Diagnoses: Bilateral acute necrotizing aspergillus pneumonia with gangrenous involvement of the anterior segment, LUL (A. fumigatus). Calcium oxalate crystals in gangrenous lung and kidney.

Comment: The gangrenous lung was caused by invasive aspergillus pneumonia that involved a large segmental bronchus and produced thrombosis of its accompanying artery. In the lung, oxalate crystals were present only in and around the gangrenous area. It is possible that the oxalic acid generated by the organisms contributed to the oxidation and blackening of the necrotic tissue, but crystals were present in the adjacent viable lung tissue and kidney with no inflammatory response or darkening of tissue. The lack of crystals in the lesions of the right lung suggests that different growth conditions can suppress oxalic acid production, or perhaps that a different species of aspergillus was present. The fall in the patient's serum calcium level several days before he died was probably related, in part, to the formation of the calcium oxalate crystals, which contributed to his renal failure. Corticosteroid therapy and diabetes mellitus predisposed this patient to the aspergillus pneumonia.


Discussion: Pulmonary Aspergillosis

Introduction: Pulmonary diseases caused by fungi can be divided into 2 categories: those caused by hyphal forms and those caused by yeast forms. Hyphal fungi include aspergillus, with a diameter similar to that of a red blood cell, dichotomous (about 45°) branching, and septa; candida, with a diameter less than that of a red cell, and yeast and pseudohyphal forms; and zygomycetes (example, mucor), with a diameter greater than that of a red cell, 90° branches, and no septa. A fourth common hyphal fungus--Pseudallescheria boydii--is identical in tissue sections to aspergillus.

Aspergillus is ubiquitous in the environment. It is prevalent in water and air (including the hospital environment), as well as being found in decaying plant matter. After the spores (conidia) are inhaled, host factors determine whether the organisms become saprophytic, cause allergy, or become invasive (see Classification) [1].

Classification of Aspergillus-Related Diseases

Mechanism

Disease

Inhalation of conidia

Hypersensitivity pneumonia

Colonization

Allergic bronchopulmonary aspergillosis

Aspergilloma

Involvement of airways

Tracheobronchitis

Invasion of parenchyma

Acute necrotizing aspergillus pneumonia

Lung ball

Granulomatous aspergillosis

Chronic necrotizing pulmonary aspergillosis

Initiation of Disease

Conidia, which are shed from the tips of environmental aspergillus conidiophores, are the infectious particles. As they are 2-5 µm in diameter, they may reach the alveoli. The arrow marks a cluster of shed conidia. (C = conidiophore) Identification of the species of aspergillus is based on the structure of the conidiophore.

In patients with aspergillus disease, conidiophores may be found in well-aerated places, such as airways or cavities, but not in parenchymal infiltrates.

Acute Necrotizing Aspergillus Pneumonia (syn: Invasive pulmonary aspergillosis)

Introduction: Acute invasive pulmonary aspergillosis (IPA) typically occurs in patients with hematologic malignancies, who are treated with intensive cytostatic therapy and have severe neutropenia for prolonged periods of time. In the recent past, IPA has increased in frequency in these patients and can be found in 15 to 40% of patients who die of acute leukemia [1]. Early diagnosis and treatment can now lead to recovery if neutropenia resolves [2]. IPA also occurs in patients undergoing bone marrow or organ transplants including lung transplant [3], in patients with AIDS [5-7], and in some "normal" hosts [8]. Usual risk factors include neutropenia, steroid therapy, or broad spectrum antibiotics. Marijuana smoking may also be a risk factor [5]. Although the patient may have symptoms and signs of pneumonia, sputum production is unusual, and blood cultures are usually negative. Hematogenous dissemination to other organs is common [1].

Clinical features: Invasive disease in neutropenic patients usually begins with fever, pleurisy, nonproductive cough, dyspnea, or hemoptysis (from destruction of blood vessels by organisms) [1]. In a retrospective study of 27 patients with acute aspergillus pneumonia, many (14/27) with acute myelogenous leukemia, all had fever unresponsive to broad-spectrum antibiotics. Physical signs of pneumonia were often absent [4].

