Atraumatic Heterotopic Ossification in the Setting of Prolonged Intubation because of H1N1 Influenza: a Case Report

Introduction

Heterotopic ossification (HO) is defined as ectopic mature lamellar bone formation and most often occurs in the vicinity of large joints, including the shoulder, elbow, hip, and, less frequently, the knee1. HO is usually contiguous with the bone but situated outside the periosteum. Non‐contiguous islands of bone can develop in soft tissue early in the course of this condition. HO forms in the surrounding soft tissue and develops a distinct vascular supply. It is a common complication of major orthopaedic procedures, such as knee and hip arthroplasty, and of orthopaedic trauma. During follow‐up, Spinarelli et al. found HO in 28.7% of patients who had undergone total hip arthroplasty2. Gordon et al. studied outcomes after fixation of long‐bone fractures proximal to traumatic amputations and found that 76% developed HO, 39% of them requiring operative excision3. Furlong et al. studied HO after femoral nailing for fixation of subtrochanteric fractures, ipsilateral femoral neck and shaft fractures, and isolated femoral shaft fractures4. They found evidence of HO on anteroposterior radiographs of the hip in 35.7% of the reamed group and 9.4% of the unreamed group.

Heterotopic ossification is also frequently associated with burns, traumatic brain injury and spinal cord injury (SCI)5, 6. HO was found in 19.1% of patients who underwent radiographic examination after severe traumatic brain injury5. Wittenberg et al. found that 20% of patients with SCIs developed HO within two year minimum follow‐up6.

While the cause of HO is still unknown, there are several proposed contributing genetic, inflammatory, mechanical and local factors7. A genetic predisposition is under investigation, including assessment of human leukocyte antigen haplotypes as well as investigation of bone morphogenic protein‐4 in patients with fibrodysplasia ossificans progressiva sporadic, which has characteristics that are similar to those of traumatic HO1, 8. At sites of inflammation, T‐cell cytokines have been shown to increase expression of bone morphogenic protein‐2, leading to mesenchymal cell differentiation into osteoblasts and subsequent HO formation9. Additional risk factors for HO are associated with prolonged immobilization and include profound central nervous system compromise, diffuse axonal injury, prolonged coma, decreased serum calcium and increased serum alkaline phosphatase concentrations10, 11.

We describe here a 29‐year‐old woman with no history of trauma, orthopaedic surgical intervention, burns, traumatic brain injury or SCI who we found to have HO of the distal right femur and left shoulder following prolonged intubation and respiratory failure secondary to H1N1 influenza and acute respiratory distress syndrome (ARDS). The authors have obtained the patient's informed written consent for print and electronic publication of this case report.

Case Report

A 29‐year‐old obese, Caucasian female presented to another hospital with fever, chills, nonproductive cough and back pain in October 2009. She had previously required a splenectomy for injuries sustained in a motor vehicle accident in July 2006 and had a history of gestational diabetes. Initial assessment upon admission after the motor vehicle accident in 2006 had revealed no obvious trauma to her lower extremities. Discharge physical examination after her accident in 2006 had revealed no functional deficits in the lower extremities with strength 4/4 + for hip flexors, 4/4 + for knee flexors, and 5/5 throughout the rest of her lower extremities. She was prescribed an unknown antibiotic and discharged home. Two days later, she returned to her primary care provider with on‐going symptoms and cyanosis. She was admitted and later found to have an oxygen (O₂) saturation of 60%–70%, after which she progressed to respiratory failure requiring intubation. Empirical treatment with vancomycin, levofloxacin, oseltamavir, and dexamethasone was started and she was transferred to our institution, where she was admitted to the medical intensive care unit with suspected respiratory failure and pneumonia. Initial assessment revealed she was afebrile with a heart rate of 102/min and blood pressure of 99/65 mm Hg. She had an 85% O₂ saturation on pressure‐controlled ventilation with fraction of inspired oxygen of 100% and positive end‐expiratory pressure of 25 mm Hg at a rate of 25 breaths per min. Physical examination showed diminished, coarse breath sounds bilaterally. An admission chest X‐ray film revealed dense consolidation in the right upper lobe. Throughout her admission, multiple chest X‐ray films demonstrated bilateral patchy infiltrates. Her white blood cell count was increased to 22.7 × 10³ per μL (normal 4.5 × 10³–11.0 × 10³ per μL) and her serum lactic acid concentration normal. An echocardiogram demonstrated a dilated right ventricle and a decreased ejection fraction of 45%–50%, all of which raised the possibility of sepsis. Her condition was found to be secondary to H1N1 influenza, this being confirmed by influenza A polymerase chain reaction, and ARDS. She was started on venous to venous extracorporeal membrane oxygenation, after which she improved substantially. She was confined to bed for a total of 33 days. After successful transition off extracorporeal membrane oxygenation and a prolonged recovery (including nosocomial methicillin‐resistant Staphylococcus aureus pneumonia and urinary vancomycin‐resistant Enterococci infection), she was discharged home in a stable condition.

She was referred back 8 months later for evaluation of left knee pain that she had first noticed a few months earlier after physical therapy had been initiated because of her prolonged immobility and poor physical condition. She described no recent acute injuries or trauma prior to the onset of her knee pain. She was able to bear weight, but physical examination revealed an antalgic gait favoring the left lower extremity, a 15°−90° range of motion in the left knee and 5°−110° in the right knee. She had a firm palpable mass in the left quadriceps tendon that was tender to palpation. In addition, she had noted a decreased range of motion in her left shoulder, but had minimal discomfort associated with this. She had no other complaints.

