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Invasive Pulmonary Aspergillosis

IPA is a severe and often fatal pulmonary infection.

In recent decades, the innocuous nature of Aspergillus fumigatus, a saprophytic fungal species, has markedly changed. Due to the widespread use of chemotherapy, immunosuppressive agents, and immune-modulating drugs, A. fumigatus is now considered the foremost airborne, opportunistic fungal pathogen in the immunocompromised and immunosuppressed.

In these patient populations, A. fumigatus is the foremost cause of invasive pulmonary aspergillosis (IPA), a severe and often fatal pulmonary infection.

With the incidence and prevalence of IPA dramatically increasing over recent decades, little is known about the agent-host immune factors related to A. fumigatus infections and which factors become destabilized by immunosuppressive therapies.

In the case of the immunosuppressed patient, the care provider must determine which immunosuppressive medications, antifungals, or surgical therapies may be effective in managing and treating IPA, while also maintaining an appropriate level of immunosuppression to treat various malignancies, autoimmune disorders, or prevent graft rejection.1, 2

Pathophysiology

Aspergillus species have a simple biological cycle with its virulence attributed to a high sporulating capacity. A. fumigatus releases high concentrations of conidia into the air which are continuously inhaled by humans. The major cellular innate defense mechanisms that the fungus must overcome include: alveolar macrophages, cytokines, T cells, neutrophils, and reactive oxygen species (ROS). Of the innate cellular responses listed, alveolar macrophages and polymorphonuclear neutrophils (PMNs) are the key components in responding to infections by A. fumigatus.

SEE ALSO: Pulmonary Hypertension in Children

Alveolar macrophages are primarily responsible for the phagocytosis of the conidia through receptor-binding. After phagocytosis, lysis and breakdown of conidia occurs after six to eight hours; yet, the killing rate by alveolar macrophages is surprisingly slow, only 10% or less in reduction of spores. PMNs infiltrate the lung tissues when the spore burden is high, typically following extracellular fungal germination. Neutrophils stick to the surface of the hyphae and the resultant contact between the PMNs and the hyphae triggers a surge of ROS and degranulation. In contrast to the alveolar macrophages, PMNs kill hyphae rapidly- 50% over the course of two hours. 1-6

In the immunocompetent host, A. fumigatus is seldom pathogenic because it is destroyed by the innate immune system specifically alveolar macrophages and PMNs. Within the lung parenchyma, various antigen receptors, such as toll-like receptors and dectin-1, recognize components within the fungal cell walls stimulating cytokine release and neutrophil chemotaxis.2 In the immunosuppressed patient, however, the immune system undergoes a downregulation through the use of medications and therapies, often leading to neutropenia. As a result, conidia overwhelm the innate immune response through germination and production of branched mycelium, leading to invasion of the lung parenchyma. The neutropenic physiological state (absolute neutrophil count [ANC] < 500 cells-mm3), in addition to the biological characteristics of the fungus (small conidia size, rapid mycelial growth at temperatures > 37°C, limited nutritional requirements), contribute to the virulence for this high-risk patient population.1-3, 6

IPA and the Immunosuppressed Patient

IPA continues to pose a major threat to immunosuppressed patients. In the United States, the number of patients at risk for IPA continues to expand due to: increased use of intensive chemotherapeutic regimens for solid tumor and other hematologic malignancies; increased number of bone marrow and solid organ transplantations; and, the use of immunosuppressive medications for treatment of autoimmune disorders.7, 8 Other comorbid conditions such as diabetes, renal impairments, prior respiratory disease, metabolic acidosis, trauma and environmental factors, including climate, hospitalization, gardening, and tobacco use, have also been associated with an increased risk of contracting IPA.5, 9

