Disseminated Aspergillus terreus Infection in Immunocompromised Hosts

KEVIN S. HARA, M.D.,* JAY H. RYU, M.D., Division of Thoracic Diseases and Internal Medicine; J . T. LIE, M.D., Division of Pathology; GLENN D. ROBERTS, Ph.D., Division of Laboratory Medicine

Aspergillus terreus is ubiquitous in the environment but has rarely been found to be pathogenic. When recovered from clinical specimens, it is commonly considered a saprophyte. We report two cases of fatal disseminated A. terreus infection. The first patient was receiving corticosteroid therapy for immune thrombocytopenia when the condition developed, and the second patient was receiving immunosuppressive therapy after bone marrow transplantation for myelodysplasia. We also describe the frequency of recovery of A. terreus in our laboratory. The serious pathogenic potential of A. terreus in immunocompromised hosts should be recognized.

Aspergillus terreus is widespread in the environ­ment. When recovered clinically, it is commonly regarded as a saprophyte. Sporadic reports, how­ever, have described serious infections caused by this organism. Recently, Chang and King1 de­scribed a case of invasive pulmonary A. terreus infection, and an earlier report by Tracy and associates2 was the only case of disseminated A. terreus infection we found in the literature. Herein we report two additional cases of dissem­inated A. terreus infection, and we also describe the rate of recovery of A. terreus in our laboratory.

REPORT OF CASES Case l.—An 80-year-old woman with a history of chronic obstructive pulmonary disease and hyper­tension was admitted to a hospital elsewhere be­cause of right lower quadrant pain, abdominal guarding, and leukocytosis. Acute appendicitis was suspected, and surgical intervention dis­closed a normal appendix but a terminal ileitis.

*Current address: Pulmonary Clinic of Hawaii, Honolulu, Hawaii.

Address reprint requests to Dr. J. H. Ryu, Division of Thoracic Diseases, Mayo Clinic, Rochester, MN 55905.

No bowel resection was performed. Postoperatively, thrombocytopenia (platelet count of 14,000/mm3) developed, manifested by extensive ecchymoses and a right inguinal hematoma. The prothrom-bin time and the activated partial thromboplas-tin time were normal. Platelet transfusions were administered, and her medications were discon­tinued. Her condition subsequently improved, the platelet count returned to normal, and the bowels began functioning adequately. On the 10th hos­pital day, however, abdominal pain recurred in conjunction with abdominal distention and guard­ing. Thus, the patient was transferred to the Mayo Clinic.

On hospital admission of the patient at our medical center, free intraperitoneal air was dis­covered, and operative intervention revealed a perforated ileum with fecal spillage and perito­nitis. A segmental ileal resection, Brooke ileos-tomy, and establishment of a mucous fistula were performed. Ampicillin, gentamicin, and metro-nidazole were administered intravenously. Post­operatively, thrombocytopenia (platelet count of 4,000/mm3) again developed. Bone marrow exam­ination showed numerous megakaryocytes. Im­mune thrombocytopenia was diagnosed. Predni-sone therapy, 60 mg/day, was begun, and her other

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medications were discontinued. The thrombocy-topenia did not improve, but no episodes of bleed­ing occurred. Her bowel function was adequate, and she was dismissed on the 30th hospital day.

One week after dismissal, the thrombocyto-penia was still present. The prednisone regimen was increased to 90 mg/day.

Three weeks after dismissal, the patient was readmitted for evaluation of persistent thrombo-cytopenia. Examination revealed ecchymoses, oral candidiasis, muscle weakness, and depression, and the platelet count was 8,000/mm3. Nystatin was administered orally. On the sixth hospital day, splenectomy, takedown of the ileostomy, and ileoileostomy were performed. Corticosteroid ther­apy was continued, and gentamicin and metro-nidazole were also administered.

On the eighth hospital day, the patient began having respiratory difficulties, manifested by in­creased pulmonary secretions, basilar rales, and decreased breath sounds. A chest roentgenogram showed bilateral pulmonary infiltrates and pleural effusions (Fig. 1). The urine output was de­creased, and she was treated with intravenous fluids. Her condition gradually deteriorated, and on the 12th hospital day, she was placed on mechanical ventilation. The leukocyte count was 14,900/mm3 with 90.2% granulocytes, and the platelet count was 52,000/mm3. Blood cultures showed no growth. In sputum cultures, many A. terreus organisms, few A. fumigatus organisms, and Acinetobacter calcoaceticus var. anitratus were identified. She continued to deteriorate and required increasing levels of inspired oxygen concentration and positive end-expiratory pres­sure to maintain adequate oxygénation. A low-grade fever was present, and the patient's course was eventually complicated by bilateral pneumo-thoraces that necessitated insertion of bilateral chest tubes. A Hypaque enema showed an intact ileal anastomosis. Computed tomography revealed bilateral pulmonary infiltrates, bilateral pleural effusions, and an abscess of the right lower lobe of the lung. No intra-abdominal abscess was seen. Bronchoscopy disclosed diffuse bronchitis and collapsible airways but no significant hemor­rhage. Culture of bronchoalveolar lavage fluid showed many colonies of A. terreus and few A. fumigatus. Therapy with amphotericin B was begun. Cardiac and renal function continued to deteriorate despite inotropic support. Myocardial infarction was diagnosed on the basis of an elevated

