ETIOLOGY OF RESPIRATORY INFECTIONS: Further Studies during...

1964;33;30-44 PediatricsHerta Wulff, Patricia Kidd and Herbert A. Wenner

ChildhoodETIOLOGY OF RESPIRATORY INFECTIONS: Further Studies during Infancy and

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ETIOLOGY OF RESPIRATORY INFECTIONS

Further Studies during Infancy and Childhood

Herta Wulif, Ph.D., Patricia Kidd, and Herbert A. Wenner, M.D.

Ihixon Memorial Laboratory, Department of Pediatrics, University of Kansas

School of Medicine, Kansas City 3, Kansas

MATERIALS AND METHODS

ure 1.

30

PEDIAnucs, January 1964

INTRODUCTION

I N RECENT YEARS viruses have been asso-

ciated �VitIl a large fraction of respiratory

illnesses of infancy and childhood. The

clinical expressions associated with such in-

fections vary greatly. Parainfluenza virus,

types 1 and 2, and influenza 22 3 and pos-

sibly ECHO type 11� among others have

been linked with “croup,” and sometimes

with pneumonia. � C Respiratory syncytial

(RS) virus may be found during upper res-

piratory tract infections, or at worst with

bronchiolitis and pneumonia. �. �.

In our previous studiesl0, an association

as rigid as those of others was not found

between RS and parainfluenza type 1 virus

and bronchiolitis or pneumonia. None of

25 infants with bronchiolitis could be linked

with RS virus, and of 39 with pneumonia

only a small fraction (13%) developed spe-

cific antibodies. Clinical observations, and

data from the laboratory suggested that of

those developing pneumonia a fraction were

of bacterial origin.

In this study specific viruses were re-

covered from half the study population.

Among these the majority included RS and

influenza B viruses, each independently as-

sociated with outbreaks of respiratory ill-

ness. On the other half respiratory illnesses

could not be associated with 14 viruses.

Available evidence suggested that some

were very likely caused by bacteria.

Nosocomial

The study includes 114 infants and chil-

dren entering the hospital or Clinics of the

University of Kansas Medical Center be-

t\veen November 20, 1961, and May 10,

1962 (Fig. 1). These patients were grouped

as follows: pneumonia, 47; bronchiolitis, 21;

laryngotracheobronchitis (LTB), 11; influ-

enza, 3; upper respiratory infection (URI),

18; and other, 14 (Fig. 2). The signs used

for grouping patients into major clinical

categories have been described elsewhere.�l

Each entry was made without knowledge

of viral or bacterial flora. When overlapping

signs were present entry was based on those

predominating at the first examination.

Pneumonia developed in 11 additional chil-

dren; from signs obtained at the first ex-

amination 8 had been classified as LTB or

bronchiolitis (see notes on entries, Fig. 2).

The 14 patients entered as “other” were

sampled on entry because they were sus-

pected as having primary respiratory ill-

nesses or because corresponding signs de-

veloped in hospital. Final diagnoses in these

patients ranged from staphylococcal septi-

cemia to diffuse “collagen” disease.

Monthly Admissions

Entries are arranged graphically in Fig-

(Submitted Ma� 3, 1963; accepted for publication August 15.)

Aided by grants from the National Foundation and the United States Public Health Service Research

Grant, No. CA 06006-02, from the National Cancer Institute; also supported in part by a Public Health

Service Research Career Program Award 5-KC-A1-13,976 from the National Institute of Allergy and

Infectious Diseases.

Dr. Wulif is Research Fellow, Section for Virus Research.

ADDRESS: (H.A.\V.) Rainbow Boulevard at 39th St., Kansas Cit� 3, Kansas.



NDJ FMAMJ ND) FMAMJ

MONTH

ARTICLES 31

Fic. 1. The patients and viruses recovered during

the studs period. Each block represents a patient;

time of entry is based on date nearest onset of

illness. For years 1961-1962.

Age and Race

Seventy-five per cent were infants.

Among 29 children, 1 1 ranged from 5 to 14

years, 9 of the 11 came to the Out-Patient

Clinic with an influenza-like illness. All

others were admitted to hospital.

Negroes comprised 40% of the study

group; the rest were Caucasians. The frac-

tion of Negroes in the clinical categories

were “other,” 29%; URI, 24%; LTB, 73%;

bronchiolitis, 38%; and pneumonia, 45%.

Specimens

Samplings included nose and throat swabs

(all patients), urine (52 patients), and feces

(6 patients). Usually samples were obtained

a few hours after admission to hospital (ex-

cept for those developing infection in hos-

pital). Paired sera were available for 74

children.

Bacteriology

Each nose and throat swab was plated

on rabbit’s blood agar (BAP); after plating

swabs were swirled in Pike’s medium.12

Bacteria grown in Pike’s medium were re-

plated on BAP. Bacteria present on all

plates were identified on the basis of colony

morphology, Gram’s strain, bile soiubility

(pneumococci), and sensitivity to bacitracin

(hemolytic streptococci).

Virology

Virus isolation: Nose and throat swabs

were placed immediately in 4 ml of veal in-

fusion broth containing penicillin (800 units),

streptomycin (800 m�i.) and amphotericin B

(1 mp.). Swabs were swirled in diluent and

excess fluid obtained by rolling them against

the wall of the collecting bottle. Antibiotics

were added to urine samples in quantities

(per ml) mentioned above. Specimens �vere

inoculated usually within 10 minutes after

collection.

Three tissue culture systems were used:

(a) primary monkey kidney, (b) primary

human amnion, and (c) HEP-2, an estab-

lished cell line.13 Procedures used in culti-

vation of these cells on glass surfaces have

been described. Each specimen was inocu-

lated into 4 to 6 tubes of each culture sys-

tem (0.1 ml/culture). Cell cultures were

racked in a drum and rotated mechanically

at 37#{176}C. Cultures were examined every

other day for specific cytopathic effect

(CPE). Twice during the incubation period,

on the fifth day and before passage, one

Ui

z

FIG. 2. Seasonal (listribution according to clinical

category. As noted earlier in the text, 11 patients

tiuring their illness developed radiographic cvi-

(ience of pneumonia. By our criteria these individ-

uals were not entered in the panel marked forpneumonia patients; they are, however, noted by

symbol (solid circle). See Fig. 1 for legend.



32 RESPIRATORY INFECTIONS

tube, representing each specimen and tissue

culture type was tested at 4#{176}Cfor hemad-

sorption (HAd) of guinea pig erythrocytes.

