Assessment of microbiological air quality in hemato-oncology units and its relationship with the occurrence of invasive fungal infections : an integrative review

Worldwide aging of the human population has promoted an increase in the incidence of neoplasia, including hematological cancers, which render patients particularly vulnerable to invasive fungal infections. For this reason, air fi ltration in hematooncology units has been recommended. However, scarce literature has assessed the impact of microbiological air quality on the occurrence of fungal infections in this population. We performed an integrative review of studies in the MEDLINE database that were published between January 1980 and October 2012, using the following combinations of keywords: air × quality × HEPA, air × quality × hematology, and airborne fungal infections. The search yielded only 13 articles, suggesting that high-effi ciency fi ltering of the ambient air in hemato-oncology units can prevent the incidence of invasive fungal infections. However, no randomized clinical trial was found to confi rm this suggestion. Currently, there is no consensus about the maximum allowable count of fungi in the air, which complicates fi ltration monitoring, including fi lter maintenance and replacement, and needs to be addressed in future studies.


INTRODUCTION
The expansion of the elderly population is a worldwide phenomenon that is also occurring in Brazil, and with this expansion comes an increased incidence of neoplasia 1 .Cancer is now a major public health problem in Brazil and many other parts of the world.It is estimated that in this country, 1 in 3 women and 1 in 2 men will develop cancer during their lifetime 2 .
Medullary neoplasias, particularly acute myeloid leukemia, are rarely diagnosed before age 40 but exhibit an exponential increase in incidence with age.The molecular and cellular mechanisms associated with this age-related increase remain poorly understood 3 .Hematopoietic stem cell transplantation has been a widely used alternative in the treatment of leukemias 4 .However, it is important to note that both the period of neutropenia prior to the grafting of these cells and chemotherapy-induced neutropenia involve intense immunosuppression of these patients, making these individuals susceptible to various infections that affect treatment outcomes 5 .Invasive fungal infections, particularly aspergillosis, are common in these patients and have high morbidity and mortality rates in immunocompromised patients 6 .
In this context, the microbiological air quality in oncological units is important, particularly in the prevention of fungal infections.The Centers for Disease Control and Prevention recommends air fi ltration using high-effi ciency particulate air (HEPA) fi lters 7 .The Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) 8 also recommends that places designated as a protective environment be separated from the rest of the hospital and have a heating, ventilation, and air conditioning system with a HEPA fi lter that completes at least 12 full exchanges of air per hour 8 .
The minimum acceptable limits for fungal growth in these units remain controversial.The SEIMC sets a limit of 0.5 CFU/m³ in the air of protective environment areas.This limit entails the detection of no more than one colony of fi lamentous fungi within a 2-m³ sample of air.This recommendation is justifi ed by evidence that concentrations as low as 1 CFU/m³ can cause infection in high-risk patients.However, it has also been suggested that studies be conducted at individual centers to fi rst determine the normal concentrations and then detect signifi cant increases 8 .
Given that this topic is scarcely discussed and controversial in the literature and that there is no consensus on the safety limits for air fi ltration, this study aimed to review the literature on air quality and its association with fungal infections in hematooncology patients.

GENERAL OBJECTIVE
To review the literature on air quality and its association with fungal infections in hemato-oncology patients.

SPECIFIC OBJECTIVES
1) To identify the impact of air fi ltration on the incidence of invasive aspergillosis in patients with hemato-oncological cancers during restructuring periods.2) To identify the impact of air fi ltration on the routine incidence of invasive aspergillosis in patients with hemato-oncological cancers outside of restructuring periods.3) To identify the maximum fungal concentration in HEPA-fi ltered air above which there would be a correlation between the fungal concentration and an increased incidence of aspergillosis.

METHODS
This study is an integrative review of the literature, which is an approach that can make research results more accessible, reduce certain barriers to the use of scientifi c knowledge, and enable a reader to gain access to various surveys conducted in a single study 9 .The main question in this integrative review was What scientifi c knowledge is there regarding air quality and its association with fungal infections in hemato-oncology patients?
This survey was conducted using the MEDLINE database and the following combinations of keywords: air × quality × HEPA, air × quality × hematology, and airborne fungal infections.The inclusion criteria established in this selection were the availability of full-text articles published between January 1990 and October 2012 in English or Portuguese that were primary studies focused on air quality and its association with fungal infections in adult hemato-oncology patients.Articles that discussed air fi ltration in operating rooms, patients with cystic fi brosis or asthma, or air quality in kindergartens and homes were excluded.
To collect the data, we used an instrument that allowed: 1) the identifi cation of publications (title of the article and journal, main author, year of publication, and study sites); 2) the characterization of publications regarding the evaluation criteria in the studies (type of fi lter used); and 3) the characterization of methodological characteristics (type of study, study objectives, results, limitations, and conclusions).

