journal of epidemiology · nosocomial aspergillosis involving a total of more than 100 patients....

Eur. J. Epidemiol. 0392-2990

June 1989, p. 131-142 EUROPEAN

JOURNAL OF

EPIDEMIOLOGY

Vol. 5, No. 2

NOSOCOMIAL ASPERGILLOSIS: ENVIRONMENTAL MICROBIOLOGY, HOSPITAL EPIDEMIOLOGY,

DIAGNOSIS AND TREATMENT

T.J. WALSH *1 and D.M. DIXON**

*Section of Infectious Diseases, Pediatric Branch, Building 10, Room 13N-240, National Cancer Institute, Bethesda, MD 20892.

**Wadsworth Center for Laboratories and Research, New York State Department of Health, Albany, NY 12201-0509.

Key words: Aspergillosis - Hospital epidemiology - Nosocomial infections.

The purpose of this review is to characterize the environmental microbiology, hospital epidemiology, diagnosis and treatment of nosocomial aspergillosis. Appropriate environmental control measures are important in preventing or arresting an outbreak of nosocomial aspergillosis. These include selective environmental microbiological surveillance and floor to ceiling barriers during construction or renovation. These is particularly important for the bone marrow transplant units and units with persistently granulocytopenic patients. We have summarized the point source and cited or formulated the environmental correction measures relating to 25 outbreaks of nosocomial aspergillosis involving a total of more than 100 patients. The most frequent settings of nosocomial invasive aspergillosis occurred in granulocytopenic patients following respiratory infection from an airborne source, associated with hospital construction or contaminated ventilation systems.

INTRODUCTION

Nosocomial aspergillosis has emerged during the past two decades as an important cause of morbidity and mortality. The Centers for Disease Control found that from 1970 to 1976 there was a 158% increase in the incidence of nosocomial aspergillosis (16), associated with an increasing number of immunosuppressed patients. A study conducted at the University of Minnesota (38) found nosocomial aspergillosis to be the single most important infection causing death in its allogeneic bone marrow transplant recipients. Estimates of the incidence of nosocomial aspergillosis are likely to be quite conservative in determining the true magnitude of nosocomial fungal infection. Patients with invasive aspergillosis often are diagnosed

t Corresponding author.

only at pos tmor tem examination, and the rate of autopsies has decreased to approximately twenty percent. Despite the extraordinary advances achieved in management of immunocompromised patients, there has been comparatively less progress in the prevention, diagnosis, and treatment of nosocomial apsergillosis during the same period. As delineated by Bullock and Deepe (10), there is a critical need for more research directed toward medical mycology. The purpose of this paper is to characterize the enviromental microbiology, hospital epiderniology, diagnosis, and treatment of nosocomial aspergillosis.

MYCOLOGY

The genus Aspergillus was named in 1729 by the Italian priest, Micheli. The scientific name may be derived f rom "aspergillum" (the Roman Catholic holy

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Walsh T.J. and Dixon D.M. Eur. J. Epidemiol.

water sprinkler), since there is a resemblance to the microscopic fruiting structures of the aspergilli (27,51). Aspergillus contains many species of moulds which produce septate, hyaline hyphae from which conidiophores with terminal vesicles develop. Conidia measure 2.5-3.5 lain in diameter in most pathogenic strains and develop as phialoconidia from flash- shaped phialides which arise from the surface of the vesicles in either a single or a double series. The mycology and terminology of the groups of aspergilli has recently been summarized by Kwon-Chung (24).

ENVIRONMENTAL MICROBIOLOGY

Aspergillus species are saprophytes which are ubiquitous in nature. In the immediate human environment as reviewed by Nolard and Detandt (35), Aspergillus fumigatus has been reported from air, furniture, dust, soil of potted plants, foodstuffs such as ground coffee and powdered milk, spices, in condensation from refrigeration appliances, and in cellars. Aspergillus flavus has been reported from many of these same sources, but has also been associated with nuts (35). AspergilIus fumigatus is thermotolerant and grows at temperatures of 40-45°C.

Spore counts of the aspergilli have been shown to undergo seasonal variation, with higher concentrations found in the winter months, and with some indications that more spores are found from air sampled inside of buildings than from outside air (51). There is also evidence that spore counts outside the hospital may be greater than those inside the building (54,60). Of course, this would be a function of the sites sampled. One study found A. fumigatus to compose 75% of all fungi cultured from the air in the immediate vicinity of a sewage composting site; whereas, this fungus constituted less than 2% of the total fungi cultured from air 8 km from the compost site (32).

In terms of the immediate patient environment in nosocomial aspergillosis, there is not only the problem of locating a source of the etiological agent, but also the issue of documenting that the environmental isolate is the same strain that is causing disease in the patient. This is complicated by the lack of convenient subspecies markers for the pathogenic aspergilli. Staib has been active in attempting to establish this correlation between the environmental isolate and the clinical isolate (58). In one study he demonstrated that precipitating antibody from human patients reacted similarly in an immunodiffusion test when comparing the patient isolates ofA.fumigatus to isolates collected from potted plants from private homes and from hospital rooms (59).

The situation is somewhat clearer where outbreaks of infection occur in the vicinity of a common point source of the etiologic agent, as in the epidemics of nosocomial aspergillosis described below. Yet we lack the specific epidemiological markers of a phage typing system, as is so useful in

bacteriology, or even the biotyping systems as described for Candida (12).

Aspergillus species are normally only transient colonizers of man. Airborne transmission is the principal route of transmission of Aspergillus within the hospital environment. The respiratory tract is the most common portal of entry. The small (2.5-3.5 la)diameter of Aspergillus conidia from most pathogenic Aspergilli permits them to reach the pulmonary alveolar spaces, where they may germinate to form hyphae.

As previously noted, conidia may be generated outside the hospital (54,60) as well as within the hospital (1, 51, 61, 70). Conidia may enter the hospital when there is an inadequate air filtration system, for outside air (42-44). Aspergillus fumigatus was readily recovered from the inanimate environment of an unventilated hospital, especially during the autumn and winter (34). Prospectively monitored corridor air samples at a bone marrow transplant station at the University of Minnesota disclosed a marked increase in airborne thermolerant Penicillium spores (61). The source of these conidia was traced to rotting cabinet wood enclosing a sink with leaking pipes in a medication room. Aspergillus was not recovered from this environmental source; however, subsequent studies showed that A. fumigatus and A. flavus could grow on this woody substrate. The authors cautioned that persistence of wet organic substrates in the hospital environment may increase the risk for propagation of conidiogenous fungi. Another environmental study (70) identified an Aspergillus "pseudoepidemic", which arose from stored respiratory culture isolates of Aspergillus spp. from bone marrow transplant recipients. Cross- contamination of other cultures processed in the same room initially suggested a true outbreak of aspergillosis in these high-risk patients.

