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Airborne fungal spores and invasive aspergillosis in hematologic units in a tertiary hospital during construction: a prospective cohort study

Airborne fungal spores and invasive aspergillosis in hematologic units in a tertiary hospital... Background: Invasive aspergillosis (IA) is an opportunistic fungal infection that mostly occurs in immunocompromised patients, such as those having hematologic malignancy or receiving hematopoietic stem cell transplantation. Inhalation of Aspergillus spores is the main transmission route of IA in immunocompromised patients. Construction work in hospitals is a risk factor for environmental fungal contamination. We measured airborne fungal contamination and the incidence of IA among immunocompromised patients, and evaluated their correlation with different types of construction works. Methods: Our tertiary hospital in Seoul, Korea underwent facility construction from September 2017 to February 2018. We divided the entire construction period into period 1 (heavier works: demolition and excavation) and period 2 (lighter works: framing, interior designing, plumbing, and finishing). We conducted monthly air sampling for environmental spore surveillance in three hematologic wards. We evaluated the incidence of IA among all immunocompromised patients hospitalized in the three hematologic wards (2 adult wards and 1 pediatric ward) during this period. IA was categorized into proven, probable, and possible aspergillosis based on the revised European Organization for Research and Treatment of Cancer/Mycosis Study Group (EORTC/MSG) criteria. Results: A total of 15 patients was diagnosed with proven (1 case), probable (8 cases), or possible (6 cases) hospital- acquired IA during period 1. In period 2, 14 patients were diagnosed with either proven (1 case), probable (10 cases), or possible (3 cases) hospital-acquired IA. Total mold and Aspergillus spp. spore levels in the air tended to be higher in period 1 (p = 0.06 and 0.48, respectively). The incidence rate of all IA by the EORTC/MSG criteria was significantly higher in period 1 than in period 2 (1.891 vs. 0.930 per 1000 person-days, p =0.05). (Continued on next page) * Correspondence: kimsunghanmd@hotmail.com Joung Ha Park, Seung Hee Ryu and Jeong Young Lee contributed equally to this work. Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro-43-gil, Songpa-gu, Seoul 05505, Republic of Korea Office for Infection Control, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Park et al. Antimicrobial Resistance and Infection Control (2019) 8:88 Page 2 of 8 (Continued from previous page) Conclusions: Airborne fungal spore levels tended to be higher during the period with heavier construction works involving demolition and excavation, during which the incidence of IA was significantly higher as well. We recommend monitoring airborne fungal spore levels during construction periods in hospitals with immunocompromised patients. Subsequently, the effect of airborne fungal spore level monitoring in reducing hospital-acquired IA should be evaluated. Keywords: Fungal spore, Invasive aspergillosis, Construction Background February 2018. We included patients with hematologic Invasive aspergillosis (IA) is an opportunistic fungal infec- malignancies who were hospitalized in three hematologic tion that mostly occurs in immunocompromised patients, wards during this period. The three hematologic wards such as those having hematologic malignancy or receiving consist of two adult wards (wards 74 and 84) and one hematopoietic stem cell transplantation [1]. The treatment pediatric ward (ward 146). Ward 74 is composed of 16 of IA is difficult and the mortality rate is reported as 30– rooms, eight of which are dedicated for hematopoietic 58%, especially among immunocompromised patients [2– stem cell transplantation (HSCT) and are equipped with 4]. Inhalation of Aspergillus spores, which are ubiquitously HEPA filters and positive pressure ventilation systems; found in soil, water, and air, is the main transmission route the remaining eight conventional rooms do not have of IA [5]. Accordingly, there have been many efforts to specific ventilation systems. Ward 84 is composed of control environmental fungal contamination using appro- conventional rooms only. The pediatric ward 146 is priate ventilation systems, such as high-efficiency particu- composed of rooms, seven of which are dedicated to late air (HEPA) filters [6–8]. HSCT and equipped with both HEPA filters and positive Construction works in hospitals are risk factors for en- pressure ventilation systems; the remaining rooms are vironmental fungal contamination and hospital-acquired equipped with HEPA filters only. The three wards are all IA [8–11]. In a previous review, construction works isolated from the other general wards by a door at the accounted for about half (49%) of the causes of hospital- ward entrance. During the construction periods, all win- acquired aspergillosis outbreaks [11]. It is recommended dows were recommended to be kept closed. We divided that clinicians conduct active surveillance for airborne the entire construction period into two periods—period fungal infection in high-risk patients and that wards for 1 (September–October) with heavier works such as these patients should be equipped with appropriate venti- demolition and excavation, and period 2 (November– lation systems based on infection-control risk assessment February) with lighter works such as framing, interior during construction periods [6]. However, it remains con- designing, plumbing, and finishing. We measured air- troversial whether elevated fungal spore level assessed by borne fungal contamination by air sampling and com- air sampling during construction works in hospitals is as- pared the incidence of IA in the three wards between sociated with the increased risk of IA [10, 12, 13], al- periods 1 and 2. Posaconazole was used as antifungal though it is well known that construction works in prophylaxis in patients who underwent induction hospitals have been associated with IA outbreaks [8, 10, chemotherapy for acute myeloid leukemia and myelo- 11]. Therefore, the recommendation of routine microbio- dysplastic syndrome or hematopoietic stem cell trans- logic air sampling before, during, or after construction is plant recipients with graft versus host disease. still under debate. We thus evaluated the correlation Micafungin was used as antifungal prophylaxis in between airborne fungal contamination and the incidence hematopoietic stem cell transplant recipients. Antifungal of IA among immunocompromised patients with prophylaxis was same during period 1 and period 2. The hematologic malignancy during hospital construction pe- study protocol was approved by the Institutional Review riods. We also investigated fungal spore levels in the air Board of Asan Medical Center. and the incidence of IA depending on the types of construction. Definition IA was categorized into proven (histopathologic evidence Methods of tissue invasion including septated, acutely branching Study design filamentous fungi, or positive culture from sterile speci- This study was conducted at Asan Medical Center, a mens), probable (presence of a host factor, a clinical criter- 2700-bed tertiary