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European Review for Medical and Pharmacological Sciences 2019; 23(2 Suppl.): 145-158 Acute and septic in children: a systematic review of systematic reviews

A. GIGANTE1, V. COPPA2, M. MARINELLI3, N. GIAMPAOLINI3, D. FALCIONI3, N. SPECCHIA3

1Orthopaedics and Traumatology, Polytechnic University of Marche, Ancona, Italy 2Clinical Orthopaedics, Department of Clinical and Molecular Sciences, School of Medicine, Università Politecnica delle Marche, Ancona, Italy 3Clinic of Adult and Paediatric Orthopaedics, Azienda Ospedaliero-Universitaria, Ospedali Riuniti di Ancona, Ancona, Italy

Abstract. – OBJECTIVE: Septic arthritis and Osteomyelitis (OM) is an of osteomyelitis are rare in children, but they are , usually due to with or difficult to treat and are associated with a high other micro-organisms (e.g., fungi), that is asso- rate of sequelae. This paper addresses the main ciated with bone destruction. Septic arthritis (SA) clinical issues related to septic arthritis and os- teomyelitis by means of a systematic review of is an infection of the synovial space that involves systematic reviews. the synovial membrane, the space, and joint 2 MATERIALS AND METHODS: The major elec- structures . tronic databases were searched for systematic SA and OM are commonly divided into three reviews/meta-analyses septic arthritis and os- types based on aetiology: haematogenous, sec- teomyelitis. The papers that fulfilled the inclu- ondary to contiguous infection, and secondary sion/exclusion criteria were selected. to direct inoculation. The distinctive anatomical RESULTS: There were four systematic re- views on septic arthritis and four on osteomy- characteristics of younger children, especial- elitis. Independent assessment of their meth- ly the presence of vessels between metaphysis odological quality by two reviewers using and epiphysis and of intracapsular metaphyses, AMSTAR 2 indicated that its criteria were not involve that a bone infection may lead to SA sec- consistently followed. ondary to OM and vice versa2. Unless an effec- CONCLUSIONS: Collectively, these works tive treatment is promptly initiated, the intense provide strong evidence regarding a large num- ber of issues including classification, epidemiol- inflammatory reaction that is often associat- ogy and risk factors, causative organisms, clin- ed with SA or OM has the potential to destroy 3 ical presentation, laboratory markers, imaging, structures such as the articular cartilage and the diagnostic needle aspiration, therapy, epiphyseal growth plate, resulting in long-term surgical therapy, and prognosis. A clinical sum- disability due to functional impairment of the mary based on the best evidence is supplied. joint or to limb asymmetry2. Since timely diag- nosis is vital for a satisfactory outcome, SA and Key Words: OM must be ruled out in any child presenting Osteomyelitis, Septic arthritis, Children. with a painful limb or joint or with a of unknown origin4. The main issues related to SA and OM are classification, epidemiology and risk factors, Introduction causative organisms, clinical presentation, lab- oratory markers, imaging, diagnostic needle Osteoarticular are complex con- aspiration, antibiotic therapy, surgical therapy, ditions, especially in paediatric patients, which and prognosis1,3,5,6. unless treated promptly and correctly can result The aim of this systematic review of systematic in limb impairment or in life-threatening con- reviews is to identify the best available evidence re- ditions1. garding the management of paediatric SA and OM.

Corresponding Author: Antonio Gigante, MD; e-mail: [email protected] 145 A. Gigante, V. Coppa, M. Marinelli, N. Giampaolini, D. Falcioni, N. Specchia

Materials and Methods Septic Arthritis (Table III)

Literature Search Strategy Classification A search of the Medline (via Pubmed), Emba- None of the SRs included in the study exami- se, Amed, and CISCOM electronic databases was ned SA classification. performed for works published from 1 January 2000 to 31 October 2017. The search terms used were: septic arthritis, osteomyelitis, children, cli- Epidemiology and Risk Factors nical trial, meta-analysis, and systematic review. Two of the SRs addressed SA epidemiology The reference lists of all the papers thus identified and risk factors. were examined for further relevant references. No Kang et al5 reported an incidence of 1 in language restrictions were applied. 100,000 in industrialized countries and a higher incidence in developing countries (1 in 20,000 Study Selection in Africa and 1 in 5000 in Malawi). These data Only systematic reviews and meta-analyses of were confirmed by Rutz et al3. The two SRs studies involving paediatric patients were included. agreed on the fact that SA affects more frequent- Non-systematic reviews, overviews, clinical trials, ly young male children (infants and toddlers and reviews of non-clinical investigations were being involved most frequently) and children excluded. The most common reasons for exclusion with respiratory distress syndrome, an umbilical were the facts that a review was not systematic or artery catheter, and conditions associated with that it did not include paediatric populations. Study heightened susceptibility to infection (e.g., pre- selection was performed separately by each author. maturity, low birthweight, sickle-cell haemoglo- The following clinical information on SA and OM binopathy, and small size for age). was extracted from the papers: classification, epi- demiology and risk factors, causative organisms, Causative Organisms clinical presentation, laboratory markers, imaging, According to both SRs3,5 au- diagnostic needle aspiration, antibiotic therapy, reus is the most frequent causative of surgical therapy, and prognosis. SA, followed by group A Streptococci (GAS) The methodological quality of the systematic and Enterobacter spp. An emerging problem ac- reviews that were included in the study was as- cording to both SRs is the increasing incidence sessed independently by two reviewers using the of infections caused by methicillin-resistant S. AMSTAR 2 tool7. aureus (MRSA), also in patients who are not at significant risk of MRSA. These community-as- Evidence Synthesis sociated (CA) MRSA strains exhibit lower an- A meta-analysis of systematic reviews is com- tibiotic resistance than hospital-acquired (HA) plex, especially due to overlaps, since some of the strains. primary studies may be included in more than one The incidence of arthritis due to Haemophilus review. To address the problem, a qualitative evi- influenzae, a highly common paediatric patho- dence synthesis was provided for each of the key gen in the past, is declining due to vaccination topics listed above. programmes, whereas is increas- ingly being isolated, probably due to the greater accuracy of current diagnostic tools. Results According to Taj-Aldeen et al8, the most com- mon fungal osteoarticular infections are due to The search identified a total number of 97 pa- Aspergillus and Candida spp, whereas hyalohy- pers on SA and 224 on OM. After evaluation of phomycetes, dematiaceous moulds, and Mucor- the abstracts, the full text of 37 publications on ales are the non-Aspergillus filamentous fungi SA and 53 on OM were examined; of these, 9 sy- isolated most frequently. The main aetiology of stematic reviews (SRs), 5 on SA and 4 on OM, fungal arthritis is direct inoculation, followed were included. Only one SR from each set discus- by haematogenous dissemination and contigu- sed all the topics addressed in this work, whereas ous spread. In immunocompetent patients, the the others focused on specific issues. most common mechanism of infection is road The methodological quality of most SRs was accidents involving knee puncture or penetrat- low to moderate (Tables I and II). ing wounds.

