A Teenager With Ear Drainage, Jaundice and Right Hip Pain

CASE A 17-year-old previously healthy male presented with a 6-day history of right ear pain and drainage. He was prescribed ciprofloxacin/dexamethasone eardrops for otitis externa without improvement. His ear pain and drainage worsened, and he had a fever of 101.2°F. He started complaining of headaches on the day of admission. He developed right-sided neck pain with neck stiffness, pain on the right side of his lower back, pelvis and hip, and was unable to bear weight on the right lower extremity. He also had yellow discoloration of the eyes, nausea and occasional vomiting. He had no history of chronic otorrhea, recent trauma, abdominal pain, diarrhea, sore throat or chest pain. He had no history of jaundice, hemolysis or gall stones. He had no known sick contacts, animal contact or recent travel history. Upon admission, he was alert and in moderate distress. His temperature was 39.4°C, pulse 122 beats/min, respirations 20 breaths/min and blood pressure 91/42 mm Hg. He had icterus of both eyes with no conjunctival injection or drainage. There was copious purulent otorrhea from the right ear with no mastoid swelling, erythema or tenderness. He had tenderness upon deep palpation of the right posterior cervical area with no palpable mass. The neck was stiff and held rotated to the left side. Neurological exam was normal except for decreased strength of the right lower extremity due to pain. He was holding the right hip in an extended position and had pain with flexion and limited range of movements. He had tenderness to palpation over the right iliac bone area, right buttock and right sacroiliac joint. He was unable to bear weight on the right lower extremity. Abdomen was soft with no distension or tenderness. The rest of the physical exam was normal. Due to tachycardia and hypotension, he received a normal saline bolus of 1000 mL and norepinephrine drip at 0.03 mcg/kg/min. His white blood cell count was 20.8 × 103/mm3 (92% neutrophils, 5% lymphocytes and 3% monocytes), hemoglobin was 10.7 g/dL, hematocrit 30.5% and platelet count 30 × 103/mm. C-reactive protein (CRP) was 347.2 mg/L. Sodium was 121 mg/dL, chloride 83 mg/dL, potassium 3.5 mg/dL, blood urea nitrogen was 13 mg/dL and serum creatinine was 0.92 mg/dL. Total bilirubin was elevated at 8.54 mg/dL with direct bilirubin 5.56 mg/dL. Liver enzymes were mildly elevated with alanine aminotransferase of 72 u/L (7–52), aspartate aminotransferase 103 (10–40) and alkaline phosphatase 255 u/L (59–164). Albumin was low at 2.9 mg/dL, and creatine kinase was elevated at 424 u/L (30–223). Prothrombin time was 14.0 seconds (9.4–11.7), international normalized ratio 1.33 (0.87–1.10) and partial thromboplastin time and fibrinogen were normal. Blood culture and ear fluid culture were obtained, and treatment with intravenous (IV) cefepime, vancomycin and metronidazole was started. Ultrasound of the abdomen showed a slightly thickened gallbladder with no biliary dilatation or acute cholecystitis. Computed tomography scans of the internal auditory canals and head with contrast showed complete opacification of the right mastoid air cells, middle ear and external auditory canal with no bony erosive changes. Magnetic resonance imaging (MRI) of the brain showed opacification and diffusion restriction in the right mastoid air cells with no intracranial abnormalities noted. MRI of the cervical (C) spine showed fluid collection along the right lateral aspect of the C1-C2 facet joints and T2 signal changes at C1 suggestive of osteomyelitis. Duplex images of the neck veins showed no thrombosis. MRI of the pelvis showed advanced osteomyelitis of the right iliac bone with osteonecrosis as well as myositis involving gluteal, iliacus, psoas and pelvic floor musculature without abscess. He underwent a right middle ear washout and tympanostomy tube placement; yellow fluid was drained. He also had debridement of the right ilium and pelvic musculature. Blood cultures did not reveal any growth. Gram stain from right ear drainage and iliac bone were negative. Cultures from ear drainage grew rare Staphylococcus epidermidis and rare Turecella otitidis, determined to represent colonization. Multiple tissue cultures from the iliac bone were negative. Anaerobic cultures from ear drainage and bone specimens were all negative. An additional laboratory test was performed that revealed the diagnosis. DENOUEMENT Bacterial DNA polymerase chain reaction (PCR) testing targeting the 16S ribosomal RNA gene (University of Washington Clinical Microbiology Laboratory, Seattle, WA) from ear fluid as well as iliac bone tissue detected Fusobacterium necrophorum.1 