Fig. 1 (case 1). Chest roentgenogram, demonstrating bilateral pulmonary infiltrates and pleural effusions (greater on right side) in 80-year-old woman with disseminated Aspergillus terreus infection.

level of creatine kinase (117 U/liter; normal, 15 to 57 U/liter) and MB isoenzyme (17%; normal, 0%). The patient died on the 16th hospital day.

Autopsy showed disseminated A. terreus infec­tion. The lungs were involved with multiple focal and diffuse lesions of hemorrhagic pneumonitis and large central necroses in the left upper lobe and right lower lobe (Fig. 2). In addition, multiple focal myocardial lesions were found in the left ventricular wall. Multiple small lesions of the pleura and peritoneal surfaces of the diaphragm, stomach, and mesentery were also identified.

Case 2.—A 28-year-old man was in normal health until the fall of 1985, when a sore throat, fullness of the sinuses, myalgias, and malaise developed. Pancytopenia was discovered (hemo­globin, 10.1 g/dl; leukocyte count, 1,600/mm3; and platelet count, 90,000/mm3). Bone marrow examination and biopsy specimens of cervical and axillary lymph nodes were interpreted as nondiagnostic. The symptoms resolved with anti­biotic therapy, but the pancytopenia progressed.

A repeat bone marrow examination performed in June 1986 was interpreted as showing myelodys-plasia. Danazol was administered but was discon-

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Fig. 2 (case 1). A, Histopathologic section of lung, showing numerous septate hyphae with 45°-angle branches in pulmonary parenchyma and angioinvasion. (Methenamine silver stain; original magnification x32.) B, Higher power magnification of lung tissue, showing morphologic details of fungal elements. (Methenamine silver stain; original magnification x200.)

tinued after 3 days when a generalized erythem-atous rash developed.

In July 1986, the patient was hospitalized be­cause of fever and leukopenia. Cultures were nega­tive, and the fever resolved after 1 week of anti­biotic therapy.

The patient was admitted to the Mayo Clinic in November 1986 to undergo bone marrow trans­plantation for refractory anemia with excess blasts in transformation. He was asymptomatic except for recurrent oral vesicular lesions. Phys­ical examination revealed oral ulcérations and a single tender, soft, and mobile submandibular node (1 cm by 1 cm). The hemoglobin concentra­tion was 9.5 g/dl, the leukocyte count was 800/ mm3 with 17% segmented neutrophils, 1% bands, 76% lymphocytes, 2% monocytes, 2% eosinophils, and 2% blasts, and the platelet count was 134,000/ mm3. A bone marrow specimen was normocellular with increased and dysplastic erythrocytes, in­creased and atypical megakaryocytes, and left-shifted granulocytes with 20% myeloblasts. A chest roentgenogram showed normal findings except for a calcified granuloma in the right lung base.

Bone marrow transplantation was performed on the eighth hospital day, after cyclophosphamide and total-body irradiation conditioning, place­ment of a Hickman catheter, and administration of cyclosporine A. On the 15th hospital day, fever, nasal congestion, and left maxillary sinus pain developed. The leukocyte count was less than 200/mm3. A chest roentgenogram disclosed an

infiltrate in the left lower lobe of the lung. Sinus roentgenograms showed thickened membranes in the maxillary and ethmoid sinuses. Intravenous therapy with cefazolin, gentamicin, and mezlo-cillin was begun. The symptoms and fever per­sisted, and another chest roentgenogram revealed the additional development of an infiltrate in the right lower lobe of the lung. Empiric treatment with amphotericin B was begun on the 18th hospital day. Hyperbilirubinemia developed and progressed. The fever persisted, and a chest roent­genogram showed progression of the bilateral pulmonary infiltrates (Fig. 3). Amphotericin B and cyclosporine A were discontinued on the 30th hospital day because of renal insufficiency (serum creatinine, 2.8 mg/dl). The patient had received 221 mg of amphotericin B. Marrow engraftment occurred on the 31st hospital day. The patient had been neutropenic (leukocyte count less than 500/mm3) for 28 days. The azotemia progressed, and hemodialysis was begun. The hyperbiliru­binemia also progressed (total bilirubin, 31.5 mg/ dl), and corticosteroid therapy was initiated for a suspected graft-versus-host reaction.

