Unremitting Pain and Fever in a 15-Year-Old Boy With Osteomyelitis

A healthy 15-year-old boy was admitted for fever and worsening toe pain in the setting of recent complicated osteomyelitis of the right great toe. Approximately 4 weeks before admission, he was evaluated by his primary care physician for cough and wheezing and received amoxicillin and clavulanate and a 6-day prednisone dose pack for presumed viral-induced reactive airway disease with possible secondary bacterial infection. His respiratory symptoms improved over 1 week. Three weeks before admission, he developed right toe pain and redness and received ibuprofen and an intra-articular dexamethasone injection at a podiatry clinic for possible gout. He presented to an outside hospital (OSH) 2 days later with new-onset fever. Inflammatory markers were elevated, with C-reactive protein (CRP) of 141 mg/L and erythrocyte sedimentation rate (ESR) of 95 mm/hour. MRI of the foot confirmed a diagnosis of osteomyelitis with an associated periosteal abscess. The patient was admitted to the OSH for an incision and drainage (I&D) procedure and received empirical intravenous (IV) vancomycin and piperacillin and tazobactam. He improved with resolution of his fever and a decreased CRP of 112 mg/L. The results of bacterial wound cultures (aerobic and anaerobic) and blood cultures remained negative. After 7 days of IV antibiotics, he was transitioned to oral linezolid and discharged from the hospital with plans to complete 2 weeks of oral antibiotic therapy. He was referred to the pediatric infectious disease clinic at our institution and was improving 1 week postdischarge with decreased pain and downward trending inflammatory markers, with CRP 75.9 mg/L and ESR 60 mm/hour. Laboratories were also significant for a creatinine of 1.06 mg/dL, which was elevated from his baseline creatinine obtained at the OSH (0.8 mg/dL).

Five days later, the patient experienced acute-onset severe pain of the right great toe, with associated fever and nausea, and presented to the emergency department for further evaluation. The patient endorsed significant pain refractory to oral pain medications, intermittent low-grade fevers, and increased drainage from the surgical site of the right great toe. He denied abdominal pain, chest pain, coughing, myalgia, sore throat, headache, or vomiting. He had remained non–weight bearing since his initial diagnosis of osteomyelitis and reported adherence to oral linezolid therapy.

His past medical history was negative for asthma, recurrent infections, or other chronic disease. His family history was unremarkable. He lived with his parents on a farm and was up to date on all immunizations. He did not report recent travel, exposure to pets and/or farm animals, or sick contacts. He denied sexual activity and tobacco or IV drug use.

On physical examination, he was nontoxic appearing and afebrile at 99.8°F, with a pulse of 99 beats per minute, blood pressure of 127/85 mm Hg, and a respiratory rate of 23 breaths per minute. He appeared distressed when evaluating the toe secondary to pain. Head and neck examination was benign, without lymphadenopathy. Cardiopulmonary, abdominal, and neurologic examinations were unremarkable. Examination of the right first metatarsophalangeal joint revealed edema and severe tenderness to palpation, with limited range of motion and intact pulses and sensation. The toe skin was ecchymotic with bloody purulent discharge from a 5-cm wound from the previous I&D on the medial aspect of the right great toe, with pooling of drainage in the wound dressing (Fig 1).

Initial laboratory data were notable for a white blood cell (WBC) count of 21.2 × 10³/μL, with a high absolute neutrophil count at 15.9, an ESR of 76 mm/hr, and a CRP of 210.3 mg/L.

Dr Potisek, what is the typical presentation and clinical course of acute hematogenous osteomyelitis (AHO)?

AHO is frequently encountered in the hospital, with an estimated incidence rate of 1.34 to 1.66 cases per 100 000 children.¹  Nearly 50% of cases occur in children <5 years of age.^2,3  Patients with AHO typically present with fever accompanied by vague symptoms of fatigue or decreased activity. Especially in older children, it is common to detect focal tenderness along with redness, warmth, and/or a decreased range of motion of the affected area. The lower extremity and pelvis region are common sites of infection, and patients may have concomitant septic arthritis and/or bacteremia.¹  Initial laboratory results may reveal an elevated WBC count, ESR, and CRP. The results of blood cultures become positive in <50% of cases.⁴  Diagnosis is confirmed by characteristic findings on MRI.