146 Table I. AMSTAR synopsis (modified from Cargnelli et al 2017).

Status Conflict A prior Two Literature of List of Study Scientific Combining Publications of Study design reviewers search publication studies characteristics quality Conclusions findings bias interest

Septic Kang et al. 2009 NO CANNOT ANSWER YES YES NO NO YES YES YES NOT YES APPLICABLE Arthritis Rutz et al. 2013 NO CANNOT ANSWER NO YES NO NO NO CANNOT CANNOT NO YES ANSWER ANSWER Farrow et al. 2015 NO NO YES YES YES YES YES YES YES YES YES Taj-Aldeen et al. 2015 NO CANNOT ANSWER YES YES NO NO NO YES YES YES YES Table I. YES YES YES YES YES YES YES YES YES NO YES Zhao et al. 2017 YES YES YES NO YES YES YES YES YES YES YES

Osteomyelitis Hotchen et al. 2017 YES CANNOT ANSWER YES YES YES YES NO YES YES NO YES Dartnell et al. 2012 NO YES YES YES NO NO NO YES YES NO YES Howard-Jones et al. 2013NO CANNOT ANSWER YES YES YES YES YES YES YES NO YES Taj-Aldeen et al. 2015 NO CANNOT ANSWER YES YES NO NO NO YES YES YES YES Gill et al. 2017 NO CANNOT ANSWER NO YES NO NO NO YES YES NO YES Mooney et al. 2016 NO CANNOT ANSWER YES YES YES YES NO YES YES NO yes; no; cannot answer; not applicable

147 Table I. AMSTAR synopsis (modified from Cargnelli et al 2017). A prior Selection Literature Selection in Extraction Excluded Study PICO design criteria search duplicate in duplicate studies

Septic arthritis Kang et al. 2009 Yes No No No Partial yes No No No Rutz et al. 2013 No No No No No No No Farrow 2015 Yes No Yes Partial yes No No No Taj-Aldeen et al. 2015 No No No Partial yes No No No De Sa et al. 2015 No Partial yes No Partial yes Yes Yes No Zhao et al. 2017 Yes Partial yes Yes P Yes Yes No Osteomyelitis Hotchen et al. 2017 No Yes No Partial yes Yes No No No Dartnell et al. 2012 No No No Partial yes Yes Yes No No Howard-Jones et al. 2013 No No No Partial yes Yes No No No Taj-Aldeen et al 2015 No No No Partial yes Yes No No No Gill et al 2017 No No No Partial yes Yes No No No Mooney et al. 2016 No No No Partial yes Yes No No No

Statistical Study Risk of Sourches combination ROB in ROB in Heterogeneity Publications Conflict of detail bias of funding method meta-analysis results expl bias interest

Septic arthritis No Partial yes no No No meta-analysis No meta-analysis Yes Yes No meta-analysis Yes Conducted Conducted conducted No No No No meta-analysis No meta-analysis No No No meta-analysis Yes Conducted Conducted conducted Yes Yes No Yes Yes Yes Yes Yes Yes No No No No meta-analysis No meta-analysis Yes Yes No meta-analysis Yes Conducted conducted conducted Yes No No No meta-analysis No meta-analysis Yes Yes No meta-analysis Yes Conducted conducted conducted Yes Yes No Yes Yes Yes Yes Yes Yes Osteomyelitis Yes No No No meta-analysis No meta-analysis Yes Yes No meta-analysis Yes Conducted conducted conducted No No No No meta-analysis No meta-analysis Yes Yes No meta-analysis Yes Conducted conducted conducted Yes No No No meta-analysis No meta-analysis Yes Yes No meta-analysis Yes Conducted conducted conducted No No No No meta-analysis No meta-analysis Yes yes No meta-analysis Yes Conducted conducted conducted No No No No meta-analysis No meta-analysis No yes No meta-analysis Yes Conducted conducted conducted No No No No meta-analysis No meta-analysis Yes yes No meta-analysis No Conducted conducted conducted yes; no; cannot answer; not applicable