The patient was diagnosed with disseminated F. necrophorum infection including septic shock, right acute otitis media, cholestasis and multifocal osteomyelitis involving C1 vertebra and right iliac bone. Cholestasis was likely due to sepsis. The likely source of infection was right otitis media. Initial blood was sent in a pediatric blood culture bottle; however, subsequent blood cultures that included anaerobic bottles were negative. Anaerobic cultures from the ear and bone were negative, likely due to improper processing and/or antibiotic treatment given before cultures. A comprehensive immunological workup up including immunoglobulin levels, T-cell, B-cell and natural killer cell assays, oxidative burst assay, mitogen culture and antibody response to vaccine antigens were all normal. HIV testing was negative. Vancomycin, ceftriaxone and metronidazole were discontinued, and antibiotic treatment continued with meropenem. Two weeks later, he continued to have intermittent pain and drainage from the wound site. MRI showed worsening osteomyelitis with osteonecrosis of the right iliac bone, right sacral osteomyelitis and septic sacroiliitis. A repeat irrigation and debridement of the right ilium and sacroiliac joint were performed. The patient was discharged after 4 weeks of hospitalization to receive IV ertapenem and oral metronidazole. However, he was readmitted 8 days later with worsening pain and wound drainage. MRI showed worsening osteomyelitis and osteonecrosis of the right iliac bone with subperiosteal abscess. A repeat incision and drainage of the right ilium and pelvis was performed; purulent material was drained from the iliac muscle off the iliac wing anteriorly and posteriorly. Due to the intractable clinical course and extensive osteomyelitis, IV ertapenem was continued for 20 weeks and oral metronidazole was continued for 24 weeks from the last debridement. Follow-up MRI studies showed improvement. He received physical therapy and was eventually able to ambulate with full range of motion of his right hip. Fusobacterium species are obligate anaerobic Gram-negative bacilli that are part of the normal flora on the oropharynx, gastrointestinal tract and genitourinary tract of healthy individuals.2 The most common clinical manifestations of fusobacterial infection are localized infections including pharyngitis, tonsillitis and peritonsillar abscess. Others include sinusitis, mastoiditis, dental infection and infections following dog bites.2 The most common Fusobacterium species that are associated with invasive infections are F. necrophorum and F. nucleatum.3F. necrophorum is the leading cause of Lamierre syndrome, characterized by septic thrombophlebitis of the internal jugular vein with emboli that most frequently affect the lungs.4 Age-related patterns have been observed with Fusobacterial infections, with young children being more vulnerable to develop F. necrophorum otitis media and mastoiditis, while older children and adolescents develop tonsilitis and peritonsillar abscess. The pathogenesis of these differences is unclear.4 Fusobacterium osteomyelitis in children most frequently affects the bones of the face and skull due to adjacent infection, such as periodontal disease, sinusitis or mastoiditis.5 Coinfection with aerobic bacteria and polymicrobial infections are associated with poor prognosis.5,6 Cases of Fusobacterium osteomyelitis in children have been reported to involve the ilium, hip, hand, foot and long bones.7,8 Predisposing conditions for Fusobacterium species hematogenous osteomyelitis in children include sickle cell disease and trauma including motor vehicle accidents.6,9 However, it has been reported in otherwise healthy children without an identified focus of infection, mostly caused by F. nucleatum.8 Emphysematous osteomyelitis following minor vehicle accident was reported in a teenager with sacrum osteomyelitis needing multiple surgeries.6 A 7-year-old had chronic tibia osteomyelitis mimicking a bone tumor.7 Hematogenous osteomyelitis of the distal tibia with concurrent septic knee arthritis have been reported in 9 children.8 All were caused by F. nucleatum and patients were males between the ages of 4 and 10 years; one had sickle cell disease, and another had recent pharyngitis but no risk factors were identified in the other cases.8 The patients did not have significantly elevated white blood cell count, erythrocyte sedimentation rate levels or documented bacteremia. The duration of symptoms varied between 4 days and 1 month.8 Delays in the diagnosis of Fusobacterium species osteomyelitis in children have been frequently reported and were attributed to subacute presentation