STANDARDS, STETHOSCOPES, STEROIDS AND STATISTICS

(1)

ADDRESS: Irvington House, Irvington-on-Hudson, New York.

CONTRIBUTORS’

SECTION

819

Pnwrmcs, May 1961

SPECIAL

ARTICLE

STANDARDS,

STETHOSCOPES,

STEROIDS

AND

STATISTICS

The Problem

of Evaluating

Treatment

in Acute

Rheumatic

Fever

Alvan R. Feinstein, M.D.

Irvington House, Irvington-on-Hudson, New York, and Department of Medicine,

New York Univers-ity School of Medicine

U

NLIKE many diseases which lack

ade-quate clinical trials of therapy,

rheu-matic fever seems to have an

embarrass-ment of riches. The physician who seeks a

treatment to reduce future heart disease can

choose from at least 10 recent studies with

10 different sets of recommendations. The

different reports, in order of their

appear-ance, make the following statements:

1. Salicylates for 9 weeks are somewhat

better than nothing.’

2. Steroids for 7 weeks are better than

salicylates or nothing.2

3. Steroids for 6 weeks are no better

than nothing.3

4. Steroids at high dosage for 14 weeks

are better than steroids in low dosage

for 6 weeks.4

5. Steroids, with or without salicylates,

are better than salicylates alone or

nothing.5

6. A prolonged course of penicillin in

massive dosage is therapeutically

valuable.6.

7. Steroids in high dosage for 1 week

virtually eradicate carditis.7

8. Steroids in high dosage for 12 weeks

are no better than salicylates.8

9. Steroids in moderate dosage for 6

weeks are no better than salicylates.9

10. Steroids in high dosage for 12 weeks

are superior to salicylates.’#{176}

All of these reports have come from

well-known investigators, all investigators have

tried to use matched comparison or control

groups, and almost all the data bear the

im-pressive scientific impnimatur of statistical

analysis. Nevertheless, the results show the

conflicts noted above.

This confusion can be explained by

decid-ing either that the disease is insurmountably

chaotic or that the data have been obtained

and interpreted with subtle variations which

lead to their discord. The latter explanation

seems more attractive and its likelihood will

become evident to the reader who turns

from the “Results” sections of these reports

to a closer inspection of their ‘Materials and

Methods”. The analysis which follows will

consider how the studies have varied in

these procedures and how these variations,

rather than the therapy, may have affected

the results.

The investigators have measured the

therapeutic response of many features of the

disease. Some of these features-such as

arthritis, fever, chorea, subcutaneous

nod-tiles, erythema marginatum and elevated

sedimentation rate-leave no residual scans

and would subside spontaneously if left

un-treated. Since they do not directly affect the

ultimate status of the patients, these

feat-tires are interesting parameters of acute

in-flammation, but they are of minor

perma-nent importance. The major test of

success-ful therapy, as all investigators agree, is

what it does for the heart. Since the burden

(2)

treat-ment lies with the heart, the crucial issue

becomes the methods tised to detect and

classify cardiac damage.

The selection of these methods must be

made with the realization that the

patient-world of acute “rheumatic fever” contains

several different groups, each with a

differ-ent cardiac prognosis. In order of

increas-ing prognostic severity, these groups have 1)

no significant murmurs, 2) organic apical

systolic murmurs without diastolic murmurs

or significant candiomegaly, 3) diastolic

mtirmurs without significant cardiomegaly

and 4) significant cardiomegaly and/on

coi’-gestive heart failure. The incidence of

fu-hire heart disease for these four groups,

re-spectively, in two large series’ ‘ was 1)

0-8%, 2) 26-29%, 3) 50-66% and 4) 70-85%. For

tests of therapy to be comparable, the

groups being tested must either initially

have equal percentages of patients in eacil

of these diagnostic categories or else tile

ne-stilts must be expressed proportionally

ac-cording to these initial categories. If the

data are not stratified in this way and are

presented merely as combined totals, it is

possible to get markedly different results

from identical tests of the same treatment

because tile compared groups inadvertently

contained unequal percentages of patients

with different degrees of cardiac damage.

FACTORS AFFECTING CLASSIFICATION

OF PATIENTS

For the reasons just given it is important

to consider in detail the critical factors that

affect the initial selection and classification

of patients. These factors are specified

here-in, and Tables I and II indicate the extent

to which the therapeutic studies have

con-formed to tile specifications.

Use of Jones Criteria for Diagnosis of

Rheumatic Rever

Unless their base populations are similar,

therapeutic studies cannot be compared.

