Aspergillosis design, and - Thorax · Paecilomyces spp, Penicillium spp Waste disposal duct Swabculture (Afumigatus, A niger, Aflavus, Aterreus) Disposal doorframe Swabculture (Afumigatus)

Thorax 1996;51:256-261

Aspergillosis in immunocompromised paediatricpatients: associations with building hygiene,design, and indoor air

Kenneth Anderson, George Morris, Helen Kennedy, John Croall, Joanne Michie,Malcolm D Richardson, Brenda Gibson

Department ofRespiratory Medicine,Western Infirmary,Glasgow Gil 6NTK Anderson

Department of PublicHealth, University ofGlasgowG Morris

Departnent ofMicrobiology, RoyalHospital for SickChildren, GlasgowH KennedyJ CroallJ Michie

Regional MycologyReference Laboratory,Departnent ofDermatology,University of Glasgowand WesternInfirmary, GlasgowM D Richardson

Department ofHaematology, RoyalHospital for SickChildren, GlasgowB Gibson

Correspondence to:Dr K Anderson.

Received 20 February 1995Returned to authors1 May 1995Revised version received7 September 1995Accepted for publication12 October 1995

AbstractBackground - Nosocomial aspergillosis isa well known complication of immuno-suppression in cancer patients and thoseundergoing transplantation and hasusually been associated with major build-ing construction or demolition. An ob-servational study is reported ofthe hospitalenvironment associated with an outbreakof aspergillosis in a paediatric oncologyward.Methods - All cases of aspergillosis wereidentified from the hospital records andcategorised as definite or probable ac-cording to the extent ofsupportive clinicaland laboratory findings. All relevant as-pects ofbuilding ventilation, air filtration,and aerosol generation considered rel-evant were examined and air samples forfungi were taken in triplicate at 25 sitesusing a slit sampler with appropriate cul-ture media.Results - Six cases of aspergillosis wereidentified over one year out of the 148patients who attended the unit - the onlypart of the hospital where cases werefound. Examination of the building ser-vices and function suggested that the causeor source was isolated to this paediatriconcology/haematology ward and may havebeen attributed to a defective disposal con-duit door as well as the dispersal of acontaminated aerosol from the ward va-cuum cleaner which had the highestmeasured concentrations of AspergillusJfumigatus in or around the building (65colony forming units (cfu)/m3 comparedwith 0-6 cfu/m3 elsewhere). No furthercases were identified in the two yearsafter these hygiene arrangements werechanged.Conclusions - The investigation of thisoutbreak ofnosocomial aspergillosis iden-tified several possible sources of fungallycontaminated aerosol which could havebeen implicated as the cause. Their mo-dification was followed by a reduction inthe incidence offurther cases. Each shouldbe incorporated as an issue ofimportancein hospital building design and hygiene.(Thorax 1996;51:256-261)Key words: aspergillosis, immunosuppression, building-related disease.

Respiratory illness associated with the genusAspergillus has three main diagnostic categories

which only rarely overlap, and each type usuallyrequires some form of deficiency in pulmonarydefence or structure': (1) colonisation of acavity within the lung can produce a fungal ball(aspergilloma); (2) a hypersensitivity-related,predominantly airway disorder (allergic bron-chopulmonary aspergillosis) which can com-plicate other lung diseases such as asthma andcystic fibrosis; and (3) invasive aspergillosiswhich occurs as a result of environmental ex-posure to Aspergillus in patients who have moresevere impairment of immunity which tends todevelop during hospital residence. Nosocomialaspergillosis has been reported followingsurgical procedures,23 large organ transplant-ation,` bone marrow transplantation,' or inassociation with leukaemias.9The major problem is that, once fungal in-

