Musculoskeletal Manifestations of Disseminated Fungal Infections

Abstract

» Disseminated musculoskeletal fungal infections, though rare, present significant diagnostic and therapeutic challenges, affecting both immunocompromised and previously healthy individuals.

» Ubiquitous species (spp.) such as Candida, Aspergillus, and Cryptococcus contrast with dimorphic fungi, including Histoplasma capsulatum, Blastomyces spp., and Coccidioides spp., which are endemic to specific regions.

» These infections typically present insidiously, with non-specific symptoms such as fever, joint pain, and swelling that mimic autoimmune, bacterial, or viral diseases, often leading to delayed diagnosis.

» Initial evaluation often includes radiographs, which may reveal lytic bone lesions, particularly in the metaphyses of long bones, as well as in less conspicuous sites such as the talus and cuboid. Even with this information, a definitive diagnosis still requires histological or microbiological evidence prior to initiating some antifungal treatments.

» This review synthesizes current knowledge on disseminated musculoskeletal fungal infections, emphasizing their epidemiology, pathogenesis, clinical manifestations, diagnostic strategies, and treatment.

Introduction

Disseminated musculoskeletal fungal infections are rare¹. Their severity poses significant diagnostic and therapeutic challenges to patient care and treatment. These infections are traditionally thought to often occur in immunocompromised individuals, including those with hematological malignancies, solid organ transplants, or long-term corticosteroid use^2,3. However, clinical experience and literature review demonstrate that previously healthy patients can be susceptible to disseminated musculoskeletal fungal infections^3,4. In late autumn at our institution in upstate New York, a previously healthy 9-year-old boy presented with numerous violaceous ulcerating skin lesions and subtle complaints of migratory joint pains without apparent arthritis on physical examination until the 2-week follow-up visit. The cutaneous findings, frequent summertime outdoor activities, known regional endemicity of local fungal pathogens, and concern for musculoskeletal dissemination prompted an investigation for endemic mycosis through multimodal diagnostics including cultures, serologies, and antigen testing as well as imaging which altogether revealed a diagnosis of disseminated blastomycosis due to Blastomyces dermatitidis. There are 7 species of Blastomyces: B. dermatitidis, B. gilchristii, B. percursus, B. helicus, B. parvus, B. silverae, and B. emzantsi. B. dermatitidis is the predominant species, followed by B. gilchristii and B. helicus, found in North America. Recently, we have seen several cases of blastomycosis from New York, indicating a possible regional environmental niche of this fungus.

Early recognition and intervention through a high index of clinical suspicion is important, as delayed treatment is associated with high morbidity and mortality³. Organisms involved in disseminated fungal musculoskeletal infections are diverse and vary by geographic region (e.g., endemic mycoses) as well as the host’s immune status. Common ubiquitously found species (spp.) include Candida spp., Aspergillus spp., and Cryptococcus spp. Dimorphic fungi such as Histoplasma capsulatum, Blastomyces spp., and Coccidioides spp. have restricted environmental niches and are endemic to specific regions. Opportunistic pathogens, such as the Mucorales order and Fusarium spp, have gained recognition in recent years, particularly in patients with profound immunosuppression⁵. Polymerase chain reaction (PCR)–based assays and next-generation sequencing have improved pathogen identification. However, gaps remain in early and accurate diagnosis. This is true in resource-limited areas, which are the most susceptible population given their geographic location in rural settings closer to riverbeds and valleys that have fungi endemic to the soil⁶.

The nonspecific and indolent nature of clinical presentations poses a significant challenge in diagnosing disseminated musculoskeletal infections. Common symptoms such as fever, joint pain, and swelling can mimic numerous autoimmune conditions, viral, or bacterial infections. Magnetic resonance imaging (MRI), positron emission tomography (PET) scans, and computed tomography (CT) scans can be used to assess bone and joint involvement in fungal infections, but require confirmation through histology or microbiological evidence⁷. Therefore, understanding the host-pathogen interaction and the mechanism of fungal virulence is critical for optimizing treatment strategies and predicting disease outcomes⁸.