Throughout the literature, the incidence of IPA ranges from 0.2-40% with the solid organ transplantation and acute myeloid leukemia populations having the highest incidence of approximately 25%.9 From 1960 through 1970 alone, the United States saw a 160% increase in cases of aspergillosis reported by autopsy. Denning reviewed the therapeutic outcomes in 1223 cases of invasive aspergillosis from 1972-1995, concluding a mortality rate of 86% for pulmonary aspergillosis. According to Denning's review, the case-fatality ratio for solid organ transplant recipients was roughly 50-70% despite use of antifungal agents.7, 8

In a study conducted by the Stanford University Medical Center, data from 620 heart transplantation patients were analyzed for infectious disease over a 16-year period. The leading cause of early death was noted to be rejection; however, infection was the leading cause of late death. Of the infectious deaths post-transplantation, 10.2% were caused by fungal pathogens, with the most common being Aspergillus and Candida species accounting for 83% of cases.

Of the cases caused by Aspergillus species, A. fumigatus caused 85.6% of pulmonary infections. Although fungal infections accounted for only 10.2% of all opportunistic infections post-transplantation, nearly 50-70% of cases prove fatal due to localized or diffuse pulmonary disease, the highest mortality rates within the study population.10 Therapeutic outcomes often vary according to underlying disease, site of infection, and antifungal management; however, despite supposed improvements in existing management, IPA remains an overpowering opportunistic infection.7, 8

Guidelines for IPA: Presentation, Diagnosis, and Pharmacological Treatment

Aspergillus species have emerged as a significant source of fatal infections in immunosuppressed. This expanding population is composed of those patients with prolonged neutropenia, advanced human immunodeficiency virus (HIV) infection, bone marrow and solid organ transplants, and inherited immunodeficiency. Restoration of host innate defenses and reduction of systemic corticosteroid therapy are vital for improved patient outcomes in management and treatment of IPA; however, patients with autoimmune disorders and those who are recipients of solid-organ transplants may not be able to achieve this without risking serious complications, including graft rejection.10

Presentation

Clinical manifestations of Aspergillus infections vary depending on the immune status of the host.8 IPA infections characteristically present as non-specific lower respiratory tract infections, mimicking bronchopneumonias. Typical symptoms include: fever unresponsive to antibiotic therapy, dyspnea, cough with or without hemoptysis, sputum production, and pleuritic chest pain. In the neutropenic host, a scarcity of symptoms may be exhibited due to the inability of the host to mount an immune response. As a result, hemoptysis and pleuritic chest pain are the most prevalent signs of IPA in immunosuppressed patients and may be associated with cavitation and angioinvasion. Signs of systemic disease include seizures, cerebral infarcts, intracranial hemorrhage, and meningitis indicating central nervous system involvement.  Other end-organ damage can occur, such as the heart, kidneys, and liver, however, this is unlikely.7, 8

Diagnosis

Early diagnosis of IPA is challenging especially in the immunocompromised patient where a high level of suspicion is necessary in the presence of risk factors. The gold standard of IPA diagnosis is histopathological analysis of lung parenchymal tissue by video-assisted thoracoscopic or open-lung biopsy. The presence of branching hyphae and septate, in conjunction with a positive Aspergillus culture, is diagnostic for IPA. Culture confirmation is critical to distinguish Aspergillosis from other filamentous fungal antigens and a negative culture does not rule out a diagnosis of IPA. Blood cultures provide limited results and are often negative in the presence of disseminated infections; however, cultures gathered from bronchoscopy with bronchoalveolar lavage (BAL) have been shown to have a sensitivity and specificity of about 50% and 97% respectively for positive results. 2,3,10

Imaging studies tend to favor high-resolution computed tomography (HRCT) over chest radiography. Chest radiography findings are nonspecific and findings typically include rounded densities, pleural-based infiltrates, and cavitations. With HRCT, increasing recognition of the halo sign (an area of ground-glass opacity surrounding a pulmonary nodule) and air-crescent sign (a crescent-shaped region around a nodule due to necrosis) has greatly facilitated the diagnosis of IPA leading to early diagnosis and improved outcomes. Although these radiological features are not diagnostic, they are characteristic of IPA as well as other fungal infections and some bacterial infections, including Pseudomonas aeruginosa. 2,10