The diagnosis of rheumatic fever was made

uniformly, using the Jones criteria,” in all

but two of the investigations cited here.

One of the exceptions2 augmented the Jones

criteria to allow a prolonged P-R interval

per se to serve as evidence of canditis. The

other exception7 deviated from the standard

criteria by permitting the diagnosis of

carditis to be based upon such features as

electrocardiographic abnormalities, reduced vital capacity and locally unique

fluoro-scopic standards that found at least slight

cardiac enlargement in every patient. Tile

“carditis” group of tile latter two studies

will therefore contain 5Otfld I)atients Wilo

would have been excluded from tile others.

Distinction and Separation of Rheumatic

Fever from Rheumatic Carditis

It is now vell established1217 that many

patients do not have carditis dtining the actite attack of rheumatic fever and that these patients almost invariably remain free

of rhetimatic cardiac damage thereafter.

These new restilts contradict tile old

con-cept that valvular scarring can develop

in-sidiously in patients who escaped cardiac

involvement during a known attack of

rheti-matic fever. It has been suggested that the

heart disease which appeared to develop in

the earlier studiesl21 was (hid to

then-unavoidable errors in auscultation and in

follow-up techniques. The newer concept

implies that patients with rhetimatic fever

must be separated according to those who

have carditis and those who do not. Tests

of treatment silould be restricted to patients

with earditis, because those who lack

car-ditis will emerge free of heart disease

re-gardless of therapy.

This distinction has been recognized in

all but three of tile sttidies cited above. In

two2’ (which did not use the Jones criteria),

the designation of carditis has apparently

been given to all patients with rileumatic

fever. In tile third, all patients were

con-sidered to have valvulitis, either fixed or

non-fixed. The apparently excessive

diag-nosis of carditis in certain studies is an

im-portant aspect of their data. If carditis is

said to be present in patients who do not

really have it, its later disappearance may

be a triumph of physiology rather than of

(3)

Prolonged Separation P-R In- of Results terral not According

Used as to Initial

Evidence Severity of

of C’arditis (‘arditis

Thorough

Differen-tiation of Systolic if arm iirs

Illingwortll ci (F1

l)one et a!.2

Harris ci (Il.

Roy and Massell1

lllingwortli et al.5

Mortimer et al.6 \Vilson and Li,n7t

Collihined Study8 U.K-U.S. .JOiIIt Study9

l)orfmari ci al.’#{176}

*Legend : 0- flot (bile ;+ (lofle ; ± (lone part ially (see text).

t Tabulation based 011 published report. Author’s reprints coiltaill souse additional material.

TABLE I

SPF:cIFIcATIoNS FOR SF:IEcTioN OF PATIENTS AND PRESENTATION OF RESULTS IN

10 STUDIES OF ‘I’REATMENT OF ACUTE RHEUMATIC FEVER

Use of Investigators .Jones

Criteria

Separate

Separation Presentation of Results of Results

f or Patients for

Pa-117th and tients with

11 it/tout Prerious

(‘arditis .1ttacls of

(‘arditis

(‘oneurrent Study of

(‘om

para-tire Groups

Separation

of Results

According

to Initial

Diastolic

vs. Only

Systolic

Murmurs

+ + + + + 0 + 0

0 0 + -f- 0 0 0 0

+ + + + + 0 0 0

+ + + 0 + 0 0 +

+ + + 0 + 0 + 0

+ ± ± + + 0 0 ±

0 (1 0 0 0 0 (1 0

+ + + + + + + ±

Separation of Data for Patients with

Pre-vious Attacks of Carditis

Patients whose valves have been scanned

by previotis attacks of rhetimatic fever

pre-sumabiy have a different prognosis from

those who are in their first episode of

car-(litis, and the data shotild i)e assessed

sep-arately. “sIO5t investigators have avoided

this problem by accepting only patients

viio had had no previous attacks; other

workers have used patients with recurrent

carditis I)ut have analyzed them separately.

In one study,7 however, the reported results

combined the data of the “rectinrent”

pa-tients with those who were previously free

of canditis. The assessment of tile total data

is therefore diffictilt.

Another group of workens assumed that

any patient vllOse murmurs were

un-changed during the first 3 days of therapy

must have had previous rheumatic activity

Wilieh left him vitii “fixed valvtilitis.” Tile

data for sucil patients were then separated

from tile data for those with murmurs of

flticttiating intensity, who were said to have

ilon-fixed valvulitis. This type of

retro-spective separation is not valid, hecatise it

allows post-therapeutc events to alter the

pretherapeutic classification . (The concept

of fixed and non-fixed valvtilitis also

ap-pears to lack validity, as a careful recent aflaiySiss2 has shown. This will he disctissed

further in this presentation.)

