Atypical Infections

Radiography

Radiography should be the initial imaging modality in evaluation of any musculoskeletal infection. Differentiation of tuberculous and atypical mycobacterial musculoskeletal infection is not possible in most cases.

Early radiographic findings include soft tissue swelling related to inflammatory changes, followed by bone involvement. Radiographic characteristics of atypical mycobacterial musculoskeletal infections have not been well delineated for each group. Multiple lesions predominate over solitary lesions, the metaphyses and diaphyses of long bones are commonly involved, and discrete lytic lesions may have sclerotic margins. Osteoporosis may not be as prominent as in tuberculous infection, there may be a tendency for development of abscesses and sinus tracts, and articular disease can simulate tuberculosis or rheumatoid arthritis.

Atypical mycobacterial osteomyelitis shares similar morphologic abnormalities with tuberculous spondylitis (Pott disease).

The findings in mycobacterial osteomyelitis of the spine may include involvement of one or several contiguous vertebral bodies that may result in kyphosis, destruction of the intervening disks, absence of reactive sclerosis, and formation of soft tissue abscesses, usually containing calcifications. Soft tissue abscesses may extend into the epidural space or may spread into adjacent soft tissue structures. The infection may include a single end plate or noncontiguous levels.

The triad of Phemister, consisting of osteoporosis, peripheral marginal erosions, and slowly progressing destruction of articular cartilage, characterizes mycobacterial arthritis. If untreated, mycobacterial arthritis can result in severe osseous destruction and fibrous ankylosis. Less frequently, a linear periostitis and bone proliferative changes may be seen.

Magnetic Resonance Imaging

Magnetic resonance imaging is regarded as the most sensitive imaging method for the early detection of osteomyelitis and may show the absolute extent of the inflammatory process, thus contributing to preoperative planning. Infected areas demonstrate decreased signal intensity on T1-weighted sequences and increased signal intensity on T2-weighted and short tau inversion recovery (STIR) sequences. T1-weighted imaging with fat saturation after the intravenous administration of a gadolinium-based contrast medium may allow detection and delineation of the extent of epidural involvement in spinal infection, may indicate whether the infection is limited to soft tissues or to bones and joints, and may show the absolute extent of the inflammatory process and delineate abscesses, thus contributing to preoperative planning ( Figs. 70-1 through 70-3 ; also see eFig. 70-3 online at ExpertConsult).

Multidetector Computed Tomography

Computed tomography is superior to radiography in depicting early cortical erosions, bone fragmentation, small fluid collections, cloacae, bone sequestra, and increased intraosseous density that corresponds to the accumulation of pus replacing bone marrow fat. Contrast-enhanced CT may also facilitate visualization of abscesses and necrotic tissue, may provide supplemental diagnostic information regarding paraspinal and intraspinal extension of infection, and may characterize the extent of bone and disk involvement, which may be not be visible on radiography. In addition, CT can be used to facilitate percutaneous biopsy of infected areas (see Fig. 70-3 and eFig-70-3).

Ultrasonography

Ultrasonography may be used in diagnosis of atypical mycobacterial soft tissue infection and septic joint. It can be used to guide percutaneous aspiration, biopsy, or drainage of the infected soft tissue structures or joints. Ultrasonography has a limited value in diagnosis of osteomyelitis.

Nuclear Medicine

Technetium-99m methylene diphosphonate ( ^99m Tc-MDP) scintigraphy may be useful in differentiating cellulitis from subjacent osteomyelitis. It is also useful in evaluation of multifocal infection. In patients with cellulitis, accumulation of the radionuclide in the infected area is increased during the angiographic and blood pool images of a three-phase scintiscan, whereas in patients with osteomyelitis a focal increase in the accumulation of the radionuclide is evident in all three phases of the scintiscan. Indium-111–labeled leukocytes may be helpful in differentiating cellulitis from osteomyelitis. However, MR imaging is the preferred imaging modality for evaluation of musculoskeletal infections and should be performed, if there are no contraindications, rather than bone scintigraphy.

Positron Emission Tomography/Computed Tomography

The value of positron emission tomography (PET) in evaluation for atypical skeletal mycobacterial infection has not been determined. PET is usually performed for unrelated reasons (e.g., oncologic imaging) and may be of value for detection of occult foci of infection in patients with sepsis of unknown origin.

Medical Treatment

Patients with tuberculosis caused by atypical mycobacteria are treated by regimens containing amikacin, a fluoroquinolone, rifabutin, clarithromycin, or clofazimine, to which they are more susceptible, along with other standard chemotherapeutic drugs. The outcome of treatment in patients with mycobacterial infections is more favorable in previously healthy individuals than in patients with underlying disease.

Surgical Treatment

Antimycobacterial chemotherapy alone usually is not sufficient. Whenever possible, surgical débridement of infected tissue, followed by chemotherapy is recommended.

