EPIDEMIC PLEURODYNIA (BORNHOLM DISEASE) DUE TO COXSACKIE B-5 VIRUS

(1)

ARTICLES

EPIDEMIC

PLEURODYNIA

(BORNHOLM

DISEASE)

DUE TO

COXSACKIE

B-5 VIRUS

The

Interrelationship

of

Pleurodynia,

Benign

Pericarditis

and

Aseptic

Meningitis

H. W. Bain, M.D., F.R.C.P.(C), D. M. McLean, M.D.,

and Selma J. Walker, B.Sc.

Department of Paediatrics (H.B.) and the Research Institute, the Hospital for Sick Chikiren, Toronto

ADDRESS: (H.B.) 555 University Avenue, Toronto 9, Ontario, Canada

889

Ped iulrics

VOLUME 27 JUNE 1961 NUMBER 6

D

UffiNG THE months of July to October, 1958, there occurred in Southern

On-tario a widespread outbreak of Coxsackie B5

virus infection. Three main disease entities

were encountered: epidemic pleurodynia

(Bornholm disease), acute benign

pericardi-tis and aseptic meningitis, alone or in

com-bination.

The present report deals with 69 patients

admitted to the Hospital for

Sick Children,

Toronto, with any of these syndromes. In

all, 36 patients with pleurodynia, 7 with acute benign pericarditis and 26 with

aseptic meningitis were studied. Five of the

patients with pericarditis had pleurodynia

as well, and seven of those with

pleuro-dynia

had

associated aseptic meningitis.

Viral studies were carried out for all but

one of the patients with aseptic meningitis

and acute benign pericarditis and for 21 of

the patients with pleurodynia (with and

without aseptic meningitis.) The results

indicated Coxsackie B5 virus as the

etio-logic

agent

in all three of the syndromes

encountered in this epidemic.

Another patient, not included in the presr

ent series, but who also had Coxsackie B5

pericarditis and pleurodynia in September,

1958, was found to have severe constrictive pericarditis in May, 1959, indicating that

viral pericarditis might be an important

etiologic factor in some

cases

of so-called idiopathic constrictive pericarditis.

EPIDEMIC PLEURODYNIA

Previous Studies

Some of the previous literature on pleuro-dynia is of much interest.1-4 The disease is most frequently referred to as Bornholm

disease or epidemic pleurodynia, following the report1 of an epidemic that occurred on Bornholm Island in the Baltic in 1930. The

condition was first observed in Iceland, by Finsen.5 Daae#{176} reported an epidemic in

Norway.

BacherT reported an epidemic

with

complications including pleurisy,

pen-carditis, orchitis and croupous pneumonia. In 1897, another epidemic of 4,158 cases

was reported from

Norway,

under the title “Bamble Disease.”

(2)

890

PLEURODYNIA

The first epidemic in North America8

was referred to locally as the “Devil’s Grip,” which aptly describes the nature of the pain, the most outstanding feature of

pleu-rodynia.

In the Bornholm Island epidemic, pleurisy and orchitis were the only complications noted. Other investigators#{176}12 have reported cases of pericarditis that they, like Bacher

in Norway, attributed to the same virus as

Bornholm disease.

In the large (12,000 cases) epidemic13 of 1931 in Sweden, penicarditis, orchitis, pneu-monia, bronchitis, peritonitis, otitis media

and encephalitis were noted. Pickles

stressed the ease with which isolated cases

in non-epidemic areas could be confused with acute surgical conditions such as

in-tussusception, retrocecal appendicitis or a

perforated viscus.

Epidemics’4#{176} have been reported in

which there was an association of

pleuro-dynia with involvement of the central

nerv-ous system. Scadding’T reported the fre-quent occurrence of pleural friction rubs. In an Oxford epidemic’8

10%

of the adult

males had orchitis as a complication. Re-lapses occurred in approximately 30% of 277 cases, sometimes within the first month and

sometimes after an interval of up to 6

months.

Coxsackie viruses have been isolated

from patients having a polio-like illness.19,lO

Similar viruses were isolated from patients

with an illness similar to poliomyelitis and

also from a patient with pleurodynia2l;

three of

the

laboratory workers later

de-veloped pleurodynia, and the virus was isolated from their feces.2’ Still further virus

isolations in Bornholm disease have been

reported.’8’

Present Study

In the present study, 36 patients with

pleurodynia were admitted to

the

hospital.

Seven of these had associated aseptic

men-ingitis. The results are summarized in Table I.

SEASONAL INCIDENCE: As in most other reported epidemics, the majority of

our

cases occurred in August and September,

with the first appearing on July 20 and the

last on November 5.

AGE:

The

age

range

is listed as 4 to 14 years, although two infants, aged 6 weeks and 4 months, almost certainly were

afflicted. Because of their inability to talk,

one could not be certain that they were

ex-periencing the pain of pleurodynia. Clinical

aspects

of these

two cases

will be discussed

separately, since it is felt that in an epidemic

area

one should

be alert

to the syndrome

as

it presents in tiny infants.

DURATION: Most of the patients had

in-termittent signs and symptoms for 2 or 6

days before admission to hospital. In a few,

however, the onset was so abrupt and

startling

as

to cause referral to hospital as acute medical or surgical emergencies. Most

of the patients improved quickly in the

hos-pital and were discharged in 2 to

5 days,

al-though a few had symptoms for as long as

7

weeks. Follow-up was inadequate in most

of the cases.

COMPLICATIONS AND SEQUELAE: Compli-cations were not seen in any of this group,

although one of our interne staff, who

con-tracted pleurodynia, developed orchitis 5

days after the onset, while the pleuritic type

pain was still present. One month later, this

same interne developed precordial pain and

a penicardial friction rub which disappeared

the following day. Vague precordial pain

recurred for a further month. Many of the

patients had prolonged fatigue and

low-grade fever and seemed unwell to their

parents for several weeks after the acute

episode.