Fluid harvests from positive cultures

(CPE + or HAd + ) were often frozen

( - 70#{176}C)prior to passage to form a virus

stock. Virus stocks were dispensed into

ampoules, glass-sealed, and stored at

-70#{176}C. Some strains later identified as RS

virus were very unstable stored at -70#{176}C

even with added chicken serum (20%, macti-

vated) or gelatin (0.5%). Unstables viruses

procured from CPE + cultures were main-

tamed in continuous passage until condi-

tions providing for stability were estab-

lished. Subsequently such vinises retained

infectivity to titer for at least 2 months when

mixed �vith an equal volume of glycerin,

stored in a dry-ice box.

Negative cultures were observed for 2 to

3 weeks; eacil �s’as subcultured if nonspe-

cific CPE interfered with readings. Cultures

were frozen ( - 70#{176}C) and thawed; then

fluid overlays were harvested for passage

(0.2 ml) into fresh tissue cultures. Each

negative sample was subcultured 3 times;

at tile end of the tilird passage the cell

“sheet’ was cilecked for HAd with guinea

pig erythrocytes.

Type Determinations

Type-specific antisera for influenza, para-

influenza, reo-, adeno-, and enteroviruses

were procured from monkeys and rabbits.bO

Antiserum for respiratory syncytial virus

(strain 87) was prepared in monkeys.

Following passage, and formation of virus

stocks, infectivity endpoint (TCID50) of

each isolate was determined using the tissue

culture system yielding CPE. One hundred

TCID�I) of stock virus was mixed with an

equal volume of 1:8 dilution of antiserum.

Virus-serum mixtures were incubated for

1 hour at 37#{176}C;immediately thereafter they

were placed in an ice-water bath. Each mix-

ture was inoculated into 3 or 4 cultures;

each culture received 0.2 ml. Tests were

scored after 3 to 4 days incubation when

coiltrol cultures indicated CPE and 40 to

100 ID�0 of virus in the test.

Some viruses were typed by ilemadsorp-

tion-inilibition. Cultures were inoculated

with 1 : 10 or 1 : 100 dilution of virus, and

incubated 3 to 4 days at 37#{176}C.After dis-

carding fluid overlays, cell sheets were

washed twice with phosphate buffered sa-

line; tilen 0.2 ml of pretreated antiserum

(absorbed with guinea pig erythrocytes)

added to all except control cultures. Thirty

minutes later 0.2 ml of 0.4% suspension of

guinea pig erythrocytes was delivered to

each culture. After incubation for 20 mm-

utes at 4#{176}Ctile cultures were read for

presence or absence of HAd.

Antibody Determinations

By serum neutralization : Procedures have

been described.10 Human sera inactivated

at 56#{176}Cfor 30 minutes were diluted in

fourfold steps and tested for serum dilution

endpoints neutralizing about 100 ID50 of

each of the 11 viruses entered in the study.

Paired sera were always included in the

same test. Antibody measurements were

made by serum neutralization for all except

influenza C and adenoviruses. By hemag-

glutination inhibition: Antibodies against

influenza C were measured by this method.

Nonspecific inhibitors were removed using

methods described pre�’iousl�.1#{176} By corn plc-

ment-fixation: Tile metllod used for measur-

ing antibodies for adenoviruses has been

described also.’#{176}

Bacterial Flora

RESU LTS

Satisfactory cultures of the nasopharynx

were obtained from 80 of 100 infants and

cilildrefl (excluding 14 children entered in

tile “other” category). The analysis is based

Oil the frequency of recovering pneumo-

cocci (Str. /)neumoniae) and influenza bacilli

(H. influenzae); Group A hemolytic strepto-

cocci were recovered only from the oro-

pilarynx of 3 children.

A portion of the data is summarized in

Table I. Pneumococci were recovered from

half, influenza bacilli from a third, and one,

the other or both bacteria, from two-thirds



Clinical Category

No. of Persons Frequency (%)

in Group Cultured “PN” “hi. Influ”

“P.V.’+

� �. flu”Either one

or Both

URI

LTB

Bronchiiolitis

Pneumonia

Totals

21*

11

21

47

100

8

11

20

41

80

50

64

40

46

48

25

36

20

46

36

25

27

10

12

15

50

73

50

76

69

* Includes 3 patients with influenza-like illness. Abbreviations: URI, infection limited largely to the PlIilrYIIx

LTB, laryngotracheobronchitis; “PN,” Sir. pneuinoniae; “H. miEn,”Hemophilus influenza, smooth l)hIase.

The data were subgrouped and scored for virus-positive and virus-negative individuals. The fraction of virus

Ilegative individuals in the categories were for LTB, 45%; bronchiohitis, 40%; and pneumonia, 51%. Rates ob-

tained by such subgrouping were not significantly different.

TABLE II

Kind of Pneumonia (‘lass

No. of Persons Frequency (%)

- PV+ I��ither one

In Group (‘u/lured “PN” “ii. influ” II. infii” or Both

Lobar Virus +Virus 0

5

12

5

11

40

45

40

46

0 8()

9 82

Bronchopneunionia Virus +Virus 0

24

17

21

14 79

43

43

14

21

60

100

ARTICLES 33

See Table I for abbreviations. Eleven infants, noted symbolically in Figure 2, developed Pneumollia; they are

included in this table.

TABLE I

RECovERY OF Str. jnteuinoiiiae AND H. influenzae FROM THE N&sovii�jiyxx

of the patients. The total rates obtained

for clinical groupings were not only similar

to one another, but did not differ signifi-

cantly from total over-all rates. Subgroup-

ing for age differences disclosed that older

infants (12 to 24 months) with LTB yielded

pneumococci and those of corresponding

age with pneumonia yielded influenza ba-

cilli about twice the expected rate. Further

subgrouping by clinical category according

to the presence or absence of virus showed

among the latter a slightly larger associa-

tion of pneumococci among patients with

bronchiolitis and pneumonia. The numbers

are small, and the differences statistically

insignificant.

Fifty-eight patients presenting with or de-

veloping pneumonia during illness were

subdivided according to type of pneumonia

( from radiographic evidence) and whether

or not they yielded virus (Table II). No

differences in rates between the classes were

found for lobar pneumonia. But for the

larger group with bronchopneumonia pneu-

mococci were recovered with greatest fre-

quency (� 3:1) from patients not yielding

virus. Other data on age-specific rates for

patients with lobar pneumonia, however,

showed that older children yielded pneu-

mococci more often (100%) than young in-

fants (17%). Rates for influenza bacilli were

consistently 2 to 3 times higher among older

children than among infants.