fection is present in these immunosuppressedpatients, invasive aspergillosis is very difficultand expensive to treat. Hitherto, the principalmanceuvres have been to prevent or minimiseexposure by filtering air for isolated patients.910Although outbreaks of invasive aspergillosishave been associated with the environmentaldisruption of construction around a hospitalsite,"l-the precise source of the fungus is oftendifficult to trace with certainty. Furthermore,hospital buildings are subjected to continuousand sometimes haphazard alteration which maynot be consistently followed by a measurablechange in airborne fungal counts or asper-gillosis.'5 While the hypothesis of nearby con-struction as the cause of an outbreak may beattractive, the other aspects of buildings andindoor air quality which may be relevant shouldnot be overlooked,'6 although very few of thesefactors have been characterised with specificregard to immunosuppressed patients.We report the environmental investigation of

a paediatric haematology and oncology wardwhich recorded a rise in the number of in-fections caused byAfumigatus and other speciesof Aspergillus.

MethodsStaff within a haematology/oncology unit in-creasingly suspected that the incidence ofaspergillosis had risen over a period of monthswithin their department where only one casehad occurred over the previous five years. Inresponse, an outbreak committee was as-sembled with the aim, firstly, to confirm thatan outbreak of aspergillosis had occurred and,secondly, to investigate the possible causes.

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Aspergillosis in immunocompromised paediatric patients

Table 1 Probable and definite cases of aspergillosisAge Diagnosis Tissue Organism

11 years ALL BAL A fumigatus4 years ALL Pericardial fluid, cardiac vegetation A fumigatus10 years Neuroblastoma (post BAL A fumigatus

BMT)6 years Neuroblastoma Blood culture A flavus9 months AML Necroscopic lung A terreus (1 colony)

Aspergillus sphistology

10 years ALL (post BMT) Blood culture A niger

ALL= acute lymphatic leukaemia; BAL=bronchoalveolar lavage fluid; BMT=bone marrowtransplant; AML= acute myeloid leukaemia.

The committee gathered representatives fromall staffing groups within the building who hadany possible connection with air quality andthe clinical management of the patients. Inaddition, a group of individuals from outwiththe hospital, who had previous experience ofbuilding-related disease and associated out-breaks of respiratory disease, were invited tojoin the investigation.

PATIENTSAny cases of aspergillosis during 1993 in thispaediatric hospital were identified through themicrobiological records and details were veri-fied by consulting the hospital case notes. Onlythose cases with isolates from tissue or bodyfluids were considered to have either definiteor probable aspergillosis. Definite aspergillosiswas diagnosed if tissue histopathologicalexamination showed septate acute branchinghyphae or if, in the absence of histologicalevidence, a positive culture was obtained by aninvasive procedure. Probable aspergillosis wasdiagnosed if, in the context of neutropenia,a patient developed chest radiological ab-normalities or other clinical findings com-patible with aspergillosis.

BUILDING SURVEYAfter consulting the building engineers, allfloors of the structure (modem multistoreyconcrete building completed in the early 1 970s)were assessed by two of the investigators (KAand GM) to identify all sources of air intakeand the dispersal routes of air throughout thehospital. The haematology ward was visitedand walked through on several days at differenttimes to judge whether particular activities orfunctions of the ward seemed relevant. Allrecent building records were discussed withthe building services managers and engineers.External ventilation contractors were consultedregarding the overall function of the buildingventilation.

FUNGAL ISOLATIONAir samples were taken in triplicate from 25sites throughout the hospital, at the intakes,inside, and exhausts of each of the mechanicalventilation units and in each ward. In the sus-pect ward 15 sites were sampled, including theceiling void, soft toys (encouraged to releaseaerosol by firm handling), and the exhausts ofthe ward vacuum cleaners. The air sampler

used (SAS, Cherwell Laboratories, Oxford,UK) was hand held for ease of access andincorporated appropriate culture media (Cza-pek-Dox and Rose Bengal). Settle plates ofsimilar media were distributed through the sus-pect ward and several other sites in the hospital.Swabs were taken from surfaces throughoutthe hospital and the suspect ward.

AIR DUST SAMPLINGAirborne dust concentrations were calculatedfrom a change in dry filter weight (Whatman47 mm glass fibre A; Whatman Ltd, Maidstone,Kent, UK) before and after air was drawnthrough an open face filter at 100 1/min for aperiod of 10 minutes (L100 pump; Rotheroeand Mitchell Ltd, Middlesex, UK). The filterswere weighed on a balance sensitive to 1,g(Sartorius R 200 D; Sartorius Ltd, Epsom,Surrey, UK).