PA: Pain was the outstanding symptom

and occurred most frequently in the

epigas-trium, upper quadrants of the abdomen,

the hypochrondrium and the chest, and less

frequently in the pen-umbilical region or

one of the lower abdominal quadrants.

Definite shoulder-tip pain was present in

four patients. The onset was usually

alarm-ingly

sudden

and

of such

severity

as to

cause the patient to stop in his tracks,

(3)

ab-ARTICLES

891

domen or chest, the respirations during an

exacerbation were usually rapid, shallow

and grunting, and similar to those of

pa-tients with pneumonia or pleurisy. The pain

tended to occur in spasms, lasting a few

minutes to several hours, with the usual

duration being about one-half hour. The

older children described it as stabbing or

knife-like; coughing, deep breathing or

yawning made it worse. When it occurred

in the abdomen it was often described as

crampy

or colicky and the patient

fre-quently

doubled

up and

was

unable

to walk

or even move. Fever was usually at its

height during the bouts of pain. Between

attacks, patients usually acted and felt quite

well. Tenderness to pressure over the

pain-ful area was present in eight patients; it

probably would have been found more

fre-quently if it had been diligently looked

for. Sylvest elicited this sign in 72 of

93 patients. Muscle swelling was not

ob-served.

FEvER: Fever, often intermittent, was

present in all and as mentioned usually was

at its height during exacerbations of pain.

PLEURAL FRICTION RUBS: Pleural friction

rubs were present in seven of the patients

with pleurodynia and, as will be discussed

later, in four of the five patients who had

associated pleurodynia and penicarditis. At

times the rub disappeared when the pain

disappeared and reappeared when the pain

recurred.

ASSOCIATED FINDINGS: Anorexia, nausea or vomiting were present in 17 patients,

al-though only 6 had frank vomiting. Pickles

reported that vomiting was absent or quite

rare in epidemics studied by him and felt

that this was quite important in helping to

rule out the presence of an acute surgical

abdomen. Although this observation is a

useful and important one, it is unfortunately

not constant enough to be completely relied

upon.

Sore throat was present in 11 patients and headache in 8, although

7

of these were

the patients with aseptic meningitis.

Shaking chills were present in five

pa-tients, again suggestive of the presence of

pneumonia, septicemia or some other

bac-terial infection.

Hiccups were not seen in any of the

present series, although Sylvest witnessed them in 12 of 93 patients. However, two pa-tients in the epidemic area had severe hic-cups lasting several days. As no other signs

or symptoms of illness could be elicited in these patients, the hiccups were believed to

be of psychogenic origin. In retrospect, it

seems likely that they were due to Born-hoim disease. Cough was a minor feature

in three patients only.

Routine laboratory tests were not too

helpful. The leukocyte count ranged from

2,600 to 18,000/mm3 with the usual being 3,000 to 8,000/mm3. Even with the low

counts, however, there was frequently a

marked increase in the polymorphonuclear

neutrophils, with a shift to the left. The

erythrocyte

sedimentation

rate

was

usually

normal or slightly elevated, but on occasion was extremely high. This occurred mainly

in patients with penicarditis and will be dis-cussed later. Roentgenograms of the chest

were obtained for most of the patients and

were normal.

FAMILY HISTORY: It was our impression that there was a high attack rate in the

com-munity and in the families of our affected

patients. Unfortunately, this information

was not requested in many instances and in

only seven of our case histories were other

members of the family stated to have been

ill. In such families, it appeared that the incubation period was usually a few days to

a week.

ADMIrFING DIAGNOSES: Until the

house-staff and other medical personnel in the community became aware of the fact that an epidemic was upon us, many of the cases

were quite puzzling. Admission diagnoses included the following: acute abdomen, possible appendicitis, possible duodenal

ul-cer, pyelonephnitis, pneumonia, pleurisy with pneumonia, rheumatic fever, pain of

unknown origin, trauma (fractured rib), myositis (infiuenzal), collagen disease, tu-berculosis and intussusception.

(4)

TABLE I

VIRUS STUDIES ON 1 PATIENTS WITH PLEURODYNIA

.

Palment Syndrome

Feces

ann m

ereoro-.

.

sponalFlnod

.

Obtained

(days after onset)

,

(ox8acIne B5 1’mis

era

,

Obtained (days after

,

(ox.aekme 111

,

4nith4dy

,

.

Ti/er ma

,

in I e(’es in (

erebro-.?JinaI Fluid

W.M. Pleurodynia and aseptic meningitis

4 + - S

6

50

5()

K.N. Pleurodynia and

aseptic meningitis

4 - + 2

‘20

250+

Q50+

G.H. Pleurodynia and

aseptic meningitis

8 + + .. Not done

A.M. Pleurodynia and aseptic meningitis

7 + + 4

8

5O

250+

P.R. Pleurodynia and

aseptic meningitis

12 + + 10

3

5O+

P.J. Pleurodynia and

aseptic meningitis

1 + 1

S

< 10

5O+

S.N. Pleurodynia 5 +

. ,

.. Not done

L.K. Pleurodynia 7 + .. .

,

Not done

W.H. Pleurodynia 5 + .. 5 20

oo+

P.11. Pleurodynia 2 + .. S

8

0

50+

G.C. Pleurodynia 8 +

,

. 8

17

50 50

J.V. Pleurodynia 15 + .. 15

33

50

250+

D.B. Pleurodynia 4 + .. ..

7

..

50+

D.C. Pleurodynia 7 + .. 8

17

5O+

50+

R.T. Pleurodynia 3 + .. 3

17

< 10 100

w.C. Pleurodynia 7 + ..

