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C OPYRIGHT Ó 2014 BY T HE J OURNAL OF B ONE AND J OINT S URGERY, I NCORPORATED

Primary Epiphyseal or Apophyseal Subacute

Osteomyelitis in the Pediatric Population
A Report of Fourteen Cases and a Systematic Review of the Literature
Dimitri Ceroni, MD, Wilson Belaieff, MD, Abdessalam Cherkaoui, MD, PhD, Pierre Lascombes, MD, PhD,
Jacques Schrenzel, MD, PhD, Geraldo de Coulon, MD, Victor Dubois-Ferrière, MD, and Romain Dayer, MD

Investigation performed at the Children’s Hospital of Geneva, University Hospitals of Geneva, Geneva, Switzerland

Background: Primary epiphyseal or apophyseal subacute osteomyelitis (PEASAO) is a rare condition that typically has
mild symptoms and lack of a systemic reaction, according to opinions, case reports, and case series. We reviewed
fourteen consecutive cases of PEASAO treated at our institution over a thirteen-year period to characterize this disorder.
Methods: We retrospectively reviewed the medical records of all children and adolescents who had been surgically managed
for PEASAO at our institution from January 2000 to December 2012. A systematic review of the literature was also performed to
identify trends in causative organisms and formulate evidence-based recommendations for diagnosis and treatment.
Results: Fourteen children (median age, 27.8 months) with PEASAO were included in the study. Fever (rectal temper-
ature, >38°C) was present at admission in two children, C-reactive protein was within the normal range (<10 mg/dL) in
eleven, the erythrocyte sedimentation rate was >20 mm/hr in eight, and the white blood-cell count was normal in all. The
pathogen was not identified on blood cultures in any child and was identified on classical cultures of bone samples in only
one. Use of PCR (polymerase chain reaction) assays allowed the pathogen to be identified in an additional eight children.
The pathogen was Kingella kingae in eight and methicillin-sensitive Staphylococcus aureus in one.
Discussion: The use of organism-specific real-time PCR assays markedly improves the detection rate of the pathogen
responsible for PEASAO, and K. kingae is the most commonly detected pathogen. The literature highlights a biphasic age
distribution of PEASAO in children. The infantile form affects children from one to less than four years of age, accounting
for approximately 75% of all PEASAO cases. The second form, in older children, is more likely to be associated with fever
and systemic symptoms. The femur and the tibia are the most commonly affected long bones. Laboratory data are usually
noncontributory for diagnosing PEASAO, and blood cultures are often sterile. Although K. kingae is the most commonly
detected microorganism in children less than four years of age, S. aureus is responsible for most PEASAO in older children.
Antibiotic treatment is usually sufficient to eradicate the pathogen.

Peer Review: This article was reviewed by the Editor-in-Chief and one Deputy Editor, and it underwent blinded review by two or more outside experts. The Deputy Editor
reviewed each revision of the article, and it underwent a final review by the Editor-in-Chief prior to publication. Final corrections and clarifications occurred during one or
more exchanges between the author(s) and copyeditors.

P
rimary epiphyseal or apophyseal subacute osteomyelitis togenous epiphyseal or apophyseal subacute osteomyelitis may
(PEASAO) in children is a rare condition1. Epiphyseal or display an acute or subacute clinical picture. In most cases, sub-
apophyseal subacute osteomyelitis can occur by hema- acute clinical manifestations prevail and correspond to either type
togenous primary seeding of the epiphysis; by contiguous spread IIb (crossing the physis and involving both the metaphysis and the
of infection from the metaphysis through transphyseal vessels (in epiphysis) or type V (a primary epiphyseal lesion) according to the
children less than eighteen months of age); and, less commonly, Roberts classification2. Subacute hematogenous osteomyelitis is an
by direct inoculation resulting from a penetrating injury. Hema- infectious process characterized by moderate localized pain, mild

Disclosure: None of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of any
aspect of this work. One or more of the authors, or his or her institution, has had a financial relationship, in the thirty-six months prior to submission of this
work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. No author has
had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this
work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.

