Judy H. Angelbeck, PhD

Two of the most difficult challenges facing the clinician providing care for allogeneic hematopoietic cell transplant (HCT) patients are graft-versus-host disease and infectious complications.¹ Fungal infections such as invasive aspergillosis continues to be one of the major causes of infectious morbidity and mortality after allogeneic HCT. In addition, patients with acute leukemia, heart and lung transplant, AIDS and major burns are also at risk for invasive fungal diseases.^2,3


Figure 1. Chart shows the incidence of invasive aspergillosis in lung transplants is 14% and in allogeneic bone marrow transplant 28%.⁴

Figure 2. The rates of infection for invasive aspergillosis increased in one bone marrow transplant center from 4% to 12% in 8 years. Many centers report infections rates of 10-15%.^3,5


Figure 3. Patterson reports the overall mortality rate for invasive aspergillosis at 60% with the mortality rate in severely immune compromised patients between 80% and 90%.²

The diagnosis and treatment of this disease, particularly in the immune compromised patient is challenging.

In 2003, Patterson reported that in a study with 595 patients with invasive aspergillosis:

• Favorable outcomes occurred in less than 25% of severely immune compromised patients who received amphotericin B therapy

• Death due to or with Aspergillus occurred in 66% of the cases.²
  

While clinicians seek and trial new antifungal agents and better diagnostic tools, the number of immune compromised patients continues to increase. This makes the prevention of opportunistic fungal infections of major importance in managing infection control in the hospital setting.⁶

Aspergillosis is primarily identified as an airborne infection often acquired by inhalation. The following is emphasized by the Centers for Disease Control in their 2003 Guidelines for Environmental Infection Control in Health Care Facilities:⁷

• Severely immune compromised patients are to be housed in the hospital in protected environments.

• The exposure of severely immune compromised patients (solid organ transplant or allogeneic bone marrow transplant patients) must be minimized to activities that might cause aerosolization of fungal spores (e.g. vacuuming or disruption of ceiling tiles).

• Minimize the length of time that immunocompromised patients in protected environments are outside of their rooms for diagnostic procedures and other activities.

• Provide respiratory protection for severely immunocompromised patients when they must leave their protected environment rooms for other procedures.

• Use central or point-of-use HEPA filtration filters for incoming air.

• Ensure that rooms are well sealed.

• The use of laminar airflow rooms may also be used for severely immune compromised patients requiring a protected environment.

• During periods of construction and renovation near protected patient environments, elaborate measures are outlined in the guidelines to assure greater measures to protect patients from dust and particles.

• Nosocomial outbreaks of invasive aspergillosis are a well recognized complication of construction and renovation in or near wards housing high risk hospitalized immune compromised patients.⁷

• Patients being colonized prior to hospital admission.

• Patients with undetected infections.

• Other hospital sources of exposure.
  

Nosocomial Aspergillosis May Be Waterborne
What do we know about Aspergillus as a waterborne species

Figure 4. Aspergillus flavus colony

Aspergillus is a group of molds found everywhere especially in the Northern Hemisphere in the autumn and winter. Molds are also called fillmentous fungi. These filamentous fungi are ubiquitous in nature including being common to water environments. They are also resistant to many water disinfection treatment processes. Failure of water treatment can then provide a pathway for spores and fungi filaments to enter water distribution systems. Once in a water distribution system fungi like Aspergillus can quickly establish themselves at sites of biofilm development.^8,9

Figure 5. Conidia — spores from Aspergillus flavus

Is there evidence that Nosocomial aspergillosis may be waterborne in the hospital environment?
In 2002,  Anaissie et al published a 3-year prospective study¹¹ demonstrating the presence of Aspergillus species from a hospital water system. In this study Anaissie et al sampled the air, environmental surfaces and the water distribution system of a hospital with a history of known cases of aspergillosis to identify possible sources of transmission/infection.

Figure 6. This chart shows the percentage of samples from 416 samples of hospital water sites as well as the municipal water positive for Aspergillus species. Aspergillus species were recovered from 33% of municipal water samples, 55% of samples of water from hospital water storage tanks and 21% of samples of hospital water from patient areas. The frequency of isolation and the mean concentration of Aspergillus were highest in hospital water storage tanks, particularly the cold-water storage tank.¹¹

This study was conducted at a 350-bed teaching hospital with two separate bone marrow transplantation (BMT) units with a total of 43 beds. One BMT unit was located in a new patient care tower that opened in 1998 and the other was located in an older hospital building which opened in 1955. No significant differences were found in the rate of isolation or the concentration of Aspergillus species between water samples from the older building or the newer building.¹¹

