ACUTE HEMATOGENOUS OSTEOMYELITIS

(1)

By Morris Green, M.D., William L. Nyhan, Jr., M.D., and Mildred D. Fousek

Department of Pediatrics, Yale University School of Medicine

TABLE I

OSTEOMYELITIS YEARLY I)ISTIIIBUTI0N

}‘ears of Patients

ACUTE

HEMATOGENOUS

OSTEOMYELITIS

O

PTIMAL management of patients with

acute hematogenous osteomyelitis is

dependent upon early clinical diagnosis and

institution of vigorous therapy. Treatment

must be initiated before confirmatory

labo-ratory data are available. Intimate

knowl-edge of the symptomatobogy, early clinical findings and the response to therapy is essential.

In order to elucidate these and other

as-pects of the disease the clinical records

of infants and children with acute

hemato-genous osteomyelitis admitted to the

Grace-New Haven Community Hospital were

re-viewed.

PATIENT MATERIAL

During the 31-year period from 1924 through

1954 there were 99 such patients less than 15 years of age. Table I depicts the distribution

of cases over these years. The patients in this

series ranged in age from less than 1 month to 15 years. A tendency to a decrease in incidence

with increase in age is demonstrated by the

fact that 47 patients were less than 5 years of

age, 30 were from 5 to 10, and 22 were 10

years or older. There were 58 boys and 41 girls.

PATHOGENESIS

A review of the pathology and pathogenesis

of acute hematogenous osteomyelitis affords a

better understanding of the clinical features

of the disease. The infection begins usually in

the metaphysis of bong bones. It is thought that

ill the presence of small terminal capillaries,

trapping of bacteria occurs in this region with resultant thrombosis, ischemia, necrosis and

abscess formation. Multiple small abscesses may later coalesce. Extension of the process may

occur either toward the medullary canal or toward the overlying cortical bone. The

re-sistant epiphvseal plate usually prevents direct

extension into the epiphysis, but secondary epiphysitis does occur. Rarely, osteomyelitis

19’14-’28 16

19’19-33 25

1934-38 16

1939-43 18

1944-48 11

1949-53 8

1954 5

Total 99

begins in the epiphysis rather than in the

meta-phvsis.

Subpeniosteal spread of the infection fol-lows escape through the cortex in the region of

the metaphysis. The cortical bone is thinner

here than in the diaphysis, especially in infants,

and offers a point of relatively reduced

re-sistance. Because the periosteum is more loosely attached, stripping of periosteum from the

un-derlying bone occurs more readily in infants than in older children. It is unusual for

pen-osteal stripping to extend beyond the epi-physeal cartilage because of the firm

attach-ment of the peniosteum at that point. Osteogenic cells of the elevated peniosteum produce new

bone over a period of weeks.

In joints such as the hip in which the joint

capsule surrounds a portion of the metaphysis as vcll as the epiphvsis, direct involvement of

the joint occurs following extension through the peniosteum without passage through the

epiphyseal cartilage.

With continued progress of the infection,

rupture of the peiosteimm may lead to the

development of a soft tissue abscess. This may occur rapidly, especially in infants, and be

ap-parent within 48 hours after onset. Cree& has pointed out that in infants the anatomic

struc-tune of the bone with its large cancelbous spaces, spongy character and allowance for ready

de-compression permits an almost universally good

(Submitted June 29, accepted September 30, 1955.)

ADDRESS: (MG.) 333 Cedar Street, New Haven 11, Coiinecticmit.

(2)

SYMvroMs IN 99 PATIENTS WITh OSTEOMYELITIS

A0. of Patients

Fever (Chills 10)

Pain Local swelling Malaise or irritability

Anorexia Local erythema

Vomiting Local heat

84

84 80

53

50

47

18 9

8

6

outlook for the OS5OU5 lesions. If the pressure

is not relieved, further involvement of the

medullary portion may occur, leading to necrosis

of bone and formation of a sequestrum. The

oc-currence of sequestration is particularly rare in

infants, and sequestra that do form are rapidly reabsorbed.

ANALYSIS OF CLINICAL RECORDS

OF PATIENTS

Symptoms

Some patients in this series presented

with chiefly local manifestations

attribut-able to the infection in the bone. On the

other hand, the onset in many other chil-dren suggested a systemic septic illness.

The marked constitutional reaction in these

instances often overshadowed whatever

local signs were present. Osseous lesions at times were not susl)ected until local signs appeared. The onset was considered to be toxic in 48 patients and not toxic in 51. All but 4 patients were admitted to the hospital within 14 days of the appearance

of symptoms; 80 per cent were admitted

within 7 days after the onset. No

relation-ship existed between the age of the patient

or the etiologic organism and the duration

of symptoms prior to admission.

The initial symptoms in 21 patients were fever and pain. In 18 other children the

illness began with fever alone. Pain or

tenderness characterized the onset in 17

other patients. Limp was the first symptom

in 2 children, and failure to move the lower

extremities in 2. Swelling was the initial

complaint in 1 child. In the remaining

pa-tients it was not possible to determine from

TABLE II

the clinical data which of the presenting

symptoms was the initial one.

Symptomatology and the physical find-ings at the time of admission are presented in Tables II and III. Fever was present

before admission in 91 patients and! was

noted at the time of admission in 84. Fever

occurred in 96 patients either prior to or

following admission. Only 3 patients had completely afebnile courses. Absence of fever in patients with proven osteomyelitis

is an exception to the rule but does occur.

The 15 patients who were without fever at the time of admission ranged in age

from 3 weeks to 12 years. Six were less than

2 years of age. Eight of these fifteen pa-tients had mild disease, but the disease in the other 7 was severe. In 7 of the patients

who were afebnile at the time of admission

no organism was obtained on culture. Fifty-four per cent of the patients in whom an etiologic diagnosis could not be established were afebrile at the time of admission. In

63 per cent of the patients the temperature

was 39#{176}C.or more at the time of admission

and in 33 per cent, more than 40#{176}C.Chills

occurred on 1 or more occasions in 10 patients.

At the time of admission pain or tender-ness were recorded in 80 patients either in the history or by physical examination.

