Download Clinical risk factors for invasive aspergillosis

Medical Mycology April 2011, 49(Suppl. 1), S7–S12
Original Article
Clinical risk factors for invasive aspergillosis
JOHN W. BADDLEY
University of Alabama at Birmingham, and Birmingham Veterans Affairs Medical Center, Birmingham, Alabama, USA
Keywords Aspergillus, clinical risk factors, invasive aspergillosis
Introduction
Invasive aspergillosis (IA) is an important cause of morbidity and mortality in immunocompromised patients. Despite
improvements in the antifungal armamentarium and in
diagnostic modalities, mortality remains unacceptably high
[1,2]. There is much interest in development of prevention
measures, and identification of clinical risk factors will
play a key role in focusing prevention efforts.
There are many risk factors for IA, which can be related
to underlying disease of the host (malignancy, transplant
type, age); co-morbidities (graft-versus-host disease, diabetes, cytomegalovirus infection, renal or liver dysfunction, COPD, post-surgery); medications (steroids, TNF-α
inhibitors, chemotherapy); environment or nosocomial risk
factors (air filtration, water, hospital construction), and
those that deal with the host/pathogen interactions [3–
12]. Risk factors for IA have been studied extensively in
patients with hematologic malignancy and transplants;
however, clinical risk factors are less well defined for nontraditional patient groups. Several emerging groups at risk
for IA include intensive care unit (ICU) patients; patients
with chronic obstructive pulmonary disease (COPD);
post-operative patients; HIV patients and patients on newer
Received 22 March 2010; Accepted 28 June 2010
Correspondence: John W. Baddley, MSPH, University of Alabama
at Birmingham, Department of Medicine, Division of Infectious Diseases, 1900 University Boulevard, 229 Tinsley Harrison
Tower, Birmingham, AL 35294-0006, USA. Tel: 1 205 934 5191;
fax: 1 205 934 5155; E-mail: [email protected]
© 2011 ISHAM
immunosuppressive therapies (TNF-α inhibitors) [13–20].
Studies to identify clinical risk factors for IA are often
difficult for several reasons: First, studies may be limited
by small numbers of patients because of the low incidence
of IA in some patient groups. Second, there are important
methodologic issues, specifically regarding the impact of
risk factors over time, and defining the period at risk. Finally,
because of diagnostic limitations in non-traditional hosts,
it is difficult to understand the true impact of IA in some
groups. Herein, clinical risk factors for IA are reviewed, with
a focus on emerging patient populations at risk for IA.
Hematopoietic stem cell transplant
(HSCT) recipients
Because of the poor outcomes associated with invasive
fungal infections in HSCT patients there has been much
interest in prevention and treatment measures in hopes of
improving survival. Identification of clinical risk factors
for IA has been well studied in HSCT recipients, and
important risk factors include prolonged neutropenia, corticosteroid use (dose and duration), underlying diseases
and transplant-related variables (Table 1) [6,11,12,21–23].
In addition, the environment as a risk factor, including concentration of Aspergillus spore counts in air samples, and
impact of hospital construction on nosocomial IA, has
become important [9]. Recently, clinical risk factors for IA
and other invasive fungal infections have been associated
with timing of IA in relation to transplant (early, 40 days;
or late, 40–80 or 100 days) [21,23–25]. For example, risk
DOI: 10.3109/13693786.2010.505204
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Despite improvements in the antifungal armamentarium and diagnostic modalities,
invasive aspergillosis (IA) remains an important cause of morbidity and mortality in
immunocompromised patients. There is an emergence of non-traditional groups at risk
for IA, including intensive care unit (ICU) patients, post-operative patients, those with
chronic pulmonary diseases, patients with AIDS and patients on immunomodulating
drugs (TNF-α inhibitors). Identification of clinical risk factors for IA may help in determining which patients require risk modification and other prevention measures.
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Baddley
Solid organ transplant recipients
Invasive aspergillosis in solid organ transplant patients
continues to be a major cause of morbidity and mortality.
