Multifocal Acute Osteomyelitis or Chronic Nonbacterial Osteomyelitis: Is It Always Easy to Diagnose?

To the Editors: Osteomyelitis is defined as inflammation involving bone and/or bone marrow. Although many infectious and noninfectious causes may result in osteomyelitis, it is almost exclusively the result of bacterial infection of the bone.1 Chronic nonbacterial osteomyelitis (CNO) is a rare, noninfectious inflammatory bone disease of unknown cause, primarily affecting children and adolescents. CNO, with an unknown cause and being an autoinflammatory, noninfectious inflammatory bone disease, should be distinguished from bacterial osteomyelitis.2 Despite increased awareness of CNO over the past decade, misdiagnosis and delays in treatment persist.3 In this article, we aimed to emphasize the importance of investigating not only multifocal acute bacterial osteomyelitis but also CNO in a patient with fever and multiple bone lesions. Also, we aimed to share our clinical experience with a CNO diagnosis obtained in a very short time, contrary to the literature. An otherwise healthy 7-year-old female patient was referred with a diagnosis of possible acute osteomyelitis to our center with left shoulder pain, simultaneous pain and swelling in the left big toe that had begun 4 weeks earlier without any history of trauma or infection and a 4-day history of fever. On physical examination, pain was noted on palpation of the distal left fifth metatarsal, with restricted dorsiflexion and plantar flexion of the foot, and swelling and pain were detected in the proximal phalanx of the left big toe. Laboratory findings showed elevated white blood cell count (14,900/µL), elevated erythrocyte sedimentation rate (90 mm/h) and C-reactive protein (136 mg/L), while serum lactate dehydrogenase and uric acid were within normal ranges and no growth in blood cultures. The foot, ankle and shoulder radiographs were performed. Radiograph images revealed lucent-lytic areas in the proximal phalanx of the first toe, in the fifth metatarsal, distal metaphysis of the tibia and proximal metaphysis of the left humerus (Fig. 1A). These results supported acute osteomyelitis, and the patient was started on intravenous clindamycin and ceftazidime. On fat-saturated T2-weighted magnetic resonance imaging (MRI), images showed hyperintense lesions with surrounding bone marrow edema and soft tissue edema in the distal tibial metaphysis, fifth metatarsal and proximal phalanx of the first toe on the left-hand side. These findings were consistent with osteomyelitis (Fig. 1B). Bone culture results were all negative including aerobic, anaerobic, fungal and mycobacterium tuberculosis. Despite antibiotic treatment, her complaints did not improve and her fever continued. However, after starting nonsteroidal anti-inflammatory drugs, bone pain decreased dramatically. To differentiate the diagnosis, a bone marrow aspiration and positron emission tomography (PET) imaging were performed. Bone marrow aspiration showed cellular marrow with adequate megakaryocytes, increased myeloid series, increased eosinophil precursors and plasma precursors, no atypical cells and findings consistent with autoimmune processes. Tumor PET imaging showed increased fluorine-18 fluorodeoxyglucose uptake in the distal left tibia, proximal left big toe and left fifth metatarsal bone (SUVmax: 3.09). Similar increased fluorine-18 fluorodeoxyglucose uptake was observed in the bilateral iliac bones, left femoral head, bilateral proximal tibias and right distal tibia (Fig. 1C). Pathology results were consistent with chronic inflammation with no microorganisms observed. With the exclusion of infection and malignancy, the patient was reevaluated by pediatric rheumatology and diagnosed with CNO. The patient was started on oral methylprednisolone and subcutaneous methotrexate. After starting treatment, she had no residual pain or tenderness and was able to resume normal activity with no restrictions.FIGURE 1.: Radiologic involvement of multifocal acute osteomyelitis. A: On the radiograph images, lucent-lytic areas in the proximal phalanx of the first toe, in the fifth metatarsal, distal metaphysis of the tibia and proximal metaphysis of the left humerus were seen (arrows). B. On fat-saturated T2-weighted coronal and axial plan MRI images showed hyperintense lesions with surrounding bone marrow edema and soft tissue edema in the distal tibial metaphysis, fifth metatarsal and proximal phalanx of the first toe on the left-hand side. C: Increased F-18 FDG uptake in the bilateral iliac bones, left femoral head, bilateral proximal tibias, bilateral distal tibia, proximal left first toe and left fifth metatarsal bone. F-18 FDG indicates fluorine-18 fluorodeoxyglucose.Previously considered a relatively mild and self-limiting condition, CNO is now recognized as a serious and, in some cases, debilitating disease due to potential complications such as vertebral body fractures.4 The annual incidence rate has increased from approximately 0.4 per 100,000 in 2010 to ≈2.3 per 100,000 children in 2019.5 Despite recommended diagnostic criteria, CNO should be distinguished from clinically and radiologically similar diseases, and bone biopsy may be indicated to exclude critical differential diagnoses such as malignancy and bacterial osteomyelitis based on clinical presentation and imaging findings.3 Imaging studies are essential for the diagnosis and follow-up of CNO. MRI is considered sensitive in detecting CNO and is regarded as the gold standard for disease monitoring.2 Studies have shown that the median time from the initial symptoms to the diagnosis of CNO is 2 years.4 In this article, we aim to draw attention to the fact that the time from the patient’s presentation to diagnosis was ≈1 month, contrary to the literature. This case is presented to emphasize that CNO should be kept in mind in the early period in patients with multiple bone lesions, no growth in cultures and clinical and laboratory unresponsiveness to antibiotics. In such patients, whole-body MRI or PET imaging will be useful in making the diagnosis.