care teaching hospital in Seoul, South ion, and a mycological criterion compatible with IA), and Korea. A radiotherapy facility construction was carried possible (presence of a host factor and a clinical criterion out behind the main buildings from September 2017 to without mycological evidence) aspergillosis based on the Park et al. Antimicrobial Resistance and Infection Control (2019) 8:88 Page 3 of 8 revised European Organization for Research and Treat- either proven (1 case), probable (8 cases), or possible (6 ment of Cancer/Invasive Fungal Infections Cooperative cases) hospital-acquired IA during period 1. In period 2, Group and the National Institute of Allergy and Infectious 14 patients were diagnosed with either proven (1 case), Diseases Mycoses Study Group (EORTC/MSG) criteria probable (10 cases), or possible (3 cases) hospital- [14]. To identify patients with IA, a researcher (JH Park) acquired IA. In the entire construction period, four and retrospectively reviewed the demographic characteristics, three pediatric patients were included in periods 1 and clinical manifestations, laboratory findings, and imaging 2, respectively. Of a total of 29 IA patients, two (1 in studies of all suspected IA patients based on electronic period 1 and the other in period 2) were diagnosed with medical records. The results of air sampling and the study proven invasive Aspergillus sinusitis, and the remaining period were concealed from the researcher to avoid bias. patients were all diagnosed with invasive pulmonary as- Patients who were diagnosed with IA using the aforemen- pergillosis. These two patients with invasive fungal si- tioned criteria were finally included in this study. We only nusitis, not invasive pulmonary aspergillosis, had analyzed cases of patients who were presumptively classi- undergone paranasal sinus magnetic resonance imaging. fied as having hospital-acquired IA, defined as those diag- The remaining 27 patients had all undergone chest com- nosed with IA at least one week after admission [15]and puted tomography scan at hospitalization. Acute myeloid had no clinical or radiological signs of IA at admission. leukemia was the most common underlying hematologic disease (47% vs. 33%) in both periods. Neutropenia was Air sampling for environmental surveillance common in both periods (82% vs. 80%) and patients Air sampling for environmental surveillance was con- who underwent HSCT accounted for 41 and 33% in pe- ducted once a month in the three hematologic wards riods 1 and 2, respectively. Patients were usually treated during the construction periods. Airborne fungal con- with voriconazole or amphotericin B. Four patients in tamination was determined by the total mold spore con- each period had microbiologically confirmed IA by a centration and the level of Aspergillus spp. spores in air. fungal culture of respiratory specimens or biopsy tissues; We collected 1000 L of air three times every 20 min by four yielded Aspergillus fumigatus, three yielded Asper- using a portable air sampler (AirPort MD8, Sartorius gillus flavus, and one yielded Aspergillus niger. Of these AG, Germany) located at each nurse station in the three patients, seven tested positive for serum galactomannan, hematologic wards. Air was plated onto Sabouraud dex- and the remaining patient with invasive Aspergillus si- trose agar and incubated at 30 °C for five days. After in- nusitis tested negative for serum galactomannan. cubation, we counted colonies and expressed the data as median colony-forming units (CFU) per 1000 L of air. Air sampling for environmental surveillance Colonies were identified at the genus level based on Figure 1 shows the airborne fungal spore levels (both total macroscopic and microscopic findings (lactophenol cot- mold and Aspergillus spp.) in three hematologic wards ton blue-stained preparation). Finally, quantitative re- during the 6 month construction period. Compared with sults were generated for both Aspergillus spp. and total that of period 1 (9.95 CFU/1000 L), the total mold spore molds. level tended to be lower in period 2 (5.60 CFU/1000 L), which is depicted by the linear regression line of best fit Statistical analysis (p = 0.06). Of the total mold spores, those of Penicillium In comparing the clinical characteristics of patients be- spp. were the most common. Aspergillus spp. spore levels tween periods 1 and 2, categorical variables were com- were also lower in period 2 (1.70 CFU/1000 L) than in pared using the χ or Fisher’s exact test as appropriate, period 1 (2.35 CFU/1000 L), although the difference was and continuous variables were compared using the not significant (p = 0.48). Ward 84 had the highest total Mann-WhitneyU test. We assessed P for trend of total mold and Aspergillus spp. spore levels at 12.12 and 3.86 mold and Aspergillus spp. spores using a linear regres- CFU/1000 L, respectively (p = 0.01 and 0.03). sion model. Also, we compared the incidence of IA be- tween the two periods using a Poisson regression model. Incidence of invasive aspergillosis All tests of significance were two-tailed and p values Figure 2 shows the incidence of IA in the three ≤0.05 were considered statistically significant. All ana- hematologic wards during the 6 month construction lyses were performed using SPSS for Windows, version period. The incidence of all IA by the EORTC/MSG cri- 21.0 (IBM Corp., Armonk, NY, USA). teria was also higher in period 1 than in period 2 (1.891 vs. 0.930 per 1000 person-days, p = 0.05). Thus, the inci- Results dence of IA was higher in period 1 when airborne fungal Study population spore levels tended to be higher. In the entire study The clinical characteristics of patients with IA are shown period, of the three wards, ward 84 had the highest inci- in Table 1. A total of 15 patients was diagnosed with dence of total IA (1.996 per 1000 person-days, p =0.049). Park et al. Antimicrobial Resistance and Infection Control (2019) 8:88 Page 4 of 8 Table 1 Clinical characteristics of patients with invasive aspergillosis at the time of IA diagnosis a b Period 1 (n = 15) Period 2 (n = 14) Age, median years (IQR) 44 (17–60) 59 (43–63) Male gender, no. (%) 10 (59) 11 (73) Underlying hematologic disease, no. (%) Acute myeloid leukemia 8 (47) 5 (33) Acute lymphoid leukemia 1 (6) 2 (13) Myelodysplastic syndrome 3 (18) 0 (0) Lymphoma 2 (12) 1 (7) Others 3 (18) 7 (47) Immunocompromised condition Neutropenia 12 (80) 11 (79) Hematopoietic stem cell transplant 6 (40) 5 (36) Steroid use 3 (20) 3 (21) T-cell immunosuppressant 2 (13) 3 (21) f f Human immunodeficiency virus infection 1/15 (7) 0/12 (0) Symptoms at the time of IA diagnosis Fever 13 (87) 11 (79) Cough 4 (27) 4 (29) Sputum 2 (13) 4 (29) Dyspnea 6 (40) 3 (21) Positive results for serum galactomannan 9 (53) 12 (80) f f Positive results for beta-D-glucan 8/14 (57) 9/12 (75) Positive results for culture specimens 4 (24) 4 (27) Hospitalization days before IA diagnosis, median days (IQR) 23.0 (9.0–58.0) 43.5 (12.8–86.3) Antifungal prophylaxis Micafungin 2 (13) 1 (7) Posaconazole 1 (7) 2 (14) Fluconazole 2 (13) 2 (14) No antifungal prophylaxis 10 (67) 9 (64) Antifungal agent Voriconazole 11 (65) 11 (73) Amphotericin B 5 (29) 1 (7) Echinocandin 1 (6) 1 (7) Others 0 (0) 2 (13) 30-day mortality 5 (29) 3 (20) IQR interquartile range From September 