148 Acute osteomyelitis and septic arthritis in children: a systematic review of systematic reviews

Table III. Classification Not mentioned in the SRs included in the study

Epidemiology 1/100,000 in industrialized countries; 1/20,000 to 1/5000 in developing countries

Risk factors Young age (neonates and toddlers); invasive catheterization; host status (all -associated conditions)

Causative organisms S. aureus is the most common agent. The incidence of MSSA, MRSA, GAS, group B streptococci, and Enterobacter spp is rising. H. influenzae in non-vaccinated children, K. kingae in younger children

Clinical presentation Age-related. Neonates: pseudoparalysis, paradoxical irritability. Infants and toddlers: refusal to bear weight. Older children: pain, ROM loss, antalgic position

Laboratory markers WBCs: age-related (higher values in older children); their threshold in association with other parameters is > 12 x 109/L. CRP: high predictive value, threshold > 20 mg/L. ESR: useful when SA is suspected (threshold, 40 mm/h). PCT: high diagnostic value (threshold, 0.5 ng/mL)

Imaging US: useful to detect and monitor . X-rays: mandatory to exclude other conditions. MRI: highly sensitive and specific

Microbiological Joint aspiration: Mandatory when SA is suspected. A and a WBC count investigations (threshold > 50,000 with > 75% of polymorphonuclear leukocytes) should be performed to confirm the diagnosis. Synovial culture is required to confirm diagnosis and target therapy, but is positive in 34 to 82% cases. If no is fluid obtained, injection of 3-5 mL sterile saline solution and reaspiration is recommended. : should always obtained

Antibiotic therapy Empirical antibiotic should be started immediately and targeted treatment should be administered as soon as the causative micro-organism is isolated; short IV course (2-4 days) followed by oral antibiotic (6 weeks) in case of non-complicated SA

Surgical therapy Should be adopted in case of frankly purulent fluid on diagnostic aspiration, absence of response to , late presentation (> 5 days from symptom onset)

Clinical Presentation markers besides hyperpyrexia are required to rule According to the three SRs mentioned above3,5,8, out SA. clinical presentation varies depending on patient Late presentation is associated with systemic age and causative organism. manifestations and oedema involving the entire In neonates and infants, the clinical presentation lower limb, , or formation. may be barely appreciable or completely absent. As regards joint infections related to fungi, In the early stage, symptoms are non-specific and Taj-Aldeen8 reported that fever alone is not suffi- may include irritability, refusal to walk, absent or cient to exclude SA and that the most characteris- limited spontaneous movement of the limb (pseu- tic findings are local pain and inflammation. doparalysis), and/or paradoxical irritability. In old- er children, the most common findings are local Laboratory Markers , especially at the onset. Clini- count. According to Kang et cal findings typically include a swollen and painful al5, the white blood cell (WBC) response is age-re- joint associated with the typical signs of inflam- lated: leukocytes are rarely elevated in newborns mation (pain, effusion, functional impairment, with SA, they may be raised in younger children, tenderness, and local warmth). In SA involving the and are commonly elevated in older children, al- , the limb is often held in an antalgic position though the authors do not report a threshold val- (slightly flexed, externally rotated, and abducted) ue. Rutz et al3 described 6 studies where the WBC to reduce intracapsular pressure. Loss of passive threshold, associated with other parameters suspi- ROM is often an early symptom, at least in hip SA3. cious for SA, was > 12 x 103/L. As regards fever, Kang et al5 stressed that other Erythrocyte sedimentation rate. According clinical signs, imaging studies, and inflammatory to Kang et al5, the erythrocyte sedimentation rate

149 A. Gigante, V. Coppa, M. Marinelli, N. Giampaolini, D. Falcioni, N. Specchia

Table IV. Summary Key Points

Classification Several classifications have been described. Those for clinical use should include bone involvement, antimicrobial resistance patterns of the causative micro-organisms, host status, and soft-tissue coverage

Epidemiology From 1.94 to 13 new cases in 100,000 in developed countries rising to 43 in 100,000 in Polynesia and to 200 in 100,000 among Aboriginal populations

Risk factors Systemic infection; penetrating trauma; SCD. Risk factor are not found in nearly 50% of cases Causative organisms S. aureus is the most common pathogen, but the incidence of MRSA is rising. H. influenzae must be suspected in non-immunized children. K. kingae is becoming one of the most common Gram-negative causative and must be suspected in younger children

Clinical presentation Local signs and symptoms are the most common clinical elements; 40% of children can be afebrile

Laboratory markers WBCs: elevated values may indicate a severe form of OM. ESR: > 55 mm/h is highly suspicious for abscess formation, whereas a value < 22 mm/h seems to rule out SA. CRP: > 100 mg/L values seem to be indicative of associated arthritis and of the need for longer IV antibiotic therapy. ESR and CRP combined are the most sensitive diagnostic markers

Imaging US: poor sensitivity and specificity. Useful to depict and monitor complications (e.g. periosteal thickening, soft-tissue / periosteal abscess, joint effusion); X-rays: mandatory to exclude other conditions: the typical findings do not appear in the early stage; MRI: gold standard with high sensitivity and specificity, especially in early-stage disease; CT: the best approach to assess bone status (e.g. cortical destruction, sequestrum): it should be reserved for selected cases; bone scan: discordant sensitivity and specificity data; useful to exclude multifocal OM Microbiological Biopsy: usually unnecessary to diagnose OM; early biopsy, recommended in the past, investigation is now rarely performed