Diagnosis: As aspergillus is a ubiquitous organism that often colonizes the respiratory tract, strict definitions are required for diagnosis (table) [1, 9]. Blood cultures are almost always negative. Open biopsy is necessary if cultures are negative [1]. However, typical findings on CT and a positive culture from BAL fluid signify a high probability of disease [4]. Identification of a heat-stable, carbohydrate, aspergillus antigen--galactomannan--in serum is a promising means of diagnosis that is still under investigation [10].

Table: Diagnostic criteria for invasive aspergillosis

Definite

Probable

Histologic changes: Histologic features depend on host factors (see animal studies cited below). In the neutropenic patient, hemorrhagic, coagulative necrosis is the rule. When PMNs return, they may surround and digest the peripheral necrotic tissue to produce a lung ball. In the non-neutropenic host, a neutrophilic pneumonia without a fibrous wall or with variable degrees of walling off by granulation tissue occurs. Cavitation may occur secondarily. The organisms ignore lobar and pleural boundaries in local spread, and they invade vessels and spread to other organs. Vascular invasion is associated with thrombosis and angiitis.

Summary of histologic features:

Example: Several cavitating nodules were noted in the CT of a 12-year-old girl with acute myelocytic leukemia. Two subpleural nodules that developed during a period of neutropenia are shown here. A plain film showed fewer opacities. All cultures and bronchial lavages were negative, and the nodule on the right was biopsied after the PMNs had returned.

Histologic changes: Sections showed an abscess with a fibrous wall around purulent exudate. A GMS stain showed a few degenerating organisms that resembled aspergillus. The inset shows the PMNs at a higher magnification.

Pathologic features in an animal model by type of immunosuppression: In a rabbit model designed to examine differences in host response that depend on type of immunosuppression, animals were given methylprednisolone (MP), cyclosporine (CSA), MP + CSA, or Ara-C (to produce severe neutropenia) [12]. The neutropenic animals all died by 10 days. Lungs were heavy and lesions consisted of agranulocytic, hemorrhagic infarcts, hyphal invasion of large vessels, a low concentration of aspergillus organisms, and frequent extrapulmonary lesions. In contrast, animals treated with the other regimens all survived. Animals treated with cyclosporine alone cleared the organisms like control animals given saline. Animals given MP or MP + CSA developed a greater neutrophilic and lesser monocytic response than control or CSA-treated animals. Interestingly, the tissue burden of aspergillus in the MP or MP+CSA animals was 6-30 times greater than that of the other groups (p<0.05).

Virulence factors: Little is known about virulence factors of aspergillus, and they may vary depending on the type of disease--saprophytic, allergic, or invasive. Proteases are produced by the organism to provide nutrients from degradation of dead organic matter, but whether they are virulence factors for humans is not known. For example, most clinical isolates produce elastase, but histologic sections show no evidence of elastolysis in vessel walls [13].

Aspergillus produces catalase, a definite virulence factor in patients with chronic granulomatous disease (CGD). The fungal catalase, just as bacterial catalases, prevents killing by the host phagocyte that does not have an effective respiratory burst in CGD [14]. Phospholipases have been identified and may alter membrane permeability or increase adherence of pathogens [14].

Host factors of myelosuppression or corticosteroid therapy appear to be the most important virulence factors. Normal alveolar macrophages appear to be the first line of defense against aspergillus conidia, whereas PMNs, which are active against the hyphal form, are a secondary defense. Humoral and cell-mediated responses apparently do not have a role in host defense of acute invasive disease [15].

Aspergillosis in lung transplant patients: Aspergillus was cultured from sputum or BAL fluid of 31/141 (22%) of patients who had undergone lung transplantation [3]. In most patients (N=19) positive cultures represented colonization. In the remaining 12 (8.5%), positive cultures were associated with bronchitis, aspergilloma, or invasive parenchymal disease with dissemination or empyema. Of the single lung transplant patients, disease began in the native lung in 4/7 (57%). The risk of infection was higher after single (15%) than double (5%) lung transplantation (p<0.05). Although 11 patients had aspergillus infection at death, it was considered to be the cause of death in only 3.

