Antimicrobial Agents

ELSEVIER International Journal of Antimicrobial Agents 6 (1996) 135-140

Current clinical issues on mycoses in neutropenic patients

FranGoise Meunier*

Ave E. Mounier 83111. B-1200 Brussels, Belgium

Accepted 13 November 1995

Abstract Invasive fungal infections, which are associated with high morbidity and mortality rates, are an increasing challenge for the

management of immunocompromised hosts, particularly neutropenic cancer patients. Due to the ageing population, recent progress in cancer therapy and better prognosis of bacterial infections, the numbers of patients at risk of life-threatening mycoses are increasing. The percentage of cancer patients with evidence of an invasive fungal infection ranges from approximately 5% to 30%. The most common opportunistic fungal pathogens are Candida spp. and Aspergillus spp. but recently unusual pathogens including Fusarium, Trichosporon and many others have been increasingly reported. Although some progress has been made in the last decade, several controversial issues need to be addressed by clinicians as well as by medical microbiologists and mycologists involved in the care of patients experiencing fungal infections. A comprehensive clinical strategy, such as that initiated under the auspices of EORTC is a meaningful approach to ensure high quality clinical research in that field in order to define guidelines for more effective diagnosis, prevention and treatment approaches of invasive fungal infections in cancer patients at the European level.

Keywords: Mycoses; Neutropenia; Clinical issues

1. Epidemiological background

Invasive fungal infections are nowadays a major cause

of morbidity and mortality, not only in severely im- munocompromised patients such as those with neu- tropenia but in other types of patient population as well. However, the lessons that have been learnt in cancer patients may be immediately applicable to other patient populations for example, solid organ transplantations, intensive care, AIDS and other groups with immune

defects [ 11. In the 1.5 countries of the European Union (EU), there

are about 2 million new cancer patients diagnosed every year, of whom 1 million die each year. Major autopsy surveys, both in the U.S. and Europe, have shown that

the incidence of fungal infection in this population is as high as 5% in solid tumor patients, lO-15% in lymphoma patients and 15-30% in acute leukemia and/or bone mar- row transplant patients. Although most cancer patients have solid tumors, this incidence of 5% of mycoses still

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represents several thousand patients dying every year in

Europe as a result of invasive fungal infections. In addi-

tion, treatment for most solid tumors is becoming more and more aggressive leading to higher risk of severe op-

portunistic fungal infections. Furthermore, there are cur- rently more than 3,000 bone marrow transplants per year in Europe, and the number of other immunocompro- mised patients is also increasing due to the greater num- ber of solid organ transplants (liver, kidney, heart, lung) which are performed.

In a review of more than 4,700 patient autopsies from various countries, Bodey et al. [2] found that the overall rate of invasive fungal infection was 1 l%, ranging from 7% in Austria to 18% in The Netherlands (Table 1). It is sometimes difficult to determine whether a patient has died as an immediate result of invasive fungal infection

as most patients with an invasive fungal infection who die are those who have a very severe underlying disease. However, there are too many patients who develop fatal fungal infection during the first course of chemotherapy, or who have a very good prognosis for the cancer, but who die from disseminated candidiasis, aspergillosis or other mycoses. Thus, it is not only in terminally ill pa-

136 I? Meunierllnternational Journal of Antimicrobial Agents 6 (1996) 135-140

tients that fatal invasive fungal infections are currently observed and these opportunistic complications should nowadays be considered as major obstacles to the cure of serious underlying diseases.

During the last decade, there has been a major change in the distribution of pathogens causing nosocomial in- fections in most hospitals whether cancer centers or not. Gram-negative septicemias are no longer the only major cause of death in many immunocompromised patients. In fact, there is an increasing incidence of infections caused by Gram-positive cocci, such as coagulase-nega- tive staphylococci, MRSA, and enterococci, and also of fungal infections caused mainly by Candida species. Fungemia now represents up to 7-10% of all nosocomial bloodstream infections [3,4].

Moreover, it should be stressed that the overall inci- dence of fungal infection is still underestimated as a re- sult of multiple factors. The definite diagnosis of invasive fungal infection should rely mainly on histology and culture of some relevant clinical specimens, but biopsy is often precluded in high risk patients particularly in neutropenic patients who also have low platelet counts. Furthermore, correct interpretation of cultures (for ex- ample, from sputum) is also controversial. Therefore, there are numerous patients for whom the diagnosis of invasive fungal infection remains uncertain or unsus- pected.

In addition, there is still a major need to increase the awareness of medical professionals about the incidence of fungal infection and their protean clinical presenta- tions. Finally, more effective and rapid diagnostic proce- dures would also allow, early in the course of disease, the accurate diagnosis of invasive fungal infection. However, pending appropriate tackling of these issues, particularly for neutropenic patients, the exact incidence of life- threatening fungal infections will most likely remain un- derappreciated.

