Author's response to reviews Title: Childhood osteomyelitis-incidence and differentiation from other acute onset musculoskeletal features in a population-based study Authors: Øystein Riise (oystein.riise@rikshospitalet.no) Eva Kirkhus (eva.kirkhus@rikshospitalet.no) Kai Handeland (kai.handeland@sb-hf.no) Berit Flatø (berit.flato@rikshospitalet.no) Tor Reiseter (tor.reiseter@ulleval.no) Milada Cvancarova (miladacv@student.matnat.uio.no) Britt Nakstad (britt.nakstad@medisin.uio.no) Karl-Olaf Wathne (karl-olaf.wathne@hod.dep.no) Version: 2 Date: 21 July 2008 Author's response to reviews: see over
1 Dear Editor, Thank you very much for your reply and valuable feedback. The comments and questions raised by the referees have been studied carefully and we have revised our manuscript where we found it appropriate. Please find below our responses to the individual comments and questions of the reviewers. Reviewer: Sheldon L Kaplan Reviewer's report: Major Revisions 1. Page 6, under recruitment. What do the authors mean by not caused by trauma? In many and possibly most children with osteomyelitis, some type of blunt trauma precedes the onset of osteomyelitis. In fact, trauma may be an important factor in the pathogenesis of osteomyelitis leading to disruption of endothelium or some other mechanism allowing bacteria to invade the bone. This needs to be clarified. By the term not caused by trauma we wanted to avoid including patients whith larger injuries or fractures. It cannot be excluded that some patients who actually had osteomyelitis were not referred. We never excluded patients due to a history of trauma. Old version after P14, line 13, new version P14, line 14-15 We wanted to avoid including children with larger injuries or fractures. However, on admission patients with a history of trauma were not excluded. 2. page 7, inclusion criteria. Pus from a bone biopsy was a criterium but did the authors also consider histology showing acute or chronic inflammation as evidence of osteomyelitis? Patients with chronic osteomyelitis, in particular, may not have purulent collections but have evidence of inflammation on bone biopsy. We also considered histology as evidence of osteomyelitis. Two of our patients were positive on histology and had a negative bone culture. This has been added in the new version. Old version P7, new version P7, line 7-8.Positive culture from bone biopsy and/or histology showing inflammation Old version P11, line 8-10, new version P11, line 8-11 In addition to clinical signs and symptoms the diagnosis of osteomyelitis was based on bone biopsy and MRI in 11 patients (2 had a negative culture but were positive on histology), only MRI in 24 patients and bone scan in 2 patients (MRI and/or bone biopsy not assessed). 3. page 10, under incidence of osteomyelitis-incidence of vertebral osteomyelitis is high relative to other sites of osteomyelitis based on previous reports. Although the authors indicate that none of these patients with vertebral osteomyelitis had pure discitis, this
2 diagnosis is fairly common and apparently was not encountered in any of the patients referred for the study or retrospective search of medical records based on figure 1. On page 13 the authors state the most frequent radiographic findings for the nine vertebral osteomyelitis cases was impression or erosion of vertebra, ----. What is the meaning of impression in this context? We have removed the term impression in the new version. The most frequent findings in the nine vertebral osteomyelitis patients were decreased height of vertebral bodies (n=8), decreased disc space with endplate irregularities on both sides of the disc (n=7) and pathological angle of the vertebral axis (n=4). Two patients had initially no involvement of the disc, however one of them developed a Schmorl s node. No patients had isolated discitis. What were the ages of the children with vertebral osteomyelitis versus those with osteomyelitis of long bones? The median age of the vertebral osteomyelitis patients was 2.5 years (range 1.3-14.9) versus 4.3 years (range 0.0-13.9) for patients with non-vertebral osteomyelitis. Did any of the patients with vertebral osteomyelitis have positive blood cultures or bone biopsies? Two of the nine vertebral osteomyelitis patients had positive microbiological cultures. One had S. aureus cultured from the vertebra and one had S. aureus cultured from m. iliopsoas and blood. One of them had concomitant discitis. The two microbiological positive patients were 8 and 14 years and the microbiological negative patients were aged 1 to 13 years (not significant) Typically children with vertebral osteomyelitis are older