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Address reprint requests and correspondence to Joseph Kaplan, MD, Division of Pulmonary Medicine, Mayo Clinic Jacksonville, 4500 San Pablo Rd, Jacksonville, FL 32224
Affiliations
Division of Pulmonary Medicine and Internal Medicine, Mayo Clinic Jacksonville, Jacksonville, Fla
Aspergillus osteomyelitis of the spine with acute diskitis has been well documented in immunocompromised hosts but is rare in immunocompetent patients. Predisposing factors to infection are prolonged neutropenia, hematologic malignancies, chemotherapy, history of prior spinal trauma or surgery, allograft transplantation, or any condition requiring the use of long-term immunosuppressive agents or systemic corticosteroids. Patients with chronic obstructive pulmonary disease (COPD) treated with systemic corticosteroids for either long-term management or frequent exacerbations are at potential risk for such infections. Patients with severe COPD treated primarily with inhaled corticosteroids are considered immunocompetent. This report describes 2 cases of Aspergillus osteomyelitis with acute diskitis in apparently immunocompetent patients with COPD who, aside from brief courses of systemic corticosteroids, were using inhaled corticosteroid therapy. One patient was treated with intravenous amphotericin B alone, whereas the other received amphotericin B and underwent surgical débridement. Both have done well and were symptom free at 6-month follow-up.
Invasive or disseminated disease seems to develop after infection of the bronchopulmonary tract with Aspergillus species. The disease may spread to other sites by either hematogenous or contiguous routes. One such site is the vertebral spine.
Vertebral Aspergillus osteomyelitis is uncommon but has been described in patients with hematologic malignancies
Patients with severe chronic obstructive pulmonary disease (COPD) managed with long-term systemic corticosteroids may also be at risk for the development of invasive vertebral disease with Aspergillus. Whether patients with COPO managed with inhaled corticosteroids alone have any risk of invasive disease is unknown. A recent case report described Aspergillus spondylodiskitis in an apparently immunocompetent patient with asthma.
We describe 2 cases of vertebral “Aspergillus osteomyelitis with acute diskitis in apparently immunocompetent patients with COPD who were treated primarily with inhaled corticosteroids.
Report Of Cases
Case 1
A 76-year-old man with a history of severe COPD and coronary artery disease underwent assessment because of rapidly progressive midthoracic back pain of 4 months' duration. His COPD had been managed with an inhaled corticosteroid (triamcinolone acetonide, 800 μg/d) and bronchodilators. During the past 2 years, he had been hospitalized 4 times for acute exacerbations of COPD. Each time, he was treated with intravenous corticosteroids for 3 to 5 days and then with oral corticosteroids, the dose of which was tapered over 2 to 3 weeks. He had never required mechanical ventilation. His most recent exacerbation of COPO occurred 4 months before admission, at which time a routine sputum culture yielded growth of Aspergillus. One month later, his back pain began. Initially, he was treated conservatively with muscle relaxants and nonsteroidal anti-inflammatory drugs without relief. A radiograph of the spine revealed osteopenia and a compression fracture of the T6 vertebral body. A trial of calcitonin was administered subcutaneously, but his pain persisted until he needed narcotic analgesics. Thus, he was admitted for further assessment.