Forty-one virus-positive persons, all ex-

cept 4 with lower respiratory tract infec-

lions were subgrouped according to their

REcovERY OF Sir. pneuinoniae AND hi. influenzae FROM THE NAsoI’II�Jt�Nx OF PERSONS WITH




viruses. Rates for influenza bacilli were

twice and pneumococci half the expected

values among patients yielding influenza B

and adenoviruses. Since RS and influenza B

comprised the majority of the virus isolates,

patients yielding these viruses were sub-

grouped by age, the presence or absence of

pneumonia, and compared with the fraction

from whom no virus was recovered. Pneu-

mococci and influenza bacilli were found

more often with virus-associated pneumonia

than not; however, only rates for H. in-fi uenzae exceeded the mean values noted in

Table I.

Leukocytosis

Patients presenting counts of 15,000 or

more cells per cu mm, chiefly polymorpho-

nuclear leukocytes, were deemed to have

leukocytosis. Approximately half (49%) had

leukocytosis. Counts ranged from 15,000 to

54,600, with a mean value of 16,640 ±7,000. Virus-negative patients developed

leukocytosis about twice as often as virus-

positive patients. Virus-positive infants

more than a year of age presented more

often (�3: 1) with leukocytosis than either

younger infants or older children. Rates

among virus-negative infants of the same

age corresponded with those of the virus-

positive group; however, in this group

leukocytosis in younger infants and children

exceeded (2: 1) those found in correspond-

ing members of the virus-positive group.

The data are summarized in Table III.

The 2: 1 ratio of leukocytosis for virus-

negative and virus-positive patients varied

for several clinical categories. Among 18

patients with bronchiolitis the ratio was 3:1;

among 11 patients with LTB the ratio was

1 : 1; and among 46 patients with pneumonia

the ratio was 2: 1. Rates also varied for the

kind of virus recovered. Approximately a

third of patients yielding RS and influenza

B viruses presented leukocytosis. Only 1 of

7 patients yielding RS virus in the presence

of pneumonia had leukocytosis. In contrast

5 of 8 patients with pneumonia yielding

either adeno-, reo-, or paramnfluenza types

2 and 3 viruses presented with leukocytosis,

occasionally quite marked (e.g., 40,800).

Accessory Clinical Data

Significant differences were not found

either in the magnitude or duration of

febrile responses based on the presence or

absence of virus within several clinical cate-

gories. Since a large fraction (73%) of the

patients received antimicrobial therapy only

a crude analysis was made to compare the

TABLE III

TIlE LEUKOCYTE RESPONSES FOR ThOSE �IELDING AND NOT \IELDING VIRUSES: ACCORDING TO AGE AND

SEVERAL CLINICAl. CATEGORIES

Category Class

Jirus + hrus 0

No. of

Persons

> WI/C

No %

,?5o. of

Persons

> WI/C

No. %

Age <12 mo.

12-23 nio.

>24mo.

27

11

14

6

8

4

22

73

29

21

16

13

11

13

7

52

81

54

Clinical URILTB

Bronc’litis

Pneumonia

4

6

13

21

0

3

3

7

0

50

23

33

6

5

8

25

5

3

4

19

83

60

50

76

See Table I for abbreviations. >WBC, >15,000leukocytes � cu mm. Of interest was coniparison of bacte-

rial recovery rates with the leukocyte response by age. Just as leukocytosis was more pronounced among olderinfants so was the frequency of encountering H. infiuenzae. The ratios were 4:7:1 in the order of age entered above.



.\O. (ifSamples �

I/s

Ill-

/ih1e1h�(5

B

Parainfluen:a

( iii per)

1 � 2 �3

I/co .ldeno � Mump.r

lolal

“N,,

Influ, influenza virus; “X,” unidentified viruses. These agents, one obtained in I)ecensber from a 5-year-oldlioy with bronehopneumonia, and the other in April front a 10-month-old i�oy with bronchiolitis could not be

recovered from the original samples. These agents produced CPE like RS, and were lost during storage at - 70#{176}C.

Mump virus was isolated once from the oropharynx and urine of a 9-month-old infant. This virus and a strain

of adenovirus were the only agents recovered from 32 urine samples. A strain of reovirus, type 1 was detected only

in feces; feces were not obtained from 4 other patiehlts yielding reovirus in pharyngeal samples.

ARTICLES

TABLE IV

S.��IPI�INGS Thi AT ‘�IELDED Sp�’IFI ED \IRUSES

Jirus

35

Nasopharyngeal (N) � 114 10 5 1 1 1 18

Oropharyngeal (0) � I 14 2 3 1 1 3 2 2 14

N+O . . 6 7 3 4 3 2 25

Urine+O I 52 I I

Urine+N+() . I I

Feces 6 1 � 1

Totals � 286 18 15 3�6�5� 5 � 5 � I � ‘2 60

febrile course of patients in any group. The

febrile course was seldom prolonged; a

crude average was 2.2 days for all patients

with fever; the range varied from 1.8 days

(pneumonia) to 3 days (upper respiratory

infections).

Viruses

RECOVERY RATES. Fifty-eight patients

yielded 60 viruses; 56 yielded one and 2

yielded 2 viruses (see Table IV and Fig. 1).

RS and influenza B comprised 55%, para-

influenza 23%, and adeno- and reoviruses

each about 8% of the virus isolates. Except-

ing one strain of reovirus all were detected

in either nose or throat.

RS and influenza B viruses involved more

patients than any other serotype. Influ-

enza B virus, first recovered early in Janu-

ary, kept reappearing until mid-March. RS

virus detected first in mid-February in-

volved at least 18 infants and children dur-

TABLE V

I)ISTJI1BITIoN OF \IJttSES A((ORDING TO (‘h.INIcAI� CATEGORI ES

. .(linical

Category

.vo. jPer-

Sons

RS Influenza B� Parainftucnza, Types

�-�- � -i I I S�-�---�--�� -�_________--�� -�---

xo. % .\-o. % �y0 � c� �y0 � % xo. %

Reo

��

� � �

.ldeno � Slumps � So Virus

� Recovered�-�-�--�0 % x�. � No. %

“Other” I� I 8 3 �5 0 . . 0 . I 8 0 . I 8 0 . Ii 50

(RI �0’ 10 6 30 0 .. 0 .. 0 .. l�5 0 .�I .5 10 50

Ll’B ft I 10 0 . . 0 � . . I 10 0 . � 0 � � . S 33

Bronchiolitu, IS ii I 7 1 � 7 is is o . . � 0 . . 0 . . 7 47

Pneumonia 58t I� �0 S 9 4 4 1 4� � 4 7 0 . . 30 5�

A1Icategories� 114 � 18 16 15 13 3 � 3 6 .5 5 4 5 4 � 5 4 1 1 56 49

S Includes S children entered in Figure � with influenza.

t Includes 11 patients listed in other categories who subsequently were found to have pneumonia.