Comparative Groups Studied Concurrently

Because the natural severity of the

dis-ease may vary, it is preferable not to

com-pane patients who were treated during one

interval of time with others who were

treated at a different interval, several years

later. This type of seqtiential comparison is

sometimes employed when the number of

patients is too small to be divided or when

tile tise of untreated controls seems

unjus-tified, btit the conciasions of such a

coin-panison (as clone in three studies’ ‘ 7) cannot

be accepted without skepticism.

Elimination of Prolonged P-R Interval as

Evidence of Carditis

Tile electrocardiogram was first used in

the sttidy of rheumatic fever in the hope

(4)

non-auscul-TREATMENT IN RHEUMATIC FEVER

tatory evidence of carditis. When a

pro-longed P-R interval became a regular

find-ing23 in the disease, it was assumed that the

long-awaited test for carditis had finally

ar-rived. Numerous subsequent investigations

have disproved this assumption. It is now

firmly established that a prolonged P-R

in-terval per se does not indicate earditis. It

occurs in 25 to 40% of patients witll

rheu-matic fever; it does not correlate with the

presence or absence of cardiac damage or

with cardiac 24, 25; it is not

listed among the latest Jones diagnostic

criteria” for carditis, and it is cited there

only as a minor manifestation of rheumatic

fever. It can occur in uncomplicated

strepto-coecal infections,26 in scarlet fever,2’ and in

a variety of diseases and states unrelated to

streptocoecal infeetions28, 29; it is present in

about 5% of normal children.30 The one

existing study3’ that stated that the P-R

in-terval was an important prognostic sign has

never been confirmed and has been

sus-832 of significant errors in

ausculta-tory procedures.

Nevertheless many physicians maintain

their faith in the P-R interval as a diagnostic

test. One group of investigators33 has altered

the Jones criteria to include a prolonged

P-R interval as evidence of earditis; a

re-spected textbook’ of pediatric cardiology

has called this electrocardiographic finding

“a sensitive index of active carditis.” Studies

which contnue to use a prolonged P-R

in-terval as the only evidence of heart

involve-ment may thereby indicate a higher

mci-dence of carditis than the others. This usage

has occurred in 22’7 of tile 10 papers

con-sidened here.

Separation of Carditis According

to Prognostic Features

SEviirry: Patients with severe

manifesta-tions of earditis, such as significant cardiac

enlargement and congestive heart failure,

have more residual heart damage than those

in whom carditis consists only of abnormal

murmurs or minimal 20 21

(The distinction between slight and

signifi-cant heart enlargement is also an area in

which investigators may inadvertently use

different criteria.35’ 36) Here again, the

pa-tients with mild carditis must be separated

from those who those who have more

severe cases, to avoid a single analysis of

two groups with different prognoses.

Al-though

all the

studies under consideration

have indicated how many patients had

con-gestive heart failure, only three reports’#{176}

have separated the cardiac sequelae of this

group in the tabulations. If the percentage

of patients with congestive heart failure is

unequal in different groups, the therapeutic

results may differ for this reason alone.

Table II shows the numbers of patients

with congestive failure in each treatment

group, compared to the total number of

pa-tients with carditis. (It should be noted that

criteria for congestive failure may also vary.

A falsely high incidence of congestive

fail-ure would be expected when the diagnosis

is based only on tachyeardia and

“hepat-omegaly,” because the palpability of the

liver is often a subjective measurement and,

in other instances, its enlargement may be

a noneardiac complication of therapy3T)

The percentages range from 0 to 36%; they

are frequently different in the two groups

of the same study and are markedly

differ-ent among different studies. Those groups

with higher percentages of “failure”

pa-tients would a priori be expected to have

poor results, regardless of therapy.

FATE OF SYSTOLIC AND DIASTOLIC

MUR-MURS: With the separation of patients who

have congestive heart failure, there remain

the patients whose main manifestations of

carditis are murmurs. Here, patients with

diastolic murmurs have a worse

prog-17 than those whose only

ausculta-tory abnormality is a systolic murmur; these

two groups therefore need separate

analy-sis. 46 7 of the 10 investigators have

not reported their results according to this

distinction. One7 listed the differences in

murmurs at the onset but not at the end of

treatment.

Table II shows the available data for the

initial status of patients according to the

(5)

Illingworth et a!.’ 2/15 0/17

13 0

8/7 6/11

Done et al.2 (Controls)+salicylates Steroids

4/34 4/46

12

9

Harris et al.3 (Controls)

Steroids

6/26 19/53

23 36

?