The most recent advance in IPA diagnosis is the detection of Aspergillus antigens in bodily fluids: galactomannan, a polysaccharide released by Aspergillus during growth.  Utilization of enzyme-linked immunosorbent assay (ELISA) for detection of galactomannan has been validated and approved by the US Food and Drug Administration (FDA) for the diagnosis of IPA with a marker threshold of 0.5 ng-mL-1. Sensitivity and specificity for this test range from 78-90% and 82-94%, respectively.5 One major limitation of galactomannan testing is the lack of species-specificity to Aspergillus; therefore, careful microbiological and clinical evaluation is needed. With the use of serum galactomannan testing and presence of the halo or air-crescent sign on early CT, the detection of IPA should improve and allow for earlier initiation of antifungal therapy in the immunosuppressed patient population.2,5,6,10

Pharmacological Treatment

The FDA has approved and licensed the following drugs for the treatment of Aspergillus and IPA: D-AMB, L-AMB, AMB colloidals, itraconazole, voriconazole, posaconazole, and caspofungin. In the case of IPA, voriconazole is the optimal medication for primary treatment; however, in patients whose IPA is refractory to voriconazole, limited data exists to guide management. Other therapeutic options include a change in class to an amphotericin B (D-AMB) formulation or an echinocandin, such as caspofungin (B-II), or a combination of agents including other azoles. D-AMB acts by binding ergosterol leading the formation of ion channels and fungal cell death. Echinocandins are a different class of semisynthetic drugs acting through noncompetitive inhibition of the synthesis of 1,3-β-glucan, a polysaccharide critical to cell wall formation in many pathogenic fungi. Other antifungal triazoles, including itraconazole and posaconazole, are synthetic compounds that target ergosterol biosynthesis similar to D-AMB; however, these inhibit lanosterol 14-α-demethylase, a fungal P450-dependent enzyme, resulting in cell membrane dysfunction and apoptosis. Antifungal management comprises oral or intravenous therapy, therapeutic monitoring of drug levels, modification of drug class, and use of combination therapy. Although initial combination therapy is not routinely recommended due to lack of proven data, the addition of another agent or change in drug class may be considered in individual patients.2,3,6,10

Medical Management vs. Surgical Resection

Without adequate therapy, IPA almost always progresses into an unrelenting, lethal pneumonia complicated by disseminated central nervous system disease or extension into adjoining intrathoracic structures, including the great vessels, pericardium, and chest wall. For patients with the need for chronic immunosuppression, continuing antifungal therapy throughout the duration of immunosuppression is often unsatisfactory due to drug interactions with immunosuppressive medications.2,10,11

Standard antifungal medical therapy of IPA that occurs in immunocompromised patients with hematologic disease or in solid organ transplant patients leads to less than 5% survival rate.12 Surgical resection, alone or in combination with antifungal therapy, may be beneficial for patients with lesions that are adjacent to the great vessels, the pericardium, the pleural space or ribs, or in patients with cavitary lesions or single pulmonary nodules. According to the American Thoracic Society, IPA therapy should be individualized based on the patient's clinical presentation and radiological findings and surgical cases should be limited to those patients with massive hemoptysis, pulmonary lesions adjacent to great vessels or pericardium, or patients in need of chronic immunosuppressive therapy.13 The goal of surgical therapy is to confirm diagnosis, prevent lethal hemoptysis, eradicate remaining infection, and prevent recurrence during future immunosuppressive therapy.11, 14

In a study conducted by Pidhorecky et al., 13 bone marrow transplant (BMT) patients with suspected IPA underwent lung resection. IPA diagnosis was based on the following: history and physical, presence of symptoms (cough, fever, hemoptysis, shortness of breath, chest discomfort), presence of halo or air crescent sign on CT, and BAL results. Selected surgical procedures included wedge resections, lobectomies, and pneumonectomies with varying approaches. Postoperative complications included operative bleeding requiring transfusion; prolonged air leaks; hepatic and/or renal failure; and multisystem aspergillosis, resulting in death. Of the surviving seven patients, no further aspergillosis recurrence was noted despite resuming immunosuppressive therapies.14

