaria was not obtained as many patients

returned to malaria endemic areas to continue their work. There were two patients each from Papua‑

New Guinea and Kalimantan and one case from India who relapsed after one course oftherapy. Twopatients from Kalimantan and one patient from Papua‑New Guinea were radically cured by the second
course of primaquine treatment. Another case from Papua‑New Guinea was reinfected in the same
area and another case from India is free from malaria for 6 months after the second primaquine treat‑
ment.
Three patients relapsed after two successive courses of primaquine treatment at an interval of two

to three months and were radically cured by 30 mg of primaquine given over seven days.
3) All the six ovale malaria patients were radically cured by one course of primaquine treatment.
4) P. falciparum gametocytes were sensitive to primaquine irrespective of the chloroquine‑resistanceof the asexual form of the parasites. There was indication that the response to primaquine in the second
treatment was a little slower than in the first treatment.

The gametocytes in the untreated with primaquine patients, after they reached a peak level,
decreased logarithmically and their trend was expressed as logy=‑ax+b, where x is the day after
treatment with schizontocidal drug, ̲y the parasite count per p I of blood, and a and b constants.

The equations in two patients were as follows. Iogy=‑0.1366x+4.3870 and logy=‑0.0869x+
3.6497.

Laboratory of Tropical Epidemiology, Institute of Medical Science, the University of Tokyo, Tokyo

l08, Japan. Part of this work was supported by the WHO M2/181/125.

Ja pan. J. Trop. Med. Hyg., Vol. 5, No. 3, 4, 1977, pp. 191‑246

191

PATHOLOGICAL STUDY ON EARLY CHANGESOF CHOLERA PATIENTSBased on 21 Autopsied Materials‑
ICHIRO SEKINE
Received for publication 10 November 1977

Abstract: l) Morphological observations were made on 2 1 cholera patients who
were autopsied soon after death. Since 19 of the cases were those dying within 41 hours
after the onset, the changes with time in the early stage of cholera were studied.

2) Small intestinal mucosal abnormalities are represented by acute inflammatory
reactions and subsequent atrophic alteration of villous architecture. In these changes, theincreased reproduction of epithelial cells in crypts by inflammatory stimulus seems to play

an important role.
3) Increased secretion of excretory glands was seen in goblet cells of the small andlarge intestines, in Paneth's cells of the intestine, and in goblet cells of the bronchi in casesof aspiration of gastric content. Increased secretion of pancreatic juice and bile was also

observed.
4) It is speculated that cholera toxin is absorbed by the intestine or some stimulating
substance is produced in the intestine. This is suggested by a) reactions of the mesentericlymphnodes and spleen, b) fatty changes of the liver and kidney, and c) increased secretionof pancreatic exocrine system.
5) The death may be attributed to cardiac failure and swelling of the brain resulting

from dehydration. Respiratory disturbance due to aspiration of gastric content should
also be considered. Renal changes in the early stage of the disease are mild and conse‑
quent renal failure could have been prevented by proper transfusion.

INTRODUCTION
There have been few reports of pathological studies on systemic organs ofautopsied cholera patients except for the recent reports by Sun et al. (1971) and
Norris ( 1 973) . Studies on pathological changes in a specific organ of cholera patientssuch as the intestine, kidney or adrenal are also scarce.
The present paper is to describe in detail the morphological findings of systemicorgans on the basis of autopsy materials, as well as to discuss the pathogenesis andpathophysiology of the changes in cholera patients.
An attempt was made to find the characteristic changes of organs resulting fromcholera infection and development of the disease by observing morphological changesof organs with the tirne after the onset. It was also attempted to study whether
or not the changes in systemic organs other than the gastro‑intestinal tract which is
Department of Pathology, Atomic Disease Institute, School of Medicine. Department of Pathology,
Institute for Tropical Medicine, Nagasaki University, Nagasaki 852, Japan.

192

the site of infection can be explained only by dehydration, as well as to verify whether

or not cholera toxin or some unknown factor is taken into the body.
The 2 1 autopsied cholera cases used as materials of this study were characterized
by the following.
l ) The interval between onset and death was within 41 hours except in two caseswith the intervals of 7 days and 3 weeks.
2) Most of the patients were infants and children. Of the 21 cases, 16 cases
were at the age of I O or younger.
3) These cases were autopsied shortly after death (within 2 hours in 20 cases),and consequently the intestine and other organs could provide informations as wellas biopsy specimens.

MATERIALS AND METHODS
Among the patients who diedthe cholera ward of the San Lazaro Hospitalin Manila between 1968 and 1970, 21 cases autopsied shortly after death were usedmfor this study (Table 1).

The occurrence of diarrhea was regarded as the onset of the disease. The
21 cases consisted of 1 1 cases of death within 14 hours after the onset, eight cases
Table lAutopsy

Autopsy cases of cholera in 1968‑1970 in Manila

Age

Time

Admission

after onset

time

1

45

a few hs.

O: 05

1: lO

2

6

a few hs.

l: 10

4: OO

3

3

7 hs.

O: 25

O: 45

4

63

8

O: 05

O: 40

5

6

lO

2: 10

1 : 25

6

20

lO

3: 20

l : 50No .

Postmortem Vlbrro Drarrhea
timeTrans‑ Dehy‑

fusion dration

+
+
+
+
+

++

+
+

+

21

+
+

+++
,.

11

+++

++

11

++

7

8

10

8: 15

l : OO

8

2

ll

2: lO

O: 50

9

4

12

2: lO

O: 40

lO

3

13

O: 30

l : 30ll

14l I : OO

0: 55

12

6 mons
65

24

0: lO

l: lO

13

2

24
30

18: OO

O: 50,.

24: OOl : 05

+++

1.6 l

+++

?

+

21
21
31

14

+
+
+
+
+
+

15

3

32

29 : OO

2 : 40

‑

16

4

33

28 : OOl : 20

17

8

40

+

35 : 30

1 : OO

18

14

40

38 : OO

2 : 0541

32 : OOl : OO

19

20

2

7 ds.

0: OO

l : 4521

6 mons

3 ws.

3 ws.

O: 50

+++

3.5 l

+++

+++

21

++

+f +

11

+++

++

l/4 l

++

+++

l!4 l

+++

+++

+
+
+

+++

+
+
+
+

+
+++

?

+

+++
+++
+++

l.5 l
+}+

p

+++

193

during 24‑41 hours and one case each of 7 days and 3 weeks. As classified by age,l 6 cases were infants and children at age I O or younger, two cases were at age 60 orolder, and three cases were between age 10 and 60. Frequent and voluminous
diarrhea and vomiting were observed in all the cases. At the tirne of death, 1 7 cases

showed severe dehydration.

Fever of 39‑40 C was noted in seven infants and children. Transfusion of
lactated Ringer's solution and administration of antibiotics were provided according
to the degree of dehydration after the admission. However, therapy was not provided
for the cases of death soon after the admission.
Bacteriological examination using rectal swab or intestinal content obtained at
autopsy was positive in 1 6 cases, negative in three cases and was not performed in
two other cases, in which, however, typical symptoms of cholera were manifest.
Efforts were made to perform autopsy as soon as possible after death and to open
the intestine for prompt fixation in order to prevent post‑mortem changes, partic‑
ularly autolysis of the intestinal mucosa. In fact, all the cases in this study were
autopsied within 4 hours after death. The blocks of tissues resected at autopsy were

fixed in Zenker‑formalin solution and 10 per cent formalin solution, and tissue
sections were stained by ordinary stains and special staining methods for specificorgans and specific purposes.

RESULTS AND COMMENTS

SMALL INTESTlNE
Macroscopic findings :Macroscopic findings described in autopsy protocols were available for 1 8 cases(Table 2). Distension was noted in the cases of death over 24 hours after the
onset. In typical cases, a large amount of watery content, moderate edema of theintestinal wall and advanced anemia of the mucosal surface were observed. The
mucosal surface was thickly covered with dense mucus in most cases. The intestinal
content was, at the early stage after the onset, turbid in whitish color mixed withmucus appearing as so‑called rice‑watery stool, but with the lapse of time, it became

thick and the color turned to bile‑stained green and yellow. Blood components
were contained in one case (No. 12). Ascaris and small roundworms were observedin many cases. Ascaris occasionally formed a mass and the adjacent mucous
membrane was hyperemic.
Dissecting microscopic findings :The dissecting microscopic pictures of the mucous membrane resected from theupper and lower parts of the jejunum and the lower part of the ileum of 18 cases were
examined and photographed, and consequently the appearance of villi was classifled
into flve types (Table 2).

I : finger‑1ike II: tongue‑shaped 111: Ieaf‑like
IV: ridge‑formation (Photo. 1) V: convolution (Photo. 2)
There was no case of completely normal appearance. Even in type I, the villi

194

were swollen showing cobblestone‑1ike appearance (Photo. 3). The appearance ofvilli in cholera is considered to represent atrophy‑1ike changes being essentially thesame as the changes of coeliac disease and non‑tropical sprue. Deformity of villi
was more frequent in the jejunum than in the ileurn and more remarkable in the ridgeof circular folds than in the vallecula. Between the cases dying within 14 hours andthe cases dying after 24 hours atrophic changes were more remarkable in the latter
cases, suggesting that cholera is a progressive disease.
Table 2

No. Age

Macroscopic and dissecting microscopic findings of small intestineTime
after onset

2
3

6

a few hs.