X‐ray films revealed extensive bony overgrowth superior to the patella that likely represented ossification (Fig. 1). CT and whole body three‐phase bone scans revealed ossification within the soft tissues medial to the distal right femur and knee joint (Figs 2, 3). A technetium‐99 m bone scan showed mildly increased radiotracer activity in the soft tissue anteromedial to her left distal femur (Fig. 4). Taken in conjunction with the CT findings, she had evidence of ossification within the distal quadriceps compartment and mild hydrostatic edema in the surrounding soft tissue. Her left shoulder also showed changes consistent with HO.

Figure 1.

(A) Anteroposterior and (B) lateral radiographs showing extensive bony growth superior to the patella consistent with HO.

Figure 2.

(A, B) CT axial images of the left femur demonstrating ossification within the soft tissues medial to the distal femur and knee joint and disuse osteopenia. (C) CT coronal and (D) sagittal images of the left femur demonstrating ossification within the soft tissues medial to the distal femur and knee joint.

Figure 3.

CT axial image of the left femur demonstrating medial soft tissue ossification with a well‐developed cortex and medullary space.

Figure 4.

Anterior technetium‐99 m whole body three phase bone scan demonstrating mildly increased radiotracer activity in the soft tissue anteromedial to the left distal femur compatible with HO.

A diagnosis of a HO was made, and excision of the left lower limb mass with possible repair/reconstruction of the left extensor mechanism was scheduled. The indications for surgery were decreased range of motion and pain. She underwent resection of HO of her left distal femur in November 2010. Intra‐operatively, her passive range of motion was assessed to be 0^°–100^° of flexion without excessive tension. She received radiation therapy (7 Gy, one fraction) to the operative site on post‐operative day 1 to decrease the risk of recurrence. Pathologic examination of the excised specimen showed areas of HO measuring 5.7 cm × 4.3 cm × 1.2 cm and 10.0 cm × 5.2 cm × 2.2 cm. Follow‐up after 2 weeks showed decreased pain, a range of motion of 8° less than full extension and flexion to 80°. Her 8‐week follow‐up demonstrated no clinical evidence of recurrence of heterotrophic bone with a range of motion of −5° extension and flexion to 90°. Her shoulder remains clinically stable and non‐painful, and she elects to monitor this with serial assessments.

Discussion

Heterotopic ossification has been extensively discussed in the setting of orthopaedic trauma, joint arthroplasty, traumatic brain injury, burns, SCI and various other conditions characterized by compromised neurological function. In this case, we present a unique situation in which HO formed after prolonged immobilization because of H1N1 influenza requiring ventilatory support. This patient presented without the major classic risk factors for HO. There had been no incidents of traumatic brain injury or SCI. Prolonged immobilization is associated with HO, including that due to prolonged coma. However, the most commonly reported underlying reason for periods of immobilization associated with HO formation has been some form of compromise of the neurological system, for example neuromuscular blockade, Guillain‐Barré syndrome, carbon monoxide intoxication, and moyamoya disease12, 13, 14. Although we cannot prove a direct link, in the absence of other previously described causes, the most likely cause for our patient's Ho is prolonged immobilization associated with ARDS pneumonia secondary to H1N1 influenza.

A review of published reports revealed few cases of HO in an atraumatic setting. Ohnmar et al. in 2010 described a case of massive, diffuse, bilateral HO in the shoulders, hips and elbows causing restricted passive range of motion12. In this case, HO was caused by complications of Guillain‐Barré syndrome, including a prolonged stay in an intensive care unit, mechanical ventilation and long‐term flaccid paralysis/immobility12. Chen et al. described a case of HO involving carbon monoxide intoxication in which a 26‐year‐old woman developed HO in her right upper quadriceps femoris muscle13. During the clinical course of this case, prolonged ventilator support was not instituted and symptoms presented three months after the initial injury13.

In 1993, Clements et al. described three cases of HO in the setting of critical care15. The first case described had severe inflammatory response syndrome with pneumococcal pneumonia and developed HO around both distal femurs, both shoulders and the pelvis. Their second case of atraumatic HO was secondary to Pseudomonas aeruginosa pneumonia. The last case they detailed was in the setting of ARDS and anoxic encephalopathy; they did not identify any responsible microbe. In each of these cases, HO occurred bilaterally and symmetrically (suggesting a neurologic cause) in a setting of significant respiratory compromise, either ARDS or respiratory failure, two of the cases having an identifiable organism. To our knowledge, there have been no case reports of HO in the setting of H1N1 influenza. Although our case did not have symmetric involvement, involvement of two joints (knee and shoulder) suggests an underlying systemic cause, consistent with prior reports.

These cases highlight a small group of patients with apparently atraumatic HO. In these patients, unique causative factors resulted in prolonged ventilatory compromise, intubation and hypo/immobility. These findings help to identify components of HO causation in atraumatic settings. Our case is characterized by the absence of two of the usual factors that lead to HO: compromise of the neurological system and trauma. However, our case was subject to prolonged immobilization and intubation, two other major factors often associated with formation of HO. Although HO has been classically described as secondary to orthopaedic procedures or neurological pathology, it is possible that HO could occur within a clinical scenario of immobilization and/or respiratory failure requiring ventilatory support. Future studies of the pathogenesis of HO should focus on the factors of immobilization, impaired ventilation, and genetic predisposition. In addition, possible preventive measures could be studied or implemented to help reduce the incidence of HO in those identified as being at risk of its development. Potential preventive measures include passive range of motion with physical therapy and the use of non‐steroidal anti‐inflammatory drugs.

Here we present a unique case of a HO that presented after prolonged ventilation secondary to ARDS and H1N1 influenza and lacked the usual trauma or neurologic injury most often associated with HO. This case demonstrates a unique clinical situation in which HO may develop, and should alert clinicians to the need for increased awareness and institution of preventive strategies (such as passive motion therapy) in patients in similar clinical scenarios who have an increased risk of HO.