Received for publication Feb 21, 1986; accepted March 31, 1986. No reprints available.
PEDIATRICS (ISSN 0031 4005). Copyright © 1986 by the
American Academy of Pediatrics.
Osteoarticular
Infections
in Children
With
Sickle
Cell Disease
George A. Syrogiannopoulos, MD, George H. McCracken, Jr, MD, and
John D. Nelson, MD
From the Department of Pediatrics, University of Texas Health Science Center at Dallas,
Dallas
ABSTRACT. Thirteen children with sickle cell disease
were identified as having 14 episodes of osteoarticular infection in a review of 27 years’ experience. There were eight episodes of osteomyelitis or osteoarthritis and six of suppurative arthritis alone. The etiologic agents in osteomyelitis or osteoarthritis were Salmonella sp in four cases, Escherichia coli in one, Enterobacter aerogenes in one, Staphylococcus aureus in one, and Haemophilus in-fluenzae type b in one. Five of the cases with infection limited to the joint were caused by Streptococcus pneu-moniae; the sixth was caused by H influenzae type b. Fever (38.3#{176}C) was present in all children and the temperature was in excess of 39#{176}Cin 62%. The mean duration of pain before admission was 4.5 days. The initial total white blood cell count ranged from 5,200 to 29,700/L (mean 19,436/ML) and the total band neutro-phil count ranged from 0 to 5,103/FL (mean 1,660/tL). The ESR was greater than 20 mm/h in eight of the ten patients who were tested. Management consisted of an-tibiotic therapy in all. Needle aspiration was performed
in two patients with osteomyelitis and in three with suppurative arthritis. Incision and drainage was per-formed in two cases of osteomyelitis and in four with suppurative arthritis. The outcome was satisfactory in all except one patient who had several complicatiops as a consequence of femoral neck osteomyelitis. Recurrence was reported in only one patient. Pediatrics 1986;78: 1090-1096; osteoarticukzr infection, sickle cell disease, os-teomyelitis, suppurative arthritis.
tions in patients with sickle cell disease with regard to the etiologic agents, clinical presentation, labo-ratory findings, and differential diagnosis from noninfectious processes, in an attempt to provide recommendations for medical management.
PATIENTS AND METHODS
We reviewed retrospectively the medical records of all children with major sickle
hemoglobinopa-thies (Hb 55 and Hb SC), discharged from
Park-land Memorial Hospital and Children’s Medical
Center, Dallas, with the diagnosis of osteomyelitis, suppurative arthritis, or both during the 27-year period from January 1959 through December 1985. The records of all children with sickle cell disease followed since 1977 in the hematology clinic of Children’s Medical Center were also reviewed for episodes of bone and joint infections for which they were hospitalized in other area hospitals.
The records of patients who were treated for a presumptive diagnosis of bone or joint infection but in whom the diagnosis was not confirmed bacteri-ologically were not analyzed. Also, patients with bacteremia but without strong clinical evidence of bone or joint involvement were excluded.
RESULTS Bone and joint infections in patients with sickle
cell disease are caused by a spectrum of uncommon pathogens.7 Furthermore, osteomyelitis repre-sents a diagnostic challenge because differentiation from bone infarction is difficult8’9 and the criteria for diagnosis remain controversial.
We reviewed our cases of osteoarticular
infec-Patient Characteristics
We identified 13 children with 14 episodes of osteoarticular infections during the 27-year period. Eight children had osteomyelitis and in two of them the contiguous joint was also involved. Five chil-dren had six episodes of suppurative arthritis with-out bone involvement.