Antibiotic therapy A short course of IV antibiotics followed by 3 weeks oral antibiotics for uncomplicated OM. The clinical condition (persistent fever and elevated CRP) is the best indicator of the need for continuing IV antibiotics

(ESR) alone has a sensitivity of 79%, but com- CRP. However, as in the case of the other blood bined with other measures (e.g., high temperature, indices, PCT alone cannot diagnose or exclude increased WBC count, very painful weight-bear- SA, whereas combined with other factors it may ing) it is an important exclusion parameter whose help diagnose an infected joint (threshold value, sensitivity exceeds 98%. Rutz et al[3] reported 0.5 ng/mL). the results of 5 studies where ESR (threshold, 40 mm/h) was considered as a key diagnostic param- Imaging eter for SA. . Rutz et al3 and Kang et al5 reported C-reactive protein. According to Kang et al[5], that ultrasound (US) is very useful to detect joint the values of C-reactive protein (CRP) have the effusion, especially at the level of the hip joint. highest predictive significance for SA; in contrast, However, given that the rate of false negatives is Rutz et al3 reported that CRP levels > 20 mg/L in 5%, Rutz et al3 suggest that a negative US scan patients with intense pain on weight-bearing are should be interpreted with caution, particularly in highly suggestive for SA and should be further patients where symptoms have arisen less than 24 explored, whereas a negative CRP and the ability h earlier. They also stated that US is not sufficient to bear weight are consistent with transient syno- to discriminate SA from . vitis of the hip. X-rays. Kang et al5 noted that plain radio- . Zhao et al9 conducted a meta-a- graphs are required to differentiate SA from other nalysis on the ability of procalcitonin (PCT) to conditions (e.g., OM, fracture, neoplasms), and distinguish SA from non-septic arthritis and con- that an increase in joint space is an indirect sign cluded that it has a greater diagnostic value than of effusion. In contrast, Rutz et al3 stressed that

150 Acute osteomyelitis and septic arthritis in children: a systematic review of systematic reviews plain radiographs, though essential, are not suffi- The empirical treatment should consider patient ciently sensitive to diagnose or exclude SA. age and condition (disease severity, risk factors, Magnetic resonance imaging. As regards and immune status), local epidemiological pat- magnetic resonance imaging (MRI), Kang et al5 terns, the antibiotic susceptibility of local isolates, and Rutz et al3 both reported that SA is associ- and Gram stain results. The two SRs state that the ated with a signal change in bone marrow and initial antibiotic therapy should cover Gram-pos- with a signal alteration of surrounding soft tis- itives (particularly S. aureus and GAS) and that sues on contrast-enhanced scans. In patients with is effective to treat infections due to transient synovitis of the hip, the relevant MRI clindamycin-sensitive MRSA. Hib (H. influenzae findings are effusion in the contralateral, asymp- type B) coverage is also mandatory in non-vac- tomatic hip joint and absence of bone marrow cinated patients and in young children with K. changes. In addition, MRI is extremely sensitive kingae infection. The authors of the two SRs also and specific in diagnosing SA, particularly of the agree that the initial antibiotic treatment should hip, and in differentiating it from other conditions be intravenous (IV), although the ideal time of the (such as OM or non-infectious arthritis)5. switch to oral therapy and total treatment dura- tion are debated. There is mounting evidence for Diagnostic Aspiration short-course (2-4 days) IV antibiotic treatment in According to Rutz et al3, there is an agreement case of a positive response and clinical improve- in the literature that diagnostic needle aspiration ment, and agreement on the fact that prolonged is required to confirm a diagnosis of SA, to isolate IV antibiotics should be reserved for patients who the pathogen and initiate an appropriate antibiotic do not respond or have clear clinical or microbio- treatment. They also stressed that the procedure is logical contraindications. Rutz et al3 reported that mandatory in the presence of four clinical factors treatment duration (IV + oral) used to range from that are highly suggestive for SA – a CRP value > 10 days to 24 weeks, whereas in the more recent 20 mg/L; pain on weight-bearing; fever ≥ 38.5°C; studies it ranges from 20 to 31 days. Kang et al5 and a serum WBC count > 12 × 109/L – and in stressed that a shortened treatment (< 6 weeks) unclear situations. If no fluid is drawn, the aspira- does not involve adverse effects. tion should be repeated after injection of 3-5 mL Farrow’s SR on use in SA10 re- sterile saline solution. ported that their addition to antibiotic therapy is A positive Gram stain (found in < 40% of pa- held to reduce symptom duration and the levels tients according to Kang et al5), a positive cul- of the inflammatory indices, with a possible pro- ture, purulent aspirate, and > 50,000 WBCs/mm3 tective effect exerted on the articular cartilage, with a predominance of polymorphonuclear cells without side effects. The author concluded that in are all suggestive of SA. The “…There is however insufficient evidence to make threshold of 50,000 WBCs ,however, should be treatment recommendations at present … Long- correlated with the clinical picture, to diagnose or term safety data and the determinations of the op- exclude juvenile idiopathic arthritis. timum route, dose, and timing of According to Kang et al5 and Rutz et al3,5, a are also required”. blood culture has an important diagnostic role, Surgical therapy. Although paediatric SA and in some cases, it may show the causative mi- is considered as an emergency, neither Kang et cro-organism even in the presence of a negative al5 nor Rutz et al3 found a consensus in the lit- synovial fluid culture. The authors thus suggest erature on the timing and type of to be performing both examinations. performed, although both SRs reported that ar- Kang et al5 noted that since SA diagnosis based throtomy is accepted in patients with hip arthri- on blood and synovial fluid culture is obtained in tis. However, the SR on hip arthritis by Rutz et 34 to 82% of cases, a negative culture should be al3 suggests that recent disease (symptoms onset correlated with other parameters such as laborato- < 5 days) without complications could initially be ry, clinical, and imaging findings, to exclude SA. treated without surgery; however, “at all times a septic joint condition should be treated as an Treatment emergency and after finding by the diagnostic Antibiotic therapy. Kang et al5 and Rutz et al3,5 needle aspiration, or arthroscopic ir- agreed that empirical antibiotic treatment should rigation should be performed immediately”. The be initiated immediately, and later modified once authors also stated that surgery becomes neces- the causative micro-organism has been isolated. sary if the clinical picture does not improve and