Radiography

Radiographic findings of brucellar spondylodiskitis resemble those of pyogenic or tuberculous infection and include destructive changes of the affected vertebrae and intervertebral disks, sclerosis, paravertebral abscess formation, and healing with bony fusion and osteophytosis. Large parrot beak–like osteophytes can be seen with spinal brucellosis ( Fig. 70-4A ). In early disease, initial radiographs may be normal and the diagnosis can be delayed. The earliest radiographic finding is epiphysitis of the anterosuperior angle of the vertebra. Osteoporosis, large soft tissue abscesses, and paraspinal calcifications are more common in tuberculosis than in brucellosis. Brucellar spondylodiskitis shows less disk space loss and more common bony ankylosis of the affected vertebrae than is seen in tuberculous infection. Peripherally located gas within the intervertebral disk can be seen in brucellar infection.

Radiologic findings of sacroiliitis include poor definition of the cortex, narrowing or widening of the joint space, erosive changes, sclerosis, and ankylosis. With involvement of peripheral joints, joint effusion, periarticular soft tissue swelling, and joint space narrowing can be observed that may be associated with osteomyelitis. Initial radiographs are frequently unremarkable. In patients with periarticular brucellosis, soft tissue swelling is seen on radiographs.

Magnetic Resonance Imaging

Magnetic resonance imaging is the study of choice in the diagnosis and evaluation of the extent of disease in brucellar spondylodiskitis and osteomyelitis. Vertebral destruction, epidural abscesses, and spinal cord and nerve root compression are nicely demonstrated by MRI. Involvement of the apophyseal joints is common. Abnormal signal in vertebral bodies without morphologic changes and enhancement of the facet joints after intravenous gadolinium-based contrast agent injection have been identified as specific MRI features of brucellar spondylitis. The lesions display low signal intensity on the T1-weighted images, high signal intensity on the fluid-sensitive sequences, and enhancement on the postcontrast images ( eFig. 70-4 ). Postcontrast images are useful in delineation of paraspinal and intraosseous abscesses (see eFig. 70-4DE ). MRI is the study of choice in the evaluation of brucellar arthritis, osteomyelitis ( eFig. 70-5A-C ), and periarticular soft tissue infection.

Multidetector Computed Tomography

Computed tomography is useful in evaluation of brucellar spondylodiskitis (see eFig. 70-4B ). However, it has been reported that some cases were initially misdiagnosed as lumbar disk herniation or tuberculosis. CT is also useful in evaluation of brucellar arthritis and osteomyelitis.

Ultrasonography

Ultrasonography may be used in evaluation of joint effusions, synovitis, and bursitis caused by brucellar infection and may provide guidance for fluid aspiration. It has particular roles in detecting abscess formation and is better than MR in this function. Ultrasonography is the best means of guiding biopsy and aspiration.

Nuclear Medicine

Radionuclide bone scintigraphy with ^99m Tc-MDP is useful in the evaluation of osteoarticular brucellosis and shows increased radiotracer uptake in the affected regions. Bone scintigraphy is particularly useful in searching for multifocal disease. However, scintigraphy is not very useful in determining the outcome of brucellar musculoskeletal infection, because the abnormal radiotracer uptake persists for a long time.

Positron Emission Tomography/Computed Tomography

The utility of PET/CT in evaluation of brucellar musculoskeletal infection is to be determined. There is a case report suggesting the usefulness of PET scanning in detection of skeletal brucellar infection in a patient with human immunodeficiency virus (HIV) infection.

Medical Treatment

Osteoarticular brucellosis is treated with a combination of two or three antibiotics, including ciprofloxacin, doxycycline, tetracycline, rifampicin, and streptomycin, with median duration of therapy of 6 to 8 weeks. If the patient does not respond to the usual treatment regimen or the disease relapses, longer treatment of 3 to 6 months or different regimens are sometimes needed.

Surgical Treatment

Each patient should be evaluated individually, based on clinical findings, laboratory data, and radiologic results, when undergoing treatment for brucellar spondylodiskitis. In the patients with spinal involvement and spinal instability or radiculopathy, surgery is performed. If abscesses are found, a longer course of treatment and even surgical intervention may be needed.

Radiography

Radiography in patients with lymph node enlargement shows soft tissue swelling, mass, or both. Bone lesions may develop remote from the inoculation site, involving the axial and appendicular skeleton. The radiographic appearance of bone lesions is nonspecific and resembles other lytic lesions, such as eosinophilic granuloma or malignancies. The lesions are generally lytic, although associated sclerosis and periosteal reaction have been described.

Magnetic Resonance Imaging

Magnetic resonance imaging is a useful modality for evaluation of both lymphadenopathy and rare skeletal lesions. An enlarged lymph node, which is typically seen in the axillary and epitrochlear regions, demonstrates heterogeneous low signal intensity on T1-weighted images and high signal intensity on fluid-sensitive sequences. On T1-weighted images after intravenous administration of gadolinium-based contrast medium, peripheral enhancement of the lesion may be seen with nonenhancement of a central necrotic region. Diffuse heterogeneous enhancement of infected lymph nodes can also be observed. Surrounding soft tissue edema is common ( eFig. 70-6 ). Bone lesions demonstrate intermediate-to-low signal intensity on the T1-weighted images and high signal intensity on the fluid-sensitive sequences ( eFig. 70-7 ). *

* References .