Roy and Massell’ Steroids, low doses

Steroids, high doses

10/41 10/47

24 21

?

Illingworth et a.5 (Controls) +salicylates

Steroids ± salicylates

2/62 19/53

3

36

Mortimer ci al.6 No penicillin

Massive penicillin

4/28 1/32

13

3

Wilson and Lim’ Steroids, early

Steroids, late

0/36 6/17

0 35

Combined (;roup8 Salicylates

Steroids

2/25

3/29

U.K-U.S. Joint Study’ Salicylates

Steroids

7/61 26/121

11 21

Dorfmaii et al.’#{176}

114

55

23/39 59

21/28 75

4/25 16

5/12 42

8 18/7 257

10 22/7 314

29/25 116

60/35 171

5 13/28

0 11/33

?

2/41

0/44

SPECIAL ARTICLE

823

TABLE II

COMPARISON OF SEVERITY OF PRETREATMENT MANIFESTATIONS OF CARDITIS IN 10

STUDIES OF TREATMENT OF ACUTE RHEUMATIC FEVER

Ratio of Numbers of Patients with

Cardiac Features as Noted

!ni’e.stigutors Therapy Congestive Failure*:

Card itist

Diastolic Murmurs:

Systolic Murmurst

Ratio % Ratio %

(Controls) Salicylates

Salicylates+ (Controls)

Steroids ± salicylates

46

33

6‘Fliis iflClU(les all patients who developed congestive failure, initially or during treatment. The data usually did

not permit a differentiation. III one paper,’ this also includes patients with pericarditis.

t In patients who lacked (liastolic murmurs, apical systolic murmurs of only Grade 2 or higher intensity were cOflsi(lered as carditis.

murmurs. The percentages differ

dramati-eally, ranging from 16% to 314%. In only three investigations were there more

pa-tients with diastolic murmurs than with

systolic murmurs. Studies that contain

dif-ferent percentages of patients with diastolic

and systolic murmurs will have different

outcomes if their results are expressed in

combined totals instead of separately. As

noted elsewhere’ and below, the diagnosis

of eanditis is often tenuous in the absence

of diastolic murmurs because of the

difficul-ties in separating physiologic from organic

apical systolic murmurs. Studies in which a

majority of patients have only systolic

mur-murs are likely to have better results,

be-cause they may inadvertently be reporting

the disappearance of physiologic systolic

murmurs.

(6)

MURMURS: The one diffictilty Wilich

prob-ably accounts for most of the discrepancies

and inconsistencies in this field is the

differ-entiation of physiologic from organic apical

systolic murmurs. This has been a

pernici-Oils, persistent and still-unsolved problem.35

Systolic murmurs, arising in the area of the

pulmonary valve-artery, occur

physiologi-cally in 50 to 90% of normal children and adolescents.39_12 45 When such a murmur is

loud (and it becomes louder whenever

blood flow is increased) or when the

posi-tion of the heart or of the patient brings the

pulmonary artery down, forward and

left-ward, a murmtir will be audible at the apex

and it may even be heard in the axilla. An

apical systolic murmur will therefore be

en-countered frequently in the examination of

any group of acutely ill young patients.

When it is found in a patient with febnile

polyarthnitis or chorea, it is suspected of

coming from a rheumatically inflamed

mitral valve, and its cause must be

distin-guished as organic on physiologic.

The four properties of murmtirs generally

used to make this distinction are intensity,

radiation, pitch and quality. Most

exami-ners state that the organic mitral systolic

murmur is lotid, transmitted to tile axilla,

high-pitched and blowing. Each of these

features is sufficiently nonspecific to allow

considerable divergence in its acoustic

in-terpretations. The intensity at the apex can

he a helpful point in that physiologic

mur-murs are usually soft and organic ones are

loud. But this criterion will fail in tile

fre-quent instances when the physiologic

mur-mur is loud. Transmission to the axilla is

merely a property of the lotidness of the

murmur’3 and cardiac position; it may

sometimes occur with physiologic

mun-murs.39 The high pitch and the blowing

quality of the murmtir are sometimes

use-fui, but at other times they can be

decep-tive. As the elegant work of Bruns’4 has

shown, “The position of listening as it

re-lates to a column of moving blood modifies

the perceived frequencies to a remarkable

degree.” Since these frequencies provide

the overtones which affect pitch and

qual-ity, it is possible for a physiologic

mun-mur to have one pitcil and quality in the

pulmonary area (where it is heard “in

front” of blood flow) and a different pitch

and quality at tile apex (where it is heard

“behind” blood flow). In such a situation,

there would appear to be two different

sys-tolic murmtirs and the apical one might be

regarded as “organic.”