Tenderness is a finding of great importance in the diagnosis of osteomyelitis. Detection of localized tenderness is the most

signifi-‘FABLE III

PHYSICAL FINDINGS AT THE TIME OF ADImssIoN IN 99 PATIENTS WITh OSTEOMYELITIS

Fever Local swelling Tenderness

91 Limitation of joint motion

80 Local erythema

*59 Local heat

39 Local fluctuation

3 Effusion into joint

29 Apparent weakness or failure to use an

23 extremity

12 Xuchal rigidity

(3)

370 GREEN - ACUTE HEMATOGENOUS OSTEOMYELITIS

cant early clinical finding and indicates that

the peniosteum has been involved. In some, pain was present in the absence of active or

passive motion. Others did not complain of pain until an effort was made to examine or otherwise handle the affected area. The presence of pain or tenderness is suggested

whenever a child refuses or fails to use an

extremity, protests movement, maintains the part in a fixed position, limps or otherwise

favors a part. Pain was occasionally the only

local manifestation of osteomyelitis for as long as 2 days. While pain in some patients

was excruciating, in others it was of mild

degree and of ill-defined character. In most patients the pain was localized to the

af-fected area, but in some it was diffuse and

poorly localized. Pain in some instances was thought to arise from muscle rather than from bone. Extreme hyperesthesia was present in some patients, the child pro-testing even to the slightest touch. Local-ized tenderness is more readily elicited in older children than in infants. Although

gentle palpation should be used initially, tenderness may not become evident unless

deep iressure is employed. It is difficult

to establish the presence of point tenderness

in the presence of massive edema.

Tender-ness could be elicited in some patients by pressure over or along the involved bone;

in others, however, considerable pressure could be exerted without protest. When osteomyelitis occurred in a long bone, ten-derness was noted, at times, by gentle tap-ping on the end of the extended extremity.

vIore often, however, this sign was absent. While point or localized tenderness is an important diagnostic sign, it is by no means

a common one. This finding was present at

the time of admission in only 17 patients. Limitation of joint motion occurred in 53

patients. In infants it was occasionally the

only initial finding. The factors that

con-tribute to limitation of motion are pain,

protective muscle spasm and joint effusion. Some patients were not only disinclined to

move the involved extremity actively but also resisted passive motion. Others, though

they failed to make voluntary movements at

a joint, permitted the joint to be moved

passively through a moderate range of

mo-tion provided this was done with gentleness.

Characteristically, the joint nearest the

in-volved metaphysis was held in a position

of flexion. Dickson2 stated that extension at

such joints was always met with pain and

resistance, but that flexion might be

per-mitted. Although this was noted among the

present patients, the reverse was

occasion-ally found, and, in most, pain and limitation

of joint movement were present in both

flexion and extension. In some instances no

joint motion was possible at all. The marked

diminution in movement suggested, at

times, the presence of paralysis.

Swelling was present in 84 patients at the time of admission. Swelling did not

gen-enally occur early but rather appeared 1

or more days after the onset. In only 1

patient was this the first symptom. In

gen-eral, swelling appeared earlier in infants

than in older children. While this finding

was moderately well localized in many

patients, in others, and particularly in

in-fants, it was quite diffuse, at times involving

an entire extremity. It varied in degree from

a minimal, barely detectable swelling to

Olie that was massive and pitting.

Occasion-ally a feeling of induration was noted. Other

signs of local inflammatory reaction such as

redness and heat were seen with much less

frequency than was local swelling at the

time of admission.

Fluctuation was present in 18 patients at the time of admission. A relatively late sign to appear, fluctuation indicates that rupture of the periosteum has occurred. When the

fluctuation was superficial in location there

was little question of its presence. Deep

fluctuation was more difficult to ascertain.

Early, nonspecific symptoms such as

ma-laise, irritability, anorexia and vomiting were frequent. Toxic delirium and

convul-sions occurred infrequently.

Differential Diagnosis

It is of interest to review the diagnoses

considered in these patients at the time of

(4)

‘I’ABLE IV

I)1.dGNosEs ENTERTAINED INITIALLY IN TIlE DIFFERENTIAL I)IAGN0SIs

. .

Diagnosis No., of Patients in

Ii horn (onsmdered

Rheumatic fever 13 (7)*

Septicernia without lOCaliZatiOtI 10 (7)

Suppurative arthritis 5 (3)

Poliomyelitis 4 (‘2)

Bone tumor 4(4)

Cellulitis 3 (‘2)

Typhoid ‘1

Abscess: l)erumePilric; pelvic ‘2(1)

Fracture I

Serum sickness I

Rheumatoid arthritis 1

46 (‘26)

* The miumbers in parentheses refer to patients in whom the diagnosis of osteolnyeiitis was either not

mi-tiaily Colisidered or not considered as the most likely

diagnosis.

of patients in whom diseases other than

osteomyelitis were seriously considered. The

numbers in parentheses refer to patients

in whom osteomyelitis was either not

initi-ally considered or in whom it was not

con-sidered to be the most likely possibility.

Differential diagnosis was of more than

aca-demic interest in these latter children

be-cause failure to consider osteomyelitis often

led to a delay in the initiation of therapy.

Rheumatic fever was strongly considered

in 13 patients and considered most likely in 7. The area about the knee was most

commonly involved in these patients and, at

times, symptoms were ascribed to more

than 1 joint. The early differentiation of

osteomyelitis from rheumatic fever without

carditis may be extremely difficult. The

presence of a coexisting staphylococcal

pen-carditis in 1 patient exemplified this

diffi-culty. Diagnostic uncertainty sometimes

arises in patients with osteomyelitis

accom-panied by a sterile joint effusion or

compli-cated by a pyarthrosis. Careful examination

of the involved area may be helpful. In

rheu-matic fever maximal tenderness is usually

confined to the joint, whereas in

osteomye-litis it is generally at the metaphyseal end

of the bone. As has been noted, however,

good localization of the tenderness in early

osteomyelitis is uncommon. Also, in some

patients with rheumatic fever, pain and tenderness are not initially referred only to the outline of the joint but may extend both above and below this area.

That the diagnosis of septicemia without localization was made in patients later proven to have osteomyelitis is understand-able. In some the localized process may

initially have been overlooked but more

often was not manifest. It is well to

con-sider the possibility of pyogenic metastases

to bone in any patient who presents the clinical picture of sepsis. It would also appear advisable to examine very ill

pa-tients, especially infants, periodically for

evidence of pyogenic bone or joint involve-ment. This should apply in the presence of local infections in debilitated infants as well

as in the presence of definite septicemia.

An absolute clinical differentiation from

septic arthritis cannot be made in all

in-stances since these processes may coexist.

In the presence of a primary septic arthritis the signs are usually confined to the area

immediately surrounding the joint, while in

patients with osteomyelitis these findings tend to be more diffuse. Nicholson has

em-phasized, however, that in infants the first

symptom of septic hip may be swelling over

the buttock or thigh with the involved hip

held in flexion. Muscle spasm is especially marked in the presence of septic arthritis,

and motion is markedly limited in both

flex-ion and extension. While this is the case in

some patients with osteomyelitis, a greater amount of joint motion is generally possible.