During the last three years, the European Organiza- tion for Research and Treatment of Cancer (EORTC) Invasive Fungal Infections Cooperative Group has con- ducted two surveys among hospitals dealing with cancer patients in order to collect data on the main clinical

Table 1

Incidence of invasive fungal infections at autopsy

Country Total autopsy

Austria 719

Belgium 418

Canada 67

Germany 2028

Italy 236

Japan 1109

Netherlands 128

United Kingdom 58

4823

From Bodey et al., 1992 [2].

Fungal involvement (%)

57 (7%) 48 (12%)

27 (40%)

170 (8%)

37 (16%)

162 (15%)

23 (18%)

16 (28%)

540 (28%)

Table 2

Fungemia in cancer patients in Europe: a 2-year survey conducted by

the EORTC Invasive Fungal Infections Cooperative Group

Number of patients 244

Median age [range] (years) 47 [l-90]

Underlying disease

Hematological malignancy 136 (55%)

Lymphoma 25 (10%)

Solid tumors 82 (34%)

Number of patients with neutropenia 127

Main Pathogens

C. albicans 109 (45%) C. parapsilosis 27 (11%)

C. tropicalis 23 (9%) C. glabrata 21 (9%) C. krusei 21 (9%) C. guilliermondii 11 (5%)

Outcome

Number of patients who died _ within 15 days 74 (30%) _ within 30 days 94 (39%)

From Viscoli et al.. 1995 [5].

entities, i.e. fungemia, aspergillosis and fusariosis, and also including patients undergoing bone marrow trans- plantation (BMT). For two years, information on more than 280 patients with fungemia were provided [5] (Table 2) as well as from 120 patients with invasive aspergillosis [6]. In addition, collaboration between the EORTC and the EBMT registries also provided a unique opportunity to further concentrate on specific issues related to BMT [7]. These three surveys are presently under final analysis.

2. Sources of infection

There are numerous sources for invasive fungal infec- tions in neutropenic patients either exogenous or en- dogenous. Candida spp. are the commonest cause of fun- gal infections in both cancer and other immunocompro- mised patients. Candidiases are generally considered to be endogenous infections resulting from the proliferation of yeasts, either on the skin or mainly in the gastrointes- tinal tract. These yeasts invade deep tissues secondarily to breaches or breaks in the mucosa due to chemother- apy, catheters, or to invasive procedures such as endo- scopy or surgery, and thereafter fungal pathogens dis- seminate via the bloodstream [S]. However, there are several exceptions to this concept; some candidiases occur as a direct result of exogenous sources, such as infusion of an intravenous product which is contami- nated; epidemics of candidiasis are also observed as a result of direct contamination and spread from a nurse or other health care professional [9-l 11. For example, a series of candidiases has been reported post-cardiac sur- gery and in neonates. Typing of the pathogenic strains identified a single pathogenic strain from a carrier as well as from the patients.

I? Meunierllnternational Journal of Antimicrobial Agents 6 (1996) 135-140 137

Most mould infections *are exogenous and result from the contamination of the air and the environment where fungi are ubiquitous. Thus, particularly in areas where very severely immunocompromised patients or patients undergoing bone marrow transplantation are hospital- ized, heavy contamination of the environment is a crucial risk factor against which these patients must be protected [12]. It may be necessary not to perform bone marrow transplants in situations where there is heavy contamina- tion such as during renovation or construction work within or outside the hospital and severe epidemics of aspergillosis have been reported in these circumstances [ 131. Food also has to he carefully selected for neu- tropenic patients both for yeasts [8] and for moulds since, for example, ground pepper is very frequently contami- nated by Aspergillus spores [14].

3. Causative organisms

The common fungal pathogens in neutropenic patients are Candida spp., mainly C. albicans but also other spe- cies such as C. tropicalis., C. parapsilosis, C. krusei and C. glabrata, are increasingly identified. In fact, non-albi- cans species now account for about half of the cases of candidiasis and several large studies on fungemia in hos- pitalized patients have shown a high incidence of non- albicans species as causative yeast pathogens [5,15-201. Aspergillus spp. [3,6] are also common pathogens.

However, there are more and more new opportunistic fungi being observed in all these categories of patients; it is therefore important that they are recognized and correctly identified so that suitable antifungal therapy can be instituted [21]. It is now accepted that all fungi, including those previously considered as contaminants, are occasionally responsible for life-threatening infec- tions [22].