In a similar retrospective study conducted by Salerno et al., 13 immunocompromised BMT patients underwent surgical management for IPA, including single and multiple wedge resections, lobectomies, and chest wall resections, or a combination of these listed procedures. All 13 patients received antifungal therapy preoperatively and surgical resection cleared the Aspergillus infection in 69% of patients. Additionally, in a study conducted by Robinson et al., 16 patients underwent resection of acute localized pulmonary masses suggestive of IPA. Operative procedures included two pneumonectomies, one bi-lobectomy, nine lobectomies, and five wedge resections. All patients were treated with antifungal agents preoperatively and postoperatively; as a result, 64% of patients survived hospitalization with no evidence of recurrent Aspergillus infection after a median of eight months of follow-up.12,15

Quick and correct diagnosis of IPA in the patient who is immunosuppressed or immunocompromised is critical. Based on the studies listed above, prophylactic or early initiation of antifungal therapy is warranted in these patients; additionally, when antifungal therapy fails, pulmonary resection of IPA is a safe and effective form of therapy and should be strongly considered in the immunosuppressed individual.

References
1. Latgé  JP. The pathophysiology of Aspergillus fumigatus. Trends in Microbiology. 2001;9(8):382-389.
2. Kousha M, Tadi R, Soubani, AO. Pulmonary aspergillosis: A clinical review. Eur Respir Rev. 2011;20(121):156-174.
3. Thompson GR, Patterson TF. Pulmonary aspergillosis: Recent advances. Semin Respir Crit Care Med. 2011;32(6):673-681.
4. Tochigi N, Okubo Y, Ando T, et al. Histopathological implications of Aspergillus infection in lung. Mediators of Inflammation. 2013;2013:1-8.
5. Patterson KC, Strek ME. Diagnosis and treatment of pulmonary aspergillosis syndromes. Chest. 2014;146:1358-1368.
6. Kosmidis C, Denning DW. The clinical spectrum of pulmonary aspergillosis. Thorax. 2015;70: 270-277.
7. Lin SJ, Schranz J, Teutsch SM. Aspergillosis case-fatality rate: Systematic review of the literature. CID. 2001;32:358-366.
8. Denning DW. Therapeutic outcome in invasive aspergillosis. CID. 1996;23:608-615.
9. Herbrecht R, Bories P, Moulin JC, et al. Risk stratification for invasive aspergillosis in immunocompromised patients. Ann N. Y. Acad. Sci. 2012;1272;23-30.
10. Montoya JG, Giraldo LF, Efron B, et al. Infectious complications among 620 consecutive heart transplant patients at Stanford University Medical Center. CID. 2001;33:629-640.
11. Walsh TJ, Anaissie EJ, Denning DW, et al. Treatment of aspergillosis: Clinical practice guidelines of the Infectious Diseases Society of America. CID. 2008;46: 327-360.
12. Robinson LA, Reed EC, Galbraith TA, et al. Pulmonary resection for invasive Aspergillus infections in immunocompromised patients. J Thorac Cardiovasc Surg. 1995;109(6):1182-1197.
13. Limper AH, Knox KS, Sarosi GA, et al. An official American Thoracic Society statement: Treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med. 2011;183:96-128.
14. Pidhorecky I, Urschel J, Anderson T. Resection of invasive pulmonary aspergillosis in immunocompromised patients. Ann Surg Oncol. 2000;7(4):312-317.
15. Salerno, CT, Ouyang, DW, Pederson TS, et al. Surgical therapy for pulmonary aspergillosis in immunocompromised patients. Ann Thorac Surg. 1998;65:1415-1419.

Allyson McNally is a family nurse practitioner student at the University of North Florida.

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