Common causative organisms for AHO include methicillin-sensitive Staphylococcus aureus, methicillin-resistant S aureus (MRSA), Streptococcus pneumoniae, and group A Streptococcus. Group B Streptococcus must be considered in infants, particularly if the upper extremities are involved. Kingella kingae should be considered when encountering AHO in the toddler age group.⁵  Osteomyelitis is rarely caused by unusual organisms, including endemic fungi (eg, Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum, and Cryptococcus neoformans), other fungi (eg, Aspergillus spp. in patients with chronic granulomatous disease), Mycobacterium tuberculosis, and anaerobic bacteria (eg, Actinomyces spp.).

Empirical antibiotic therapy should be directed against the suspected causative organisms and local resistance patterns. Previously, children with AHO received an extended course of IV antibiotic therapy for a minimum of 4 weeks; however, several studies have demonstrated early transition to extended therapy with oral antibiotics is safe, with similar rates of treatment failure.⁶  The timing to transition to oral antibiotic therapy can be guided by clinical examination findings and CRP trends.⁷ 

Dr Potisek, what were your initial thoughts on why this patient was presenting with worsening symptoms and clinical examination?

The majority of children with AHO respond well to oral antibiotic therapy, so the fact he had worsening symptoms and an upward trend of his inflammatory markers was worrisome. In his age group, MRSA and methicillin-sensitive S aureus will be the predominant organisms responsible for AHO, which should respond well, and initially did, to linezolid. With his clinical change, I would be worried about reaccumulation of the abscess previously drained, treatment failure, potential nonadherence to the oral antibiotic regimen, an unusual pathogen not covered by the current antibiotic regimen, or less likely, a rheumatologic or oncologic process.

As a result, I would admit the patient with a plan to repeat imaging of the toe with an MRI, looking for any abscess reaccumulation, and consult the pediatric infectious disease team regarding antibiotic therapy with this unusual course. Once an antibiotic regimen was determined, I would trend CRPs, along with clinical symptoms, to gauge the patient’s response.

The patient was admitted to the pediatric hospital service for failure of outpatient therapy, and the pediatric infectious disease team recommended initiating IV daptomycin for empirical antibiotic therapy for AHO.

Dr Shetty, why was daptomycin selected as the first antibiotic? What are possible adverse effects of daptomycin in a 15-year-old patient?

Antistaphylococcal antibiotics, such as vancomycin and clindamycin, were also considered for empirical therapy. However, this patient had an elevated serum creatinine level one week before presentation, causing concern for potential nephrotoxicity. The rise in serum creatinine is likely related to the continued use of nonsteroidal antiinflammatory agents and use of vancomycin and piperacillin and tazobactam during his recent hospitalization. Given the need for optimal coverage for MRSA for complicated osteomyelitis in the setting of possible renal complications, IV daptomycin was chosen as alternative antistaphylococcal therapy while awaiting culture data.⁸ 

Daptomycin, a bactericidal cyclic lipopeptide antibiotic, reveals concentration-dependent killing of MRSA and other Gram-positive bacteria. Compared with other standard-of-care agents, daptomycin has comparable efficacy for S aureus bacteremia and complicated skin infection in children.⁹ 

Daptomycin is generally safe and well tolerated; because myositis is a potential adverse effect, a creatine kinase level was obtained before antibiotic administration in this patient.^9,10 

Repeat MRI revealed enhancement in the great toe proximal phalanx, with multiple areas of cortical destruction compatible with acute osteomyelitis. Osteomyelitis was also noted in the base of the great toe distal phalanx and the first metatarsal head, with soft tissue inflammation and phlegmonous change extending circumferentially around the great toe.

The patient was taken to the operating room for biopsy, where a large amount of necrotic tissue and nonviable bone of the great toe proximal and distal phalanges were identified. The first metatarsophalangeal joint revealed septic arthritis associated with a deep tissue abscess necessitating I&D. Bacterial (aerobic), fungal, and mycobacterial cultures were obtained.

After the procedure, the patient reported significant reduction in pain but continued to have intermittent fevers up to 100.9°F. Repeat laboratories revealed improvement in inflammatory markers, with WBC count of 14.9 × 10³/μL and CRP of 111.3 mg/L.