FUNGAL IDENTIFICATIONAll fungal isolates were identified by standardculture and morphological appearance. 17

OUTCOMEAfter the investigation, factors were identifiedwhich were considered relevant to the outbreakand the case incidence was reviewed one yearlater.

STATISTICAL ANALYSISThe Mann-Whitney U test was used to assessthe significance of the measured values whenappropriate.

ResultsDuring 1993 148 patients with paediatric neo-plasms (predominantly leukaemia) attendedthe unit and were admitted intermittently forperiods of treatment (chemotherapy, radio-therapy, and bone marrow transplantation).From April to December 1993 six cases ofinvasive aspergillosis associated with A fumi-gatus or other species of Aspergillus were iden-tified whereas only one case of aspergillosis hadoccurred in the previous five years. The detailsof the cases where Aspergillus infection waspresent or probable are shown in table 1. Allcases were treated with liposomal amphotericinand broad spectrum antibiotics and thisregimen became standard as treatment ofpyrexias within the ward before bacteriologicalconfirmation of the cause.The ward where the cases were identified

(haematology/oncology) occupied part of theseventh floor of a tower of wards with mainlymechanical ventilation from air handlers on thefloor above and a lesser amount of naturalventilation through the stairwell from theground floor entrance and the service ducts. Asummary of the building characteristics is

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Table 2 Principal features and enclosures of the buildingwhich directed the method of investigation and influencedsites for air sampling

Eight storey stack: two columns, central lift/stairwellSeveral intercommunicating corridors to adjoining buildings

Ventilation:Natural - windows, stairwells, basement ventsMechanical - 8th floor air handler units dedicated to eachcolumn

Communication spaceElectrical ductsWater pipesPneumatic specimen/result transport ductsSuspended ceiling spaces (insulation material)Clinical waste disposal

Haematology/Oncology wardHEPA unitsDay treatment areaDrug preparation cabinetSoft toysHygiene equipment (vacuum cleaner)

Table 3 Isolation offungi from the building

Site within building Fungi detected

Indoor/outdoor air A fumigatus (0-6 cfu/m')Mechnical ventilation A fumigatus (0-6 cfu/m')HEPA filters Swab culture (A fumigatus)Ceiling insulation A fumigatus, A niger, A terreus,

Paecilomyces spp, Penicilliumspp

Waste disposal duct Swab culture (A fumigatus, Aniger, A flavus, A terreus)

Disposal door frame Swab culture (A fumigatus)Pneumatic transport outlet Swab culture (mixed

Aspergillus spp)

cfu = colony forming units.

shown in table 2. A notable feature of thebuilding was the specimen transport systemwhich operated by pneumatic principles froma compressor in the basement of the hospital.This would effectively push columns of base-ment air around as determined by a ward or

laboratory despatch, thereby emitting the distalcolumn of air beyond the despatch at severalend points, one of which was the haematology/oncology ward.

Building work and redecoration had beencarried out during May/June in a ward nearbyserved by a different ventilation supply. Twoof the cases preceded this work and the othersseemed evenly spaced over the six months,suggesting continued exposure rather than an

illness which developed in response to a singleepisode. Similarly immunosuppressed patientswere treated in another ward area (renal trans-plant) on a different level in the same columnof the building but no suspected cases were

identified in that ward. Likewise, no patientswere identified in the intensive care unit whichwas in a different area of the hospital. Theseobservations when taken together suggestedthat the source ofthe infection should be soughtwithin the confines of the haematology/on-cology area.The initial results of the aeromycology stud-

ies (table 3) showed a generally low level ofAfumigatus in the air sampled throughout thebuilding (0-6 colony forming units/m3) withsimilar measurements in outdoor air.The suspended ceiling of the haematology

ward consisted of tiles which had been removedand replaced many times over the years to allowservice access. No airborne A fumigatus was