In the presence of clinical findings

suggest-ing pyogenic arthritis, diagnostic aspiration of the joint should be performed and the

material aspirated examined by smear and

culture.

Cellulitis may present a most difficult

problem in differential diagnosis. In the presence of deep cellulitis or subfascial abscess, osteomyelitis cannot be immedi-ately excluded. When inflammatory changes

(5)

(‘alcalleus ‘I’alus Culleiforlll

4 ‘2 1

Fr( )11t1L1 P11rietal Occipital

t I 1

‘21) ‘18

‘10

It) 1)

(1

(;

a 5 a 4

‘3 ‘2 ‘2

Metatarsals

Ribs Caivariulll

Radius Clavicle

Phalanges, hand

Phalanges, foot

Scapula

Pubis

lschiuni

Iuitiple homiy involvement occurred in ‘24 per cent of the cases.

metaphysis, tile diagnosis of osteomyelitis is

less likely. Precise differentiation of these

3 conditions, cellulitis, septicemia and

sep-tic arthritis, from osteomyelitis may be

im-possible early. In such event, the treatment initiated should be that designed for

osteo-inyelitis.

Apparent weakness or failure to use au

extremity was reported! in 8 patients and

was sufficiently notable to raise the

possi-bility of poliomye!itis in 4. Poliomyelitis was considered as the primary diagnosis in

2 patients. Nuchal rigidity was marked

enough in 6 patients to warrant the per-formance of a lumbar puncture. An onset

characterized by the occurrence of

convul-sions, delirium, and nuchal rigidity would also raise the possibility of meningitis in the differential diagnosis.

Differentiation between a neoplasm and

osteomyelitis may be possible only by

hi-opsy. This is especially true of the Ewing’s

sarcoma which may present with pain,

fever, swelling and leukocytosis. In addition, osteomyelitis may appear as a mass unac-companied by fever or local inflammatory

changes.

The differential diagnosis also includes

j:ractures and other traumatic injuries,

leui-kemia, thronthoplllebitis, and scurvy. Crises

ill patients with sickle cell anemia may, at

times, be suggestive of osteomyelitis.

Roent-genographic changes in the bones of pa-tients with sickle cell anemia may resemble

those of osteomyelitis. Transient synovitis of the hip joint,4 characterized by limitation of

joint motion, fever and occasionally

leuko-cytosis, may be a consideration. Osteitis pubis, a rare disease in childhood, is char-actenized by extrelrle pain and marked tenderness on palpation over the symphy-sis pubis. Pain may also occur in tile

in-guinal regions and along the medial aspects of the thighs. Roentgenographic evidence of destructive changes in the pubic bones

appears about 1 week after the onset of symptoms. The diagnosis of osteomyelitis of a pelvic bone is a difficult one. Symptoms

and signs may suggest the presence of a

perinephric or pelvic abscess.

Bones Involved

The distribution of bony lesions is

pre-sented in Table V. One hundred fifty-four bones were involved! in 99 patients. In 24 patients more than 1 bone was involved.

As in most series,1 5-7 the femur, the tibia amid! the humerus were the most frequent sites of bony involvement. With regard to

the femur amid! the tibia, the proximal and

distal portions were involved with equal

frequency; in the humerus osteomyelitis

was found almost twice as frequently in

the proximal as in the distal portion.

Osteomvelitis of the small bones of tile hand or foot was often a manifestation of a severe septic process with multiple bony

involvement. However, in 4 patients osseous

disease was limited to tarsal bones and in 4 others to phalanges. In half of these the disease was of mild degree and well

local-izedi by the time of admission, bitt 3 patients

with isolated tarsal involvement and 1 with isolated phalangeal involvement were

se-verely ill.

Osteomyelitis in a rib occurred as an

iso-latedi findling in 4 of the 6 patients with

‘l’ABLE V

BONES INvo1vEu

Felim ur

Iil)1II I Ititiertis Fihula

(6)

‘l’raullla Respiratory

ill fection

Skimi infection \Iiscella It(’OtlS

None

20

I0

‘11 ‘1 4

1(1 8 1 ‘2

‘1(1 3 ‘2

17 6 ‘1

(;s ‘21 .5 1:1

18

‘3

2

STAPH. -STREPMIXED OTHER UNKNOWN

ORIGINAL ARTICLES

FIG. 1.

rib involvement. Each of these 4 patients

was less than 3 years of age. One, a

7-IIiomitli-Ol(i infant vi th pmieim rnococcal se1)SiS

and! osteomyehtis, died!. None of the others

were very ill, uiOr (lid! they have positive

blood! cultures.

Attention is called to the frequency of

imivolvemetit of the bony pelvis in this series.

Failure to consider osteomyelitis occurring

ill these bones ledi to a delay in diagnosis

in some patients.

Predisposing Factors

Antecedlent illness or traunia that might

have I)redisPosedl to osteomyehtis or

fa-voredi its localization occurred! in 70 per

cent of the patients (Table VI). In 8

pa-tients more than 1 antecedent was present.

Antecedent respiratory infections

oc-curred in 21 per cent of the patients and

were significantly iTiore frequent in patients

vith streptococcal dhsease (50 per cent)

thami iii I)atielits with staphylococcal dii5-ease (12.5 per cent) (X2 7.25; p. <.01).

The skin was incriminated as a portal of

entry iii 27 per cent. Tile incidence in

pa-tients with staphylococcal and

streptococ-cal osteomyelitis was similar. The skin

be-sions were furunculosis in 10 patients,

im-petigo ill 7, infected woundis, including 1

circumcision, in 5, vanicella in 3, burns in 1,

amidi imifected dermatitis venenata in 1.

A desperately ill infant developed! sepsis

aIi(1 osteoniyelitis caused by Escherichia

dOli following hemolytic d!isease of the

new-‘FABLE -1

born and kernicterus. Another infant,

ad-initted because of pyloric stenosis,

clevel-O1)edl a postoperative infection of the

ab-diomninal WOuld! with dehiscemice, and an in-fection at tile site of a venous cut-down,

with subsequent tllromlibO1)hlebitis. He, too,

developed E. coli sepsis and! osteomyelitis.

A history of local trauma was oi)tained

in 27 per cent. These injuries were

gener-ally slight and! occurred! shortly before the

onset of symptoms attributable to

osteo-myelitis. Differences in the incidlence of

preceding trauma 1)etween I)ttients witil staphylococcal and streptococcal

osteomiiy-elitis were not statistically significant.

Bacteriologic Findings

A specific bacteriologic diagnosis was

made in 87 per cent of the patients (Fig. 1).