On the 38th hospital day, a sputum culture grew A. terreus. Progressive pleural effusions developed, and culture of the right pleural effusion also eventually grew A. terreus. Amphotericin B ther­apy was reinstituted, and treatment with keto-conazole was begun. Susceptibility tests showed that the organism was resistant to amphotericin B. Respiratory failure ensued, and mechanical

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Fig. 3 (case 2). Chest roentgenogram, demonstrating bilateral pulmonary infiltrates in 28-year-old man with disseminated Aspergillus terreus infection.

ventilation was instituted. A chest tube was in­serted on the right side, and 1,800 ml of serosan-guineous effusion was removed. Amphotericin B was administered into the pleural space. The patient showed evidence of improvement, and attempts were begun to wean him from mechan­ical ventilation. On the 51st hospital day, how­ever, his condition suddenly worsened. An echo-cardiogram showed a pericardial effusion, and pericardiocentesis removed 450 ml of serosan-guineous fluid. Culture of the fluid grew A. ter­reus, as did cultures of urine and a skin ulcer. He continued to be febrile. He then became co­matose, and his right pupil became dilated and unresponsive to light. A computed tomographic scan of the head showed massive edema of the right hemisphere, a small right frontal lobe hemorrhage, and a transtentorial herniation. The patient died on the 54th hospital day. Autopsy revealed disseminated A. terreus infection involv­ing the brain, lungs, pleura, heart, pericardium, liver, spleen, thyroid gland, and kidneys (Fig. 4).

DISCUSSION Only a few investigators have found A. terreus to be an invasive pathogen. Tracy and asso­ciates2 reported a case of disseminated A. terreus

infection. Their patient had acute nonlympho-cytic leukemia and invasive pulmonary A. terreus infection that disseminated and failed to re­spond to treatment with amphotericin B and 5-fluorocytosine. At the time of initial examina­tion, the patient had multiple pulmonary nodules; subsequently, involvement of the kidneys, thy­roid gland, méninges, and brain became evident. The diagnosis was based on an open-lung biopsy. Chang and King1 described a patient with acute myelomonocytic leukemia and an apparently iso­lated invasive pulmonary A. terreus infection that responded to treatment with amphotericin B. The initial manifestation was a patchy left upper lobe infiltrate, which subsequently cavi-tated, developed an air-fluid level, contracted, and left a small fungus ball. The diagnosis was based on a transbronchial lung biopsy. Similarly, Moore and colleagues3 reported a case of fatal invasive pulmonary A. terreus infection that occurred in a patient with poorly differentiated lymphocytic lymphoma who was receiving chemotherapy and corticosteroids. These three cases were the only published reports we found of disseminated asper-gillosis and invasive pulmonary aspergillosis from A. terreus in humans.

Serious infection due to this organism has re­portedly occurred in dogs. As in humans, dissem­inated aspergillosis or A. terreus infection,in dogs is considered rare. Kabay and associates,4 how-

Fig. 4 (case 2). Histopathologic section of kidney, showing numerous septate hyphae with 45°-angle branches in renal parenchyma and angioinvasion. (Periodic acid-Schiff stain; original magnification x64.)

774 ASPERGILLUS TERREUS INFECTION Mayo Clin Proc, July 1989, Vol 64

ever, recently described a series of 10 dogs with disseminated A. terreus infection. The dogs had no apparent risk factors and no apparent portal of entry for the infection. Multiple systemic gran-ulomas and infarcts were found.

A. terreus has been identified in other superficial and deep infections, including onychomycosis,5

primary cutaneous aspergillosis,6 otitis externa,7

postoperative infection of the aural cavity,8"10

subcutaneous abscess,11 orbital infection,12 lymph­adenitis,13 osteomyelitis,14,15 meningitis,16'17 prosthet­ic valve endocarditis,18"20 pulmonary aspergilloma,20

and allergic bronchopulmonary aspergillosis.20"22

A. terreus has also been reported as a saprophyte in a patient with chronic pulmonary disease.23

Both of our patients had received immunosup-pressive therapy for hématologie disorders and also multiple courses of antibiotics. Prolonged granulocytopenia and antibiotic use have been found to be associated with invasive aspergillo-sis.24,25 Granulocytopenia was present in only one of our patients (case 2). The probable portal of entry in both patients was the lungs, although in our first patient the perforated viscus may have been the portal of entry. This theory seems unlikely, however, because of the interval since the perforation and because the initial clinical manifestations were in the lungs. Our second patient had nasal symptoms and sinus disease, both of which sites may have been infected with A. terreus and may have served as the portal of entry before dissemination. Invasive aspergillo­sis has previously been correlated with the isola­tion of the organism on cultures of nasal tissue.25