Multidetector Computed Tomography

On CT images, enlarged lymph nodes often appear ill defined and may display a central low attenuation consistent with necrosis. Extensive soft tissue edema in an efferent lymphatic distribution is observed. Skeletal lesions demonstrate the same characteristics as on radiographs.

Ultrasonography

Ultrasonography can be used in evaluation of lymphadenopathy and soft tissue edema as well as liver and splenic lesions.

Nuclear Medicine

On bone scintigrams, the lesions demonstrate increased radionuclide uptake.

Positron Emission Tomography/Computed Tomography

A PET/CT scan shows increased radiotracer uptake in the affected lymph nodes and visceral and skeletal lesions.

Medical Treatment

In most patients who are immunocompetent, cat-scratch disease is self-limited, and symptoms resolve in 2 to 4 months. Effective antibiotics used in treating cat-scratch disease include rifampin, ciprofloxacin, trimethoprim-sulfamethoxazole (TMP-SMX), and gentamicin. Clarithromycin, azithromycin, and tetracycline are likely to be effective. Although data are lacking, patients with cat-scratch disease who are treated should receive treatment for 10 to 14 days. Immunocompromised patients may require much longer courses of therapy and multidrug therapy.

Surgical Treatment

In a patient with lymphadenopathy and skeletal lesions caused by cat-scratch disease, surgical treatment is typically not indicated. If needed, biopsy is performed. In a few cases in which the diagnosis was not initially recognized and simulated soft tissue sarcoma and osteomyelitis, surgical drainage and evacuation of the suppurated lymph node was performed. In one case, irrigation and débridement of spinal infection was performed. The patients recovered without sequelae.

Coccidioidomycosis

Coccidioidomycosis (valley fever) is a systemic infection caused by the soil fungi Coccidioides immitis and Coccidioides posadasii . It is endemic in northern Mexico and the southwest part of the United States, including Texas, New Mexico, Arizona, California, and parts of South America. The fungus is saprophytic but highly infective. It exists in the mycelial form within the soil and becomes infective when the airborne arthrospores are inhaled. In the infected host, the arthrospore develops into a spherule, which may contain a few to several hundred endospores. Each endospore may then enlarge to spherule form ( Fig. 70-5 ). The endospore-spherule cycle in the host continues indefinitely unless it is altered by an immune reaction or the endospore is extruded from the tissue. The extruded endospore may germinate in the soil within a week to produce hyphae and the mycelial-arthrospore cycle. There is no known human-to-human or animal-to-human transmission. The lungs are the primary focus of infection, but less than 40% of patients have symptomatic disease. Of these, less than 1% develop disseminated disease, which is often fatal and may involve any organ, including skin, lymphatics, lungs, osseous structures, liver, kidneys, and CNS.

Skeletal coccidioidomycosis is seen in 10% to 50% of patients with disseminated disease. It is frequently multicentric and may involve almost any bone, although the axial skeleton is more frequently involved. At least three risk factors have been described that may lead to disseminated coccidioidomycosis: ethnicity (Filipino, African American, Native American, Hispanic), gender (male more often than female), and immunosuppression. All age groups can be affected, but patients younger than 5 years or older than 50 years are more likely to develop disseminated disease. Symptoms and signs can be prominent and include pain, swelling, and draining abscess. Skeletal involvement can be seen as osteomyelitis or septic arthritis. A self-limited migratory sterile polyarthritis (“desert rheumatism”) occurs as a hypersensitivity syndrome in 33% of cases. Septic arthritis usually occurs due to direct extension from an adjacent bone and rarely due to hematogenous spread. The most commonly involved joints are ankles and knees. Coccidioidal bursitis, tenosynovitis, and soft tissue abscesses can occur.

In 2009, Adam and colleagues performed a retrospective analysis of 150 cases (at that time, the largest series) with extrapulmonary nonmeningeal disseminated coccidioidomycosis seen from 1996 to 2007 at the referral medical center in an endemic region. In this study, hematogenous dissemination was associated with high mortality and occurred primarily in immunocompromised patients, but only 30% of patients with more limited forms of dissemination were immunocompromised. As in the prior studies, the disease was more common in male patients (nearly 2 : 1) and patients of African or Asian descent. In contrast, Hispanics and diabetic patients were not at increased risk. Serology was frequently negative in immunocompromised patients, and the diagnosis could be established by isolation of the organism in culture or in histologic or cytologic specimens. Twenty-eight patients (21 male) had involvement of the axial skeleton and 26 (18 male) of the appendicular skeleton. Soft tissue (muscle or lymph node) involvement was present in 15 patients (13 male); skin involvement was present in 16 patients (9 male). Fifteen patients (10 male) had multisystem disease. The skeletal system was involved in 13 of the patients with multisystem disease and 3 of those with hematogenous infection, in addition to those with axial and appendicular skeletal disease, for a total of 70 (47%). In the axial skeleton, vertebrae were almost always infected, and one of the patients had calvarial involvement. Despite the lack of mortality, there was high morbidity, including a frequent requirement for multiple surgical débridements. Of 26 patients with appendicular skeletal disease, 14 presented with joint disease. Eleven of those with articular infections had radiographic evidence of associated osteomyelitis. Patients with soft tissue abscesses most often had lymphadenitis or muscle abscesses with 75% involving the upper part of the body. In the lower extremities, soft tissue involvement was typically seen in the thigh or pelvic regions.