Finally, the local epidemiology of each hospital (and even of some special units) should be assessed on a regu- lar basis and these data are indeed crucial for the clini- cians in order to develop the optimal strategies of pre- vention and treatment for their neutropenic patients. In- deed, these approaches will differ in units facing a high incidence of aspergillosis compared to units facing mainly disseminated candidiasis.

4. Diagnosis

Definitive diagnosis of invasive fungal infection is par- ticularly difficult in neutropenic patients, especially at the beginning of infection, because they have a sup- pressed inflammatory response. As these patients have no white blood cells they do not produce infiltrates, and most patients who have invasive aspergillosis do not have a positive chest X-ray early enough to confirm the

clinical suspicion. CT scans and even bronchoscopies must therefore be used in order to make a definitive diagnosis. Clinicians must suspect fungal infections, es- pecially in skin lesions, however innocuous they may appear. Unfortunately, due to low platelet counts, bi- opsy of deep tissues is often contraindicated.

Another major difficulty is to distinguish between col- onization and infection, particularly for infection caused by Candida species but also, to some extent, for Aspergil- lus. If Aspergillus spores are isolated from the broncho- alveolar lavage of neutropenic patients, these patients should be treated with antifungal agents even though some patients may occasionally only be colonized. The distinction between colonization and infection can be even more difficult for Candida albicans because these yeasts can be isolated from various clinical specimens, including respiratory tract secretions and urine, but this laboratory finding does not confirm that the patient has invasive candidiasis. For some species, such as C. gla- brata and C. tropicalis, the value of surveillance cultures to assess colonization is probably less controversial [23,24].

Despite all the new methods to detect fungemia, posi- tive blood cultures are often still missing in patients who die with disseminated candidiasis discovered at autopsy. Almost half the patients who have histologically-proven candidiasis do not have a positive blood culture pre- mortem.

Aspergillus can be difficult to identify in laboratory specimens stained with KOH but a calcofluor prepara- tion can confirm a diagnosis of invasive aspergillosis within minutes. It is therefore important that the correct staining techniques are employed. Although this method is not completely sensitive it can help prevent the patient from receiving toxic drugs for other infections agent such as Pneumocystis, Legionella, or CMV which can be alter- native diagnoses.

Serology has been of limited help; antibody titres are not useful, at least initially, when a diagnosis of candid- iasis or aspergillosis has to be made. By definition, these neutropenic patients are immunosuppressed and do not make enough antibodies. There may also be problems with the kits and tests currently used to detect antibodies and antigens because, although they may be specific, they may not be sensitive enough. This could be due to the techniques used, uncertainty over which antibodies and antigens to detect, or the fact that there are several antigens or metabolites circulating at the same time with very short half-lives. As a result, no reliable test is avail- able on a commercial basis to guide clinical management at the bedside of neutropenic patients at risk.

5. Main clinical entities and current challenges

Optimum therapeutic strategies need to be established

138 E Meunierllnternational Journal of Antimicrobial Agents 6 (1996) 135-140

for each fungal infection. In the case of candidiasis, there are many clinical entities and the presentation takes many forms. Thus, the management is also variable since there is no one single therapeutic regimen that can cover such different presentations as disseminated infection, esophageal or hepatosplenic candidiasis. In addition, the optimal management of candidemia is still difficult to assess facing lack of evidence of dissemination. There- fore, clinicians should integrate various parameters such as the presence of intravenous devices and the degree and duration of neutropenia.

The exact incidence of complications such as Candida endophthalmitis is extremely difficult to establish be- cause these patients are not followed by the same special- ist and there is often a lack of adequate follow up after a hospital stay for a specific surgical procedure. Indeed, these patients may develop Candida endophthalmitis up to 6, 8 or 24 months afterwards. However, such patients will not necessarily return to the same surgeon or inten- sive care unit and will be seen by different specialists. Nevertheless, there is a general consensus that in all in- stances, whether candidemia is catheter-related or not, every patient with candidemia (even without neu- tropenia) should receive antifungal therapy [25-261.

Significant progress has recently been achieved in this field [27]. In the 1970s the overall mortality from can- didemia in cancer patients was 79% [15], but now most studies show that the mortality has dropped to 45-50% [5,17-19,271 and fluconazole is now considered as a safe alternative to amphotericin B for patients with C. albi- cam candidemia 1271. In addition to fluconazole, various lipid preparations of amphotericin B have been studied in patients with invasive fungal infections. Unfortu- nately, there are no comparative trials of fluconazole versus any of the lipid preparations of amphotericin B. However, anecdotal reports indicate adequate control of fungemia in a few patients who had persistent positive blood cultures for Candida despite conventional ampho- tericin B therapy, even in patients who did not recover adequate granulocyte counts [28]. Most studies of am- photericin B lipid preparations performed so far have been mainly in compassionate use programs studies. However, a recent study compared amphotericin B lipid complex with amphotericin B for the treatment of inva- sive candidiasis [29].