J Bone Joint Surg Am. 2014;96:1570-5 d http://dx.doi.org/10.2106/JBJS.M.00791

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or no systemic manifestations, noncontributory laboratory results, abstract of each article identified by the above search terms were examined, and the
negative blood cultures, and positive radiographic findings1-11. full text was then examined if the article appeared potentially eligible for inclusion.
Articles were excluded if the location of the osteomyelitis was not specified or if
According to King and Mayo, any osseous infectious process
it represented primary metaphyseal osteomyelitis with secondary epiphyseal or
with a duration of more than two weeks and without acute apophyseal involvement. The reference list of every included article was searched
symptomatology can be referred to as subacute osteomyelitis9. for additional relevant articles, which were subjected to the same screening process.
The clinical course of subacute hematogenous osteomyelitis is A total of 203 articles underwent full-text review, and 108 of these were
most likely the result of an atypical host-pathogen relationship discarded because of irrelevant or noninterpretable content. The full text of each
that may comprise any combination of increased host resistance, of the remaining ninety-five articles was then assessed in greater detail. Forty-four
decreased virulence of the causative organism, and/or prior an- articles were considered relevant with respect to identifying PEASAO location,
age groups (neonate, infant less than four years of age, child, adolescent),
tibiotic exposure2,4,5,12,13. In many cases, cultures fail to identify
causative organisms, biological and bacteriological investigations, and treatment.
the causative organism, especially when a fine-needle aspiration The total number of patients included in this review
1,2,9,10,13,15-44
, in-
technique is used. Surgical drainage may yield positive cultures cluding our own cases, was 116. The study represented Level-4 evidence ac-
in 40% to 75% of patients. When culture results are positive, cording to the CEBM (Centre for Evidence-based Medicine) classification, and
Staphylococcus aureus is the most common organism isolated6,12. this evidence yielded only a Grade-C recommendation on both the CEBM and
Some reports suggest an increasing incidence of this form of SORT (Strength of Recommendation Taxonomy) scales.
osteomyelitis8 and a higher prevalence in certain countries7.
Because of the many existing hypotheses regarding the Source of Funding
pathogenesis and management of primary hematogenous sub- There was no external funding source for this study.
acute osteomyelitis of the epiphysis or apophysis, we reviewed our
clinical experience and bacteriological investigation model for Results
this condition. A systematic review of the literature was also con- Case Series
ducted to identify trends in causative organisms and to attempt to
formulate evidence-based recommendations for diagnosis and
treatment of this condition.
O ur case series included fourteen children (ten girls and
four boys) with PEASAO; the infection site was the distal
femoral epiphysis in six, proximal humeral epiphysis in two,
proximal tibial epiphysis in two, proximal femoral epiphysis
Materials and Methods in one, distal fibular epiphysis in one, and femoral apophysis

A fter approval from the Children’s Hospital Review Board, medical charts of
all children and adolescents who had been surgically managed for PEASAO
at our institution from January 2000 to December 2012 were retrospectively
(greater trochanter) in two. The median age of the children with
PEASAO was 27.8 months (range, twelve to fifty-four months).
Fever (rectal temperature, >38°C) was present at admission in
reviewed. Demographic information; body temperature; the bone involved; and