6

50 50

MC. Pleurodynia 13 +

,

. 14

8

< 10

(5)

TABLE I (Continued)

.

Pa/men!

,

syndrome

Feces

and

Cerebro-.

spinal Fluod

.

Obtained

(days after

onset)

.

(‘oxsaekme B5 I irns ,

hera

.

Obtained (days after

onset)

.

(ossackie B,

.

Antibody

.

Toter on Sera

in h’ces

-,

in

(erebro-spinal Fluid

S.K. Pleurodynia + .. 1

18

0

100

SR. Pleurodynia + .. .. Not done

F.B. Pleurodynia S + .. 0

6

< 10

50

RB. Pleurodynia 5 - .. 5

19

250+

Totals .. 19 4

..

17

the tiny infants, a convulsive disorder was suspected. This 4-month-old infant had

re-current episodes of gasping for breath with rapid, shallow and jerky respirations, ex-treme pallor and a great deal of mucus in

his throat.

Lumbar

puncture

revealed

nega-tive findings, and the child recovered

corn-pletely in 24 hours. His mother volunteered the observation that he seemed to have pain

in the central part of his chest, making his breathing difficult!

Another 6-week-old infant had sudden

onset of fever 39.4#{176}C(103#{176}F), with

vomit-ing, recurrent bouts of tachypnea, mottling,

abdominal distension, poor peripheral

circu-lation, periodic rigidity and tremors. At times he appeared desperately ill and a few

hours

later appeared quite well again.

Lum-bar puncture showed 510 cells. Coxsackie B5

virus was grown from his feces and serum antibody titers against Coxsackie B5 virus

rose from less than 10 to more than 250 in 7 days. In retrospect, it is felt that he almost

certainly had pleurodynia, in addition to aseptic meningitis.

In the Brooklyn epidemic,14 all eight

chil-dren under

2 years

of age

had

generalized

convulsions. Disney

et

al.26 reported recur-rent screaming attacks with fever, malaise,

dyspnea and drowsiness in the infantile

group. In such infants, a diagnosis of in-tussusception must be considered.

VIRUS Si’urns

(

TABLE

I ) :

Stool samples

were collected as soon as possible after the

onset of symptoms from 21 patients who had pleurodynia. In six of these patients

there was an associated aseptic meningitis. The stools were examined for virus content

by

inoculation of extracts of ultracentri-fuged deposit into roller tubes of

trypsin-dispersed monkey-kidney epithelial cells ac-cording to methods described previously.28 Fresh virus isolates were typed in neutrali-zation tests in monkey-kidney cultures

em-ploying antisera to the following viruses: Coxsackie A9, B1, B,, B3, B4, B5, ECHO

types

2,

6, 9, 13, and a pool of antisera to

poliovirus types 1, 2 and 3. Samples of cere-brospinal fluid were inoculated directly into monkey-kidney cultures.

Samples of serum were obtained from

pa-tients as soon as possible after onset of ill-ness and again 2 to 3 weeks later.

Speci-mens of serum taken during the acute and during the convalescent phase of the same

(6)

894 PLEURODYNIA T.C.D.SO of Coxsackie B5 virus, Faulkner

strain.28

Of the six patients who had aseptic men-ingitis associated with pleurodynia,

Cox-sackie B5 virus was isolated from the stool in five and from the cerebrospinal fluid in

four. Increasing or high titers against Cox-sackie B5 virus were detected in paired

serum specimens of five of these patients. Of the remaining 15 cases, Coxsackie B,

virus was isolated from stools of 14 patients, obtained between 1 and 15 days after onset of illness. Increasing or high titers of anti-body against Coxsackie B virus were

de-tected in paired specimens of 12 patients

and

confirmed

that Coxsackie B, virus

in-fected the patient at the time of illness.

ACUTE BENIGN PERICARDITIS

Bacher7 was the first to report the

oc-currence of penicarditis as a complication of pleurodynia. Bing9”#{176} reported six

cases

of benign penicarditis occurring in an epi-demic pattern in August. All cases began with typical Bornholm disease; all patients had pericardial, to-and-fro murmurs that disappeared in a week; all had high sedi-mentation rates, and three had pleural fric-tion rubs as well. Bing labeled the

condi-tion “epidemical penicarditis,” referred specifically to the mild course of the illness

in these patients, and to pain as a

promi-nent feature. He assumed that it was due to some type of infection.

At the same time, and in the same

epi-demic, Heckscher” reported 11 patients with a Bornholm-like disease, 5 of whom had pleural friction rubs and 1, penicarditis. Headache was a prominent feature in six.

He stressed this occurrence of “serositis,” but felt that his patients were probably

similar to patients with Bornholm disease in whom “serositis” was not found.

Dalsgaard-Nielsen” reported three cases

of transitory penicarditis occurring in a Swedish epidemic of Bornholm disease.

Sylvest did not witness any cases of pen-carditis in the Bornholm epidemic of 1930.

Barnes and Burchell29 reported 14 cases of acute penicarditis, simulating acute

coronary occlusion, occurring in adults. Most of their cases occurred in 1939 and

1940 and six had their onset between June and October with three in December. It is

interesting to speculate that some of these

cases

may

have

been

associated

with

Cox-sackie virus infection. Penicarditis has since

been in other epidemics of

Bornholm disease.