Table 4 Results of air sampling taken close to the wardvacuum cleaner before and during use and subjectivemeasure (agreement offour observers) of air quality

Before use During use

Airborne particulates (mg/m') <0.01 0.10Airborne A fumigatus (cfu/m') 24 62Air quality Fresh Fusty

cfu = colony forming units

isolated in the airspace cavity overlying thesuspended ceiling by air sampling but theorganism was identified from the insulatingmaterial enclosed by the tiles. A fumigatus wasrecovered from the intake filters of the two highefficiency particulate air (HEPA) filtration unitsin the ward, but the air in the high dependencyroom served by the filters was sterile (one roomwhile unoccupied). Numerous soft toys werepresent in most areas of the ward but no fungalsource was found when several were sampled.The ward disposal unit for bags of clinical

waste was sited in the central part of the wardand led by a vertical conduit directly to thebasement. A draught of cool air was detectedeven when the door was firmly closed becauseof an ill-fitting rubber gasket, and plumes offine dust were deposited close to these draughtsaround the door frame from which a mixedAspergillus population was cultured (table 3).

Airflow studies throughout the building col-umns performed by the external contractorrevealed that the handling of the air ventilationwas balanced slightly in favour of exhaust,which implied that some of the air within thebuilding was drawn in away from the main airhandling units (possibly through doors, win-dows, and communication ducts, including thedisposal conduit).The ward vacuum cleaner (dry vacuum

cleaner incorporating a large particle filter),which had only been used in the haematologyward, was taken from the ward so that roomair could be sampled for particles and fungibefore and during operation of the machine.Both samplers were positioned 0.5 metresabove and lateral to the exhaust of the machine(table 4). The airborne concentration of Afumigatus was significantly different from theother measurements taken in the hospital(p<0.002). The level of airborne particulateswas initially at the lower limit of the detectablerange for the air sampler and increased after thevacuum cleaner was switched on. The vacuumcleaner was dismantled and a contact platecontaining fungal culture medium on the ex-haust filter produced an overgrowth of Afumigatus. Vacuum cleaners from four otherwards in the hospital close to the outbreakward were also sampled but none producedparticulates or fungi in a higher quantity thanthe background level measured within the hos-pital.No further cases of aspergillosis have been

identified in the ward over a period of 18months since the disposal door was sealed andthe vacuum cleaner was replaced by a machineof higher efficiency. Air samples have beentaken at regular intervals over one year at 10sites within the hospital and at specific points

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outside the building and no significant changein the concentration ofAspergillus spp has beenfound. A decision was also taken to introduceprophylaxis with itraconaole to all patientsundergoing bone marrow transplantation but itshould be noted that not all of the patients whodeveloped aspergillosis in the outbreak werebone marrow transplant patients. Nasal swabshave been taken routinely from all patientssince the outbreak and only one case of col-onisation with Aspergillus spp has been found.

DiscussionInvasive fungal disease as a complication ofimmunosuppression has been an increasinglydifficult issue in transplantation and oncologyover the past 20 years as the number of caseswith fungal complications follows the increasingnumber of patients."" This is mainly a re-flection of the more rapid advances in trans-plantation procedures than in the rate ofdevelopment of effective antifungal therapy. Airfiltration was considered to be the only possiblesolution, although antifungal prophylaxis hasrecently been used more often. 19 20 Despite earlysuggestions that HEPA filter systems effectivelyreduced spore counts,'0 and a supportive casecontrol study which detected 14 cases of asper-gillosis out of 74 without HEPA and none in39 patients with HEPA,8 reports of cases andoutbreaks of nosocomial aspergillosiscontinue.12 21-23 Moreover, improper oper-ation or poor maintenance of sophisticatedventilation systems can lead to outbreaks ofaspergillosis on units fitted with HEPA facil-ities.24The environmental control of nosocomial

