Trends in the postmortem epidemiology of invasive fungal infections at a University Hospital

Journal of Infection (1996) 33, 23-32

Trends in the Postmortem Epidemiology of Invasive Fungal Infections at a University Hospital A. H. Groll*t, P. IVI. Shah, C. Mentzel, IVI. Schneider, G. Just-Nuebling and K. Huebner Department of Pathology and Department of Medicine, Johann Wolfgang Goethe University Hospital, Frankfurt~Main, Germany Accepted for publication 10 March 1 9 9 6

Background. Due to the lack of reliable diagnostic tools, clinical data on the significance of most invasive fungal infections are difficult to assess and information on frequency, disease pattern and prognostic impact still IaNely relies on autopsy data. Methods and results. To determine temporal trends in im~asivefungal infections, we analyzed data firm 8124 autopsies performed between 1978 and 1992 on patients who died at the University Hospital of Frankjhrt/Main. During that period, a total of 278 invasive fungal infections were found. The prevalence rose fwm 2.2% (1978-82) and 3.2% (1983-87) to 5.1% in the most recent years (P
Introduction Along with the increased and prolonged survival of patients with life-threatening underlying diseases but impaired immunologic status, invasive fungal infections have emerged as a major cause of morbidity and mortality in the hospital.L 2 With the exception of cryptococcal meningitis and perhaps catheter-associated candidaemia, these infections remain difficult to diagnose, in particular at an early stage. 3 Definitive diagnosis largely relies on bioptic procedures with histological and cultural confirmation of the organism from affected tissues, but unfortunately, biopsy specimen often can not be obtained because of the critical overall condition of the patient. I

* Address correspondence to: Dr Andreas H. GrolI, Pediatric Branch, National Cancer Institute, National Institutes of Health, Building 10, Room 13N240, 10 Center Drive Msc 1928, Bethesda, Maryland 208921928, U.S.A. These findings were presented in preliminary form at the 34th Interscience Conference on Antimicrobial Agents and Chemotherapy, October 1994, Orlando, F1, abstract no. J 109. Dr groll was supported by a Fellowship Award of the Walter-Marget-Foundation for Infectious Diseases, Germany. t Present affiliation: Pediatric Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, U.S.A. 0163-4453/96/040023 + 10 $12.00/0

The limitations of diagnostic methods and the overwhelming n a t u r e of invasive fungal infections in imm u n o c o m p r o m i s e d patients frequently necessitate the initiation of antifungal therapy on an empirical basis. 4 In true or established infections, however, the response to currently available antifungal agents mainly depends on the correction of the underlying deficiency in host defenses and the prognostic significance of fungal disease in severely ill patients often remains unclear, x' 5-7 Clinical data on incidence and impact of most invasive fungal infections are thus difficult to assess and m a n y of these infections remain undetected antemortemfi Alt h o u g h limited by the exclusion of patients w h o survive their infection or die and do not undergo examination, autopsy studies are still a major source for information on incidence and significance of invasive fungal infections. 1 Most information has derived from autopsy studies in patients with malignant diseases, but studies on the epidemiology at a general hospital are currently lacking. To determine temporal trends in invasive fungal infections at autopsy and to describe frequency, disease pattern and prognostic significance of these infections, we analyzed data from 8 1 2 4 autopsies performed between 1 9 7 8 and 1992 at a large university hospital with a relatively high autopsy rate. © 1996 The British Society for the Study of Infection

24

A.H. Groll e t al. Patients and Methods

The study was conducted at the University Hospital of Frankfurt/Main, a 1120 bed facility with all major medical specialties but no bone marrow transplantation unit up to 1990 and no burn unit. The survey is based upon retrospective analysis of all 8124 consecutive autopsies performed on patients who have died at the hospital between 1 january 1978 and 31 December 1992 (10 891 patients in total). The overall autopsy rate was 74.6%, dropping from 77.6% in 1 9 7 8 - 8 2 and 74.0% in 1 9 8 3 - 8 7 to 71.9% in 1 9 8 8 - 9 2 (P= 0.0001). As there is no federal or state law regulating the performance of autopsies, all patients who die at the university hospital undergo postmortem examination, except in cases of a veto from the patient himself during his lifetime or his relatives after death and a reportable infectious disease or an unnatural cause of death is not suspected. In contrast, the 3953 examinations performed on patients from affiliated teaching hospitals on a consulting basis, which were included in our preliminary data, 9 represented sporadic cases selected by the attending physicians and were therefore excluded from this survey.