Bower et a!.” reported four cases of acute benign penicarditis occurring in

child-hood. Three were taken from a series of 40

cases

of penicarditis

seen in a 10-year-period

at the Birmingham Children’s Hospital. Of the remaining 37, 27 were rheumatic, 8 pyogenic, 1 tuberculous and 1 urernic in

etiology. Each of the four children reported had associated pleurisy. As to etiology, it

was pointed out that acute benign pen-. carditis has many features in common with

Bornholm disease. Both diseases run a benign, sometimes relapsing, course with

severe abdominal, thoracic and even shoulder pain. Virus studies were done for one of the patients, but it was impossible to demonstrate recent infection with two

strains of group A or one strain of group B

Coxsackie virus. Another of the patients was taken ill during an outbreak of epidemic

myalgia.

During

this

same outbreak, two

adults with acute benign penicarditis were

seen.

Fletcher and Brennan” reported the case of a 28-year-old woman with benign pen-carditis. Samples of serum taken during her

convalescence revealed titers indicating a Coxsackie type B4 infection. Weinstein30 reported a single case of acute benign

penicarditis in a 25-year-old man in which serologic evidence suggested that group B Coxsackie virus might be responsible.

Movitt et al.’ reported the isolation of Coxsackie B, virus from the feces of a 22-year-old man who developed

serosanguine-ous penicarditis. A 30-fold increase in the level of neutralizing antibody against this

virus in specimens of serum obtained 12

(7)

in-895

dicated that Coxsackie B, virus was the

cause of the patient’s illness.

The present authors28 reported four

chil-dren with acute benign penicarditis, occur-ring during an outbreak of pleurodynia. These children excreted Coxsackie B5 virus

in their feces at the time of illness and paired serum specimens showed elevated antibody titers against Coxsackie B, virus indicating that this virus was the cause of

the penicarditis. These four cases are in-cluded in the seven reported in the ap-pendix.

Finally, infection of the newborn

in-fant’5’7 with Coxsackie B viruses has been followed frequently by severe or fatal myo-carditis, while in an older child nonfatal myocarditis has been reported following

Coxsackie B virus infection.

Present Study (See Appendix)

During the present epidemic, seven chil-dren presented with acute benign

pericardi-tis. Of these

seven

patients,

five had

pleuro-dynia as well, and four of these had pleural as well as penicardial friction rubs.

CLINICAL FINDINGS: The clinical features

of these seven cases are summarized in Table II. As can be seen, the seasonal

inci-dence was striking, with all of the cases occurring between late July and October,

the peak incidence being August and Sep-tember. This coincides with the widespread occurrence of Bornholm disease in the area. Most of the patients were initially felt to be

suffering from rheumatic heart disease, and the fact that four of them had sore throat or tonsillitis, 1 to 3 weeks before discovery

of the cardiac signs, served to strengthen this impression. In five of the patients, how-ever, it was specifically noted that they did not look as ill as one would expect, had the cardiac findings been due to acute

rheu-matic fever.

It is not known how soon the penicardial

signs

developed

after

the

onset

of illness,

since the signs were usually present when medical advice was first sought. Several of

the patients were believed to have a variety of organic cardiac murmurs, but all of these

“murmurs” disappeared coincidentally with

disappearance of the penicardial friction rub. It, therefore, became apparent that it

was hazardous to state definitely that any murmur was present as long as the pen-candial rub was still discernible. The pen-candial rubs disappeared 2 to 16 days after

they

were

first

heard.

Pain was not a feature in those patients who had penicarditis alone, but it was prominent in those who had associated pleurodynia. In four of these, pleural

fnic-tion rubs were heard and the pain was usually intermittent and of a pleunitic

na-tune.

In five there was enlargement of the

cardiac shadow, which usually returned to

normal

in a few

days.

In

only

one

patient

was

it necessary to perform penicardial paracentesis because of impending tam-ponade.

Electrocardiograms showed nonspecific

T-wave changes compatible

with

the

diag-nosis

of

penicarditis

in

six

patients;

they

were normal in one. In a few of the pa-tients, the changes were quite marked.

Sedi-mentation rates were moderately elevated in

five and extremely high in one. Leukocyte

counts were usually normal on low, but were

slightly

elevated

in two

of the

patients.

An-tistreptolysin-O titers were determined for five patients and were low in all.

Five of the patients did not receive any treatment after admission to hospital,

whereas one was given pnednisolone be-cause of progression of the penicardial effu-sion and another received prednisolone and

aspirin while the results of laboratory in-vestigation, to rule out rheumatic fever, were being obtained.

All of the patients appeared to have made

a complete recovery within a few weeks of the onset. A family history of Bornholm-like disease was prominent in two patients.

VIRUS SruDIEs (TABLE

III):

Coxsackie B,

virus

was isolated from feces obtained from

five patients between 7 and 23 days after the

(8)

896 PLEURODYNIA

a

I’

z

5’ F,

z 5’

cr2

z

a

- F,

5,

C

a

5,

a

c)

z

.3

.a

a .a .a

C

a

C

E a a

.C

.a

C .C

a

C

a .C C

a

(9)

Since Coxsackie B, virus had not been

prevalent to a significant degree in the

Toronto area before the summer of 1958,

it appears likely that these elevated anti-body titers were produced following infec-tion with Coxsackie B, virus at the time of the patients’ illness.

ASEPTIC MENINGITIS SYNDROME

Meningitis has frequently been reported

as a complication of 26,39

There is ample evidence that both

pleuro-dynia

and

aseptic

meningitis

may

be caused

by Coxsackie B virus infection.’8’ 2127

Present Study

Between June and December, 1958, 69 patients who presented with the aseptic meningitis syndrome of headache, fever,

vomiting, stiff neck and pleocytosis of the cerebrospinal fluid, were studied. Fecal specimens from all 69 patients were

ex-amined for virus content by inoculation of monkey-kidney tissue culture. Entenoviruses

were isolated from 43 patients, 33 of whom

yielded

Coxsackie

B5 virus.

From

cerebro-spinal fluids of 46 patients, Coxsackie B, virus was isolated in 17 instances.