2017 – October 2017, during demolition and excavation works From November 2017 – February 2018, during framing, interior designing, plumbing, and finishing works 1 chronic myeloid leukemia, 6 aplastic anemia, 1 multiple myeloma, 1 hemophagocytic lymphohistiocytosis, 1 neuroblastoma d 3 Absolute neutrophil count < 500/mm for more than 10 days > 0.3 mg/kg/day prednisolone for more than 3 weeks Excluded patients who did not undergo appropriate tests Antifungal agent that was used for the treatment of current invasive aspergillosis for over 75% of the total duration Discussion to have higher levels of airborne spore levels than in We investigated the relationship between airborne construction period 2 (framing, interior designing, fungal contamination and the incidence of IA during plumbing, and finishing), both in terms of total mold construction periods in a tertiary care hospital. Con- spores (9.95 vs. 5.60 CFU/1000 L) and Aspergillus spp. struction period 1 (demolition and excavation) tended spores (2.35 vs. 1.70 CFU/1000 L). The total incidence Park et al. Antimicrobial Resistance and Infection Control (2019) 8:88 Page 5 of 8 Fig. 1 Airborne fungal spore levels in three hematologic wards during a 6 month construction period. CFU, colony-forming unit rate of IA was significantly higher in period 1 than in level could serve as an indirect marker of air contamin- period 2 (1.891 vs. 0.930/1000 person-days). ation that may be associated with the spore levels of other The incidence of IA was higher in period 1, when air- pathogens. borne fungal spore levels tended to be higher, than in Construction works are regarded as a possible source period 2. All demolition and excavation works were per- of IA outbreaks in hospitals [8–11]. For this reason, the formed in period 1; although one study showed that Centers for Disease Control and Prevention recommend demolition of a hospital building significantly increased active surveillance for airborne fungal infection cases in fungal spore levels in hospital external and non-protected high-risk patients in hospitals during constructions [6]. internal air [16], the correlation between specific construc- However, there are some problems in conducting active tion types and airborne fungal contamination and the inci- surveillance in patients. First, the diagnostic perform- dence of IA has not been well-studied [8]. According to ance of serum galactomannan or fungal culture from our data, demolition and excavation works seemed to have clinical specimens is relatively low [17]. Some IA pa- affected the airborne total mold and Aspergillus spp. spore tients may go undiagnosed if the diagnosis is made levels and may have contributed to the increased inci- based on the EORTC/MSG criteria due to the low sensi- dence of IA. This finding may be explained by the risk of tivities of the diagnostic tests. There is also the possibil- large amounts of fungal spore being dispersed during ity of false positivity of serum galactomannan or demolition and excavation works than during other types colonization of the respiratory tract of patients by Asper- of construction works. The differences in spore levels be- gillus spp. Second, there are problems defining hospital- tween periods 1 and 2 were more pronounced for total acquired IA because the incubation period of IA is yet mold spores than for those of Aspergillus spp. Although to be clearly defined [7, 15, 18]. In this context, it is the pathogen of IA is Aspergillus spp., high total mold possible that patients who were exposed in period 1 spore levels may indicate ineffective air filtration and/or could have developed IA in period 2 and IA in period the existence of conditions that favor the settling of molds, 1 could reflect exposure during the preceding weeks including Aspergillus spp. [9]. Therefore, total mold spore of hospitalization. Park et al. Antimicrobial Resistance and Infection Control (2019) 8:88 Page 6 of 8 Fig. 2 Incidence of invasive aspergillosis in three hematologic wards during a 6 month constructionperiod. Incidence: number of cases per 1000 * a b person-days. IA, invasive aspergillosis. Incidence: number of cases per 1000 person-days. 7,934 person-days during period 1. 15,050 person-days during period 2 To prevent IA during construction periods, the The recommendation of routine environmental sur- Centers for Disease Control and Prevention guideline veillance before, during, or after construction is still recommends implementation of infection-control under debate. There are several issues with environ- measures, such as sealing windows and specific venti- mental surveillance by air sampling. Importantly, lation systems, based on infection-control risk assess- there is no gold standard for sampling air for envir- ment [6]. However, studies on the efficacy of HEPA onmental surveillance, such as the appropriate vol- filters for controlling air contamination have shown ume, number, and location for collection. In addition, conflicting results [9, 10, 19]. In our current study, there is no consensus on the cut-off value for desig- ward 84 without any specific ventilation system had nating fungal spore level as either safe or dangerous. the highest levels of both total mold and Aspergillus According to a previous study, airborne fungal con- spp. spores, and the incidence of IA was also higher tamination during IA outbreaks in several hospitals than in other wards. Although we did not describe varied widely from 0 to more than 100 spores/m the exact efficacy of the HEPA filters, our data show [11]. Nevertheless, based on our current results, we that fungal contamination tended to be higher in con- suggest that airborne fungal spore levels be monitored ventional wards and lower in the wards equipped with during construction in hospitals with immunocom- HEPA filters. promised patients, and that further studies are needed Park et al. Antimicrobial Resistance and Infection Control (2019) 8:88 Page 7 of 8 to set a cut-off value for a “dangerous” level of fungal only 6 months, and there was no significant change or de- spore contamination. velopment in the treatment strategies, diagnostic criteria This study has several limitations. First, we performed or technology, this effect seemed to be less influential. air sampling only three times on a given day on a Fifth, although we found a relationship between the inci- monthly basis, and the spore levels of one day may not dence of IA and total mold spore levels during construc- be representative of the spore levels of the month as a tion works, we could not reveal the direct relationship whole. However, standardized methods of air sampling between the incidence of IA and Aspergillus spp. spore such as determining where, how often, or how much air levels. However, considering that identification of Asper- should be sampled have not been established yet. Thus, gillus spp. is usually difficult, total mold spores could be a further studies are needed in this area. Second, we could surrogate marker of air contamination contributing to IA. not account for the various factors that may affect the Finally, we did not perform a genomic analysis of the As- spore levels of airborne molds, such as season, weather, pergillus spp. isolated from the clinical and air samples. It and ventilation