laboratory data, including bacterial cultures, PCR (polymerase chain reaction)
two children; the other twelve children were afebrile. One child
assays, WBC (white blood-cell) count, platelet count, ESR (erythrocyte sedi- presented with local swelling and erythema. Functional impair-
mentation rate), and serum CRP (C-reactive protein) level, were analyzed. Bone ment was present in all children. None of the children had un-
aspirate specimens were sent to the laboratory for Gram staining and immediate dergone prior antibiotic treatment.
inoculation onto Columbia blood agar (incubated in a CO2-enriched atmo- All of the children had undergone imaging investiga-
sphere), CDC anaerobe agar with 5% sheep blood (incubated under anaerobic tions, including radiography and MRI. Epiphyseal lesions were
conditions), chocolate agar (incubated in a CO2-enriched atmosphere), and
seen on radiographs in six of the children, and MRI visualized
brain-heart broth. The incubation time was ten days. All samples collected from
2007 to 2012 were analyzed with use of broad-range PCR and a new real-time lytic osseous changes in the remaining eight.
14
PCR assay specific to Kingella kingae that is designed to detect two independent The CRP level was normal (<10 mg/L) in eleven of the
genomic targets in the K. kingae RTX toxin locus, namely rtxA and rtxB. DNA children and was 11, 12, and 32 mg/L in the remaining three.
was extracted with a MagNA Pure LC instrument and MagNA Pure LC DNA The ESR averaged 33 mm/hr (range, 11 to 102 mm/hr) and was
Isolation Kit II (Roche Molecular Biochemicals) according to the manufacturer’s >20 mm/hr in eight of the fourteen children. The WBC count
instructions. TaqMan Universal PCR Master Mix with AmpErase UNG (Applied averaged 8980 cells/mL (range, 4900 to 15,240 cells/mL) and was
Biosystems) was used with 0.5 mL of input DNA and nuclease-free water
(Promega). Every PCR analysis was performed in duplicate.
normal in all children. The platelet count averaged 406,000
Imaging of the affected anatomic region was available for every child and platelets/mL (range, 221,000 to 700,000 platelets/mL) and was
included radiography and MRI (magnetic resonance imaging), interpreted by a abnormal in ten of the fourteen children. The WBC count, ESR,
board-certified radiologist experienced in pediatric radiology and by a senior and CRP were within the normal range in seven of the fourteen
pediatric orthopaedic surgeon. Results were analyzed within four different age children, abnormal for one marker in five children, and abnormal
groups (neonate, infant less than four years of age, older child, and adolescent). for two markers in two children (Figs. 1-A, 1-B, and 1-C).
Blood cultures were obtained for every child. Open or
Review of the Literature percutaneous surgical drainage and aerobic and anaerobic bac-
We searched the MEDLINE database, the Cochrane Library, and the Google terial culturing of bone material were carried out in all children.
Scholar search engine without date restriction until December 31, 2012. The
For the nine most recently treated children, PCR assays were also
keywords used were ‘‘p(a)ediatric,’’ ‘‘acute,’’ ‘‘subacute,’’ ‘‘epiphysis,’’ ‘‘epiphyseal,’’
‘‘apophysis,’’ ‘‘apophyseal,’’ ‘‘osteomyelitis,’’ ‘‘hematogenous,’’ ‘‘bone infection,’’
performed. The pathogen was not identified from blood cultures
‘‘abscess,’’ ‘‘Brodie,’’ ‘‘antibiotics,’’ ‘‘drainage,’’ ‘‘culture,’’ and ‘‘surgery.’’ The research in any of the children and was identified on classical cultures from
was conducted simultaneously in English and French. Various Internet search bone samples in only one. Use of PCR allowed the identification
engines were also screened for web pages with further references. The title and of the causative microorganism in eight of nine children. The
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Fig. 1-A Fig. 1-B