I Yielded RS and reovirus type I.

I One yielded influenza B and reovirus type I.

Percentages total 99; � agents not identified are not included in the table.



5

BRO NC H OL IllS

0

z

0

4

2

0

SI

4-6 25-367-12 >37


PNEUMONIA

<3 3:244-6 25-36

7-IS >37

AGE IN MONTHS

Fic. 3. Distribution by age of patients in clinical

categories. The kinds of virus recovered are �‘n-

tered. See Fig. 1 for legend.

ing the ellSuillg 3 months. Reovirus (type 1)

was encountered ciliefly during the peak

prevalence of influenza. Parainfluenza type

2 was recovered only during early winter

ITloiltils. ParaillfluellZa types 1 and 3 were

encountered oiil�’ at sporadic intervals.

CLINICAL RELATIONSHIPS. Data depicted

ill Figure 2 and tabulated in Table V ilhis-

trate a random distribution of virus sero-

ty�)es \Vithill the arbitrary clinical cate-

gories. Approximately half the patients in

each category yielded viruses. Of the 30

viruses recovered from 58 patients with

pneumonia 11 (37%) were RS, 5 (17%) were

influenza B, and 4 (13%) were adenoviruses;

the 10 remaining comprised parainfluenza,

reovirus, and one unidentified agent. Among

the 16 viruses recovered from 32 persons

(left, upper 2 panels, Fig. 2) presenting

mainly with signs of URI, 9 (56%) were in-

fluenza B, 3 (19%) were RS, and the 4 re-

maining were either parainfluenza, reo-,

adeno-, or mumps virus. Although the fre-

dj11e11c�y distributions for serotypes vary (e.g.,

predominance of RS, adeno-, and parain-

fluenza, type 2 with infections of the lower

respiratory tract) the general pattern was

tile same in the several categories. But ap-

proximately half the patients not only failed

to yield virus, they also failed to convert not

only against prevailing viruses, but also

several others (Fig. 6) entered in the study.

ACE RELATIONSHIPS. Forty-two of the 58

patients yielding viruses were less than 2

years of age. Fifteen of 18 RS and 13 of 14

parainfluenza viruses were recovered from

infants mostly under a year of age. A similar

distribution was obtained for reo-, and

adenoviruses, oftentimes, however, in older

infants than among those just mentioned.

In contrast, 10 of 15 influenza B vinises

were recovered from children ( > 2 to 14

years of age). The data are summarized in

Figure 3.

Seventy-nine of the 95 infants had infec-

tion of the lower respiratory tract. Thirty-

five of the 79 yielded viruses. Thirteen, or

14 (including an unidentified virus), were

RS virus; of these all except 2 were asso-

ciated with bronchitis or pneumonia. Para-

influenza, adeno-, and reoviruses (20 strains)

were encountered almost always (85%)

among infants with LTB, bronchiolitis, or

pneumonia. Influenza B was associated with

URI in older children; this virus was re-

covered also from 4 of 5 infants, and one

child ill of bronchiolitis or pneumonia. Five

of 10 children with lower respiratory in-

fection yielded virus: 2 with influenza B,

and one each with RS, parainfluenza, type

1, or an unidentified virus.

Seroconvers ion

Twenty-seven of 36 patients from whom

virus was recovered developed specific

antibodies (Table VI); a fraction (e.g., RS,

3 of 11 persons) had maximal or near maxi-

mal levels of specific antibody in the first

serum sample. Four infants failed to de-

velop antibodies to the serotype (e.g., para-

influenza, type 2).

Among 36 patients from whom virus was

not recovered seroconversion was obtained

for 4 viruses; rates were highest for RS

(17%) lowest for influenza B (6%), with inter-

mediate values for adeno- and parainflu-

enza, type 3 viruses. Data charted in Fig-

ure 4 illustrate that seroconversion may

occur while failing to recover viruses. Dur-



01

80

U-,hrLU

LU

>z

�40

� 2:

U) -

zw

<-I-

0>

�LU

4

3�2�

0

ARTICLES 37

ing the peak prevalence of RS and influenza

B viruses conversion rates exceeded isola-

tion rates by a factor of two.

FOR Moiu� THAN ONE VIRUS. Eleven of

15 patients yielding virus and 4 others

from W11OIT1 virus was not recovered de-

veloped antibodies to two or more viruses

(Table VII). All 11 patients yielding viruses

developed antibodies to the serotype. Het-

erologous conversions to RS and influenza B

viruses were obtained more often than

others. However, 7 converted to parainflu-

enza; of these 5 converted to type 1. Among

virus-positive patients 5 converted to one,

3 to two, and possibly 3 to three viruses

other than those recovered during their ill-

ness. Similar findings apply to 4 virus-nega-

tive individuals.

Heterotypic antibody responses were

analyzed using data illustrated in Table

VIII. The serologic data relate to infants,

sillce their antibody responses were more

likely primary and not yet complicated by

re-infection from singular serotypes. Al-

though heterologous responses were not

always associable with specific viruses , such

viruses were often recovered from convert-

ers, even during (a) an existent seropositive

status for another virus, or (b) seroconver-

5iOIl to such viruses. Moreover, infants

already seropositive for a singular serotype

occasionally harbored virus in the oro-

pharynx.

Among 13 infants converting either to

parainfluenza types 1 or 3 virus, 4 con-

verted to heterotype and 2 yielded the virus

serotype. Among 4 infants seropositive for

type 1, 2 converted to type 3 and 1 yielded

type 3 virus. Among seropositive infants

homologous viruses were recovered less

often than heterotypic viruses to which anti-

bodies had developed. These data indicated

a general specificity of antibody response.