The complexity of disseminated musculoskeletal fungal infection management involves a combination of surgical intervention, effective antifungal therapy, and supportive care. Introducing antifungal agents such as echinocandins, azoles, and liposomal formulations of amphotericin B has significantly improved survival rates⁹. Unfortunately, treatment failure remains a concern due to drug resistance, host factors, or delayed diagnosis. Emerging therapies including immunomodulatory approaches and combination antifungal regimens hold promise but require validation through clinical trials¹⁰. This review synthesizes current knowledge on disseminated musculoskeletal fungal infections, focusing on epidemiology, pathogenesis, clinical manifestations, diagnostic strategies, and treatment.

Epidemiology

Disseminated musculoskeletal fungal infections are relatively uncommon but are recognized in immunocompromised populations such as those with malignancy, undergoing chemotherapy, afflicted with HIV/AIDS, having solid organ transplantation, or using immunosuppressive or corticosteroid therapy¹¹. Immunocompetent individuals with high-risk exposures, occupations, or outdoor activities in endemic areas can also have these infections; they arise from hematogenous spread of fungi to bones, joints, and soft tissues. Common organisms involved are Aspergillus, Candida, Histoplasma, Coccidioides, Blastomycosis, and Cryptococcus species, which vary in incidence and prevalence depending on geography and patient populations (Table I and Fig. 1)¹². Invasive fungal infections are particularly concerning due to their high morbidity and mortality rates, which can exceed 50% in severely immunocompromised hosts¹³.

Fig. 1.

Map of common fungi in the United States. Reproduced, with permission, from: [Created in BioRender. Light, J. (2025) https://BioRender.com/02tdu6r].

TABLE I.

Disseminated Musculoskeletal Fungal Infections Stratified by Geographical Region and Patient Population

Region/Population	Pathogen	Incidence/Prevalence	Notes
Southwestern United States	Coccidioides	∼100,000 infections/year; ∼1% (∼1,000 cases) disseminated, some to musculoskeletal sites	Endemic in Arizona, California; higher risk in immunocompromised and outdoor workers
Ohio/Mississippi River Valleys	Histoplasma	Millions infected/year; 0.05–0.1% (∼5,000-10,000 cases) disseminated globally, some musculoskeletal	Common in immunocompromised; underreported due to diagnostic challenges
Ohio/Mississippi River Valleys, Great Lakes, Southeastern United States	Blastomyces	<1 per 100,000 in endemic states; up to 40 per 100,000 in hyperendemic areas (e.g., Vilas County, Wisconsin)	Disseminated disease in 25%–30% of cases, including musculoskeletal involvement; higher incidence in males and outdoor workers
Diabetic patients	Mucor	∼14 per 100,000 in India; increasing incidence throughout the world; can cause disseminated musculoskeletal infections in diabetics	Higher burden in developing countries
Solid organ transplant recipients	Candida, Aspergillus	Invasive fungal infections: 3.1–42%; osteomyelitis as a subset	Vertebral osteomyelitis common with Aspergillus
Hematological malignancies	Candida, Aspergillus	Invasive fungal infections: 3–8%; musculoskeletal involvement rare	Higher risk due to neutropenia
HIV/AIDS patients	Cryptococcus, Histoplasma	Disseminated infections common with musculoskeletal involvement in endemic areas
Pediatric (Neonates)	Candida	1%–2% in very low birth weight infants	Long bones (femur, humerus) commonly affected
General population	Various	1–5 per 100,000 in developed countries; up to 20 per 100,000 in developing countries	Underreported due to diagnostic challenges