The patients ranged in age from 1 1 months to
13/12 years (mean 5 years, median 4 years) (Tables
con-TABLE 1. Clinical and Laboratory Characteristics of Children With Sickle Cell Disease and Osteomyelitis or
Osteoarthritis
Patient No./Yr/ Anatomic Site Blood Culture Finding Bone#{176}or Joint Fluidb Total WBC
Age/Race/Sex Aspirate Culture
Finding
Count/Band Neutrophil Count (No./iL)
1/1959/2 yr/B/M Humerus Escherichia coli Not done 25,100/1,004
2/1961/4 yr/B/M Metacarpal No growth Salmonella enteritidis4 26,000/780
3/1966/6 yr/B/M Humerus, elbow No growth Enterobacter aerogenes” 14,400/0
4/1974/8 yr/B/F Humerus Salmonella group C1 Salmonella group C1#{176} 5,200/884
5/1980/19 mo/B/F Thumb Haemophilus influenzae
type b
No growth#{176} 22,500/2,025
6/1982/13 yr/B/M Femur Staphylococcus aureus S aureus4 13,600/544
7/1983/4 yr/B/F Pelvis, hip No growth Salmonella group Bb 29,700/4,158
8/1984/22 mo/B/M Radius, humerus Salmonella heidelberg No growth#{176} 22,500/4,950
TABLE 2. Clinical a nd Laboratory Characteristics of Children With Sickle Cell Disease and Sup purative Arthritis
Patient No./Yr/ Age/Race/Sex
Anatomic Site Blood Culture Finding Joint Fluid Aspirate
Culture Finding
Total WBC Count/Band
Neu-trophil Count
(No./tL)
1/1963/21 mo/B/M 1/1965/4 yr/B/M 2/1963/7 yr/B/F 3/1966/14 mo/B/M 4/1976/11 mo/B/F
5/1976/13/12 yr/B/F
Hip, ankle Ankle Hip Ankle Ankle Knee
Streptococcus pneumoniae S pneumoniae
S pneumoniae No growth No growth No growth
S pneumoniae No growth No growth S pneumoniae
Haemophilus influenzae type b Gram stain: Gram-positive
di-plococci
28,700/2,009 11,700/585 24,300/5,103 14,300/0 17,100/1,197 17,000/0
firmed by hemoglobin electrophoresis; 1 1 patients had homozygous sickle cell disease and two had SC disease. There was no patient with sickle 3-thalas-semia and osteoarticular infection.
Manifestations
On admission to the hospital, all of the children were febrile with body temperatures of from 38.3#{176} to 40.6#{176}C(mean of 39.4#{176}C,median 39.2#{176}C).
Local swelling was present in ten of 14 episodes. The duration of pain ranged from one to 14 days before admission (mean 4.5 days). Range of joint movement was decreased in all patients with ar-thritis.
There was a history of recent trauma to the infected area in two patients with arthritis.
Laboratory Findings
The initial peripheral blood leukocyte count ranged from 5,200 to 29,700/xL (mean 19,436/jL). The absolute segmented neutrophil counts ranged-from 1,976 to 23,247/L (mean 11,1344tL), and the absolute band neutrophil counts were from 0 to
5103/tL (mean 1,660/L). The ESR was elevated
in eight of the ten patients who were tested. In all eight patients with osteoarthritis or suppurative arthritis alone, purulent material was aspirated from the joint, and the joint fluid cultures yielded
an organism in five of them and in one case Gram-positive diplococci were seen on Gram stain.
Two patients with osteomyelitis had normal roentgenographic findings on admission and three
had evidence of soft tissue swelling. In one case,
there were lytic areas in bone present on admission, but the onset of illness ws 2 weeks before the patient
was admitted. Follow-up radiographs showed lytic
areas in five patients, with concomitant periosteal elevation in one of them and new bone formation
in another. The remaining three patients had new
bone formation with concomitant periosteal
eleva-tion in one.
In one case of suppurative arthritis the radio-graphic findings were normal, and in four a joint
effusion was seen, with concomitant soft tissue
swelling in two of them. The remaining patient had only soft tissue swelling.
Five patients were subjected to technetium
bone-imaging studies. Increased uptake was found in all three patients with osteomyelitis. One of the two patients with suppurative arthritis had increased
uptake in the area of the affected joint. In the
second case that involved a suppurative knee, in-creased uptake was present at the middle of the tibia, which, based on the history and the clinical
presentation, was thought to represent a previous bone infarction.