151 A. Gigante, V. Coppa, M. Marinelli, N. Giampaolini, D. Falcioni, N. Specchia

CRP does not decline within 24 h of antibiotic Analysis of its skeletal distribution showed that initiation. the metaphyses are the sites affected most com- Neither SR found studies showing the superi- monly, due to the characteristic circulation and ority of one surgical treatment over another. The the presence of sinusoids, especially in the femur procedures described were i) arthrotomy and joint and tibia. lavage and ii) daily US-guided aspiration and irri- The same paper6 stressed that in more than 50% gation with arthroscopic drainage. of cases it is impossible to find underlying risk The SR on hip by de Sa et al11 stated factors or causes, and that a history of systemic that the procedure is a “safe and effective treatment infection or penetrating trauma accounts for the option for selected patients (e.g., no deformity, no majority of the remaining cases. Sickle-cell dis- bacterial infections, and not immunocompro- ease (SCD) is an established risk factor for OM. mised)”; they reported no complications, particu- The skeletal distribution of lesions is similar to larly in paediatric or adolescent patients suffering that found in non-SCD-associated OM, but multi- from conditions such as acute slipped capital fem- focal forms are more frequent. Aetiopathogenesis oral epiphysis, avascular necrosis, premature phy- is related to the effects of SCD on the microcir- seal closure, or proximal femoral growth arrest. culation, including intestinal and bony micro-in- farcts that facilitate bacterial penetration and OM Prognosis development. Kang et al5 described a reduction in SA mor- The SR by Gill et al13 has found that non-ty- tality from 50% in 1874 to < 1% in 1973, due to phoidal Salmonella OM in immunocompetent diagnostic and therapeutic advances. They listed children without haemoglobinopathy involves a five negative prognostic factors: young age, since low risk; in particular, only 14% of the cases de- diagnostic problems involve delay in treatment scribed in their SR were associated with recent initiation; transepiphyseal vessels in newborns, foreign travel or exposure to undercooked food or which are also associated with immune system reptiles. immaturity; therapeutic delay (excellent results are obtained in 75% of patients treated promptly Causative Organisms and in only 15% of those treated ≥ 4 days from In children less than 4 years old, 60% of cas- symptom onset); causative bacteria (S. aureus, es of infection are related to and particularly MRSA, is associated with a more se- Gram-negative bacteria; the remaining cases are vere course); and site (the hip has the worst out- due to S. aureus. In children older than 4 years, come). The three SRs3,5,11 concurred that prompt the most common bacterium is S. aureus. In the diagnosis and treatment are the most critical past decade, several studies have reported an in- prognostic factors. crease in the frequency of MRSA compared with community-related infections, either CA and HA. The Hib vaccine has significantly reduced the Osteomyelitis incidence of OM due to H. influenzae type B in paediatric patients. However, in areas where its Classification diffusion is limited or vaccination programmes Hotchen et al12 reported that several variables are poor the bacterium is still a frequent cause of for OM classification are described in the litera- paediatric OM. ture. However, only bone involvement, antimicro- The rate of culture-confirmed OM due to K. bial resistance pattern of the causative micro-or- kingae has been increasing and has overcome Hib ganism, host status, and soft-tissue coverage as the most common Gram-negative cause of OM correlate therapeutic response and prognosis. in young children. This aerobic Gram-negative is Parameters such as aetiopathogenesis and onset usually found in the respiratory tract of children, (acute/chronic) do not show a close correlation. it is characterized by slow growth, and it is noto- riously difficult to isolate in culture. Epidemiology and Risk Factors According to Dartnell et al6, the most common Dartnell et al6 reported that the incidence of causative agents of SCD-associated OM are S. OM varies widely, from 1.94 to 13 new cases in aureus and . Gill et al13 reported that 100,000 in developed countries, to 43 in 100,000 non-typhoidal Salmonella OM is an uncommon in Polynesia and to 200 in 100,000 in Aboriginal disease that is however associated with a high populations. rate of complications such as abscess formation,