Incidence of IA ranges from 2–40% and is dependent on
the organ transplanted [29–32]. The most important risk
factors for IA, common to all SOT patients, are the net state
of immunosuppression and intensity of the immunosuppressive regimen, which may be affected by corticosteroid
dose, treatment for rejection and immunomodulatory
viruses such as CMV [31–33]. There are many other organspecific clinical risk factors for IA, as described in Table 2;
however, because of the rarity of IA in some transplant
Table 1 Clinical risk factors for invasive aspergillosis in HSCT patients.
Older age [7,23]
Underlying disease (aplastic anemia, myelodysplastic syndrome,
multiple myeloma) [7,21,22]
Donor type and source (unrelated or HLA-mismatched peripheral blood
stem cells; allogeneic vs. autologous transplants) [7,21,22,24]
Transplantation with T-cell depleted or CD34-selected products [21]
Corticosteroid dose and duration [10,21,23–26]
Conditioning regimen [23]
Graft-versus-host disease presence and treatment [21,26,27]
Neutropenia (pre- and post-engraftment) [21,23]
Lymphopenia [23,25]
Cytomegalovirus disease [23,25–27]
Iron overload, elevated ferritin [11,12,25]
Previous invasive aspergillosis
Lower respiratory tract infections caused by respiratory viruses [10,25]
Antifungal prophylaxis (posaconazole) [6,22]
Environmental factors (hospital construction) [6,9]
Table 2
Clinical risk factors for invasive aspergillosis in SOT patients.
Lung [31–33,35]
Single lung transplant
Rejection, development of bronchiolitis obliterans
Reperfusion injury
Aspergillus colonization (pre-transplant or within one year post-transplant)
Ischemia at the anastamotic site
Acquired hypogammaglobulinemia (IgG <400 mg/dl)
Presence of bronchial stents
Cytomegalovirus disease
Liver [29,31–34]
Primary allograft failure or severe dysfunction
Pretransplant hepatic failure
Re-transplantation
Renal insufficiency or hemodialysis
High transfusion requirement
Heart [32,33,36]
Cytomegalovirus disease
Aspergillus respiratory colonization
Reoperation
Posttransplant hemodialysis
Kidney [32,33]
Graft failure requiring hemodialysis
Prolonged, high-dose corticosteroids
populations, studies evaluating clinical risk factors are
uncommon [30–36].
A recent case-control study by Gavalda and colleagues,
as part of the Spanish Network for Research on Infection
in Transplantation, highlighted some important clinical
risk factors for IA and the relationship of period of IA risk
post-transplantation [37]. Controls included the two
patients who underwent the same type of transplant before
and after the enrolled IA case, provided a minimum of
18-month follow-up was documented. Overall, 156 cases
of proven or probable IA were diagnosed; 80 (51.3%) in
liver recipients, 47(30.1%) in heart recipients, 17(10.9%)
in lung recipients, 10(6.4%) in kidney recipients, and
2(1.3%) in pancreas-kidney recipients. Independent risk
factors for early IA (3 months after transplantation)
included use of vascular amines, additional ICU stay, posttransplantation renal failure or hemodialysis, CMV disease
or 1 episode of bacterial infection. In contrast, older age,
renal failure, immunosuppressive agents, CMV disease,
1 bacterial infection, chronic graft rejection and immunosuppressive-related neoplasm were independent risk
factors for late IA (3 months after transplantation) [37]
Additional data on clinical risk factors for IA in solid organ
transplant recipients, especially renal or heart transplant
patients, is needed.
Intensive care unit patients
There has been increasing interest in the emergence of IA
among critically ill patients, especially those admitted to
the ICU [4,13,38,39]. Although IA incidence in the ICU
© 2011 ISHAM, Medical Mycology, 49(Suppl. 1), S7–S12
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factors for late IA include GVHD and its treatment (corticosteroid therapy), lymphopenia and viral infection [21].
In contrast, early-onset IA is associated with neutropenia,
host (underlying malignancy) or transplant (stem cell
source) variables. This aspect of risk period post-transplant
has important implications for prevention efforts.