Course
Bacteria Sickle Cell Disease Without Sickle Cell Disease
Osteomyelitis Arthritis Osteomyelitist Arthritist
Staphylococcus aureus 1 (12.5) 0 179 (53.8) 97 (16.5) Haemophilus influenzae type b 1 (12.5) 1 (17) 14 (4.2) 148 (25.2)
Streptococcuspneumoniae 0 5 (83) 6 (1.8) 15 (2.5)
Salmonella sp 4 (50) 0 2 (0.6) 4 (0.7)
Enterobacter sp 1 (12.5) 0 0 8 (1.4)
Escherichia coli 1 (12.5) 0 0 3 (0.5)
Others 0 0 132 (39.6) 313 (53.2) II
* Results are numbers (percentage) of total cases.
t Experience at Children’s Medical Center and Parkland Memorial Hospital, 1959 to 1984. :1:Children’s Medical Center and Parkland Memorial Hospital, 1955 to 1984.
§In 76 of the 132 cases the microbial etiology was not identified. IIIn 201 ot the 313 cases the microbial etiology was not identified. from 11 to 28 days (mean 23 days) in patients with
infection limited to the joint.
Patients with Salmonella or Haemophilus
influ-enzae osteomyelitis were treated with chloram-phenicol or ampicillin, and those with coliform infection were given aminoglycoside or chloram-phenicol. The patient with Staphylococcus aureus
osteomyelitis received an antistaphylococcal
peni-cillin, and all patients with Streptococcus pneumo-niae arthritis were treated with penicillin. Three
patients were treated with meperidine
hydrochlo-ride or morphine for relief of pain.
Surgical procedures included needle aspiration of
pus in two patients with osteomyelitis and in three
with suppurative arthritis. Incision and drainage
was performed in three patients with osteomyelitis and in three with suppurative arthritis. Hip arthro-desis was required for a patient in whom avascular
necrosis of the femoral head developed as a
conse-quence of femoral neck osteomyelitis. This patient
had an initial incision and drainage soon after he
was hospitalized, but at that time he had a 2-week
history of illness. The same patient required the
placement of a spica cast, because he had a
patho-logic fracture through the proximal metaphysis of
the femur, possibly extending to the epiphyseal
plate. Cast for immobilization was also used in
another patient with osteomyelitis and in one with suppurative arthritis. Physical therapy was applied
in four patients.
The duration of hospitalization was longer for
patients with bone involvement and ranged from
23 to 74 days (mean 38 days), whereas in patients
with infection limited to the joint, it was from 11
to 26 days (mean 19 days).
The outcome was satisfactory in all except the
patient with avascular necrosis of the femoral head, pathologic fracture in the femoral neck, and a neu-ropraxic injury of the femoral nerve probably
fol-lowing surgery. Follow-up was available for 12 of
TABLE 3. Frequency of Various Bacteria
Disease*
the 13 patients (mean 8.2 years, range 53 days to
26.5 years). Recurrence was reported in only one
patient.
DISCUSSION
The increased risk of serious bacterial infections in patients with major sickle cell
hemoglobinopa-thies is well known.’ Overwhelming sepsis with or
without meningitis, usually caused by S
pneumo-niae, is the most serious infection.’#{176}’2 In our ex-perience, osteomyelitis and/or suppurative arthritis is uncommon.
In 1977, a special clinic for sicklemic patients was established at Children’s Medical Center. Since
then, 315 patients with 55 and SC disease have
been continuously or intermittently followed in
that clinic. Only eight of 315 (2.5%) had a
docu-mented episode of osteoarticular infection.
Barrett-Connor’ reported that, among 166 patients with
sickle cell anemia hospitalized at least once during
an 11-year period, there was strong evidence of
osteomyelitis in nine patients (5.4%), eight with
positive cultures and one with sterile pus.
When osteomyelitis occurs, Salmonella is the
most commonly reported pathogen,3”’6 although
its exact frequency varies depending on epidemio-logic factors of the geographical area. Susceptibility to Salmonella infections is characteristic for pa-tients with sickle cell disease, not only during
child-hood but throughout their life.’7 Salmonella
Os-teoarticular infections in children without sickle
cell disease are rare (Table 3). Salmonella bone
infection in patients with sickle cell anemia was
initially reported in 1925,18 but the association
be-tween those two diseases was first recognized in
1951.’#{176}Although several factors underly the in-creased susceptibility to bacterial infection,20 the
impaired function of macrophages has been
pro-posed to be the principal mechanism that leads to
increased susceptibility to Salmonelkz.2’ Normally,
invasion by Salmonella is controlled by
macro-phages of the reticuloendothelial system. It is
sug-gested that in patients with sickle cell disease
phag-ocytosis by macrophages of the breakdown products
of RBCs reduces the capacity of these cells to ingest and kill Salmonella.22 Using a model of
experimen-tal hemolysis in mice, Kaye and Hook23 found
in-creased susceptibility to Salmonelki, Escherichia
coli, and S aureus.