Increas-ing antibody titers against Coxsackie B, virus, which were detected in paired serum

specimens from 12 patients, all of whom

excreted this virus in the feces or

cerebro-spinal

fluid,

confirmed

that

these

patients

were infected with Coxsackie B, virus at the time of their illness.

As discussed previously in this article, in

seven patients there was an association of

pleurodynia with aseptic meningitis. Six of

these had virus studies, five grew Coxsackie B5 virus from their stools, four grew it from the cerebrospinal fluid, five showed high on increasing antibody titers to Coxsackie B,

virus.

Headache, and/or stiff neck were

promi-nent in all of the patients. Two patients had convulsions. General malaise, drowsiness and vomiting were also common.

Cerebrospinal fluid showed evidence of pleocytosis in all patients. The leukocyte

count varied from 18 to 2,000/mm’; in

seven patients it was greater than 500.

In most of the patients, the increased count

was due to lymphocytes, although seven had 40 to 50% polymorphonuclear leuko-cytes. It was our policy to treat the latter as though they were bacterial in etiology for 24 to 48 hours while awaiting bacteriology

reports. The decision as to whether on not

to treat was also based on the clinical con-dition of the patient and a family history of a similar illness. Sugar in the cerebrospinal

fluid was estimated in those with an

ex-tremely high leukocyte count and in those with an increase in percentage of leuko-cytes; it was normal or slightly high in all.

The leukocyte count in the blood was of some help, usually ranging from

4,500

to

10,000/mm’, but with an occasional value

as high as 18,000.

Paralysis, panesis or reflex changes were

not noted and there were no complications

or sequelae.

COMMENT

A review of the historical background of Bornholm disease reveals that encephalitis

and pericarditis have frequently been wit-nessed as “complications” since 1896.’ 918

Isolated cases of “acute benign penicardi-tis” have occurred during epidemics of Bornholm disease, and it has been

postu-lated that the etiologic agents were identi-cal.” 12, 16, 30,31

Virus studies’’6’ 32-34 have tended to

incriminate Coxsackie B viruses as the

etio-logic agent in outbreaks of Bornholm dis-ease and aseptic meningitis as well as in

sporadic

cases

of “acute

benign

penicanditis.”

The present clinical and laboratory study of 69 patients, during a widespread

epi-demic, afforded an opportunity to correlate the clinical syndromes with the results of detailed virus studies. Pleurodynia was found to occur alone or in association with

penicarditis or aseptic meningitis, and

simi-larly

acute

benign

penicarditis

and

aseptic

meningitis occurred alone on in association with pleunodynia.

(10)

898

PLEURODYNIA

* Also had pleurodynia.

whom virus studies were done, Coxsackie

B5 virus was isolated from the feces (Table

I), and in all 17 tested, high or increasing antibody titer against Coxsackie B, virus were demonstrated. Six of the patients with pluenodynia had aseptic meningitis as well,

and Coxsackie B, virus was isolated from the cerebrospinal fluid in four, strongly sug-gestive of Coxsackie B, as the common etio-logic agent.

Coxsackie

B, virus

was

also

isolated

from

feces of five of seven patients with acute

benign penicarditis, and all seven patients showed high on rising titers against Cox-sackie B5 virus (Table III). Of the seven

patients with acute benign penicarditis, five had associated clinical pleurodynia.

Un-fortunately, in only one patient (M.M.) was penicandial fluid obtained and virus was not

isolated from it. However it again seems likely that Coxsackie B, virus was the com-mon etiologic agent.

Although no complications were observed

TABLE III

VIRUS STUDIES FOR PATIENTS WITH PERICARDITIS

Pa-tzent Feces . Obtained (days after onset) . Coxsackze B, Virus in Feces Sera

.

Obtained (days after onset) Coxsackie B, Antibody Titer in Sera

P.K. 13 + 13

30

250+ 250+

AS. 7 + 9

43

250+

250+

J.T.4 15 + 16

23

800

800

J.G.* 7 + 6

12

100

200

D.A.* 23 + 23

36 800 800 M,M,* 8 21 -8 15 2,500 2,500

E.E.* 21 - 16

21

200

800

in these seven cases of acute benign

pen-carditis, a 13-year-old male child was ad-mitted to the Hospital for Sick Children on June 18, 1959, with constrictive pen-carditis, following an attack of pleurodynia and penicarditis in September, 1958. During his initial illness Coxsackie B, virus was grown from his stool and paired serum

specimens

revealed

high

titer

(1 :2,000) of

antibody to Coxsackie B,. Unfortunately a

blood

specimen obtained at the onset of his

illness was lost, so an increasing titer could not be demonstrated. However, on his latest admission the antibody titer to Coxsackie B,

was

1

:

1,250.

Unfortunately,

this patient

died

following surgical correction of the lesion. Because of the interesting data obtained from viral studies, cardiac catheterization

and necropsy, this case will be the subject of a separate publication.

Rabiner et al.8 postulated that many of

the reported cases of chronic constrictive penicarditis are the end-result of so-called

acute benign penicarditis, and they have

presented

such

a case.

Viral

studies

were

not done for their patient.

Of the reported cases of chronic

constnic-tive penicarditis, 25 to 57% are “idiopathic,” and it is probable that some of these are a

sequel to penicarditis of viral etiology.

SUMMARY

During the months of July to October, 1958, a widespread outbreak of epidemic

pleurodynia

(Bornholm

disease)

occurred

in Southern Ontario. In this epidemic three

main

disease

entities

were

encountered:

epi-demic

pleurodynia,

acute

benign

penicardi-tis and aseptic meningitis, alone or in com-bination.