A positive serology test is diagnostic.

However, serologic testing can be negative, especially in immunocompromised patients. Enzyme immunoassays (EIAs) are available commercially and are probably more sensitive than other tests, but there are occasional false-positive results, especially for immunoglobulin M. The gold standard complement fixation (CF) test is less widely available and has been replaced in authors' institution by an immunodiffusion (ID) assay. The CF and ID tests (as well as EIA) can be titered, and higher titers (typically greater than 1 : 16) are correlated with disseminated disease. However, in the authors' experience, about half of patients had a negative serologic test or a titer less than 1 : 8 at the time of initial presentation.

Biopsy reveals granulomatous lesions similar to tuberculosis with monocytes, giant cell epithelial cells, necrosis, and caseation. Differentiation requires isolation of the causative organism.

The differential diagnosis includes lytic metastatic disease, multiple myeloma, Kaposi sarcoma, and other fungal or mycobacterial infections.

Coccidioidomycosis is a reportable disease in the United States. In 2006, 8917 new cases were reported. Most of these cases occurred in California and Arizona. During the period 2000 to 2006, the number of reported cases and hospitalizations for coccidioidomycosis in California increased each year, before decreasing in 2007. Increasing numbers of people moving into endemic regions and advances in medical treatment that result in impaired cell-mediated immunity may increase the risk for disease.

North American Blastomycosis

Blastomycosis is caused by the fungus Blastomyces dermatitidis and is most common in the southeastern United States, the Ohio-Mississippi Valley area, and the mid-Atlantic states. It is also endemic to part of Africa. The primary infection is often pulmonary, but the skin may be a portal entry for infection in some cases after cutaneous injuries. Hematogenous dissemination may occur to lungs and other organs. The most common sites for dissemination include skin, skeletal structures, and the genitourinary tract. An abscess can develop in the subcutaneous soft tissue and spread to the other viscera, lymph nodes, and skeletal structures. The peak age is between 20 and 50 years, but both males and females may be affected at any age.

Osteomyelitis is seen in 14% to 60% of patients with disseminated blastomycosis, which can be the result of hematogenous seeding or direct extension from the adjacent soft tissues. The most common sites of skeletal involvement are the vertebrae, skull, ribs, and distal half of the extremities, but any bone can be affected. In the long bones, the infection typically begins in the epiphysis or subarticular region. Metaphyses of the long bones and small bones are also frequently involved. Blastomycotic septic arthritis is common after dissemination, with most frequent involvement of the elbows, knees, and ankles. The presentation of blastomycosis clinically and radiographically is nonspecific and often mistaken for a neoplasm. Delay in diagnosis is common. Patients with osseous blastomycosis may present as pain, swelling, abscesses, septic joints, and draining sinuses. The osseous lesions may also be asymptomatic.

The definite diagnosis is made through identification of B. dermatitidis in body fluids, tissue, or cultured material. Serologic testing is available but not reliable.

Histologic examination reveals round and broad-based budding yeast with an associated pyogranulomatous reaction. Another important finding is thermal dysmorphism on cultures.

South American Blastomycosis

South American blastomycosis is caused by the fungus Blastomyces (Paracoccidioides) brasiliensis . The disease is endemic to South America and parts of Mexico and Central America. The causative fungi invade the pharynx and then spread locally or hematogenously to other body sites. The musculoskeletal involvement is similar to that of North American blastomycosis.

Cryptococcosis

Cryptococcosis (torulosis, European blastomycosis, Busse-Buschke disease) is a worldwide fungal infection caused by the encapsulated fungus Cryptococcus neoformans , which has an unusual predilection for the CNS. The causative fungus can be found in the respiratory tract, intestinal tract, or skin in healthy individuals or can be recovered from the soil, pigeon droppings, or fruit. The disease starts after inhalation of C. neoformans aerosolized spores to the lungs with possible hematogenous spread to the brain, meninges, visceral organs, bones, and joints. Cryptococcosis is the fourth most life-threatening infection in patients with AIDS. It can also be seen in the other immunocompromised patients and patients with chronic diseases, including leukemia, lymphoma, Hodgkin disease, sarcoidosis, tuberculosis, diabetes mellitus, and transplant patients. Less often, this disease occurs in otherwise healthy individuals or immunocompetent patients. Neurologic manifestations include dizziness, ataxia, diplopia, headache, and convulsions; the disease is frequently lethal.