Aspergillosis in AIDS: AIDS is not considered to be a risk factor for aspergillosis, and it used to be rare (5/3170 cases (0.16%), 1983-4) in these patients. Recently, however, there have been several reports of series of patients with some form of aspergillosis [5-7, 9]. Many, but not all, have had neutropenia (related to therapy) or steroid therapy, but most have had advanced disease with low CD4 counts [5, 6, 9]. Review of cases indicated that multiple forms of the disease--chronic cavitary, invasive, and bronchial types--rather than a single type, as seen in other risk groups, can occur in these patients [16]. A special feature in AIDS patients is the frequency (13/36) of cavitary upper lobe disease and the high frequency of fatal hemoptysis (42%) with it. As expected, focal invasive disease responded to therapy better than bilateral diffuse disease. Mortality related to aspergillosis was around 50% [9]. Radiographic changes include thick-walled cavities mainly in the upper lobes, nodules, consolidation, and pleural effusions [17].

Aspergillosis without predisposing cause: Finally, cases of invasive pulmonary aspergillosis without typical predisposing factors have been described [8]. Underlying diseases include pulmonary fibrosis, cystic fibrosis, influenza A, asthma, diabetes mellitus, alcoholism, and COPD. In 22 of 25 cases, the diagnosis was made postmortem. The authors conclude that the presence of aspergillus in tracheobronchial secretions from a "normal" host with pneumonia should not be considered to represent colonization.

Radiographic changes in patients with hematologic malignancies: Several patterns have been described: bronchopneumonia, segmental or lobar consolidation, multiple nodules, and cavities [1]. Patients with neutropenia and fever develop opacities significantly later than those with neither (median of 9 d vs 3 d). Changes described in 27 patients were [4]:

A CT "halo sign," a zone of low attenuation around a mass that appears when the patient is neutropenic, occurred in 7 patients and preceded an air crescent sign in 4. The "halo" is thought to represent a zone of hemorrhage around the pneumonia. CT also showed cavities, angiotropic lesions, infarcts, and atelectasis [4].

Treatment: It is important to diagnose aspergillosis specifically, as the dose of amphotericin used for empirical therapy of fungal disease is less than the high dose used for therapy of known disease [1,18]. In patients with hematologic malignancy, GM-CSF probably prevents some aspergillus infections by decreasing the length of neutropenia. Resection of localized pneumonic foci has been recommended for patients with normal blood counts and pulmonary function, who have a strong probability of localized IPA. In 18 patients, resection was performed for lesions refractory to amphotericin B therapy. Aspergillus was found histologically in all but 2. There were no perioperative complications [19]. Comparison of the outcome of surgical and medical treatment is still needed.

Course in patients with hematologic malignancy: In a study that correlated recovery from neutropenia with radiographic changes, it was found that in patients who recovered from neutropenia, cavities occurred in the lesions in 11/15 (73%) at an average of 2 d after PMNs exceeded 500/µl [2]. Also, of 10 patients with hemoptysis, most were in patients who recovered, rather than in those who did not. Massive hemoptysis occurred only in patients with recovery and was preceded by the appearance of a cavity in 3 of 4 patients. Overall mortality in one series of 27 patients was about 50%, but mortality was less if therapy was begun early after onset of pneumonia [4].

Prevention: Most cases are hospital acquired. Contaminated air conditioners, construction sites, and even ward vacuum cleaners have been shown to be a source of aspergillus [1, 20].

References

1. Walsh T. Invasive pulmonary aspergillosis in patients with neoplastic diseases. Sem Respir Infect 1990; 5:111-122.

2. Albelda S, Talbot G, Gerson S, Miller W, Cassileth P. Pulmonary cavitation and massive hemoptysis in invasive pulmonary aspergillosis. Influence of bone marrow recovery in patients with acute leukemia. Am Rev Respir Dis 1985; 131:115-120.

3. Westney G, Kesten S, de Hoyos A, Chapparro C, Winton T, Maurer J. Aspergillus infection in single and double lung transplant recipients. Transplantation 1996; 61:915-919.