Despite clinical improvement, the right great toe was amputated because of the substantial necrosis of the phalanx. CRP continued to decline to 101.5 mg/L while the results of wound cultures remained negative. Because of the complicated course, the decision was made to place a peripherally inserted central catheter (PICC) line for long-term antimicrobial therapy.

Dr Potisek, what is the role of parenteral antibiotics in AHO requiring amputation? What are some of the benefits and complications of PICC lines in AHO?

In the case of AHO requiring amputation, parenteral antibiotics are used after the procedure to ensure microbial eradication. On the basis of experience in adults with diabetes complicated by lower-extremity osteomyelitis, a 2-week course of pathogen-directed therapy is recommended by experts if there is microbial and pathologic evidence that surgical debridement yielded clean margins. Parenteral antibiotics may be administered until the patient is stable for discharge, at which point this treatment may be exchanged for highly bioavailable oral antibiotics. If clear margins cannot be confirmed, then it is recommended that parenteral antibiotics be maintained for 4 to 6 weeks, at which point a PICC line is beneficial for safe administration.¹⁰ 

PICC lines allow for long-term IV delivery of high concentrations of antibiotics, which may be helpful in more complex or refractory cases of AHO. Some of the complications we see in PICC lines in AHO are infections, thrombosis, and mechanical issues, especially with use longer than 2 weeks.^11,12 

After PICC placement, a postprocedure chest radiograph revealed diffuse patchy and nodular opacities (Fig 2). Pathology from the bone specimen revealed numerous budding fungal yeast elements within granulomatous inflammation, but the results of preliminary fungal cultures remained negative.

The pediatric infectious disease team was further consulted, and the patient was started on empirical oral itraconazole.

Dr Sangueza, what did you see on the pathology specimen? Which pathogens did you suspect were causing this infection?

A skin biopsy of sections stained with hematoxylin and eosin revealed well-formed granulomas admixed with neutrophils in the mid-deep dermis and subcutaneous tissue. At higher magnification, there were numerous round to oval organisms with a thick capsule. These organisms were highlighted with periodic acid–Schiff and Grocott’s methenamine silver (GMS) stains. GMS staining revealed organisms with a simple bud, which suggested infection with B dermatitidis, as opposed to South American blastomycosis, which has multiple buds (Fig 3). Another fungus to include in the differential diagnosis is C neoformans, which has a characteristic halo that was not seen on pathology assessment.

Dr Shetty, which fungal pathogens did you suspect were involved in this infection? Which antifungals would you recommend, and are there any complications we should consider with these medications?

The differential diagnosis of invasive fungal infection in previously healthy hosts includes endemic mycoses (such as blastomycosis, histoplasmosis or coccidiomycosis). Cryptococcus should also be considered. Blastomycosis was the most likely pathogen because the disease occurs in the southeastern United States. For mild to moderate disease, oral itraconazole for 6 to 12 months is recommended; in moderate to severe disease, treatment with liposomal formulation of amphotericin B followed by 6 to 12 months of oral itraconazole is recommended. Common adverse effects of lipid formulations of amphotericin include fever, chills, infusion-related reactions, nephrotoxicity (although this is relatively less frequent compared to amphotericin B deoxycholate), and hepatotoxicity. Common adverse effects of oral itraconazole include gastrointestinal symptoms, rash, headache, and increased QT interval. Our patient received treatment with itraconazole for 12 months on the basis of Infectious Diseases Society of America guidelines for treatment of blastomycosis osteomyelitis.¹³ 

Dr Shetty, why was the patient improving when the IV antibiotics used were not covering fungal pathogens?

The transient clinical improvement with decline in laboratory markers of systemic inflammation noted in our patient could be due to the I&D of the abscess and serial debridement procedures at the OSH.

Dr Shetty, given the initial culture results and the appearance of the chest radiograph, what workup should be considered for disseminated fungal infections?

Individuals with endemic mycoses may develop disseminated disease that affects various extrapulmonary sites, including skin, bone, central nervous system (CNS), and rarely visceral organs. Therefore, abdominal ultrasound was obtained to exclude liver, spleen, and kidney fungal abscesses. Echocardiogram was obtained to exclude endocarditis. Urine antigen tests and serology for blastomycosis and histoplasmosis were ordered as part of evaluation of endemic fungal infection. A cryptococcal antigen test was drawn, and the result was negative. MRI of the brain with and without contrast was considered but not obtained because there were no concerns of meningitis or CNS disease on the basis of history and physical examination findings.