HOSPITAL EPIDEMIOLOGY

Two principal mechanisms of nosocomial transmission of Aspergillus to patients are known: (1) airborne transmission of the respiratory tract or operative site and (2) contact transmission (e.g., direct inoculation from occlusive materials). The former is the most common mechanism of nosocomial transmission of Aspergillus spp. to patients (Table 1).

AIRBORNE TRANSMISSION. Aspergillus has been cultured from various sources within the hospital evironment as the apparent source of nosocomial aspergillosis: A) unfiltered air; B) contaminated ventilation systems at intake and/or exhaust ducts; C) dust dislodged during hospital renovation and construction; D) horizontal surfaces, food, and soil of potted plants (58).

A) Non-Filtered Non-Ventilated Air: Rose (46) observed that following a move from an older hospital

Vol. 5, 1989 Nosocomial aspergillosis

Table 1. - Summary of Outbreaks, Clusters, and Case Series of Nosocomial Aspergillosis Associated with Environmental Sources

Number Environmental Environmental Corrective Ref. Authors of Patients Fungi Source Measures Taken

1 Aisner 8 Aspergillus false ceil ing; fireproofing avoidance of building materials with high selectivity for spp. material sprayed wet during Aspergillus growth prevention of fungal growth on

construction and allowed to air hospital construction materials: copper-8-quinolinolate dry

3 Allo et al. 9 Air supply system to operating room

5 Arnow 3 renovation work one floor et al above patients caused dust to

filter down through pores in acoustical tiles of false ceiling of renal transplant ward

13 Burton 4 air ducts in isolation room; et al. pigeon excretions at external air

inlets

17 Gage et al. 4 pigeon excreta on outside window sills and moss growing on hospital roof adjacent to air intake ducts; operating room; postoperative recovery room

19a Grossman armboards; IV cannulae; et al. 6 storeroom with false ceiling

damaged by water leak

23 Krasinksi 2 dust above hospital's false et al. ceiling

A. JTapus

A. fumigatus

A. fumigatus

A. fumigatus A. glaucus

A, flavus A. fumigatus A. niger

Aspergillus Zygomycetes

25 Kyriakides 3 A. fumigatus air contaminated by bird et al. droppings after removal of bird

screen on hospital roof from air ducts leading to transplant unit

26 Lentino 10 A. fumigatus et al. A. flavus

26a Lie et al. 5 Aspergillus spp.

28 Mahoney 5 Aspergillus

36 Opal et al. 11

37a Perraud 22 et al.

39 Petheram 7 and Seal

41 Prystowsky 4 et al.

43 Rhame 10

46 Rose et al. 11

47 Rosen and 175 Sternberg

A. j~avus A. niger Other Aspergillus spp

recent road construction; window air conditioners used in renal transplantation ward

flower bench in hall beside the ward

airborne contamination by cross-ventilation via contaminated air-conditioning system; shutdown of exhaust fan for repairs

hospital renovation

A. fumigatus false ceilings, fibrous thermal and/or acoustic insulation materials, and roller blind castings

A. fumigatus spore contamination of operating theatre

A. flavus paper-covered boards or adhesive tape securing intravenous- infusion sets

Aspergillus possibly low efficiency of bone marrow transplant air filters and simultaneous external construction

Aspergillus naturally ventilated hospital spp.

Aspergillus Mucoraceae

unventilated and non-filtered air

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renovation of air supply system to operating rooms; vacuuming air supply ducts

cultures of dust above ceiling tiles before false ceilings are disturbed; relocation of patients; constructing impermeable barriers; cleaning work areas; periodically culturing dust above ceiling tiles and cleaning contaminated areas

air intake system revised to be inaccessible to pigeons

cleaning operating room, recovery room and air ducts; installation of better filters in air-conditioning system; barriers against pigeon roosting; elimination of moss on hospital roof

cleaning storeroom

impervious airtight barriers between patient and construction areas; vacuuming areas above false ceilings; traffic control patterns to prevent dust from being tracked into patient areas; ventilating construction areas with negative pressure with respect to adjacent patient care areas; cleaning construction areas

ducts modified to be inaccessible to birds; ducts inspected in transplant unit at regular intervals

n o n e

removal of presumptive source of Aspergillus from hospital environment

cleaning of air-conditioning equipment and contaminated hospital rooms

construction of airtight plastic and dry wall barriers about construction sites; negative-pressure ventilation in the work area; area decontamination with copper-8- quinolinolate; installation of high efficiency particulate air (HEPA) filters in rooms housing immunocompromised patients

suggested hospitalization of aplastic patients in isolated rooms with filtered and sterile ventilation systems or transfer of these patients to another hospital and cleaning of air conditioning systems

changing air filters

suggested changing intravenous sites regularly and changing tape periodically

HEPA laminar air-flow rooms for bone marrow transplantation, highest efficiency filters; increased air change rate

suggested improved mechanical control of hospital ventilation

improved ventilation system

Walsh T.J. and D ixon D.M. Eur. J. Epidemiol.

Table 1. (continued)

Number Environmental Environmental Corrective Ref. Authors of Patients Fungi Source Measures Taken

49 Rotstein 10 Aspergillus et al. spp.

49a Ruutu 8 A. fumigatus et al.

52 Sherertz et 14 A. fumigatus al. A. flavus

58 Staib et al. not given A. fumigatus

59 Stalb not given A. fumigatus A. flavus

62 Stewart 1 (see A. fumigatus et al. (ref. 48)

70 Weems 39 Aspergillus et al. spp.

70a Weems 55 Aspergillus et al. spp.