Only 50% of cancer patients with a documented fungemia were treated with amphotericin B in the 1970s but now the majority of patients receive some form of antifungal therapy. The empiric management of patients with fever has also improved but there is still a long way to go to overcome the unacceptably high mortality rate of 40% following fungemia.

Infection with Aspergillus spp. can produce a number of clinical patterns. However, pulmonary lesions are the most common leading to hemorrhage, infarctus or fun- gus ball. Cavitation can occur, like an aspergilloma, and

may also develop very rapidly in severely neutropenic patients. The most common complication of aspergillosis is secondary focus of infection in the CNS, liver, and spleen and the potential for dissemination is usually un- derestimated. All these types of infection require very aggressive management and the prognosis remains poor [30]. The mortality rate of aspergillosis in neutropenic patients remains as high as 80% if the patients do not recover adequate granulocyte counts.

The clinical manifestations of invasive fungal infec- tions caused by the recently described unusual fungi are also protean although skin lesions are more common in fusariosis. During the 1980s there was a major increase in the presumptive diagnosis of invasive fungal infection amongst physicians and a corresponding increase in ini- tiation of empiric treatment with amphotericin B. How- ever, numerous questions, such as when and for which patients to consider early empiric antifungal therapy, mean that this is still a controversial subject.

New classes of antifungal agents, new azole drugs and alternative modalities to administer amphotericin B have been developed but the specific indications and potential differences between these drugs remain to be assessed. Further progress will only result from a multidisciplinary approach involving mycologists, clinicians from various disciplines (e.g. hematologists, infectious disease special- ists, surgeons) and pharmaceutical companies. For ex- ample, the role of cytokines and growth factors as ad- juvant therapy in the treatment of fungal infections is still unclear.

Granulocyte transfusions were widely used in the 1970s but the indications for their use have decreased dramatically since then, mainly due to the risk of allo- immunization and the poor recruitment of donors. How- ever, a new approach consists of infusing cells from do- nors who have been previously treated with growth fac- tors [31]. This technique, although experimental at pres- ent, is a promising development which is worthy of fur- ther research and study to clarify its role as adjuvant therapy.

6 The need for high quality clinical research and the EORTC Invasive Fungal Cooperative Group’s perspective

The increasing interest in this developing field of fun- gal infections has resulted in the development of new, safer and more effective antifungal drugs. Although new agents have been developed, there are still major obsta- cles to the effective treatment of invasive fungal infec- tions in neutropenic patients as well as amongst trans- plant patients. This a waste of both human and financial resources.

Due to the heavy burden caused by invasive fungal infections in cancer patients, in terms of both the quality of life of the patients and the economic costs of health

P Meunierllnternational Journal of Antimicrobial Agents 6 (1996) 135-140 139

care provision, a compre’hensive clinical strategy is re- quired to ensure the optimal diagnosis, prevention and treatment of invasive fungal infections, particularly for cancer patients undergoing aggressive and expensive therapeutic procedures for their underlying disease. Such a strategy has recently been initiated in Europe under the auspices of the EORTC which created the EORTC Inva- sive Fungal Infections Cooperative Group with the aim of building up a comprehensive approach to clinical re- search on invasive fungal infection in cancer patients. The group aims are to conduct, develop, coordinate and stimulate clinical research on the epidemiology, diagno- sis, prevention and treatment of invasive fungal infec- tions. The activities of this group are also aimed at stress- ing the economical burden for society and the health care system.

In addition to ongoing therapeutic trials, several epi- demiological studies and surveys on aspergillosis, fungemia and fusariosis have already been performed as described above. Such studies will increase awareness of physicians and nurses, still underestimating the morbid- ity and mortality related to invasive fungal infections. One of the key roles of such international efforts consists of providing the optimal forum to define state-of-the-art strategies for prevention and treatment and to identify ineffective or redundant approaches.

Invasive fungal infections are still a major cause of mortality in Europe, and only well conducted multicen- ter studies will be able to evaluate rapidly and profes- sionally the appropriate management for therapy and prevention. These studies do not only involve drug devel- opment but also optimal strategies such as when to ini- tiate empiric therapy and the role of growth factors for a patient with documented invasive fungal infection.

Overall, there is now the willingness and commitment of clinical investigators in Europe to tackle this difficult field. The situation is better than ever and such a group should bring a significam contribution to improve the prognosis of cancer patilents at risk of invasive fungal infections. This is a major challenge for all medical pro- fessionals but also a fantastic opportunity to perform high quality clinical research and to preserve our capac- ity for medical excellence at the European level.

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