Because the patient was undergoing evaluation for disseminated fungal infection, he developed a mildly tender subcutaneous nodule located on the anterior left lower extremity. No significant surrounding erythema or warmth was noted (Fig 4).

Dermatology was consulted, and a punch biopsy of the lesion was performed for routine histopathology and for tissue culture. Histopathology revealed numerous budding yeast organisms with granulomatous inflammation. Tissue cultures were positive for Blastomyces.

Dr Strowd, could this new subcutaneous nodule be consistent with a disseminated fungal infection? Are these findings consistent with any particular type of fungal infection?

Patients can develop cutaneous blastomycosis in 2 ways. Patients can have direct inoculation of the skin with blastomycosis from skin trauma by a fomite containing Blastomyces. Alternatively, patients can develop disseminated blastomycosis to the skin, with the site of origin most commonly being the lungs because patients tend to inhale Blastomyces spores, which can then be spread through the bloodstream to the skin.¹⁴  A small minority of blastomycosis infections result in cutaneous blastomycosis, and this is typically seen in immunocompromised patients, such as those on active chemotherapy regimens or those with inherited immunodeficiency syndrome or AIDS.¹⁵  Cutaneous blastomycosis has a variety of clinical cutaneous manifestations. Most commonly, blastomycosis presents on the skin as a crusted plaque that often resembles a squamous cell carcinoma.¹⁴  All dimorphic fungi can present clinically as violaceous nodules or papules, as in the case presented here.¹⁶ 

Dr Shetty, what is the typical presentation of blastomycosis, and where do you suspect he encountered this pathogen?

Blastomycosis is endemic in many regions of the United States, including the midwestern, southeastern, southcentral (Mississippi and Ohio River basins), and Great Lakes and St Lawrence Seaway regions. Isolated pulmonary infection with systemic manifestations (eg, fever and high inflammatory markers) is the most common presentation of pediatric blastomycosis, although infection may be self-limited in previously healthy hosts without the need for antifungal therapy.¹⁷  Extrapulmonary disease may occur in 25% to 40% of patients. Involvement of the bone and skin is common in patients with extrapulmonary disease followed by genitourinary tract or CNS. Disseminated disease is common in immunocompromised hosts (such as HIV and organ transplant recipients). Chronic pulmonary infection may mimic tuberculosis, other fungal infections, and neoplastic disease.¹⁸ 

Our patient lived on a farm and routinely participated in outdoor activities including excavation. He likely developed primary pulmonary infection after exposure to soil during farm work. Administration of corticosteroids for possible reactive airway and gout during his initial presentation may have resulted in disseminated disease to the bone, with progressive infection.

The patient returned for a follow-up appointment with the pediatric infectious disease team one week after discharge. He was clinically improving, with reduced pain and swelling of the foot. He complained of occasional tinnitus but reported no history of headache, emesis, altered mental status, or weakness. He denied severe pain in the right lower extremity and fever, cough, dyspnea, or chest pain. He was taking his oral itraconazole daily without missing any doses. Serum itraconazole trough level was measured at the follow-up visit to achieve a desired target concentration of 1 to 2 µg/mL. Complete resolution of the pulmonary infiltrates was noted after completion of ∼5 weeks of oral itraconazole therapy. He completed one year of oral itraconazole, with regular follow-up with the pediatric infectious disease team. At his last follow-up appointment, he was asymptomatic.

In the initial evaluation of this patient, his symptoms were attributed to osteomyelitis, likely of S aureus origin. As his course evolved, it became evident this was not a typical bacterial infection of the bone. Clues about the unique nature of this infection became more apparent as his clinical picture and inflammatory markers failed to improve with standard-of-care antibiotics. This caused the multidisciplinary team to reevaluate the etiology of his presentation and treatment as more definitive pathology testing was reviewed.