In 62 patients (63 per cent) the

staphylococ-cius was the etiologic agent. In iiiost of

these, the organisni isolated! was a hemolytic

Staphylococcus aureus, but a hemolytic

StapilYlococcims all)ils was noted! in a few.

When tested these organisms were

coagu-lase amid! mannitol positive. A beta-hemolytic streptococcus was considered the etiologic

agent in 18 patients. There were 2 mnixed infections. Staphylococci and 1)eta-hemo-lytic streptococci were isolated from 1 of

these patients and staphylococci and E. coli

NO.OF PATIENTS 62

60

ETIOLOGY

.NTE(EI)ENT ILLNESSES

“tU/)h!J1O- Ileniolytic Other

(0(1115 “tre/)to- knOWl?

(‘01(05

40

(7)

BACTERIOLOGY

N 0. OF

PATI ENTS

20

*

23 Li

* 15

ri

* 17 Li

I

BLOOD CULTURE

LOCAL CULTURE

0 NO ORGANISM

* NO.OFSPECIFIC

Dl AGNOSES

*

ri

0

1924-28 1929-33 934-38 1939-43 1944-48 1949-54

Fic. 2.

:374 GREEN - ACUTE IIEMATOCENOUS OSTEOMYELITIS

from tile other. Aniong the 4 1)atietitS

die-scribed in Figure 1 as infected with other

organisms, 2 harbored E. coli, 1 harbored

pneumococcus type 4, and 1 Hemophilus

influenzae type b. In 13 patients an etiobogic

diagnosis could not be established.

Al-though not encountered! in this series,

osteo-myelitis may occur as a complication of

brucellosis or salmonellosis.

Bacteriologic diagnosis was established in all bitt 2 patients by isolation of the

or-ganism from the blood or from the local

area of osteomyelitis (Fig. 2). Two patients were considered to have streptococcal

osteo-myelitis on the basis of elevated

anti-streptolysin and autoclaved streptococcus agglutinin titers. A pure culture of beta-hemolytic streptococci was obtained from the nasopharynx of 1 of these patients. Posi-tive blood cultures were obtained in 53 per

cent of tile patients. The incidence of

posi-tive blood cultures did not differ in

differ-ent age groups. Likewise the incidence of positive blood cultures was similar for the

different etiologic agents. Sixty per cent of

those with staphylococcal and 61 per cent of those with streptococcal osteomyelitis had positive blood cultures. The 4 patients

with osteomyelitis due to other organisms had positive blood cultures.

In 71 per cent of the patients local

cul-tures of niaterial oi)tained i)V aspiration or

encountered at operation were positive. The etiologic agent was obtainedi from sucil

material in 87 per cent of the I)atiellts vith

stapilylococcal and! in 61 per cent of those

with streptococcal osteomyelitis. In both patients whose osteomyelitis was associ-ated with a mixed flora, the organisms were obtained by culture of material obtained at

operation ; blood cultures were negative. Through tile years

tue

incidence of

posi-tive blood cultures has changed little. With

changes in therapeutic regimen the num-ber of patients in whom the site of the

os-teomyelitis has yielded material for use in

establishing an etiobogic diagnosis has

de-dined sharply. Concomitantly there has been an increase in the number of imlstances

in wilicil an exact diagnosis could not be

reached by culture. Undoubtedly the

in-creasing number of patients admitted with

all forms of infectious disease who have received antibiotics in treatment of unex-plained fever has contributed to this latter

situation.

Age at onset as it relates to bacteriologic diagnosis is presented in Figure 3. The 2 patients with mixed local flora are repre.

sented under both agents. Among infants

less than 2 years of age osteomyelitis was

(8)

strepto-AGE DISTRIBUTION

NO.OF _ STAPHYLOCOCCUS

PATIENTS

c:

p-H(MOLYTIC STREPTOCOCCUS

25 D

#{149}

OTHCR ORGANISMS

UNKNOWN

20

‘5

10

‘2 2-4 4-6 6-8 8-10 IO-I2 2-IS

AGE IN YEARS

LEUKOCYTE COUNTS IN 98PATIENTS

NO. OF

PATIENTS MAXIMAL LEUKOCYTE COUNT

0

ADMISSION LEUKOCYTE COUNT

<10. 10-14.9 15-19.9 2O249 25r29.9 30#{176}’>

WBC IN THOUSANDS

FIG. 3 (Upper). Fuc. 4 (Lower).

coccal in 27 per cent. Among the patients more than 2 years of age osteomyelitis was

staphylococcal in 71 per cent and

strepto-coccal in 17 per cent. All of the patients from whom organisms other than

staphylo-cocci or streptococci were isolated were less than 2 years of age. The staphylococcus was

the most frequent offending agent in all

age groups. This is at variance with the

ex-penience of Green and Shannon’ in whose series of patients less than 2 years of age osteomyelitis was streptococcal in 63 per cent. It is consistent with the more recent

series of Self5 in which staphylococcal

in-fection was found in 64 per cent of those

less than 2 years of age and of Blanche,6

who reported that in his series 84 per cent

of patients less than 1 year of age had

staphylococcal disease. In the present series the incidence of streptococcal infection among children more than 2 years of age

(17 per cent) is somewhat higiler than that

reported by any of these authors, all of

whom found staphylococcal disease in more

than 90 per cent of patients of this age.

Leukocyte Response

A polymorphonuclear leukocytosis is the expected response to a pyogenic process of the sort encountered in acute osteomyelitis.

Analysis of the leukocyte counts of the 98

patients in whom counts were recorded!

(Fig.

4) was consistent with this

expecta-lion. Forty-seven per cent ilad maximal counts greater than 20,000 and 15 per cent had counts greater than 30,000. The level of leukocyte response bore no consistent

relation to the age of tile patient or to the

infecting organism.

Significant leukocytosis whell present nlav

be diagnostically useful, bitt its abseulce

does not militate strongly against the

diag-nosis. In this series 16 per cent of the

pa-tients had white blood counts less than 10,000 at the time of admission, and! 24 per

cent never had counts greater than 15,000.

While the disease in many of these patients

was mild and well localized, some patients

had severe systemic disease and positive blood cultures. Severe illness in the absence of leukocytosis was not confined to the younger age groups, nor was it always a

manifestation of the overwhelming process

commonly associated with failure of

leuko-cyte response.

Roentgenographic Findings

The importance of roentgenographic

evaluation in confirming the clinical

diag-nosis of osteomyelitis and in following its

course has increased with the advent of

antibiotic therapy and the concomitant

de-dine in operative intervention.

Unfortu-nately a positive roentgenographic diag-nosis can seldoni be made early.