The incidence of fungal musculoskeletal infections has increased as life expectancy for immunocompromised individuals has increased from advancements in medical care. Global estimates suggest 6.55 million invasive fungal infections annually, but the direct data on the incidence involving the musculoskeletal system are limited due to underdiagnosis and underreporting^14,15. Patients undergoing hematopoietic stem cell transplantation or those receiving biologic therapies for autoimmune diseases are at elevated risk compared with the general population¹⁶. Candida and Aspergillus species account for a significant proportion of these infections, with Candida causing septic arthritis and osteomyelitis, and Aspergillus resulting in vertebral osteomyelitis and epidural abscesses¹⁰. In the United States, candidemia has an incidence of 7 per 100,000, with a portion involving the musculoskeletal system¹⁷. Musculoskeletal manifestations of Aspergillus are uncommon, with a systematic review reporting 310 cases from 1936 to 2010¹⁸. Geographically, Coccidioides and Histoplasma are predominant in specific regions such as the southwestern United States and the Ohio and Mississippi River Valleys, respectively^19,20. These fungi can lead to disseminated disease, including musculoskeletal involvement. In the southwestern United States, Coccidioides causes around 100,000 yearly infections with around 1% of those cases disseminating¹⁵. Between 1938 through 2013, over 100 outbreaks involving approximately 3,000 cases of Histoplasma have been reported in 26 states and the territory of Puerto Rico, and around 0.05 to 0.1% of those cases caused disseminated disease²¹. Blastomyces, also endemic in the Ohio and Mississippi River Valleys, Great Lakes region, and southeastern United States, has an annual incidence of less than 1 case per 100,000 in affected states (e.g., Wisconsin, Mississippi), with higher rates (up to 40 per 100,000) in hyperendemic areas such as Vilas County, Wisconsin; disseminated disease, which can include musculoskeletal involvement, occurs in 25% to 30% of cases, though specific musculoskeletal incidence is not well documented^22,23. Factors, such as global warming, have expanded the geographical distribution of many endemic fungi, posing a risk to both immunocompetent and immunocompromised individuals.⁴

Disseminated fungal infections are more common in men than women, possibly due to higher exposure risks in occupational settings or other environmental factors²⁴. Outdoor occupations traditionally held by men such as construction, excavation, landscaping, hunting, or agricultural work could explain this trend as these occupations are more likely to have exposure to fungi endemic in the dust and soil where they work⁴. Older adults and young children are at increased risk, particularly those with congenital or acquired immunodeficiencies. In pediatric populations, Candida infections are seen in neonates with low birth weight or those undergoing invasive procedures in neonatal intensive care units²⁵. Finally, increased global travel and the rising prevalence of invasive medical devices, such as central venous catheters and prosthetic joints, have contributed to the broader dissemination of fungal infections that are insidious and hard to diagnose^26,27. Table I summarizes fungal epidemiology.

Orthopaedic surgeons should be aware of fungal infections with a pattern of noncontiguous spread to 1 or more long bone or joint and spine (and ribs), as a general trend. Though direct inoculation is more common than disseminated fungal infections, common locations for disseminated fungal infections reflects that of bacterial hematogenous infections²⁸. The metaphysis of long bones is a culprit for infection because of the enriched blood supply by the metaphyseal and nutrient arteries²⁹. In adults, the pelvis is extremely rare (N = 0) according to some estimates²⁸. The lower extremities (LE), particularly the knee (67.8%), are more common sites of infection (94.6% of fungal infections involved the LE) compared with upper extremity joints²⁸. Generally, 1 joint involvement (78.8%) is more common than 2 (17.7%) or more (4%), but poly joint involvement can still occur in the immunocompromised host²⁸.

Pathogenesis

Disseminated musculoskeletal fungal infections are rare, but manifestations caused by the spread of fungal pathogens to bones, joints, and surrounding soft tissues can be devastating. The pathogenesis begins with fungal entry into the host through the respiratory or gastrointestinal tracts, directly through trauma or surgical procedures. Common causative agents include Aspergillus, Candida, Histoplasma, Coccidioides, Blastomycosis, and Cryptococcus. These pathogens can establish a localized infection and disseminate hematogenously to the musculoskeletal system in both immunocompetent and immunocompromised individuals¹⁰.