aspergillosis is a complex subject given thateven HEPA units are not completely effectivefor preventing disease. The possibility that apatient is inhaling fungi outside areas withHEPA filter systems implies isolation failureand, in these subjects, fungal exposure wouldbe more precisely studied using a personal airsampling device but there is no fungal samplercurrently available which can be used in thisway. There are also severe limitations on theduration of the sampling time of fungal sam-plers so transient peaks of fungi in aerosolsmight be better detected by gravity plates.Gravity plates may also be an imperfect com-promise because ofvarying airflows determinedby the activity of the occupants and externalinfluences on the indoor microclimate - forexample, solar heat gain or nocturnal heat loss.The finding of peak spore counts in March

and June in the recent study by Goodley et alin London'5 was unexpected as previouswork25-27 had suggested that Aspergillus levelswere higher in autumn and winter. A seasonalincidence of invasive aspergillosis has neverbeen reported, although there is evidence tosupport an increase in the incidence of allergicbronchopulmonary aspergillosis in winter.28Aspergillus species are found widely as con-taminants - for example, in potting compost,nuts, soiled linen, pharmacy solutions, pigeonexcreta29 - so reasonable avoidance measuresare appropriate if minimal exposure is the only

necessary component to induce the de-velopment of invasive aspergillosis in trans-plantation patients.We had initially expected that the air hand-

ling units, ceiling design, or recent buildingwork would have been the most likely sourceof the fungal infection and, although our resultsdo not entirely exclude a transient peak frominside or outside air, the combination of thedisposal duct, the negatively balanced air hand-ling system, and the entrapped dust within theward cleaning machine seem to have produceda suitably contaminated aerosol which wouldbe dispersed over a long enough time to explainthe incidence pattern which was observed. Weare unaware of any previous reports to in-criminate this type of cleaning machinery as acause of infection in immunosuppressedpatients, although the theoretical disseminationofAspergillus by vacuum cleaning has previouslybeen discussed.30An outbreak of aspergillosis was recently at-

tributed to carpet contamination following abuilding fire close to a hospital after which thecarpeting was cleaned with a "bonnet buffing"machine.22 Wet cleaning was instituted insteadand the outbreak of cases ceased. Anotherimportant feature of this report was that build-ing construction nearby could have led theinvestigators to attribute the cases to that causehad they not investigated the environmentwithin the hospital more thoroughly. The widerissue is whether an aerosol of this type couldbe associated with the development of lungdisease in normal or less susceptible subjectswith pre-existing lung disease such as asthma.Whether or not this aspect is also important inpatients with asthma or immunocompromisedpatients outwith hospital remains to be ad-dressed.The specific relevance of building con-

struction near a transplant unit to the de-velopment of a fungal infection does not seemclearcut in view of the results presented here.Hospitals are buildings of continuous changeand adaptation, so construction may extend tovarious sites throughout the year. Our generalfeeling is that the wide range of individualsresponsible for controlling the components ofindoor air quality are unaware of the potentiallycatastrophic complications of a failure in thesystem where even the least likely and un-suspected connecting fragment in a long list ofinterrelated factors might be incriminated. Ourbuilding survey (table 2) presents each com-ponent of the site which required assessment.This approach to buildings uses the analogyof standard clinical evaluation to clarify whatmight seem initially to be an almost impossibletask. Each section of the building could havecontributed in some way to the developmentof aspergillosis and was gradually excluded bysimple investigation. At an early stage we con-sidered that the specimen transport systemmight be guilty since air was transported aroundfrom various parts of the hospital, thus facili-tating communication between the laboratoryservices and the wards. This had been installedwith general agreement but the question ofan influence on air quality was never fully