3

7

4

63
20
8
4

8

12

3

13

6
7

9
10

lO
lO

ll

6 mons

14

12
13

65

24
24
30

14
15
16
17
18
19

2

4

32
33

8
14

40
40

3

41

20

2

7 ds.

21

6 mons3 ws.

I: finger‑like, I I :Distension Anemia Color
of

Lower

of Ascaris Jejunum jejunum 1leumofintestine mucosa content
++

+
++

++
++
++
++

++

white
yellow
white
white
white
white
white
yellowreddish

many

green
green

5

++
++

+

+

+
+
+

green
yellow

+

green
green

++

wh i te

+

green

+

++

++

yel low

I¥'

lc
III
lc

9
6

IV

IV

IVc

15

Ilc

lc
Ilc

58
9

Vc

Vc

IIlc

IV

IV
IV

15
l

30
90
25

many
20

V

IIlc

V

V

IIlc
IIlc

V

V

V

IV

IV
IV

IV

V

IV
IV

V
V

lc

III

Ilc
IIlc

V
V
V

lc

III

IIlc
IIlc
lc
IIlc
III
lc

IIlc

IVc
IIlc

V

tongue‑shaped, 111: Ieaf‑like, IV: ridge‑formation, V : convolution,

c: cobblestone‑likeHistological changes :The histological changes of the small intestine were noted mostly in the mucosa
and were classified into two major types. In the first type, the basic architecture of
the mucosa was maintained but severe inflammatory cell inflltration of the lamina
propria and advanced desquamation and sloughing of the epithelial cells of villi
were noted (Photos. 4, 22). The second type involved architectural alteration ofvilli together with blunting and fusing, resulting in the appearance of atrophy(Photos. 5, 8, 14). The former was common in cases within 14 hours and the latterin cases over 24 hours.
i) Changes of intestinal epithelial layer

No marked degeneration and necrosis were noted in the epithelial cells, but
cytoplasmic vacuolization of the upper half of villi was noted in one case (No. I I)

(Photos. 6, 7). Edematous slit adjacent to the basement membrane was seen
occasionally (Photo. 8) . Although some reports imposed a significance to this change,

195

it seemed to be a postmortem change or an artifact change during the preparation(fixation) ofspecimens, since this change is seen also in the intestine of usual autopsy

other than cholera. As a postmortem change, desquamation and sloughing of theepithelium are also noted in usual autopsy materials. In the present study, thischange was advanced (Photo. 22) in cases within 14 hours and slight in cases over
24 hours (Table 3). In consideration of the fact that the subjects of this study were
autopsied within a short time after death, the epithelium must have been in the state

to readily slough in the cases within 14 hours. Normal villous epithelium being
20‑30 p in height is taller than the cryptal epithelium but the height in cholera cases

was reduced to 16.8p in mean being shorter than the cryptal epithelium. The
epithelium in severely atrophic villi was cuboidal or flat (Photo. 9). The brushborder of the epithelium was preserved by PAS stains (Photo. 10). In the caseswith marked inflammatory cell infiltration of the lamina propria, the epithelium
was invaded by lymphocytes (Photos. 7, 9).
ii) Changes in larnina propria
The lamina propria was swollen by inflammatory cell infiltration and the villi

as a whole became blunting. Hyperemia was not noted. Only No. 12 showed
Table 3No.

Epithelial changes and villous fusion of small intestineTime
Age after
onset

Desqua‑mationDege, n‑Height of epithelium
Villus (p) Crypt (p)ofepithelium epithelium
eratron
of

19

21

14

22

++

19

22

8

++

14

18

lO

++

19

21

10

+

lO

11

8

lO

++

19

23

8

2

ll

18

19

9

4

12

++

15

23

10

3

13

++

17

21

ll

14

15

20

12

6 mons
65

24

17

19

13

2

24
30

13

19

20
20
22

18

23

18

22

20

23

18

20

l

45

a few hs.

2

6

a few hs.

++

3

3

7

4

63

5

6

6

20

7

14
15

3

32

16

4

33

17

8

40

18

14

40
41

19

+

++

+
+
+

+

14

20

2

7 ds.

21

22

21

6 mons

3 ws.

15

19

Villuos fusion

Epithelial Proprial

+

+
+

+
+
+
+

+
+
+

+++

+

++

+
+
+

++

++

+++

+

196

hemorrhagic enteritis. The central lacteal showed dilatation in part (Photo. lO)
but this was not characteristic. Inflammatory cell reaction was strong in the cases
within 14 hours (Table 4). Plasma cells were dominant (Photo. 1 1) with minimal
neutrophils in most cases but lymphocytes were dominant in some cases. Histiocytes
were increased in the cases over 24 hours (Photo. 12). In some of the cases within
14 hours, focal invasions of eosinophils were noted but there was no relation to theparasitism of ascarides.
iii) Atrophy of villi

Three sections each of the jejunum and ileum were obtained from the cases forwhich the entire intestine was preserved upon formalin fixation, and histologicalmeasurements were performed (Table 5).
The average mucosal height was 510 p in cases within 14 hours and 442 p incases over 24 hours, the latter being reduced by 13 per cent. The height of thevillus was 294 p in cases within 14 hours and 206 p in cases over 24 hours showing a
reduction by 30 per cent, and the depth of the crypt was 182 p in the former groupand 212 p in the latter group with an increase by 16 per cent. The mean value ofratio of villous height and cryptal depth was I .6 in cases within 14 hours and I .O incases over 24 hours. In comparison with the cases within 14 hours, the cases overTable 4 Infiltration of inflammatory cells to lamina propria

No.

Time Severity Type of cell

Age after onset of Lympho‑ Plasma Histio‑ Eosinophil

infiltration cyte cell cyte (focal)

45

a few hs.

++

2

6

a few hs.

+++

3

3

7

4

63

8

+
+

++

5

6

+

10

++

++

++

6

20

lO

++

8

+

++

7

10

+++

8

2

11

+++

9

4

+

++
++

12

+f +

++

lO

3

13

++

++

11

6 mons

14

++

+++

12

65

24

++

13

2

24
30

+

14
15

32

16

4

33

17

8

40

18

14

40

19

1

41

20

2

7 ds.

21

6 mons

3 ws.

+
+

++

++

+
+

++

++

+
+
++

++
++

+
+

+
+
+
++

+

+++

+

++

+
+
+
+
+
+
+

+
+++

++

+
+

+

+

+

++
++

+

+
+

+

++

++

+
+

+++

++

+
+

197

Table 5 Measurements of villus and crypt

Timeonset
Heightof Depth
Age after
ofvillusof VillusjCrypt inmitosis
10 crypt

Number of

HeightNo.
1mucosa crypt45

a few hs.

510

294

l 82

1 .6

l0.5

254
464
296

l 80

l .4

20.6

226

2.l

7.7

l 64

l .8

4. 7

2 94

l 82

l .6

7.3

400
440
510
516
520
560

l 40

2 40

0.6

3.2

2 48

l 72

1 .4

8.9

350

1 40

2.5

7.8

320
346

1 76

1 .8

8. 1

156

2.2

5.3

236

l 92

l .2

7.l

510

294

1 82

1 .6

476
440
416
496

296

1 60

1 .9

3.3

l 90

230

0.8

12,0

96

300

0.3

12.3

2 40

236

l .O

8. 1

3 44

120

2.9

4.7

236
316

2 OO

l .2

6.0

2 90

l.l

12.0

l 88

0.8

7.0

96

216
220

0.4

5,0

64

152

0.4

3.4

206

212

1 .O

2

6

a few hs.

48 6

3

3

7

710

63

8

6

lO

456
510

4
6

20

10

7

8

lO

8

2

ll

9

4

12

lO

3

13

ll

6 mons

14

Average
12

65

13

2

14

5

32

15

16

24
24
30

4

33

18

14

40
40

19

l

41

20

2

7 ds.

21

6 mons

3 ws.