Once these fungi disseminate through the bloodstream, they adhere to and penetrate the endothelium. In osteoarticular tissues, the fungi trigger an intense inflammatory response mediated by proinflammatory cytokines such as tumor necrosis factor-alpha and interleukin (IL)-1β, IL-8, and particularly IL-17, which either helps to eliminate fungal infection or potentiate bone and cartilage damage (Fig. 2). Cytokines and the proinflammatory state promote local osteolysis, joint destruction, and granulomatous tissue formation³⁰. Bacterial osteomyelitis is frequently caused by Staphylococcus aureus and is characterized by severe systemic symptoms such as high fevers, chills, rigors, and sweating from robust immune activation by pathogen-associated molecular patterns and endotoxins³¹. This is in contrast to fungal osteoarticular infections, which typically have a more localized inflammatory response with mild or absent constitutional symptoms due to lower levels of pyrogenic cytokines and a lack of endotoxins seen in bacterial infections³². The fungi modulate host immune responses by altering macrophages and dendritic cells, suppressing antigen presentation and T-cell activation and allowing for further fungal dissemination. In advanced cases, fungal invasion of the musculoskeletal system can cause extensive bone necrosis, fistula formation, and soft tissue abscesses. The immune system is usually unable to eliminate the infection completely, causing extensive complications such as amyloidosis and systemic inflammatory response syndrome³³. Overall, this is less common and frequent than bacterial osteomyelitis³⁴.

Fig. 2.

Fungal inflammatory effect of T-cell activation on bone and cartilage destruction. Reproduced, with permission, from: [Created in BioRender. Light, J. (2025) https://BioRender.com/italuii]

Clinical Manifestations

Disseminated musculoskeletal fungal infections are clinically significant due to their often aggressive nature and potential for widespread tissue damage. Initially, these infections may present as upper respiratory tract infections or pneumonia refractory to antibiotics⁴. From there, they can disseminate to involve the bones, joints, skin, and soft tissues in the musculoskeletal system. Symptoms of these disseminated cutaneous and osteoarticular infections include localized pain, swelling, and erythema. Endemic fungal infections can mimic bacterial infections or malignancies, which commonly confounds the clinical picture and delays diagnosis. As the infection disseminates hematogenously and results in musculoskeletal disease, fever and systemic signs of infection such as fatigue and weight loss are more commonly but not always seen (Table II).

TABLE II.

Diagnostic Test Performance Metrics

Test	Sample Type	Sensitivity (%)	Specificity (%)	PPV (%)	NPV (%)
β-D-glucan	Serum	81	61	19	97
Galactomannan	Serum (cutoff 1.0)	79	88	-	-
Galactomannan	BAL (cutoff 1.0)	90	94	-	-
Aspergillus PCR	Blood/Serum (single +)	80.5	78.5	28	98
Aspergillus PCR	BAL	90.2	96.4	62	98
Histoplasma antigen	Urine/Serum	81.4	98.3	84–94	94–98
Blastomycosis urinary antigen	Urine	92.9	79.3	-	-
Coccidioides urine antigen	Urine	70.8	97.8	-	-
Coccidioides serology (EIA)	Serum	81.6–100	96–100	-	-
Histopathology	Tissue	∼50–80	95–100	-	-
Culture	Tissue/Fluid	∼50–70	∼100	-	-

PCR = polymerase chain reaction.

Clinically, patients may exhibit localized tenderness, reduced range of motion in adjacent joints, and chronic, refractory bone pain. Radiological findings may reveal osteolytic lesions, periosteal reactions, and soft tissue swelling which can be mistaken for malignancies or bacterial osteomyelitis³⁵. Joint involvement, or fungal septic arthritis, typically presents with monoarticular arthritis affecting large joints such as the knee or hip. Symptoms include joint pain, effusion, and warmth, with a reduced range of motion. Synovial fluid analysis shows elevated white blood cell counts with neutrophilic predominance, but cultures are required for definitive diagnosis. Candida species are a frequent cause of fungal arthritis, particularly in patients with prosthetic joints or those receiving long-term corticosteroid therapy³⁶.

Soft tissue fungal infections can manifest as cellulitis, abscesses, or necrotizing fasciitis. These infections can often follow trauma or surgical procedures and rapidly progress once the patient is fungemic. Necrotizing infections may exhibit severe systemic toxicity, requiring prompt surgical debridement and antifungal therapy. Common pathogens such as Mucorales and Aspergillus species thrive in ischemic or necrotic tissue environments³⁷.

