Invasive Aspergillosis Treated With Adjunctive Hyperbaric Oxygenation: A Retrospective Clinical Series at a Single Institution
http://www.medscape.com/viewarticle/432440
Lisardo García-Covarrubias, MD, Diana M. Barratt, MD, MPH, Robert Bartlett, MD, Stephen Metzinger, MD, and Keith Van Meter, MD
South Med J 95(4):450-456, 2002. © 2002 Southern Medical Association
Abstract and Introduction
Abstract
Background. Invasive aspergillosis is the leading cause of early death in many transplant centers and has a major impact on the management of hematologic malignancies. The mortality rate with current therapy (amphotericin B and surgery) has remained unacceptably high. In vitro data along with a few case reports have suggested a potential benefit of hyperbaric oxygen (HBO).
Methods. We retrospectively studied all patients referred to our service when histologic specimens suggested invasive aspergillosis. Our main assessment of outcome was survival 3 months after initiation of HBO.
Results. Ten patients were included. All received adjunctive HBO along with the standard of care. Rhinosinusinal infection was the primary presentation. The most common underlying conditions were hematologic malignancies. Six patients were free of signs of infection 3 months after the first HBO treatment.
Conclusions. Adjunctive HBO appears to be a valuable tool in this devastating condition. Further studies are warranted to clarify its role.
Introduction
Invasive aspergillosis is the leading cause of early death in many transplant centers and has a major impact on the management of leukemia.[1,2] The Aspergillus fungi are widespread in nature and usually do not cause disease in healthy individuals, but they are responsible for opportunistic infections in immunocompromised patients. The most common clinical presentations are pulmonary and rhinosinusinal infections. Oxygen levels are often decreased in the infected tissue of patients with aspergillosis, since this fungus invades blood vessels, causing occlusion, thrombosis, and hypoxia.[3] This hypoxic environment results in tissue necrosis, diminishes the oxidative antifungal effect of amphotericin B (AMB),[4] and impairs the oxidative killing capacity and phagocytosis of white cells.[5,6]
The current standard of care involves intravenous antifungal agents, surgical debridement, and correction of the predisposing condition. Despite such modalities, the mean mortality was recently reported as 77% in the context of leukemia and neutropenia, and 66% for the subset of rhinosinusinal invasion.[7] Furthermore, a large clinical series showed that surgical debridement of aspergillus sinusitis increases mortality among neutropenic patients, apparently because of major delayed postoperative hemorrhage.[8] Therefore, novel noninvasive therapeutic tools are needed.
Hyperbaric oxygen therapy (HBO) is a safe noninvasive modality defined as breathing 100% oxygen pressurized to at least 1.4 atmospheres absolute.[9] It increases the oxygen tension in normal and infected tissue,[10] providing the needed oxygen for the killing mechanisms of neutrophils and the oxidative antifungal effect of AMB. In vitro studies along with clinical series have suggested a beneficial role of HBO in the management of invasive fungal infections.[11,12] However, the literature reveals only two case reports of invasive aspergillosis in which HBO was used as an adjunct.[13,14] Therefore, a retrospective study to address the potential role of HBO in the management of invasive aspergillosis was undertaken.
Methods
A retrospective study was done at Palmetto Richland Memorial Hospital Hyperbaric Medicine Program. Records of all patients with histologic specimens suggestive of invasive aspergillosis treated with adjunctive hyperbaric oxygenation from 1985 until 1999 were reviewed. Inclusion was based on the pathology report describing septate, acute branching hyphae suggestive of aspergillosis infection as depicted in Figure 1. Patients' demographics, initial clinical manifestations, diagnostic tools, and management were recorded, as well as time elapsed between the onset of symptoms and commencement of every therapeutic intervention. Delay in commencing therapeutic interventions was analyzed with Student's t test. The type of AMB and its total dose per patient were recorded. With this respect, empirical AMB therapy was included in the calculations of the total dosage. Number of surgical interventions and the procedures done were also documented. Data on the HBO protocol included pressure and duration per session as well as total number of treatments. Because severe neutropenia carries a poorer prognosis, white blood cell counts obtained within 1 week before or after the initial HBO treatment were recorded. All complications related to HBO were also documented. Isolated species was included when available.