On examination, the patient was afebrile, normotensive, and nontachypneic but had a pulse rate of l04/min. He denied having any respiratory symptoms. The spinous processes of the midthoracic spinal column were tender to palpation. His lungs were clear on auscultation. A radiograph of his chest revealed no infiltrates. An electrocardiogram showed sinus tachyeardia with evidence of an old inferior myocardial infarction. Findings on a complete blood cell count (CBC) and chemistry profile were remarkable for a normochromic, normocytic anemia with a hematocrit value of 33% and normal renal function with a serum creatinine level of 0.6 mg/dL. The leukocyte count and differential were normal. The erythrocyte sedimentation rate was 55 mm/h (normal, <30 mm/h). Blood cultures for bacteria and fungi were negative for growth. Sputum cultures revealed occasional yeast forms identified as Candida species. A magnetic resonance image of the spine showed an infiltrative lesion involving the bodies of T6 and T7 vertebrae and the intervertebral disk (Figure 1). Computed tomographic (CT)–guided needle biopsy of the lesion was performed; culture of the biopsy specimen grew Aspergillus fumigatus. Because of the patient's poor cardiopulmonary status, he was treated with amphotericin B deoxycholate, 0.5 mg/kg per day, and had no surgical intervention. His back pain diminished, but his serum creatinine level increased. After he had received 400 mg of amphotericin B deoxycholate, his treatment regimen was changed to amphotericin B lipid complex (ABLC), 5 mg/kg per day. He received a total dose of 12 g of ABLC, and his serum creatinine level subsequently normalized. The patient was transferred to a rehabilitation unit and continued antifungal treatment with itraconazole, 400 mg/d. Adequate absorption of itraconazole was verified by assay of serum levels. On 2 occasions, total serum itraconazole levels (itraconazole plus hydroxyitraconazole) by high-performance liquid chromatography were 2.7 μg/ml, and 3.9 μg/ml., One month later, the patient reported recurrence of mild back pain; a second magnetic resonance image of the spine revealed progression of disease to involve the vertebral bodies of T5 through T8 and T12. Itraconazole therapy was discontinued, and treatment with ABLC was reinitiated. The patient's symptoms resolved rapidly, and he received an additional 10 g of ABLC. At 6-month follow-up, he had no recurrence of back pain.
Figure 1Case 1. T1-weighted magnetic resonance image of spine, showing infiltrative lesion involving T6 (open arrowhead), T7 (closed arrowhead), and intervertebral disk. Spinal cord encroachment was also identified (arrow).
A 47-year-old man with severe COPD and a history of inhaled corticosteroid (triamcinolone acetonide, 800 μg/d) use was admitted to our institution for back pain of 3 weeks' duration, which had progressed rapidly over 2 days. He reported bilateral lower extremity paresthesias and loss of bowel and bladder function suggestive of evolving spinal cord compression. Four months before the onset of these symptoms, he had required temporary mechanical ventilation for an acute exacerbation of COPD with hypercapnic respiratory failure. At the time of intubation, a chest radiograph showed no infiltrates or bony abnormalities. An electrocardiogram showed only sinus tachycardia. Results of a CBC with differential and chemistry panel were unremarkable. A serologic test for the human immunodeficiency virus (HIV) was negative. During hospitalization for respiratory failure, he received systemic corticosteroids for a total of 9 days. He also received broad-spectrum intravenous antibiotics for gram-negative nosocomial pneumonia. The organism was identified as Enterobacter species. The patient subsequently underwent tracheostomy due to prolonged intubation, but the tube was removed rapidly after resolution of his pneumonia. After being discharged from the hospital, he had no further complaints of respiratory symptoms.
On admission to Mayo Clinic Jacksonville for back pain, the patient was afebrile, and his vital signs were normal. Oxyhemoglobin saturation while he was breathing room air was 92% by pulse oximetry. The physical examination was remarkable for tenderness on palpation of the lower thoracic spine. His lungs were clear on auscultation.