system, which may ultimately act as po- remains a difficult task to identify a direct epidemiological tential confounders for the difference in IA incidence. linkage between environmental and clinical fungal isolates, Because our data could not be compared with the base- with two recent studies showing conflicting results on the line data on airborne fungal contamination prior to con- correlation between A. fumigatus spore levels in the air struction, it was difficult to evaluate the impact of and the incidence of IA during constructions in hospitals construction works on airborne fungal contamination [12, 13]. Further studies are needed to clarify the genomic independently. In general, the spore levels of airborne correlation between environmental and clinical fungal molds were significantly higher during summer than isolates. during the other seasons [20–23]. However, Aspergillus spp. spore concentration did not correlate with various Conclusions meteorological data, such as temperature, precipitation, We found that the incidence of IA was significantly and humidity [13, 20, 22], although there were some re- higher during heavy hospital construction works such as ports about seasonal variation of Aspergillus spp. spore demolition and excavation, during which airborne fungal levels [24, 25]. Therefore, it is not yet clear how meteoro- spore levels also tended to be higher. We recommend logical variation affects Aspergillus spp. spore levels, not that airborne fungal spore levels be monitored during total molds spore levels, and the incidence of IA. It is construction periods in hospitals with immunocom- worth noting that we have prospectively monitored weekly promised patients. Subsequently, the effect of airborne cases of Aspergillus spp. isolates from clinical specimens fungal spore level monitoring in reducing hospital- from January 2016 to December 2018 (Additional file 1: acquired IA should be evaluated. Figure S1). There were no seasonal variations in Aspergil- lus spp. isolation from clinical specimens. A previous Additional file study revealed that there was a significant correlation be- tween Aspergillus spp. colonization from respiratory tract Additional file 1: Table S1. Baseline characteristics of admitted patients and airborne fungal contamination of patients’ rooms on during periods 1 and 2. Figure S1. Cases of Aspergillus spp. isolation from clinical specimens from January 2016 to December 2018. (ZIP 671 kb) multivariate analysis [26]. Taken together, it is less likely that increased airborne spore levels and incidence of IA during the construction period might be caused by sea- Abbreviations IA: Invasive aspergillosis; EORTC/MSG: European Organization for Research sonal variation, although the absence of baseline year- and Treatment of Cancer/Mycosis Study Group; HEPA: High-efficiency round air sampling before construction work makes it dif- particulate air; HSCT: Hematopoietic stem cell transplantation; CFU: Colony- ficult to arrive at a firm conclusion on seasonal variations. forming units Further studies are needed to clarify this area. Third, there Acknowledgments might be several variables affecting the risk of IA other Not applicable. than construction works. Particularly, different clinical characteristics of patients who were exposed during Authors’ contributions period 1 and period 2 might account for the differences in JH Park, SH Ryu, J Jung, and S-H Kim designed the study. JH Park, SH Ryu, JA Lee, H Sung, and S-H Kim collected and analyzed the data. SH Ryu, JY Lee, the incidence of IA. However, there were no significant HJ Kim, SH Kwak, and J Jung conducted air sampling and analyzed the differences in the duration of neutropenia or type of results. All authors read and approved the final manuscript. hematologic diseases except for acute myeloid leukemia among patients admitted between periods 1 and 2 (Add- Funding This study was supported by a grant from the Korea Health Technology R&D itional file 1: Table S1). Fourth, there might be a learning Project through the Korea Health Industry Development Institute (KHIDI), effect over time and improved diagnostic technology for funded by the Ministry of Health & Welfare, Republic of Korea (grant no. diagnosing IA. However, because we analyzed data during HI16C0272). Park et al. Antimicrobial Resistance and Infection Control (2019) 8:88 Page 8 of 8 Availability of data and materials infections cooperative group and the National Institute of Allergy and The datasets used and/or analyzed during the current study are available Infectious Diseases mycoses study group (EORTC/MSG) consensus group. from the corresponding author on reasonable request. Clin Infect Dis. 2008;46(12):1813–21. 15. Patterson JE, Zidouh A, Miniter P, Andriole VT, Patterson TF. Hospital epidemiologic surveillance for invasive aspergillosis: patient demographics Ethics approval and consent to participate and the utility of antigen detection. Infect Control Hosp Epidemiol. 1997; The study protocol was approved by the Institutional Review Board of Asan 18(2):104–8. Medical Center. The need for informed consent was waived because of the 16. Bouza E, Pelaez T, Perez-Molina J, Marin M, Alcala L, Padilla B, et al. nature of this study. Demolition of a hospital building by controlled explosion: the impact on filamentous fungal load in internal and external air. J Hosp Infect. 2002; Consent for publication 52(4):234–42. All the authors gave final approval of the version to be published. 17. Patterson TF, Thompson GR 3rd, Denning DW, Fishman JA, Hadley S, Herbrecht R, et al. Practice guidelines for the diagnosis and Management of Competing interests Aspergillosis: 2016 update by the Infectious Diseases Society of America. The authors declare that they have no competing interests. Clin Infect Dis. 2016;63(4):e1–e60. 18. Benet T, Voirin N, Nicolle MC, Picot S, Michallet M, Vanhems P. Estimation of Author details the incubation period of invasive aspergillosis by survival models in acute Department of Infectious Diseases, Asan Medical Center, University of Ulsan myeloid leukemia patients. Med Mycol. 2013;51(2):214–8. College of Medicine, 88, Olympic-ro-43-gil, Songpa-gu, Seoul 05505, Republic 19. Eckmanns T, Ruden H, Gastmeier P. The influence of high-efficiency of Korea. Office for Infection Control, Asan Medical Center, University of particulate air filtration on mortality and fungal infection among highly Ulsan College of Medicine, Seoul, Republic of Korea. Department of immunosuppressed patients: a systematic review. J Infect Dis. 2006;193(10): Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, 1408–18. Seoul, Republic of Korea. Department of Laboratory Medicine, Asan Medical 20. Alshareef F, Robson GD. Prevalence, persistence, and phenotypic variation Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. of Aspergillus fumigatus in the outdoor environment in Manchester, UK, over a 2-year period. Med Mycol. 2014;52(4):367–75. Received: 29 January 2019 Accepted: 19 May 2019 21. Cho SY, Myong JP, Kim WB, Park C, Lee SJ, Lee SH, et al. 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De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T, et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of cancer/invasive fungal http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Antimicrobial Resistance & Infection Control Springer Journals