RESULTS AND DISCUSSION
The fi nal sample consisted of 13 articles.Figure 1 describes the inclusion process, as recommended by the PRISMA fl owchart 10 .
Regarding the characterization of the studies' year of publication, Figure 2 shows that the studies were fi rst published in 1998; since 2009, no further studies have been published on this topic.We also observed that the distribution was homogeneous in the number of articles published, and no single year was divergent.An analysis of the articles enabled grouping according to the following subthemes: 1) effectiveness of HEPA fi lters in preventing invasive fungal infections in hemato-oncology patients during non-restructuring periods; 2) effectiveness of HEPA fi lters in preventing invasive fungal infections in hematooncology patients during restructuring periods; and 3) effi cacy of HEPA fi lters in reducing the fungal concentration in the air in hemato-oncology units, without addressing patient outcomes.
Effectiveness of HEPA fi lters in preventing invasive fungal infections in hemato-oncology patients during non-restructuring periods: This subtheme included six studies [11][12][13][14][15][16] , fi ve [11][12][13][14][15] of which showed a benefi t for air fi ltration via reduced CFU values and a subsequent reduction in the number of fungal infections and/ or decreased patient mortality after transplantation.However, Hospenthal et al. 16 questioned the impact of HEPA fi lters on the prevention of invasive aspergillosis.Table 1 presents the core fi ndings of these studies.

Effectiveness of HEPA fi lters in preventing invasive fungal infections in hemato-oncology patients during restructuring periods:
This theme included three studies [17][18][19] demonstrating that HEPA fi lters effectively reduced the fungal concentration in the air, thus possibly preventing cases of invasive fungal infections during restructuring periods.Table 2 presents the main fi ndings of these studies.

Effi cacy of HEPA fi lters in reducing the fungal concentration in the air in hemato-oncology units, without addressing patient outcomes:
This theme included four studies [20][21][22][23] that evaluated the effi cacy of HEPA fi lters in reducing the fungal concentration in the air in hemato-oncology units but did not address patient outcomes.Two of the studies found that HEPA fi lter performance was no better than regular air fi ltration 20,21 .Another study found that HEPA fi lters effectively reduced the fungal concentration in the air but that water systems could be a source of Aspergillus spp., which are not completely eliminated by air fi ltration 22 .Finally, Cornet et al. 23 reported that HEPA fi lters did not effectively prevent air contamination by fungi during a construction period, unless combined with laminar airfl ow 23 .Table 3 presents the core fi ndings of these studies.

CONCLUSIONS
Scientifi c observations evaluating the microbiological air quality in hemato-oncology units and the relationship between air quality and the incidence of invasive fungal infections in patients admitted to these units are relatively scarce.Compounding this lack of data, we found no randomized controlled trials evaluating the effectiveness of the cited preventive measures, which was likely due to the serious ethical restrictions associated with such trials.Taken together, the available studies suggest that there is a certain clinical benefi t associated with the treatment of ambient air in hemato-oncology units using HEPA fi lters and positive pressure.However, the studies were subject to selection bias because most of the studies analyzed non-randomized patients, and several of the investigations were performed in specifi c restructuring situations.Moreover, invasive fungal infection is an outcome related to many other risk factors, including the following: the degree of immunosuppression induced by either a hematologic disease and/or its treatment; comorbidities, including previous pulmonary diseases; the use of anti-fungal prophylaxis; and the microbiological quality of the tap water in the units.Thus, from a scientifi c perspective, one cannot be sure that the benefi ts observed in the cited studies were strictly related to air fi ltration.
It is important to highlight that HEPA fi lter installation alone is likely insuffi cient to guard against infection; proper maintenance must also be performed.If any preventive benefi t is actually associated with the use of this type of system, this benefit will likely occur only when the equipment is operated according to the manufacturer's recommendations, using unsaturated filters.Larger doubts remain regarding the maximum allowable count of fungi in the air because levels vary widely between studies.This lack of consensus makes it difficult to estimate a cutoff above which we can establish a direct association with the incidence of fungal infections.We believe that this issue should be addressed by future studies.

FIGURE 2 -
FIGURE 2 -Number of included articles in the review according to the year of publication.

TABLE 1 -
Results of studies evaluating the effectiveness of HEPA fi lters in preventing invasive fungal infections in hemato-oncology patients during non-restructuring periods.

TABLE 2 -
Results of studies evaluating the effectiveness of HEPA fi lters in preventing invasive fungal infections in hemato-oncology patients during restructuring periods.

TABLE 3 -
Results of studies evaluating air filtration and performing a mycological analysis of the air in hemato-oncology units, without analyzing patients.HEPA: high-efficiency particulate air; CFU/m 3 : colony-forming units per cubic meter.