Data collection and review process Cases for analysis were obtained from the files of the Department of Pathology and included the final autopsy report, histologic sections and abstracted information with established and suspected clinical diagnoses and treatment prior to death. Microscopic slides, gross and microscopic diagnoses and clinical information were reviewed and coded by two authors. In case of discrepancy, the case was reviewed by a third author and the discrepancy resolved: In each case, the following parameters were noted: Age, sex, hospital service, length of hospitalization, established and suspected clinical diagnoses with treatment prior to death; autopsy diagnoses including the type of fungus and fungal lesions and their distribution, other infectious and non-infectious pathologic findings and their distribution, and a morphologic bone marrow and lymph node evaluation; final diagnoses divided into major and minor diagnoses, stage of the major underlying disease process, causes of death and whether fungal infection was related to death or an incidental finding and whether fungal infection had clinically been established or empirically treated or not.

Autopsy procedure A complete autopsy was performed in all cases. The routine microscopic examination included sections from

all major organs (heart, both lungs, liver, spleen, kidney, bone marrow, one representative lymph node) and was extended according to the individual macroscopic findings. Tissues were placed in 10% buffered formalin for fixation, paraffin-embedded and stained with Hematoxylin-Eosin. If considered necessary, as in all cases of fungal infection, additional staining methods were carried out.

Diagnostic criteria Invasive fungal infection was defined by the presence of fungal elements in tissues other than mucosal surfaces with tissue necrosis and etiologic classification was made upon morphologic criteria alone, supported by special stains (PAS, Grocott, Alcian-PAS-Blue). Disseminated disease was diagnosed if two or more organ systems not directly contiguous were affected. The morphologic features and staining reactions utilized for recognition of fungi in tissues included the following 1°' n: For Candida spp.--oval, budding yeast ceils, 3-6 #m in diameter with pseudohyphae and occasionally true hyphae; for Aspergillus spp.--small and uniform, dichotomously branching hyphae, septate at regular intervals, 3-6 #m in width; for Agents ofMucormycosis--broad, thinwalled irregularly shaped and infrequently septate hyphae, 5-25 #m wide with wide angle branching at random; for Cryptococcus spp.--pleomorphic budding yeast cells, 2 - 2 0 #m in size, without hyphae and Alcian-PAS-Blue positive capsules. Fungal elements which did not match the described criteria and which could not be attributed to one of the endemic fungal organisms were reported as unclassified fungal pathogens. Cultures from fresh tissues as well as immunologic or molecular techniques were not routinely performed.

Definitions The major underlying diagnosis was established by reviewing the patient's clinical and autopsy information and included the principal underlying disease and the primary cause of death in contrast to processes that contributed to death in a terminally ill patient, secondary diagnoses that were related to the major diagnosis and other conditions that may ultimately have affected the patient's prognosis. 8 Major underlying diagnoses were coded into haematologic malignancies (with subdivision according to the Kiel-classification), aplastic syndromes characterized by pancytopaenia, the acquired immunodeficiency syndrome (AIDS), 12 congenital immunodeficiencies, solid organ transplantation, solid tumours regardless of origin and stage, chronic diseases,

Postmortem Epidemiology of Fungal Infections Comparisons and statistical analysis

Table I. Distribution of underlying diseases in cases with invasive fungaI infections. No. of patients (%)

Primary diseases

Haematol. malignancies AIDS Solid mmours Chronic diseases Acute events Aplastic syndromes Organ transpiantation SCID None

1978-82 (n=66)

1983-87 (n=86)

32 (48) -15 (23) 9 (14) 7 (11) 3 (05) ----

32 (37) 11 (13) 13 (15) 10 (12) 5 (06) 10 (12) 3 (04) 1 (01) 1 (01)

1988-92 (n=126) 43 49 9 7 8 4 6

(34) (39) (07) (06) (06) (03) (05) -

25

In order to analyze trends occurring over time, the study period (1978-92) was subdivided into three equal time periods and compared. Statistical evaluation of categorical data was performed by 2 × 2 or 3 × 2 contingency table analysis and continuous data was analyzed by the Mann Whitney U-test or Kruskal Wallis H test. A result of P
Results

-

--

Identified cases, demographic characteristics and underlying conditions

AIDS, Acquired Immunodeficiency Syndrome; SCID, Severe Combined hnmunodeficiency Disease.

acute events requiring intensive care, and no underlying disease processes. Endstage disease was considered, if the major underlyi~ag disease itself or complications other than invasive fungal infection had led to an inexorable chain of events terminating in death, regardless of time. In neoplastic diseases, remission was laid down by the microscopic absence of malignant cells at autopsy. The immediate cause of death was defined as the disease process present in ~he organ system that clinically appeared to have failed or that had severely affected a vital organ. When more than one process seemed important in a patient's demise, both were considered as causes of death. Accordingly, invasive fungal disease was judged to be the immediate or significantly contributory cause of death or an incidental finding.