(9)

litis was noted in 89 patients. In 10 patients films were either negative or not obtained,

usually in the presence of a fulminating course with rapid demise. In all but 1 of these instances the diagnosis was confirmed

at operation or at necropsy. The 1

excep-tion was a child who had a typical clinical

course and response to antibiotic therapy,

but was inadequately followed from a

roentgenographic point of view.

An interval of 7 to 14 days from the onset of symptoms to the development of positive roentgenographic signs has been generally

accepted.” Obviously, precise analysis of

this point would require daily examination,

but a few observations seem pertinent.

Among patients in whom films were taken

with sufficient frequency to permit this

evaluation, the average interval was 10

days; the range from 3 to 17 days. The

presence in some patients of a shorter period may have represented a truly briefer

interval from infection to visible evidence

or an early period of silent infection. The

occasional rather long interval is more

dis-turbing. In 1 patient, roentgenograms were

negative at 14 days and positive at 16. In

another, roentgenograms were negative at

4 days and positive at 13, but findings at this time were so minimal that it was only

when more definite signs were seen at 19

(lays that tile positive findings were noted

in the earlier films.

The occurrence of soft tissue swelling

with loss of the usual tissue planes is an

early nonspecific finding that may suggest the presence of underlying osteomyelitis.

In general, the first roentgenographic sign

of osteomyelitis is the presence of 1 or more areas of radiolucency, usually in the meta-physis.9’ #{176} This was true of 56 patients. These areas, either in the cortex or in the medullary portion, may be very small in

size or quite extensive. In 10 patients the first finding was periosteal elevation or new bone formation. While periosteal new bone

formation may be apparent only in the

region of the metaphysis, it may at times

appear to surround the entire length of the

shaft. In 23 patients both signs were

pres-ent at the time of the first definitive

roent-genographic examination. Sequestra, when

they appeared, did so relatively late in the

course of the illness as dense, sclerotic shadows in the shaft of the bone.

Osteomyelitis in infancy occasionally presents as a silent swelling of or over a

bone. In these instances tile diagnosis of bone tumor is strongly suggested. Roent-genographic differentiation may be difficult

or impossible since tumors may lead to bone destruction, bone production and periosteal thickening. One patiellt, a 5-month-old

in-fant, was admitted with a diagnosis of neo-plasm following 3 weeks of progressive swelling in the area of a rib. On roentgeno-graphic examination a lobular area of de-creased density was noted within the rib

with expansion and thinning of the cortex

but with little periosteal reaction. Following this confirmation of the clinical impression, an operation was performed and an area of osteomyelitis encountered. Recovery was

imneventIul. In dealing with somewhat older

lesions, Hatchert I has noted that periosteal

new bone formation in osteomyelitis may assume the onion skin appearance often said to be pathognomonic of Ewing’s tumor. A lesion which suggested this latter diag-nosis was seen in 1 of tile present patients following a period of healing. Shortly there-after an exacerbation of active disease

oc-curred, and the diagnosis of osteomyelitis

was proved at operation.

Once roentgenographic evidence of

osteo-n’iyelitis has appeared, serial films may

mi-tially be taken every 2 to 3 weeks; later, this interval may be lengthened. It should be pointed out that a progressive increase

in roentgenographic findings may occur even though the infectious process is under control, and healing is occurring. In the

course of such examinations during ilealing,

the differences between osteomyelitis in infancy and in older children are striking. The more rapid and limxuriant formation of periosteal new bone, the infrequency of

sequestration and its rather rapid resorption

when present, noted by Green’ and by

(10)

ORIGINAL ARTICLES

in infancy, are consistent with the present

experience. Follow-up roentgenograms

should also be obtained in patients with septic arthritis since some of these patients

may later demonstrate the presence of

os-teolytic lesions in the metaphysis.

Prognosis

Twenty-one of the ninety-nine patients

(lied. The mortality rate (Table VII) of those

less than 2 years of age (23 per cent) was little different from that of the other

chil-dren (21 per cent). Likewise the mortality

TABLE VII

MORTALITY

Beta

Staphyl-coccus

Ilemolytic

Strepto-Other

Total

coccus

<‘2 yr. ‘3 (33%) 1 (17%) 1 (‘2.5%) .5

>‘2 yr. 14 (‘26%) ‘2 (17%) 16

‘21 (‘21%)

rates were similar when considered in terms

of the different infecting organisms. The progressive decline in mortality through the

years is shown in Table VIII.

Morbidity as measured by duration of

hospitalization has also decreased

progres-sively (Table VIII). The protracted stormy courses so frequent in the early years of this study are rare today.

TABLE VIII

DtICATI0N OF HOSPITALIZATION

Days in hospital

>150 Deaths

<50 5o-1cK 100-150

1924-’28 S ‘3 1 5 4

19’29-33 8 4 ‘2 11

1934-38 9 4 3

1939-43 ii 5 1 1

1944-48 9 ‘2

1949-54

Totils

11 ‘2 0

51 18 4 5 ‘21

Therapy

The therapeutic approach to acute

hema-togenous osteomyelitis has varied con-siderably over the years represented in this

study. In general, during the first 15 years,

emphasis was on early incision and

drain-age. Drainage of the bone itself was

em-ployed in most instances, but, in some, only the soft tissue abscess overlying the bony lesion was drained. The introduction of the

sulfonamides changed this program little. It was only as experience with penicillin

developed that early and vigorous treatment

with antibiotics obviated the necessity for

surgical intervention in many instances. The over-all results of these different therapeutic regimens are shown in Table IX.

Patients noted here as having experienced

unusual morbidity were those with multiple

exacerbations requiring repeated

hospitali-zation and usually extensive surgery;

drain-ing sinuses of more than 3 months’ duration,

chronic osteomyelitis, active longer than 1

year, or residual bony deformity. One of tile

most common complications of acute osteo-myelitis is the occurrence of sterile effusion

into the adjacent joint. Septic involvement

of a joint may also occur, more commonly

in infants than in older children. Because the pyogenic exudate may destroy the

cartilaginous head of the femur and lead to

TABLE IX

THERAPY

No: f

Patients Deaths Morbidity

Supportive only 6 1 1

Surgery only

(a) bone ‘33 I’2 14

(I)) soft parts 19 5 5

Surgery and chemo-therapy

(a) bone 14 8

(b) soft parts 3

Chemotherapy alone

Totals

‘24 3 0

99 ‘21 ‘28

Morbidity=chronic draining sinus >3 mo.; residual

(11)

Presulfonalnide

Sulfoltalnide Penicilli 1111(1

s(llfollalllide

Pellicillill

ltlItipl(’ IllItiI)iOtK’S

‘l’otals

Treatment in this series was generally

-

-:::::: started within 6 hours of admission. Choice

\ o. of Deaths % of antibiotics at this time is in the nature

Patients

of an ‘educated guess as to the infecting organism and its probable antibiotic sus-ceptibility. The frequency of staphylococcal infections and their degree of resistance to

most commonly used antibiotics are

impor-tant considerations in initial therapy. A

combination of an agent to which recently

isolated staphylococci are usually

suscepti-ble, such as chloramphenicol or

erythromy-cm,

and a bacteniocidal drug, such as

peni-cillin or streptomycin, is employed.