17

8

Average

484
456
626
424
364
236
442

24 hours show the following characteristics; (1) the mucosal height is decreased,(2) the height of the villus is decreased, and (3) the crypt is elongated.

iv) Fusion of villi
Fusion of villi which is usually considered characteristic to chronic enteritis wasobserved in the subjects of this study. Fusion was seen only between the epithelial
layers of villi in mild cases (Photo. 13) but it involved the lamina propria in severecases (Photos. 5, 14). Thus the degree of fusion increased with time as shown in
Table 3. The architecture of reticulum fibers was observed by silver impregnation
for reticulum. This ranged from essentially normal architecture with broadening ofreticulum fibers due to the infiltration of inflammatory cells (Photo. 15) to what iscalled colonization where reticulum fibers were already increased and communicatedwith the lamina propria ofthe adjacent villi (Photo. 16) . The villous fusions observedin this study were not all the same. It was understood that some of the fusions had
been present prior to the onset and some others appeared after the onset.

v) Number of mitoses in the crypts

198

The crypts are the sites of mitoses of epithelial cells and elongation of crypts
was observed in the subjects of this study (Photos. 4, 5, 14). In view of this, thenumber of mitoses per crypt was measured instead of mitotic index, using 10 crypts
sectioned longitudinally exactly at the middle of cryptal lumens from among the six
intestinal sections per case (Table 5). The value in the subjects of this study was
0.78 per crypt against 0.5 in normal Japanese, indicating increase of cell division of
the epithelial cells.

vi) Goblet cells
Goblet cells as a whole showed increased secretion of mucus and were classified
into the following four phases : (1) Enlarged and filled with secretory granules(Photo. 1 7), (2) secreting, (3) inside becomes reticular with the progress of excretion(Photo. 18), (4) reduced in size upon cornpletion of excretion (Photo. 10). In each
villus, the change from (1) to (4) was observed in order from the base to the tip.
The phases (1) and (2) were common in the cases within 14 hours and the phases(3) and (4) in the cases over 24 hours. Most goblet cells of the crypt were in phases(1) and (2), indicating slower reaction (Photo. 19).
vii) Paneth's cells
The secretory granules of Paneth's cells were eosinophilic in Hematoxyline‑Eosin
stain, and were stained red with azocarmine in Heidenhain's stain and with Ponceau‑
Fuchsin and Orange G in Masson's trichrome stain.
Excretion of granules were enhanced in most of the cases. Granules were being
excreted into the cryptal lumen in some cells and excretion was completed in someother cells becoming empty (Photo. 20) . Granules were hardly recognized in thecells of advanced change. Some granules were irregular in size and some others
were conglomerate to form coarse granules (Photo. 19). Some cells contained only
immature granules that were stained pale blue with Heidenhain's azocarmine stain
and light green with Masson's trichrome stain (Photo. 21). These findings wereseemed to be the result ofenhanced secretion. There was no difference by the courseof time. In comparison between regions, degranulation was somewhat advancedin the jejunum than in the ileum.
viii) Lymphoid tissues in intestine
Hyperplasia of solitary lumph follicles and Peyer's patches were seen in mostof the infants and chidren (Photo. 22). Reaction was strong in the ileum but
hyperplasia of lymph follicles was also remarkable in the duodenum and the jejunum.

Follicles were swollen and the margin became indistinct. Nuclear debris in thehyperplastic germinal center was also noted (Photo. 23). The changes in adultcases and infant cases of 7 days and 3 weeks were minimal.
Comment on small intestine :Morphological studies on the intestinal mucosa of cholera patients were origi‑
nated by an autopsy report by Virchow (1879). He considered that the epitheliumof intestinal villi was denudated and the serum leaked from the lamina propria of themucosa, resulting in voluminous diarrhea. This concept was supported by Koch(1892) and Deycke (1892) and had been believed to be correct for about 80 years.
However, Cohnheim (1889) and Goodpasture (1923) thought that denudation of the199epithelium was rather a postmortem change.
Gangarosa et al. ( 1 960) performed intestinal biopsy in cholera patients using anapparatus devised by Crosby (Shiner, 1957) and demonstrated that the intestinal
epithelium of cholera patients was not denudated. He further described that thehistopathological abnormality of the small intestine in cholera patients was acuteenteritis manifested by mononuclear cell infiltrantion, vascular congestion, marked
hyperplasia of goblet cells with eventual exhaustion atrophy and increased turn‑overof epithelial cells. He attributed atrophic alteration of villi in cholera to the super‑
imposition of acute inflammation due to cholera on chronic atrophic enteritis due topredisposing dietary and nutritional factors in individuals in epidemics. This conceptthat acute inflammation due to cholera is superimposed on chronic enteritis is generally
supported in Western countries (Fresh et al., 1964). Recently, Pastore et al. (1976)
reported that his histological biopsy study of cholera patients during an epidemic in

Southern Italy revealed no chronic sprue‑like enteropathy in Western cholera
patients.

Certainly many investigators have reported that atrophy of villi is observed evenin individuals without diarrhea in tropical regions where cholera may be prevalent(Russell et al., 1966; Chacko et al., 1969). Stransky and Dizon‑Santos‑Ocampo(1957) found severe atrophy of the intestinal mucosa at autopsy of Philippinos withmalnutrition. Sprinz et al. (1962) examined intestinal biopsy specimens of Thai‑landers and reported that the intestinal mucosa of Thailanders of the lower socio‑
economic straturn showed changed which were essentially the same as the changes inpatients of non‑tropical sprue and idiopathic steatorrhea in Western countries, andthat the morphologic findings of the intestine in patients who had had the disease
one year previously and recovered from the disease were similar to the findings ofother Thai people who had never had cholera or any known gastrointestinal disease.
Watanabe et al. ( 1 970) who reported previouly the morphological abnormalitiesof the intestinal mucosa in 12 patients included in this study, flrst classified thealteration of villi into the following three stages.

First stage : stage of inflammation ‑ Inflammatory cell infiltration is marked
in the small intestinal mucosa.

Second stage : Stage of villous fusion ‑ Blunting and fusing of villi dominate
the histological scene resulting in a tremendous decrease of surface area, while
inflammation in the lamina propria is subsiding.
Third stage : villous resolution ‑ Fused villi are again spearated.
According to the relation between the time course of the disease and the featuresof villous alterations, he paid attention to epithelial fusion observed in the second
stage and postulated that the fusion was an acute change. As the materials consistingwith the third stage were not obtained, this stage is still a theoretical one.

In the present study with nine additional cases those in Watanabe's report,
alterations were classified into the first stage and the second stage. In comparisonof the cases within 14 hours and over 24 hours, reduced inflammation, flattenedepithelium, atrophy of villi and elongation of crypts were observed in the latter group,and these alterations were considered to have resulted from cholera.
Sheehy et al. ( 1 964) reported that partial villous atrophy was seen in infectious

200

hepatitis. Collins (1965) and Collins and Isselbacher (1965) demostrated thatsevere villous atrophy was observed in cases other than celiac disease and tropicalsprue, and reported that villous atrophy could be caused by numerous factors. This
indicated that, when a stimulus of any cause is applied to the small intestinal mucosa,
the intestinal villi may possibly result in atrophy (Gottlieb and Brandborg, 1966 ;Schenk et al., 1967; Klipstein and Schenk, 1975).
The mitosis of epithelial cells in the intestinal mucosa occurs in the crypt andthe regenerated epithelium rises like an escarater on the surface of villus and is ejectedfrom the edge of the villus (Leblond and Walker 1956 Kaku et al 1962). The
life span of the epithelium of the small intestinal mucosa is very short being 27 to
30 hours in mouse, 48 hours in rat (Altmann and Enesco, 1967) and 2 to 3 days inman. This suggests that advanced alteration of architecture of the small intestinal
mucosa may possibly take place during a short period of 2 to 3 days in acute enteritis.

Based on the experimental study by administration of Salmonella typhimurium
into the intestine of the guinea pig, Kunita (1972) reported that villous shortening,
villous adhesion, decrease of the villus‑crypt ratio, and atrophic change noted insprue may possibly occur within a day in acute enteritis.
Abram et al. ( 1 963) observed atrophy of villi and elongation of crypts in ex‑
perimental Salmonella typhimurium enteritis, and also confirmed acceleration of epithelial

regeneration on autoradiography and concluded that this played an important rolein alteration of architecture of the mucosa.
Fujita (1971 ) has described from the aspect of cell dynamics that, when a certain
offensive factor is applied to the villus, extrusion of epithelial cells is accelerated andproliferative reaction of the cells is enhanced ; and consequently the crypt becomes
hyperplastic and the villus atrophic, and the small intestinal mucosa is covered withimmature villous cells and its absorptive function decreases. This theory is useful toexplain architectural alteration of the small intestinal mucosa caused by various
factors.

Vlbrro cholerae does not directly Invade the ep thelium of vill and cons quently

the damage to epithelial cells is minimal. However, the enhanced desquamation
as observed in the cases within 14 hours leads us to estimate the degeneration inconsideration of postmortem changes. Moreover, the advanced inflammatory cell
infiltration of the lamina propria suggests a great influence of offensive factors on theintestinal mucosa. The number ofmitoses ofepithelial cells in the crypt was increasedin the subjects of this study.

Kent and Lindenbaum ( 1 967) observed dense infiltration of inflammatory
cells in the lamina propria, decreased villus to crypt ratio and cuboidal change inthe epithelial cell in cholera patients, which were essentially the same as those ofotheracute diarrheal disease found in the biopsy specimens in East Pakistan.
Asakura et al. ( 1 973) conducted a biopsy study of cholera patients and control

subjects at the San Lazalo Hospital in Manila and observed atrophy of villi andelongation of crypts in cholera patients, endorsing the results of examination in thesubjects of this study.

Inflammatory cell infiltration of the lamina propria is a finding which is un‑
failingly described in all reports of autopsy and biopsy materials of the disease (Fresh20 l

et al., 1964). The same finding has been observed also in experimental cholera withadministration of Vibrio cholerae (Goldstein et al., 1966) . There has been a reportthat inflammation was not caused by the adrninistration of cholera toxin (Steinberg
et al., 1975) . This indicates the possibility that intestinal changes in cholera cannot be

explained only by cholera toxin.