Zygomycetes

outside construction and low efficiency filters

previous window renovations with concomitant fiber deposits on ventilation grids, poor sealing of air filter fittings in patient rooms, occasional ventilation through windows in the ward, low speed of booster fans in ventilation system

ventilation system

aspergillosis patients, clinical material sampled from them, decaying plant material, used clothes and linen

soil of indoor plants; nuts

visibly contaminated and leaking bags of a commercial peritoneal dialysis fluid supplied in plastic containers

pseudoepidemic caused by laboratory contamination

hospital construction

improved air filtration

cleaning of ventilation ducts and change of filters in the ventilation system

whole-wall high=efficiency particulate air filtration units with horizontal laminar air flow

numerous recommendations concerning hospital, work site, and laboratory

elimination of potted ornamental plants; suggested replacement of soil by hydroculture

suggested inspection of every plastic bag carefully and rejection of containers with more than a fface of moisture inside the outer envelope

isolates of filamentous fungi to be handled under a laboratory exhaust hood

minimized exposure of seriously immunocompromised patients to major construction activity; sealed off patient-care areas from construction activity with impermeable barriers; critically reviewed indications for performing environmental cultures; ensured that hospital ventilation systems produced proper air exchange rates and pressure relationships in critical areas near construction activity and that air was not circulated from construction areas into other hospital areas; contacted engineers about special mantenance and cleaning of ventilation systems likely to be affected by construction, assured that ventilation systems were balanced to design specifications and that filters w e r e visually examined for plugging or leakage; cleaned n e w and renovated wards before admitting (or readmitting patients).

without filtered air to a new hospital with pre-filtered, non-recirculating air, the rate of new cases of pulmonary aspergillosis declined from 11 cases per five years to no cases on the next five years. Rosen and Sternberg (47) observed that the frequency of aspergillosis and zygomycosis decreased from 145 cases in a three year period to 30 cases over the next three years after moving from an older hospital with no central ventilation to a new hospital with central filtered ventilation.

B) Contaminated Ventilation Systems: Ventilation systems may be colonized with Aspergillus along (1) intake ducts (including filters), and (2) exhaust ducts. Involvement of the intake arm of a ventilation system is usually associated with a source of Aspergillus on or near the exterior portion of the intake duct. When exhaust ducts are involved, a faulty exhaust fan is commonly implicated.

1) Contamined Air Intake and Supply: Air intake ducts have been the source of several outbreaks of nosocomial aspergillosis (3, 13, 17, 39). An outbreak of

Aspergillus prosthetic endocarditis was associated with Aspergillus contamination of an operating room air intake system (17). "A luxuriant growth of moss" on the roof and collections of pigeon feces on the window ledge were adjacent to the operating room air- intake duct. Both sites grew Aspergillus species. Following removal of the moss and pigeon excreta, cleaning the air ducts, and changing intake filters to a more efficient particle extraction grade, no new cases of Aspergillus endocarditis developed. Another investigation (13) of a cluster of aspergillosis in four renal transplant recipients identified pigeon excreta at the air intake ports of the transplatation unit ventilation system. The external duct inlets were modified to prevent access to birds. Another outbreak of prosthetic valve endocarditis due to A. fumigatus in seven patients was ascribed to the air intake ducts and intake filters of the operating room (39). The first three cases prompted an environmental investigation, which grew A. fumigatus from dust and fibers within the ducts. The ventilation ducts were cleaned and

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operating rooms were painted. However, four more cases of A. fumigatus prosthetic valve endocarditis subsequently developed. Contaminated air intake filters, which had not been changed during the initial investigation, were the sources of Aspergillus conidia in these subsequent cases. Air-intake filters with limited efficiency also may have contributed to nosocomial aspergillosis in allogeneic bone marrow transplant recipients (43,49).

Air-supply ducts to four operating rooms at another hospital were identified recently as the source of A flavus causing primary cutaneous aspergillosis at the site of insertion of Hickam intravenous catheters. Nine patients were infected. All nine were granulocytopenic with leukemia or aplastic anemia (3). No viable fungal particles were found and no additional cases of postoperative wound infection or colonization were identified after renovation of the air-supply system to the four operating rooms and vacuuming of air-supply ducts to all other operating r o o m s .

2) Contaminated Exhaust Ducts: An outbreak of aspergillosis related to air backflow through exhaust ducts occurred ten days after an exhaust fan on a pediatric oncology floor was closed for, maintenance (28). The air-conditioning system became contaminated with Aspergillus, and five leukemic children over the next two months acquired Aspergillus pneumonia and sinusitis. After the contaminated rooms were cleaned, only two cases of aspergillosis occurred over the next 12 months and these occurred in other rooms. Back-flow of air from a common exhaust duct into patients' rooms on a renal transplant unit also was construed as the source of nosocomial pulmonary aspergillosis in three renal transplant recipients (25). A bird screen removed from the exhaust duct opening during repairs had not been replaced. Bird excreta accumulated in the duct as the substrate for Aspergillus. When the exhaust fan malfunctioned, air flow reversed and evidently carried Aspergillus conidia into the rooms of the three renal transplant recipients.

These outbreaks of nosocomial aspergillosis emphasize the importance of appropriate construction, maintenance, and monitoring of air- filtration ventilation systems, and support the following recommendations: (1) bone marrow transplant units should be ventilated with HEPA filters; (2) ventilation systems of bone marrow transplant units and operating rooms should be routinely monitored for thermotolerant fungi; and (3) a clustering of nosocomial aspergillosis should prompt a close inspection of ventilation systems as a potential source of conidia.

C) Construction-Associated Transmission. 1) Inside Construction. Construction and

renovation inside the hospital constitute another source of air-borne transmission ofAspergillus conidia associated with outbreaks of nosocomial aspergillosis (1,5). Such an outbreak occurred when the Baltimore Cancer Research Program moved into a new hospital

(1). A clustering of eight new cases of aspergillosis initiated environmental studies that identified Aspergillus spp. in cellulose-based fireproofing material coating steel girders and dust on pipes and ceiling panels. Aspergillus spp. had likely colonized the fireproofing material after it had been sprayed on the girders. Following a cluster of aspergillosis cases in renal transplant recipients, Arnow et al. (5) found that dust was jarred loose by hospital renovations on one floor and filtered through holes in ceiling acoustical tiles. This construction-associated dust grew A. fumigatus and was the probable source of pulmonary aspergillosis in the renal transplant recipients who were hospitalized on the floor below. Amow et al. recommended the following measures during hospital construction and renovation: (1) removal of patients from renovation sites; (2) establishing impermeable plastic barriers between patient floors and renovation sites; and, (3) vacuuming and damp dusting horizontal surfaces and false ceiling tiles for environmental and infection control.

A subsequent study (23) attributed nosocomial aspergillosis and zygomycosis in two premature infants to inadequate barriers, which permitted a high density of spore transmission from the construction site to a newborn special care unit. An outbreak of invasive aspergillosis also developed during hospital renovation in a large military center (36). The incidence of nosocomial aspergillosis during this latter outbreak increased from 4 cases/30 months preconstruction to 11 cases/24 months during construction without control measures (p < 0.05). The incidence of invasive aspergillosis decreased to one case over 18 months after the following measures were implemented: (1) establishing airtight plastic and dry wall barriers around construction sites; (2) maintaining negative-pressure ventilation in the work area; and (3) decontamination with copper 8- quinolinolate and (4) installation of HEPA filters in rooms for immunocompromised patients.

