A Pain in the Neck: An Adolescent with Neck Pain

PRESENTATION

A previously healthy 15-year-old male presents with several years of intermittent neck pain, which has acutely worsened over the past four days. He has decreased range of motion of his neck secondary to pain and cannot recline comfortably. He reports three days of subjective fever. The day prior to presentation, he experienced several episodes of non-bloody, non-bilious emesis and an episode of near-syncope associated with headache and blurry vision. Two weeks prior, he had a febrile respiratory illness. Although his cough has persisted, he denies sore throat, abdominal pain, diarrhea, myalgias, weakness, or numbness. Outside of playing soccer, he has had no trauma. He travelled to Mexico two months prior, and his mother recently returned from Malaysia.

In the emergency department, he is awake and alert, although he appears uncomfortable. His temperature is 100.9° (38.3°), heart rate is 100 beats/min, respiratory rate is 18 breaths/min, blood pressure is 109/61 mmHg, and oxygen saturation is 98% on room air. Physical exam reveals bony tenderness over the C4 spinous process and pain with neck movement. There are no rashes or overlying skin changes. Neck is without lymphadenopathy or meningismus. Head is normocephalic and atraumatic. Conjunctivae are non-injected and non-icteric. Oropharynx reveals moist mucous membranes without exudate or erythema. Neurologic exam shows intact cranial nerves and normal strength, sensation, and reflexes throughout. On initial laboratory testing, leukocyte count is 5,900/μL (5.90×10⁹/L) (reference range, 3,400–10,200/μL [3.40–10.20×10⁹/L]), lymphocyte count is 1,010/μL (1.01×10⁹/L) (reference range, 1,700–4,500/μL [1.70–4.50×10⁹/L]), platelet count is 115,000/μL (115×10⁹/L) (reference range, 150,000–400,000/μL [150–400×10⁹/L]), and hemoglobin is 13.7 g/dL (137 g/L) (reference range, 12.0–16.0 g/dL [120–160 g/L]). C-reactive protein (CRP) is 7.3 mg/dL (73 mg/L) (reference range, 0.01–0.17 mg/dL [0.1–1.7 mg/L]). Lactate dehydrogenase (LDH) is 433 U/L (7.23 μkat/L) (reference range, 130–250 U/L [2.17–4.17 μkat/L]). Phosphorous, uric acid, and peripheral smear are normal. Complete metabolic panel shows elevated transaminases, with an aspartate aminotransferase of 116 U/L (1.94 μkat/L) (reference range, 13–35 U/L [0.22–0.58 μkat/L]) and alanine aminotransferase of 121 U/L (2.02 μkat/L) (reference range, 8–24 U/L [0.13–0.40 μkat/L]). Viral respiratory panel and mononucleosis spot test are negative. A chest radiograph reveals no focal consolidation. Neck contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) are obtained and show anterior C4 sclerosis and periosteal reaction without local inflammation (Figure 1). The patient is admitted to the pediatric hospital medicine service for further management.

Figure 1.

Sagittal T2-weighted magnetic resonance images of the cervical spine on presentation, showing erosion of the C4 vertebral body. Area of involvement indicated by arrow.

DISCUSSION

Differential Diagnosis

This patient’s vertebral body sclerosis without significant inflammation indicates a probable insidious infectious, rheumatologic, or oncologic process. Infectious causes include vertebral osteomyelitis, which is most commonly due to Staphylococcus aureus or Escherichia coli. However, infections with these virulent organisms typically result in significant local inflammation and vertebral body destruction. They are also more likely to involve multiple consecutive vertebral bodies due to hematogenous spread.¹ Other pathogens causing non-pyogenic vertebral osteomyelitis include Mycobacterium tuberculosis, Brucella, and fungal mycoses, such as Histoplasma, Blastomyces, and Coccidioides. Chronic non-bacterial osteomyelitis (CNO), also known as chronic recurrent multifocal osteomyelitis (CRMO), is a rare autoinflammatory skeletal condition that can present with insidious bone pain. CNO is typically characterized by multifocal nonbacterial lesions in the metaphyses of long bones, vertebral column, and pelvis, although unifocal lesions have been described.^2,3 Langerhans cell histiocytosis (LCH) can also present with a singular, lytic, painful vertebral lesion. Without other constitutional symptoms or supportive laboratory findings, an oncologic process is believed to be less likely.

