Authors: Jamie Fey1,2, Maria N. Gamaletsou3,4, Nikolaos V. Sipsas4, Barry Brause3,5, and Thomas J. Walsh3#
1 Albany Medical College, Albany, NY, USA, 2 The Floating Hospital for Children at Tufts Medical Center, Boston, MA, USA, 3 Weill Cornell University Medical Center, New York, NY, USA, 4 University of Athens Medical Center, Athens, Greece, 5 Hospital for Special Surgery, New York, NY, USA
Aspergillus osteomyelitis is an uncommon manifestation of invasive aspergillosis (Denning & Stevens 1990). Aspergillus osteomyelitis may involve bones of the axial or appendicular skeleton. Aspergillus osteomyelitis is a particularly important cause of morbidity and mortality in immunocompromised hosts, especially in patients with chronic granulomatous disease, solid organ transplantation (SOT) and hematopoietic stem cell transplantation (HSCT), diabetes mellitus, and chronic corticosteroid use. Furthermore, Aspergillus osteomyelitis also is reported in alcoholics and illicit intravenous drug use. Notably, Aspergillus osteomyelitis is reported in patients without apparent immunodeficiency (van Tol & van Riswijk, 2009; Corrall et al, 1982).
As symptoms and signs of Aspergillus osteomyelitis tend to be non-specific, a high index of clinical suspicion is required. The diagnosis of osteomyelitis is based on clinical, radiological, microbiological and histological findings. Histopathology and microbiologic examination of bone tissue biopsy are the gold standards for identification of Aspergillus spp. Of note, false negative results, particularly in patients who receive antifungal therapy or prophylaxis, should not exclude the diagnosis of Aspergillus osteomyelitis.
Imaging is an essential tool in the diagnosis of Aspergillus osteomyelitis. Radiologic abnormalities on plain radiographs, magnetic resonance imaging (MRI) and computerized tomography (CT) are characteristically observed in cases of AO. MRIs and CTs are considered the hallmark of radiological diagnosis and evaluation of therapeutic response. However, imaging techniques per se fail to resolve the differential diagnosis from other infectious etiologies.
Enzyme immunoassay for serum galactomannan, a component of the Aspergillus cell wall released during fungal growth, is increasingly utilized in the diagnosis of invasive aspergillosis. There are limited data available on its role in Aspergillus osteomyelitis. Due to the relatively low tissue burden of isolated Aspergillus osteomyelitis, serum galactomannan may be negative. Alternatively, serum galactomannan may occasionally be positive in the setting of disseminated aspergillosis involving multiple bones or in contiguous involvement of a rib or vertebral body in patients with invasive pulmonary aspergillosis.
Another non-culture based circulating biomarker, (1®3)-b-D-glucan, when found in the serum, is a strong indicator of the presence of an invasive fungal infection, albeit not specifically so for aspergillosis (Obayashi et al, 1995; Ostrosky-Zeichner et al, 2005). Serum (1®3)-b-D-glucan has been documented to be directly correlated with Aspergillus osteomyelitis burden in a liver transplant recipient (Kaneko et al, 2002). Finally, the non-specific inflammatory markers C-reactive protein and erythrocyte sedimentation rate may be elevated in patients with Aspergillus osteomyelitis and should be considered, along with other laboratory data may also be used to support a diagnosis of Aspergillus osteomyelitis. Polymerase chain reaction-based-technology (real-ime PCR) has been utilised on fresh tissue biopsies (Lass-Florl, 2011) and on bone (Dayan et al, 2007). It is more likely to be useful directly on tissue samples than in blood in the context of osteomyelitis.
Successful treatment of Aspergillus osteomyelitis usually requires combined medical therapy, surgical intervention, and reversal of immunosuppression (Walsh et al, 2008). Isolated cases have been reported to be successfully managed with surgery alone. However, the potential for recurrent infection following surgical intervention warrants medical management.
The pharmacology of antifungal agents has been reviewed in detail elsewhere. As voriconazole is the preferred antifungal agent for treatment of invasive aspergillosis, this recommendation is logically extrapolated to medical management of Aspergillus osteomyelitis (Walsh et al, 2008). The medical literature describes a larger experience of treatment of Aspergillus osteomyelitis with deoxycholate amphotericin B as a reflection of greater length of time that this compound has been available. The evidence supporting any medical intervention for Aspergillus osteomyelitis is based upon individual case reports and small case series. Despite these limitations, the limited available data support voriconazole as primary therapy. Based upon the use of voriconazole for successful treatment of invasive pulmonary aspergillosis in comparison to that of amphotericin B, there is a rational basis for this recommendation. Moreover, voriconazole has been successfully administered in both primary and salvage therapy of Aspergillus osteomyelitis with a better acceptable side-effect profile than amphotericin-B (Mouas et al, 2005).