Sources of antemortem isolates were the sputum and bronchoalveolar lavage fluid in our first pa­tient and sputum, urine, skin ulcer, pleural effu­sion, and pericardial effusion in our second pa­tient. Pleural and pericardial aspergillosis are uncommon but recognized features of dissemi­nated aspergillosis.26"28 Both of our patients had pleural aspergillosis, and one of them (case 2) had pericardial aspergillosis as well. Walsh and Bulkley28 described a series of six immunocom-promised patients with pericardial aspergillosis, all of whom had invasive pulmonary aspergillo­sis and two of whom had pleural aspergillosis and effusions. Postmortem fungal cultures re­vealed A. flavus.

Disseminated A. terreus infection in both of our patients and the patient described by Tracy and associates2 was uniformly fatal despite treatment

with amphotericin B in all three patients and ketoconazole and 5-fluorocytosine in one patient each. Although amphotericin B seemed to control the infection clinically in the two patients de­scribed by Chang and King1 and Moore and colleagues,3 persistent infection was evident at the time of death. Susceptibility testing demon­strated amphotericin B resistance in one of our patients. Resistance to amphotericin B is of con­siderable concern because it severely limits our therapeutic options. Earlier diagnosis and treat­ment of A. terreus infections may improve the outcome.29,30

A review of the records in the Mayo Clinic mycology laboratory between November 1984 and February 1987 revealed 39 isolates of A. terreus from 37 patients, in addition to our two cases. Included were 24 sputum specimens, 10 trachéal and bronchial washings, 2 gastric wash­ings, and 1 skin, 1 palate, and 1 stool specimen. In only the two reported cases did patients have disease caused by this organism.

The reason for the recent recognition of dissem­inated disease caused by this organism is un­known. One theory is that the virulence of strains of A. terreus may have changed.4 Rippon and associates17 have shown that the strain of A. terreus recovered from their patient with menin­gitis after a spinal surgical procedure was more virulent than the usual strains of A. terreus found in soil. The possibility exists that this finding represents an increasing trend of disease caused by this organism.

CONCLUSION A. terreus is clearly capable of producing serious and disseminated disease in humans. The recov­ery of this organism in clinical specimens should not be casually dismissed as representing colon­ization. The possibility of a pathogenic A. terreus infection should be considered, particularly in immunocompromised hosts.

ACKNOWLEDGMENT We thank Sharon M. Peterson for assistance with preparation of the submitted manuscript.

REFERENCES \. Chang S-W, King TE: Aspergillus terreus causing inva­

sive pulmonary aspergillosis with air-crescent sign. J Nati Med Assoc 78:248; 251-253,1986

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2. Tracy SL, McGinnis MR, Peacock JE Jr, Cohen MS, Walker DH: Disseminated infection by Aspergillus ter­reus. Am J Clin Pathol 80:728-733,1983

3. Moore CK, Hellreich MA, Coblentz CL, Roggli VL: Asper­gillus terreus as a cause of invasive pulmonary asper­gillosis. Chest 94:889-891,1988

4. Kabay MJ, Robinson WF, Huxtable CRR, McAleer R: The pathology of disseminated Aspergillus terreus infec­tion in dogs. Vet Pathol 22:540-547,1985

5. Onsberg P, Stahl D, Veien NK: Onychomycosis caused by Aspergillus terreus. Sabouraudia 16:39-46,1978

6. Suseelan AV, Gugnani HC, Ojukwu JO: Primary cutane­ous aspergillosis due to Aspergillus terreus (letter to the editor). Arch Dermatol 112:1468,1976

7. Gregson AEW, La Touche CJ: The significance of mycotic infection in the aetiology of otitis externa. J Laryngol Otol 75:167-170,1961

8. English MP, Dalton GA: An outbreak of fungal infec­tions of post-operative aural cavities. J Laryngol Otol 76:1-11,1962

9. Powell DEB, English MP, Duncan EHL: Clinical, bac­teriological and mycological findings in post-operative ear cavities. J Laryngol Otol 76:12-21,1962