than those with discitis and reporting their age and culture/bone biopsy results would provide some confirmation that these patients indeed had vertebral osteomyelitis. (Pediatrics 2000;105:1299-1304) 4. Page 16, second paragraph. Whether our patients actually had vertebral osteomyelitis or not is a matter of definition. According to some authors discitis is inflammation restricted to the disc space and spondylodiscitis is used where both the disc and the adjacent bone structures are affected. (Kayser, Spine 2005;30 (3):318-323; Cottle J infect 2008 Jun; 56(6): 401-12) However, other authors use the term discitis also for spondylodiscitis. (Early, J Am Acad Orthop. Surg 2003; 11(6): 413-20; Fernandez, Pediatrics 2000; 105:1299-1304). Seven of our vertebral osteomyelitis patients could be defined as spondylodiscitis. On the other hand our patients would also fit into the criteria adopted in several papers on vertebral osteomyelitis. (Mylona, Semin Arthritis Rheum 2008 Jun 10; Grammatico Epidemiol Infect. 2008 May; 136(5): 653-60; Mc Henry Clin Infect Dis 2002 May 15; 34(10): 1342-50; Sapico Rev Infect Dis 1979 Sept-oct; 1(5):754-76) We found the radiological definition of vertebral osteomyelitis in the paper by Fernandez (Pediatrics 2000; 105:1299-1304) vague typical vertebral bone involvement.
3 As none of our patients had an isolated inflammation of the disc we considered the term discitis inappropriate in this context. There are no verified classification criteria on how to distinguish discitis from vertebral osteomyelitis. (Ring, J Pediatr Orthop. 1995; 15(5):652-60) The authors indicate that vertebral osteomyelitis accounted for 19% of cases in one series (reference 19) but this reference dealt with subacute or chronic osteomyelitis and not the typical child with acute osteomyelitis. We have made the following correction: In a retrospective series from the US, vertebral involvement was found in 19% of patients with subacute and chronic osteomyelitis. Old version P13, line 18-20, new version P13, line 15-19 The most frequent findings in the nine vertebral osteomyelitis patients were decreased height of vertebral bodies (n=8), decreased disc space with endplate irregularities on both sides of the disc (n=7) and pathological angle of the vertebral axis (n=4). One of the two patients without disc inflammation developed a Schmorl s node. No patients had isolated discitis. New text added in Table 5 Two of the nine vertebral osteomyelitis patients had positive cultures for S. aureus. Change in old version P16, line l4, new version P 16, line 8. In a retrospective series from the US, vertebral involvement was found in 19% of patients with subacute and chronic osteomyelitis. Old version P16, line 15, new version P16, line 10-15. Seven of our patients could have been defined as spondylodiscitis. As none of our patients had an isolated inflammation of the disc we found the term discitis inappropriate in this context. Such cases have been variously diagnosed as osteomyelitis, spondylitis or discitis which make a comparison difficult (old version ref 35). There are no verified classification criteria on how to distinguish discitis from vertebral osteomyelitis.(ring, J Pediatr Orthop. 1995; 15(5):652-60)
4 Reviewer: Agnès Ferroni Abstract : The annual incidence (13 per 100 000) is repeated twice. Change in old version P4, line 1, new version P4, line 1 The annual incidence of osteomyelitis in Norway remains high. Introduction : P6, line 4 : the sentence is not clear ( the patient?) We have rewritten the sentence: (new version P6, line 3-5) In addition, we wanted to compare the age, sex, doctor s delay, clinical and MRI characteristics of children with acute and subacute osteomyelitis. Results P11, line 9 : the diagnosis is based on MRI for 27 patients while table 5 shows 6+6+5+9= 26 patients. We have rewritten the sentence: (new version P11, line 9-12) In addition to clinical signs and symptoms the diagnosis of osteomyelitis was based on bone biopsy and MRI in 11 patients (2 had a negative culture but were positive on histology), only MRI in 24 patients and bone scan in 2 patients (MRI and/or bone biopsy not assessed). We have rewritten table 5 regarding increased signal/and or thick synovia on MRI. The denominator should be 22 (acute osteomyelitis) and 13 (subacute osteomyelitis). Increased signal/and or thick synovia 6/22 (22) vs. 5/13 (38) P13, line 9 : the combination of two betalactamine (cloxacillin and ampicillin) for 12 patients is surprising. The authors should explain why this treatment has been chosen. Our protocol did not give any recommendations regarding treatment. Although we have read the medical records carefully, we can only speculate on the reasons for this combination. This combination was particularly common in one of the hospitals. Local traditions, negative microbiological tests and in some cases young age could be explanations. We have therefore not made any changes in the manuscript. P12, two last lines, the percentages seem inverted between acute and subacute osteomyelitis. We have corrected this in the revised manuscript. (new version P12, two last lines) An MRI sign of subacute osteomyelitis was found in 9 (69%) of the patients with subacute osteomyelitis and in 6 (27%) of those with acute osteomyelitis (p =.013)