Among 20 patients with Aspergillus osteomyelitis described by Mouas and colleagues, spondylodiskitis occurred in 9, sternum or rib infection in 6, and appendicular osteomyelitis in 5. This report represents the largest study of cases of Aspergillus osteomyelitis treated with the same antifungal agent. Fourteen patients were immunocompromised. Two patients received voriconazole as first-line therapy and 18 as salvage treatment. The median duration of voriconazole therapy was 83.5 days (range, 4–395 days). Using Global Response criteria, 11 (55%) of the 20 patients has a complete response (n=4) or partial responses (n=7). Among the four patients with complete response, there were no relapses of Aspergillus osteomyelitis.
For patients who are intolerant of or whose infections are refractory to voriconazole, one of the following agents is indicated: lipid formulations of amphotericin B (liposomal amphotericin B, amphotericin B lipid complex) or an anti-Aspergillus triazole (itraconazole, posaconazole). The data supporting the role of an echinocandin in management of Aspergillus osteomyelitis are more limited. An echinocandin (caspofungin, micafungin, or anidulafungin) may be best utilized in combination with an antifungal triazole or lipid formulation of amphotericin B either as primary therapy or salvage therapy.
Duration of medical therapy of Aspergillus osteomyelitis is not well defined. The study by Mouas and co-authors found that there was a direct relationship between length of therapy and successful treatment. Among the 11 patients with complete or partial responses, the median duration of voriconazole therapy was 180 days, as compared with 14 days among the 9 patients with unsatisfactory responses. However, one must also consider that the patients who received longer therapy may have had an intrinsically more favorable prognosis to survive to receive a more extended course of treatment.
Surgical intervention consists primarily of debridement of necrotic bone, which achieves the effect of reduction of organism burden and increased perfusion of antifungal agent into residual infected tissue. Additional orthopedic interventions are warranted where structural instability is threatened in weight bearing bones, such as the vertebral bodies and femurs. The presence of prosthetic material in the form of a joint, cement, or other inanimate matrices promotes biofilm formation and precludes adequate perfusion of the antifungal agent to that site. Consequently, prosthetic material is removed where possible in order to achieve successful local eradication of Aspergillus osteomyelitis. While the study by Mouas and colleagues did not discern a difference in outcome between patients with adjunctive surgery and those without surgery, some patients within the latter population may have been considered ill to undergo surgical intervention. Nonetheless, there may be a role for medical therapy to be followed by surgical resection if the former is not successful.
Innate Host Defenses
The status of innate host defenses is an important determinant of outcome in Aspergillus osteomyelitis. Mouas et al. found that among six patients who were considered to have no “significant” immunosuppresion five (83%) had a complete or partial response to voriconazole therapy of their Aspergillus osteomyelitis in comparison to six (43%) of 14 patients with significant immunosuppression. Reversal or amelioration of immunosuppression is important for a durable therapeutic response for Aspergillus osteomyelitis. Withdrawal of corticosteroids and recovery from neutropenia are critical factors in restoring innate host defenses. Other strategies for augmenting innate host response host are control of graft versus host disease (GVHD) and treatment of concomitant cytomegalovirus infection in HSCT recipients and use of interferon-gamma in patients with chronic granulomatous disease (Al-Tawfiq and Al-Abdely, 2010). The role of interferon-gamma is not well defined for other immune impairments. G-CSF and GM-CSF are used for recovery from neutropenia in most protocols where protracted courses of chemotherapy-induced neutropenia are anticipated. Attainment of remission of an underlying neoplastic process, especially in hematological malignancies, is critical for survival as well as in mounting an effective host response to Aspergillus spp.
Duration of therapy is predicated largely on the experience of bacterial osteomyelitis. When a combined medical and surgical intervention has been achieved with reversal of immunosuppression, duration of treatment of 6-8 weeks is recommended. Nonetheless, despite these measures, local recurrence of Aspergillus osteomyelitis may still develop. For those patients in whom reversal of immunosuppression is not achievable, protracted antifungal therapy for the duration of immunosuppression is necessary in order to prevent recurrence or progression. Such patients include those with primary immunodeficiencies, refractory aplastic anemia or myelodysplasia, as well as those with persistent requirements of corticosteroid therapy for GVHD and other autoimmune disorders.