Water Sample Source	No of positive/ no of samples (%)	Aspergillus Species	No of samples that yielded species/ no positive samples	Mean concentration cfu/L
Municipal Water	6/18 (33%)	A.niger  A.flavus	5/6 1/6	1.86
Hospital Water Storage Tank — Cold	15/16 (94%)	A.niger A.fumigatus  A.terreus	8/15 8/15	6.43 6/15
Hospital Water Storage Tank — Hot	7/24 (29%)	A.niger A.flavus	6/7 1/7	1.14

Patient Care Areas:	No of positive/ no of samples (%)	Aspergillus Species	No of samples that yielded species/ no positive samples	Mean concentration cfu/L
Cold Water Tap	17/81 (21%)	A.niger  A.fumigatus A.terreus	17/17 1/17	1.44
Hot Water Tap	12/81 (15%)	A.niger  A.fumigatus  A.flavus	10/12 1/12 1/12	3.42
Cold Water  Shower	22/989 (22%)	A.niger  A.fumigatus A.terreus	18/22 2/22  2/22	2.39
Hot Water  Shower	23/98 (23%)	A.niger  A.fumigatus  A.terreus	19/23 1/23  1/23	1.83

The data of Anaissie et al appears to support their hypothesis that the growth of Aspergillus species like the growth of Legionella species may be amplified in hospital water tanks.

Anaissie et al also took indoor and outdoor air samples.  Aspergillus species were recovered from patient rooms, patient bathrooms and hospital hallways. The authors noted that significantly fewer airborne Aspergilli were recovered when the laminar airflow system was activated in 4 patient rooms then when it was turned off indicating according to the authors that the system was functioning properly.  Air samples from HEPA-filtered hospital units had significantly lower mean concentrations of Aspergillus than did samples of outdoor air suggesting that air purity infection control precautions (sealed windows and HEPA filtration) were adequate. However, even though the laminar airflow was activated in patient rooms, more Aspergillus organisms were recovered from the adjoining bathrooms then were recovered in the rooms themselves.¹¹

Figure 7. Concentrations of Aspergillus species were highest in the air in bathrooms than in the air from the patient’s room and the hallway. This data supports the hypothesis of Anaissie et al that there is an increase in the aerosolization of Aspergillus species before and after allowing the hot shower to run 10 to 20 minutes. Anaissie et al suggest that in a hospital with adequate air filtration, Aspergillus organisms can be secondarily airborne from hospital water (grown from propagules aerosolized from the water source) rather than primarily airborne (i.e. grown from unfiltered outside air introduced into the hospital).¹¹

Anaissie et al found that in patient rooms with laminar airflow systems activated the concentration of airborne Aspergillus species was 6-fold higher in the patient’s adjoining bathrooms than in the patient’s rooms. This finding appears to contradict the current thinking that airborne Aspergilli are transmitted from outdoor sources such as human traffic in the hospital hallways. If Aspergillus species were coming from outside the hospital, it would have seemed logical to find a higher concentration in the hallway of Aspergillus species rather then in the patient’s bathrooms.¹¹

Figure 8. The rank-order distributions for Aspergillus species recovered from air and water from the study hospital were similar as shown in the chart above showing the percent of samples that were positive for each Aspergillus species.¹¹

Anaissie et al believed their results to be among the first to suggest the possibility that nosocomial aspergillosis in patients with cancer could be acquired from hospital water. During this 3-year study,  A. fumigatus recovered from a patient with relapsed lymphoma who became ill during a hospitalization proved to be genotypically identical to an isolate recovered from the shower wall in the bathroom adjoining the patient’s room.¹¹

What other evidence is there in the literature for the presence of Aspergillus species in hospital water?

Warris et al (2001)¹² identified filamentous fungi such as Aspergillus species in hospital water in a pediatric bone marrow transplant unit in Oslo, Norway. The results were as follows:

• Water samples were taken from the taps and showers in the pediatric bone marrow transplant units and from the main pipe supplying the pediatric department with water. Water samples were also taken from the intake
  reservoir supplying drinking water to the city of Oslo.
• Filamentous fungi were recovered from 94% of all water samples taken inside the hospital with a mean colony forming unit (cfu) count of 2.7/500mL of water.
• Aspergillus fumigates was recovered from 49% and 5.6% of water samples from the taps and showers, respectively.
• 38.8% of water samples from the main pipe supplying the pediatric department were positive for Aspergillus fumigates.
• At the intake reservoir, 85% of samples were positive for Aspergillus fumigates.¹²

Figure 9. Shows the percent of samples from various sites that were positive for Aspergillus fumigates for a Pediatric BMT unit.¹²

VandenBergh et al (1999) also suggested that water and aerosolized spores could be routes of transmission form Aspergillosis.⁶

Arvanitidou et al (2000) identified a high recovery of fungi such as Aspergillus species from hemodialysis aqueous environments. In 86 hemodialysis centers in Greece, Aspergillus species were among the most frequent species identified. The authors noted that this recovery implied a potential high risk for hemodialysis patients.¹³