AGE-SPECIFIC RATES. Very young infants

were recruited by RS (72%), parainfluenza

(14 to 20%), and adenoviruses (17%); 16% of

these infants converted to influenza B virus.

Sero-conversion to influenza C. HGP, and

reovirus took place largely during late in-

fancy and childhood. Seroconversion was

FIG. 4. The seasonal character of influenza B andRS virus infections. Entries in the lower panel rep-resent about one-half the patients from whom sat-

isfactory paired sera were available. Conversion

rates in the upper panel relate to the fraction (0-

tcred in the lower panel (solid lines) awl an addi-

tiOITh�1l group (broken lines) who converted, but

failed (see text for intervals between collection of

sera) to yield virus on admission to the hospital.

not obtained for influenza A�, Coxsackie

A21 and ECHO 28 viruses. These data are

summarized graphically in Figure 5.

CLINICAL CATEGORIES. Patients with pneu-

inonia converted more often than others to

RS, influenza B, parainfluenza, type 1, and

adenoviruses. The conversion rate for RS

(32%) was at least twice that of any

other virus. Patients with bronchiolitis con-

verted chiefly to RS (29%), and a

substantial fraction (6 to 18%) coil-

verted to paramnfluenza and influenza B

viruses. Patients with LTB converted \Vitll

equal frequency to 6 serotypes. While in

general conversions obtained among pa-

tients with predominantly upper respiratory

infections were fewer, these as well as those

in “others” converted mainly to RS and in-

fluenza B virus. The data are summarized

in Table IX.



Seroposilire (1st serum) Conrcrters

.Vo.

Persons

in (lass

36

Ii

10

4

4

4

(‘lass

No virus

115

Influenza Ii

Parainfluenza, type I

Parainfluenza, type �

Parainfluenza, type 3

Reo

Adeno

All virus-positive

RS

47

80

0

0

I)

Influ

B

31

36

10

0

0

0

0

0

Parainfluenza

1 e

0 0 9

�7 0 0

.4deno

11

0

Parainftuenza

- -�--� Reo Adeno

1 3

8 43 17 47

18 0 3.5 18 64

�() 10 30 60 44

0 0 30 50 30

0 0 50 �3 75

�3 0 0 .50 0

0 0 0 0 0

0 0 .50 Q5 �5

RS

17

73

0

100

50

Reo

0

0

0

0

Irif Ia

B

6

0

90

50

0

0

10

50

0

0

0

0

0

.50

0

0

0

36’ 36

0

50

100

0

0

1$ II

0

0

0

0 �5t

100 0

0 50

9� 844 36 .50 41 3-1 17 6 17

‘Flie totals, seropositir e f-converters �lo not always 100%, because seceral patients yielding viruses failed to develop measuratle anti-

111)(IieS h,y the methods used. See ‘rable IX for paCents (-onverting to more than one virus.

* Includes one of the infants shedding I viruses. S’era from I persons yielding the unknown agents, and one yielding mumps virus are not

entered.

t An infant yielding parainfluenza type S converted to the homologous, but not the prototype. This patient also converted to adenovirui

(<I:8to 1:64).

RESPIRATORY INFECTIONS

FOR BOTH AGE AND CLINICAL EXPRESSION.

Seroconversions for parainfluenza viruses

occurred more often (2: 1) before than after

1 year of age. dll(l (leveloped principally in

association \Vith lower respiratory tract in-

fections. Among 37 infants with pneumonia

and bronchiolitis the rates were: RS, 33%;

parainfluenza type 1, 17%; parainfluenza

type 3, 11%; and influenza B virus, 11%. Five

infants with LTB each converted to a single

serotype (Table IX). RS virus recruited

about equally among infants and young

children, the principal but not dominant

clinical expression being pneumonia and

bronchiolitis. Older children as noted were

recruited by influenza B virus. Among 11

children with pneumonia seroconversion oc-

curred only for influenza B, RS, and adeno-

viruses.

Nosocomial and Other Considerations

Three infants and a young child de-

veloped respiratory illnesses within 5 to 14

days following entry to hospital. Two of 3

developed upper respiratory infections dur-

ing March and April, 1962; RS virus was

recovered from one and antibodies to RS

developed in another. The fourth patient

contracted pneumonia 9 days after admis-

SiOil for iron-deficiency anemia; iSolatioll of

parainfluenza, ty�)e 3 virus atteil(le(l de-

velopment of specific antibodies. Patients

in hospital are at risk of infection from

viruses (and other microbes) unrelated to

those, if any, harbored on admittance.

Data presented earlier indicated that re-

cently acquired heterologous antibodies

were found more often in patients where

a delay of a month or more transpired be-

tween serum samples (Table VII). The in-

tervals, for many spanned the seasonal

prevalence of influenza B and RS virus.

Very likely during this period antibodies

were engendered to these and other viruses.

Simultaneous infection with 2 viruses was

noted in 2 infants (one age 17 months with

pneumonia; the other age 1 year with LTB;

see Fig. 3). In one of these, antibodies had

already developed or was engendered for

these viruses, and additively within the

TABLE VI

CoNv:JLsIoN RATES (%) AMONG PATIENTS �IELD1NG SPECIFIED \‘IRUSES



�troconrersion f-r

115

Influenza II

Parainfluenza,

type 1

Parainfluenza,

type I

Parainfluenza,

type 3

Reovirus,’

type I

Adenoviruses

type I

No virus

recovere-l

interval

(days)

Beta-c-en

1st and 2nd

$erum

8, 33, 90

5, 67, 139

186

51

97

9

165

98, 99,

138, 183

Patient’s

Virus

+

+

+

+

+

3 7mo

3 7yr

I lOmo

I 6mo

1 6mo

1 17 nil)

1 lOmo

4 I3mo

RS

+++

+

+

+

+

Pa;ainfluenzulifts _______________

B � � � 3

+++ +,-.-

+ + +

+ + +

+ +

+

-‘

In.flu Rhino

C 1!GP

+

Reo -Ideeto

+

+

t

No. converting to the Heterotype 9/il 411 5/14 0,14 314 I,� 14

ARTICLES

TABLE VII

SEROCONVF:IOSION OBTAINED TO Two OR MORE \IRUSES

39

Kind of Virus No. of A�e

Recovered Persons (mean)

+, +.

1, 14 1 13 1/15

* Patient yielded influenza B virus from the nasopahrynx.

t Seropositive, first serum; no increase in titer. Symbols: + signs indicate a positive serologic response, �four-fold increase. Each + repre-

sents a person, and is related linearly to the interval between first and second serum sample. Open areas indicate a negative serologic response.