ASPERGILLUS OSTEOMYELITIS OF DISTINCT ANATOMIC SITES
Vertebral Osteomyelitis and Discitis (spondylodiscitis)
Vertebral osteomyelitis with or without discitis is the most common osteoarticular manifestation of Aspergillus.  It may be caused by hematogenous dissemination from a distant site, by traumatic or surgical inoculation, or more rarely, from adjacent tissues, usually lungs. Host factors associated with Aspergillus vertebral osteomyelitis include chronic granulomatous disease, primary monocyte killing deficiency, chronic obstructive pulmonary disease treated with inhaled or systemic corticosteroids, intravenous corticosteroid treatment, solid organ transplantation, HSCT, diabetes mellitus, hematological malignancies, illicit intravenous drug use, pulmonary aspergillosis, and prior back surgery. Finally, there are several case reports of Aspergillus vertebral osteomyelitis in apparently immunocompetent individuals (Vaishya & Sharma, 2004).
Clinical manifestations of Aspergillus spondylodiscitis vary dramatically and may include back pain that ranges from mild to severe, fever, weight loss, and neurological symptoms as sequelae of epidural abscess or structural damage. When aspergillosis extends into the epidural space there is a higher likelihood of spinal cord compression.
Indications for timely surgical intervention depend on the presenting clinical symptoms, the extent of injury, and the likelihood that the patient is clinically stable in order to withstand surgery. Surgical intervention may include emergent decompression in cases of symptomatic compression of neural structures, abscess drainage, laminectomy, discectomy, partial or radical debridement, and spinal stabilization or use of autograft, i.e., rib or iliac crest bone.
Sternal aspergillosis is strongly associated with thoracic surgery.  The route of infection is likely through direct inoculation of the wound through surgery, post-operative wound care or airborne transmission of conidia. Consistent with the airborne route of inoculation is a report about a nosocomial outbreak of documented Aspergillus flavus sternal osteomyelitis during hospital construction, a known risk factor for Aspergillus infection.
Aspergillus sternal osteomyelitis may present in the immediate post-operative period, or later in the ensuing weeks, months, or even years after the operation. Intravenous drug users are also susceptible to develop sternal aspergillosis, particularly in the sternoclavicular joints. Sternal aspergillosis is commonly associated with concurrent mediastinal abscesses or polymicrobial wound infections. Another report associates A. flavus sternal osteomyelitis with relapse despite medical and surgical treatment.
Surgical debridement and removal of any hardware (e.g., wires commonly used in surgical procedures) is an important aspect of treatment when possible. If an abscess is present, drainage, and marsupialization with part of the omentum majus or other plastic reconstructive procedures have been successfully performed.
Osteomyelitis of the Ribs and Long Bones
Patients with chronic granulomatous disease, immunosuppressed recipients of solid organ transplants and individuals who have experienced traumatic or surgical inoculation of affected bones are commonly affected by aspergillosis of ribs and long bones.  Case reports have documented aspergillosis of ribs postoperatively after coronary artery bypass grafting, or associated with intravenous drug usage in cases of vertebral aspergillosis. Primary rib and long bone aspergillosis in immunocompetent individuals may rarely occur.
MRI and CT of thorax are the gold standards for diagnostic imaging of rib osteomyelitis. Of note, pericostal edema can be diagnosed by ultrasound scan.
Surgical management may involve debridement, drainage of associated abscesses, resection of affected ribs and skeletal stabilization when necessary. Occasionally, irrigation of open surgical wounds with antifungal agents may be utilized.
Invasive Aspergillus Mastoiditis
Invasive Aspergillus mastoiditis may develop as an extension of infection from the middle ear into the mastoid process, petrous and temporal bones.  Characterized by otalgia, otorrhea, hearing loss and cranial nerve deficits, Aspergillus mastoiditis may be indolent or rapidly progressive. Chronic fungal otitis media and regional surgical procedures may progress to invade the petrous bone, transverse venous sinus, and the cranial nerves, resulting in sinus thrombosis, cranial nerve palsies, and high mortality.
Among the patients reported with Aspergillus mastoiditis are those with diabetes mellitus, hematologic malignancy, chronic granulomatous disease, systemic lupus erythematosus treated with prednisone and azathioprine, and post-operative wound infections (Moh’s micrographic surgery for Bowen’s disease of the ear). However, Aspergillus mastoiditis may also occur in the immunocompetent host. The integrity of the tympanic membrane may or may not be impaired. Masked mastoiditis is a subclinical infection with intact tympanic membrane.
CT and/or MRI are essential to evaluate the extent of disease, and guide and provide the indications for surgical otolaryngologic intervention. Serial scans are warranted for postoperative monitoring.
Since concurrent pyogenic infection may complicate diagnosis having a high index of suspicion of both bacterial and fungal pathogens is important, as progression of untreated disease may cause permanent hearing loss, or CNS involvement, and eventually death.