Figure 1. (Patient 7) Histopathologic appearance of aspergillosis infection of paranasal sinuses. Hyphae are seen permeating wall of blood vessel. (Gomori methenamine silver stain, original magnification x 400)
Our main assessment of outcome was response to HBO. Patients who survived longer than 3 months after the initiation of HBO were classified as responders. This time frame has been used by others for assessing therapeutic outcome in invasive aspergillosis.[7,15]
Results
We identified 10 patients who had specimens suggestive of invasive aspergillosis during the 15-year study period. All cases involved primary rhinosinusinal infection. Hematologic malignancies accounted for the most common underlying diseases. Diagnosis was based on clinical grounds, imaging studies, and histopathologic analysis. All histologic specimens showed submucosal involvement and/or angioinvasion. The characteristic radiologic orbital apex syndrome of the rhinocerebral presentation is depicted in Figures 2 and 3. Speciation of the organism was accomplished only in 50% of cases. Tables 1 and 2 summarize information on the 10 patients.
Figure 2. (Patient 4) Axial computed tomography before complete endoscopic right sphenoethmoidectomy and hyperbaric oxygen therapy. Right ethmoid opacification, proptosis, and periorbital edema are evident.
Figure 3. (Patient 4) Axial computed tomography 4 months after sinus surgery and hyperbaric oxygen therapy shows improvement in proptosis and periorbital edema.
All patients were treated with AMB, surgery, and HBO. In addition, throughout the HBO course patients 1, 2, 4, and 5 were given granulocyte colony-stimulating factor (G-CSF), whereas patient 7 received granulocyte infusions. The mean time between the onset of symptoms and initiation of AMB therapy was 10.6 days, whereas for HBO initiation, it was 44.1 days. The most common surgical procedures included sphenoidectomy, ethmoidectomy, maxillary antrostomy, and middle turbinectomy. The mean time between the onset of symptoms and the first surgical intervention was 7.1 days. Hyperbaric oxygen treatments were administered at a pressure of 2 ATA (atmospheres absolute) for 90 minutes. Patients received an average of 19.8 hyperbaric treatments. Five patients were neutropenic at the initiation of HBO. Patient 3 did not have a white blood cell count determination within 1 week before or after the first HBO treatment.
There was a significant time delay between initiation of HBO and AMB (P = .046) as well as between HBO and surgery (P = .029). No statistical significance was found between the time to initiation of AMB and surgery (P = .29). Patient 2 was neither included in the calculation of the mean time elapsed between the onset of symptoms and initiation of AMB nor in the statistical analysis, because she was already receiving AMB before the onset of symptoms. Regarding HBO complications, patient 2 was febrile and experienced coughing and vomiting during the first treatment, requiring removal from the hyperbaric chamber. She tolerated subsequent treatments until the sixth one, during which she had a seizure. At this point, it was determined that her condition was terminal, involving dissemination of the fungal infection to the lungs. The family decided not to pursue aggressive management, and HBO was discontinued. The patient died the next day. Patient 3 had mild confinement anxiety, which responded to sedatives and family support. Patient 4 had two self-limiting episodes of shortness of breath during treatments 11 and 16. However, a physical examination during her HBO consultation, before the first treatment, revealed scattered coarse rhonchi bilaterally. Patient 7 experienced shortness of breath after all of his 8 treatments, but pulmonary aspergillosis had already become established. When his medical stability declined, HBO therapy was discontinued. The patient's death 20 days later was attributed to disseminated fungal infection.
The response rate in this study was 60%. Of the 4 deaths, 3 (patients 2, 6, 7) were attributed to disseminated aspergillosis. When patient 5 died, she was believed to be free of infection. She had received AMB, and completed a course of 30 treatments with HBO. She had significant clinical improvement, and specimens taken 1 month after completion of HBO therapy as well as findings on bronchoalveolar lavage 3 days before her death were negative for fungal elements. She died 3 days after bone marrow and immunologic ablative therapy that was complicated by congestive heart failure and pulmonary edema.
