Title : An overview of changing trends in systemic fungal infections.
Rajdeep Das1*, Ramesh Ranganathan2
1. Dept. Of Clinical Pathology, Gulf Medical University, United Arab Emirates
2. Dept. Of Microbiology, Gulf Medical University, United Arab Emirates
*Corresponding Author: Dr. Rajdeep Das
Email Id : rajdeep.ngg@gmail.com
Contact Number: 00971-503724815
1
Abstract:
Background:
Invasive mycoses are a significant and growing public health problem. The increasing use of
invasive monitoring and aggressive therapeutic technologies in intensive care units has resulted
in improved survival of individuals with life-threatening illnesses, but has also contributed to an
increase in number of persons at risk for fungal infections. This review discusses the changing
patterns in the risk factors, epidemiology; the impact of changes in medical practice on the
incidence of systemic fungal infection and the emergence of antifungal resistance.
Materials and Methods:
Relevant English-language articles were identified through search on four databases [PubMed,
ProQuest, Medline and Embase (all, 2005-2011)] conducted in June 2011 using keywords
“systemic fungal infection”, “aspergillosis”, “candidosis” and “antifungal”. Original research and
review articles related to patients with systemic fungal infection were considered for the review.
Result:
Despite marked reduction in the rates of invasive fungal infections, in developed countries, the
burden is increasing largely in developing countries. Infections with Candida albicans may be
decreasing in frequency, the number of persons at risk for them continues to grow. Prolong and
deep neutropenia and treatments neutralizing macrophage inflammatory cytokines have
increased the likelihood of opportunistic infections. Extensive use of fluconazole in neutropenic
patients has resulted in marked decrease in the incidence of invasive candidosis but it has
resulted into a shift from highly susceptible to less susceptible Candida spp
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Conclusion:
Continued research is required to meet the challenges associated with changes in epidemiology
and resistance development.
Introduction
Emerging and re-emerging infectious diseases have shaped the landscape of medicine for the
past three decades. Invasive fungal infections are a significant cause of morbidity and mortality
in severely immunocompromised patients including those with human immunodeficiency virus
(HIV) infection, hematologic malignancies, recipients of immunosuppressive therapies and
solid-organ or hematopoietic stem cell transplantation (HSCT), burns or indwelling medical
devices and low-birth-weight infants. These infections are being seen in increasing numbers and
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gained a much greater importance, largely because of the increasing size of the population at
risk. In addition, advances in medical care are extending the survival of critically ill patients,
rendering them more vulnerable to invasive fungal infections.
Prolonged prophylaxis or treatment with antifungal agents has reduced the incidence of a number
of invasive fungal infections. Unfortunately, such strategies in some situations have
iatrogenically driven the emergence of new fungal pathogens.
Although Aspergillus and Candida species remain the most common pathogens, the spectrum of
invasive mycoses is changing with emergence of other opportunistic fungal pathogens such as
Fusarium, Zygomycetes and Scedosporium [1-3]. These invasive infections which are potentially
life-threatening along with mold (aspergillosis) tend to be particularly serious [4,5].
Therapy for serious Candida infections has been difficult because of the limited number of
available antifungal agents. Amphotericin B since its discovery has been the cornerstone of
antifungal therapy due to its broad activity against a wide range of fungi including Aspergillus
and Candida species. However, due to its lack of selective activity against fungal cell
membranes, conventional amphotericin B (C-AMB) is toxic [6]; significantly limiting its
therapeutic utility.
The objective of this review is to discuss the changing patterns in the risk factors, epidemiology,
changes in medical practice on the incidence of systemic fungal infection and the emergence of
antifungal resistance.
Materials and Methods:
In the review relevant English-language articles were identified through searches on three
databases [PubMed, Medline and Embase (all, 2000-2010)] conducted in September 2010 using
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the keywords using the keywords “antifungals”, “aspergillosis”, “candidosis”. Original research
and review articles related to patients with fungal infection were considered for the review.