Sixty-nine patients were studied at the

Hospital for Sick Children, Toronto, and viral studies were carried out for many of

them. Five of seven patients with pericardi-tis had associated pleurodyri.ia, and seven

patients

had

associated

pleurodynia

and

aseptic meningitis. The clinical features of each of the three major entities encountered

are presented.

(11)

viruses

may

be

important

etiologic

agents acute benign penicarditis.

APPENDIX

Patients with Pericarditis with and without

Associated Pleurodynia

ARTICLES

as the common etiologic agent in the various

disease

entities

encountered

in

this

out-break.

It seems

likely

that

the

Coxsackie

B

Case 1

HISTORY: P.K., a 4-year-old female child, was

admitted to the Hospital for Sick Children,

To-ronto, on July 28, 1958, with a diagnosis of acute rheumatic fever and rheumatic carditis. Ten days prior to admission she developed tonsillitis; 4 days prior to admission she was examined by her phy-sician and found to have a heart murmur. She was hospitalized in another city where investigation re-vealed a hemoglobin value of 8.8 gm/100 ml; leu-kocyte count, 11,800/mm’, with 55% neutrophils,

5% band cells, 2% metamyelocytes and 38%

lym-phocytes. The erythrocyte sedimentation rate was 117 mm in one hour. The antistreptolysin-O titer was less than 12 units (nonreactive). An electro-cardiogram revealed normal findings. A roentgeno-gram of the chest revealed an enlarged cardiac shadow.

PHYSICAL EXAMINATION: Physical examination

on admission revealed that the child did not ap-pear acutely or seriously ill but was rather pale and had a pharyngitis and enlarged tonsils. A loud to-and-fro friction rub was heard over the entire precordium. The blood pressure was 80/40 mm Hg, and the temperature was 39#{176}C.

LABORATORY FInrnNcs: Fluoroscopic

examina-tion of the chest revealed enlargement of the cardiac shadow, with a cardiothoracic ratio of 10.6:19. An electrocardiogram revealed flattening of T-waves in leads V5 and V6 and inversion in V4. The antistreptolysin-O titer was less than 12 units. The C-reactive protein value was +; sheep cell agglutination, negative; hemoglobin, 12.2 gm/100

ml; and result of intracutaneous tuberculin test, negative. Coxsackie B, virus was isolated from a

sample of feces obtained 13 days after the onset of

illness. Serum samples obtained 13 and 26 days after onset of illness revealed high titers of neu-tralizing antibody against Coxsackie B virus.

THERAPY AND COURSE: No specific treatment was

given. The pericardial friction rub disappeared 3 days after admission and the temperature became normal in 4 days. Recovery was uneventful. Fol-low-up examination by the family physician 6

months after discharge, including an

electrocardio-gram and roentgenogram of the chest, showed completely normal findings.

in acute benign penicarditis.

Chronic constrictive penicarditis occurred as an end-result in one of the patients with

Case 2

HISTORY: A.S., a 7-year-old female child, was

admitted to the Hospital for Sick Children, To-ronto, on August 3, 1958. One week prior to ad-mission she developed fever and severe sore throat that did not respond to antibiotic therapy. The temperature ranged from 38.4#{176}Cto 40#{176}C.One day prior to admission a pericardial friction rub was heard over the entire precordium.

Family history revealed that two siblings had sore throat, abdominal pain and fever, while an-other sibling had sore throat and fever.

PHYSICAL EXAMINATION: On physical

examina-tion the patient did not look ill. A loud to-and-fro pericardial friction rub was still audible. Heart sounds were normal.

LABORATORY FINDINGS: The hemoglobin value

was 13.2 gm/100 ml. The leukocyte count was 2,200/mm’, with 32% neutrophils, 1% eosinophils,

63% lymphocytes and 3% monocytes. The erythro-cyte sedimentation rate was 24 mm in 1 hour;

ex-amination for lupus erythematosus cell, negative;

antistreptolysin-O titer, 100 units; and intracutane-ous tuberculin test result, negative. .Coxsackie B, virus was isolated from a fecal sample obtained 6 days after the onset of illness. High titers of Cox-sackie B, neutralizing antibody were detected in serum specimens obtained 5 and 44 days after onset.

TREATMENT AND COURSE: The child was not

given any specific treatment. During her 8-day stay in hospital, her temperature ranged from 36.8#{176}C to 37.6#{176}C. Pericardial friction rub diminished markedly in intensity but was still audible at the

time of discharge.

FOLLOW-UP: The pericardial friction rub

disap-peared 1 week following discharge from hospital. Fatigue was prominent for 1 month. A complete examination in December, 1958, resulted in nor-mal findings.

Case 3

HISTORY: J.T., an 11-year-old boy, was

ad-mitted to the Hospital for Sick Children, Toronto, on August 30, 1958. Two weeks prior to admission he developed sudden onset of severe precordial pain aggravated by deep inspiration. The pain was pleuritic in nature and was referred to the left

shoulder-tip. Fever, general malaise, weakness,

ex-ertional dyspnea and orthopnea were also present.

(12)

900 PLEURODYNIA

HISTORY: MM., a 7-year-old male child, was

ill. There was a loud pericardial friction rub along the left sternal border and out to the cardiac apex, and a pleural friction rub was audible over the left pulmonary base. The liver was palpable 2 cm

be-low the right costal margin and was slightly tender on palpation. There was moderate jugular venous

distension.

LABORATORY FINDINGS : The hemoglobin value

was 10.7 gm/100 ml. The leukocyte count was

8,600/mm’, with 58% neutrophils, 3% band cells, 3% eosinophils, 27% lymphocytes and 9% monocytes.

A roentgenogram of the chest indicated that the

lung fields were clear; the cardiac shadow was

slightly enlarged, with a cardiothoracic ratio of

12.5 :21 .5. An electrocardiogram revealed flatten-ing and inversion of the T waves in all chest leads. The result of an intracutaneous tuberculin test was negative. Coxsackie B5 virus was isolated from

feces obtained 16 days after onset of chest pain.