4. von Eiff M, Zühlsdorf M, Roos N, Hesse M, Schulten R, van de Loo J. Pulmonary fungal infections in patients with hematological malignancies--diagnostic approaches. Ann Hematol 1995; 70:135-141.

5. Denning D, Follansbee S, Scolaro M, Norris S, Edelstein H, Stevens D. Pulmonary aspergillosis in the acquired immunodeficiency syndrome. N Engl J Med 1991; 324:654-662.

6. Klapholz A, Salomon N, Perlman D, Talavera W. Aspergillosis in the acquired immunodeficiency syndrome. Chest 1991; 100:1614-1618.

7. Pursell K, Telzak E, Armstrong D. Aspergillus species colonization and invasive disease in patients with AIDS. Clin Infect Dis 1992; 14:141-148.

8. Karam G, Griffin Jr F. Invasive pulmonary aspergillosis in nonimmunocompromised, nonneutropenic hosts. Rev Infect Dis 1986; 8:357-363.

9. Miller Jr W, Sais G, Frank I, Gefter W, Aronchick J, Miller W. Pulmonary aspergillosis in patients with AIDS. Clinical and radiographic correlations. Chest 1994; 105:37-44.

10. Verweij P, Dompeling E, Donnelly J, Schattenberg A, Meis J. Serial monitoring of Aspergillus antigen in the early diagnosis of invasive aspergillosis. Preliminary investigations with two examples. Infection 1997; 25:86-89.

11. Horvath J, Dummer S. The use of respiratory-tract cultures in the diagnosis of invasive pulmonary aspergillosis. Am J Med 1996; 100:171-178.

12. Berenguer J, Allende M, Lee J, Garrett K, Lyman C, Ali N, Bacher J, et al. Pathogenesis of pulmonary aspergillosis. Granulocytopenia versus cyclosporine and methylprednisolone-induced immunosuppression. Am J Respir Crit Care Med 1995; 152:1079-1086.

13. Hogan L, Klein B, Levitz S. Virulence factors of medically important fungi. Clin Microbiol Rev 1996; 9:469-488.

14. Birch M, Robson G, Law D, Denning D. Evidence of multiple extracellular phospholipase activities of Aspergillus fumigatus. Infect Immun 1996; 64:751-755.

15. Schaffner A, Douglas H, Braude A. Selective protection against conidia by mononuclear and against mycelia by polymorphonuclear phagocytes in resistance to aspergillus. Observations on these two lines of defense in vivo and in vitro with human and mouse phagocytes. J Clin Invest 1982; 69:617-631.

16. Nash G, Irvine R, Kerschmann R, Herndier B. Pulmonary aspergillosis in acquired immune deficiency syndrome: autopsy study of an emerging pulmonary complication of human immunodeficiency virus infection. Hum Pathol 1997; 28:1268-1275.

17. Staples C, Kang E-Y, Wright J, Phillips P, Müller N. Invasive pulmonary aspergillosis in AIDS: radiographic, CT, and pathologic findings. Radiology 1995; 196:409-414.

18. Ruchlemer R, Yinnon A, Hershko C. Changes in the natural history of invasive pulmonary aspergillosis in neutropenic leukemic patients. Isr J Med Sci 1996; 32:1089-1092.

19. Baron O. Guillaumé B, Moreau P, Germaud P, Despins P, De Lajartre A, Michaud J. Aggressive surgical management in localized pulmonary mycotic and nonmycotic infections for neutropenic patients with acute leukemia: report of eighteen cases. J Thorac Cardiovasc Surg 1998; 115:63-69.

20. Anderson K, Morris G, Kennedy H, Croall J, Michie J, Richardson M, Gibson B. Aspergillosis in immunocompromised paediatric patients: associations with building hygiene, design, and indoor air. Thorax 1996; 51:256-261.

Clinical summary

Comments to: mw6825@itsa.ucsf.edu

Last revised 5/1/98

Copyright 1998 by Martha L. Warnock. All rights reserved.

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