Hospital construction and renovation are not associated invariably with increased frequency of nosocomial aspergillosis. During the last six years, for example, considerable renovation has occurred at the NIH Clinical Center without measurable increment in the incidence of nosocomial aspergillosis in granulocytopenic patients.

2) Outside Construction: Construction outside the hospital has been associated with concurrent nosocomial aspergillosis. Retrospective autopsy review revealed a clustering of ten cases of invasive aspergillosis in immunocompromised patients within a 27 month period at the Milwaukee County Medical Center (26). There was a correlation identified between the clustering, contaminated air conditioners and road construction outside the Medical Center.

Major excavations of soil and demolitions seem to be especially associated with nosocomial aspergillosis. Excavation of massive volumes of soil and demolition of an apartment building on the windward side of a major oncology center were indentified as possible

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sources of airborne Aspergillus conidia during a concurrent outbreak of nosocomial aspergillosis in allogeneic bone marrow transplant recipients (43). Moreover, Streifel et al. (60) found that during demolition of a seven-story building within the University of Minnesota Hospital complex, the outdoor ambient concentration of A. fumigatus and A. niger increased ten-fold. Windows and doors of the nearby hospital had been sealed and air-handling systems were turned off or adjusted for complete recirculation of internal air to minimize airborne transmission of conidia.

3) Multiple Variables: Several variables may contribute simultaneously to an increase in Aspergillus within the hospital environment. For example, Sarubbi et al. (50) found increased respiratory colonization by A. flavus in patients at the North Carolina Memorial Hospital associated with construction adjacent to the hospital and a defective mechanical ventilation-filtration system. Environ- mental sources of Aspergillus conidia and host susceptibility often are simultaneously important. Nevertheless, construction, excavation activity, and contaminated ventilation systems can only be linked to some but not all clusters of nosocomial aspergillosis (21).

CONTACT TRANSMISSION: Aspergillus conidia may reside on surfaces of the inanimate hospital environment, including dressings and materials applied to the skin. This mechanism of contact transmission is less common than that of airborne transmission of conidia. Nevertheless, established cutaneous aspergillosis is potentially lethal in granulocytopenic patients. A report from Prystowsky et al. (41) described locally invasive cutaneous aspergillosis developing under adhesive tape or paper-covered extremity boards in three granuloytopenic children. The lesions of nosocomial cutaneous aspergillosis were locally invasive and descructive of skin, subcutaneous tissue and bone. Cutaneous aspergillosis was the apparent portal of entry for fatal disseminated aspergillosis. Although the patients described by Burch et al. (11) and Allo et al. (3) had necrotizing cutaneous lesions due to A. flavus, transmission of fungus in three cases was airborne.

Percutaneous intraperitoneal infection by A. fumigatus was described in a 22-years old woman with Aspergillus peritonitis who received peritoneal dialysis (48, 62). A. fumigatus was isolated from culture samples of various sites in the labor room. Numerous filamentous fungi were found in leaking dialysis fluid bags. The A. fumigatus in this case may have been inoculated into the peritoneal cavity via the dialysis fluid.

AIRBORNE OR CONTACT TRANSMISSION: Postoperative Aspergillus osteomyelitis also may develop by airborne and or contact transmission of conidia. The two most common sites of postoperative

Aspergillus osteomyelitis are post-thoracotomy sternal osteomyelitis (6, 63, 72) and post-operative vertebral osteomyelitis (9, 19, 53, 63). Initial surgery in these cases is usually for a non-infectious process. Nosocomial postoperative Aspergillus lumbar disc space infection (29) and postoperative Aspergillus vertebral osteomyelitis develop under similar conditions. Aspergillus mycotic pseudoaneurysm of an aortic bypass graft with contiguous vertebral infection is yet another setting for Aspergillus osteomyelitis (9, 19). No environmental sources were sought or identified by culture in these cases.

Nosocomial burn wound infection also may occur either through contact or airborne transmission (33, 56). Since the introduction of topical mafenide acetate (Sulfamylon cream), a tenfold increase in burn wound infections due to Aspergillus and Zygomycetes was observed at the Brooke Army Medical Center (33) possibly due to elimination of competing bacterial flora. Deep biopsies of suspicious lesions are necessary to distinguish between colonization and infection.

CLINICAL MANIFESTATIONS

The main portal of entry of Aspergillus is the respiratory tract and is also the primary focus of infection. Aspergillus pneumonia is the most common form of lower respiratory tract infection and Aspergillus sinusitis is the most common form of upper respiratory tract infection in patients with nosocomial aspergillosis.

Invasive Pulmonary Aspergillosis: Invasive pulmonary aspergillosis is the most common manifestation of nosocomial aspergillosis. The primary defenses against invasive pulmonary aspergillosis are phagocytic cells, including pulmonary alveolar macrophages and granulocytes. Aspergillus is an opportunistic pathogen to which patients with quantitative or qualitative defects in granutocytes are especially susceptible (14, 55, 73). In most institutions, granulocytopenia is the most common predisposing factor to nosocomial aspergillosis. The predilection of patients with granulocytopenia was demonstrated in an analysis of risk factors in cancer patients with aspergillosis (18). Protracted duration of granulocytopenia, especially greater than twenty-one days, was the single most important independent variable predisposing to pulmonary aspergillosis. Gustafson et al. (20) also demonstrated a correlation between invasive pulmonary aspergillosis and high doses of corticosteroids (~ 1.25 mg prednisone/kg/d) in transplant recipients.

Pulmonary aspergillosis generally presents with spiking temperatures in the immunosuppressed patient who is already receiving broad spectrum antibacterial antibiotics. Pulmonary infiltrates may be absent early in the course of aspergillosis in the granulocytopenic patients. Non-productive cough and tachypnea often develop. The propensity of

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Aspergillus to invade blood vessels often results in the clinical manifestations of pulmonary infarction, including fever, pleuritic pain, pleural rubs, and segmental pulmonary infiltrates (31).

Aspergillosis causes a necrotizing pneumonia associated with hemorrhagic infarction due to direct invasion of blood vessels by Aspergillus spp. Pulmonary infarction, hemorrhage and cavitation may develop despite administration ofamphotericin B (37).

Massive hemoptysis is a catastrophic complication of pulmonary aspergillosis. This frequently lethal complication may occur during granulocytopenia due to hemorrhagic infarction or as the granulocytopenia is resolving due to ruptured mycotic aneurysms (2, 37). Polymorphonuclear leukocytes infiltrate the elastin fibers of arterial wall at the site of invasion by Aspergillus. The two processes appear to combine in disrupting the pulmonary arterial wall.