There have been many reports that indicate congestion and hyperemia in thelamina propria and submucosa (Fresh et al., 1964; Norris et al., 1965 ; Norris andMajno, 1968; Sun et al., 1971). Morishita (1977) observed redness and hyperemia
in his endoscopic studies. The subjects in the present study were anemic except for
one case (No. 12) with bleeding of the mucosa.
Increment of permeability of blood vessels has been known as another importantbiological activity of cholera toxin (Ghosh and Mukerjee, 1959 ; Craig, 1970;
Kamisaka, 1972). This activity has been observed mostly in the skin (Finkelstein
et al., 1966; Richardson, 1969; Hashimoto et al., 1974) but the relation with diar‑rhogenic activity in the intestine is being discussed (Sprinz, 1962). Increased
permeability is not participated by dilatation of vessels but is described as a cytotoxic

change of the endothelium (Dalldorf et al., 1969). There has been a report of ex‑
perimental study that accumulation of fluid in dogs with Thiry‑Vella loops was not
reduced despite the decrease of blood pressure of the mesenteric artery (Carpenter
et al., 1969).

These results indicate that hyperemia or congestion is not required for excretionof water and that anemic intestinal mucosa in some cases of this study is notunreasonable.

Enhanced excretion of goblet cells have been reported on many human andexperimental cases (Norris and Majno, 1968; Elliott et al., 1970; Blackman et al.,1974) . Since the decrease of goblet cell mucus was seen only in cholera toxin incomparison between shigella toxin and cholera toxin (Steinberg et al., 1975), enhanced
excretion of goblet cells may be the effect of cholera toxin. In this study also,enhanced excretion was remarkable and the surface of the mucosa was covered witha thick mucous coat. Increased production and excretion of mucus were observed
also in goblet cells of the colonic mucosa and the bronchial mucosa, and these changes
were considered to have the same mechanism as in the small intestine, namely cholera
toxin.

Paneth's cells were present at the base of crypts and contained in the supranuclear

region granules of equal size measuring approximately I p and being eosinophilic
in staining. The secretory granules are known to be digestive enzymes but their
quality and physiological activity have not been thoroughly elucidated (Hally, 1958).
Thurbeck et al. (1960) repoted that the number of Paneth's cells increased in tropicalsprue, whereas Shiner and Doniach (1960) have found no remarkable change.
There have been no report on the number of Paneth's cells and their excretion incholera, but considerably enhanced excretion was noted in this study.
The intestinal changes in the subjects of this study may be summarized as follows.
1 . The villous architecture of the small intestine showed sprue‑like changes
in the course of tirne such as shortness of villi, villous fusion and elongation of crypts.

In some cases of this study, the sprue‑like changes seemed to have been present prior

202

to the onset of cholera but it was suggested that the changes were intensified during
the course of cholera. Cholera is an acute intestinal infectous disease with quite ashort course and little epithelial injuries, but the changes resulting therefrom aresprue‑Iike changes.

2. The intestinal epithelium seemed to be degenerated slightly. This was
suggested by the intensified epithelial desquamation as the change in agonal andpostmortem states. This desquamative change was remarkable in the cases within
14 hours.

3. The inflammatory cell infiltration in the lamina propria involving mostly
plasma cells and lymphocytes was remarkable in the cases within 1 4 hours. The
infiltrative cells were then replaced by histiocytes. The small intestine was anemic
without congestion and dilatation of blood vessels. Hyperplasia of lymphoid tissue
and reaction of germinal center were remarkable.
4. The number of mitoses increased in the crypt. This was considered due toinfiammatory stimulation. This resulted in expansion of the proliferative zone,i.e., elongation of the crypt.

5. The exocrine cells such as goblet cells and Paneth's cells showed enhanced
secretion.

STOMACH
Macroscopic findings :Dilatation was noted in half of the cases and the internal cavity was filled withgas, watery content and sometimes coffee ground‑like material. There was no
erosion or ulcer and the mucosa was pale.
Histological findings :Histological examination of the stomach was performed on 1 7 cases. Edemaof the lamina propria and submucosa, and inflammatory cell inflltration were notobserved (Photos. 24, 25). Slight desquamation of the mucous epithelium was seenin half of the cases. Mucous cells of the epithelium showed enhanced excretion(Photo. 24) . Probably because of the enhanced excretion of zymogenic granules in
the chief cells, coarse density of intraplasmic zymogenic granules was noted in 60
per cent of the subjects, and such granules almost disappeared in four severe cases.
Parietal cells showed large vacuoles in the cytoplasm in six cases. Particularly insevere cases, the cytoplasm was almost vacuolated (Photo. 26). Changes wereintensive in the neck portion of the gastric gland. Atrophic change of the mucosa
was noted in one (No. 4, age 63) of the two senile cases but not in the other case (No.
1 2, age 65) with hemorrhagic gastritis.

LARGE INTESTlNE
Macroscopic findings :Trichuris was seen in 10 cases. Meteorism (gas containing) was noted in fourcases and marked dilatation or relaxation of the colonic wall in five cases. The

203

content ranged from rice‑water like fluid to that mixed with bile and occasionallywith minimal blood coagula. The mucosa was covered with white mucus, and insome cases, the content was scarce. The mucosa was pale except in four cases withhyperemia.
Histol ogical findings :The main changes were increased secretion of goblet cells with slightly increased

desquamation of the epithelium of the free surface of the mucosa. The epithelial
desquamation was more intensive in the cases within 14 hours. Goblet cells were
either filled with mucus (Photo. 27), marked with secretion together with dilatationof the gland (Photo. 29), or reduced in size upon completion ofsecretion (Photo. 29).
Round cell infiltration of the lamina propria was more intensive (Photo. 29) in thecases within 14 hours. There was no infiltration of neutrophils. In case No. 20(7 days), acute colitis with features such as dilatation of glands, formation of cryptal

abscess and severe inflammatory reaction of the lamina propria was noted.
Comment on stomach and large intestine :Concerning findings of the stomach in cholera, no change is reported in some
reports and mild inflammatory reaction in some others (Gangarosa et al., 1960;
Pastore et al., 1976). Inflammatory flndings were scarce in this study. An increaseof secretion was suggested in exocrine cells, particularly chief cells and parietal cells.

A Iarge amount of Vibrio cholerae and cholera toxin was included in the regurgitatedfluid from the intestine and it was possible that the exocrine glands of the gastric
Table 6 Findings of stomach and large intestineTime

No. Age after onset

StomachVacuoli‑ Decrease Desqua‑zation ofofmationinfiltra‑parietal granules

tion to Accumu‑ Secre‑ Post‑

cell

of

in epithelium
chief cell

2
3

4

a few hs.

9

63
8
4

10

3

11

12

6 mons
65

13

2

7

14
15

3

16
17
18
19

4
8
14
l

8
10

+
+

12
13

14

24
24
30
32
33

40
40

+

+

+
+
+
+
+

41

20

2

7 ds.

21

6 mons3 ws.

Goblet cell

propria rationtion
secretion

+

+ ++

++

+
+

++
++

++
++

+

+
+
+
+

++

+
+
+
+
+
+
++

+
+
+

+++

++
++

++

+
+

+

++

Large intestine
Cell

+

+++

++

++

+++

++
++

+

++
++
++
++
++
+++
+++

++

+++

+

++

+++

+++

+
+
++

+

++
++

+

++
++
++
++
++

++

+

+

++

204

mucosa were stimulated by cholera toxin.
In the large intestine, inflammatory reactions of the lamina propria and increaseof goblet cells in the epithelial layer were observed. These findings were compatible
with the reports by other investigators.

MESENTERIC LYMPHNODESMacroscopic findings :Examination of mesenteric lymphnodes was performed on 1 8 cases. Lymph‑
nodes were palpable in all the cases and the swelling was remarkable especially ininfant and child cases within 14 hours. Lymphnodes of index finger size were seenin heaps. The size was small in the cases of 7 days and 3 weeks. In the adult cases,
the number as well as the size were small. The swelling of lymphnodes in the otherregions was milder.
Histological findings :The following three types were observed separately or in combination.
i) Swelling of lymph follicles and reaction of germinal centers (Photo. 3 1 )ii) Diffuse proliferation of lymphocytes (Photo. 32)iii) Swelling and proliferation of reticulum cells.

There was no infiltration of neutrophils, eosiophils and plasma cells. Hyper‑
plasia of lymph follicles with reaction of germinal centers was remarkable in the infant

and child cases within 14 hours, mild in the cases over 24 hours, and not seen in thecases of 7 days and 3 weeks. Proliferation of lymphocytes filling the cords andsinusoids was severe except in one case of 3 weeks and adult cases. Swelling ofreticulum cells and diffuse, scattered or sinusoidal proliferation were seen in half ofthe cases and were severe in three cases. The reaction in all adult cases was mild.

SPLEEN
Macroscopic findings :Moderate swelling of the spleen weighing 225 g and 190 g was respectively noted
in two of four adult cases. There was no definite swelling in the other two cases aswell as in the infant cases.
Histological findings :There were great differences between infant and child cases and adult cases but
no differences by the lapse of time. In infant cases, Iymph follicles increased in sizeand particularly the germinal centers showed sizeable swelling, reaction and atendency of necrosis (Photo. 33). Larger germinal centers reached 600 p and manycell debris showing destruction were seen (Photo. 34). The red pulps were abundantin blood content which was distributed in both sinusoids and cords but mostly in theformer. Resolution of tissue was evident in seven cases. Most of cords showed
distension. Inflammatoly cell infiltration was generally mild, but polymorphonuclear
leukocytes, eosinophils, Iymphocytes, plasma cells and reticulum cells were occasion‑
ally noted. The above changes were slightest in the adult cases.