In addition to Salmonella sp, other members of the family Enterobacteriaceae were encountered as etiologic agents of osteomyelitis in our series.
An-zona kinshawii, Edwandsiella tanda, E coli, and Shi-gella sonnei have been reported in the literature as causing osteomyelitis in patients with sickle cell disease.”2’46’24 Barrett-Connor3 reported two sick-lemic patients in whom suppurative arthritis
devel-oped as a result of Entenobacten-Kiebsiella sp follow-ing bacteremia secondary to urinary tract manipu-lation.
The majority of the studies on osteoarticular
infections in the sicklemic population are focused
on the etiologic agents of osteomyelitis, providing relatively little information about the organisms causing infection limited to the joint. When only suppurative arthritis was present, S pneumoniae was the etiologic agent in all but one of our cases.
Bone and joint manifestations of noninfectious
etiology are frequent in children with sickle cell
anemia. The great majority of those episodes rep-resent acute vasoocclusive crises,8 caused by infarc-tion of bone marrow, bony cortex, or synovium.25’26
The typical presentation is pain in one or more locations. If fever occurs, it is usually low grade.
Physical findings can be present but usually are not prominent. Local swelling is the most common, and the involved areas can be tender, warm, and ery-thematous.27’28 If the infarctions occur in long bones, the clinical presentation tends to be more severe9. If a joint effusion occurs, most commonly in the knees and elbows,27 the aspirated fluid is straw colored and usually of a “noninflammatory” character.25 Sterile purulent exudates have also been reported.28
Patients with fever, well-localized physical signs, and leukocytosis represent a challenge for the phy-sician, because the differentiation between bone infarction and osteomyelitis can be difficult. High fever is less common in patients with bone
infarc-tion, but it can occur. In two series of acute bone infarction,9’29 21% of the episodes were character-ized by body temperatures greater than 39#{176}C,and in our patients with bone and/or joint infections,
the percentage was 62% (Table 4).
Rao
et al29reported that 75% of patients with sickle cell
dis-ease and osteomyelitis had body temperatures
greater than 39#{176}C,and in another series,’6 only 58% of sicklemic patients with osteoarticular infections had similar temperature elevations. Patients with
bone infarctions usually become afebrile within a
few days.9
Toxic appearance is considered to be attributed to an infectious process, although a few patients with acute long bone infarctions were so described.9 Local physical findings appear to be common in
TABLE 4. Clinical and Labora Long Bone Infarction (Keeley
tory Findings in Pa and Buchanan9)
tients With Sickle Cell Disease: Acute Versus Osteoarticular Infection (Our Experience)
Finding Acute Long Bone
Infarction9
Long Bone All Osteoarticular
Osteomyelitis Infections
No. ofepisodes 41 5 14
Age
Range 9 mo-18 yr 22 mo-13 yr 11 mo-134/12 yr
Mean 7yr Gyr Syr
Duration of pain before ad-mission (d)
Range 1-30 3-14 1-14
Mean 4.3 6.4 4.5
% of patients with fever
>39#{176}Con admission 21 40 62
Total WBC count (No./jsL)
Range 7,200-43,500 5,200-25,100 5,200-29,700
Median 16,800 14,400 19,800
Total band neutrophil count (No./L)
Range 0-2,940 0-4,950 0-5,103
Median 155 884 944
ESR (mm/h)
Range 3-66 2-55 1-89
both of the clinical entities,8 although they are more prominent in osteomyelitis. Involvement of multi-ple sites makes the diagnosis of bone infarction more likely.8
A finding of leukocytosis is not helpful in the differential diagnosis, because it is common in both clinical entities.8’3#{176}A finding of an absolute band neutrophil count greater than 500/tL may be useful in the differential diagnosis.31 This criterion was fulfilled in all but one of our patients with osteo-myelitis, whereas it was present in only one fourth of the reported patients with long bone infarctions.9 Half of our cases had an absolute band neutrophil count of greater than 1,000/tL, a finding that may be more suggestive of active infection in these pa-tients.8’3#{176}In a series’6 of osteoarticular infections in children with sickle cell disease, the absolute band
neutrophil count was greater than 500/FL in 64%,
whereas counts greater than 1,000/tL were ob-served in only 45%. An elevated ESR (>20 mm/h) is suggestive of osteomyelitis, although the ESR is also elevated in some children with bone infarc-tion.9 In one series of patients with osteoarticular
infection, the ESR was greater than 20 mm/h in
82%.16 It can be valuable to repeat the test for ESR, especially if the first value is within normal limits and there is clinical evidence of persisting osteoar-ticular inflammation.