High titers of neutralizing antibody against Cox-sackie B, virus were detected in serum specimens obtained on the sixteenth and twenty-third days of illness.

TREATMENT AND COURSE : No specific treatment

was given. Low-grade fever persisted for 5 days after admission. The pericardial friction rub dis-appeared 7 days after admission. Pleural friction

rub was still audible at the time of discharge 17 days following admission. An electrocardiogram indicated considerable improvement of the patient at the time of his discharge.

FOLLOW-UP: This boy lived in a small farming

community, and follow-up was inadequate. Verbal report from his physician, 1 month after discharge, stated that he appeared clinically well.

Case 4

HISTORY: J.G., a 10-year-old female child, was

admitted to the Hospital for Sick Children, To-ronto, in September, 1958. Four days prior to ad-mission she developed fever; dull, aching pain in both costovertebral angles; and sudden onset of pleuritic type pain in the right lower region of the chest anteriorly. One day prior to her admission, her temperature rose to 40.6#{176}C,and there was a pleuritic pain in the left lower region of the chest.

PHYSICAL EXAMINATION: Physical examination,

on admission, revealed an extremely apprehensive child with shallow respirations. She complained of knife-like pain anteriorly, aggravated by deep breathing. There was a loud, pericardial friction rub in the second right interspace anteriorly and a pleural friction rub over the right lower part of the chest anteriorly. There was tenderness in both costovertebral regions.

was 11.4 gm/100 ml. The leukocyte count was 6,600/mm’, with 60% neutrophils, 2% eosinophils, 30% lymphocytes and 15% monocytes. The

erythro-cyte sedimentation rate was 22 mm in 1 hour;

antistreptolysin-O titer, 50 units; and intracutane-Ous tuberculin test result, negative.

Roentgeno-graphic studies revealed normal lung fields and a

slightly enlarged cardiac shadow, with a cardio-thoracic ratio of 11.5:20.8. An electrocardiogram

revealed inversion of the T wave in lead, V4 and

biphasic T wave in lead V5. Coxsackie B5 virus

was isolated from a fecal sample obtained 7 days

after onset of illness. Elevated levels of antibody against Coxsackie B3 virus were detected in serum

specimens obtained at 6 and 12 days after onset.

TREATMENT AND COURSE: No specific treatment

was given. Pericardial friction rub disappeared on the fifth hospital day, and the patient was

dis-charged on September 17, 1958.

FOLLOW.UP : Findings on a complete examina

-tion in the Cardiac Clinic, 1 month following dis-charge, were normal, and the cardiothoracic ratio

was 9.5:19.5.

Case 5

HISTORY: D.A., a 15-year-old boy, was admitted

to the Hospital for Sick Children, Toronto, on Sep-tember 24, 1958. Three weeks prior to admission he developed sore throat, fever and pleuritic pain over the anterior part of the chest and right upper abdominal quadrant. The pleuritic type pain and

swinging fever persisted in spite of antibiotic and aspirin therapy. A diagnosis of rheumatic fever was

made by the physician, and the boy was referred to hospital.

PHYSICAL EXAMINATION: On the patient’s

ad-mission, his temperature was 39.6#{176}C; a to-and-fro

pericardial friction rub was present over the whole precordium. He did not look as ill as the history

and physical findings indicated.

9,000/mm’. The result of an intracutaneous tuber-culin test was negative. A roentgenogram of the

chest revealed normal lung fields and a normal cardiac shadow, with a cardiothoracic ratio of 12.4: 27.5. An electrocardiogram revealed T-wave changes in all leads, consistent with a diagnosis of pericarditis. The erythrocyte sedimentation rate was 30 mm in 1 hour. The antistreptolysin-O titer was 50 units. Coxsackie B, virus was isolated from a fecal sample obtained 23 days after onset of the illness. Elevated levels of antibody against Cox-sackie B, virus were detected from sera obtained both 23 and 45 days after onset.

TREATMENT AND COURSE: No specific treatment

was given. His temperature became normal on the day following admission to hospital. The pen-cardial friction rub disappeared 2 days after ad-mission. Convalescence was uneventful; there was

no follow-up.

(13)

admitted to the Hospital for Sick Children, To-ronto, on October 14, 1958. Thirteen days before

admission he developed fever and sudden onset of acute abdominal pain which persisted. One day

prior to admission he developed severe anterior

chest pain of a pleuritic nature and had difficulty in breathing. Several hours later, he awakened screaming with pain in the epigastrium and an-tenor part of the chest.

Family history revealed that on September 17,

1958, his mother had developed typical pleuro-dynia; at the same time an 8-year-old sibling was given a diagnosis of virus pneumonitis. On Sep-tember 10, 1958, a 3-year-old sibling developed a transient pericardial friction rub.

PHYSICAL EXAMINATION : On admission the boy

did not look particularly ill and was not in acute

distress. There was slight inflammation of the

pharynx. There was a loud to-and-fro pericardial friction rub over the entire precordium. The blood pressure was 105/70 mm Hg; the heart was con-siderably enlarged to percussion; the liver was palpable 2 cm below the right costal margin and was very tender.

14,000/mm’, with 73% neutrophils, 1% band cells,

1% basophils, 17% lymphocytes, and 8% mono-cytes. The result of an intracutaneous tuberculin

test was negative. The erythrocyte sedimentation rate was 24 mm in 1 hour. Roentgenographic

studies revealed normal lung fields and a mark-edly enlarged cardiac sh,dow, with a cardiotho-racic ratio of 12.5:21.2. An electrocardiogram showed reduced voltage and flattening of T waves

in standard leads; P-R interval, 0.12 seconds; and T wave in V4, inverted. Changes were believed to be equivocal.

