The increased susceptibility of sickle cell disease patients to infections, including osteomyelitis, has long been recognized with several mechanisms postulated including hyposplenism, impaired complement activity and the presence of infarcted or necrotic bone. A recent French study of a cohort of 299 patients followed in four Parisian centres, found a prevalence of osteomyelitis of 12%. Interestingly, the prevalence was significantly lower in those patients with the Bantu haplotype (Neonato et al, 2000). This finding is in keeping with other studies where it was found that patients with more severe haplotypes such as Benin and Senegal, not only have more severe organ damage because of sickling, but also have increased incidence of infectious complications (Padmos et al, 1991).
The most common cause of osteomyelitis in sickle cell disease is Salmonella (especially the non-typical serotypes Salmonella typhimurium, Salmonella enteritidis, Salmonella choleraesuis and Salmonella paratyphi B), followed by Staphylococcus aureus and Gram-negative enteric bacilli (Atkins et al, 1997; Burnett et al, 1998), perhaps because intravascular sickling of the bowel leads to patchy ischaemic infarction (Table II). Osteomyelitis in sickle cell disease has also been reported in association with tuberculosis (Kooy et al, 1996) and systemic spread of Mycobacterium ulcerans from a Buruli skin ulcer (Pszolla et al, 2003).
Diagnosis of osteomyelitis in sickle cell disease
Diagnosis of osteomyelitis can be one of the most common management dilemmas in sickle cell disease: failure to identify it may result in severe bone damage and life-threatening infection while an erroneous diagnosis subjects the patient to at least 6 weeks of unnecessary intravenous and oral antibiotics. Osteomyelitis usually presents with pain, swelling and tenderness over the affected area. The most common sites are the femur, tibia or humerus (Stark et al, 1991). Most patients also have fever and elevated inflammatory markers (Chambers et al, 2000; Skaggs et al, 2001) but the fever may be modest (Bennett, 1992). These signs and symptoms are similar to those found in vaso-occlusive crises, making the distinction between a painful crisis and osteomyelitis extremely difficult on clinical grounds; indeed osteomyelitis may not be suspected until the signs and symptoms of a typical painful crisis have failed to resolve after 1–2 weeks of standard therapy (Jean-Baptiste & De Ceulaer, 2000). Blood cultures are often sterile when taken at this stage, as it is common practice to treat patients with vaso-occlusive crises with broad-spectrum antibiotics upon admission, especially if they are febrile. Thus, confident diagnosis of osteomyelitis in such patients tends to rely on various imaging techniques. However, in some cases, osteomyelitis presents late, as a more indolent process often with abscess formation, in which case there is usually little diagnostic difficulty (Barrett-Connor, 1971; Dirschl, 1994).
On plain radiographs, the changes seen at the early stages of osteomyelitis, namely periostitis and osteopenia, are non-specific and also seen in vaso-occlusion and therefore of limited value (Lonergan et al, 2001). Lucent areas are not seen until much later in the natural history of the infection (Fig 1). Ultrasonography shows the extraosseous pathology in acute osteomyelitis and may show periosteal elevation (William et al, 2000). It has also the advantage of being rapid, non-invasive and fairly simple to target to the area(s) of maximum pain (Sidhu & Rich, 1999). The sensitivity of ultrasonography in diagnosing osteomyelitis in sickle cell disease has been reported to be as high as 74% (Rifai & Nyman, 1997; Sadat-Ali et al, 1998; William et al, 2000; Riebel et al, 2003). However, as with computer tomography (Stark et al, 1991), the main ‘diagnostic’ finding (subperiosteal fluid) is not specific and can also be present during vaso-occlusive crises, although greater fluid depths (>4 mm) are reported to be highly associated with a diagnosis of osteomyelitis (William et al, 2000).
As mentioned above, radioisotope bone scanning is also reliable in distinguishing osteomyelitis from infarction with confidence in sickle cell disease (Amundsen et al, 1984; Rao et al, 1985; Crowley & Sarnaik, 1999; Kim & Miller, 2002). A combination of 99mTc-sulphur colloid and 99MTc-diphosphonate (Buchanan, 1996; Skaggs et al, 2001; Kim & Miller, 2002) or 99MTc with gallium seems to improve accuracy (Amundsen et al, 1984), as marrow uptake tends to be normal in osteomyelitis while it is usually increased in infarction; however, as both false positives and false negatives still occur, we no longer use this approach. Radiolabelled leucocyte scans similarly fail to reliably discriminate between osteomyelitis and infarction (Buchanan, 1996).
The MRI is increasingly being used to help diagnose osteomyelitis (Lonergan et al, 2001). As with other imaging modalities, there is overlap between the changes seen in infection and infarction: in both situations MRI shows reactive marrow oedema together with surrounding hyperaemia (Bonnerot et al, 1994; Umans et al, 2000). The accuracy of MRI is greater when gadolinium enhancement is used (Deely & Schweitzer, 1997; Umans et al, 2000) but even this is not 100% specific for differentiating osteomyelitis from infarction (Frush et al, 1999; Lonergan et al, 2001). However, once osteomyelitis was confirmed by culture results, it is very useful for accurate localization of the lesion and for monitoring for response to treatment once antibiotic therapy has been initiated (Bonnerot et al, 1994).
Therefore, despite the progress made in the development and use of imaging techniques, a definitive diagnosis of osteomyelitis in sickle cell disease still relies more upon clinical assessment together with positive cultures from blood or bone obtained by aspiration or biopsy, than upon any single imaging modality. It is also useful to remember that bone pain in sickle cell disease is much more likely (in one series (Keeley & Buchanan, 1982) it was 50 times more likely), because of a vaso-occlusive crisis than to osteomyelitis.
Treatment of osteomyelitis in sickle cell disease
The choice of antibiotics is generally dictated by the microorganism detected. Our first line treatment for confirmed or suspected osteomyelitis is a third line cephalosporin such as ceftriaxone, in order to make sure Salmonella infections are covered. Ciprofloxacin is a useful alternative for older children with Salmonella osteomyelitis, having the advantage of excellent oral bioavailability. In adults, other species such as Staphylococcus, should also be covered by empirical antibiotic therapy (Sadat-Ali, 1998). Treatment of confirmed cases should continue for at least 6 weeks.
When there is radiological evidence of accumulation of fluid at the site of infection, drainage is recommended (Sadat-Ali, 1998). However, there is no firm consensus regarding when to drill or drain and these invasive procedures tend to be reserved for those who are not responding to antibiotic therapy or those who have localized encapsulated septic collections (Syrogiannopoulos et al, 1986; Atkins et al, 1997; Sadat-Ali, 1998).