Meanwhile the in-t’itro susceptibility to available antibiotics is determined for the

99 ‘21 ‘21

Jislocation of the hip, septic involvement of the joint in infants is an especially serious

complication. This unfortunate result oc-curred in 1 infant in the series. Other com-plications included pathologic fractures and

limitation of joint mobility due to flexion

contractures. Involvement of the epiphyseal plate may lead to a variety of bony

deformi-ties. While an increase in the local blood supply may lead to an acceleration in the growth of the extremity, damage to the epi-physeal plate may lead to shortening or

other local deformity. A decline in mortality

and morbidity associated with the use of

antibacterial therapy is evident. The

occur-rence of 3 deaths among the patients treated

with chemotherapy alone might suggest

that a combination of chemotherapy and

surgery constituted optimal therapy as none

of the patients who were treated in the latter fashion died. Evidence that this is not the case is presented in Table X, where the mortality rates for the various

ap-proaches to antibacterial therapy are shown. The 3 deaths occurred in patients treated with a sulfonamide or with a combination

of penicillin and a sulfonamide. In the light of recent experience the doses of penicillin used during this period seem quite small.

There have been no fatalities among the

patients treated with what might be con-sidered ad!equate antibiotic therapy.

TABLE X

RESULTS OF TJIEImAPY

58 18 31

it; 1)

11 ‘2 7

4

10 0)

DISCUSSION OF THERAPY

Optimal therapy for patients with acute

hematogenous osteomyelitis today must

in-volve a flexible program. A vigorous search

for the infecting organism should be made.

As surgical intervention and culture of the

organism directly from the site of the osteo-myelitis is no longer employed in most

pa-tients, reliance for precise bacteriologic diagnosis must be placed on cultures of

the blood. Helpful information may be

oh-tamed from cultures of the nasopharynx, throat, or skin lesions, and in the case of streptococcal disease, from serologic studies. This information should routinely be

sought, but complete reliance on it is never

entirely satisfactory. In recent experience

with patients with staphybococcal sepsis it

has not been uncommon to isolate from the

nasopharynx, even in pure culture, staphy-lococci which, measured in terms of their

in-vitro susceptibility to the various anti-biotics, are quite different from those iso-lated from the blood. After initial evaluation

of a patient considered to have acute

osteomyelitis, a number of blood cultures

should be obtained. The interval of time

diuring which therapy is withheld in an attempt to secure tile etiobogic organism is

obviously dependent upon the severity of

the illness and the degree of prostration in

each particular patient. Thus no rigid

schedule of timing should be employed. It

seems reasonable that even in the most toxic patients a minimum of 2 blood cultures may

(12)

ORIGINAL ARTICLES

organisni isolated!. Disc sensitivity tests have

usually correlated well with the

tube-dilu-tion ITtetliod, bitt the latter provides so much more precise information that wherever

available it should be employed in severe

infections sitch as osteomyelitis. The fact

that the maximal penicillin content of discs

ill routine use is 10 units while serum

con-centrations of penicillin of the order of 50

units/ml. are easily achieved in children

points out the advantages of the tube-dilu-tion method!. In add!ition, antibiotic

combi-nations are somewhat more readily tested

\Vitil the latter method.

OIl the basis of sitch further information from the laboratory the therapeutic regimen

may be changed. The drug of choice in

strel)tOcOccal osteoniyelitis is penicillin.

Al-thougll a successful outcome in

streptococ-cal osteomyelitis has been associated with

very small doses of penicillin, it would

seem wise to administer sufficient

penicil-un to maintain serum levels of between 10

and 20 units/ml. The use of probenecid

(BeneInid) has simplified the achievement

of ratiler high serum levels of penicillin in

tile treatment of severe infections. In

treat-ment of staphybococcal osteomyelitis a

COil-1)ination of 2 antibacterial agents to which the organism isolated is susceptible is

em-pioyed. Combination therapy is employed

itl the hope that a greater antibacterial

ac-tivity may be achieved than with any 1

agent alone, but, more important, in order

to prevent, as demonstrated by Purcell,’2

the development of resistance characteristic

of the staphylococcus. Another principle to

be emphasized in tile therapy of

staphylo-coccal infections is the necessity for intensive

treatment given over an extended period of

time in order to prevent relapse. Whenever

penicillin-sensitive staphylococci are

en-countered, this drug is used. With the use of

crystalline penicillin G in aqueous

suspen-sion given intramuscularly and probenecid given by mouth, serum penicillin levels 10

to 20 times the demonstrated in-vitro

sensi-tivity of the organism are achieved. The

initial dose of penicillin employed is usually

I,000.000 units every 2 hours. Later the

dosage is modified so that the above levels

are maintained. Procaine penicillin is often satisfactory for this purpose. Probenecid is

given initially in a loading dose of 25 mg./

kg. followed by 10 mg./kg. every 6 hours.

Because of the rising incidence of highly

resistant strains isolated from patients with

staphybococcal disease,t1 the benefits of this

antibiotic are more often not realized. Most

patients treated recently have received chloramphenicol or erythromycmn in

com-bination with penicillin or streptomycin; if sensitivity to these latter antibiotics cannot be demonstrated, chloramphenicol and ery-thromycin have been used together, or one of these has been used in combination with a tetracycline. In 1 infant bacitracin was

giveul intramuscularly in conjunction with erythromycin, the dosage scheditle of

bacitracin consisting of 200 units/kg. every

8 hours. The drug was discontinimed after

6 days because of the development of

albuminuria and cylindruria. This patient

also received irrigations of abscess cavities with a solution of bacitracin containing 75

units/ml., but total dosage by both routes

of administration did not exceed 900 units/ kg./day. One other infant was treated with

local irrigations utilizing a solution contain-ing bacitracin. Because of experience with

the previous patient, the concentration of

bacitracin in the irrigation fluid was

calcu-lated so that no more than 200 units/kg.

were administered locally in an 8-hour period. Within 10 days this patient devel-oped albuminuria and cylmndrutria, and the

medication was discontinued.

In those instances in which the causative

organism is not isolated, changes in the initial antibiotic therapy are dependemit

upon the clinical response.