Patient Course

After admission, additional work-up is obtained including an abdominal ultrasound, which reveals mild splenomegaly. A full-body MRI and nuclear bone scan reveal no evidence of additional osseous lesions. Blood cultures, QuantiFERON-TB Gold, Bartonella henselae serologies, Brucella total antibody, Blastomyces total antibody, Blastomyces urine antigen, Coccidioides serologies, Histoplasma serum and urine antigen, and Histoplasma serologies are all negative. His CRP peaks at 115.2 mg/dL (1,152 mg/L) (reference range, 0.01–0.17 mg/dL [0.1–1.7 mg/L]). Due to the lesion’s anatomic location, the risks of a biopsy are felt to be higher than the benefit of initiating empiric treatment. In consultation with colleagues in infectious diseases, doxycycline and rifampin are started for presumed chronic osteomyelitis. Doxycycline is selected to target gram positive organisms including Staphylococcus aureus and Streptococcus species, which are considered the most likely pathogens. Rifampin is included to avoid developing resistance to doxycycline monotherapy with anticipated long-term use. After initiation of antimicrobials, fevers resolve, his CRP decreases to 45.3 mg/dL (453 mg/L) (reference range 0.01–0.17 mg/dL [0.1–1.7 mg/L]), and he is discharged on long-term oral antibiotics. Five weeks after discharge, he denies neck pain or fever. He has a normal physical exam. His neck is non-tender and has normal range of motion. Repeat MRI is obtained to evaluate for improvement and reveals increased vertebral body destruction and new retropharyngeal and epidural phlegmons (Figure 2). Fluid cultured from the retropharyngeal phlegmon grows Salmonella Oranienburg, suggesting this as the etiology for vertebral osteomyelitis. Fungal and acid fast bacterial cultures are negative. Based on susceptibility testing results (sensitive to amoxicillin-clavulanate, third- and fourth-generation cephalosporins, levofloxacin, piperacillin-tazobactam, trimethoprim-sulfamethoxazole, and tetracycline), failure on previous regimen, and fluoroquinolone pharmacokinetic considerations (including reliable macrophage and bone penetration^4,5), he is changed to 12 weeks of levofloxacin. Interim MRI after six weeks of therapy shows improvement. He develops right wrist pain concerning for fluoroquinolone-induced tendinopathy during his eleventh week of treatment and changes to trimethoprim-sulfamethoxazole for the final week of therapy. His neck and wrist pain are resolved at one week and three month post-treatment visits.

Figure 2.

Sagittal T2-weighted magnetic resonance images of the cervical spine after completion of five weeks of doxycycline and rifampin, showing progressive erosion of the C4 vertebral body and new involvement of C5 vertebral body when compared to initial imaging. There is also an ill-defined prevertebral and epidural fluid signal and enhancement extending from C2 to C6. Area of involvement indicated by arrow.

Note: This case is based on a presentation by Drs. Lauren S. Starnes, Alison Carroll, Marni Krehnbrink, Ashley Blaske, Kaitlin Williamson, Gregory Wilson, Sophie Katz, Brent Graham, Daniel Dulek, and Charlotte Brown at the 2020 American Academy of Pediatrics National Conference and Exhibition.

The Condition

The genus Salmonella consists of gram negative bacteria belonging to the Enterobacteriaceae family.^6,7 It is divided into two species: S. bongori, typically confined to cold-blooded animals, and S. enterica, which affects warm-blooded animals and is responsible for infections in humans. S. enterica is further divided into subspecies and serotypes,⁶ with Salmonella Oranienburg belonging to serogroup C1.⁸ In the United States, Salmonella causes an estimated 1.2 million cases of illness and 450 deaths each year.⁹ Salmonella Oranienburg, however, is an uncommon human pathogen. In 2016, only 692 cases of Salmonella Oranienburg were reported to the CDC, accounting for 1.5% of all Salmonella cases.¹⁰