Thus, none of the four properties cited

above, singly or in combination, can be

confidently relied upon for an accurate

sep-aration of organic from physiologic apical

systolic murmurs. In the past diagnostic

cni-tenia of the New York Heart Association4

this inadequacy has been recognized by in-sistence that cardiac enlargement be

pres-ent in order to consider an apical systolic

murmur as organic. Nevertheless, most

cx-aminers have believed that this

require-ment is too confining and that auscultation

alone can be tised to recognize mitral valve

involvement in patients without

cardio-megaly. Their criteria for this diagnosis

generally fuse a combination of the four

properties previously noted, with perhaps

some of the properties to he noted later,

into one acoustic gestalt, based on

stibjec-tive experience. The gestalt is usually

ap-plied consistently by the individual

cx-aminer in a single study, hut the gestalt

may vary in studies by different examiners. Because patients without cardiomegaly

sd-dom come to early surgery or necropsy, an

individual examiner can maintain and

es-tablish ilis concepts through many years of

observations, unchallenged by specific

ana-tomic confirmation.

In recent years, tile differentiation of

sys-tolic murmurs has been aided by the use

of two additional properties: the duration

and the site of maximal intensity.

Physio-logic murmurs are usually short and are

loudest medial to the apex and along the

left sternal bonder, while organic mitral

murmurs are holosystolic and lotidest at the

apex and laterally. By these criteria, an

apical systolic murmur, regardless of its

in-tensity or quality at tile apex, is thought to

(7)

pos-SPECIAL ARTICLE

825

sibly a non-mitral organic) source if it does

not fill systole or if an equally low!, or

louder, systolic mtirmtir is heard anywhere

else in tile chest. These additional specifica-tions have been applied with considerable

success in several but

they have not become generally appreciated

and they were used in only one4 of tile

studies considered here.

It should be noted that tile objective aid

of phonocandiography is not particularly

valuable for tile systolic mtinmur problem at

the present time. Its only real contribution

is in timing the duration of the murmur, since its graphic record cannot effectively

indicate the pitcil on qtiality of the murmur,

or the relative intensities at different parts

of tile chest, a role for which tile ordinary

stethoscope is still unsurpassed.

Since canditis is not present9’ ‘‘ ‘ in at

least one-third of patients with chonea on

febrile polyanthnitis, it is important that

in-vestigators indicate how they identify and

separate the apical systolic murmurs that

can be expected physiologically in these

pa-tients and which might mistakenly be

at-tnibuted to mitral valve damage. This part

of the “i\’latenials and Methods” of the in-vestigations is crucial; yet it is often given

less description than any other feature of

the reports. Of tile 10 studies cited here, in

only one’ have the authors stated that they classified organic apical murmurs according

to all six of the properties cited above. Two

studies2 7 gave no description or reference

to the criteria for differentiating systolic murmurs. One study3 tised transnlission to tile axilia as tile major distinguishing

fea-ttire. One studyc, which did not separate

systolic from diastolic organic niurmtirs afl(I

which did not give the details of its

iclenti-fication of systolic murmurs, introduced the

term “non-fixed valvulitis” for patients who,

in the first 3 days of therapy, “experienced

at least 1 day on which no (organic)

mur-mur was heard.” Since the timing of the

transient “non-fixed” murmurs was not

in-dicated and since physiologic systolic

mur-murs characteristically have a fluctuating

intensity (which may make them seem like

“changing murmurs”), it is highly possible

that some of the “non-fixed valvulitis” was

due to physiologic rather than organic causes. Four reports1’ ‘ “ 10 listed systolic

murmurs according to their intensity at the

apex but not according to their site of max-imal intensity. In two of it was stated that “an element of doubt” was

pres-ent “when there was a Grade 1 or 2 systolic

mtirmur.”

The

most recent report’#{176} qualifies its selections somewhat by stating that mur-inurs heard best at the left sternal border

were regarded as physiologic, but it does

not indicate the classification of murmurs

in which intensity was the same at the apex

and base. In another study5 that used apical

intensity as a sole criterion, the autllors ac-cepted for “carditis” only systolic murmurs of Grade 3 intensity.