A neurologic examination revealed no objective sensory level or motor loss, but laxity of the anal sphincter was noted, as were hyperreflexive deep tendon reflexes in both lower extremities. A Babinski sign was evident bilaterally. Catheterization resulted in a large residual volume of urine. Results of the CBC with differential and chemistry panel were again within normal limits. The erythrocyte sedimentation rate was 70 mm/h. High-dose intravenous corticosteroids were initiated, and an emergent CT scan of the spine revealed a destructive process involving T10 and T11 vertebrae with angulation and cord impingement (Figure 2). CT-guided -guided needle biopsy of the lesion was performed; culture and histological study of the specimen revealed A fumigatus. Blood, urine, and sputum cultures for bacteria and fungi were negative for growth. A chest radiograph showed no evidence of pneumonia. The patient underwent decompressive TIO through T11 partial hemilaminectomy with débridement. Open reduction and internal fixation with stabilization of the thoracic spine were also performed. Amphotericin B deoxycholate was initiated at a dosage of 0.5 mg/kg per day. The patient's back pain resolved completely, and he regained complete bowel and bladder function as well as lower extremity strength and sensation. Because of an increase in the serum creatinine level, his treatment regimen was switched to ABLC, 5 mg/kg per day, after he had received only 181 mg of amphotericin B deoxycholate. His serum creatinine level subsequently normalized after he had received 750 mg of ABLC. Amphotericin B deoxycholate was then reinstituted, and the patient completed a 2-g course with no further nephrotoxicity. He was transferred to a rehabilitation unit. At 6-month follow-up, he was doing well and was free of symptoms.
Figure 2Case 2. Reconstructed computed tomographic scan of thoracic spine, showing destruction of T10 (open arrowhead) and Til (closed arrowhead) vertebrae with angulation and cord impingement (arrow).
in: Mandell GL Bennett JE Dolin R 4th ed. Mandell, Douglas and Bennett's Principles and Practice of Infectious Diseases. Vol 2. Churchill Livingstone,
New York, NY1995: 2306-2311
In humans, Aspergillus has been found in the respiratory tract without evidence of producing disease. The spectrum of Aspergillus infection may range from noninvasive forms, such as allergic bronchopulmonary aspergillosis
in: Mandell GL Bennett JE Dolin R 4th ed. Mandell, Douglas and Bennett's Principles and Practice of Infectious Diseases. Vol 2. Churchill Livingstone,
New York, NY1995: 2306-2311
in: Mandell GL Bennett JE Dolin R 4th ed. Mandell, Douglas and Bennett's Principles and Practice of Infectious Diseases. Vol 2. Churchill Livingstone,
New York, NY1995: 2306-2311
In the immunocompetent host, invasive aspergillosis is rare; however, it has been reported in the immunocompromised patient.
The immune mechanisms in humans thought to be responsible for preventing Aspergillus species from producing disease involve the intact phagocytic functions of both the neutrophils and the mononuclear cells.
Selective protection against conidia by mononuclear and against mycelia by polymorpho-nuclear phagocytes in resistance to Aspergillus: observations on these two lines of defense in vivo and in vitro with human and mouse phagocytes.
Any underlying condition that disrupts effective phagocytosis or the number of effective phagocytes can predispose to the development of invasive or disseminated aspergillosis.
Selective protection against conidia by mononuclear and against mycelia by polymorpho-nuclear phagocytes in resistance to Aspergillus: observations on these two lines of defense in vivo and in vitro with human and mouse phagocytes.
Neutrophil dysfunction or neutropenia has a larger role in increasing the risk of potential disease from Aspergillus than does monocytopenia; however, the competence of both cell types is necessary for adequate host defense.
Selective protection against conidia by mononuclear and against mycelia by polymorpho-nuclear phagocytes in resistance to Aspergillus: observations on these two lines of defense in vivo and in vitro with human and mouse phagocytes.
Risk factors for Aspergillus infection include hematologic malignancies, chronic granulomatous disease (seen in children), chemotherapy, or conditions requiring the use of long-term immunosuppressive agents, systemic corticosteroids, or broad-spectrum antibiotics.
Aspergillus osteomyelitis involving the spine and disk space is rare. Vertebral Aspergillus osteomyelitis has been reported in immunocompromised patients with chronic granulomatous disease
Significance of isolation of Aspergillus from the respiratory tract in diagnosis of invasive pulmonary aspergillosis: results from a three-year prospective study.