of patients and slow bacterial growth in cultures.8 Delays can also result from not sending anaerobic bone or joint fluid cultures.7,8 Our patient developed F. necrophorum otitis media with secondary hematogenous osteomyelitis of the cervical spine, pelvis and sacroiliac joint. There was no history of trauma and no antecedent Lemierre syndrome. The patient had no predisposing oropharyngeal conditions or immunodeficiency. He presented with signs of sepsis due to F. necrophorum and his clinical course was complicated by the need of multiple bone debridement procedures, whereas most reported cases in the literature were subacute in presentation, and most were caused by F. nucleatum.7,8F. necrophorum seems to be more virulent than F. nuceatum and more commonly associated with thrombotic complications.3,10 Complicated disease with F. necrophorum may also be related to virulence factors such as lipopolysaccharide capsule, toxin production and proteases.2 F. necrophorum otitis media has been reported mostly in infants and young children less than 4 years of age with history of recurrent otitis media.10 It is unusual in adolescents, like our patient. Clinical presentations include uncomplicated otitis media, acute mastoiditis and otogenic variant of Lemierre syndrome.10 In a review of 12 cases of F. necrophorum otitis and mastoiditis in infants and young toddlers, all were nonimmunocompromised.11 Most had leukocytosis and elevated CRP values with epidural and subdural abscesses in 83% and Lemierre syndrome in 58% of cases.11 Complications of otogenic infections in children include subperiosteal abscess, intracranial abscess, suppurative thrombophlebitis of the lateral or cavernous sinuses, meningitis, septic shock, distant metastasis or osteolysis of the temporal bone.10–13 Intracranial complications typically follow mastoiditis. Surgical management is often needed in patients with established F. necrophorum mastoiditis, underscoring the virulence of this organism. Bacteremia and intracranial complications can occur due to the proximity of the mastoid to the intracranial venous sinuses or delays in appropriate antibiotic therapy.12 Our patient had no clinical findings of mastoiditis and computed tomography showed mastoid opacification without bony erosion. Early rupture of the tympanic membrane may have prevented mastoiditis and intracranial complications. Laboratory findings in Fusobacterium sepsis and Lemierre syndrome are nonspecific and may include leukocytosis with increased band forms and elevated CRP.14 Hyperbilirubinemia with slight elevation of liver enzymes has been reported in 11%–49% of Lemierre syndrome patients, but frank jaundice is uncommon.14 Thrombocytopenia and disseminated intravascular coagulopathy are also reported.4 Confirming Fusobacterium infection by culture can be challenging and requires proper specimen collection and transport conditions, appropriate culture media and accurate identification techniques. PCR-based molecular methods, including 16S ribosomal RNA PCR, are increasingly utilized to confirm fusobacterial infections as in our patient.3,10 Due to the potential for resistance and β-lactamase production, antimicrobial susceptibility testing of Fusobacterium species is recommended to guide treatment, particularly in severe or invasive infections.14 Metronidazole provides excellent activity against F. necrophorum, however, monotherapy is not recommended for serious infection because cultures may not be properly obtained and infection can be polymicrobial. The carbapenems provide excellent coverage. β-lactam-β-lactamase inhibitors such as piperacillin-tazobactam are likely to be active against Fusobacterium species, as well as other anaerobes and aerobes that may be present in polymicrobial infection. Clindamycin susceptibility should be documented due to increasing resistance rates in Fusobacterium species.15 For complicated or severe infection, initial combination treatment is recommended that may include high-dose penicillin, metronidazole and clindamycin.14 Alternatively, β-lactam-β-lactamase combination therapy such piperacillin-tazobactam or a carbapenem may be used. The duration of antibiotic therapy depends on the severity of illness, clinical response and normalization of inflammatory markers. The median reported therapy duration for Lemierre syndrome is 42 days.14 Surgical intervention to drain abscesses and remove necrotic tissue is crucial. Our patient had an intractable clinical course and required a prolonged course of antibiotics and multiple surgeries. The presence of osteonecrosis warrants a prolonged antibiotic course to prevent the development of chronic osteomyelitis.