Hematogenous dissemination of Aspergillus distributes hyphal fragments to various tissues. Infection of the central nervous system (CNS) is common and may present as abrupt onset of a focal neurologic deficit or as a focal seizure (69). Computerized tomography may reveal a ring- enhancing lesion or infarction. Early CNS aspergillosis may have no radiologic changes. Repeated studies will later demonstrate changes. CNS aspergillosis is frequently misdiagnosed initially as a progression of the underlying disease. Aspergillus may infect the gastrointestinal tract to cause necrosis, infarction and bleeding. Aspergillus also may disseminate to cause mural endocarditis, myocarditis, or pericarditis (68).

Invasive aspergillosis is diagnosed by clinical manifestations and confirmation of the presence of the Aspergillus spp. A positive nasal surveillance culture or positive sputum culture for Aspergillus in a persistently febrile granulocytopenic patient with pulmonary infiltrates is strongly indicative of invasive aspergillosis. Bronchoscopy with bronchoalveolar lavage or open lung biopsy also may be necessary to establish the diagnosis of pulmonary aspergillosis. Transbronchial biopsy often misses the site of Aspergillus invasion. The presence of hemorrhage or infarction by histology should suggest pulmonary aspergillosis. Immunodiagnostic assays are promising but remain investigational (7, 15, 64).

Invasive Aspergillus Sinusitis: The paranasal sinuses are often infected in granulocytopenic patients. A recent study (66) found that profound (< 500/lal) and protracted (mean of 42 days) granuloytopenia as well as prolonged antibiotic therapy (mean duration of 22 days) were major factors apparently predisposing to nosocomial Aspergillus sinusitis. The maxillary sinuses are the most frequently infected. Patients often complain of nasal discharge, paranasal sinus congestion, or pressure. Physical examination may not demonstrate classical tenderness of the maxillary sinuses in granulocytopenic patients. Erythema or congestion of the ipsilateral portion of the hard palate may be evident. Definitive diagnosis of Aspergillus sinusitis is

established by culture of an aspirate of an infected sinus. If a sinus aspirate is not feasible, then a nares or turbinate culture with radiographically compatible sinusitis may also establish the diagnosis. Conventional radiographs, computerized tomography, and magnetic resonance imaging are useful in staging and following this infection. Aspergillus sinusitis may occur when the primary neoplastic disease relapses or when more chemotherapy is required, despite initially successfull treatment with amphotericin B.

PREVENTION AND TREATMENT

Environmental Measures: Environmental efforts to prevent nosocomial aspergillosis are based upon elimination of Aspergillus conidia from high risk patients as discussed in the Hospital Epidemiology section. Laminar air-flow measures may be effective in preventing nosocomial aspergillosis. The cost and inconvenience of laminar air-flow protected environments, however, is considerable (4). Nevertheless, such facilities are highly effective in filtering Aspergillus conidia and preventing pulmonary aspergillosis (8, 45).

Antifungal Prophylaxis: Intranasal aerosol of amphotericin B is another strategy for prevention of nosocomial aspergillosis. A study conducted by Meunier et al. (30) suggests that intranasal aerosolized amphotericin B may be effective in reducing the incidence of nosocomial aspergillosis.

There is no systemic antifungal agent which has been proven to be effective for prevention of pulmonary aspergitlosis (57). Perhaps itraconazole (67), saperconazole (65), or SCH-39304, which have expanded activity against Aspergillus spp., will be effective as prophylactic agents for prevention of aspergillosis.

Antifungal Chemotherapy: Once a diagnosis of invasive aspergillosis is established, definitive treatment in our opinion consists of IV amphotericin B at 1.0 to 1.5 mg/kg/d for the duration of granulocytopenia and for a total dose of 1.0 to 2.0 g of amphotericin B. These doses are higher than conventionally recommended. However, those higher doses of amphotericin B have been associated with improved outcome especially when combined with flucytosine (11, 22) . Survival from pulmonary aspergillosis is critically dependent upon recovery from granulocytopenia or reversal of other immunologic deficits.

If the patient later becomes granulocytopenic again, aspergillosis frequently recurs in the sites of former infection. We recommend that similar doses of amphotericin B and fiucytosine be reinstituted in these patients at the onset of fever and granulocytopenia. A recent study by Karp et al. (22) found routine administration of high dose amphotericin B and flucytosine to be well-tolerated in leukemic treated empirically for recurrent pulmonary aspergillosis. We suggest that the dose of flucytosine

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should be adjusted, however, to maintain serum levels of 40 to 60 lag/ml to avoid toxicity. Higher serum levels, especially those greater than 100 iag/ml, are associated with toxicity. The higher dose (1.0 to 1.5 mg/kg/d) of amphotericin B appears as an important factor for treating pulmonary aspergillosis and usually is well-tolerated with appropriate hydration.

Persistently granulocytopenic patients in whom fever and new pulmonary infiltrates develop while receiving broad-spectrum antibiotics have a 50% probability of having a fungal cause of the new pulmonary infiltrate (13a). Early initiation of amphotericin B in these patients improves the likelihood for successful antifungal therapy. Amphotericin B should be given empirically to high risk granulocytopenic patients, even though a microbiologic or histopathologic diagnosis cannot be safely established (13a, 40).

Summary of Sources and Environmental Corrective Measures

Twenty-six reported clusters, outbreaks, and case series of nosocomial aspergillosis are summarized in Table 1. One of these episodes was considered a pseudoepidemic (70a). The 186 cases of aspergillosis and zygomycosis reported in the series by Rose (46) and Rosen and Stemberg (47) were associated with non-ventilated unfiltered air. Nosocomial aspergillosis was temporally and geographically related to a defined environmental source in 151 other cases. Eight episodes of nosocomial aspergillosis associated with contaminated ventilation systems were reported in a total of 54 cases (3, 13, 17, 25, 28, 39, 49a, 52). Six episodes of nosocomial aspergillosis were associated with construction activities in a total of 51 cases (1, 5, 23, 36, 37, 70a). Concomitant events of contaminated

TABLE 2. - Environmental Monitoring, Preventive and Corrective Measures for Nosocomial Aspergillosis

Environmental Monitoring:

(1) Surveillance and review of new cases of aspergillosis to detect changes in previous patterns.

(2) Periodic sampling of air, ceiling tiles ventilation ducts, and filters where immunocompromised patients are located and where construction may be active.

Environmental Preventive and Corrective Measures:

Construction:

(1) Avoid using building materials with high concentrations of Aspergillus conidia.

(2) Relocation of patients prior to initiating construction.