Since the various examiners have not

agree on tileir written criteria for

differ-entiating apical systolic murmurs and since

they ilave not calibrated themselves

to-gether regarding their actual application of

individual criteria, it is not stirpnising that

subtle variations would occur through the

tise of similar written or verbal “labels” for

acoustic phenomena which are really inter-preted differently. As Table I shows, a ntim-ben of studies cannot be completely ac-cepted because of significant omissions in

tile data. The three most satisfactory

tnials#{176} are also the most recent. In tile first tw& of these trials, different dosage

and duration of steroid therapy was used

but tile same conclusions were reached. In

tile third10 tile same steroid program was used as in a previous test,s but a different conclusion was reached. In comparing these

two studies (Table II), it is apparent that in

the latest one there were fewer patients

with severe carditis or diastolic murmurs

and that more of “carditis” was manifested

only by systolic murmurs and cured by

their disappearance. It is this feature of the

initial patient population that probably

ac-counts for tile differences in the two reports.

The preceding elaboration of the pitfalls

in distinguishing apical systolic murmurs

(8)

completely satisfactory objective methods

for doing so, that the stethoscopic

differen-tiation only by apical intensity or radiation

is inadequate, that the duration of the

mur and comparison of its relative

inten-sities are useful but have not been generally

applied, that different investigators may

consistently but inadvertently use

conflict-ing criteria, and that the magnitude of the

problem is doubled by the need for

differ-entiating systolic murmurs both during the

acute attack and at follow-up examinations.

It is in the details of these distinctions,

rather than from therapy, that most of the

disagreements in results appear to emanate.

Other Aspects

Two other important procedural aspects

will be noted only in passing. One of these

is the need for allocating patients to their

initial therapeutic groups in a truly random

manner and not merely by alternation or

other fixed patterns. The second is the need

for “blind” auscultation in the

interpreta-tion of heart murmurs. For truly objective

auscultation, before and after treatment,

tile examiner should not be aware of the

therapy or of any recorded opinion

(in-cluding his own) in the patient’s chart.

CONCLUSIONS

The different results of recent studies of

the treatment of rheumatic fever seem to be

due not to therapeutic effects but to the

inclusion in compared groups of different

percentages of patients with inherently

dif-ferent cardiac prognoses. The

homogeniza-tion of heterogeneous groups has occurred

either through insufficient attention to the

details of cardiac classification or through

inadverent use of different criteria for the

classification. The situation has been aptly

described by Hill,4T who wrote, “the essence

of a successful controlled clinical trial lies

in its minutiae-in a painstaking, and

some-times very dull, attention to every detail.”

Until the deficiencies in some of these

“minutiae” are remedied, many contentions

remain unproved.

Massive penicillin treatment, as

com-pared to none, has not demonstrably

re-duced heart disease. Since massive

treat-ment was not tested against an ordinary

streptococcal-eradicating dose of penicillin,

the advantages claimed for massive

treat-ment, even if valid, would not pertain to

use of the latter regimen. With regard to

anti-inflammatory therapy, steroids have

been unequivocally superior to salicylates only in temporarily suppressing the acute,

overwhelming carditis of a small percentage

of patients who are moribund, but even

here, steroids have not affected ultimate

cardiac status. Such severely ill patients

are uncommon. For most patients with

rheumatic carditis, the three most

sat-isfactony trialsS_bO of steroids versus

sali-cylates have indicated a two-to-one vote

against any stipenionity for steroids. In the

minority report,1#{176} the patient population

differed significantly from that of the other

two reports, and its different results

prob-ably arise from this feature. It still remains

to be shown convincingly that steroids,

salicylates, or both produce more

perma-nent cardiac benefit in most instances than

symptomatic therapy alone.

For the practicing clinician, the

preced-ing discussion is intended as a guide for use

in reviewing the evidence and making his

choice of treatment. For the investigator

who performs therapeutic trials, it is

in-tended to indicate the subtle details which

are required for a successful study. For

both, it should recall the old admonition of

an investigative clinician39 : “Unless

prog-nosis springs from solid diagnostic roots, the

tree is unstable.”

REFERENCES

1. Illingworth, R. S., et al.: Salicylates in

rheu-matic fever: an attempt to assess their

value. Quart. J. NIed., 23:177, 1954.

2. Done, A. K., et al.: Therapy of acute

rheu-matic fever. PEDiATRICS, 15:522, 1955.

3. Harris, T. N., et al.: Therapeutic effects of

ACTH and cortisone in rheumatic fever:

cardiologic observations in a controlled

series of 100 cases. PEDIATRICS, 17: 11, 1956.