20 5

Table 7Microscopic findings of mesenteric lymphnode and spleen

Mesenteric lymphnodeTime

No. Age after onsetoffollicle

1,
::c.

1:l

::
, c:$

F

1

:

s

1'

<

prolifera‑oftion of reticulum

a few hs.

++

+++

7

+++

++

+++

++

++

+++

+++

+

++
++

+
+

13 2
14 5
15 3
16 4
17 8
19 l
20
2
21 6 mons

24
30

12

45
63
20
65

18

14

4
6

Follicle

Swell‑ Necrosis
ing

lymphocyte cell

2 6
3 3
5 6
7 8
9
4
10 3

l 1 6 mons

SpleenReaction Diffuse Reaction

lO
10
12
13
14

32
33

40
41

+

+
+

+

++

7 ds.

+

++
++
++
++
++
+++

3 ws.

+

+
+
+

++

8
lO

++

+

+
+

+

+
++

+

+

tion 'tron
+

+
+

+
+
+

+

++
++

++
++
++
++
++

++
++

++
++

++
++

++

+

+

+
+

++

+

++

a few hs.

24
40

++
++

++
++

of germ‑
inal center

Red pulp
Conges‑ Resolu‑

+
+

+

+

+
+

++

+
+
+
+

+

+

+

Comment on mesenteric lymphnodes and spleen :Hyperplasia of lymphoid tissue in the intestinal wall has long been known.
Hyperplasia of mesenteric lymphnodes was noted also by Norris ( 1 973). Reactionsof lymph follicles in the spleen were observed by Norris ( 1 973) and Sun et al. ( 1971).

Norris (1973) described that the size of mesenteric lymphnodes and lymph follicles
in the spleen did not change.
It was clarified in this study that reactions of the spleen and mesentericlymphnodes were more remarkable in infants and children like lymphoid tissue ofthe intestinal wall. The reactions of lymphoid tissues of the intestinal wall,
mesenteric lymphnodes and the spleen, especially lymph follicles, showed similarity
and were considered to have been developed by the same agent. It has been known
that the germinal centers of lymph follicles react to a shock but are not swollen.

The fact that only mesenteric lyrnphnodes were swollen among other lymphnodes
may suggest that this reaction was enterogenic, i.e., the possibility that some stimu‑
lating substance was absorbed from or produced in the intestine.

LIVER
Macroscopic findings :liver

There was no manifest increase in weight nor swelling in the parenchyma of theAcute congestion of moderate or severe degree was noted in 1 2 cases. The

206

consistency was somewhat decreased. Fatty metamorphosis frequent in the cases
over 24 hours. The gall bladder was filled with a large amount of pale green bilewith hypoviscosity in many cases.
Histol ogical findings :Severe degeneration and necrosis of liver cells were not observed. Fatty
metamorphosis was observed in all cases (Photo. 35) except for case No. 4 and caseNo. 5 with cirrhosis. Table 8 shows the degree of metamorphosis, size of fat dropletsand distribution in acini in corse of time. Since fatty liver in malnutrition was
frequent, nutritional state at the autopsy was also described. Fatty metamorphosis
was definitely severer in the cases over 24 hours as compared with the cases within
14 hours. Fat droplets were large in the cases of severe fatty metamorphosis (Photo.
36) and were fine in the cases of mild fatty metamorphosis (Photo. 37). The dis‑tribution in acini showed a tendency to shift from centroacinar one to diffuse one.
In the subjects of this study, nutritional state was not always poor as shown in the
Table and consequently there was no correlation between nutritional state and thedegree of fatty metamorphosis.
Mobilization of Kuppfer's cells was seen in most cases (Photo. 38) . Lymphocytes
Table 8Fatty change of liver

Fatty change

No.

Age

Time

DegreeSize offat droplet

+
+

S
S
s

+++

L

after onset
l

2
3

4

45
6

a few hs.

3
63
6

7

a few hs.

8

20
8

10
10
10

8
9

2

11

4

12

10

3

13

11

6 mons
65

14

5
6
7

12

13
14
15
16
17
18
19

++

2

5
3

4
8
14

24
24
30

+
+

+++

L

++
+f +

+
+++

2

7 ds.

+++

21

6 mons

3 ws.

+++

D: diffuse

D
P

+++

P: peripheral

C
C

DM
P

20

L : Iarge

M
M

S
S

40
40

C: central
M : medium M : mid zonal

D

ML

+++

S : small

L

C
C

++
++
++
++

32
33

41

S

Distribution

G: good
N: normal
bad

M
M
M
L
S

L
L
L

D
D

PC

PM
D

Nutritional
state

G
N
N
G
N
N
N
G
B

C

G
N
G
G

PM
D

B

D
D

207

and neutrophils, though few in number, were seen in the sinuses in half of the cases.
In the portal areas, mild round cell infiltration was seen, and dilatation of the branchesof the portal veins was noted in 1 3 cases.
Comment on liver :In the autopsy reports by Sun et al. (1971 ) and Norris ( 1973), fatty metamorpho‑

sis of the liver was observed in numerous cholera patients. They attributed thefatty metamorphosis to malnutrition and considered no relation to cholera infection.
In the present study, the nutritional state of patients was not necessarily poor. Fatty
metamorphosis was positively severe in the cases over 24 hours after the onset ofcholera as compared with the cases within 14 hours. It is possible that some of thepatients in this study had fatty metamorphosis before the onset of cholera. Never‑theless, it is certain that fatty metamorphosis of the liver was intensifled by cholera

infection, and it is suggested that cholera infection may possibly induce fatty
metamorphosis of the liver.
As the possible mechanism, ( I ) direct effect of absorbed cholera toxin on the liver

through the portal tracts, (2) ischemia and anoxia due to shock resulting fromdehydration, and (3) acute nutritional deflciency resulting from dysfunction of thesmall intestine because of cholera, can be considered.

PANCREAS
Histol ogical findings :Inflammatory changes were not seen in either the interstitium or parenchyma.
To examine the secretory condition of the pancreatic juice, zymogen granules inacinar cells that are enzymic component were studied. Zymogen granules were
stained by Hematoxyline‑eosin stain, PAS stain, Heidenhain's azocarmine stain
and Launoy's method, but Heidenhain's azocarmine stain was the most effective.
In three cases dying within 8 hours after the onset, the secretion of zymogen
granules was likely to be just completed and the supranuclear portion or the entire

cytoplasm was foamy with a scanty amount of zymogen (Photo. 39). However,the quantity and distribution of zymogen were different by acinus or individual cell.
Among six cases of 10‑14 hours, zymogen granules were increased filling the cyto‑
plasm in four cases (Photo. 40), and a moderate amount of zymogen granules together
with somewhat large vacuoles at the base of the cytoplasm were observed in twoother cases. A variety of quantity with a tendency of gradual decrease with time
was seen in seven cases of 24‑41 hours. Mild atrophy of the acinus was shown in
one case of 40 hours (Photo. 41).

In two cases of 7 days and 3 weeks, zymogen granules were hardly recognized,
the acinus was atrophic and the lumen of the acinus was dilated containing dense
fluid material. Fibrosis was seen in the interacinar space (Photo. 42).
Comment on pancreas :The results of this study suggest that the exocrine system of the pancreas might
be stimulated in its function for production and secretion of digestive juice in cholera.

208
Table 9Time

Microscopical findings of pancreas

Amount of' after onset zymogen granule of acinus
2

a few hs.

foamy in apex+

3

Others

4
6

10

++

7

lO

8

ll

++
++

foamy in supranucleus

8

foamy in cytoplasm

9

12

+

vacuole in base

10

13

+

vacuole in base

ll

14

++

13

14

24
30

++

15

32

16

33

17

40

18

40

19

41

+

+
‑h

+

20

7 ds.

++

dilatation of lumen

21

3 ws.

++

dilatation of lumen, fibrosis

In the very early stage of the disease, microscopical examination of the acinar cell
yields the feature which is usually found after the secretion of zymogen granules.
In the second stage, I 0‑14 hours after the onset, the acinar cell is accumulated withthe granules. The cases with long time course show the exhaustion of acinar cells.
Watanabe (1968) described in his paper entitled "The importance of pancreatic
excretion from the standpoint of acute diarrheal diseases", that as for the mechanismof hypersecretion of digestive juice, taking cholera as an example, the following points
are to be taken into consideration :l) Cholera toxin contains a secretin‑like substance stimulating secretion of
pancreatic juice.

2) Cholera toxin directly stimulates the duodenal mucosa to release secretin.
3) Cholera toxin‑induced inflammation of the duodenum itself leads to releasing
secretin.

The data reviewed here are concerned with secretion of zymogen granules that aredigestive enzymes. Greenough (1965) proposed the hypothesis that cholera is a
syndrome of hypersecretion of secretin or secretin‑1ike hormons, secondary to stimu‑
lation of the upper gut mucosa by cholera vibrios. Secretin causes the pancreas tosecrete a large amount of fluid containing bicarbonate with little enzymic activity.
Pancreozymin causes secretion of digestive enzymes. When they act coordinately,a large volume of enzyme‑rich pancreatic juice is secreted from the pancreas. Besides,

the pancreatic exocrine response is probably mediated by gastrin, glucagon andvasoactive intestinal peptide (VIP). It is interesting to note whether the level of209

these hormones in blood is raised or not in the cholera patient (Morishita et al., 1976).