(3) Constructing barriers (plastic or drywall) impermeable to conidia from floor to ceiling between patient care areas and construction areas.

(4) Cleaning work areas of construction and new wards before patients enter the area.

(5) Vacuuming areas above false ceilings located under or adjacent to construction areas.

(6) Directing pedestrian traffic through construction areas to prevent dust from being tracked into patient areas.

(7) Ventilating construction areas with negative pressure relative to patient care areas.

(8) Eliminating any damp paper, pulp, or wood-base material which can harbor Aspergillus.

(9) Copper-8-quinolinolate (efficacy in sustained environmental control ofnosocomial aspergillosis remains to be clarified).

Ventilation Systems:

(1) Routine inspection of air supply ducts to high risk patient care areas.

(2) Installation of quality HEPA filters in rooms supporting patients with profound, protracted granulocytopenia.

(3) Preventing access by roosting birds to hospital air intake ducts.

(4) Coordinating repairs on air supply and exhaust fans and ducts with hospital engineering.

(5) Vacuuming of contaminated air-conditioning equipment, air supply ducts and rooms.

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ventilation systems and construction occurring outside of the hospital were described in three episodes of nosocomial aspergillosis in 30 cases (26, 43, 49). Other hospital environmental sources of nosocomial aspergillosis in 16 other cases included armboards for IV therapy (1%, 41), potted flowers (26a), and contaminated peritoneal dialysate (48, 62). Staib and colleagues (58, 59) in separate studies also identified potted flowers, nuts, and soiled linen as potential sources of Aspergillus spp. in the hospital environment. Thus, most outbreaks and clusters of nosocomial aspergillosis have been related to construction activity or to contaminated ventilation systems.

The environmental corrective measures for nosocomial aspergillosis associated with construction or with contaminated ventilation systems may be classified as monitoring, prevention, and correction. Comprehensive prevention and treatment of nosocomial aspergillosis requires a coordinated management of patients and the hospital environment. Approaches to environmental monitoring preventive, and corrective measures are summarized in Table 2.

FUTURE DIRECTIONS

The problem of an increasing incidence of nosocomial aspergillosis will likely continue as the facilities, interventions, and patient populations at risk continue to expand. Comprehensive research efforts should be directed toward the following areas: (1) environmental and nosocomial infection control, (2) phenotypic and molecular markers for identifying strains of Aspergillus, (3) rapidly performed immunodiagnostic and biochemical assays for early diagnosis of invasive aspergillosis, (4) more effective and less toxic antifungal agents, especially those which would be administered to high risk patients for prevention of nosocomial aspergillosis, and (5) augmentation of host defenses with immuno- modulatory agents.

A c k n o w l e d g e m e n t

The authors thank Mr. Mark Miller for his assistance in review of the literature.

R E F E R E N C E S

1. Aisner J., Schimpff S.C., Bennet J.E. et al. (1976): Aspergillus infections in cancer patients: association with fireproofing materials in a new hospital. - JAMA 235: 411-412.

2. Albelda S.M., Talbot G.H., Gerson S.L., Miller W.T. and Cassileth P.A. (1985): Pulmonary cavitation and massive hemoptysis in invasive pulmonary aspergillosis. - Am. Rev. Resp. Dis. 131: 115-120.

139

3. Allo M.D., Miller J., Towsend T. and Tan C. (1987): Primary cutaneous aspergillosis associated with Hickman intravenous catheters. - N. Engl. J. Med. 317: 1105-1108.

4. Armstrong D.A. (1984): Protected environments are discomforting and expensive and do not offer meaningful protection. - Am. J. Med. 76: 685-689.

5. Arnow P.M., Anderson R.L., Mainous P.D. et al. (1978): Pulmonary aspergillosis during hospital renovation. - Am. Rev. Respir. Dis. 118: 49-53.

6. Attah C.A. and Cerruti M.M. (1979): Aspergillus osteomyelitis of sternum after cardiac surgery. - N.Y. State J. Med. 79: 1420-1421.

7. Bennett J.E. (1987): Rapid diagnosis of candidiasis and aspergillosis. - Rev. Infect. Dis. 9: 398-402.

8. Bodey G.P. (1984): Current status of prophylaxis of infection with protected environments. - Am. J. Med. 76: 678-684.

9. Brandt S.J., Thompson R.L. and Wenzel R.P. (1985): Mycotic pseudoaneurysm of an aortic bypass graft and contiguous vertebral osteomyelitis due to Aspergillus osteomyelitis. - Am. J. Med. 79: 259-262.

10. Bullock W.E. and Deepe G.S. (1983): Medical mycology in crisis. - J. Lab. Clin. Meal. 102: 685-693.

11. Burch P.A., Kalp J.E., Merz W.G, Kuhlman J.E. and Fishman E.K. (1987): Favorable outcome of invasive aspergillosis in patients with acute leukemia. - J. Clin. Oncol. 5: 1985-1993.

12. Burnie J.P., Odds EC., Lee W., Webster C. and Williams J.D. (1985): Outbreak of systemic Candida albicans in intensive care unit caused by cross infection. - Brit. Med. J. 290: 746-748.

13. Burton J.R., Zachary J.B., Bessin R., Rathbun H.K., Greenough W.B. et al. (1972): Aspergillosis in four renal transplant recipients. Diagnosis and effective treatment with amphotericin B. - Ann. Int. Med. 77: 383-388.

13a. Commers J.R., Robichaud K.J. and Pizzo P.A. (1984): New pulmonary infiltrates in granulocytopenic cancer patients being treated with antibiotics. - Pediatr. Infect. Dis. 2: 56-60.

14. De Gregorio M.W., Lee W.M., Linker C.A. et al. (1982): Fungal infections in patients with acute leukemia. - Am. J. Med. 73: 543-548.

15. De Repentigny L. and Reiss E. (1984): Current trends in immunodiagnosis of candidiasis and aspergillosis. - Rev. Infect. Dis. 6: 301-312.

16. Fraser D. W, Ward J.L, Ajello L. and Plikaytis B.D. (1979): Aspergillosis and other systemic mycoses: the growing problem. - JAMA 242: 1631-1635.

17. Gage A.A., Dean D.C., Schimert G. and Minsely N. (1970): Aspergillus infection after cardiac surgery. - Arch. Surg. 101: 384-387.


18. Gerson S.L., Talbot G.H., Hurwitz S., Strom B. and Lusk E. J. (1984): Prolonged granulocytopenia: the major risk factor for invasive pulmonary aspergillosis in patients with leukemia. - Ann. Int. Med. 100: 345-351.