Discussion
Hyperbaric oxygenation appears to have improved the outcome of these patients. Our observation is supported by previous in vitro studies in which clinically applicable HBO has shown a fungistatic effect on various fungal species, including Aspergillus.[11]
Phagocytes, particularly macrophages and neutrophils, play a major role in controlling fungal infections. Their fungicidal activity against Aspergillus species is mediated by means of various oxygen intermediates,[16] and their killing capacity is directly proportional to available oxygen.[5] In addition, the fungicidal activity of pulmonary alveolar macrophages is augmented when exposed to 100% oxygen.[17]
Amphotericin B remains the mainstay of therapy for invasive aspergillosis. Sokol-Anderson et al[4] reported that under hypoxic conditions AMB's fungicidal capacity is reduced as much as 80% compared with normoxic conditions. Hyperbaric oxygenation elevates oxygen levels in severely hypoxic tissue[18] and has an additive fungicidal effect when combined with AMB.[19] In addition, adjunctive HBO reduces mortality and the number of debridements in nonfungal necrotizing infections.[20]
A MEDLINE search revealed only one case of adjunctive HBO in the treatment of invasive aspergillosis.[13] The patient was an 11-year-old boy with no apparently predisposing condition who sustained an extensive abdominal and perineal injury from the rotating drum of a silage wagon. The abdominal wound was complicated by a fungal infection involving Aspergillus species, Absidia species, and Rhizopus species. Management included multiple debridements, broad spectrum antibiotics, and AMB. In addition, the patient received 38 HBO treatments. After a 75-day hospitalization, the patient was discharged home, and he remained free of infection 9 months after discharge.
Farmer and Kindwall[14] described another case. The patient had non-Hodgkin's lymphoma, and the fungal infection developed after a homologous bone marrow transplantation. Maxillary and ethmoidal exenteration failed to halt the infection and success was achieved after 40 HBO treatments at 2.4 ATA for 90 minutes. No further details were available on this case.
There are many case reports of rhinocerebral mucormycosis treated with adjunctive HBO. Price and Stevens[21] reported the first case of an invasive fungal infection treated with adjunctive HBO. They reported a case of rhinocerebral mucormycosis in a diabetic patient who had refused radical surgery and whose condition was deteriorating rapidly despite maximal medical management of diabetes, high-dose AMB, and sinus drainage. Her condition stabilized shortly after HBO therapy was started. Fungal tissue cultures became negative after a course of 22 treatments. This case was followed by others that showed an improved outcome after HBO was incorporated.[22,23]
Despite the similarities in their affinity for blood vessels and in their clinical presentation,[24]Aspergillus and Mucor species belong to different classes and possess different characteristics, which precludes an accurate extrapolation of the results.
Denning[7] reported a retrospective review that included 90 patients with invasive aspergillus rhinosinusitis and underlying hematologic malignancies revealing an overall 34% (31/90) response rate. All patients received medical therapy, and patients treated exclusively by surgery were excluded. Our study's response rate was 60% (6/10), even when we excluded patient 5, who apparently had recovered from the fungal infection. However, because of the retrospective nature of these studies, as well as our small sample, it is difficult to accurately compare both rates. In addition, an important issue that needs to be considered when evaluating response rates as opposed to mortality rates is that patients who live longer tend to receive more treatment and their survival is attributed to the treatment, but it may actually be due to the pace of the disease and other factors.
Another potential benefit of HBO could be through its action on phospholipases. A theory that has been gaining acceptance is that phospholipases play an important role in the pathogenesis of some fungal infections such as aspergillosis, candidiasis, and cryptococcosis.[25] These groups of enzymes have the ability to destroy cells by means of hydrolyzing membrane phospholipids. Birch et al[26] showed that Aspergillus fumigatus phospholipase C activity is significantly increased at 37°C. Their role in some other necrotizing infections, such as gas gangrene, has been widely studied.[25]
Extensive literature supports the benefit of HBO in the management of gas gangrene.[9] According to the Undersea and Hyperbaric Medical Society, it is one of the 13 accepted indications for HBO.[9] An essential HBO mechanism of action is the inhibition of the production of Clostridium perfringens alfa-toxin, a phospholipase, when exposed at an oxygen tension of at least 250 mm Hg.[27] In addition, Giulivi et al[28] reported that rat lung phospholipase A activity is significantly decreased by hyperbaric oxygenation at 2 ATA. This inactivation is apparently mediated by superoxide ions produced under the HBO oxidative stress. However, the effect that HBO may exert on Aspergillus species' phospholipases remains to be proven.
Pulmonary infection is the most common clinical presentation of this disease. The fact that all of our patients had primary rhinosinusinal involvement may reflect that the referral physicians are more acquainted with the use of HBO for this particular site, probably associating it with the few reported cases of rhinocerebral mucormycosis treated with adjunctive HBO. With respect to delay in initiating treatment, it appears that HBO was initiated later than AMB and surgery. This delay seems to indicate that HBO was used as a last resort in most of our patients.