Sera were obtained on the day of admission and again at intervals thereafter: 34 were obtained within I weeks, II within 1 month, and 7 within

I month., after onset of illness. For II patients the intervals between first and second serum samples ranged from 60 to 186 days.

fortnight he acquired antibodies for in-

fluenza C virus (Table VII). Still others de-

veloped multiple antibodies within a week;

for these infection must have been acquired

outside the hospital. Finally, patients do not

often arrive at hospital at the onset of ill-

ness. Some may have acquired antibodies

from a current primary infection but were,

without recovery of virus, inseparable from

the already antigenically experienced mdi-

vidual.

COMMENT

Another attempt11 has been made in this

study to assess the relationship of several

viruses with infections of the respiratory

tract. Fifty-eight of 114 infants and children

presenting with several clinical expressions

of infection yielded viruses; among the frac-

tion providing satisfactory serum samples

the majority (58%) experienced seroconver-

sion. Fifty-six patients of similar ages and

presenting with similar illnesses failed to

yield virus; nevertheless a fraction (30%)

converted to 4 viruses (Table VI) entered

in the study. Thus, specific viruses were

associated with infections (see below for

mitigating circumstances) involving the res-

piratory tract of at least half the study

population.

A satisfactory correlation was obtained

between viruses recovered and develop-

ment of specific antibodies. Four virus-

positive infants failed to convert (largely

paramnfluenza type 2 virus), and 11 virus-

negative patients collectively converted to

RS, adeno-, parainfluenza type 3 and in-

fluenza B viruses. Fifteen patients, all in-

fants, except one experienced dual infec-

tions either simultalleously as evidenced by

recovery of 2 viruses, or in rapid succession

as evidenced by rapid development of het-



00

80

60

hr 40Ui0. 20

00

80

60

40

20

00

80

60

40

20

4-6 3-24 >37 4-6 I324 >37 4-6 3-24 >37

AGE IN MONTHS

JII�

FREQUENC’

PERCENT

o NO VIRUS ISOLATED 49

URS 16

0 INFLUENZA TYPE B I 3

o PARA INFLUENZA TYPE I 3

0� - �2 S

- - _3 4

#{149}REOVIRUS TYPE I 4

O ADENOVIRUS 4

I� MUMPS I

51 NOT IDENTIFIED I

Fic. 6. Proportionate association of several viruses

with respiratory infection involving 1 14 infants and

children.

* RS viruses recovered from these patients are

not serologically identical with the prototype Long.

The differences will be reported in a separate

study.


INFLUENZA C

ECHO 28

NO MEASURABLE

#{149}� ANTIBODIES

Fic. 5. Serological contour maps for 14 viruses. The

solid contours depict conversions; the stippledcontours the fraction already seropositive on admis-

sion to hospital. Our strain, designated RS-related,

has serological distinctions from the prototype RS

virus. Data derived from 74 paired sera.

erologous antibodies . Heterologous anti-

body rises could not be related to a sharing

of antigens between viruses.

The long intervals lapsing after the pri-

mary illness and collection of some sera

represent obstacles in relating the clinical

expression to the antibody response. Inter-

pretations are difficult, particularly for pa-

tients from whom virus was not recovered.

Since during infancy many of these viruses

recruit rapidly, and in successive waves, it

is quite possible that antibodies developing

from infections were unrelated to the illness

that brought the patient to hospital. More-

over, even with optimal samples, the asso-

ciation of virus (and antibody development)

with disease may not be definable with

complete assurance.

RS and influenza B viruses comprise 55%

of the viruses. These viruses were prevalent

in the community during the Winter and

Spring of 1962. Two-thirds of the patients

yielding RS virus developed pneumonia; a

corresponding fraction yielding influenza B

virus had illness referable principally to the

upper respiratory tract. Both viruses were

found also, however, with infections of

greater or lesser severity. Adeno-, reo-, and

parainfluenza viruses were associated also

with LTB, bronchiolitis, and pneumonia. An

accounting of the virus serotypes encoun-

tered among these patients is given in Fig-

ure 6.

Infants are prime targets for most of the

viruses entered in the study. The primary

infection provides immunity, complete or

partial. Infection intervenes (Fig. 5) very

probably even before maternal antibodies

disappear. Young infants during outbreaks

have sharper clinical expressions of dis-

ease (bronchiolitis) than young children,

although many of the latter develop pneu-

monia, apparently another manifestation of

infection from RS virus. But in our earlier

studiesbo,1 we failed to find an association

between RS virus and bronchiolitis or pneu-

monia. Infection was largely at the sub-

clinical level. Although the clinical expres-

sion, and epidemicity may have been modu-

lated by passive immunity, this explanation

is unsatisfactory. Nor is there any evidence

of increased virulence; while our RS strain

is not identical* with the prototype (Long)



Virus

No. of

Paired

Sera

Serologic Class

Rates

Sero-Response Recovery of Virus

RS � Influenza B RS � influenza B

Pair I . RS/Irtfluenza B Virus Pairs

RS 37 1st serum RS+, converting to BCollversion to RS and B

20

17

3 (15%)

3 (18%)

�2 (10%)

7 (41%)

3 (100%)

0

Influenza B �21 1st serum B+, conserting to RS

Conversion to B and RS

6 (46%)

S (38%)

13

8

3 (50%)

0

0

4 (50%)

Pair �. Parainfluenza Type I/Type 3

Parainfluenza

Type 1 Type 3 Type 1 Type 3

Para 1 10 1st S�FUH1 Type 1 +, converting to T3

Conversion to Types 1 and 3

4

6

(50%)

� (33%)

0

1 (17%)

1 (50%)

1 (50%)

Para 3 �7 1st serum Type 3+, converting to Ti

Coisversiors to Types 3 and 1

0

� (�9%)

�0

7

0

1 (50%)

1 (5%)

� (�9%)

This table illustrates but ‘2 of 6 virus pairs, and additionally included RS/parainfluenza, type I ; illflUenza B/

l)arItiflfluenza, ty�)e 1, influenza B/reovirus type 1; and influenza C/reovirus type 1. These data highlight the fre-quencies of both honsotypic and heterotypic antibodies (seropositives and converters) and the viruses associated

with specific seroconversion. Thus, using entries for RS in the first row, among ‘�O RS seropositive persons S con-

verted to and yielded influenza B virus. In row �i, among 17 RS seroconverters 3 also converted to influenza B;while 7 yielded ItS, none yielded influenza B virus.