19. Glotzbach R.E. (1982): Aspergillus terreus infection of pseudoaneuriysm of aortofemoral vascular graft with continguous vertebral osteomyelitis. - Am. J. Clin. Pathol. 77: 224-227.

19a. Grossman M.C., Fithian E.C., Behrens C., Bissinger J., Fracaro M. and Neu H.C. (1985): Primary cutaneous aspergillosis in six leukemic children. - J. Am. Dermatol. 12: 313-318.

20. Gustafson T.L., Schaffner W., Lavely G.B., Stratton C.W., Johnson H.K. and Hutcheson Jr. R.H. (1983): Invasive aspergillosis in renal transplant recipients: correlation with corticosteroid therapy. - J. Infect. Dis. 148: 230-238.

21. Kallenbach J.J., Dusheiko J., Block C.S., Bethlehem B., Koornohff H.J. et al. (1977): Aspergillus pneumonia-cluster of four cases in an intensive care unit. - S. Afr. Med. J. 52: 919-923.

22. Karp P.A., Burch P.A., Merz W.G. and et al. (1988): An approach to intensive antileukemia therapy in patients with previous invasive aspergillosis. Am. J. Meal. 85: 203-206.

23. Krasinkski K., Holzman R.S., Hanna B., Greco M.A., GraffM. et al. (1985): Nosocomial fungal infection during hospital renovation. Infection Control. 6: 278-282.

24. Kwon-Chung K.J. Aspergillus." Diagnosis and description of the genus. In: Vanden Bossche H., Mackenzie D.W.R., Cauwenbergh G., eds. Aspergillus and aspergillosis. New York: Plenum, (1988): 11-19.

25. Kyrialddes G.K., Zimmerman H.H., Hall W.H., Arora KK., Lifton J. et al. (1976): Immunologic monitoring and aspergillosis in renal transplant patients. - Am. J. Surg. 131: 246-252.

26. Lentino J.R., Rosenkranz M.A., Michaels J.A. et al. (1982): A retrospective review of airborne disease secondary to road construction and contaminated air conditioners. - Am. J. Epidemiol. 116: 430-437.

26a. Lie T.S., Hofer M., Hohnke Ch., Krizek L., Kuhnen E., Iwantscheff A., Koster 0., Overlack A., Vogel J. and Rommelscheim K. (1987): Aspergillose nach lebertransplantation als hospitalismusinfekion. - Dtsch. Med. Wschr. 112: 297-301.

27. Mackenzie D.W.R., Aspergillus in man. In: Vanden Bosschc H., Mackenzie D.W.R., Cauwenbergh G., eds. Aspergillus and aspergillosis. New York: Plenum, (1988): 1-8.

28. Mahoney D.H.Jr., Stenberg C.P., Starling K.A. et al. (1979): An outbreak of aspergillosis in children with acute leukemia. - J. Pediatr. 95: 70-72.

140

29. Mawk J.R., Erickson D.L., Chou S.N. and Seljeskog E.L. (1983): Aspergillus infections of the lumbar disc spaces. - J. Neurosurg. 58: 270-274.

30. Meunier F, Leleux J., Gerain J., Ninove D. et al. (1987): Prophylaxis of aspergillosis in neutropenic cancer patients with nasal spray of amphotericin B: a prospective, randomized study. Abstracts of the 1987 Intersci. Conf. Antimicrob. Agents. Chemoter. New York, NY, Abstr 1346.

31. Meyer R.D., Young L.S., Armstrong D. et al. (1973): Aspergillosis complicating neoplastic disease. - Am. J. Med. 54: 6-15.

32. Millner P.D., Marsh P.B., Snowden R.B. and Parr J.F. (1977): Occurrence of Aspergillus fumigatus during composting of sewage sludge. - Appl. Environ. Microbiol. 34: 765-772.

33. Nash G., Foley F.D., Goodwin M.N. et al (1971): Fungal burn wound infection. - JAMA 215: 1664- 1666.

34. Noble W.C. and Clayton Y.M. (1963): Fungi in the air of general hospital wards. - J. Gen. Microbiol. 32: 397-402.

35. Nolard N., Detandt M. and Beguin H. Ecology of Aspergillus species in the human environment. In: Vanden Bossche H., Mackenzie D.W.R., Cauwenbergh G., eds. Aspergillus and aspergillosis. New York: Plenum Press, (1988): 35-41.

36. Opal S.M., Asp A.A., Cannady P.B., Morse P.L., Burton L.J. et al. (1986): Efficacy of infection control measures during a nosocomial outbreak of disseminated aspergillosis associated with hospital continuation. - J. Infect. Dis. 153: 634-637.

37. Panos R., Barr L., Walsh T.J. and Silverman H.J. (1988): Factors associated with fatal hemoptysis in cancer patients. Chest. (in press).

37a. Perraud M., Piens M.A., Nicoloyannis N., Girard P., Sepetjan M. and Garin J.P. (1987): Invasive nosocomial pulmonary aspergillosis: risk factors and hospital building works. - Radium Inf. 99: 407-412.

38. Petersen P.K., McGlave P., Ramsay N.K.C., Rhame F., Cohen E. et al. (1983): A prospective study of infectious diseases following bone marrow transplantation: emergence of Aspergillus and Cytomegalovirus as the major causes of mortality. - Infection Control 4: 81-89.

39. Petheram LS. and Seal R.M.E. (1976): Aspergillus prosthetic valve endocarditis. - Thorax. 31: 380-390.

40. Pizzo P.A., Robichaud K.J., Gill F.A. et al. (1982): Empiric antibiotic and antifungal therapy for cancer patients with prolonged fever and granulocytopenia. - Am. J. Med. 72: 101-111.

41. Prystowsky S.D., Vogelstein B., Ettinger D.S. et al. (1976): Invasive aspergillosis. - N. Engl. J. Med. 295: 655-658.


42. Rhame F.S., Streifel A.J., Kersey J.H. Jr. and MeGlave P.B. (1984): Extrinsic risk factors for pneumonia in the patient at high risk of infection. - Am. J. Med. 76 (5A): 52-52.

43. Rhame F.S. (1985): Lessons from the Roswell Park bone marrow transplant aspergillosis outbreak. - Infect. Control. 6: 345-346.

44. Rhame F.S. (1986): Endemic nosocomial filamentous fungal disease: a proposed structure for conceptualizing and studying the environmental hazard. - Infection Control 7:124-125 (suppl.).

45. Rogers T.R. (1986): Infections in hematologic malignancy. - Infection Control 7:140-142 (suppl.).

46. Rose H.D. (1972): Mechanical control of hospital ventilation and Aspergillus infections. - Am. Rev. Respir. 105: 306-307.