The limited experience with HBO in treating invasive aspergillosis precludes strong recommendations. Nevertheless, on the basis of the pathophysiology of invasive fungal infections and sound physiologic principles of HBO, prompt initiation of HBO appears reasonable either in patients with overwhelming rhinocerebral fungal infections or in those who are immunocompromised. In the setting of mucormycosis, adjunctive HBO has been suggested in patients who exhibit progression of the infection despite adequate conventional therapy.[14]
The protocol routinely used for our patients is 10 to 20 initial treatments of 90 minutes at 2.0 to 2.5 atmospheres absolute, followed by reassessment of their condition. Patients are initially treated every 8 hours during the first day and twice a day thereafter. A 5-minute air break is given every 25 minutes. Once the patient's condition has stabilized, treatments are given once a day until no further evidence of fungal infection is noted. Higher pressures (2.5 to 3.0 atmospheres absolute) are used for necrotizing soft tissue infections such as gas gangrene and necrotizing fasciitis. However, the treatment benefit of higher pressures for invasive fungal infections must be weighed against the risk of oxygen toxicity seizures.[12]
Side effects to HBO have an overall incidence of around 2%, the most common being middle ear barotrauma.[9] Four of our patients had some type of HBO side effects. The emetic episode of patient 2 during her first treatment could have been a premonitory sign of central nervous system (CNS) oxygen toxicity, since she was slightly febrile, which is known to be a predisposing factor to CNS oxygen toxicity.[29] Her further seizure activity could have been an overt sign of CNS oxygen toxicity, since she remained febrile throughout her unavoidable clinical deterioration. Alternatively, cerebral aspergillosis could have been the cause of the seizure activity. However, no post-mortem studies were done to document this possibility.
Oxygen-induced seizures can be easily prevented with antipyretics or with pre-HBO anticonvulsant medication in patients who need to be treated urgently.[30] Central nervous system oxygen toxicity is rare during HBO therapy. In the experience of Duke University Medical Center, HBO-induced seizures occur in less than 1 in 6,000 treatments at 2 ATA.[12]
Some degree of confinement anxiety is common in monoplace chambers. Indeed, 1 in 10 patients will have claustrophobia severe enough to preclude the treatment.[30] Presedation with a benzodiazepine usually allows successful completion of the treatments, as with patient 3. Many clinical multiplace chambers are walk-in chambers large enough to accommodate a nurse or technician and 10 seated patients, or several patients on stretchers. Confinement anxiety is much less a problem in multiplace chambers. Two of our patients had shortness of breath. One of them had pulmonary dissemination of the fungal infection, which may have rendered the lungs more susceptible to oxygen toxicity. Patient 4 may have had a concomitant lower respiratory tract process, since he was severely neutropenic at the initiation of HBO therapy.
Finally, patients with pulmonary aspergillosis who have just recovered from severe leukopenia are prone to spontaneous pneumothorax.[31] Spontaneous pneumothorax is a relative contraindication to HBO. Although none of our patients had this complication, patients should be closely monitored during the course of this therapy.
We believe this is the largest reported series on the use of hyperbaric oxygenation in the management of invasive aspergillosis. The main weaknesses of our study are its retrospective nature, small sample size, and the lack of a control group. Although our findings suggest a beneficial role of adjunctive HBO, prospective controlled trials are needed to clearly define its role in the treatment of this devastating infection.
Tables
Table 1. Characteristics of 10 Patients With Invasive Aspergillosis Treated With Adjunctive Hyperbaric Oxygenation
AML = Acute myelogenous leukemia, ALL = acute lymphocytic leukemia, CLL = chronic lymphocytic leukemia, DM = diabetes mellitus, CT = computed tomography, MRI = magnetic resonance imaging, NA = not available.
Table 2. Treatment of Patients With Rhinosinusinal Aspergillosis
HBO = Hyperbaric oxygen therapy, WBC = white blood cell count. Numbers in parentheses indicate the time elapsed (days) between the onset of symptoms suggestive of aspergillosis and initiation of therapy or first surgical intervention.
*Patient started receiving amphotericin B 20 days before onset of symptoms.
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Sidebar: Keypoints
- Hyperbaric oxygen can increase oxygen tension and improve white blood cell killing capacity in hypoxic infected tissues.
- Hyperbaric oxygen may inactivate phospholipases, one of the pathophysiologic mechanisms of this disease.
- Outcome appears to have improved with adjunctive hyperbaric oxygen.
- Further investigations are warranted.
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