While there is certainly more to learn about the potential for hospital water to be another source of Aspergillus species in protected environments in the hospital, consider the evidence currently supporting this hypothesis:

The Case for Waterborne Nosocomial Aspergillosis

• Reports of near drowning accidents in otherwise healthy individuals have demonstrated that opportunistic molds such as Aspergillus species can cause fungal pneumonia with exposure to only a small amount of water (150mL)⁹
• Aspergillus species inhabit hospital water systems worldwide.^9,10
• Waterborne Aspergillus species can aerosolize and their concentration is highest near water activity.^10,11
• The distribution of Aspergillus species in hospital water is identical to that of hospital bioaerosols.¹¹
• Aspergillus has been shown in, at least, one case to be acquired from hospital water.¹¹
• Aspergillus is similar to other waterborne infections
  
  
  • Amplification in reservoirs like Legionella species
  • Established association with biofilms like Legionella species
  • The association between construction and infections with these infectious agents
  • Mode of transmission is similar — aerosolization, ingestion, contact
  • Similarities between aspergillosis and other waterborne fungal infections such as disseminated Fusarium solani infections¹⁰
    
    
• Despite the widespread use of expensive air filtration systems the incidence of aspergillosis is increasing.^1,2,5,6,10
• The epidemiological data supporting Aspergillus transmission as primarily airborne is incomplete.^6,10

There is still far more to learn, for example, how many cases of aspergillosis are truly nosocomial or is the patient admitted with community-acquired aspergillosis? Even the evidence incriminating hospital air as an environmental source is circumstantial, but with the continuing increase in the number of immunocompromised patients and the devastating outcomes of opportunistic aspergillosis — prevention of transmission is of major importance.

Warnock of the CDC cites Anaissie’s work identifying hospital water as a source of exposure, and a basis for prudent action such as cleaning of patient showers prior to use.⁸

Since the latest Guidelines for Environmental Infection Control in Health-Care Facilities provides a Category 1B recommendation* to minimize the exposures of severely immune compromised patients (e.g. solid-organ transplant patients or allogeneic neutropenic patients (in BMT units) to activities that might cause aerosolization of fungal spores such as vacuuming or disruption of ceiling tiles⁷ — shouldn’t point-of-use water sources such as taps and showers be a matter of concern? With the use of HEPA air filtration units likely already in place, the use of point-of-use sterilizing grade filters for taps and showers seems a reasonable next step in added infection control measures to manage aerosolization of Aspergillus species as well as other bacteria such as Pseudomonas species to manage patient exposure.

IN HOSPITALS WITH APPROPRIATE AIR PRECAUTIONS IN PLACE — (HEPA CENTRAL OR POINT-OF-USE FILTERS), TO FURTHER MANAGE THE AEROSOLIZTION OF ASPERGILLUS SPECIES “AS NOTED IN THE CDC’S CLASS 1B RECOMMENDATION”*⁷ — ISN'T THERE NOW A NEED TO ADD HOSPITAL WATER POINT-OF-USE PROTECTION FOR PROTECTED ENVIRONMENTS FOR IMMUNE COMPROMISED PATIENTS?

* Category 1B Recommendations are strongly recommended for implementation and supported by certain experimental, clinical or epidemiologic studies and a strong theoretic rationale.

A Plea for Action

Anaissie et al in their 2002 article in Archives in Internal Medicine estimate that 1400 deaths occur each year in hospitals in the United States as a result of waterborne nosocomial pneumonia caused by Pseudomonas aeruginosa alone. In addition,  Anaissie also cites nosocomial infections linked to the exposure from the hospital water supply to Fungi such as Aspergillus fumigatus and Fusarium solani.¹⁴

Anaissie et al point to biofilm as a haven for these bacteria and fungi in hospital water distribution systems as the primary cause of diminished water quality in the hospital.¹⁴

Available methods to manage the risk of exposure to waterborne pathogens in the hospital include: 

• Restriction of water use
• Prophylactic antibiotic use
• Water treatment and system decontamination
• Alternative water sources — bottled sterile water/bottled water

Now consider adding a new emerging infection control measure:

• Point-of-use sterilizing grade filters

Pall-Aquasafe™ point-of-use sterilizing grade filters meet the standard for providing high quality water — In the Guidelines for Environmental Infection Control in Health Care Facilities, the recommendations of the CDC and the Healthcare Infection Control Practices Advisory Committee define high quality water for the use of rinsing disinfected endoscopes and bronchoscopes — …use water of the highest quality practical for the system’s engineering and design (e.g., sterile water or bacteriologically filtered water [water filtered through 0.1 or 0.2 µm filter]. Category 1B recommendation….”⁷

Point-of-use sterilizing grade filters for taps and showers have already been reported in use to effectively manage the potential of exposure from point-of-use water to Pseudomonas aeruginosa and Legionella species in a hematology oncology unit,¹⁵ a bone marrow transplant unit,¹⁶ a pediatric nephrology unit¹⁷ as well as having been extensively used in a large French hospital.¹⁸

MANAGE THE RISK OF WATERBORNE NOSOCOMIAL INFECTIONS AT THE POINT-OF-USE IN THE HOSPITAL WITH STERILIZING GRADE POINT-OF-USE PALL-AQUASAFE^TM WATER FILTERS.