4. Roy, S. B., and Massell, B. ‘F. : Comparison

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SPECIAL ARTICLE

treatment of acute rheumatic carditis.

Cir-culation, 14:44, 1956.

5. Illingworth, R. S., et at.: Acute rheumatic

fever in children: a comparison of six forms

of treatment in 200 cases. Lancet, 2:653,

1957.

6. Mortimer, E. A., et at.: The effect of

penicil-lin on acute rheumatic fever and valVular

heart disease. New Engi. J. Med., 260:101, 1959.

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hormone therapy: its effect in active rheu-matic carditis of varying duration. New

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comparison of the effect of prednisone and

acetylsalicylic acid on the incidence of

re-sidual rheumatic heart disease. New Engl.

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Re-port : The evaluation of rheumatic heart

dis-ease in children : Five-year report of a

co-operative clinical trial of ACTH, cortisone

and aspirin. Circulation, 22:503, 1960.

10. Dorfman, A., Gross, I., and Lorincz, A. E.:

The treatment of acute rheumatic fever.

PicmAi-mcs, 27:692, 1961.

11. American Heart Association: Report of

Corn-mittee on Standards and Criteria for

Pro-grams of Care of the Council on Rheumatic

Fever: Jones criteria (modified) for

guid-ance in diagnosis of rheumatic fever. Mod.

Cone. Cardiov. Dis., 24:291, 1955.

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rheumatism, with special reference to the

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Med., 7:

251, 1914.

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in-fection iii childhood: early diagnosis and

preventive treatment. Brit. Med. J., 2:788,

1925.

14. Boone, J. A., and Levine, S. A. : The prognosis

in “potential rheumatic heart disease” and

“rheumatic mitral insufficiency.” Amer. J.

Med. Sci., 195:764, 1938.

15. Brown, M. C., and Wolff, L. : Recovery from

acute rheumatic fever without permanent

cardiac damage. New Engl. J. Med., 223:

242, 1940.

16. Engleman, E. P., Hollister, L. E., and KoIb,

F. 0. : Sequelae of rheumatic fever in men:

four-to-eight-year follow-up study. J.A.M.A., 155:1,134, 1954.

17. Feinstein, A. R., and DiMassa, R. : The

prog-nostic significance of valvular involvement in acute rheumatic fever. New EngI. J. Med., 260:1,001, 1959.

18. Feinstein, A. R. : The stethoscope: a source

of diagnostic aid and conceptual errors in

rheumatic heart disease. J. Chron. Dis., 91:101, 1960.

19. Bland, E. F., and Jones, T. D. : The delayed

appearance of heart disease after rheumatic

fever. J.A.M.A., 1 13: 1,380, 1939.

20. Bland, E. F., and Jones, T. D. : Rheumatic

fever and rheumatic heart disease: a twenty

year report on 1,000 patients followed since

childhood. Circulation, 4:836, 1951.

21. Ash, R. : Rheumatic infection in childhood:

fifteen to twenty year follow-up : caution

against early ambulant therapy. Amer.

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Dis. Child., 76:46, 1948.

22. Stollerman, G. H. : Prognosis and treatment

of acute rheumatic fever: the possible effect

of treatment on subsequent cardiac disease.

Progr. Cardiov. Dis., 3:193, 1960.

23. Cohn, A. E., and Swift, H. :

Electrocardio-graphic evidence of myocardial involvement

in rheumatic fever. J. Exp. Med., 39:1,

1924.

24. Keith, J. D. : Overstiniulation of the vagus

nerve in rheumatic fever. Quart. J. Med.,

7:29, 1938.

25. Wyckoff, J., DeGraff, A. C., and Parent, S.:

The relationship of auriculo-ventricular

con-duction time in rheumatic fever to salicylate

therapy. Amer. Heart J., 5:568, 1929-30.

26. Rantz, L. A., Spink, W. W., and Boisvert,

P. J.: Abnormalities in the

electrocardio-gram following hemolytic streptococcus sore

throat. Arch. Intern. Med., 77:66, 1946. 27. Levander-Lindgren, M. : Electrocardiographic

studies in scarlet fever. Acta Paediat.

(Suppl.), 91:1, 1952.

28. Shnier, M. H. : The Wenckebach phenomenon

and auricular-ventricular dissociation in

childhood. Arch. Dis. Child., 33:246, 1958.

29. Sutton, G. C., Schaffner, F., and Scherbel,

A. L. : Instability of auriculoventricular

con-duction in acute rheumatic fever. I.

Fre-(ItlencY and extent. II. Effect of position

on first degree heart block. U.S. Armed

Forces Med. J., 7:481, 1956.