Viral lower respiratory tract infections have been an
important problem in HSCT patients and increase the risk
of IA [25–27]. This was confirmed recently by Martino and
colleagues, who evaluated risk factors for IA among reducedintensity allogeneic HSCT patients [27]. Among 219 patients,
27 (12.3%) developed proven or probable IA, as defined by
standard criteria [28]. Independent risk factors for IA were
steroid therapy for moderate-to-severe GVHD, CMV disease
and lower respiratory tract infection caused by respiratory
viruses. The most common viruses causing lower respiratory
tract infection in patients with subsequent IA were influenza
A or B, parainfluenza, adenovirus, and metapneumovirus. It
is important to reinforce the role that respiratory viruses may
play in development of IA, especially with the emergence of
novel H1N1 infection and other viruses.
Clinical risk factors for IA
Post-operative invasive aspergillosis
Post-operative IA is an uncommon and underestimated
complication of surgery [17,18]. This entity is rare, but
approximately 500 cases have been reported to date
[17]. Jensen and colleagues estimated an incidence of 2
cases/10,000 surgical procedures [18]. Infection may arise
after colonization of surgical sites from airborne Aspergillus spores, and the onset of disease is variable, ranging
from days to months after the surgical procedure [17,18].
Because of the rarity of post-operative IA, it has been difficult to determine clinical risk factors. As noted in recent
studies, post-operative IA usually occurs among patients
without classic predisposing conditions for aspergillosis;
however, in some cases, the disease has affected SOT
patients and others receiving corticosteroids [17,18]. Highrisk procedures appear to be cardiothoracic surgery, vascular surgery, and ophthamologic or dental surgery. Although
the presumed primary source of infection is colonization
of surgical sites from airborne Aspergillus spores, it is
unclear if elevated Aspergillus spore levels in operating
rooms is a risk factor [18,41].
Patients with COPD
Among immunocompetent patients there have been increasing descriptions of the importance of COPD as a risk factor
or an underlying co-morbidity in patients with IA [4,14,15,
42–44]. From these studies, mostly case reports, single-center
© 2011 ISHAM, Medical Mycology, 49(Suppl. 1), S7–S12
case series, or reviews of published cases, it is estimated that
up to 10% of cases of IA occur in patients with COPD, and
that up to 5% of patients with COPD have IA. Moreover, the
risk may have increased over the past decade [13,15,45]. An
important limitation in identifying IA in COPD patients is
related to the criteria used for diagnosis. Clinical manifestations are often non-specific, and diagnostic criteria have been
adapted from standardized guidelines developed for immunocompromised patients [46]. Bulpa and colleagues have
developed COPD-specific diagnostic criteria, but these
require further validation [14]. Although the true incidence
of IA among COPD patients is unknown, a recent singlecenter study documented a rate of 3.6 cases per 1000 COPD
admissions, and determined that COPD was the most common predisposing condition for the development of IA at the
hospital, representing 53% of all IA episodes [15]. This study
screened COPD patients for IA only if respiratory tract cultures were positive for Aspergillus, perhaps missing cases
with IA who did not have positive cultures, and likely underestimating the true rate of IA in the COPD population.
There are few well-controlled studies detailing clinical
risk factors for IA among patients with underlying COPD
[3,4,15]. Rello and colleagues reported a summary of eight
cases and a review of the literature and noted that corticosteroid treatment, usually at daily oral doses of 20 mg of
prednisone, and previous antibiotic use were common among
IA patients [3]. In several other review articles, late-stage
COPD, prolonged steroids, viral infection, and inhaled steroids are suggested as possible risk factors; however, these
findings were derived from anecdotal case reports and not
controlled studies [45,47,48]. Guinea and colleagues, describing a large retrospective cohort of patients from a single institution, determined four independent risk factors for probable
IA among patients with COPD: admission to the ICU (OR
2.4, 95% CI 1.19–5.29); previous antibiotic treatment (OR
2.57, 95% CI 1.2–5.49); and cumulative steroid dose in past
3 months prior to admission (OR 2.98, 95% CI 1.26–7.06)
or from admission to diagnosis (OR 2.02, 95% CI 1.2–5.49)
[15]. Clearly, there is a great need to identify risk factors for
IA among patients with underlying COPD, and larger, adequately powered multi-center studies will be necessary.