In the patients with disseminated disease, skeletal involvement occurs in 5% to 10% of cases. The most common site of skeletal involvement is the spine. The other common locations are pelvis, ribs, skull, tibia, and bones about the knees. Bony prominences can be involved. A single site of infection can be present, but the disease can also be multifocal. On occasion, the infection can be implanted into bone during soft tissue injury.

Cryptococcal septic arthritis is rare and usually is a result of extension from the adjacent bone. This can later result in destructive changes of the involved joint. Bursal infections or tenosynovitis are rare.

Adults are affected more frequently than children. Patients present with swelling and pain.

For definitive diagnosis, a tissue sample is needed. The diagnosis can also be made by positive serology.

The granulomatous infection caused by C. neoformans is similar to that of sarcoidosis, and differentiation between the two disorders may be difficult. There is a striking paucity of cellular reaction. Absence of suppuration and necrosis is typical.

Sporotrichosis

Sporotrichosis is a chronic fungal infection caused by Sporothrix schenckii . This fungus resides as a saprophyte on vegetation and in soil. It can invade the human body through a skin wound or a thorn puncture. Sporotrichosis is a recognized occupational hazard of florists and farmers, in whom the dominant upper limb is commonly affected. Human disease can also result from animal bites from rats, mice, gophers, cats, and parrots.

Most of the time, this infection is limited to the skin and subcutaneous soft tissues, but hematogenous dissemination that includes bones and joints can occur. The disease starts with an erythematous, ulcerated, or varicose nodule on the skin with common subsequent nodular lymphangitic spread. Extracutaneous sporotrichosis results from hematogenous spread from the primary inoculation site or from inhalation of conidia. Disseminated disease is more common and can be fatal in immunocompromised patients. Sporotrichosis is seen worldwide but mainly in warm and tropical areas.

The skeletal involvement includes osteomyelitis or septic arthritis. The osteomyelitis progresses slowly and can affect a single location or be multifocal. The most commonly involved bones are tibia, fibula, femur, humerus, and short tubular bones of hands and feet. Both large and small extremity joints can be involved. The synovial bursae can be involved. Indolent tenosynovitis can be observed, usually around the wrist and ankle.

Skeletal findings of sporotrichosis are similar to those seen in tuberculosis and other fungal disorders, but involvement of small joints of hands and feet is more common.

Definitive diagnosis is made by fungal culture. The organisms are rarely seen in biopsy specimens owing to their small number.

Histoplasmosis

Histoplasmosis is an infection caused by a dimorphic fungus Histoplasma capsulatum , which is present in the United States predominantly in the Ohio and Mississippi river valleys as well as in certain areas of Central or South America, or H. capsulatum var. duboisii , present in Africa. Both species cause the same disease. H. capsulatum is a soil fungus.

The disease usually starts in the lungs after inhalation of fungal spores, but the gastrointestinal tract can be the portal of entry in some patients. The fungi proliferate in the reticuloendothelial system. The vast majority of human infections are self-limited and asymptomatic. The disease can spread hematogenously to other organs, including bones. Skeletal involvement is more common with H. capsulatum var. duboisii infection with predilection to flat and small tubular bones. The radiologic findings are similar to those in tuberculosis and sarcoidosis.

With H. capsulatum infection, children are infected more commonly than adults. Joints as well as bones can also be affected. Sometimes, joint involvement is a result of hypersensitivity reaction to H. capsulatum . Tenosynovitis caused by this fungus can occur. Fasciitis and myositis caused by this organism have also been reported.

With histoplasmosis caused by H. capsulatum var. duboisii , granulomatous ulcerating and papular skin lesions can be associated with bone and joint involvement in as many as 80% of patients. The disease is frequently multifocal, predominantly involving the flat bones, but the spine and tubular bones can be involved.

The diagnosis can be made with antigen testing from urine or blood. Fungal cultures from the affected tissues are also useful. With the involvement of bone marrow, noncaseating granulomas are seen in histologic specimens. Histologic findings of histoplasmosis are similar to those in sarcoidosis and tuberculosis.

Aspergillosis

Aspergillosis is a fungal disease defined as any illness other than mycotoxicosis caused by various Aspergillus species. These fungi are ubiquitous and include the human upper respiratory tract, but disease is uncommon. The severe and invasive form of aspergillosis is typically seen in immunocompromised patients, in whom it represents an opportunistic infection with a high mortality rate. The most common causative organism is A. fumigatus .

Skeletal involvement is rare and usually occurs as a result of hematogenous dissemination, which is more common in adults, or of direct invasion of pulmonary disease into the chest wall, which is more common in children. Vertebral, rib, or sternal involvement follows after respiratory infection, but the other skeletal sites can be involved. Aspergillous spondylitis can occur in both immunocompetent and immunocompromised patients of any age. This is generally related to a contiguous spread of pulmonary disease, with the thoracic spine most commonly involved. Spinal involvement resembles tuberculous spondylitis. Contiguous spread of this infection is also observed in the orbital bones. Involvement of the appendicular skeleton is rare. Aspergillous arthritis is rare and usually associated with osteomyelitis.