Infectious complications in adults with bone marrow transplantation and T-cell depletion of donor marrow; increased susceptibility to fungal infections.
and as a result of prior spinal or disk trauma, factors that seem to predominate in the immunocompetent host.
Patients with severe COPD who are treated with long-term systemic corticosteroids are at high risk for the development of invasive aspergillosis as a result of altered mononuclear phagocytic function and abnormalities in the effective adherence, chemotaxis, and recruitment of phagocytic cells. To date, most cases of invasive aspergillosis in patients with COPD have occurred in the bronchopulmonary system.
Our 2 cases represent 2 of the 3 reported cases of Aspergillus osteomyelitis with diskitis in patients with COPD who were treated predominantly with inhaled corticosteroids and who had no other underlying immunocompromising disease. A common factor in these 3 patients was a self-admitted lack of compliance with their inhaled corticosteroid regimens, a situation supporting their nonimmunocompromised status. Despite poor compliance, exacerbations of their COPD that necessitated treatment with short-term systemic corticosteroids ranged from 1 to 4 episodes during the 2 years before invasive vertebral disease developed. In our patients, the most recent episode occurred 4 months before diagnosis of fungal infection of the disk space. In the first patient, the sputum culture grew Aspergillus before his symptoms had developed. However, this was thought to represent colonization at the time of isolation of the organism, rather than disease. Neither of our patients had signs of invasive aspergillosis before the diagnosis of infection of the disk space. In addition, chest radiographs obtained at the time of admission and during the most recent episode of COPD exacerbation revealed no infiltrates or findings consistent with aspergilloma or invasive or disseminated pulmonary disease. Hematologic seeding of the vertebral spine may have occurred during short-term administration of systemic corticosteroids for exacerbation of COPD; thus, a state of transient immunosuppression may have been created that allowed invasive aspergillosis to occur. Alternatively, Aspergillus may have reached the spine by hematologic seeding or contiguous spread caused by local immunosuppression due to highdose inhaled corticosteroids interfering with the effective fungicidal activities of the alveolar macrophage. Vertebral Aspergillus osteomyelitis by contiguous spread from the lung to the thoracic spine has been seen in children but is reportedly uncommon in adults.
Although these mechanisms are only speculative, they seem plausible in our patients. Of note, both our patients had well-localized vertebral disease with no other signs or symptoms of pulmonary or systemic infection.
In addition, the role of a patient's underlying lung disease and prior history of COPD exacerbation must be considered in the development of invasive aspergillosis. In both our patients, COPD had been diagnosed, and they had had chest radiographic findings consistent with emphysema. The previously reported case of vertebral Aspergillus spondylodiskitis was in a patient with asthma whose chest radiograph had showed normal findings.
Significance of isolation of Aspergillus from the respiratory tract in diagnosis of invasive pulmonary aspergillosis: results from a three-year prospective study.
Several studies of invasive aspergillosis in patients with COPD have been reported, and the management of the patient's COPD, the anatomical condition of the lung, and the patient's underlying immune status seem to be important in determining the risk of invasive disease. Invasive aspergillosis involving the lung in patients with COPD managed with short courses of systemic corticosteroids
This increases the likelihood of Aspergillus invading bronchopulmonary tissues because of local immunosuppression in an already colonized area. Concerns have been raised about the potential of high-dose inhaled corticosteroids producing adverse systemic effects. Two recent reviews on the controversies of high-dose inhaled corticosteroids in patients with asthma reported that the adverse effects on adrenal function, bone metabolism, and growth (in children) are unlikely with beclomethasone at dosages of 800 µg/d in adults or 400 ug/d in children, but at higher doses, systemic adverse effects may be possible.
Both our patients were taking triamcinolone acetonide at 800 μg/ d but were not always compliant. A study evaluating relative topical and systemic potencies of different inhaled corticosteroids in rat and mouse models showed that beclomethasone and triamcinolone acetonide were comparable.