30. Reyersbach, G., and Kuttner, A. G. : Studies

on the auriculoventnicular conduction time

of normal children and of rheumatic

chil-dren without signs of rheumatic activity.

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31. Weinstein, L., Boyer, N. H., and Goldfield,

M. : Rheumatic heart disease in scarlet fever

patients treated with penicillin: a follow-up

study after seven years. New Engl. J.

Med., 253:1, 1955.

32. Feinstein, A. R., and DiMassa, R. : The

un-heard diastolic murmur in acute rheumatic

fever. New Engi. J. Med., 260:1,331, 1959.

33. Denny, F. W., et al.: Prevention of rheumatic

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strepto-coccic infection. J.A.M.A., 143 : 151, 1950.

34. Nadas, A. S. : Pediatric Cardiology.

Phila-delphia, Saunders, 1957.

35. Maresh, M. NI. : Growth of the heart related

to bodily growth during childhood and

adolescence. PEDIATRICS, 2:382, 1948.

36. Frieden, J., et a!.: Evaluation of heart size in

children and adolescents who have had

rheumatic fever. Circulation, 20:697, 1959.

37. Baldwin, J. S., and Rusoff, J. H. : Significance

of hepatomegaly in children with rheumatic

fever receiving adrenal cortical hormone

therapy. Ann. Rheum. Dis., 11:310, 1952.

38. McEwen, C. : The treatment of rheumatic

fever. Amer. J. Med., 17:794, 1954.

39. Thayer, W. S. : Reflections on the

interpreta-tion of the systolic cardiac murmurs. Amer.

1.

Med. Sci., 169:313, 1925.

40. McKee, M. H. : Heart sounds in normal

chil-dren. Amer. Heart J., 16:79, 1938.

41. Lessof, M., and Brigden, W. : Systolic

mur-n3urs in healthy children and in children

with rheumatic fever. Lancet, 273:673, 1957.

42. Groom, D. : The “normal” systolic murmur.

Circulation, 18: 1,044, 1958.

4:3. Levine, S. A., and Likoff, W. B. : Some notes

on the transmission of heart murmurs. Ann.

Intern. Med., 21:298, 1944.

44. Bruns, D. L. : A general theory of the causes

of murmurs in the cardiovascular system.

Amer. J. Me(l., 27:360, 1959.

45. New York heart Association: Nomenclature

and Criteria for Diagnosis of Diseases of

the Heart and Blood Vessels, Ed. 4. New

York, 1939, p. 55.

46. Kuttner, A. C., and Markowitz, M. : The

diagnosis of mitral insufficiency in rheumatic

children. Amer. Heart J., 35:718, 1948.

47. Hill, A. B. : The clinical trial. Brit. Med. Bull., 7:278, 1951.

48. Fogel, 1). H. : The innocent systolic murmur

in children: a clinical stud of its incidence

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1960.

PHYSIOLOGY OF PREMATURITY, Transactions

of the Fifth Conference (March 16, 17,

and 18, 1960, Princeton, N.J.), edited by

Muriel Kowlessar, M.D. New York, Josiah

Macy, Jr., Foundation, 1961, 238 pp.,

$5.50.

The Fifth Conference on Prematurity is

re-ported in the manner already familiar to

read-ers of publications of the Josiah Macv, Jr.,

Foundation. The editing succeeds again in

maintaining clarity of expression without losing

the feeling of spontaneity.

This conference is devoted to the premise

that the best approach to the problem of

pre-maturity is to eradicate it. Accordingly the

stress is On factors leading to the termination

of pregnancy with the inference that these

may eventually be controlled. The major

pres-entations are concerned with the effect of

oxvtocin on the activity of the pregnant uterus

(Calcieyro-Barcia), the effect of progesterone

on the isolated uterine muscle cell (Csapo),

the role of the “incompetent cervix” in

caus-ing prematurity (Reid), and the relation of

asymptomatic bacteriuria ii, the pregnant

womai to prematurity alici perinatal death (Kass).

This 1)00k iS not designed for the reader

who is forced by pressure of time or interest

to limit himself to material of immediate

prac-tical valtie. Much of the data is original and,

as et, tintesteci in other laboratories, and the

subject itself lies traditionally in the field of

obstetrics. There is much that is provocative and interesting to the investigator concerned

with problems of the newborn infant and to

the more castial reader who enjoys keeping

pace with pioneering thinkers in medicine.

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1961;27;819

Pediatrics

Alvan R. Feinstein

Evaluating Treatment in Acute Rheumatic Fever