5 Discussion : P14, lanes 11-12 : the sentence in addition..duration is not useful. We have rewritten the sentence (P14, line 11-12): Subacute MRI signs were present in 69% of the osteomyelitis patients with more than 14 days disease duration. The percentage of 43% of long bone involvements is repeated 2 times (p14, line 7 and p16, line 3) We have removed 43% from P14, line 9. P16, lines 5-7 : why do the authors state that the higher rate of subacute osteomyelitis could be linked to the Haemophilus vaccination? In addition, the implicated bacteria are not less virulent than those implicated before. We have removed the part about Hemophilus influenzae and less virulent bacteria. (new version P 16, line 4-5) The development of a higher proportion of subacute osteomyelitis and a lower proportion of long bone involvement could be linked to improved standards of living and hygiene P16, lines 7-10 : the sentence as there was..admission is not clear. We have removed the sentence and made a new paragraph at the end of the discussion section. Why is doctor s delay so common in subacute osteomyelitis? In the acute osteomyelitis patients concomitant septic arthritis was rare however, elevated body temperature and acute phase reactants were more common. Hence these patients seemed to appear more ill. The subacute osteomyelitis patients tended to be older and it is possible that parents and doctors are less concerned about the signs and symptoms these children present. It would have been interesting to know whether the acute phase reactants had been more elevated prior to hospital admission. In Norway, CRP is frequently used as a marker of inflammation in primary care. Perhaps more use of ESR could help to identify patients at an earlier stage. P17, line 2 : predictive and not prospective (new version P17, line 1) The correction has been made in the revised manuscript Figure 1 : Abbreviations must be explained : JIA, SLE The abbreviations are explained in the revised manuscript (figure 1). JIA Juvenile Idiopathic Arthritis SLE- Systemic Lupus Erythematosus
6 Table 2 : It must be specified that the number in brackets is a percentage. The following information is added in table 2: Values in brackets are % I do not understand why ESR<20 is mentioned on table 2 since it is a normal Value We consider it important to show that patients with osteomyelitis may have normal ESR. Table 3 : Title : clinical and laboratory characteristics of patients would be preferable than patient and laboratory characteristics of patients. The authors could also start the title with characteristics of patients with The septic arthritis should be separated from skin infections. We have changed the title to: Characteristics of patients with osteomyelitis versus patients with other acute onset musculoskeletal features. We have added the numbers of patients with septic arthritis (n = 7) and skin infection (n = 19). These patients were characterised by the need for antibiotic treatment. We believe that the number of patients with septic arthritis is too small to allow for a meaningful statistical comparison with the osteomyelitis patients. Other changes in the manuscript: Table 5 We have added a line on number of patients with concomitant septic arthritis. Concomitant septic arthritis: (acute osteomyelitis) 3 (13) and (subacute osteomyelitis) 0 (0) All names of microbes are changed to italic. Doctor s delay, not doctors delay (old version) P11, line 21-23 Removed the sentence beginning patients who. (new version) P14, end of first paragraph New sentence: The median doctor s delay was 63 days in the subacute osteomyelitis patients.
7 (new version) P15, line 2-3 Twenty-four, not twenty-seven. Old version P16, line 12-13, and only one patient did not have concomitant discitis. An isolated. was removed from the manuscript. We hope that this clarifies the points raised by the reviewers and that the improved manuscript can be considered for publication in BMC Pediatrics. Yours sincerely, Øystein Riise, MD, MPH