Figs. 1-A, 1-B, and 1-C A three-year-old boy with PEASAO.

Fig. 1-A Radiograph showing a radiolucent lesion in the
epiphysis of the proximal aspect of the tibia. A bone aspirate
sample tested with a K. kingae-specific real-time PCR assay
targeting the toxin-encoding rtxB gene gave a positive result.
Fig. 1-B 3D-IR (three-dimensional inversion recovery) T2-
weighted coronal FSE (fast spin echo) MRI showing that the
lytic lesion does not cross the physis. Fig. 1-C Anteropos-
terior radiograph made six months after the end of treatment
showing complete resolution of the lytic lesion without
osteonecrosis or growth disturbance.

Fig. 1-C

pathogen was thus identified in nine of the fourteen children. for a mean of 25.3 days (range, twenty-one to thirty days). No
The responsible microorganism was K. kingae in eight children infection recurrence was noted during follow-up. Neither osteo-
and methicillin-sensitive S. aureus in one. The use of PCR assays necrosis nor growth plate disturbance was observed. However, the
markedly improved our diagnostic yield, as the responsible path- duration of follow-up was less than twenty-four months for six
ogen was identified in all children treated after the introduction of children. The mean follow-up duration was 34 ± 28.1 months.
this assay.
Eight osseous lytic lesions were aspirated percutaneously, Systematic Review of the Literature
and six osseous lytic lesions required open drainage and curettage. There were 116 patients, including the fourteen in our case
Children received intravenous cefuroxime for a mean of 3.5 days series, in the systematic review. The median age of the children
(range, two to six days) after surgery, followed by oral cefuroxime with PEASAO was 46.4 months (range, ten months to fourteen
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years), and 74% were less than four years of age. One child was
TABLE I Skeletal Distribution of PEASAO* less than one year of age.
Site, N = 116 No. (%)* The presence or absence of a rectal temperature of >38°C
was the only clinical feature that could be extracted from the
Proximal femur 5 (4) review; 79% of the children with PEASAO were afebrile. When
Greater trochanter 11 (9) fever was present, the mean temperature was 38.8°C (range,
Distal femur 68 (59) 38.3°C to 40°C). Fever was associated with an 80% chance of
Proximal tibia 14 (12) obtaining positive cultures of the causative pathogen.
Distal tibia 4 (3)
More than 70% of PEASAO cases affected the femur, with
the next most common site being the tibia; 88% of PEASAO cases
Proximal fibula 1 (1)
occurred in these two bones (Table I).
Distal fibula 4 (3) The prevalence of abnormal WBC, ESR, and CRP values is
Proximal humerus 3 (3) summarized in Table II. It was not possible to determine mean
Distal humerus 2 (2) values for these parameters, as some studies only reported
Proximal ulna 2 (2) whether values were normal or abnormal, whether values were
Distal radius 1 (1) increased or not, or whether leukocytosis was present or absent.
Metatarsus 1 (1) Also, various analytical techniques were used.
Seventy-two children underwent various bacteriological
*Values are calculated on the basis of articles that provided ad- studies, which failed to identify the pathogen in 47% of these
equate information. The table refers to cases in the entire litera- children. When cultures or PCR assays were positive, S. aureus
ture review, including the fourteen cases at our institution. was the most commonly isolated microorganism (in 50% of
these children), followed by K. kingae (34%). K. kingae was
the most commonly identified microorganism in children less
than four years of age (72%), whereas S. aureus was the most
common microorganism in older children (65%). Only 11%
TABLE II Inflammatory Markers*
of blood cultures were positive. When positive, blood cultures
Abnormal identified S. aureus in all (Table III; see Appendix).
Marker No. Values (%)
Discussion
WBC count 72 22
ESR
CRP
68
28
76
21
P rimary subacute epiphyseal osteomyelitis was first described
by King and Mayo in 19699, and it was thought to represent a
Brodie abscess in the epiphysis. In infants, this condition must
be differentiated from metaphyseo-epiphyseal osteomyelitis,
*Values are calculated on the basis of articles that provided ad- in which a bone infection spreads into the epiphysis through
equate information. The table refers to cases in the entire litera-
ture review, including the fourteen cases at our institution. transphyseal vessels. As the child reaches fifteen to eighteen months
of age, these vessels are usually obliterated and the physis acts as a
physical barrier to bacterial spread from the metaphysis. The
vascular architecture of the epiphysis, as described by Brookes,
Morgan, and Trueta, is similar to that of the metaphyseal circu-
TABLE III Bacteriological Results According to Age* lation and is prone to sluggish blood flow through the vascular
loops45-47. Primary infections may occur when bacteria are deliv-
Age (No.) Result No.
ered to venous sinusoids by terminal branches of the epiphyseal
0 to <4 yr, n = 51 Sterile 31 arteries, as in the metaphyseal region.
Kingella kingae 13 Two main clinical forms of PEASAO were revealed in this
Staphylococcus aureus 6 systematic literature review and differ depending on the patient
Salmonella enteritidis 1 age. The infantile form affects children from one to less than four
4 to 16 yr, n = 21 Sterile 3
years of age and represents approximately 75% of all PEASAO
cases. The second form affects children at least four years of age,
Staphylococcus aureus 13
and these children are more likely to be febrile and ill-appearing.
Streptococcus pyogenes 2
This particular distribution of PEASAO according to age is
Streptococcus pneumoniae 1
characteristic of invasive osteoarticular infection caused by
Mycobacterium tuberculosis 2
K. kingae. Since the 1980s, the reported number of K. kingae
osteoarticular infection cases has increased markedly, and several
*Values are calculated on the basis of articles that provided ad-
equate information. The table refers to cases in the entire litera- studies indicate that K. kingae is becoming a leading cause of
ture review, including the fourteen cases at our institution. bacterial osteoarticular infection in children between six and