Airborne fungal spores and invasive aspergillosis in hematologic units in a tertiary hospital during construction: a prospective cohort study

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Abstract

Background: Invasive aspergillosis (IA) is an opportunistic fungal infection that mostly occurs in immunocompromised patients, such as those having hematologic malignancy or receiving hematopoietic stem cell transplantation. Inhalation of Aspergillus spores is the main transmission route of IA in immunocompromised patients. Construction work in hospitals is a risk factor for environmental fungal contamination. We measured airborne fungal contamination and the incidence of IA among immunocompromised patients, and evaluated their correlation with different types of construction works. Methods: Our tertiary hospital in Seoul, Korea underwent facility construction from September 2017 to February 2018. We divided the entire construction period into period 1 (heavier works: demolition and excavation) and period 2 (lighter works: framing, interior designing, plumbing, and finishing). We conducted monthly air sampling for environmental spore surveillance in three hematologic wards. We evaluated the incidence of IA among all immunocompromised patients hospitalized in the three hematologic wards (2 adult wards and 1 pediatric ward) during this period. IA was categorized into proven, probable, and possible aspergillosis based on the revised European Organization for Research and Treatment of Cancer/Mycosis Study Group (EORTC/MSG) criteria. Results: A total of 15 patients was diagnosed with proven (1 case), probable (8 cases), or possible (6 cases) hospital- acquired IA during period 1. In period 2, 14 patients were diagnosed with either proven (1 case), probable (10 cases), or possible (3 cases) hospital-acquired IA. Total mold and Aspergillus spp. spore levels in the air tended to be higher in period 1 (p = 0.06 and 0.48, respectively). The incidence rate of all IA by the EORTC/MSG criteria was significantly higher in period 1 than in period 2 (1.891 vs. 0.930 per 1000 person-days, p =0.05). (Continued on next page) * Correspondence: kimsunghanmd@hotmail.com Joung Ha Park, Seung Hee Ryu and Jeong Young Lee contributed equally to this work. Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro-43-gil, Songpa-gu, Seoul 05505, Republic of Korea Office for Infection Control, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Park et al. Antimicrobial Resistance and Infection Control (2019) 8:88 Page 2 of 8 (Continued from previous page) Conclusions: Airborne fungal spore levels tended to be higher during the period with heavier construction works involving demolition and excavation, during which the incidence of IA was significantly higher as well. We recommend monitoring airborne fungal spore levels during construction periods in hospitals with immunocompromised patients. Subsequently, the effect of airborne fungal spore level monitoring in reducing hospital-acquired IA should be evaluated. Keywords: Fungal spore, Invasive aspergillosis, Construction Background February 2018. We included patients with hematologic Invasive aspergillosis (IA) is an opportunistic fungal infec- malignancies who were hospitalized in three hematologic tion that mostly occurs in immunocompromised patients, wards during this period. The three hematologic wards such as those having hematologic malignancy or receiving consist of two adult wards (wards 74 and 84) and one hematopoietic stem cell transplantation [1]. The treatment pediatric ward (ward 146). Ward 74 is composed of 16 of IA is difficult and the mortality rate is reported as 30– rooms, eight of which are dedicated for hematopoietic 58%, especially among immunocompromised patients [2– stem cell transplantation (HSCT) and are equipped with 4]. Inhalation of Aspergillus spores, which are ubiquitously HEPA filters and positive pressure ventilation systems; found in soil, water, and air, is the main transmission route the remaining eight conventional rooms do not have of IA [5]. Accordingly, there have been many efforts to specific ventilation systems. Ward 84 is composed of control environmental fungal contamination using appro- conventional rooms only. The pediatric ward 146 is priate ventilation systems, such as high-efficiency particu- composed of rooms, seven of which are dedicated to late air (HEPA) filters [6–8]. HSCT and equipped with both HEPA filters and positive Construction works in hospitals are risk factors for en- pressure ventilation systems; the remaining rooms are vironmental fungal contamination and hospital-acquired equipped with HEPA filters only. The three wards are all IA [8–11]. In a previous review, construction works isolated from the other general wards by a door at the accounted for about half (49%) of the causes of hospital- ward entrance. During the construction periods, all win- acquired aspergillosis outbreaks [11]. It is recommended dows were recommended to be kept closed. We divided that clinicians conduct active surveillance for airborne the entire construction period into two periods—period fungal infection in high-risk patients and that wards for 1 (September–October) with heavier works such as these patients should be equipped with appropriate venti- demolition and excavation, and period 2 (November– lation systems based on infection-control risk assessment February) with lighter works such as framing, interior during construction periods [6]. However, it remains con- designing, plumbing, and finishing. We measured air- troversial whether elevated fungal spore level assessed by borne fungal contamination by air sampling and com- air sampling during construction works in hospitals is as- pared the incidence of IA in the three wards between sociated with the increased risk of IA [10, 12, 13], al- periods 1 and 2. Posaconazole was used as antifungal though it is well known that construction works in prophylaxis in patients who underwent induction hospitals have been associated with IA outbreaks [8, 10, chemotherapy for acute myeloid leukemia and myelo- 11]. Therefore, the recommendation of routine microbio- dysplastic syndrome or hematopoietic stem cell trans- logic air sampling before, during, or after construction is plant recipients with graft versus host disease. still under debate. We thus evaluated the correlation Micafungin was used as antifungal prophylaxis in between airborne fungal contamination and the incidence hematopoietic stem cell transplant recipients. Antifungal of IA among immunocompromised patients with prophylaxis was same during period 1 and period 2. The hematologic malignancy during hospital construction pe- study protocol was approved by the Institutional Review riods. We also investigated fungal spore levels in the air Board of Asan Medical Center. and the incidence of IA depending on the types of construction. Definition IA was categorized into proven (histopathologic evidence Methods of tissue invasion including septated, acutely branching Study design filamentous fungi, or positive culture from sterile speci- This study was conducted at Asan Medical Center, a mens), probable (presence of a host factor, a clinical criter- 2700-bed tertiary care teaching