Diagnosis

Establishing a diagnosis of a disseminated musculoskeletal fungal infection begins with a thorough history collection with special attention to outdoor activity and travel to endemic regions and any preceding history of respiratory infections. A detailed physical examination and laboratory findings may further support the diagnosis. Commonly abnormal laboratory results include elevated inflammatory markers such as C-reactive protein and erythrocyte sedimentation rate. A complete blood count can offer additional clues that an infectious process is involved if there is an observed increase in leukocytes³⁸. Molecular tests can detect fungal antigens (e.g., galactomannan for Aspergillus) or fungal-specific antibodies to suggest presence or absence of a fungal organism, but can be nonspecific, confounded by receipt of other medical interventions, and exhibit cross-reactivity. Therefore, definitive diagnosis requires cultures and histopathology³⁹. Consultation with an infectious diseases specialist is advised to assist in establishing a diagnosis and treatment plan.

Initial diagnosis can include radiographs to visualize bony abnormalities. If affecting the upper extremities, radiographs can show lytic lesions in the radius or ulna metaphysis. In the lower extremities, radiographs would show similar lytic lesions primarily affecting the distal metaphysis of femur, tibia or fibula. Along with lytic lesions, subtle lucency of the foot and ankle, including the talus and cuboid, and distal tibia can also be found in the lower extremities. Advanced imaging modalities such as MRI and CT are more sensitive, providing detailed information on the extent of pulmonary, bone, joint, and soft tissue involvement. MRI is an increasingly useful tool for detecting early bone marrow edema and soft tissue abscesses, suggestive features of osteomyelitis and cellulitis⁴⁰. Soft-tissue enhancement on MRI would be indicative of abscess from fungal infections and can point to dissemination in the musculature. On MRI, the ankle can have destructive lytic lesions found in the distal tibial metaphysis violating the cortex and extending to the margin of the distal tibial physis, along with soft tissue edema and periostitis. The foot shows T2 hyperintense and slightly T1 hyperintense peripherally enhancing collections within the cuboid, severe marrow and soft tissue edema, calcaneocuboid joint effusions, and increased T2 signaling in the talar head with microabscesses in the subtalar head. In the upper extremity, the following can be seen on MRI: destructive lytic lesions in the distal ulnar metaphysis that erodes the cortex in multiple locations, a thick-walled T1 hyperintense solid capsule, edematous and enhancing surrounding soft tissues with overlying subcutaneous edema, and increased signal in the physis. These radiographic findings are further supported in Supplemental Figures 1 to 6. Newer nuclear medicine imaging techniques such as PET/CT and Single-Photon Emission Computed Tomography (SPECT)/CT are ways to diagnose musculoskeletal infections, potentially improving diagnostics for infection of bones and joints⁴¹.

To evaluate fungal etiology from these nonspecific history, physical examination, laboratory, and radiographic findings above, microbiological or serologic confirmation is required. Blood cultures are the gold standard for diagnosing fungemia, particularly in those caused by Candida or Cryptococcus. Note, however, that many environmental and dimorphic (endemic) fungal organisms do not grow on aerobic blood cultures and require invasive tissue sampling. Synovial fluid, tissue, and bone biopsies should be evaluated for bacterial and fungal cultures, histopathological examination through fungal-specific stains such as periodic acid-Schiff (PAS) or Gomori methenamine silver (GMS), and molecular testing such as fungal species-specific PCR can also aid in making a timely diagnosis, as cultures may require a prolonged incubation period to grow or may be too fastidious to grow at all⁴². Finally, urine antigen and blood serologic testing should be considered in discussion with an infectious diseases specialist. These techniques, when used in conjunction, are useful in identifying fungal pathogens and guiding targeted antifungal therapy (see Supplemental Tables 1 and 2).