The diagnosis can be made with serology, but the result can be false negative. The definite diagnosis is made by fungal culture.

Candidiasis

Candidiasis (moniliasis) is a fungal infection caused by several species of Candida . The major causative organism is C. albicans . Other pathogenic Candida species include C. tropicalis, C. guilliermondii, C. krusei, C. lusitaniae, C. rugosa, C. pseudotropicalis, C. parapsilosis, C. glabrata , and C. lambica . This fungus is common in normal human flora and presumably resides on mucous membranes. Candidiasis represents an opportunistic infection that is mainly seen in patients with indwelling catheters, in intravenous drug abusers, and in immunocompromised patients.

In disseminated disease, involvement of bones and joints is uncommon and occurs in 1% to 2% of patients. Candidal osteomyelitis can affect any age group. The most commonly involved bones are the pelvis, sternum, and scapula. The ribs, spine, and tubular bones of the extremities can also be involved. Spine infection can occur from the direct extension of a contiguous infection or secondary to hematogenous seeding, with involvement of the lumbar spine most common. Candidal osteomyelitis cannot be differentiated from other bacterial or fungal infections by imaging.

In a recently published series of 207 patients in the period 2007 to 2011 in a large academic center, median patient age was 30 years (range, 1 month or less to 88 years) with a male : female ratio greater than 2 : 1. Most patients (90%) were not neutropenic. Localizing pain, tenderness, and/or edema were present in 90% of patients. Mechanisms of bone infection followed a pattern of hematogenous dissemination (67%), direct inoculation (25%), and contiguous infection (9%). Coinciding with hematogenous infection, most patients had two or more infected bones. The most common distribution of infected sites for adults was vertebra and for pediatric patients femur. Non- albicans Candida species caused 35% of cases.

Septic arthritis caused by C. albicans can occur by hematogenous spread owing to direct invasion from infected adjacent osseous or soft tissue structures, or from joint replacement surgery. The most commonly affected joint is the knee. Monarticular involvement is more common than polyarticular involvement.

Candidal pyomyositis is rare. Septic bursitis can also occur. Osteoarticular candidiasis is seen in approximately one third of heroin addicts with most typical osteochondral involvement.

Systemic candidiasis is an iatrogenic disease of modern neonatal intensive care that deserves urgent attention for its prevention as well as effective treatment to minimize neonatal morbidity and mortality. The sources of candidiasis in neonatal intensive care units are often endogenous after colonization of the newborns with fungi. About 10% of these newborns are colonized in the first week of life, and up to 64% are colonized by 4 weeks of hospital stay. Disseminated candidiasis presents very much like bacterial sepsis and can involve multiple organs, such as the kidneys, brain, eyes, liver, spleen, bones, joints, meninges, and heart.

Confirming the diagnosis by laboratory tests is difficult, and a high index of suspicion is required. The definitive diagnosis of fungemia can be made only by recovering the organism from blood or other sterile body fluids. With bone or joint involvement, the diagnosis is made by isolation of the organism from joint aspirate or sampled material.

Mucormycosis

Mucormycosis is the most acute, fulminant, and fatal of all fungal infections in humans. It is also known as zygomycosis and phycomycosis. This infection is caused by fungi of the class Zygomycetes and order Mucorales, usually including the genera Rhizopus, Absidia, Mortierella , and Mucor . The organisms exist in soil and air.

The frequency of mucormycosis has been increasing over the past 10 years; infections have been identified in up to 6.8% of patients at autopsy. The most common route of transmission for Zygomycetes fungi is inhalation of spores from the environment. Patients at highest risk for infections caused by Mucorales fungi include those with profound immunosuppression or diabetes, intravenous drug abusers, premature infants, those receiving deferoxamine, and recipients of bone marrow transplants. Mucormycosis commonly presents as rhinocerebral or pulmonary disease; gastrointestinal presentations also occur. The preexisting disease influences the port of entry, but usually the lesions start from the paranasal sinuses. Hematogenous dissemination of the disease can also occur. Clinical manifestations of invasive mucormycosis are tissue necrosis and subsequent thrombosis. Common features of pulmonary disease include fever, dyspnea, hemoptysis, and cavitation on radiologic examination.

From the paranasal sinuses, the infection extends to the adjacent structures: to the lateral wall of the middle turbinate, hard palate, ethmoidal sinus, maxillary sinuses, orbit, retrobulbar region, and sphenoidal sinus. Intracranial extension and maxillary sinus thrombosis can occur. Imaging shows destructive osteolytic lesions in the involved osseous structures, but in chronic cases osteosclerosis is also evident.

The differential diagnosis of mucormycosis includes other types of osteomyelitis and neoplasm.

Involvement of other osseous structures is rare and reported in spine, femur, knee, tibia, and cuboid bones.

The Zygomycetes are easily identified in a tissue sample by the presence of predominantly aseptate (pauciseptate) wide, ribbon-like hyphae and of tissue necrosis and angioinvasion. The diagnosis can be made by fungal culture, but the result is frequently false negative.