TREATMENT AND COURSE: On the day following

admission a pleural friction rub was heard over the right lower part of the chest. Three days after admission moderate respiratory distress ensued. Rales were heard at both lung bases, and the liver was enlarged 3 cm below the right costal margin and was tender. The temperature, which had be-come normal on the day following admission, in-creased to 39.6#{176}Cwith this exacerbation of dysp-nea and discomfort. Heart sounds became muffled, and there was considerable jugular venous disten-sion. The blood pressure was 90/60 mm Hg. Re-peat roentgenograms revea’ed some infiltration in the left mid-lung field and fluid in the left pleural space. The cardiothoracic ratio was 12.7:19.9. The

leukocyte count was 19,000/mm’.

Because of this sudden worsening of the boy’s condition, a pericardial paracentesis was performed and 15 cc of serosanguinous fluid removed. Ad-ministration of prednisone, 15 mg every 6 hours, was commenced and continued in gradually

de-creasing dosage for 9 days. There was marked

improvement in his condition immediately

follow-ing pericardial paracentesis, and the pericardial

friction rub became much louder. Two weeks

fol-lowing admission, all evidence of pericarditis had

disappeared and the erythrocyte sedimentation

rate was 7 mm in 1 hour. Repeat roentgenograms

revealed normal lung fields and a cardiothoracic ratio of 9.9:21.3.

Results of bacterial and viral studies carried out

on the pericardial fluid were negative. Virus was not isolated from fecal specimens obtained on

October 2 and 15. However, high titers of

neu-tralizing antibody to Coxsackie B, were detected

in serum specimens obtained 15 and 21 days after the onset of illness.

Prolonged follow-up by his pediatrician revealed no sequelae or complications.

Case 7

HISTORY: E.E., a 12-year-old female child was

admitted to the Hospital for Sick Children on

October 25, 1958. Two weeks prior to admission

she developed sudden onset of fever, malaise and pain in her shoulders and back.

Ten days prior to admission she developed re-current, sharp, retrosternal pain which seemed to be of the same nature as the pain in her shoulders and back.

One week prior to admission she was given

therapeutic doses of aspirin and a sulfonamide;

there was no clinical improvement.

The course prior to hospitalization was marked by remissions and exacerbations of pain and fever. Two days prior to admission vomiting became a prominent feature, and the patient was referred to the hospital with a diagnosis of acute rheumatic

fever.

PHYSICAL EXAMINATION: On admission of the

patient, her temperature was 38.2#{176}C,and she ap-peared acutely ill. There was a pleural friction rub over the right lower part of the chest anteriorly and a penicardial friction rub over the entire

pre-cordium. The blood pressure was 100/55 mm

Hg. There was also an apical systolic murmur that had the characteristics of the murmur of mitral insufficiency.

LABORATORY FINDINGS: The hemoglobin level

was 14.7 grn/100 ml. The leukocyte count was 10,500/mm’, with 52% neutrophils, 10% band cells,

4% eosinophi!s, 25% lymphocytes and 9% mono-cytes. Results of an intracutaneous tuberculin test were negative. The antistreptolysin-O titer was less than 12 units. Roentgenographic studies

revealed normal lung fields and a cardiothoracic ratio of 11.1:24.2. An electrocardiogram showed

(14)

902 PLEURODYNIA

TREATMENT AND COURSE: On admission it was

believed that the likeliest diagnosis was acute rheumatic fever with pancarditis. Prednisone, 20 mg daily, was administered; the dosage was

duced to 10 mg daily after 5 days and 2.5 mg

daily after 2 weeks; it was discontinued after 3

weeks. Penicillin and aspirin were also adminis-tered in therapeutic doses.

Three days following admission, the pericardial friction rub and apical systolic heart murmurs had both disappeared.

Fecal samples obtained 20 days after the onset did not grow virus. However, high titers of neu-tralizing antibody to Coxsackie B, were detected in serum specimens obtained 15 and 21 days after onset of illness. The erythrocyte sedimentation rate decreased to 10 mm in 1 hour after 17 days.

In view of the clinical course, it was believed

that this child almost certainly had a Coxsackie

virus infection rather than rheumatic heart dis-ease.

F0LLOw.Up: The child was seen in the cardiac

clinic on December 15, 1 month after discharge from hospital. At this time, physical examination,

an electrocardiogram and a roentgenogram all showed normal findings.

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L.: Disease resembling nonparalytic

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E. C.: Infection of laboratory workers with Coxsackie viruses. Ann. Intern. Med., 33:32, 1950.

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Acknowledgment

We wish to thank Dr. John Keith, Dr. Richard

Rowe, Dr. Arthur Cole, Dr. E. Harkins, Dr. C.

Hamblin and Dr. Raymond Asquith for their help

in the work-up of these patients and for permission

to use data on their private patients.

CORRECTION

We should like to thank Dr. L. Emmett Holt,

Jr., New York University, for calling to our

at-tention errors in Tables III and IV of our article

(PEDIATRICS, 27:39, 1961).

In Table III, page 42, fourth line from bottom,

second column from right, 100% should read 78%.

In Table IV, page 42, fourth line from bottom, last

column, 88% should read 55%; last line, second

column from right, 84% should read 92%; last line,

last column, 92% should read 84%.

(16)

1961;27;889

Pediatrics

H. W. Bain, D. M. McLean and Selma J. Walker

Meningitis

VIRUS: The Interrelationship of Pleurodynia, Benign Pericarditis and Aseptic

EPIDEMIC PLEURODYNIA (BORNHOLM DISEASE) DUE TO COXSACKIE B-5

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