hospital in Seoul, South ion, and a mycological criterion compatible with IA), and Korea. A radiotherapy facility construction was carried possible (presence of a host factor and a clinical criterion out behind the main buildings from September 2017 to without mycological evidence) aspergillosis based on the Park et al. Antimicrobial Resistance and Infection Control (2019) 8:88 Page 3 of 8 revised European Organization for Research and Treat- either proven (1 case), probable (8 cases), or possible (6 ment of Cancer/Invasive Fungal Infections Cooperative cases) hospital-acquired IA during period 1. In period 2, Group and the National Institute of Allergy and Infectious 14 patients were diagnosed with either proven (1 case), Diseases Mycoses Study Group (EORTC/MSG) criteria probable (10 cases), or possible (3 cases) hospital- [14]. To identify patients with IA, a researcher (JH Park) acquired IA. In the entire construction period, four and retrospectively reviewed the demographic characteristics, three pediatric patients were included in periods 1 and clinical manifestations, laboratory findings, and imaging 2, respectively. Of a total of 29 IA patients, two (1 in studies of all suspected IA patients based on electronic period 1 and the other in period 2) were diagnosed with medical records. The results of air sampling and the study proven invasive Aspergillus sinusitis, and the remaining period were concealed from the researcher to avoid bias. patients were all diagnosed with invasive pulmonary as- Patients who were diagnosed with IA using the aforemen- pergillosis. These two patients with invasive fungal si- tioned criteria were finally included in this study. We only nusitis, not invasive pulmonary aspergillosis, had analyzed cases of patients who were presumptively classi- undergone paranasal sinus magnetic resonance imaging. fied as having hospital-acquired IA, defined as those diag- The remaining 27 patients had all undergone chest com- nosed with IA at least one week after admission [15]and puted tomography scan at hospitalization. Acute myeloid had no clinical or radiological signs of IA at admission. leukemia was the most common underlying hematologic disease (47% vs. 33%) in both periods. Neutropenia was Air sampling for environmental surveillance common in both periods (82% vs. 80%) and patients Air sampling for environmental surveillance was con- who underwent HSCT accounted for 41 and 33% in pe- ducted once a month in the three hematologic wards riods 1 and 2, respectively. Patients were usually treated during the construction periods. Airborne fungal con- with voriconazole or amphotericin B. Four patients in tamination was determined by the total mold spore con- each period had microbiologically confirmed IA by a centration and the level of Aspergillus spp. spores in air. fungal culture of respiratory specimens or biopsy tissues; We collected 1000 L of air three times every 20 min by four yielded Aspergillus fumigatus, three yielded Asper- using a portable air sampler (AirPort MD8, Sartorius gillus flavus, and one yielded Aspergillus niger. Of these AG, Germany) located at each nurse station in the three patients, seven tested positive for serum galactomannan, hematologic wards. Air was plated onto Sabouraud dex- and the remaining patient with invasive Aspergillus si- trose agar and incubated at 30 °C for five days. After in- nusitis tested negative for serum galactomannan. cubation, we counted colonies and expressed the data as median colony-forming units (CFU) per 1000 L of air. Air sampling for environmental surveillance Colonies were identified at the genus level based on Figure 1 shows the airborne fungal spore levels (both total macroscopic and microscopic findings (lactophenol cot- mold and Aspergillus spp.) in three hematologic wards ton blue-stained preparation). Finally, quantitative re- during the 6 month construction period. Compared with sults were generated for both Aspergillus spp. and total that of period 1 (9.95 CFU/1000 L), the total mold spore molds. level tended to be lower in period 2 (5.60 CFU/1000 L), which is depicted by the linear regression line of best fit Statistical analysis (p = 0.06). Of the total mold spores, those of Penicillium In comparing the clinical characteristics of patients be- spp. were the most common. Aspergillus spp. spore levels tween periods 1 and 2, categorical variables were com- were also lower in period 2 (1.70 CFU/1000 L) than in pared using the χ or Fisher’s exact test as appropriate, period 1 (2.35 CFU/1000 L), although the difference was and continuous variables were compared using the not significant (p = 0.48). Ward 84 had the highest total Mann-WhitneyU test. We assessed P for trend of total mold and Aspergillus spp. spore levels at 12.12 and 3.86 mold and Aspergillus spp. spores using a linear regres- CFU/1000 L, respectively (p = 0.01 and 0.03). sion model. Also, we compared the incidence of IA be- tween the two periods using a Poisson regression model. Incidence of invasive aspergillosis All tests of significance were two-tailed and p values Figure 2 shows the incidence of IA in the three ≤0.05 were considered statistically significant. All ana- hematologic wards during the 6 month construction lyses were performed using SPSS for Windows, version period. The incidence of all IA by the EORTC/MSG cri- 21.0 (IBM Corp., Armonk, NY, USA). teria was also higher in period 1 than in period 2 (1.891 vs. 0.930 per 1000 person-days, p = 0.05). Thus, the inci- Results dence of IA was higher in period 1 when airborne fungal Study population spore levels tended to be higher. In the entire study The clinical characteristics of patients with IA are shown period, of the three wards, ward 84 had the highest inci- in Table 1. A total of 15 patients was diagnosed with dence of total IA (1.996 per 1000 person-days, p =0.049). Park et al. Antimicrobial Resistance and Infection Control (2019) 8:88 Page 4 of 8 Table 1 Clinical characteristics of patients with invasive aspergillosis at the time of IA diagnosis a b Period 1 (n = 15) Period 2 (n = 14) Age, median years (IQR) 44 (17–60) 59 (43–63) Male gender, no. (%) 10 (59) 11 (73) Underlying hematologic disease, no. (%) Acute myeloid leukemia 8 (47) 5 (33) Acute lymphoid leukemia 1 (6) 2 (13) Myelodysplastic syndrome 3 (18) 0 (0) Lymphoma 2 (12) 1 (7) Others 3 (18) 7 (47) Immunocompromised condition Neutropenia 12 (80) 11 (79) Hematopoietic stem cell transplant 6 (40) 5 (36) Steroid use 3 (20) 3 (21) T-cell immunosuppressant 2 (13) 3 (21) f f Human immunodeficiency virus infection 1/15 (7) 0/12 (0) Symptoms at the time of IA diagnosis Fever 13 (87) 11 (79) Cough 4 (27) 4 (29) Sputum 2 (13) 4 (29) Dyspnea 6 (40) 3 (21) Positive results for serum galactomannan 9 (53) 12 (80) f f Positive results for beta-D-glucan 8/14 (57) 9/12 (75) Positive results for culture specimens 4 (24) 4 (27) Hospitalization days before IA diagnosis, median days (IQR) 23.0 (9.0–58.0) 43.5 (12.8–86.3) Antifungal prophylaxis Micafungin 2 (13) 1 (7) Posaconazole 1 (7) 2 (14) Fluconazole 2 (13) 2 (14) No antifungal prophylaxis 10 (67) 9 (64) Antifungal agent Voriconazole 11 (65) 11 (73) Amphotericin B 5 (29) 1 (7) Echinocandin 1 (6) 1 (7) Others 0 (0) 2 (13) 30-day mortality 5 (29) 3 (20) IQR interquartile range From September 2017 – October 