Although surgical intervention is rarely

necessary today, the patient must be oh-served with the idea that surgical drainage

may become indicated. In the case of tense, fluctuant subperiosteal or soft tissue ab-scesses, the advice of Green and Shannon’

recommending drainage appears as sound

(13)

infants. Such abscesses may be successfully

treated by repeated needle aspiration but, in general, the presence of very thick puru-lent material nlakes surgical incision and drainage mandatory. In addition,

suppura-tive lesions elsewhere, such as furuncles or soft tissue abscesses, should be drained.

The therapy of pyarthrosis secondary to

osteomyelitis is similar to that employed in

patients with primary septic arthritis. Drainage is essential. Following the estab-lishment of drainage an antibiotic such as

aqueous penicillin in a concentration of

5,000 units/ml. or bacitracin may be in-stilled into the abscess pocket or into the

joint cavity. Although a total daily dose of 600 units/kg. of bacitracin is generally

considered safe, this dosage may produce

nephrotoxic effects in infants even when its

a(lministration is entirely local.

When sequestra occur in infants, the

treatment should be conservative. Because

necrotic bone is readily reabsorbed,

seques-trectomy should rarely be considered. If

serial roentgenograms demonstrate that

complete absorption does not occur,

sequestrectomy is then indicated.

Immobilization and supportive therapy,

such as blood transfusion, should not be

neglected. Immobilization has been

em-ployed in patients with extensive osseous

involvement, in those with marked

deminer-alization of the bone who are in danger of pathologic fracture and in patients with a pyarthrosis. Posterior splints are adequate for these purposes. Pain may be severe in patients with osteomyelitis but seldom re-quires a more potent analgesic than codeine.

In the presence of considerable spasm of the

musculature about the

hip

in patients with

osteomyelitis of the femur, the use of trac-tion may contribute to relief of pain.

The response of antibiotic therapy among

the presently reported patients was

gen-erally manifested by a rather rapid initial

defervescence, usually within 24 hours.

Fol-lowing the initial response in the antibiotic

treated patients, low grade fever or

inter-mittent elevations to 38 to 38.5#{176}C. often persisted for 2 to S weeks.

Recommenda-tions as to the duratioul of antibiotic therapy

have been for an interval of 3 to 6

weeks.7’ ‘4-” In treatment of patients with

suspected osteomyelitis, vigorous antibiotic therapy should be continued until at least

3 weeks have elapsed since the onset of

symptoms. If at the end of that period

roentgenograms remain negative and

clini-cal signs and symptoms have been absent for at least one week, it would seem safe

to discontinue treatment, concluding either

that the lesion had been cellulitis or that successful treatment of osteomyelitis had prevented the development of

roentgeno-graphic evidence of bony changes. For pa-tients with roentgenographically proved osteomyelitis a period of 4 to 6 weeks of

vigorous antibacterial therapy would seem

adequate. Clinical experience indicates tllat, in addition, such treatment should be con-tinued for approximately 2 weeks after

sub-sidence of all local signs of inflamunation during which a normal temperature and leukocyte count are maintained. The only relapse among the patients treated with

antibiotics in the present series occurred in a patient in whom this latter precept was

neglected. The length of time for which

weight bearing is interdicted should be a

matter of individualized orthopedic jimdg-ment. Weight bearing generally may be per-mitted within 10 to 12 weeks after the onset

of the disease. In those patients witil

ex-tensive disease a somewhat longer period

may be indicated.

SUMMARY AND CONCLUSIONS

The clinical records of 99 infants and

children admitted to the Grace-New Haven

Community Hospital with acute hemato-genous osteomyelitis are reviewed.

The presenting symptomatology and

phy-sical findings are discussed. Detection of

localized tenderness is the most significant early clinical sign. This was not, however, a common finding at the time of admission.

The diagnoses entertained in these

pa-tients at the time of admission are reviewed

and the differential diagnosis is discussed.

(14)

381

similar to that noted by other authors.

How-ever, attention is called to the frequent

in-volvement of the bony pelvis.

A specific bacteriologic diagnosis was

uiiade in 87 per cent of the patients. In 63

per cent staphylococcus was the etiologic

agent. Beta-hemolytic streptococcus was

consi(!ered the etiologic agent in 18 per

cent. Staphylococcus was the most frequent

offender in all age groups. In infants less

than 2 years of age osteomyelitis was

strep-tococcal in 27 per cent.

The average interval from the onset of

symptoms to the development of positive

roentgenographic signs was 10 days. The

range was 3 to 17 days.

In treatment of patients suspected of

Ilaving osteomyelitis, vigorous antibiotic

therapy should be continued until at least

3 weeks have elapsed since the onset of

symptoms. If at the end of that period

roentgenograms remain normal and clinical

signs and symptoms have been absent for at

least 1 week, it would seem safe to discon-tinue treatment.

A detailed programli for medical therapy

is Presented and the indications for surgery

are considered. Emphasis is placed on

vigorous search for the infecting organism.

The necessity for intensive treatment given

over an extended period of time is stressed.

REFERENCES

1. Green, W. T., and Shannon,

J.

G.: Oste-omyelitis of infants. Arch. Surg., 32:462,

1936.

2. Dickson, F. D. : The clinical diagmiosis,

prognosis and treatment of acute hema-togenous osteomyelitis. J.A.M.A., 127:

212, 1945.

3. Nicholsomi,

J.

T. : Pyogenic arthritis with pathologic dislocation of the hip in in-fants. J.A.M.A., 141:826, 1949.

4. Edwards, E. G. : Transient synovitis of the hip joint in children. J.A.M.A., 148:30, 1952.

5. Self, E. B. : Acute hematogenous oste-omyelitis. PEDIATRICS, 1 :617, 1948. 6. Blanche, D. W. : Osteomyelitis in infants.

J.

Bone & Joint Surg., 34A:71, 1952.

7. Altemeier, W. A., and Wadsworth, C. L.:

An evaluation of penicillin therapy in

acute hematogenous osteomyelitis.

J.

Bone & Joint Surg., 30A:657, 1948.

8. Ober, F. R. : Osteomyelitis in children. Am.

J.

Surg., 39:319, 1938.

9. Einstein, R. A.

J.,

and Thomas, C. G.: Osteomyelitis in infants. Am.

J.

Roentgenol., 55:299, 1946.

10. Pierson,

J.

W., and Roach,

J.

F. : The roentgenology of osteomyelitis. J.A.M.A.,

126:884, 1944.

11. Hatcher, H. : In discussion of Dickson,

F. D. : The clinical diagnosis, prognosis and treatment of acute hematogenous osteomyelitis. J.A.M.A., 127 :212, 1945. 12. Purcell, E. M., Wright, S. S., and Finland,

M. : Antibiotic combinations and re-sistance to antibiotics : penicillin-erythro-mycin and streptomycin-erythromycin combinations in vitro. Proc. Soc. Exper.