After a complete evaluation by the pediatric infectious disease and hospitalist teams, histopathologic samples of the infected toe and the skin returned positive for B dermatitidis, a rare cause of osteomyelitis that can cause significant morbidity, especially in the setting of delayed diagnosis and treatment.^19,20  B dermatitidis is a dimorphic mycosis that exists in fungal form in the environment and yeast form in human tissue.²¹  Infection is often acquired through inhalation of conidia (hyphae of mycelial form) from soil and is hyperendemic to regions surrounding the Great Lakes.²²  Nevertheless, cases are reported elsewhere, and the current case presents blastomycosis acquired in Virginia.²²  In fact, Blastomyces have been identified in a large portion of the United States, notably where there are forested, sandy, and acidic soils full of decaying matter.¹⁵  A clinical suspicion of blastomycosis, therefore, is necessary in a broader region than what is generally believed.

The majority of patients infected with blastomycosis remain asymptomatic; however, in children who develop symptoms, the most common presentation is cough, fever, and chest pain consistent with pulmonary disease.^18,21,22  Extrapulmonary disease occurs in 25% to 40% of blastomycosis cases and, in adults, usually involves the skin, followed by bones and joints.²¹  In contrast, pediatric patients more commonly develop infection of the bones and joints rather than the skin.^18,21  CNS disease is rare.²²  Extrapulmonary disease is assumed to represent dissemination from a primary pulmonary infection, unless there is substantial evidence of cutaneous inoculation.^21,23,24  Our patient presented with extrapulmonary disease without known trauma, and further evaluation revealed evidence of lung and cutaneous disease. It is likely that our patient acquired primary pulmonary infection after soil-disruptive activities, which persisted and disseminated because of corticosteroid administration.

Blastomycosis can be an opportunistic infection in transplant recipients, those receiving anti–tumor necrosis factor α therapy, and those positive for HIV.²¹  Our patient received a negative result for an HIV antibody test performed at the OSH. Because he was previously healthy and had received systemic and intra-articular steroids, no additional immune evaluation (such as T-lymphocyte subset analysis) for a primary immunodeficiency syndrome was pursued.

Disseminated infection can involve any organ in the body.¹⁵  The early recognition and treatment of primary blastomycosis can prevent disseminated disease and subsequent complications, including acute respiratory distress syndrome.²⁵  However, there is often significant delay in diagnosis of blastomycosis, especially outside of hyperendemic areas, leading to greater morbidity in these cases.^26,27  Our patient was first diagnosed with gout on presentation with an inflamed great toe. Gout is exceedingly rare in pediatric populations, especially in the absence of chronic disease, yet may be considered in a clinician’s differential diagnosis more often than blastomycosis.²⁸  We present an example, therefore, that corroborates the referenced challenges in diagnosing fungal osteomyelitis in a timely manner.

The diagnosis of blastomycosis is confirmed by the growth of yeast forms in specimens. Blastomyces reproduce slowly; therefore, several days may pass before growth is established in a specimen culture. A tentative diagnosis can be made by identification of Blastomyces antigens in urine.²⁹  Although this method is less time consuming, it is not preferred because of cross-reactivity with other fungal infections.²²  Because of the challenges with definitive diagnosis, a keen clinical suspicion of the disease is necessary for timely specimen collection and incubation so that treatment can be initiated when appropriate. Itraconazole is recommended for treatment in mild to moderate disease, and duration of therapy is typically 6 to 12 months, depending on disease severity. Many experts treat blastomycotic osteomyelitis for 12 months.²² 

Although the exact mechanism of Blastomyces inoculation in the patient remains unknown, it is likely that the patient contracted blastomycosis by inhalation while chopping wood or through soil exposure while working on his family farm. The patient initially demonstrated minimal symptoms outside of musculoskeletal involvement, similar to other patients with blastomycotic osteomyelitis, making diagnostic efforts more challenging and requiring heightened clinician awareness.³⁰  Using this case, we highlight the importance of suspecting blastomycosis when encountering pediatric lung or bone infections refractory to therapy in the setting of epidemiological risk factors for endemic mycoses.

AHO

acute hematogenous osteomyelitis

CNS

central nervous system

CRP

C-reactive protein

ESR

erythrocyte sedimentation rate

GMS

Grocott’s methenamine silver

I&D

incision and drainage

IV

intravenous

MRSA

methicillin-resistant Staphylococcus aureus

OSH

outside hospital

PICC

peripherally inserted central catheter

WBC

white blood cell