Blood for cultures should be drawn when infec-tion is suspected. Stool culture might also be helpful to look for the presence of Salmonella sp in the gut. A positive blood culture favors the diagnosis of osteomyelitis. Sometimes, an initial diagnosis of septicemia with sickle cell crisis is made,’7 but this can be an early stage in the natural history of
osteomyelitis when hypoxic areas of bone are
seeded by the circulating bacteria.32
If the cultures are negative and the children have received antibiotics before admission, latex agglu-tination testing for S pneumoniae and H influenzae
type b antigen in the urine and in the joint fluid may be helpful.
Early roentgenographic findings of involved areas are usually normal or show only soft tissue swelling. After ten to 14 days, periosteal and bony destruction are usually present.33’34 These are
fea-tures common to both osteomyelitis’6 and bone
infarction.35
Radionuclide bone-imaging studies, common
tools used in the diagnosis of osteomyelitis, are not helpful in distinguishing osteomyelitis from bone infarction in patients with sickle cell disease. Tech-netium pyrophosphate and gallium citrate
scintig-raphy shows increased uptake in the majority of
the patients with osteomyelitis,33’36 but this is also common in many patients with bone infarction.9’26
Technetium-99m sulfur colloid appears to be the
most promising radioisotope at present. This is
selectively cleared from the circulation by the retic-uloendothelial system and allows for localization of those reticuloendothelial system cells residing within the bone marrow.37 With this radionuclide scan, there is decreased or absent uptake in the area of acute bone infarction.3841 In a recently published study,29 16 patients with bone infarction were examined with bone marrow scan. Uptake was markedly decreased or absent in 15, whereas five of six patients with osteomyelitis and sickle
hemoglo-binopathy had an interpretable bone marrow scan, which was normal. Although bone marrow scanning appears to be promising, a larger experience is required.
RECOMMENDED MANAGEMENT
There are two groups of sicklemic patients who
present with bone pain. In the first, the clinical and laboratory findings favor the diagnosis of a painful bone crisis: normal body temperature or low-grade fever, multiple sites of pain, mild or absent local physical findings, without significant leukocytosis or elevated absolute band neutrophil count, and an ESR less than 20 mm/h. This presentation
repre-sents the majority of the cases. Blood and stool
cultures should be obtained and the children
ob-served closely. Supportive treatment is appropriate.
Remission of symptoms after a few days without
antibiotic therapy supports the final diagnosis of bone infarction.
In the second group, there is a strong possibility for an osteoarticular infection. In one instance, osteomyelitis is strongly suspected on the basis of
such findings as high fever, toxic appearance, marked local findings with point tenderness, signif-icant leukocytosis with a band neutrophils count of
greater than 500/L or ESR greater than 20 mm!