Newer non–culture-based techniques have emerged, such as PCR and next-generation sequencing, which offer rapid and precise identification of fungal pathogen, contrary to the extensive length of time required for blood, tissue, or fluid cultures which may even fail to yield an organism. While PCR and NGS are limited to highly specialized laboratories, adding them to clinical practice can help improve the diagnosis and management of fungal infections by allowing for earlier and more accurate pathogen diagnosis⁴³. These technologies can be used in patients with prior antifungal therapy or with polymicrobial infections, enhancing treatment specificity and improving the morbidity and mortality of disseminated musculoskeletal fungal infections. Fungal osteomyelitis can be challenging to distinguish from bacterial osteomyelitis due to overlapping clinical presentations. However, fungal osteomyelitis typically presents with an indolent course, characterized by chronic, persistent pain and swelling, whereas bacterial osteomyelitis, often caused by Staphylococcus aureus, has an acute onset with severe systemic symptoms such as high fever, chills, and rigors³¹. Risk factors of fungal osteomyelitis include immunosuppression, intravenous drug use, prosthetic devices, or a history of fungal infections, while bacterial osteomyelitis is more commonly associated with trauma, surgery, or contiguous spread from soft tissue infections⁴⁴. Radiologically, fungal osteomyelitis may show lytic lesions with sclerotic margins or multifocal involvement, reflecting its chronic nature, whereas bacterial osteomyelitis often presents with acute changes such as periosteal reaction or sequestrum formation⁴⁵. When clinical and radiological features are inconclusive, definitive diagnosis relies on laboratory tests mentioned earlier and histopathological examination with stains such as PAS or GMS to reveal fungal elements⁴².

Fungal osteomyelitis must also be differentiated from granulomatous infections such as skeletal tuberculosis (TB) and syphilitic osteomyelitis. Thorough history-taking of possible infectious exposures including outdoor activity, travel to or residence in TB-endemic regions, and sexual history is critical. Skeletal tuberculosis, often manifesting as Potts disease when involving the spine, typically presents with chronic pain, weight loss, night sweats, and radiological findings of vertebral collapse or cold abscesses. Diagnosis is confirmed by acid-fast bacilli (AFB) stains, cultures, or PCR for Mycobacterium tuberculosis⁴⁶. By contrast, fungal osteomyelitis may show noncaseating granulomas or fungal elements on histopathology and is more associated with immunosuppression or endemic fungal exposure⁴⁷. Syphilitic osteomyelitis, seen in tertiary syphilis, presents with gummas, chronic bone pain, and swelling. Diagnosis is established through serological tests like VDRL or FTA-ABS, and histopathology showing granulomas with central necrosis⁴⁸. While fungal osteomyelitis is granulomatous, it can be distinguished from syphilis by fungal organisms on culture or histopathology using PAS and GMS stains along with a lack of syphilis-specific serological markers. Other granulomatous lesions, such as actinomycosis, may mimic fungal osteomyelitis but are identified by sulfur granules on histopathology and anaerobic bacterial cultures⁴⁹.

Treatment

The treatment of disseminated musculoskeletal fungal infections is multifaceted and involves antifungal therapy, surgical intervention, and management of conditions that predispose patients to infection. Initiation of antifungal therapy on suspicion has been shown to reduce mortality risk by up to 43%⁵⁰. In patients with candidemia, delaying fluconazole therapy has been shown to increase mortality by 42% per day with each day in the delay of treatment⁵¹. Empiric broad-spectrum antifungal therapy is often initiated until culture data are available when there is suspicion of disseminated fungal infection¹⁰.

Disseminated Candida species infections are often treated with first-line echinocandin agents such as caspofungin or micafungin due to their excellent pharmacokinetics⁵². Azoles, such as fluconazole, are used for susceptible strains and in step-down therapy following clinical improvement. Fluconazole is particularly helpful in fungal periprosthetic infections and has shown to have significant clinical improvement when given for an average of 12.8 weeks⁵³. Liposomal amphotericin B, with its broad-spectrum activity, is reserved for severe or refractory cases. In cases of aspergillosis, voriconazole is used as the first-line therapy. Liposomal amphotericin B or isavuconazole can sometimes be used as alternatives in cases of drug intolerance or fungal resistance. However, major side effects can occur from the administration of these medications. Long-term use of azoles can cause hepatotoxicity, hormone-related effects, hypokalemia, hyponatremia, and rarely adrenal insufficiency⁵⁴. Amphotericin B, a widely used antifungal for disseminated infections, can cause severe nephrotoxicity⁵⁵. Monitoring for changes in electrolytes and overall patient health using these antifungal therapies is paramount to prevent further decline in patient health.