47. Rosen P.P. and Sternberg S.S. (1976): Decreased frequency of aspergillosis and mucormycosis. - N. Engl. J. Med. 295: 1319-1320.

48. Ross D.A., MacNaughton M.C. et al. (1986): Fulminating disseminated aspergillosis complicating peritoneal dialysis in eclampsia. - Arch. Int. Med. 121: 183-188.

49. Rotstein C., Cummings K.M., Tidings J., Killion K., Powell E. et al. (1985): An outbreak of invasive aspergillosis among allogeneic bone marrow transplants: a case control study. - Infection Control 6: 347-355.

49a. Ruutu P., Valtonen V., Tiitanen L., Elonen E., Vo#n L., VeUalainen P. and Ruutu T. (1987): An outbreak of invasive aspergillosis in a hematologic unit. - Scand. J. Infect. Dis. 19: 347-351.

50. Sarrubi F.H. Jr., Kopf H.B., Wilson M.B. et al. (1982): Increased recovery of Aspergillus flavus from respiratory specimens during hospital construction. - Ann. Rev. Respir. Dis. 125: 33-38.

51. Seeliger H.P.R. and Tintelnot K. Epidemiology of aspergillosis. In: Vanden Bossche H., Mackenzie D.W.R., Cauwenbergh G., eds. Aspergillus and aspergillosis. New York: Plenum, (1988): pp. 23-24.

52. Sherertz R.J., Belani A., Kramer B.S., Elfenbein",G.J., Weiner R.S., Sullivan M.L. and Thomas R.G. (1987): Impact of air filtration on nosocomial Aspergillus infection. - Am. J. Med. 83: 709-718.

53. Simpson M.B., Merz W.G., Kurlinsld S.P. and Solomon M.H. (1977): Opportunistic mycotic osteomyelitis. Bone infections due to Aspergillus and Candida species. - Medicine 56: 475-4.1.

54. Solomon W.R., Burge H.P. and Boise J.R. (1978): Airborne Aspergillus fumigatus levels outside and within a large clinical center. - J. Allergy Clin. Immunol. 62: 56-60.

55. Spearing R.L., Pamphilon D.H. and Prentice A.G. (1986): Pulmonary aspergillosis in immunosup-

141

pressed patients with hematological malignancies. -Q. J. Med. 59: 611-625.

56. Spebar M.J. and Lindberg R.B. (1979):Fungal infection of the burn wound. - Am. J. Surg. 138: 879-882.

57. Speller D.C.E. (1986): Other approaches to the prevention of aspergillosis. - Infection Control. 7: 125-126.

58. Staib F. (1984): Ecological and epidemiological aspects of Aspergilli pathogenic for man and animal in Berlin (West). - Zbl. Bakt. Hyg. A 257: 240-245.

59. Staib F., Folkens U., Tompak B., Abel T. and Thiel D. (1978): A comparative study of antigens of Aspergillusfumigatus isolates from patients and soil of ornamental plants in the immunodiffusion test. - Zbl. Bakt. Hyg. I. Abt. Orig. A. 242: 93-99.

60. Streifel A.J., Lauer J.L., Vesley D. et al. (1983): Aspergillus fumigatus and other thermotolerant fungi generated by hospital building demolition. - Appl. Environ. Microbiol. 46: 375-378.

61. Streifel A.J., Stevens P.P. and Rhame F.S. (1987): In- hospital source of airborne Penicillium spores. - J. Clin. Microbiol. 25: 1-4.

62. Stewart W.K., Anderson D.C. and Wilson M.LL. (1967): Hazard of peritoneal dialysis: contaminated fluid. - Brit. Med. J. 1: 606-607.

63. Tack K.L., Rhame ES., Brown B. and Thompson R. C. (1982): Aspergillus osteomyelitis: report of four cases and review of the literature. - Am. J. Med. 73: 295- 300.

64. Talbot G.H., Weiner M.H., Gerson S.L., Provencher M. and Hurwitz S. (1987): Serodiagnosis of invasive aspergillosis in patients with hematologic malignancy: validation of the Aspergillus fumigatus antigen radioimmunoassay. - J. Infect. Dis. 155: 12- 27.

65. Van Cutsem J., Van Geruen E and Janssen P.A.J. (1988): R66905, a new potent broad spectrum antifungal triazole with topical, oral and parenteral activity. Abstracts. Tenth Congress of the International Human Animal Mycol. Revista Iberica de Micologia 5 (Supple 1): 0-2.

66. Viollier A.F., Peterson D.E., De Jongh C.A., Newman K.A., Gray W.C. et al. (1986): Aspergillus sinusitis in cancer patients. - Cancer 58: 366-371.

67. Viviani M. A., Tortorano A.M., Woenstenborghs R. and Cauwenbergh G. (1987): Experience with itraconzole in deep mycosis in Northern Italy. - Mykosen 30: 233-244.

68. Walsh T.J., Hutchins G.M., Buckley B.H. and Mendelsohn G. (1980): Fungal infections of the heart. - Am. J. Cardiol. 45: 357-366.

69. Walsh T.J., Caplan L.R. and Hier D.B. (1985): Aspergillus infections of the central nervous system:


a clinicopathologic analysis. - Ann. Neurology 18: 574-582.

70. Weems J.J. Jr., Andermont A., Dav& B.J., Tancrede C.H. et al. (1987): Pseudoepidemic of aspergillosis after development of pulmonary infiltrates in a group of bone marrow transplant patients. - J. Clin. Microbiol. 25: 1459-1462.

70a. Weems J.J., Davis B.J., Tablan O.C., Kaufman L. and Martone W.J. (1987): Construction activity: an independent risk factor for invasive aspergillosis and zygomycosis in patients with hematologic malignancy. - Infect. Control. 8(2): 71-75.

71. Weiland D., Ferguson R.M., Peterson P.K. et al.

(1983): Aspergillosis in 25 renal transplant patients. - Ann. Surg. 198: 622-624.

72. Wellens E, Potuliege C., Deuvart F.E. and Primo G. (1982): Aspergillus osteochondritis after median sternotomy. Combined operative treatment and drug therapy with amphotericin B. Thorac. Cardiovasc. Surg. 30: 322-324.

73. Young R.C., Bennett J.E., Vogel C.L. et al. (1970): Aspergillosis. The spectrum of the disease in 98 patients. - Medicine 49: 147-173.

74. Yu V.L., Muder R.R. and Poorsattar A. (1986): Significance of isolation of Aspergillus from the respiratory tract in diagnosis of invasive pulmonary aspergillosis. Results from a three-year prospective study. - Am. J. Med. 81: 249-254.

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