h. An extensive workup is required to confirm the clinical diagnosis of infection. Technetium radio-nuclide marrow scanning could be performed with
or without a concomitant bone scan. If the bone
marrow scan shows normal uptake, a bone aspira-tion (open or closed) should be performed to con-firm the diagnosis. Until the results of cultures and susceptibility studies are available, the
antimicro-bial regimen chosen for initial therapy should be broad enough to treat the likely etiologic agents including S auneus, S pneumoniae and Enterobac-teriaceae. One possible regimen would be an anti-staphylococcal penicillin such as nafcillin and
agglutination reactions are negative, continuation
of antibiotic therapy depends on the patient’s con-dition and results of other laboratory tests. The duration of antibiotic therapy depends on the pa-tient’s clinical response, the etiologic agent,
roent-genographic findings, and return of the ESR to 20
mm/h or less. If the organism is Salmonella, coli-form bacilli, or S auneus, treatment is usually for a
minimum of 3 weeks, and for streptococci and H
influenzae type b a minimum of ten to 14 days is usually required. Surgical drainage and debridment are sometimes required. Orally administered anti-biotics in large dosages can be used after clinical
improvement is noted. The oral regimen has been
extensively described elsewhere.33
If the clinical presentation is compatible with
suppurative arthritis, a joint aspiration should be promptly performed. A full cytologic and chemical analysis of the synovial fluid is performed.
Micro-biologic studies of the specimen include a Gram-stained smear, cultures, and latex agglutination. When the initial results favor the diagnosis of an infectious process, parenterally administered
anti-biotics should be started. When the stained smear is uninterpretable or no microorganisms are seen, the antimicrobial agents have to be selected empir-ically. Treatment for S pneumoniae, Salmonella,
and S auneus is required for all patients and for H influenzae type b (lactamase-producing stains in-cluded) in children younger than 5 years of age. A combination of antistaphylococcal penicillin with
chloramphenicol or a third generation
cephalospo-rin (such as cefotaxime or ceftriaxone) would be
appropriate initially. The duration of treatment is
similar to that required for osteomyelitis. Some patients require repeated joint aspirations. For hip joint infection, open surgical drainage is required; this is often the case for shoulder and elbow joint infections as well.
CONCLUSION
Osteoarticular infections in children with sickle
cell disease are not frequent. Salmonella sp and
other Gram-negative Enterobacteriaceae are the
principal pathogens in osteomyelitis or
osteoarthri-tis, whereas S pneumoniae commonly causes
ar-thritis. Although there is no hallmark for the dif-ferential diagnosis from aseptic bone infarction, high fever, especially prolonged over five days, toxic appearance, marked local findings, absolute band neutrophil count greater than 500/zL, ESR greater than 20 mm/h, positive cultures, and normal bone marrow scan findings are suggestive of
osteoarti-cular infection. Medical management usually
con-sists of needle aspiration or surgical incision, for
diagnosis and drainage, and antimicrobial therapy,
chosen on the basis of results of stained smears and cultures of aspirated material.
ADDENDUM
Since acceptance of this manuscript a patient, who was hospitalized in December 1974 for osteomyelitis of the left humerus (patient 4 in Table 1), was readmitted for osteomyelitis of the same bone. During the initial hospitalization a bone aspirate culture revealed Salmo-nella group C,. It appears that speciation was not per-formed at that time. Susceptibility testing demonstrated a minimal bactericidal concentration for ampicillin of 1.25 g/mL, and a minimal inhibitory concentration for chloramphenicol of 5 tg/mL. She was treated with par-enterally administered antibiotics for 4 weeks. No sur-gical procedure was done. Radiographs taken before the patient was discharged showed extensive changes of os-teomyelitis extending throughout the entire left humerus. Subsequent roentgenograms were not done. In May 1986 the patient was readmitted with osteomyelitis ofthe same bone. Bone aspirate culture again revealed Salmonella group C,, which was serotyped as Salmonella oranienburg.
The minimal inhibitory concentration of the isolated organism was 0.3 tg/mL for ampicillin and 7 g/mL for chloramphenicol. The patient underwent extensive surgical sequestrectomy and curettage and was treated with ampicillin. Although the serotype of the strain that was isolated during the first hospitalization is not avail-able, there is a strong possibility that the second episode represents an unusual case of relapse of osteomyelitis, 1 1#{189}years after the primary infection.
ACKNOWLEDGMENT
We thank Susan J. Smith, PNP, for providing data from the records of the special hematologic clinic for sicklemic chidren at Children’s Medical Center.
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