forty-eight months of age48-54.
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The femur and tibia are more prone to PEASAO, and the of subacute osteomyelitis and is given orally for six weeks after
distal femoral epiphysis is the most common site of infection. an initial intravenous regimen for up to five days37. It is, however,
This particular anatomic distribution of PEASAO remains un- generally agreed that treatment should not be initiated until
explained. Since the largest epiphyses seem to be the most fre- proper drainage has been performed and bacteriological sam-
quently affected, it is possible that only the largest epiphyses have a ples have been obtained2,5,9,31,37.
sufficiently well developed epiphyseal vascular architecture to lead Treatment of PEASAO in children follows the same rules;
to this infection. Alternatively, because of the mild clinical course in children less than four years of age, antibiotics should be
of subacute osteomyelitis, it is possible that the smaller affected directed against K. kingae. With documented K. kingae osteo-
epiphyses often display milder symptoms that go unrecognized. myelitis, our recommended antibiotic regimen consists of oral
Laboratory data are usually noncontributory for the di- cefuroxime or ampicillin for three to four weeks. For children
agnosis of PEASAO. In fact, abnormal WBC and CRP values at least four years of age, S. aureus is the pathogen most commonly
were noted in only 22% and 21% of cases, respectively. The lack associated with PEASAO. In this case, we believe that cloxacillin
of a substantial systemic response may reflect an adequate local is the antibiotic of choice and should be given orally for four to
host response to a pathogen of low virulence, such as K. kingae. six weeks after initial intravenous administration for up to five
Osteoarticular infection caused by K. kingae is characterized by days.
a mild-to-moderate clinical and biological inflammatory re- In conclusion, our literature review highlighted a biphasic
sponse to infection. Only 10% to 33% of children with a K. kingae age distribution of PEASAO in children. The infantile form af-
osteoarticular infection have a body temperature of ‡38°C at the fects children from one to less than four years of age, and ap-
time of admission48-51,54, and most children have normal or nearly proximately 75% of all PEASAO cases in children occur in this
normal WBC as well as CRP values48-50,55. The ESR and platelet age group. The second form affects children at least four years
counts are the most sensitive markers of inflammation due to a of age and often has accompanying fever. Laboratory data are
K. kingae osteoarticular infection48,49. usually noncontributory for diagnosing PEASAO. Blood cultures
Blood cultures were negative in most children in the are negative most of the time, and approximately 50% of biopsy
present review; however, all of the blood cultures that were specimens are also sterile on classical cultures. In children less
positive identified S. aureus. Approximately 50% of biopsies than four years of age, K. kingae is the most commonly iden-
failed to isolate the causative pathogen by means of routine tified microorganism (72% in the literature review), whereas
cultures. A large majority (91%) of these sterile cultures and all S. aureus is responsible for most of the PEASAO cases in older
proven cases of PEASAO due to K. kingae occurred in children children (65%). It is appropriate to suspect that children less
less than four years of age, whereas S. aureus was responsible than four years of age with sterile bone biopsy cultures probably
for 65% of PEASAO cases in older children. The high rate of have unrecognized K. kingae osteoarticular infection. Finally,
sterile blood cultures and the frequent failure to identify the appropriate nucleic amplification assays dramatically improve
causative pathogen even in surgical biopsy specimens support the the detection rate of pathogens responsible for PEASAO, and
theory that a large proportion of these infantile-form PEASAO a real-time PCR assay specific for K. kingae should be routinely
cases are due to K. kingae. Seeding of purulent specimens onto used in young children with osteoarticular symptoms (a Grade-C
solid culture media is suboptimal for identification of K. kingae recommendation).
and returns negative results in a frustratingly high proportion of
cases48,49,56,57. Appendix
Our case series confirmed that most PEASAO cases occur A table summarizing culture results and PCR assays of
in children less than four years of age. We also demonstrated bone aspirate samples is available with the online version
that the use of organism-specific real-time PCR assays improved of this article as a data supplement at jbjs.org. n
the detection rate of the pathogen responsible for PEASAO. It
was only in cases in which PCR assays were not performed that
no pathogen was isolated. Eight of the nine children with PCR
assays had positive results for K. kingae, and the ninth had a Dimitri Ceroni, MD
positive bone culture for S. aureus. The remaining children Wilson Belaieff, MD
Abdessalam Cherkaoui, MD, PhD
without PCR assays and with negative cultures had clinical and
Pierre Lascombes, MD, PhD
biological features that were consistent with an osteoarticular Jacques Schrenzel, MD, PhD
infection caused by K. kingae. Geraldo de Coulon, MD
Primary subacute osteomyelitis in children follows a Victor Dubois-Ferrière, MD
benign course, and the recommended treatment for subacute Romain Dayer, MD
osteomyelitis with radiographic evidence of a lucent lesion or a Pediatric Orthopedic Service (D.C., W.B., P.L., G.d.C., V.D.-F., and R.D.)
nidus is currently curettage, biopsy, and culture followed by and Clinical Microbiology Laboratory,
Service of Infectious Diseases (A.C. and J.S.),
antibiotics1,37. Many authors even suggest that antibiotics alone University Hospitals of Geneva,
may be adequate and that surgery should be considered only 6 rue Willy Donzé,
for ‘‘aggressive lesions’’ as well as those that do not respond to CH-1211 Geneva 14, Switzerland.
antibiotics6,41. Cloxacillin is the drug of choice in the treatment E-mail address for D. Ceroni: dimitri.ceroni@hcuge.ch
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