The study used inhibition of formation of ear edema and the extent of thymic involution as markers of topical and systemic potency, respectively. The major limitation of that study was the use of a system other than lung and airway inflammation, as pointed out by Kamada and associates.
The effects of high-dose inhaled corticosteroids on systemic immune function are unknown. An extensive MEDLINE search yielded no definitive information. Further studies are needed.
Both our patients responded to treatment with intravenous amphotericin B. One patient (case 2) also underwent surgical debridement and stabilization, whereas the other (case 1) received only antifungal therapy. Different approaches to treatment of invasive Aspergillus osteomyelitis have been described. Classically, a combined medical and surgical approach
has yielded good results and seems to be the treatment of choice in patients who can undergo surgery or those requiring decompression due to neurologic symptoms. Studies using only medical treatment with either itraconazole or amphotericin B, alone or in combination, as well as amphotericin B and flucytosine have yielded acceptable results.
In both our patients, acute renal insufficiency developed, demonstrated by an increase in serum creatinine levels as a result of amphotericin B deoxycholate administration, a common adverse effect. The treatment regimen for both patients was changed to ABLC, and their renal function returned to baseline levels. One patient (case 1) then received itraconazole but, despite detectable serum levels, had progression of disease that necessitated resumption of treatment with amphotericin B. The patient completed his course of antifungal therapy with ABLC and had no further complications. Why the itraconazole treatment failed is unclear; perhaps higher doses with increased serum levels would have been effective. Two recent studies on the treatment of invasive aspergillosis
NIAID Mycoses Study Group Multicenter Trial of Oral Itraconazole Therapy for invasive Aspergillosis (published correction appears in Am J Med. 1994; 97:497].
suggested that dosages of itraconazole of 600 mg/d may be more effective than dosages of 400 mg/d. However, whether dosages of itraconazole higher than 400 mg/d and higher serum itraconazole levels correlate with improved efficacy remains to be established. In our other patient (case 2), the treatment regimen of amphotericin B deoxycholate was changed to ABLC because of an increase in his serum creatinine level; after his serum creatinine level normalized, he completed his antifungal regimen with no further nephrotoxicity or adverse effects.
Conclusion
Vertebral Aspergillus osteomyelitis is a rare condition that should be included in the differential diagnosis of progressive back pain or spinal cord compression in patients with COPD who are receiving inhaled or systemic corticosteroids. Because of the high morbidity and mortality associated with this condition, the diagnosis must be made early and treatment initiated. Treatment should involve antifungal therapy in all patients and surgical intervention, when feasible. The 2 current cases show that vertebral Aspergillus osteomyelitis with acute diskitis can occur in apparently immunocompetent patients with COPD treated with brief, intermittent courses of systemic corticosteroids and regular use of inhaled corticosteroids and in persons who show no signs or symptoms of respiratory or systemic Aspergillus infection.
References
Gerson SL
Talboi GH
Hurwitz S
Strom BL
Lusk EJ
Cassileth PA
Prolonged granulocytopenia: the major risk factor of invasive pulmonary aspergillosis in patients with acute leukemia.
in: Mandell GL Bennett JE Dolin R 4th ed. Mandell, Douglas and Bennett's Principles and Practice of Infectious Diseases. Vol 2. Churchill Livingstone,
New York, NY1995: 2306-2311
Selective protection against conidia by mononuclear and against mycelia by polymorpho-nuclear phagocytes in resistance to Aspergillus: observations on these two lines of defense in vivo and in vitro with human and mouse phagocytes.
Significance of isolation of Aspergillus from the respiratory tract in diagnosis of invasive pulmonary aspergillosis: results from a three-year prospective study.
Infectious complications in adults with bone marrow transplantation and T-cell depletion of donor marrow; increased susceptibility to fungal infections.
NIAID Mycoses Study Group Multicenter Trial of Oral Itraconazole Therapy for invasive Aspergillosis (published correction appears in Am J Med. 1994; 97:497].
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