Search strategy and selection criteria of the comprehensive literature review:
First, a literature search with special emphasis on research findings published over the five years
(2005 to 2011) years on Diabetes Mellitus was carried out using PubMed, Medline and Embase
databases. PubMed and Medline contains citations published mostly from 2005-2008, whereas
Embase database dates from 2008 to 2011. The following keywords were employed to search the
above mentioned databases : “antifungals”, “aspergillosis” and “candidosis”
Second, this search was complemented with an iterative proceeding in which we consistently
reviewed reference lists of all those publications that were of relevance to address our main
objective. The bibliographies of all these recovered manuscripts were retrieved again and the
searching strategies repeated until no new information was forthcoming.
Third, we also performed search of the websites of the following organizations: National
Institutes of Health (NIH) and Centers for Disease Control and Prevention (CDC).
Fourth, dissertation abstracts were reviewed. They were searched in following databases
(assessed on 04.07.2011 and 10.07.2011):
-
www. google. com
-
ProQuest Digital Dissertation
The same keywords as described before for the peer-reviewed literature search were used for this
search.
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 A flow chart of search strategy and selection criteria of the comprehensive literature
review in given below in annexure 1
Annexure 1:
SEARCH ENGINE
PubMed
Medline
Embase
6
Original studies and review articles related to systemic and invasive fungal infection
published from 2005 to 2011
All articles concerned with
keywords systemic fungal
infection, antifungals,
aspergillosis, candidosis
(2000-2011)
All articles concerned with
keywords systemic fungal
infection, antifungals,
aspergillosis, candidosis
(2000-2011)
All articles concerned with
keywords systemic fungal
infection, antifungals,
aspergillosis, candidosis
(2000-2011)
Data tabulation
Analysis
Report preparation
Dissemination of result
Emerging population at risk for fungal infections:
The changing trend in the incidence of Aspergillus infection further illustrates that additional
patient groups may be at risk for fungal infection that have not otherwise been categorized as
having significant immune suppression by traditional criteria. Traditionally risk factors for
invasive Aspergillus included significant neutropenia (<500 neutrophils/microlitre for >10 d),
hematological malignancies, and bone marrow transplantation [7-9]. Although these individuals do
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represent the patient subset with the greatest risks of invasive Aspergillus, newer groups of
patients in the intensive care unit (ICU) setting have been revealed to have intermediate or lower
level of risk for this serious complication of immune suppression. The intermediate risk category
include individuals with prolonged treatment with corticosteroids (.4 wk) before admission to the
ICU; autologous bone marrow transplantation; chronic obstructive pulmonary disease,
particularly if receiving systemic corticosteroids; liver cirrhosis with prolonged ICU stays; solid
organ malignancy; advanced HIV/AIDS; lung transplantation; and individuals with systemic
inflammatory diseases requiring immunosuppressive therapy, including prolonged corticosteroid
therapies, chemotherapy, and newer immune suppressive agents
[7-9]
. The individuals at lower
risk consist of severely burned or malnourished patients, individuals with other solid organ
transplantation, those with prolonged stays in the ICU (>21 days), those receiving systemic
corticosteroids for more than 7 days, and postcardiac surgical patients. Not only that reports
indicate that patients in renal failure requiring renal replacement therapy and individuals with
diabetes mellitus may also have risk for this serious complication [7-9].
Epidemiology:
In the recent years, many sentinel surveillance systems has been established, particularly for
Candida blood stream infection (BSI). Although these programs have provided extremely
valuable data but they may not be regarded as representative of general population as populationbased surveillance systems. Nevertheless, the sentinel systems have the advantage of simple
8
study design and methodology and less labour-intensive than population-based systems and, as
such, can provide rapid reporting of results
[10]
. In the Mycotic Diseases Brach of CDC, efforts
have focused on conducting active population-based surveillance for a range of invasive fungal
infections [11, 12].