Non-typhoidal Salmonella is a foodborne enteric pathogen, typically presenting with gastroenteritis, bacteremia, extraintestinal focal infection, or asymptomatic carrier state.^11,12 Salmonella osteomyelitis is rare in patients without hemoglobinopathies or immunodeficiencies.⁷ It accounts for 0.8% of all Salmonella infections and 0.45% of osteomyelitis cases.¹³ Infection occurs through hematogenous seeding,¹⁴ typically of the diaphysis of long bones.¹² Vertebral involvement is rare, but when present most commonly affects the lumbar spine.¹⁵ Evidence suggests microscopic vertebral bone infarcts and increased bone marrow activity favor Salmonella growth.^7,16,17 To our knowledge, only six cases of Salmonella Oranienburg vertebral osteomyelitis have been reported in the English literature.^{11,16,18–20}

Risk factors for infection with Salmonella include foreign travel, exposure to reptiles and livestock, and ingestion of contaminated water or food, principally dairy products or undercooked eggs or poultry.⁷ Recent U.S. outbreaks have been traced to foods including wood ear mushrooms, peaches, and onions, as well as pet bearded dragons, hedgehogs, turtles, and backyard poultry.²¹ Our patient recently travelled to Mexico, where Salmonella enterica is the most commonly reported foodborne pathogen²²; however, he denied any other known causal factors. Other than recognized outbreaks, identifying the mode of Salmonella transmission is challenging. In one series, only 14% of previously healthy children with Salmonella osteomyelitis reported a characteristic exposure.¹⁶ Additionally, Salmonella has the capability of quiescence in the reticuloendothelial system or bowel,¹⁷ and the duration between inoculation and initial illness to presentation with osteomyelitis can range from months to up to 25 years.¹² This latency, together with our patient’s previously unexamined chronic neck pain, makes it difficult to determine the timing of inoculation.

Salmonella vertebral osteomyelitis commonly presents with fever and back pain, but younger children can also show non-specific signs including malaise and weight loss.^11,15,23 Although Salmonella are enteric organisms, prodromal gastrointestinal illness is uncommon.^15,23 Erythrocyte sedimentation rate (ESR) and CRP are usually elevated.^14,24 Blood culture is positive in 20–75% of cases; in the instance of negative culture, biopsy is recommended.^14,24 Approximately 65% of patients show radiographic abnormalities,¹⁵ which can include diaphyseal erosion, periosteal reaction, osteolytic foci, loss of intervertebral disc space, edema, or collapse of vertebrae.^12,25,26 CT and MRI are more accurate,¹⁵ with MRI considered the gold standard.²⁶ Imaging typically demonstrates disease in adjacent vertebrae and intervertebral discs.¹⁴ These features are absent in our patient’s initial MRI, which made diagnosis challenging.

Treatment/Management

There are no current guidelines for the treatment of Salmonella osteomyelitis.¹³ This infection is traditionally managed with surgical debridement followed by antibiotics, however there are reports of treatment with antibiotics alone.^12,26 Most cases report successful treatment with antibiotics for six to eight weeks.²⁴ Typical drugs include fluoroquinolones, ampicillin, trimethoprim-sulfamethoxazole, and third-generation cephalosporins.^6,11 Salmonella infection is considered difficult to eradicate,¹⁷ as bacteria harbor intracellularly.⁶ Although fluoroquinolones are not routinely recommended in children because of their side effect profile,⁶ they are efficacious due to good oral absorption and ability to penetrate macrophages where organisms often reside.^15,25 Unfortunately, Salmonella antimicrobial resistance is growing, especially to ampicillin and trimethoprim-sulfamethoxazole,²⁷ which can limit options for therapy. There is also growing resistance to ciprofloxacin, with 2.7% of Salmonella infections resistant.⁶ As Salmonella infections are linked to hemoglobinopathies and immunodeficiencies,^7,28 these should be considered and appropriate testing should be performed when suspected.

LESSONS FOR THE CLINICIAN

• Vertebral osteomyelitis is rare in healthy children and classically presents with back pain and fever. While commonly due to Staphylococcus aureus or Escherichia coli, a thorough exposure and travel history may point to other pathogens.

• Non-typhoidal Salmonella is a foodborne enteric pathogen that can cause a variety of illnesses including gastroenteritis, bacteremia, and focal infections such as osteomyelitis.

• Salmonella osteomyelitis is rare in patients without hemoglobinopathies or immunodeficiency and occurs via hematogenous seeding.