152 Acute osteomyelitis and septic arthritis in children: a systematic review of systematic reviews relapse, and multifocal OM. The most common OM complications, such as periosteal thickening, causative serotypes are S. enteritidis, S. typhimu- soft-tissue/periosteal abscess, and joint effusion. rium, group B, group C1, S. oranienburg, and S. Magnetic resonance imaging. Dartnell et al6 saint-paul. noted that an emergency MRI scan is the best di- agnostic imaging tool for early OM diagnosis and Laboratory Markers that it also detects complications such as abscess- White blood cells. Dartnell et al6 found no es or joint involvement. Mooney et al14 shared study addressing serum WBCs in relation to the this view and reported that MRI was consistently age of OM patients. They reported that abnormal accurate in diagnosing calcaneal OM. The latter counts at presentation are found in 35.9% of cas- authors reported that the evidence for the useful- es, that the parameter has limited sensitivity and ness of MRI is conflicting, due to the high vas- specificity, particularly in younger children, and cularization of the metaphyses which hampers that values vary widely depending on the causa- the discrimination of pathological from normal tive organism and on the presence/absence of SA. signal. They also noted that contrast-enhanced Since the highest values are found in patients with imaging is useful the when oedema is visible on particularly virulent bacteria and with concomi- unenhanced scans. tant SA, the WBC count is a useful marker that Tc99 bone scintigraphy. The data on the sen- can alert the clinician to a severe course. sitivity and specificity of this approach in OM Erythrocyte sedimentation rate. Dartnell et patients are contrasting6. Recent studies have re- al6 reported that the ESR affords high sensitivity, ported false-negative results in about half of the especially in patients with an abscess or associ- cases described. Bone scans are useful to identify ated SA. In particular, an association has been OM sites, to exclude/diagnose multifocal forms, found between an ESR value > 55 mm/h and and to predict prognosis, since cold positive scans abscess formation in a patient with pelvic OM, are often associated with a more severe course whereas a value < 22 mm/h was a negative pre- that requires more aggressive treatment. dictive factor in patients with a periosteal abscess or pyomyositis in generalized OM. Treatment C-reactive protein. Dartnell et al6 stressed Antibiotic therapy. Howard-Jones et al15 in that CRP is the most useful blood marker to dis- their SR concluded: “We suggest that uncompli- tinguish OM from the SA-associated disease. In cated acute osteomyelitis in children > 3 months particular, values > 100 mg/L are more frequently old should be treated with 3-4 days of IV anti- associated with a complicated course and are the biotics, and if the child is responding clinically, best predictor of the need for > 6 days of IV an- they can transition on oral antibiotics to a total tibiotics. According to Taj-Aldeen et al8, CRP is duration of 3 weeks (GRADE 2B). First genera- useful to monitor treatment effectiveness in OM tion and clindamycin have shown due to non-Aspergillus spp, but not in disease due similar efficacy in the treatment of acute osteo- to Candida. myelitis in geographies with low MRSA and K. kingae prevalence (GRADE 2B). There are in- Imaging sufficient neonatal data to support 4 weeks of IV X-rays. X-rays are critical for differential diag- antibiotics for neonatal osteomyelitis”. An initial nosis. However, abnormalities are rarely seen be- short IV course with anti-staphylococcal cover, fore 2 weeks, whereas the characteristics changes to be modified after delivery of the culture data may take 2-3 weeks to show in the long and and followed by 3-week oral therapy in patients up to 4-6 weeks in flat bones. with uncomplicated OM, is also supported by Ultrasound. Dartnell et al6 reported that US Dartnell et al6. Temperature > 38.4°C and a CRP affords poor sensitivity and specificity in OM value > 100 mg/L are the best indicators of the diagnosis. However, in developing countries, need for continuing the IV treatment. Dartnell et where second-level imaging may not be available, al also stated that: “Provided the oral antibiotic is the US is quite useful, especially in association effective and the correct dose is given, the child with X-rays. Deep soft-tissue swelling is an early should be converted as soon as there is a clinical sign of OM; periosteal elevation > 2 mm on US improvement and the haematological markers are indicates a periosteal abscess. In patients man- normalizing. A total of three weeks of antibiotic aged conservatively, the US can be used to mon- treatment is usually sufficient in uncomplicated itor treatment efficacy. Finally, US can depict all cases, but the clinician must be guided by the in-