2017, during demolition and excavation works From November 2017 – February 2018, during framing, interior designing, plumbing, and finishing works 1 chronic myeloid leukemia, 6 aplastic anemia, 1 multiple myeloma, 1 hemophagocytic lymphohistiocytosis, 1 neuroblastoma d 3 Absolute neutrophil count < 500/mm for more than 10 days > 0.3 mg/kg/day prednisolone for more than 3 weeks Excluded patients who did not undergo appropriate tests Antifungal agent that was used for the treatment of current invasive aspergillosis for over 75% of the total duration Discussion to have higher levels of airborne spore levels than in We investigated the relationship between airborne construction period 2 (framing, interior designing, fungal contamination and the incidence of IA during plumbing, and finishing), both in terms of total mold construction periods in a tertiary care hospital. Con- spores (9.95 vs. 5.60 CFU/1000 L) and Aspergillus spp. struction period 1 (demolition and excavation) tended spores (2.35 vs. 1.70 CFU/1000 L). The total incidence Park et al. Antimicrobial Resistance and Infection Control (2019) 8:88 Page 5 of 8 Fig. 1 Airborne fungal spore levels in three hematologic wards during a 6 month construction period. CFU, colony-forming unit rate of IA was significantly higher in period 1 than in level could serve as an indirect marker of air contamin- period 2 (1.891 vs. 0.930/1000 person-days). ation that may be associated with the spore levels of other The incidence of IA was higher in period 1, when air- pathogens. borne fungal spore levels tended to be higher, than in Construction works are regarded as a possible source period 2. All demolition and excavation works were per- of IA outbreaks in hospitals [8–11]. For this reason, the formed in period 1; although one study showed that Centers for Disease Control and Prevention recommend demolition of a hospital building significantly increased active surveillance for airborne fungal infection cases in fungal spore levels in hospital external and non-protected high-risk patients in hospitals during constructions [6]. internal air [16], the correlation between specific construc- However, there are some problems in conducting active tion types and airborne fungal contamination and the inci- surveillance in patients. First, the diagnostic perform- dence of IA has not been well-studied [8]. According to ance of serum galactomannan or fungal culture from our data, demolition and excavation works seemed to have clinical specimens is relatively low [17]. Some IA pa- affected the airborne total mold and Aspergillus spp. spore tients may go undiagnosed if the diagnosis is made levels and may have contributed to the increased inci- based on the EORTC/MSG criteria due to the low sensi- dence of IA. This finding may be explained by the risk of tivities of the diagnostic tests. There is also the possibil- large amounts of fungal spore being dispersed during ity of false positivity of serum galactomannan or demolition and excavation works than during other types colonization of the respiratory tract of patients by Asper- of construction works. The differences in spore levels be- gillus spp. Second, there are problems defining hospital- tween periods 1 and 2 were more pronounced for total acquired IA because the incubation period of IA is yet mold spores than for those of Aspergillus spp. Although to be clearly defined [7, 15, 18]. In this context, it is the pathogen of IA is Aspergillus spp., high total mold possible that patients who were exposed in period 1 spore levels may indicate ineffective air filtration and/or could have developed IA in period 2 and IA in period the existence of conditions that favor the settling of molds, 1 could reflect exposure during the preceding weeks including Aspergillus spp. [9]. Therefore, total mold spore of hospitalization. Park et al. Antimicrobial Resistance and Infection Control (2019) 8:88 Page 6 of 8 Fig. 2 Incidence of invasive aspergillosis in three hematologic wards during a 6 month constructionperiod. Incidence: number of cases per 1000 * a b person-days. IA, invasive aspergillosis. Incidence: number of cases per 1000 person-days. 7,934 person-days during period 1. 15,050 person-days during period 2 To prevent IA during construction periods, the The recommendation of routine environmental sur- Centers for Disease Control and Prevention guideline veillance before, during, or after construction is still recommends implementation of infection-control under debate. There are several issues with environ- measures, such as sealing windows and specific venti- mental surveillance by air sampling. Importantly, lation systems, based on infection-control risk assess- there is no gold standard for sampling air for envir- ment [6]. However, studies on the efficacy of HEPA onmental surveillance, such as the appropriate vol- filters for controlling air contamination have shown ume, number, and location for collection. In addition, conflicting results [9, 10, 19]. In our current study, there is no consensus on the cut-off value for desig- ward 84 without any specific ventilation system had nating fungal spore level as either safe or dangerous. the highest levels of both total mold and Aspergillus According to a previous study, airborne fungal con- spp. spores, and the incidence of IA was also higher tamination during IA outbreaks in several hospitals than in other wards. Although we did not describe varied widely from 0 to more than 100 spores/m the exact efficacy of the HEPA filters, our data show [11]. Nevertheless, based on our current results, we that fungal contamination tended to be higher in con- suggest that airborne fungal spore levels be monitored ventional wards and lower in the wards equipped with during construction in hospitals with immunocom- HEPA filters. promised patients, and that further studies are needed Park et al. Antimicrobial Resistance and Infection Control (2019) 8:88 Page 7 of 8 to set a cut-off value for a “dangerous” level of fungal only 6 months, and there was no significant change or de- spore contamination. velopment in the treatment strategies, diagnostic criteria This study has several limitations. First, we performed or technology, this effect seemed to be less influential. air sampling only three times on a given day on a Fifth, although we found a relationship between the inci- monthly basis, and the spore levels of one day may not dence of IA and total mold spore levels during construc- be representative of the spore levels of the month as a tion works, we could not reveal the direct relationship whole. However, standardized methods of air sampling between the incidence of IA and Aspergillus spp. spore such as determining where, how often, or how much air levels. However, considering that identification of Asper- should be sampled have not been established yet. Thus, gillus spp. is usually difficult, total mold spores could be a further studies are needed in this area. Second, we could surrogate marker of air contamination contributing to IA. not account for the various factors that may affect the Finally, we did not perform a genomic analysis of the As- spore levels of airborne molds, such as season, weather, pergillus spp. isolated from the clinical and air samples. It and ventilation system, which may