10. English MP: Preliminary observations on some Asper­gillus species in relation to their rôle as pathogens of aural cavities. J Laryngol Otol 77:422-429,1963

11. Cheetham HD: Subcutaneous infection due to Aspergil­lus terreus. J Clin Pathol 17:251-253,1964

12. Agarwal LP, Malik SRK, Mohan M, Mahopatra LN: Orbital aspergillosis. Br J Ophthalmol 46:559-562, 1962

13. Mahgoub ES, Ismail SA, El Hassan AM: Cervical lymph-adenopathy caused by Aspergillus terreus. Br Med J 1:689-690,1969

14. Seligsohn R, Rippon JW, Lerner SA: Aspergillus terreus osteomyelitis. Arch Intern Med 137:918-920,1977

15. Glotzbach RE: Aspergillus terreus infection of pseudo-aneurysm of aortofemoral vascular graft with contigu­ous vertebral osteomyelitis. Am J Clin Pathol 77:224-227, 1982

16. Stein SC, Corrado ML, Friedlander M, Farmer P: Chronic mycotic meningitis with spinal involvement (arachnoid­itis): a report of five cases. Ann Neurol 11:519-524, 1982

17. Rippon JW, Anderson DN, Soo Hoo M: Aspergillosis: comparative virulence, metabolic rate, growth rate and ubiquinone content of soil and human isolates of Asper­gillus terreus. Sabouraudia 12:157-161,1974

18. Drexler L, Rytel M, Keelan M, Bonchek LI, Olinger GN: Aspergillus terreus infective endocarditis on a porcine heterograft valve. J Thorac Cardiovasc Surg 79:269-274, 1980

19. Mershon JC, Samuelson DR, Layman TE: Left ventric­ular "fibrous body" aneurysm caused by Aspergillus endocarditis. Am J Cardiol 22:281-285,1968

20. Laham MN, Carpenter JL: Aspergillus terreus, a path­ogen capable of causing infective endocarditis, pulmo­

nary mycetoma, and allergic bronchopulmonary asper­gillosis. Am Rev Respir Dis 125:769-772,1982

21. Laham MN, Allen RC, Greene JC: Allergic bronchopul­monary aspergillosis (ABPA) caused by Aspergillus ter­reus: specific lymphocyte sensitization and antigen-directed serum opsonic activity. Ann Allergy 46:74-80, 1981

22. Vincken W, Schandevijl W, Roels P: Allergic broncho­pulmonary aspergillosis caused by Aspergillus terreus (letter to the editor). Am Rev Respir Dis 127:388-389,1983

23. Kennedy WPU, Milne LJR, Blyth W, Crompton GK: Two unusual organisms, Aspergillus terreus and Metschni-kowia pulcherrima, associated with the lung disease of ankylosing spondylitis. Thorax 27:604-610,1972

24. Gerson SL, Talbot GH, Hurwitz S, Strom BL, Lusk EJ, Cassileth PA: Prolonged granulocytopenia: the major risk factor for invasive pulmonary aspergillosis in pa­tients with acute leukemia. Ann Intern Med 100:345-351, 1984

25. Aisner J, Murillo J, Schimpff SC, Steere AC: Invasive aspergillosis in acute leukemia: correlation with nose cultures and antibiotic use. Ann Intern Med 90:4-9,1979

26. Weiner MH: Antigenemia detected by radioimmuno-assay in systemic aspergillosis. Ann Intern Med 92:793-796,1980

27. Zimmerman LE: Fatal fungus infections complicating other diseases. Am J Clin Pathol 25:46-65,1955

28. Walsh TJ, Bulkley BH: Aspergillus pericarditis: clinical and pathologic features in the immunocompromised pa­tient. Cancer 49:48-54,1982

29. Aisner J, Schimpff SC, Wiernik PH: Treatment of inva­sive aspergillosis: relation of early diagnosis and treat­ment to response. Ann Intern Med 86:539-543,1977

30. Fisher BD, Armstrong D, Yu B, Gold JWM: Invasive aspergillosis: progress in early diagnosis and treatment. Am J Med 71:571-577,1981

ADDENDUM We recently learned of another case of fatal dis­seminated A. terreus infection, which occurred in a 65-year-old woman with chronic lymphocytic leukemia who was receiving chemotherapy (pred-nisone, vincristine, and cyclophosphamide). The initial clinical features included decreased visual acuity and pain in the right eye, fever, and hemop­tysis. Autopsy revealed disseminated A. terreus infection involving the eyes, brain, lungs, esopha­gus, stomach, kidneys, bladder, thyroid and ad­renal glands, and the skin.