153 A. Gigante, V. Coppa, M. Marinelli, N. Giampaolini, D. Falcioni, N. Specchia dividual patient”. They stressed that benzylpeni- because a negative one is found with less viru- cillin or a should be added to the lent bacteria such as K. kingae, which have a less regimen of unvaccinated children and that the severe course); younger age (probably due to di- MRSA cover in the starting antibiotic therapy is agnostic delay, anatomical and vascular features, still a debated issue. They also noted that clinda- and immune system immaturity); and treatment mycin, due to its excellent bone penetration and delay (results are worse if treatment has been oral bioavailability, was effective against OM started > 5 days from symptom onset). caused by clindamycin-sensitive MRSA. In patients with SCD-associated OM, in the ab- sence of data on the local prevalence of S. aureus Discussion and Salmonella, the empirical treatment should include antibiotics effective against both. Acute osteomyelitis (AO) and acute septic Surgical therapy. Dartnell et al6 reported that arthritis (ASA) are serious conditions that are surgical management with early biopsy and de- viewed as emergencies, since a satisfactory out- bridement is now used less frequently than in the come depends on prompt diagnosis and treatment. past, and that there is a tendency to employ con- Given the scanty number of cases, especial- servative treatment. Several authors recommend ly in developed countries, the literature on most surgical treatment if the clinical picture does not diagnostic and therapeutic approaches (like the improve with antibiotic therapy. In addition to multidisciplinary approach, which involves the treating OM, the surgical procedure also allows intervention of several specialists) is quite limit- collecting samples of purulent material for isola- ed. Although several innovations have been intro- tion of the causative bacterium. duced, they are not mentioned in any of the SRs The surgical approach is important in case of included herein. complicated OM, for instance, to drain abscess- As regards prognosis, recent studies suggest es. According to Dartnell et al6, surgical drainage that infections involving different tissue types be- should be performed in patients with pelvic OM have differently in relation to the primary tissue showing > 2 cm and periosteal eleva- involved, with a descending hierarchy from bone tion > 2 cm in long bones on US, even though to joint, muscle, and soft tissue16,17. Children with good results have also been reported with peri- OM only and those with OM and SA have high- osteal abscesses > 3 mm. The surgical treatment er rates of bacteraemia at presentation than those should thus be guided both by lesion size and by with SA alone17. the local antibiotic response. Mooney et al14 re- ported that in patients with calcaneal OM surgi- Septic Arthritis cal treatment should be reserved for patients with The incidence of ASA is age-related and tends “continued pain, localized erythema and swelling to decline with rising age. Special care should be despite initial treatment, and the presence of an devoted to neonates, who are at high risk of bone, abscess or osseous destruction with imaging”, al- joint, and deep soft-tissue infection with CA and though the literature is not univocal on this issue. HA pathogens. In particular, neonates with inva- sive lines and catheters (especially an umbilical Prognosis artery catheter) are at high risk of developing HA Dartnell et al6 stated that OM mortality had de- infections – including MRSA and multidrug-re- creased significantly compared to the pre-antibi- sistant Gram-negative rods – as well as Candida otic era, when it was > 30% in patients with tibial spp – most often C. albicans and C. parapsilosis – OM and > 50% of those with femoral OM. They during hospitalization, but sometimes even weeks also reported that the main negative prognostic after discharge. The immature immune system of factors include infection due to MRSA, Strepto- neonates may induce an abnormal presentation, pneumoniae, or micro-organisms carry- for instance with lack of fever, unremarkable ing the Panton-Valentine leukocidin gene (PVL), levels of the inflammatory markers, and limited which are most frequently related to MRSA or pain, and pseudoparalysis may be the only sign on methicillin-sensitive staphylococcal (MSSA) in- clinical examination. fections. The gene encodes a necrotizing cytotox- (group B Streptococ- in that confers extreme virulence. Other negative ci) infection is a frequent cause of SA in infants. prognostic factors include concomitant SA, pyo- In older children, the most common cause of myositis, and abscess; a positive culture (probably musculoskeletal infection is S. aureus, although

154 Acute osteomyelitis and septic arthritis in children: a systematic review of systematic reviews

SA due to K. kingae is frequent in children aged drainage has proved safe and effective in a varie- from 6 months to 4 years. SA caused by S. pneu- ty of , including hip, knee, ankle, shoulder, moniae and H. influenzae is most frequent in un- , and wrist. Minimal soft-tissue disruption, immunized children, but it can also be caused by a shorter hospital stay, and improved joint space non-vaccine serotypes in fully immunized chil- visualization are its key advantages11,29. Advanced dren17-21. Children with suspected SA showing imaging may be required in patients who do not risk factors for and clinical features of OM in ad- exhibit clinical or laboratory improvement within jacent bones present a clinical challenge. the first 3-4 days after joint irrigation and drain- Joints with intracapsular metaphyses, such as the age30. In children not showing the expected im- proximal humerus and proximal femur, are most provement, the possibilities of contiguous OM susceptible to develop adjacent OM22. Advanced and abscess should be explored. If repeated imag- imaging should be considered to assess young chil- ing does not demonstrate an infectious cause for dren with SA and possible adjacent OM23,24. the failure to improve, conditions mimicking SA, Supplemental laboratory tests, including chem- such as leukaemia, should be considered. ical and cellular analysis of joint fluid, peripheral WBC count, and serum ESR and CRP, are often Osteomyelitis employed to diagnose SA in children25. Accord- The clinical examination of a child with OM of- ing to the widely accepted3 diagnostic algorithms ten discloses bone tenderness that is most marked reported by Kocher et al26,27 and modified by sev- over the epicentre of the disease. eral authors, patients with joint infection typically In all patients, blood cultures should be ob- have peripheral a WBC count > 12,000/mL, se- tained and laboratory tests performed (including rum CRP levels > 2 mg/dL, and an initial ESR > a with differential, ESR, 40 mm/h. and CRP), and antibiotics should not be admin- In patients where a high clinical suspicion is istered until the results of the blood culture are supported by imaging findings, blood culture and available17. joint aspiration are needed to confirm the diag- Plain radiographs should be obtained for pos- nosis. However, obtaining confirmation of an SA sible infections, to establish other causes of the diagnosis is difficult, due to the low rate of micro- symptoms (e.g., fracture, neoplasm), as well as to organism isolation from joint fluid. PCR amplifi- depict the radiographic changes that may occur in cation of DNA sequences of bacteria retrieved in advanced disease (like lytic lesions, cortical ero- joint fluid increases sensitivity and specificity, but sion, sequestrum, and involucrum). Since a loss since it is still experimental, it is neither standard- of about one-third of local bone mineral density is ized nor widely available18,21. required before the change shows on plain radio- Most patients with proved or suspected SA graphs, the key finding is deep soft-tissue swelling. are immediately started on empirical parenteral MRI has been demonstrated to be the most anti-staphylococcal antibiotics. According to the accurate imaging approach to detect early AO, most recent literature, a short course (3-4 days) of depict the anatomical and spatial extent of bone, IV antibiotics followed by short-term (< 6 weeks) joint, and soft-tissue infection, and document the oral antibiotics targeting the causative micro-or- size of any abscesses that may require surgical ganism (when known) provide good results in drainage17,31-33. Its disadvantages include cost and responders (who show improved inflammatory the need for sedation or anaesthesia in younger indices and clinical condition) with non-compli- children. Rapid acquisition protocols allow coro- cated ASA28; in patients with complicated ASA nal screening from the lumbar spine to the ankles (e.g., concomitant OM) a longer antibiotic course with minimal sedation31. is recommended. Evidence from recent comparative studies indi- If antibiotic treatment is ineffective (lack of cates that children with MRSA-related OM may improvement in the clinical picture or the in- have more severe diseases than those with OM flammatory markers), surgical treatment should due to MSSA. A prediction algorithm has been be considered. Several approaches have been devised to try to anticipate which patients will be described to treat ASA. However, given the lack confirmed to have an MRSA infection before the of evidence regarding the superiority of any one culture results are available34. However, the use of treatment over the others, surgical management such algorithms has not been confirmed in other should be selected according to the surgeon’s lev- communities, some of which have a higher inci- el of comfort with the approach20. Arthroscopic dence of MRSA-related OM35.