Surgical intervention is often necessary to achieve control of disseminated fungal infections, especially if cases involve abscesses, necrotizing soft tissue infections, or prosthetic joint infections, and should be pursued early. This not only allows for achievement of source control but also procurement of additional fluid and tissue specimens to establish diagnostic closure. Thorough and extensive debridement of infected bone and soft tissue reduces fungal load, enhances the effectiveness of antifungal therapy, and prevents further spread of infection. Antifungal beads, often made of polymethylmethacrylate or calcium sulfate, are placed in the debrided cavity to deliver high concentrations of antimicrobial agents directly to the infection site. These beads are effective in areas with poor vascularity and can be absorbable or require removal after infection control. While primarily studied for bacterial infections, antifungal bead use in fungal osteomyelitis is also possible as well, especially in cases of aspergillosis and candidiasis⁵⁶.

In severe cases, excision of the infected bone segment may be necessary, particularly if the infection is localized and the bone is not critical for structural integrity. Excision is followed by reconstruction using bone grafts or other techniques to restore stability⁵⁷. For large bone defects resulting from extensive debridement or excision, bone transport techniques, such as the Ilizarov method, are used. This involves gradually moving a healthy bone segment to fill the defect through distraction osteogenesis, promoting new bone formation. Bone transport is particularly useful in postinfectious tibial defects and has shown success in achieving bone union⁵⁸. Significant soft tissue defects require coverage with vascularized tissue, such as muscle flaps with the gastrocnemius and soleus or free flaps with the latissimus dorsi. Flaps are critical in complex cases involving both bone and soft tissue loss because they provide blood supply to promote healing, fill dead space, and prevent further infection⁵⁹. Intraoperative wound irrigation with saline or antiseptic solutions (e.g., povidone-iodine) is commonly performed during debridement to reduce microbial load and remove debris. While evidence specific to fungal osteomyelitis is limited, this practice is standard in orthopaedic infections to enhance surgical outcomes⁶⁰.

In fungal prosthetic joint infections, two-stage exchange is the most common approach and has a recurrence rate of 47.7% compared with 81.4% for debridement with implant retention and 30.0% for three-stage exchange, allowing for an overall treatment success rate of 60.2%⁵³. Knee prosthetic joint infections are associated with lower recurrence rates at 18.3% compared with hip prosthetic joint infections, having a recurrence rate of 29.6%⁵³. Complete synovectomy and implant removal are also typically required in fungal prosthetic joint infections as well^53,61. In all cases of surgical treatment, postoperative antifungal therapy is critical to prevent recurrence and should be guided by microbiological findings and clinical, and response to treatment.⁶² A treatment algorithm can help provide a systematic approach for fungal infections and approach the care of patients in a multidisciplinary manner (Fig. 3).

Fig. 3.

Treatment algorithm for disseminated musculoskeletal fungal infections. Reproduced, with permission, from: [Created in BioRender. Light, J. (2025) https://BioRender.com/1z12pjb].

Adjuvant therapies involving immunomodulation can be used as well. Granulocyte-macrophage colony-stimulating factor or interferon-gamma may be considered in highly immunocompromised patients to enhance the host’s defense mechanisms⁶³. Preexisting conditions such as diabetes should be addressed, along with tapering immunosuppressive treatment in patients with conditions such as lupus or those receiving organ transplant. In these patients with immunosuppression, long-term antifungal prophylaxis will be necessary to prevent recurrence of the disseminated infection⁶⁴. An understanding of the risk factors for recurrence is essential, which includes Candida albicans infection, Charlson Comorbidity Index ≥ 3, and elevated C-reactive protein. Protective factors include antifungal-loaded spacers and knee joint involvement^53,61.

Despite advances in antifungal therapy in disseminated infections, outcomes can vary and are sometimes suboptimal secondary to delayed diagnosis, fungal resistance, and the immunocompromised status of patients. Recurrence rates range from 18.3% to as high as 81.4%^53,61. Newer treatments such as rezafungin and ibrexafungerp, along with combination therapy strategies, are under investigation to improve outcomes in fungal infections⁶⁵. Advances in diagnostic techniques and personalized therapies tailored to each patient can help improve issues with delayed diagnosis and suboptimal outcomes, giving hope of better outcomes in patients with disseminated musculoskeletal fungal infections.

Appendix

Supporting material provided by the authors is posted with the online version of this article as a data supplement at jbjs.org (http://links.lww.com/JBJSOA/A904). This content was not copyedited or verified by JBJS.