Fujita et al. (1975) found the release of serotonin and some polypeptide but did not

find secretin nor pancreozymin from the rabbit duodenum by administration ofcholera toxin into the loop. At least, in human cholera, the severest inflammatory
condition is found in the duodenurn, the mucosa of which shows edema and marked
infiltration of inflammatory round cells, besides the structural changes such as fusing

or atrophy of villi. This acute inflammation of the duodenum might be strong
enough to release some hormones from the duodenum which stimulate the pancreas.
There might be the possibility that the natural cholera stimulates the exocrine
cells of the digestive system including the stomach, intestines and pancreas to promote
their secretion and production.

LUNG
Macroscopic fudings :Hyperemia was recognized in six cases but the other cases were all anenuc.
Mucous secretion in the trachea and bronchus was noted in one case within 14 hours
and in seven cases over 24 hours.
Histological findings :Bronchial changes and pulmonary changes probably due to aspiration of gastriccontent containing a large amount of Vibrio cholerae and cholera toxin were notable.

i) Bronchus
There was no such change as desquamation or erosion of the bronchial epithelium.
Acute bronchitis was observed in no more than two cases among 1 7 cases not including

three caseof chronic bronchitis. In some cases, the lumen of the bronchus wasfllled with fluidal content and desquamative epithelia. In half of the cases, goblet
cells in the bronchial epithelium were increased in number, indicating increased
secretion or accelerated production of mucus (Photo. 43).

ii) Aspiration pneumonia
Severe aspiration pneumonia was not recognized but inflammatory reaction
seemingly due to aspiration was noted in 15 out of 20 cases. Infiltration of eosin‑
ophils and lymphocytes and proliferation of macrophages phagotizing brown pigments
deriving from vomitus were seen in the intraalveolar or peribronchial region (Photo.

43). Inflltration of neutrophils was mostly mild. There was no appearance of
foreign giant cells.

Comment on lung :Repeated vomitings were noted in most cases. The possibility of inhalation isgreat especially in the state of cloudy consciousness. Dyspnea and cough were also
noted in many cases.
Norris (1973) reported that pulmonary pathology was noted in 87 per cent andsevere bronchopneumonia in 41 per cent. In the present study, reaction to aspiration
was recognized in 75 per cent although there was no case of severe bronchopneumonia
induced by cholera.

210

Increased secretion of goblet cells in the bronchial epithelium was noticed by
Shozawa and Sekine (1974), who later suggested the possibility that the mucus leads
to obstruction of airway and reapiratory distress.

HEART
Macroscopic findings :Despite the prominent decrease of circulating blood by dehydration, the rightatrium and the right ventricle were filled with blood and the wall was dilated. The
blood was dark red and highly viscous because of severe dehydration.
Histol ogical findings :Myocarditis and necrotic foci of myocardium were not recognized. Vacuolationof perinuclear cytoplasm was noted in 13 cases (Photo. 44). Staining of the myo‑cardium by Heidenhain's azocarmine stain was irregular in 15 cases (Photo. 45).
This change showed no difference by time course or age. Fatty change disclosedby oil‑red O stain for fat was minimal, being recognized only in two cases of 40 hours
and 7 days.
Comment on heart :The effects of cholera on hemodynamic, particularly hypovolemia and acidosis
have been described in detail by Harvey et al. ( 1 968). The central blood volume
was large especially in the right atrium and the right ventricle that showed dilatation
also in the present study.

Anitschkow myocytes that were found by Goldstein et al. (1966) upon venous
injection of Vibrio cholerae to guinea pig and by Sun et al. (1971) in their autopsy cases,

were not observed on this histological examination. Focal myocarditis describedby Norris (1973) was not observed either.
In the present study, exhaustion of the myocardium was speculated in view of
the irregularity in staining by Heidenhain's azocarmine stain and the perinuclear
vacuolar change.

Fatty change of myocytes observed in the liver and kidney was noted only in
two cases and it was quite minimal.

KIDNEY
Macroscopic findings :The kidney showed no increase of weight nor swelling of parenchyma.
Histological findings :There was neither interstitial edema nor round cell infiltration. The cortex
showed congestion in a few cases but it was obviously anemic in some other cases.
The medulla showed congestion in half of the cases. The glomeruli were not re‑markable. The tubular epithelium was tall with narrow lumen and scant content.
In eight of I I cases dying within 14 hours after the onset, severe hyaline droplet

211
Table 10 Microscopic findings of kidney

No.

2

A ge

HyalineVacuolarafter onset
dropletchange change
formation45

a few hs.

6

a few hs.

Time Fatty
+

3

3

7

++

4

63

8

++

5

6

10

+

6

20

10

++

7

8

lO

++

8

2

11

++

4

12

++

10

13

ll

6 mons

14

12

65

24

++
++
++

13

2

24

9

30

14

+
+
+
++

+

+

15

3

32

+ ++

16

4

33

+++

17

8

40

+++

18

14

40

++

19

1

41

+

20

2

7 ds.

+++

++

21

6 mons

3 ws.

+

++

+++

formation focal to the neck portion of proximal tubules was observed (Photo. 46).
Hyaline droplets were also present at the urinary pole of Bowman's capsule or in theproximal convoluted tubules in some cases. Hyaline droplet formation of theentire proximal tubules was seen in a few cases. Among the cases over 24 hours,
only two cases showed remarkable hyaline droplet formation.
Fatty change of the tubular epithelium was seen mostly in the cases over 24 hours(Photo. 47), and the change was severe in five cases. The change extended to theentire tubules in severe cases but localized to the proximal tubules in mild cases.
The fatty change of the kidney was comparable with that of the liver in its degreein each patient.

Coarse vacuolation of the tubular epithelium as noted in hypokalemia wasseen in two cases of 7 days and 3 weeks (Photo. 48).

Patchy necrosis of the tubular epithelium was recognized only in one case of
40 hours (Photo. 49). Cloudy swelling or degeneration was severe in three cases
and mild in the other cases.
Comment on kidney :The renal failure as a complication of cholera has been a matter of great concern.

212

As a cause of this disturbance, the followings have been implicated; acute fall inblood pressure (Basu, 1961), hemoconcentration, acidosis, anoxia (De et al., 1954)
and hypokalemia (Benyajati et al., 1960). Histological features in the cholera
kidney have been reported as necrosis and fatty change in the cortical tubules follow‑
ing cortical ischemia and medullary congestion (De et al., 1954), and hypokalemicvacuolation (Benyajati et al., 1960).

Many observers accept recently the concept that hyalin‑droplet formation isdue to reabsorption of the protein in the glomerular filtrate by the epithelium in theproximal tubules. As total blood volume is decreased and the plasma protein is ofhigh concentration in the patient before establishment of rehydration, the volume
e gl omerular filtrate might be decreased and its concentration of protein mightof th
be high. It is interesting that hyaline droplets were seen in many of our cases
especially in the cases dying within 14 hours and were strictly limited in and near theneck portion of the tubules, probably because of decrease of volume and high con‑centration of protein in the glomerular filtrate. Droplets in the cases over 24 hours
disappeared, which might be digested in the cells within a short time after rehydration.

Fatty change should be progressive in the early stage of cholera. It is noticed
that fatty change corresponded between the kidney and liver. This might indicate
the presence of some simultanously acting factor in the blood causing this change tothe kidney and liver.

Hypokalemic nephropathy characterized by coarse vaculoation of tubularepithelium was present in long standing cases, 7 days and 3 weeks. This is consistent

with the observation that the vacuolation takes about a week to develop in man.
In our cases of early stage of cholera patients dying before 41 hours, tubular
degeneration and necrosis were mild as some observers have reported.

ADRENALS
Histological findings :Mild hyperemia was present in some cases. Inflammatory cell infiltration,
hemorrhage and focal necrosis of the cortical cells were not observed. Functionalchanges due to hypovolemic shock were seen in the fascicular zone. Clear like cells
decreased and compact like cells (Photo. 50) increased with the course of time
especially in cases dying after 24 hours. Oil red O stain was performed on I O cases
and marked decrease of lipid was recognized in two cases (Table 1 1 ) .
Comment on adrenals :Rich ( 1 944) observed tubular formation involving inflammatory reactions of
the solid cords of the cells of the fascicular zone in diphtheria and other severe in‑fections, but no such changes were seen in the present study. De et al. ( 1955) reported

that they could not find any remarkable change by ordianary staining method in
examination of adrenals of cholera patients, and pointed out evidence of various
degrees of depletion of cortical lipid. They speculated that this might be the activerole of the cortex in response to the stress by dehydration of cholera. In our study
also, histological abnormalities were not observed in the cortex, and changes due to213

Table l I Mrcroscopic flndings of lung, heart and adrenal gland
Adrenal gland

Heart

Lung

Time Changes Hyper‑

Deple‑

No. Age after onset by Peribron‑ secretion Vacuo‑ Irregu‑

aspira‑ chitis of goblet lar larjty intion cell change stammg

45

a few hs.

6

a few hs.

3

3

7

4

63

8

5

6

10

6

20
8

10
10

8

2

ll

9

4

12

2

lO

3

13

11

6 mons

14

12

65

13

2

14

5

24
24
30

15

3

32

16

33

17

4
8

18

14

40
40

20

2

21 6 mons

7 ds.

++

+
+
+
+
+
+
+
+
+
+
+
+

41

19

+

+
+

+

3 ws.