Candidiasis
In the United States Candida species are ranked as the fourth most common cause of hospital –
acquired BSI
[13, 14]
, with an incidence of 1.5 cases per 10,000 patient days or 8 infections per
10,000 hospital discharges [11]. In comparable European studies, the incidence is slightly lower,
at 0.5-0.7 cases per 10,000 patient days or 2-5 infections per 10,000 discharges from the hospital
[15-18]
. To date, the highest reported incidence of healthcare associated candidemia (3.7 cases per
10,000 patient days) has come from an eleven center sentinel surveillance program in Brazil
[10]. The reasons for this high rate of infection are not clear, a number of factors could be
involved, including limited resources available for medical care and training programs,
difficulties in the implementation of infection control in hospitals of developing countries,
limited numbers of health-care workers to assist patients in critical care units, and less aggressive
practices for antifungal treatment of high risk patients.
Although the rates of Candida BSI were documented to be increasing among critical care
patients in the United States during the 1980s , a more recent review of data from more than 300
hospitals participating in U.S NNIS system, showed that the incidence rate of Candida BSI in
this patient group decreased between 1989 and 1999
[19]
. This decline was mostly due to a
reduction in the rate of Candida albicans infections, from 8 cases per 10,000 catheter days in
1989 to 2 cases per 10,000 catheter days in 1999. The rate of Candida glabrata infections,
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however, increased significantly (from 0.2 to 0.5 cases per 10,000 catheter days), while those of
other Candida species remained stable. Data from U.S. NCHS suggest that the number of
patients discharged from hospital with fungal sepsis has tripled over the last decade, with
Candida BSI being the most frequent cause [20].
More than 200 species of Candida have been described, but only a few have been implicated in
human disease. More than 95% of all Candida BSI worldwide are caused by five species: C.
albicans, C. glabrata, C. parapsilosis, C. tropicalis and C. krusei [10, 11, 17, 21]. The remaining
infections are caused by a number of other Candida species, including C. dubliniensis, C. famata,
C. guilliermondii, C. lusitaniae, C. norvegensis, C. pelliculosa and C. rugosa
[10, 11, 21, 22]
.
Although these species are uncommon causes of candidiasis, several have been observed to
occur in nosocomial clusters, or demonstrate innate or acquired resistance to one or more
antifungal agents [23, 24].
In the early 1990s, extensive use of fluconazole to treat HIV- infected persons with recurrent
oropharyngeal candidiasis resulted in selection of Candida species gradually less susceptible to
azoles, and in the emergence of azole-drug-resistant strains in these patients due to acquisition of
resistance by previously susceptible strains of C. albicans [25].
Candida glabrata has become the second most common cause of Candida BSI, accounting for
20-24% of cases in some recent reports [11,25, 26]. One of the studies has demonstrated that among
Candida species C. glabrata alone increased as a cause of BSI among U.S. critical care patients
between 1989- 1999
[19]
. However, for reasons which are not well understood, C. glabrata
remains an infrequent cause of Candida BSI in Latin America where C. tropicalis and C.
parapsilosis are the most frequent etiologic agents followed by C. albicans
[10]
. C. glabrata BSI
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are rare among infants and children, but increases significantly in incidence with increasing age
[27]
. The emergence of C. glabrata as an important cause of Candida BSI is of concern because of
reports that 5-10% of incident bloodstream isolates of this species are resistant to fluconazole
21, 27, 28]
[11,
. Although increasing fluconazole usage might have contributed to the emergence of C.
glabrata, it is likely that other host and healthcare factors have also had an effect on this trend [29].
Aspergillosis
Among HSCT recipients and high risk groups of solid organ transplant (SOT) recipients invasive
aspergillosis has emerged as a leading cause of infection-related mortality. Assessing the
incidence of invasive aspergillosis in these groups is difficult for a number of reasons. The lack
of a consistent case definition and the absence of effective surveillance mechanism make it
difficult to compare the incidence rates reported in different studies. This problem is not only
confined to aspergillosis but also applies to other invasive mould infections as well.
There is a widespread perception that there has been a marked increase in the prevalence of
aspergillosis over the past several decades. Although this belief may be incorrect, the evidence
most frequently cited in its support has been derived from longitudinal studies conducted among
HSCT recipients in one U.S. hospital and may not be representative of the situation in other
patient groups, institutions or countries [30].