ARTICLES 41

TABLE VIII

TIlE SpEcIFIcITY OF TIlE SEIwL0GIc RESPONSES: DATA FOIL INFANTS AND TWo ViRus PAnts

the clinical manifestations associated with

it resemble those described for RS in other

9

Viruses like RS, influenza C, and several

parainfluenza viruses recruit steadily and

rapidly during infancy; by early childhood

all have experienced past infection. Others

such as influenza A and B viruses may re-

cruit with even greater rapidity, but gen-

erally periodically, although they may

linger in the community.14 Still others like

parainfluenza type 2 recruit less rapidly and

certainly more slowly; others like ECHO

28 and Coxsackie A21 have not involved

infants and children of this area for at least

5 years. Antibodies for selected viruses in

several study populations are compared in

Table X.

Our recovery of viruses is in good agree-

ment with reports of others, particularly

for RS � 15 RS virus was associated

more often with lower respiratory tract in-

fections than in preceding years. Our data,

like those of others, indicate that RS and

parainfluenza viruses (types 1 and 2) may

be associated with croup, bronchiolitis, and

pneumonia; however, a similar association

of parainfluenza type 3, reo- and adeno-

ruT8 with the clinical complexes re-

mains, in our opinion, uncertain.

Finally, there is another fraction of pa-

tients ( � 30%) entirely dissociated from

those viruses entered in the study. The clini-

cal evidence indicated that many of these

were associated with pathogenic bacteria,

although it is not known that they were the

primary invaders. Lower respiratory tract

infections were associated with leukocytosis

twice as often in the virus-negative as the

virus-positive groups. Patients with LTB

had leukocytosis with equal frequency in

both groups. In the virus-positive group

leukocytosis accompanied infections yield-

ing adeno-, reo- or parainfluenza types 2



1requeniie.s’ (%) for Inelu’eited I iru.c

(‘Iinieal

(‘alegory

Pneumonia

Bronc’litis

LTBURI

Other

.‘so,I’ersnii.s’ ./ (Ir(Il/l/!I1(’Il (I - /of!ucit-.iain (‘lass -#{149} --

1 .? - i? (‘

__;;;__ � h�17 i�l 6 i� 6 l� 0

5 0 ‘20 ‘2() 0 ‘2() 0

15 0 0 8 0 33 0

6 O� (1 (1 0 33 0

74 8� 3 10 1 ‘21 ‘2

11/11111)

JJ(;J)

.\‘() (‘(Ill-

version.

1(1 .1ii�j

P7rus

ks [leo

Ii, jie I

Long

3’2 ‘29 3

‘29 ‘23 0

‘20 ‘20 0

13 8 7

33 ‘25 0

Totals

1(/(00

11

0

‘20

0

0

3 4’2

0 35

0 60

0 40

0 50

‘2 4’2‘27 23 3 6

Conversions ss-ere not ol)taine(1 for influellza A2, E(’Il() 28, co (‘oxsackie A21 viruses. The cous-ersjoii rates for

iiiiy virus isolated iii the several c11111(’al categories ranged from 50 to 100% (‘Fable VIII).

S Strain “87” is hot serologit’ally ideuti-al with the l)rotot�’pe strain (Long). Only a fraction of tile sera relnailled

for tests st’ith straiii “87. “ ‘l’here ssas !)5�3-� agreeisieiit between strains with ItS poSitive scm.

Age Group

(yr)


TABLE IX

Tii E CLINiCAL (‘ATEGoJuEs: RATES OF S>:1tocoN VERSION

and 3 viruses. On the other hand, H. in-

fluenzae and Str. pneumoniae were often

encountered with equal frequency in virus-

positive and virus-negative patients. The

only significant difference was the predomi-

nance of pneumococci in the nasopharynx

(in association with leukocytosis) among in-

fants with bronchopneumonia. Although

leukocytosis developed in virus-negative

patients with lobar pneumonia, no signifi-

cant differences were found in the bacterial

flora of these and tile virus-positive group.

Our results suggest that essentially similar

clinical expressions of respiratory infections

may be obtained from several viruses, some

pathogenic bacteria, or both. Such infec-

tions, although differing presumably in

pathologic detail, are not singularly corre-

lated with specific anatomical sites of in-

jury. Many of these infectious agents are

associated with infections of the upper as

well as the lower respiratory tract. Although

‘FABLE X

6 mo-I years 19

1-3 years 18

Over 3 years 80

SEItoI�oGI’AI� (‘011 I’OSITION OF SF:sF:1tA1� STUDY PoPuI�ATIoNS

i958-6�

Kind of Virus

No.of �-�- - - -�---�-------�-------�________________ -________Persons I Parainfluon:a Influenza

Years --- 115 --__________2 3 .4� B C

abc a be abc abc abc abc abc

‘t ropositire

4I41� 75 I864l44�4I3l59 65800 71540 146619

10 6 II 10 0 100 100 50 90 30 100 80 100 0 6 II 33 40 100 33

18 9 10 60 11 95 89 89 94 33 89 75 71 100 68 17 89 61 100 89

(‘inrerters

6 mo-I ye-irs 1) 11 41 3 1 0 38 1 II - 15 7 19 0 4 0 4 0 15 14 1 1(1

1-3>’ears 18 10 6 5 10 0 6 0 0 8 10 33 0 0 0 0 10 17 15 0 0

Over 3 ye irs 80 1 � 9 4 6 0 1 0 0 7 II 11 1 11 (1 5 II 67 II 0 0

(a) 19.58-59; (h) 19�9-60; (e) 161-61. ee references 10 and 11. Entr�ei un(ler kind of virus are percentage values.



ARTICLES 43

epidemiologic data indicate that these vi-

ruses have an impact on the pathogenesis

of lower respiratory tract infections, as yet

we are not completely convinced that all

die viruses recovered or those eliciting anti-

bodies in the study are the primary patho-

gens responsible for LTB, bronchiolitis, and

pneumonia. At best we have been able to

link about 50% of the infections in our pa-

tients with specific viruses; another fraction

(� 30%) may be associated with bacterialpathogens. Finally, we believe there is hid-

den among both groups a fraction in which

both viruses and bacteria may influence the

course of infection.