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appreciated. We would suggest that such sys-tems should only be installed in hospitals aftercareful consideration of the source of the air todrive the specimen transport as well as carefulpositioning ofthe exit points. Likewise, planneddisposal of clinical waste must be carefullybalanced so that materials are not allowed toaccumulate needlessly and are transportedaway regularly from particularly sensitivepatients. Unfortunately the disposal duct sys-tem within this modem building was not ap-propriate for the special nature of the unit andthe communication door to the duct was sealed.We speculate that the dust from this disposalsystem was collected by the vacuum cleanerwhich then acted as a disseminator well beyondthe disposal duct area. Since failure of thedisposal system was likely to be the initialevent resulting in contamination ofthe vacuumcleaner, the outbreak ofaspergillosis might havebeen more accurately described as having anarchitectural cause with the vacuum cleaneracting effectively as a biological trap. Duringthe investigation we also found fungal sporesin swab samples from the HEPA filters in thedrug preparation cabinet and in the filters whichserved the rooms of the neutropenic patients.This indicated that the filters were operatingcorrectly and also offered a relatively un-complicated (but unquantifiable) method ofconfirming whether fungal spores were cir-culating in the air of the ward.The overall management of immuno-

suppressed patients relies on close medical ob-servation but also necessitates a precision ofawareness in non-medical staff above thatwhich is acceptable for the patient whose im-mune system is functioning more normally.This awareness is not too difficult to provokeafter a major event, but we would suggestthat any medical unit which handles immuno-suppressed patients must have a code of prac-tice on air quality which clearly states theresponsibility ofeach ofthe supporting services.For instance, if any building works take placenearby, the implications for air quality withinthe hospital should be carefully assessed. Thebuilding engineers in this paediatric hospitalcurrently stipulate that any works within thehospital conform to the highest dust avoidancestandards and use the directives issued for theremoval of asbestos from buildings. The areaofwork must be sealed and appropriate externalair extraction installed. Likewise, the generalfabric of the building should be closely ex-amined by a responsible engineer so that nocomponent is overlooked - a checklist similarto the standard required for the surveillance ofaircraft structure would be advisable. Giventhe occasionally short term employment of an-cillary and cleaning staff within hospitals, edu-cation at this level is difficult but should bea clear responsibility of the employer whetherthe staff are based within the hospital or sub-contracted. All cleaning machinery should becleaned regularly and should conform to ahigh standard ofparticle removal. Bacterial andfungal contamination of filters in the cleanersshould be considered inevitable and these

should be cleaned regularly and monitored bythe infection control staff within the hospital.Our practical results suggest that the de-

terioration in air quality resulting from a con-taminated vacuum cleaner can be suspected bysimple observation as the air becomes fusty.Little was gained by showing that dust levelsand fungal counts also rose when the machinewas operating, although this was necessary toconfirm our suspicions. Indeed, the plume ofdust and fungus dispersal could have beenwider and the rate of emission of noxious ex-haust need not remain constant. We have pre-sented results for these contaminants whichwere limited by the method of aerosol moni-toring, but such is the difficulty of samplingaerosols consistently and rapidly in field work.We might assume that the vacuum cleaner wasoperating for periods well in excess of thesampling time and, in the enclosed space of award or single room, might produce con-centrations considerably higher than thosewhich we recorded, leading to a more severeand persistent exposure for the patient; thismight be repeated several times during a daydepending on the circumstances of the ward.The rate of change in the concentration of thefungal aerosol would be a function both of theoutput of the vacuum cleaner and the rate ofair change in the hospital ward, so that fungallevels would increase steadily until the cleanerwas turned off. Given the nature of the patientson the ward, we did not test this hypothesis.The precise circumstance required to pro-

duce an outbreak of aspergillosis in susceptiblepatients is obscure because the environmentalmycology of most outbreaks of nosocomialaspergillosis is poorly defined.7 There is a nat-ural and understandable tendency for thosewho are in direct contact with the affectedpatients to react immediately so that an en-vironment might change before more ex-perienced investigators are contacted. Thedevelopment of molecular biology techniquesthat are more directly applicable to identifyingAspergillus species may eventually help to re-solve some ofthese difficulties.2 23 In the mean-time, the identification of a source of airborneinfection in a modern building with a complexventilation system requires a rigorous ex-amination along a planned route - a processsimilar to clinical problem solving when thereare a number of abnormal findings which arepossibly interrelated in origin and the aetiologyis not immediately obvious.

The authors thank Mrs E Scott and Mr L M McHugh of theRMRL for the fungal identifications.

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