In an interim analysis of TransNet data, the incidence of invasive aspergillosis was estimated
among 4621 HSCT and 4110 SOT recipients at 19 hospitals dispersed throughout U.S. during a
22 month period in 2001 and 2002 [31]. The aggregate cumulative incidence of aspergillosis at 12
months was 0.5% after autologous HSCT, 2.3% after allogenic HSCT from an HLA-matched
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related donor, 3.2% after transplantation from an HLA-mismatched related donor, and 3.9% after
transplantation from an unrelated donor. The outcome at 3 months following the diagnosis of
aspergillus infection was dismal, with mortality rates that ranged from 53.8% among autologous
transplants to 84.6% among unrelated-donor transplants
[31]
. It suggested that the burden of risk
for aspergillosis has shifted from the neutropenic pre-engraftment phase of allogenic HSCT to
the later post-engraftment phase where the immunosuppression of graft-versus-host disease is
predominant and T-cell function is still diminished.
Aspergillus fumigatus remains the most frequent cause of invasive aspergillosis. However, it
only accounted for 56% of isolates recovered from cases in the recent interim analysis of the
TransNet surveillance program[31]. The other species of aspergillus associated with infections
after HSCT included A. flavus (19%) and A. terreus (16%) [31].
Crypotcoccosis
An uncommon infection before the HIV epidemic, cryptococcosis emerged as an important
cause of morbidity and mortality among persons living with AIDS throughout the developed and
developing world. At the present time, sub-Saharan Africa carries the greatest burden of the
global AIDS epidemic, with almost 64% of the world’s HIV-infected population, around 24.5
million individuals residing there [32]. Among HIV-infected persons, the rate was 95 per 100,000
and among persons living with AIDS, 14 per 1000 [33].
Zygomycosis
Zygomycosis is less common than other opportunistic invasive fungal infections. Over the past
decades, however, zygomycosis has emerged as an increasingly important infection, particularly
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among HSCT recipients and patients with haematological malignancies
[34,35,36]
. In addition to
causing disease in these severely immunocompromised individuals, zygomycosis can also cause
lethal infections in a broader population, including patients with diabetes mellitus, patients
receiving deferoxamine treatment, injection drug users and person with no apparent
immunological impairment
[35]
. Voriconazole, a second generation triazole agent, which is the
treatment of choice for invasive aspergillosis as well as antifungal prophylaxis in
immunocompromised patients is inactive against the etiologic agents of zygomycosis
[37]
. Other
emerging moulds are Fusarium spp. and Scedosporium spp (hyalohyphomycoses), which are
also gaining importance due to capability of these organisms to cause wide variety of infections
specially in immunocompromised patients, particularly HSCT and SOT recipients [35].
Changes in medical practice and its impact:
Normally, anatomical barriers are the first line of defence. The skin and mucosal surfaces stop
microorganisms entering the body and are themselves protected by acid pH, enzymes, mucus and
other antimicrobial secretions. Changes in medical procedures have contributed to the increased
incidence of fungal infections
[ 38, 39]
. These barriers are broken down during surgery and when
indwelling catheters are used and number of invasive procedures has increased in recent years.
Moreover, burns, chemotherapy, radiotherapy and graft-versus-host disease can damage the skin
or cause mucosal lesions thereby allowing fungal agents to reach the tissues and blood.
This scenario is different in case of healthy individuals as they are further protected by immune
system. Many diseases cause immunodeficiency, the most notorious being AIDS or certain
medications can cause immunosuppression. This can be deliberate with the use of
immunosuppressive drugs, e.g: corticosteroids, cyclosporine etc.
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Conclusion:
It is apparent that invasive fungal infections toll has increased tremendously in terms of human
life and healthcare costs, despite the fact that these diseases are still under-diagnosed and underreported. Establishing and maintaining surveillance programs for a range of fungal diseases, both
on a national basis and within individual medical centres will be essential if we are to determine
the true magnitude of the burden posed by these infections and to prioritize research and
prevention efforts.
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