• Disposable 0.2µm sterilizing grade filter for 7-day use
• Reduces waterborne microbial particulate contaminates
• Easy to use for large and small volumes of point-of-use water

References

1. Wingard JR, Leather H, A New Era of Antifungal Therapy, Biology of Blood and Marrow Transplantation 10:73-90, 2004.
   
2. Patterson, T, Recent Advances in the Management of Invasive Aspergillosis, International Symposium on Antimicrobial agents and Resistance, Seoul, Korea, 2003, http://www.ansorp.org/, ISAAR 2003.
   
3. Wingard JR, Leather H, Diagnosis and Therapy of Invasive Aspergillosis in Hematopoietic Stem Cell Transplant Recipients, Current Treatment Options in Infectious Diseases 5:517-527, 2003.
   
4. Hajjeh RA, Warnock DW, Counterpoint: Invasive Aspergillosis and the Environment — Rethinking our Approach to Prevention, Clin Infect Dis 33;1549-1552,2001.
   
5. Marr KA, Carter RA, Cripps F, Epidemiology and outcome of mold infections in hematopoietic stem cell transplant recipients, Clin Infect Dis 34:904-917, 2002
   
6. VandenBergh MFQ, Verweij PE,Voss A, Epidemiology of Nosocomial Fungal Infections: Invasive Aspergillosis and the Environment.
   
7. Schulster L, Chinn RYW, Guidelines for Environmental Infection Control in Health-Care Facilities, Recommendations of CDC and the Healthcare Infection Control Practices Advisory committee (HICPAC), Morbidity and Mortality Weekly Report, 52:1-44, 2003.
   
8. Warnock DW, Preventing Fungal Infections: In Hospital and Beyond, from: Infections in Patients with Hematologic Malignancies: Meeting the Challenge. CME Program, http://www.medscape.com/.
   
9. Geldreich EE, Biological profiles in drinking water, In: Microbial quality of water supply in distribution systems, Boca Raton, Florida: CRC Lewis, 103-158,1996.
   
10. Anaissie EJ, Costa SF, Nosocomial Aspergillosis is Waterborne, Clin Infect Dis 33: 1546-1548, 2001.
    
11. Anaissie EJ, Stratton SL,Dignani C, Summerbell RC, Rex JH, Monson TP, Spencer T, Kasai M,Francesconi A, Walsh TJ, Pathogenic Aspergillus Species Recovered from a Hospital Water System: A 3-year Prospective Study, Clini Infect Dis 34: 780-789, 2002.
    
12. Warris A, Gaustad P, Meis JFGM, Verwdij PE, Abrahamsen TG, Recovery of filamentous funi from water in a pediatric bone marrow transplantation unit, Journal of Hospital Infection 44:143-1448, 2001.
    
13. Arvanitidou M, Spaia S, Velegraki A, Pazarloglou M, Kanetidis D, Pangdis P, Askepidis N, Katsinas Ch, Vayonas G, Katsouyannopoulos V, High level of recovery of fungi from water and dialysate in hemodialysis units, Journal of Hospital Infection 45:225-230, 2000.
    
14. Anaissie EJ, Penzak SR, Dignani C, The hospital water supply as a source of nosocomial infections: a plea for action, Arch Intern Med 62:1483-1492, 2002.
    
15. Engelhart S, Krizek L, Glasmacher A, Fischnaller E., Marklein G, Exner M, Pseudomonas aeruginosa outbreak in a hematology-oncology unit associated with contaminated surface cleaning equipment, Journal of Hospital Infection 52: 93-98, 2002.
    
16. Campins M, Ferrer A, Callis L, Pelaz C, Cortes PJ, Pinart N, Vaque J, Nosocomial Legionnaire’s Disease in a children’s hospital, Ped Infect Disease J 19:223-224, 2000.
    
17. Eshuis F, Potzsch K, Aerts E, Colombo C, Positive water samples for Legionella Pneumophilia in a bone marrow transplant ward, University Hospital, Switzerland, Bone Marrow Transplantation 31, Supplement 1 p993,s300, 2003.
    
18. International Workshop on Legionella, Paris, France, 2003.