Surgical intervention depends on the patient’s clinical stability and disease burden. Although medical management alone has been reported, aggressive local debridement is indicated in most cases for optimal outcome. Depending upon the extent of disease, radical mastoidectomy may be the best surgical option. Decompression of the facial nerve should also be attempted when indicated.
Medical management is directed to systemic antifungal therapy with voriconazole as the initial therapy. As voriconazole penetrates the central nervous system well, treatment of concomitant cerebral infection will also be achieved.
Cranium and Mandible
Aspergillus osteomyelitis of the cranium and mandible may occur as a sequela of other infectious processes, e.g., invasive Aspergillus otitis or sinusitis.  There are different routes via which Aspergillus may invade the temporal bone and lateral skull base, such as the external ear or the tympanic cavity during the process of acute or chronic otitis media. Aspergillosis of the skull may also develop secondary to traumatic or surgical inoculation.
Host factors are similar to those of other forms of Aspergillus osteomyelitis. Clinical signs vary based on location and may include pain, local swelling, nasal discharge, and/or cranial nerve deficits. In a review of forty cases of invasive mycoses of the skull base or temporal bone, 70% of cases presented with an isolated paresis or palsy of the facial nerve and four patients experienced involvements of IX-XII cranial nerves. Changes in vision are particularly of concern, as at least one patient with Aspergillus sinusitis and orbital involvement was misdiagnosed with ischemic optic disk secondary to involvement of II, III, IV, and VI (along with V1) cranial nerves. When the mandible is involved, fever, local swelling, and necrotic gingivitis are common symptoms.
Combined surgical and medical therapy is usually indicated. However, because resection is likely to be incomplete, prolonged medical therapy with limited surgical intervention is frequently indicated. Surgical debridement is the mainstay of treatment, and advances in endoscopic surgical technology allow for debridement, irrigation, and minimally invasive resection of the infected bone material. In cases of aspergillosis of the temporomandibular joint, open debridement of the joint may be necessary. In patients with mandibular aspergillosis, resection of the infected and necrotic bone along with molar extraction, where necessary, is performed. Serial instillation of antifungal agents is applied by some surgeons concomitantly with systemic antifungal therapy. In cases of skeletal structural damage either due to invasive infection, or trauma, corrective surgery may be necessary. Orbital involvement may necessitate ophthalmologic intervention.
Joint space infection caused by Aspergillus spp. is uncommon. In a 1990 review of 2,121 cases of invasive aspergillosis, 33 cases were characterized by bone involvement, and of these, only 2 were associated with septic arthritis (Denning & Stevens, 1990). Septic arthritis may be subsequent to hematogenous dissemination of pulmonary aspergillosis, dissemination from adjacent bone tissue infection, or associated with traumatic or surgical manipulation. Aspergillus septic arthritis is commonly associated with intra-articular corticosteroid injections and orthopedic hardware. Other host factors that may exist simultaneously, with or independent of iatrogenic inoculation of Aspergillus into the joint, include malignancy and its management, neutropenia, solid organ or HSCT receipt, GVHD, alcoholic cirrhosis, and chronic granulomatous disease. Aspergillus septic arthritis rarely occurs in an otherwise healthy host, independent of any potential iatrogenic inoculation.
Aspergillosis of the joint space also may occur in the context of disseminated aspergillosis. An infected joint may be painful and swollen. It may be associated with limited range of motion, and severity of presentation can range from mild, indolent disease, to acute, severe, pain. Other symptoms include fever and weight loss. Arthrocentesis is both diagnostic and therapeutic, and MRI is the gold standard in the diagnosis of a possible associated osteomyelitis.
Treatment of Aspergillus septic arthritis includes medical management, as well as arthrocentesis and if indicated, debridement of the infected bone. In cases complicated by indwelling hardware, surgical management includes removal of hardware and, when necessary, staged re-implantation.
Aspergillosis of the Small Bones of upper and lower limbs
Aspergillus osteomyelitis of upper and lower limbs is seldom reported (Rajkomar & Moss, 2006; Hodiamont et al, 2009).The thumb as well as cuneiform and navicular bones have been occasionally infected in patients with aplastic anemia and chronic granulomatous disease. Surgical intervention includes resection of the necrotic part of the bone. Aspergillus osteomyelitis may mimic bacterial infections. Thus, high index of clinical suspicion is recommended for early diagnosis and prompt initiation of treatment.
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Dr. Thomas J. Walsh,
Director, Transplantation-Oncology Infectious Diseases Program
Weill Cornell University Medical Center
1300 York Ave., Rm A421
New York, NY 10065
TEL: 212-746-6320 (main office)