HIV-infected patients
Invasive aspergillosis is a relatively uncommon infection in
patients with acquired immune deficiency syndrome (AIDS),
with an incidence rate of 3.5 cases per 1000 person-years
[19]. A recent study using 2003 National Inpatient Sample
(NIS) administrative data reported that HIV infection was
an underlying condition in 3.7% of total aspergillosis cases,
with an incidence of 0.43% [49]. Fortunately, it does not
appear that the incidence if IA in HIV-infected patients is
increasing. In fact, as the population of AIDS patients with
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has been reported to be as high as 7%, the true incidence
is difficult to determine because of several important limitations of IA diagnosis in ICU patients [13]. For example,
classic radiographic signs of IA (‘halo’ or ‘air crescent’)
seen in neutropenic patients are not routinely present in
ICU patients, determination of colonization vs. infection is
problematic and diagnostic studies are less sensitive and
have not been validated adequately in non-neutropenic
patient populations [13]. Recently, Meersseman and colleagues, in a single-center study, investigated the use of
bronchoalveolar lavage fluid (BAL) galactomannan testing
as a diagnostic modality for ICU patients [40]. Among 110
patients eligible, 29 had proven IA [28]. BAL testing proved
to be useful in this population, with sensitivity of 88% and
87%, respectively. Moreover, the sensitivity of serum galactomannan was only 42%. As diagnostic methods for IA
improve and additional immunosuppressive agents are
developed, an increased incidence of IA in ICU patients
should be expected. Important non-traditional ICU patients
at risk for IA include those with cirrhosis, COPD, solidorgan malignancy, HIV infection, malnutrition, and postsurgical patients and those on immunosuppressive therapies.
Several of these groups will be discussed below.
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Patients receiving newer
immunosuppressive agents
The number of patients receiving immunosuppressive agents
has increased over the past decade and is expected to increase
substantially in the near future. Newer biologic medicines,
including the tumor necrosis factor (TNF)-α inhibitors
infliximab, adalimumab, etanercept, certolizumab and golimumab, have been approved for the treatment of one or
more of a number of diseases including rheumatoid arthritis,
psoriatic arthritis, plaque psoriasis, Crohn’s disease, juvenile idiopathic arthritis and ankylosing spondylitis. Moreover, immunosuppressive agents such as abatacept, anakinra
and rituximab are used increasingly. TNF-α plays an important role in regulation of the immune response, and use of
TNF-α inhibitors is associated with an increased incidence
of serious infections caused by a broad spectrum of pathogens, including viral, bacterial, mycobacterial, fungal, and
protozoal organisms [20,54,55]. There have been numerous
case reports describing IA among patients receiving TNF-α
inhibitors, recently summarized by Tsiodras and colleagues
[20,56,57]. The authors reviewed published reports from
January 1966 through 1 June 2007 to determine the association of fungal infections with TNF-α blockade. The
authors identified 64 cases of proven or probable aspergillosis, mostly pulmonary disease in HSCT patients. The most
common TNF-α inhibitor was infliximab, used in 75% of
cases. Among cases with data available, overall mortality
was 82%. Currently, data regarding impact of these agents
on risk of IA are limited; however, vigilance in the care of
these patients is warranted while studies are ongoing.
Conclusions and future perspectives
There has been much improvement in the care of patients
with IA in the past decade. In concert with improved
antifungal therapy, newer diagnostic modalities are decreasing the time to diagnosis, and improving the sensitivity of
diagnosis of IA. We have benefitted from recent research
into clinical risk factors for IA, especially the importance
of a well-defined risk period among transplant patients. An
enormous future challenge will be identification of precise
clinical risk factors in non-traditional patient populations,
including patients in the ICU setting, those with COPD or
HIV-infection and those receiving newer immunosuppressive therapies. Because of the rarity of IA in some of these
non-traditional host groups, large, observational studies or
case-control studies may be required to elucidate clinical
risk factors and will help to focus prevention efforts.
Declaration of interest: Dr Baddley has received grant
support from Pfizer, Inc. He has served in an advisory/
consulting role for Pfizer, Inc. and Enzon Pharmaceuticals.
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This paper was first published online on Early Online on 20 August
2010.
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© 2011 ISHAM, Medical Mycology, 49(Suppl. 1), S7–S12