155 A. Gigante, V. Coppa, M. Marinelli, N. Giampaolini, D. Falcioni, N. Specchia

There is consensus on the need for prompt em- whereas those with severe disease (markedly ele- pirical antibiotic treatment when AO is suspected: vated inflammatory markers; recurring fever on whereas in stable patients antibiotics can be with- antibiotics; and clear evidence of disseminated held until the culture results have become availa- diseases, such as deep-vein thrombosis, septic ble, in unstable patients, such as those with signs pulmonary emboli, or pneumonia) are more likely of haemodynamic instability or , early em- to require surgery, and more than one procedure pirical antibiotic therapy should be begun imme- may be needed to resolve the infection45. diately17. The starting treatment should be appro- The incidence of abscesses seems to have in- priate for patient age, underlying chronic disease creased in the MRSA era and may underpin a (e.g., SCD or primary immunodeficiency), and the higher rate of surgical interventions in children local epidemiology and antimicrobial susceptibil- with OM34,38-40. Data to guide in the selection ity of the most likely pathogens16,34,36-38. of the surgical procedure(s) that should be per- In recent years, CA MRSA has caused a high formed in OM patients are not available. Options proportion of culture-positive bone, joint, and include drainage of subperiosteal abscesses, bone soft-tissue infections which have required an in- drilling, and incision of cortical bone with irri- creased use of and clindamycin in gation and of infected cancellous place of cephalosporins, which were the medica- bone. Surgical decompression of infected bone tion of choice when MSSA infections predominat- can be effective in reducing intraosseous pres- ed35,37,39,40. The standard practice involved admin- sure, which may hamper perfusion and antibiotic istration of IV antibiotics in the hospital for 4-6 delivery to the site of the infection. In all drainage weeks. The advent of peripherally-inserted central procedures, injury to the growth plate and peri- catheters has led to catheter placement and a short chondral ring should carefully be avoided. Surgi- antibiotic course administered in hospital followed cal planning should include a review of all foci of by a course of parenteral antibiotics administered infection on advanced imaging. Abscesses due to at home. Oral treatment after a course of IV an- adjacent or contiguous OM should be drained at tibiotics has also become quite common. Several the time of bone decompression. In children with children received a short course of IV antibiotics AO, the involvement of adjacent joints may be followed by oral treatment for 3-5 weeks41-44. An- more frequent than expected16,23,33. timicrobial therapy is completed when the pre- scribed course has been administered, there are no physical findings suggesting inflammation, and Conclusions the levels of the inflammatory indices have revert- ed to normal. In patients where physical examina- In the absence of satisfactory clinical or labora- tion or the inflammatory markers remain abnor- tory improvement within 72 to 96 h from debride- mal, the antibiotic treatment should be continued, ment, repeat irrigation and debridement may be and clinical and laboratory reassessments should considered. Additional imaging is unlikely to be be performed at intervals of 1-2 weeks until nor- useful, except to document an additional suspect- malization. Lack of improvement should raise the ed focus of infection. Although the postoperative suspicion of a residual focus of infection (e.g., an MRI scans often seem to show a deteriorating abscess or sequestrum). Lack of improvement or condition, they depict the normal progression of of resolution of the inflammatory indices should the infection and should therefore be interpreted prompt repeat MRI and possible repeat incision with caution31. and debridement as well as a new culture, to ensure that the previous antibiotic is still appropriate31. Although the literature provides no clear guid- Conflict of Interest ance, surgical management is generally indicated The Authors declare that they have no conflict of interest. in children with OM and haemodynamic compro- mise consistent with septic shock or with imaging findings that are unlikely to resolve with antibi- References otics alone, like drainable intraosseous, subperi- Dodwell ER. osteal, or extraperiosteal abscesses36,45. In children 1) Osteomyelitis and septic arthritis in children. Curr Opin Pediatr 2013; 25: 58-63. with OM, disease severity at presentation is a pre- de Graaf H, Sukhtankar P, Arch B, Ahmad N, Lees 39,45 2) dictor of the need for repeat surgery . Children A, Bennett A, Spowart C, Hickey H, Jeanes A, Armon with mild illness are unlikely to require surgery, K, Riordan A, Herberg J, Hackett S, Gamble C, Shin-

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