ultimately act as po- remains a difficult task to identify a direct epidemiological tential confounders for the difference in IA incidence. linkage between environmental and clinical fungal isolates, Because our data could not be compared with the base- with two recent studies showing conflicting results on the line data on airborne fungal contamination prior to con- correlation between A. fumigatus spore levels in the air struction, it was difficult to evaluate the impact of and the incidence of IA during constructions in hospitals construction works on airborne fungal contamination [12, 13]. Further studies are needed to clarify the genomic independently. In general, the spore levels of airborne correlation between environmental and clinical fungal molds were significantly higher during summer than isolates. during the other seasons [20–23]. However, Aspergillus spp. spore concentration did not correlate with various Conclusions meteorological data, such as temperature, precipitation, We found that the incidence of IA was significantly and humidity [13, 20, 22], although there were some re- higher during heavy hospital construction works such as ports about seasonal variation of Aspergillus spp. spore demolition and excavation, during which airborne fungal levels [24, 25]. Therefore, it is not yet clear how meteoro- spore levels also tended to be higher. We recommend logical variation affects Aspergillus spp. spore levels, not that airborne fungal spore levels be monitored during total molds spore levels, and the incidence of IA. It is construction periods in hospitals with immunocom- worth noting that we have prospectively monitored weekly promised patients. Subsequently, the effect of airborne cases of Aspergillus spp. isolates from clinical specimens fungal spore level monitoring in reducing hospital- from January 2016 to December 2018 (Additional file 1: acquired IA should be evaluated. Figure S1). There were no seasonal variations in Aspergil- lus spp. isolation from clinical specimens. A previous Additional file study revealed that there was a significant correlation be- tween Aspergillus spp. colonization from respiratory tract Additional file 1: Table S1. Baseline characteristics of admitted patients and airborne fungal contamination of patients’ rooms on during periods 1 and 2. Figure S1. Cases of Aspergillus spp. isolation from clinical specimens from January 2016 to December 2018. (ZIP 671 kb) multivariate analysis [26]. Taken together, it is less likely that increased airborne spore levels and incidence of IA during the construction period might be caused by sea- Abbreviations IA: Invasive aspergillosis; EORTC/MSG: European Organization for Research sonal variation, although the absence of baseline year- and Treatment of Cancer/Mycosis Study Group; HEPA: High-efficiency round air sampling before construction work makes it dif- particulate air; HSCT: Hematopoietic stem cell transplantation; CFU: Colony- ficult to arrive at a firm conclusion on seasonal variations. forming units Further studies are needed to clarify this area. Third, there Acknowledgments might be several variables affecting the risk of IA other Not applicable. than construction works. Particularly, different clinical characteristics of patients who were exposed during Authors’ contributions period 1 and period 2 might account for the differences in JH Park, SH Ryu, J Jung, and S-H Kim designed the study. JH Park, SH Ryu, JA Lee, H Sung, and S-H Kim collected and analyzed the data. SH Ryu, JY Lee, the incidence of IA. However, there were no significant HJ Kim, SH Kwak, and J Jung conducted air sampling and analyzed the differences in the duration of neutropenia or type of results. All authors read and approved the final manuscript. hematologic diseases except for acute myeloid leukemia among patients admitted between periods 1 and 2 (Add- Funding This study was supported by a grant from the Korea Health Technology R&D itional file 1: Table S1). Fourth, there might be a learning Project through the Korea Health Industry Development Institute (KHIDI), effect over time and improved diagnostic technology for funded by the Ministry of Health & Welfare, Republic of Korea (grant no. diagnosing IA. However, because we analyzed data during HI16C0272). Park et al. Antimicrobial Resistance and Infection Control (2019) 8:88 Page 8 of 8 Availability of data and materials infections cooperative group and the National Institute of Allergy and The datasets used and/or analyzed during the current study are available Infectious Diseases mycoses study group (EORTC/MSG) consensus group. from the corresponding author on reasonable request. Clin Infect Dis. 2008;46(12):1813–21. 15. Patterson JE, Zidouh A, Miniter P, Andriole VT, Patterson TF. Hospital epidemiologic surveillance for invasive aspergillosis: patient demographics Ethics approval and consent to participate and the utility of antigen detection. Infect Control Hosp Epidemiol. 1997; The study protocol was approved by the Institutional Review Board of Asan 18(2):104–8. Medical Center. The need for informed consent was waived because of the 16. Bouza E, Pelaez T, Perez-Molina J, Marin M, Alcala L, Padilla B, et al. nature of this study. Demolition of a hospital building by controlled explosion: the impact on filamentous fungal load in internal and external air. J Hosp Infect. 2002; Consent for publication 52(4):234–42. All the authors gave final approval of the version to be published. 17. Patterson TF, Thompson GR 3rd, Denning DW, Fishman JA, Hadley S, Herbrecht R, et al. Practice guidelines for the diagnosis and Management of Competing interests Aspergillosis: 2016 update by the Infectious Diseases Society of America. The authors declare that they have no competing interests. Clin Infect Dis. 2016;63(4):e1–e60. 18. Benet T, Voirin N, Nicolle MC, Picot S, Michallet M, Vanhems P. Estimation of Author details the incubation period of invasive aspergillosis by survival models in acute Department of Infectious Diseases, Asan Medical Center, University of Ulsan myeloid leukemia patients. Med Mycol. 2013;51(2):214–8. College of Medicine, 88, Olympic-ro-43-gil, Songpa-gu, Seoul 05505, Republic 19. Eckmanns T, Ruden H, Gastmeier P. The influence of high-efficiency of Korea. Office for Infection Control, Asan Medical Center, University of particulate air filtration on mortality and fungal infection among highly Ulsan College of Medicine, Seoul, Republic of Korea. Department of immunosuppressed patients: a systematic review. J Infect Dis. 2006;193(10): Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, 1408–18. Seoul, Republic of Korea. Department of Laboratory Medicine, Asan Medical 20. Alshareef F, Robson GD. Prevalence, persistence, and phenotypic variation Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. of Aspergillus fumigatus in the outdoor environment in Manchester, UK, over a 2-year period. Med Mycol. 2014;52(4):367–75. Received: 29 January 2019 Accepted: 19 May 2019 21. Cho SY, Myong JP, Kim WB, Park C, Lee SJ, Lee SH, et al. 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Antimicrobial Resistance & Infection Control – Springer Journals

Published: Dec 1, 2019

Keywords: medical microbiology; drug resistance; infectious diseases

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