Overall, disease with the Mucorales tends to be fulminant and is uniformly fatal if not aggressively treated. Even with appropriate surgical and medical management, the vast majority of patients are expected to die of this disease process.

Maduromycosis

Maduromycosis (mycetoma) is a chronic, granulomatous, subcutaneous, inflammatory disease caused by the true fungi of the Eumycetes class or the filamentous bacteria of the Actinomycetes. These infections are most prevalent in India, sub-Saharan Africa, the southern part of the Arabian Peninsula, and Central and South America. The disease was named after the Madura District of India, where it was described for the first time by Gill in 1842.

The causative organisms are present in the soil and may enter the subcutaneous tissue by traumatic inoculation. Mycetoma commonly affects the feet in adults aged 20 to 40 years, who are usually male. Both forms of mycetoma present as a progressive, subcutaneous swelling, but actinomycetoma has a more rapid course. After soft tissue contamination, the causative organism may penetrate the underlying muscles, tendons, bones, and joints. Multiple nodules develop that may suppurate and drain through sinuses, discharging grains during the active phase of the disease with subsequent contiguous involvement of the bones. Sinus tracts arising from the affected bones are common. Infections of the hands, arms, legs, or scalp are less common. In the United States, the most frequent cause of Madura foot is Petriellidium boydii ( Monosporium apiospermum ), although Aspergillus, Penicillium, Madurella, Cephalosporium, Streptomyces , and Phialophora can be causative organisms. Outside the United States, Nocardia species ( N. brasiliensis, N. madurae ) may cause this disease.

The diagnosis may involve radiology, cytology, culture, histology, immunodiagnosis, and serology. Mycetoma lesions can be diagnosed by fine-needle aspiration biopsy and cytology. They are characterized by the presence of polymorphous inflammatory cells consisting of neutrophils, lymphocytes, plasma cells, histiocytes, macrophages, and foreign-body giant cells and grains. There is no known human-to-human or animal-to-human transmission.

Actinomycosis

Actinomycosis is an uncommon noncontagious suppurative infection caused by gram-positive filamentous obligate or facultative anaerobic bacteria of the Actinomyces species, which belong to the normal flora of the intestinal tract and oral cavity. The most common causative organism is A. israelii . These organisms represent higher bacteria and are frequently misclassified as fungi. Some of the other human Actinomyces pathogens are A. bovis, A. naeslundii, A. viscosus , and A. odontolyticus .

In tissues, Actinomyces aggregate into microcolonies and grow in a radial configuration, with the peripheral layer of organisms having club-shaped ends. These microcolonies form the characteristic sulfur granules. Actinomycosis is frequently associated with other organisms.

Actinomycosis is usually seen in debilitated patients or in devitalized tissue. Trauma is important in the inoculation of the organism into the soft tissue. Aspiration or ingestion of foreign bodies, such as teeth or fish bone, is another predisposing factor. The usual localizations of this disease are cervicofacial, pulmonary, or gastrointestinal. The cervicofacial location is the most common and is seen in 40% to 55% of patients. Contiguous spread of this disease is more common than hematogenous. There is a tendency for fistulization, and soft tissue abscesses also can occur.

Musculoskeletal actinomycosis is more commonly the result of the direct spread of disease rather than hematogenous seeding. Bone infection ranges between 1% and 15% in all patients with actinomycosis. The most commonly involved bones are the mandible, axial skeleton, as well as the major joints of the appendicular skeleton, but other bones can be involved. The lesions can occur after extraction of a tooth or after a human bite.

Diagnosis of skeletal actinomycosis is difficult and is often delayed until an advanced stage of the disease. The diagnosis is made by the isolation of the causative organism from the sampled biopsy material as well as the isolation of the sulfur granules, which are characteristic histologic findings. Successful isolation requires culturing multiple samples in enriched media under anaerobic conditions in the presence of carbon dioxide.

Nocardiosis

Nocardia are gram-positive organisms that belong to the aerobic Actinomycetes. Human Nocardia pathogens include N. asteroides, N. brasiliensis, N. farcinica , and N. caviae .

Humans are infected via the respiratory tract or gastrointestinal tract or through skin trauma. Immunocompromised patients and patients with chronic diseases are more susceptible to this disease. Pulmonary infection may extend into the chest wall. Skin infection may extend into the adjacent soft tissue and lead to cellulitis and soft tissue abscesses. Primary infection of the bursae is rare. The most common sites of nocardiosis are the lungs, followed by the CNS and soft tissues. The other extrapulmonary sites are rare.

Bones and joints are more commonly affected by contiguous extension from the adjacent tissues or rarely by hematogenous seeding. The tubular and flat bones and the spine can be affected.

The clinical and radiologic manifestations of musculoskeletal nocardiosis are nonspecific and resemble those of Mycobacterium tuberculosis and fungal infections.

The diagnosis is made by identification of branching filaments in tissue specimens, Gram staining, and culture.