+
+

chronic

++

+

+++

chronic

+

+
+

++

+
++

+

chronic

++

+

+
+

Predominant
cell incortex

+
+
+
+
+
+

clear, compact++

compactlipid(oil red O)++
clear, compact
clear+
compact

+
+

++

clear

normalclear, compact

+
+

clear

+

compact

+++

clear

++

compact
compact
compact+++tion of

+
++

++

++
++

+

+

compact, normal+++compact, normal
clear

the stress whrch seemed physiological were seen in the fascicular zone.

BRAIN
Macroscopic findings :Study of the brain was performed on five cases. The brain showed swelling(Table 12). Particularly in two cases of age 2, the swelling of the brain was re‑markable, weighing I ,300 g, and showing tonsilar herniation.
Histological findings :There were observed retraction of the nerve cell body and pericellular edema(Photo. 51), both of which were considered ischemic changes.
Comment on brain :The cerebro‑neural symptoms observed in this series were cramps in three infant

and child cases and severe disturbance of consciousness in many cases. These214

symptoms were seemed due to circulatory disturbance of the brain caused by severe

hypovolemic shock. Cerebral swelling and histological abnormalities such as
edema and retraction of nerve cells seem to have resulted from ischemia and anoxia.
It is estimated that these changes should be related to the cause of death.
Table 1 2 Findings of brain

No.

Age

WeightPressure Pericellular edema

brain (g)Basalgangliaof

8

2

1 , 300

10

3

l,130

13

2

l ,300

15

3

1,150

17

8

1,270

cone Cortex

+
+

+
+
+

+

+

CONCLUSIONSi) Effects of cholera on organs in the body
Unlike Shigella (Takeuchi et al., 1965), Vibrio choleae does not penetrate throughthe intestinal epithelium nor does enter the blood via the lamina propria as seen in
Salmonella (Takeuchi and Sprinz, 1 967; Takeuchi, 1 971). There have been reportsthat in rabbit cholera toxin was not found in the lamina propria or blood vessel
even when it was found in the supranuclear portion of the epithelium, and that inmouse cholera toxin adhering the surface of microvilli would not penetrate throughthe epithelium (Peterson et al., 1972).

The evidence that hyperglycemia and the increased levels of serum alkaline
phosphatase (SAL‑P) and glutamic‑oxalacetic transaminase (SGOT) resulting fromintravenous administration of cholera toxin in dog is not recognized in cholera
patients (Pierce et al., 1972) supports that cholera toxin is hardly absorbed. However,a minirnal amount may be absorbed since the level of antitoxic antibodies in theserum of the patients increases (Pierce et al., 1970). In the experiment of forming
two loops in the intestine of the rabbit and injecting crude cholera toxin in one loop
(Serebro et al., 1968), observed accumulation of fluid in the other adjacent loop in

which the mucosa had no direct contact with toxin, Vaughan‑William andDohadwalla ( 1 969) reported that injection of cholera toxin and Vibrio cholerae in
the intestine of one rabbit by cross circulation experiments on paired infant rabbits
resulted in accumulation of fluid and diarrhea in the intestine of the other rabbit.
These phenomena suggest that some diarrhogenic substance is present in the blood
affected by cholera toxin.
Fujita et al. (1975) found that cholera toxin administered into the rabbit duo‑
denum caused severe degranulation of enterochromaffin cells especially of those cells
secreting serotonin and some peptide (Motilin?), and pointed out the possibility thatthese are the circulating messengers of diarrhogenic action of cholera toxin.
CAMP was found by Sutherland and Rall (1958). Field et al. (1968) and Field(1971) found that cAMP, theophylline and cholera toxin demonstrate the same

215

mechanism in causing transport of fluid (Na+ and Cl‑) in the intestinal mucosa.
Subsequent studies (Chen et al., 1971 ; Kimberg et al., 1971) proved that CAMP andadenyl cyclase are diarrhogenic factors in cholera.

In addition to diarrhogenic action, cholera toxin is known to have various
effects such as increased skin capillary permeability, enhancement of lipolysis by rat
epididymal fat cells (Vaughan et al., 1970), increase of adenyl cyclase activity inmouse liver cells (Gorman and Bitensky, 1972), and stimulation of glycogenolysis in
human platelets (Zieve et al., 1971 ) and rat liver cells. Morishita (1977) has observed
increased level of CAMP in the blood of cholera patients.
If cholera is an event limited only to the intestinal lumen and its adjacent mucous
epithelium with little or no absorption of cholera toxin, the changes in the body bycholera except for gastrointestinal changes and pulmonary changes due to aspirationmust be secondary to hypovolemic shock, acidosis and hypokalemia resulting frorn
dehydration.
In this study, some findings that cannot be explained only by dehydration

resulting from diarrhea were found in some organs. First, these changes are
hyperplasia of the mesenteric lymphnodes and inflammatory reactions of the spleen.
Hyperplasia and reaction of the lymphoid tissues in the intestinal wall are under‑
standable since these tissue are located where stimuli are directly received. However,the changes of the mesenteric lymphnodes and the spleen suggest the presence in the
body of sorne stimulating substance deriving from the intestine.
Secondly, the changes are seen in the liver. Fatty metamorphosis of liver cells
is hardly explained as a change due to dehydration. The liver is an organ easily
influenced by the intestine through the portal vein. Pierce et al. (1972) observed

hyperglycemia and increased levels of SGOT. and SAL‑P after parenteral admini‑
stration of cholera toxin. The change of glycogen is related to cAMP. SGOT and
SAL‑P are also considered to derive from the liver.
The third changes are fatty change of renal cells, which is severe despite the mild
change of the tubular epithelium due to circulation disturbance. The fourth changes

are the increased production and secretion of zymogen granules in the pancreas.
Consequently, factors deriving from the intestine seem to be active in various parts ofthe body. Sun et al. (1971) noted Anitschkow myocytes in the myocardium ofcholera patients and damage to endothelial cells of the small blood vessel, althoughthese changes were not observed in our series, and he attributed these changes topossible evidence of the toxicity of cholera toxin. This may also provide anendorsement.
ii) Cause of death in cholera patients
In comparative studies of autopsy flndings between cholera patients dying before
and after 1960, Norris (1973) states that over 50 per cent ofpatients (Cash et al., 1973)

dying of cholera succumbed of renal failure before 1 960 but the frequency of renal
lesions decreased to 5 per cent after 1 960, and attributes this improvement to transfusion.

In the present study, the renal lesions were so mild as to be the possible causeof death. This may be due to the fact that most of the patients in this study diedwithin 2 days after the onset before the appearance of severe renal lesions and they
were provided with transfusion.

216

Dying ofdehydration may be explained morphologically by cardiac failure due toexhaustion of myocardium and by herniation of tonsils due to swelling of the brain.
Respiratory disturbance due to aspiration of gastric content may also be con‑sidered as the cause of death in some cases.

ACKNOWLEDGEMENTS
The author wishes to express his grateful thanks to Prof. Issei Nishimori, Depart‑

ment of Pathology, Atomic Disease Institute, Nagasaki University, for helpful
suggestions and continous encouragement, to the late Prof. Toyosuke Watanabe,
Department of Pathology, Institute for Tropical Medicine, Nagasaki University,
for guidance in this study and preparing autopsy materials, to Prof. Takeshi Schozawa,

Department of Pathology, Akita University, for valuable advices, to Dr. Kazumine

Kobari, the President of Hamamatsu Medical Center, for his kind advices andarrangement the autopsy in Manila, to Prof. Tatsuro Naito and Assis. Prof.
Masaaki lwanaga, Department of Bacteriology, Institute for Tropical Medicine, forthe opportunity in presenting this paper, to Prof. Hideo Tsuchiyama, Department of
Pathology, Nagasaki University, for kind guidance in studying about the adrenals
in this study, to Dr. Masao Nakatomi, Department of Internal Medicine, Nagasaki
University, for assistance in the autopsy in Manila, to Dr. Reyes, the Chief Doctor of

Pathology, San Lazaro Hospital, and Dr. Uylangco, the President of San Lasaro
Hospital, for permission to do the autopsy at their hospital, to Miss Toshiko Fukushima

and Miss Yukie Kunita, for their excellent technical assistance in tissue specimen
preparation.

This study was supported by U.S.lJapan Cooperative Medical Science
Program, Cholera Panel.