Biol. & Med., 82:124, 1953.

13. Spink, W. W. : Staphylococcal infections

and the problems of antibiotic-resistant staphylococci. Arch. lit. Med., 94:167,

1954.

14. Dowling, H. F. : The Acute Bacterial

Dis-eases. Philadelphia, Saunders, 1948, p. 193.

15. Trueta,

J.

:Acitte haematogenous osteomye-litis: its pathology and treatment. Bull.

Hosp. Joint Dis., 14:5, 1953.

16. DeWet, I. S.: Acute hematogenous

oste-omyelitis and suppurative arthritis of

infants. South African M.

J.,

28:81, 1954.

17. Beermami, C. A. : The treatment of acute

hematogenous osteomyelitis of the long bones in infants and children.

J.

Pediat.,

33:578, 1948.

SPANISH ABSTRACT

Osteomielitis Aguda Hemat6gena

Los autores revisaron los expedientes clInicos de 99 lactantes y niflos que se admitieron en el

Grace New Haven Commumnity Hospital con

osteomielitis aguda hemat#{243}gena. Describen Ia sintomatologla y los hallazgos fisicos

observa-dos; Ia sensibilidad localizada es el signo

clInico temprano m#{225}ssignificativo, que sin

embargo no fu#{233}frecuente al momento de ad-misi#{243}n;presentan luego los diagn#{243}sticos que de

estos pacientes se hicieran al hospitalizarse y

discuten los diagn#{243}sticos diferenciales. La

dis-tribuci#{243}n de las lesiones #{243}seases similar a Ia

descrita por otros autores; sin embargo,

recal-can el hecho de la invasion frecuente de Ia pelvis.

(15)

diagn#{243}-382 GREEN - ACUTE HEMATOGENOUS OSTEOMYELITIS

stico bacteriol#{243}gico especIfico; en el 63% el

agente etiol#{243}gicofue el estafilococo y en el 18%

el estreptococo beta hemolItico. El estafilococo

fu#{233}el agente m#{225}sfrecuente en todas las edades; en lactantes menores de dos a#{241}osde edad Ia osteomielitis fue de origen estreptoc#{243}ccico en el 27%.

El intervalo promedio entre la iniciaci#{243}n de

Ic’s sIntomas y el desarrollo de signos

radiogr#{225}-ficos positivos fu#{233}de 10 dIas, con variaciones

(le 3 a 17.

En los pacientes sospechosos de padecer

osteomielitis debe aplicarse un tratamiento

vigoroso a base de antibi#{243}ticos y sostenido hasta

iue por lo menos hayan pasado tres semanas del principio de los smntomas. Si al final de

este perlodo el estimdio radiogr#{225}fico es normal

y los signos y sIntomas clInicos han

desapare-cido por lo menos diurante una semana, la

tera-p#{233}utica puede suspenderse con gran margen de

seguridad. Los autores presentan un programa

detallado del tratamiento medico y hacen con-sideraciones sobre las indicaciones del

trata-miento quir#{241}rgico. Recalcan la importancia de

una vigorosa bmmsqueda del organismo infec-tante, asI como la miecesidad de un tratamiento

intensivo durante el perlodo se#{241}alado.

INTERLINGUA ABSTRACT

Acute Osteomyelitis Hematogene

Es passate ill revista le protocollos clinic de 99 infantes e juveniles admittite al Grace-New

Haven Community Hospital con acute osteomy-elitis hematogene. Le symptomatologia moti-vante le presentation e le constatationes physic

es discutite. Sensibilitate sub pression local es le

plus significative signo clinic initial, sed isto

non esseva inter le constatationes dietegite le

plus communmente al tempore del admissiomi. Le diagnoses formulate pro iste patientes al tempore del admission es passate in revista e le

diagnose differential es discutite. Le

distribum-tion del lesiones ossee esseva simile a lo que

es-seva notate per altere autores. Tamen, nos sig-nala specialmente le freqimente iIiv)lvimemtto die1 pelve ossee.

Un specific dliagnose bacteriologic esseva

facite in 87 pro cento diel patientes. In 6:3 () cento, staphylococco esseva le agente etiologic.

In 18 pro cento, streptococco hemolvtic beta

esseva considerate como le agente etiologic.

Staphylococco esseva le plus frequente peccator

in omne gruppos. In imifantes infra 2 amos de etate, le osteomvelitis esseva streptococcal itl 27

pro cento. Le intervallo mediami inter le declara-tion del svmptomas e le disveloppamento de

positive signos roentgenogl-apiiic esseva 10 dies, con 3 dies e 17 dies como minirno e maximo.

In le tractamento de patientes sub suspicion

de osteomyelitis, un vigorose cumrso antibiotic

deberea esser continuate usque al minus 3

sep-timallas 1)OSt le declaration del symptomas. Si

al fin de iste periodo le roentgemiogramma es

ancora normal e Si le signos e symptomas clinic ha essite absente durante al minus Un

septi-mana, il pare possibile discontinuar le therapia

Sill riScO.

Es presentate 1111 detaliate programma die

therapia medical. Le indicationes pro interven-tion chirurgic es considerate. Es simblimleate le

importantia de intense effortios a deteger Ic

organismo infectiose. Nos accentua le

necessi-tate de vigorose cursos therapeutic dumrante Un

prolongate periodo de tempore.

CoELIA: I)ISEAsE. V. SolE EXPERIMENTS ON THE CAUSE OF THE lIAIIMFUL EFFECT

OF \VHEAT CLIADIN, J. H. Van Dc Kamer and H. A. \Veijers. (Acta paediat., 44:

465, September, 1955.)

III previous studies it was denionstrated that a protein fraction of wheat, gliadin, is associated with the production of symptoms in the majority of patients with coeliac disease. The present paper describes further efforts to determine the mnainer in which

this substance exerts its harmful effects. The experiments indicate that the harmful

effects of gliadin are destroyed if it is boiled with iN hydrochloric acid for a brief period. Gliadin contains 4.3 per cent glutaniine and the effect of the acid treatment

is to convert the glutamine into glutamic acid. The author proposes the hypothesis that glimtamine, botmnd in gliadin-but not the free amino acid glutamimie-is responsi-ble for the harniful effects of wheat protein upni coeliac disease. The ratio of amid-nitrogen to non-aniicl-nitrogen in different foodstuffs was deterniined. All the protein

(16)

1956;17;368

Pediatrics

Morris Green, William L. Nyhan, Jr. and Mildred D. Fousek