Radiography

Coccidioidomycosis

Radiographs frequently show multiple lytic osseous lesions with permeative borders or well-defined punched-out lytic lesions with or without sclerotic borders. There is predilection to the metaphyses of long tubular bones and bone protuberances. In the tubular bones of hands and feet, diaphyseal lesions are common. Soft tissue swelling and periosteal reaction and periostitis can be present, but sequestration is uncommon. Sclerosis is an attempt to heal or contain the lesion. The intervertebral disks are relatively spared, and vertebral body collapse is an uncommon and late manifestation. In patients with septic arthritis osteoporosis, joint space narrowing and bone destructive changes are similar to those seen in other granulomatous infections ( Figs. 70-6 through 70-10 ).

North American Blastomycosis

Early in the disease process, there may be no visible osseous radiographic abnormalities, or there could be faint osteopenia in the involved location. Later, an area of lucency is seen with either ill-defined or well-defined borders. The radiographic appearance can be variable, but an eccentric lytic lesion without sequestrum or periosteal reaction is common. However, a periosteal reaction also can be present. The lesions are often mistaken for benign or malignant bone tumors. Skeletal lesions can appear moth-eaten and can be associated with osteoporosis. Sclerotic margins can also be seen, as well as an area of cortical erosion beneath the soft tissue abscesses. The metaphyseal lesions tend to be eccentric, well circumscribed, and lytic. In the spine the blastomycotic infection resembles tuberculosis ( eFigs. 70-8 and 70-9 ).

Cryptococcosis

The skeletal lesions may be lytic with well-defined margins and mild surrounding sclerosis. Aggressive periosteal reaction is infrequent. Spinal cryptococcosis resembles pyogenic infection with more frequent paravertebral abscesses and extradural cryptococcal granulomas. Extradural granulomas can cause myelopathy and cauda equina syndrome. There can be extension of the vertebral body infection into the pedicle or adjacent rib. Lytic lesions without a sclerotic margin and with associated soft tissue swelling can also be seen ( eFig. 70-10 ).

Sporotrichosis

Skeletal lesions are lytic or patchy or have a moth-eaten appearance, usually without periosteal reaction. The findings with joint involvement include joint effusion, periarticular soft tissue swelling, joint space loss, and destructive changes ( eFig. 70-11 ).

Aspergillosis

The radiographic features of skeletal aspergillosis resemble those of tuberculosis. Spinal involvement includes osseous and intervertebral disk destruction and paraspinal masses. If other skeletal sites or joints are involved, destructive changes of typical osteomyelitis with or without associated periostitis can be seen. With septic joints, periarticular osteopenia, joint space loss, and erosive changes are observed ( eFig. 70-12A ).

Candidiasis

In vertebral osteomyelitis caused by Candida , there are erosive and destructive changes and possible intervertebral disk involvement. Extension into the paravertebral soft tissues or spinal canal can occur.

With candidal arthritis, radiography shows massive soft tissue swelling, joint effusion, joint space narrowing, erosions, bone collapse, and fragmentation ( eFigs. 70-13 and 70-14AB ).

Maduromycosis

The many findings in maduromycosis of the foot include soft tissue swelling, bone scalloping and cortical erosions, aggressive periostitis, coarse trabeculation, sclerosis and mottling, cavitary lesions, and, in advanced disease, intraarticular osseous fusion leading to an appearance of melting snow. Bone cavities are larger, fewer, and better defined in eumycetoma when compared with actinomycetoma. These cavities are filled with solid masses of grains and fibrous tissues, providing a bone support. Because of this phenomenon, pathologic fractures in mycetoma are rare. Radiographic findings in the skull are purely sclerotic, with dense bone formation and loss of trabeculation. In advanced maduromycosis, osteoporosis is seen that occurs secondary to disuse and compression of the bone and its blood supply by a mycetoma ( eFigs. 70-15 and 70-16A ).

Magnetic Resonance Imaging

Coccidioidomycosis

Magnetic resonance imaging reveals lesions of intermediate-to-low signal intensity on T1-weighted images and increased signal intensity on T2-weighted and STIR sequences. The MR signal characteristics are nonspecific. Intraosseous and soft tissue abscesses show rim enhancement. MRI is particularly useful in finding the local osseous and soft tissue extent of disease and spinal involvement. In septic arthritis, enhancement of synovial proliferation usually indicates active disease (see Figs. 70-7C-E, 70-8C-E, 10A-C ; eFig. 70-17 ).

North American Blastomycosis

Magnetic resonance imaging is helpful in evaluation of local osseous and soft tissue extension of the lesion. MRI findings are nonspecific and include increased signal intensity on T2-weighted images and decreased signal intensity on T1-weighted images ( eFig. 70-18AB ).

Cryptococcosis

Magnetic resonance imaging is useful in detection and evaluation of local extent of cryptococcal osteomyelitis and soft tissue abscesses. The lesions can demonstrate enhancement on the postcontrast images ( eFig. 70-19 ).