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219
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o飾ntllchen
stagestheMedizin，

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コレラ初期変化の病理学的研究

一21剖検例をもとに一
関

根

一

郎

1968−1970年マニラ市サン・ラザロ病院で死亡，剖検された21例のコレラ患者の病理形態学的観察を行った。コレラは発症後短時間で治癒または死亡する疾患であるが，特に材料を時間経過にもとづいて観察することにより，コレラ特有の病像のいくつかを浮揚せしめた。また形態的変化をもとにコレラの病態生理についても言及した。

材料（21症例）は次の特徴をもつ。1）7日・3週の2例を除き，発生後41時間以内の短時間で死亡している。2）小児が多く，16／21を占める。3）死後変化を阻止するため死後短時間で剖検され，
20／21は2時間以内であった。

結論は次の通りである。
1） 小腸粘膜異常は，炎症性反応とそれに続発する絨毛萎縮である。この萎縮はコレラ感染による炎症性刺激で，腺窩に細胞分裂充進が起こったことが大きな役割を果たしていると考えられた。
2）外分泌細胞充進がみられた。小腸・大腸・気管支の杯細胞，小腸パネート細胞の分泌充進が示された。膵チモーゲン穎粒・胃底腺・胆汁の分泌充進も窺われた。

3）

コレラ毒素又は何らかの物質が体内へ侵入する可能性を示した。これは，a）腸間膜リンパ節及ぴ脾のリンパ濾胞の反応，b）肝・腎の進行性脂肪変性，c）膵外分泌充進，等により推察された。
4）

コレラの死因として，脱水にもとづく心不全，脳浮腫が挙げられる。誤飲による呼吸障害も考慮されるべきである。脱水による腎不全は初期の適当な輸液により防ぎ得ると思われた。

長崎大学医学部原爆後障害医療研究施設・病理学部門，長崎大学熱帯医学研究所病理学部門

221

Phota, l Dissecting microscopic findings of the upper jejunum of No. 4., 63‑year‑old male of 8hours. A,Imost villi are leaf like and m rry of them f'orm ridge,,s.

Photo. 2

Dissecting microscopic findings of the upper jejunum of No, 15., 3‑year‑old child of 32

hottrs. Convolution

ate predominant features, which resemble

cerebral hemisphere,

222

Dissecting microscopic {'mdings of the lower jejunum of No. 6., 20‑ye.ar‑old female of 10

Photo. 3hours. Each villus ls sep rated with tonguc shapc essentially. But the view Oi' themucosa appears cobbks.tone=1ike. because of blunting. of the villi.

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223
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1: he.' villi are.' at,rOphic̲Villus to (:ryplam.h a prOpri ,' The erypt$ are elr)ng ated.

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224

Photo' 7 Higher magnification of Photo' 6. surf'aced epitheli especially in the' tiP of the vilh̲rs
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H & E

360

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{Photo. 8 Jejunum in No. 19., 1‑year‑old child of41 hours.
Note tissue slits in the subepithelial region which contain fluidal material and inflarn‑matory round c.ells.
Heide.n, hain's azocar.mine. ).t 90.

225
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because226

Photo. 1 1 Jejunmn in No. 7., 8‑year‑eld child af 10 hours.
Note ext.en, aive infiltrat. .'on of plasma, cells to the lamina, propria.

H'. & },L x 720.

Photo, 12 Jejunum in No. 16., 4‑year‑cild child of33 hours.
Note prOlif'eration of histiocytes in the lamina propria

H, & k:',, x 720.

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Note fusion in' volVing the surfa'ced epithe'hum of the two vnh' 'rhe brush bordrr ISI)i e erved' The Size oi' goblet is increascCi'

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Note hlsion in:volving the lamina propria' f¥Iso epithchal rusiOns are se'en' Viuus tocrypt ratio i o'e to I 'o' The surf ced epithehum iS ctiboidal' The' hypercenularity
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Alcial"I blue*PAS*MassOn*g ti'i.chrome. x 720

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Alcian blue‑PAS‑Masson's trichrome, x 900.

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old chnd Of 12 hoursT Hypersecretion of' goblet

In the upper two third of the crypts' the goblct c‑dls are pale and reticular be‑

r̲aFuse of early secretory actiVity

Those af the' 1Owe'r third Preserve the rriucust The

lamina propria shaws a' mod'erate inmtrlation of innammatory ceus
Alcia'n b]'uci

P'ASl"'Ma'sson s trichrbom'e

x 240'

23s;ji;;S' S;":='>:="'='=;';""':;: ;;'::, .;: ,{.";:,:1'i's i{ ""{'{;

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Phote. 29 Colonic mucosa in No. 10., 3‑year‑old child of 13 hours. The lumina of the glands
are dilated and filled with mucus. . An amount (if mucin in the cytoplasm is decreased

by completion of secretion. The lamina propria shows advanced hypercellularity.
SQme lymphocytes migrate in,to the glandular' epithelium.

Alcian blue‑PAS‑Masson'trichrome. x 240.

Photo, 30 Colonic, mucosa in No. 20,, 2‑year‑old child of 7 days,
Note irregular dilatation (rf the crypts

ssociatcd with hypersecretion of mucus.

infiltration is prominent in the mucosa.

Alci,an blue*PAS*Masson*s tric,hrome. x 90,

C ell

236

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Photo' 3 1 Mesenteric lymphnode in Nc' 7' 8 year‑old chnd of lo homS Note mclease of num
ber and size of fouides with m rked hyperphsia of germinal center'H' & FJ' x 3(: 'i;i ;'>i

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Photo. 32;*,;; *++"''*". '+.*:;"" :';'>"':{' ;:; ;;""*"*'=""':" ':"" ;"< " "'* * " ' : =/' ̲ *'* ""=**=*iMesenteric lymphnode in No 14'* 5=year‑old chnd of 30 hours'
ration of lymphoc'‑ytes.

H. &E' x3e'

There is no hyperplasia of lymph fouides'

Notc diff lse prolif'e*237'Phot,o. 33

Spleen in No. 15., 3‑year‑(ild child of 32 hours.

Note hyperplasia of follicles especially of germinal ceuters which are necrotic, Mar‑gins of fbllicles are indistinct.

H. & E. x 36,

Photo. 34

Magnituded vicw of Phote. 33. Germinal centers show hyperplaaia with destruction
Of. tissue, Note resolution Qf red puips.

H. & E. x 120,

238

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Photo. 36

Liver in No. 13., 2‑year‑old child of 24 houts. Note advanc,ed fatty metamorphosis.
Large and small fat droplets are seen in the hepatic eells. Congestion is mrld in thisspecimen .

Heidenhain'

zocarmine. x 360

23g

Photo. S7

Liver in INTo. 15. 3‑year‑old child of 32 hours.

Fat droplets of metamorphosis are me‑dium in size.. Congestion is seen in thi case.

Heidenhain's a,zoc rmine.. x 3GO.

Photo. 38

Liver in No. 7., 8‑year‑old child of iO hours.

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noted.

Hciden.hain>s azOcatmine, x 720,

=2 d

Photo. 39 Pancreas in No. 4., 63‑year=0ld male of 7 hour ,The apical portion of the acinal.' c.ells is foamy (,r finely vacuola,ted.

It looks like thetate just after secretion of zyl nOgen granulc .

Heidenhain' azocarmine, x 480.

U
;

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Photo. 40 Pancreas in No. 6., 20‑year‑cild female of 10 hours.

A large amount of zymogen granules is accumulated in the cytoplasm oi' the acinar
cells.

Hcidenhain's azocarmil.1e, x 480

2轍

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Photo. 43 Lung in No. 18., 14‑year‑old girl of 40 hours.

The Bronchial mucos L shows hypersecretion of mucus i'rom goblet cells. The lumen
oi' the bronchus contains fluid admixed with mucus. Ir flammatory c.ell infiltration
due to inhalation of gnstrir. c,ontent is seen in the Peribrenchial

H. & E, X48.

Photo. 44 Heart in No. 19., 1‑yea,r‑old child of' 41 hours.
Note large vacuolation of myocardial c,ells,

Heideuhain'azocarmine. x 360,

egion.

243

Phot.o. 45 Heart in No. 18., 14‑year‑old girl of 40 hours.

Note irregularity of myocardial cells in staining by Heidenhain's azocarmine stain.
There is no evidence of necrosis of myocardium Or myocarditis.

Heidenhain's a'zocarmine, x 360.

Photo. 46 Kidney in No. 7., 8‑year‑old child of 10 hours.
The neck portion and proximal regi,ons of the tubuks disclose hyaline droplet forma=tion. Droplets are conglomerated in the nec.k portion.

PAS, x 480.

244

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Photo' 49 Kidney in No' 1 7" 8‑ye tr‑old chnd of 40 hours
Note patchy necrosis of the cortex' 'rhe proximal tubules are more affected'

Heldenham

Photo. 50

azocrmme x 300'

Adrenal gl ;nd in No. 4., 63‑ye r‑old male of 8 hours.
The outer half Of the cortex shows clear and ibam. y change of the cortical cells and theinner half shows cOmpact like cells, Note no evidence of severe damage of the paren‑chymal eell or inflammatory cell infiltration ih the interstitium.

Heidenhain s a.2:ocarmine. X 360.

246

Photo，51

亙3rainNotein

NG。13、，2−year−old

retraction

H．＆E，

of

the

×360．

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of24hours．

nerv鶯c礁1董b（｝dyand perinucle＆r

edema、JAPANESE JOURNALOF
TROPICAL MEDICINE AND HYGIENE
Vol 5 No. 3, 4

Decelnber, 1977

CONTENTS
Origm' al article

OKUMURA, E., NAKAI, M., MlYosHI, H., YoSHIDA, Y. AND TOYOTA, S.
Studies on the Morbidity of Foreign Visitors to a Certain Company in Japan .

171‑181EBISAWA, I. AND MuTO, T.
Primaquine Treatment of Malaria (in Japanese) . . . . . .

183‑189

SEKINE, I.

Pathological Study on Early Changes of Cholera Patients‑Based on 2 1 Autopsied Materials‑ . . . .

Published byJAPANESE SOCIETY OF TROPICAL MEDIClNE
c/o Institute for Tropical Medicine, Nagasaki University

l 2

Sakamoto‑machi, Nagasaki, 852, Japan

191‑246