SUMMARY

Sixty viruses were recovered from 58 of

114 infants and children ill of respiratory

infections. Two outbreaks, one caused by

RS and the other by influenza B viruses,

occurred during the study period. RS and

influenza B viruses totaled 55% of the virus

yield. Other viruses recovered were para-

influenza types 1, 2 and 3 (14 strains), reo-

virus, type 1 (5 strains), adenovirus (5

strains), and mumps (1 strain). Two viruses

were lost and remain unidentified.

Good correlation was obtained between

viruses and development of specific anti-

body. A small fraction of infants had dual

virus infections; heterotypic antibody re-

sponses were observed in 20% of the pa-

tients. These were considered to represent

in part successive infections with specific

viruses.

Fourteen of 18 RS viruses, 6 influenza,

and all except one of the parainfluenza vi-

ruses (type 3) were associated with laryngo-

tracheobronchitis, bronchiolitis, and pneu-

monia. None was associated with any single

clinical category. RS was associated more

often with pneumOllia than bronchiolitis;

influenza B was associated less often with

these than with upper respiratory infection.

Analysis of virus-positive and virus-nega-

tive subgroups for bacterial “pathogens”

and leukocytosis indicated that pneumonia

of virus-negative infants was very likely

bacterial in origin. Evidence was also ob-

tamed of concurrent bacterial infection in a

fraction of patients yielding viruses.

REFERENCES

1. Chanock, H. M. : Association of new type of

cytopathic myxovirus with infantile croup.

J. Exp. Med., 104:555, 1956.

2. Beale, A. J., et a!.: Isolation of cytopathic

agents from respiratory tract in acute tra-

cheobronchitis. Brit. Med. J., 1:302, 1958.3. Vargosko, A. J., et a!.: Association of type 2

hemadsorption (parainfluenza 1) virus and

Asian influenza A virus with infectious

croup. New Engl. J. Med., 261:1, 1959.

4. Philipson, L. : Aetiology of non-diphtheritic

croup. II. Virologic investigations. Acta

Pediat., 47:4, 1958.

5. Kurova, M., and Isheda, N. : Newborn virus

pneumonitis (type Sendai). II. The isolation

of a new virus possessing hemagglutinin

activity. Yokahama MCCI. Bull. 4:217, 1953.

6. Parrott, R. H., et al.: Clinical features of in-

fection with hemadsorption viruses. New

Engl. J. Med., 260:731, 1959.

7. Beem, �s-I. : Association of the chimpanzee

corvza agent with acute respiratory dis-

ease in children. New Engi. J. Med., 263:

522, 1960.

8. Chanock, R. NI., et al.: Respiratory syncytial

virus. I. Virus recovery and other observa-

tions during 1960 outbreak of bronchiolitis,

pneumonia, and minor respiratory diseases

in children. J.A.M.A., 176:647, 1961.

9. McClelland, L., et al.: Studies of acute respira-

torY illnesses caused l)% respirator� syncytial

virus. 2. Epidemiology and assessment of

importance. New Engl. J. Med., 264:1169,1961.

10. \Venner, Fl. A., et al: The epidemiology of

acute respirators’ diseases. II. Risk of infec-

tion among infants and family associates

from viruses accompanying respiratory ill-

nesses. PEDIATRICS, 28:886, 1961.

11. Wenner, H. A., et al.: The etiology of respira-

tory illnesses occurring in infancy and child-hood. PEDIATRICS, 31:4, 1963.

12. Pike, R. M. : An enrichment broth for isolating

hemolvtic streptococci from throat swabs.

Proc. Soc. Exp. Biol. Med., 57:186, 1944.

13. Toolan, II. �V. : Transplantable human neo-

p1�isms m:iintained in cortisone-treated lab-orator� animals: lIS. # 1; 1-1. Ep. # 1;

I-I. Ep. #2; II. Ep. #3; and H. Emb. Rh.

#1. Cancer Res., 14:660, 1954.

14. Jordon, W. S., Jr., et al.: A study of illness

in a group of Cleveland families. XVI. The

epidemiology of influenza, 1948-1953. Amer.

J. Hyg., 68:169, 1958.




SAMUEL J. For%Lorc, M.D.

15. VivelI, 0., et al.: Serologische und klinische

Untersuchungen #{252}berViruserkrankungen desRespirationstraktes. IV. Epidemiologische

Beobachtungen bei Respirationstrakterkran-kungen der Jahre 1957-1961. Z. f. Kinderh.,

86:55�3, 1962.

16. Dienhardt, F., et al: The isolation of adeno-

virus type 1 from a fatal case of viral “pneu-monitis.” Arch. mt. Med. 102:816, 1958.

17. Chany, C., et a!.: Severe and fatal pneumonia

in infants and young children associated

with adenovirus infection. Amer. J. Hyg.,

67:367, 1958.

18. Jen Kuie-Fang, et a!.: The role of adenovirus

in the etiology of infantile pneumonia andpneumonia complicating measles. Chin.

Med. J., 81:141, 1962.

PROTEIN METABOLISM, INFLUENCE OF

GROWTH HORMONE, ANABOLIC STEROIDS

AND Nu-nirrioN IN HEALTH AND DISEASE.

An International Symposium, edited by

F. Gross, Berlin: Germany, Springer-

Verlag, 1962, 521 pp.

Even among scholarly pediatricians, fewexcept those with particular dedication to en-

docrinology will be motivated to read througha major portion of this book. Most of thepresentations concern mode of action or re-

sults of laboratory or clinical trials with ana-bolic steroids. Discussions after each of theformal presentations provide some interestingdata and opinions, but in many instances thesediscussions appear to be nearly verbatim tran-

scriptions in which the trend of thought is at

times difficult to follow and some irrelevant

material is included.

The strong points of the publication from tilepediatrician’s viewpoint are the assembling in

one volume of much relatively recent material

not easy to find elsewhere, a comprehensivelist of references, a valuable and concise chap-ter, “Metabolic Effects of Growth Hormone in

Man,” by M. S. Raben, et al., an excellentanalysis of human growth by J. M. Tanner,

“Evaluation of Growth and Maturity in Chil-dren,” and a chapter by A. Prader and R. Illigon use of anabolic agents (including anabolic

steroids and growth hormone) in disorders ofgrowth.



1964;33;30-44 PediatricsHerta Wulff, Patricia Kidd and Herbert A. Wenner

ChildhoodETIOLOGY OF RESPIRATORY INFECTIONS: Further Studies during Infancy and

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