A total of 278 cases (3.4%) met the criteria for invasive fungal infection. One hundred and seventy-seven patients were male (64%) and 101 were female (36%). The mean age was 49 years (range: 2 months to 83 years). All but one patient (pulmonary and cerebral cryptococcosis) had significant underlying diseases. Altogether, haematologic malignancy was the leading major diagnosis, followed by AIDS and a variety of solid tumours. However, during 1987-92, AIDS has emerged as the most common primary condition. Chronic diseases (autoimmune disorders, n = 7 ; liver cirrhosis, n = 4 ; type [ diabetes mellitus, n = 4 ; chronic obstructive pulmonary disease, n = 3 ; chronic renal failure requiring haemodialysis, n=2; miscellaneous other, n = 6), acute events requiring intensive care (major reconstructive surgery, n = 7; acute life-threatening primary infectious diseases, n = 5 ; complications of premature birth, n = 4 ; polytrauma, n = 3 ; acute pancreatitis, n = 1), aplastic syndromes, solid organ transplantation (liver, n = 6; kidney,

Table II. Base-line characteristics in cases with invasive fungal infections. Condition

No. of patients (%)

P value

1978-82 (n=66)

1983-87 (n=86)

1988-92 (n=126)

Endstage primary disease Bone marrow insufficiency Lymphatic tissue depletion Other pathologic findings --lung --CNS Other infectious processes

35 (53) 41 (62) 33 (50) 66 (100) 49 (74) 23 (35) 32 (48)

51 (59) 71 (83) 54 (63) 86 (100) 68 (79) 41 (48) 47 (55)

101 (80) 101 (80) 102 (81) 126 (100) 113 (90) 63 (50) 91 (72)

Hospitafization (mean/days)

21

27

* Increase over time significant by 3 × 2 Chi-square test. "~Increase over time significant by KruskaI-Wallis H test.

35

0.0001" 0,0057* 0.0001" 0.0150" 0.1221 0.0019" 0.0008)

26

A . H . Groll e t al.

Table Ili. Prevalence of invasive fungal infections at autopsy. Fungus

No. of patients (%) 1978-82 (n=2956)

1983-87 (n=2718)

Candida Aspergillus Cryptococcus Mucor AspeN.+Cand. AspeN. + Crypt. Unclassified

51 (1.7) 11 (0.4) -4 (0.1) ----

47 32 5 ---2

Total

66 (2.2)

86 (322)

(1.7) (1.2) (0.2)

(<0.1)

P vaIue

1988-92 (n=2450) 31 76 3 1 6 1 8

(1.3) (3.1) (0.1) (<0.1) (0.2) (<0.1) (0.3)

126 (5.1)

0.3110 0.0001" 0.0790 0.1075 0.0010" 0.3141 0.0020*

-~ '~

0.0001" I

* Increase over time significant by 3 x 2 Chi-square test.

r

78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 Year

n = 3 ) and congenital immunodeficiency (severe combined immunodeficiency disease, SCID, n = 1) were considerably less frequent (Table I). Most of the patients had been terminally ill in regard to their primary disease and were hospitalized for a prolonged period prior to death as compared with the mean length of hospitalization for all patients admitted to the hospital (13, 13 and 12 days for the three time periods). Bone marrow hypoplasia or aplasia as well as cellular depletion of lymphatic tissue were found in the overwhelming majority and only 17% (17, 16 and 19% for the three time periods, P = 0 . 7 5 2 4 , N.S.) of patients with neoplastic diseases were in remission at the time of death. A high proportion of patients had significant other pathologic findings in strategic organs and concurrent other infectious processes. Over time, there was a mostly highly significant increase in the overall morbidity of patients dying with invasive mycoses along with a significant increase in the length of hospitalization prior to death (Table II).

Figure 1. A n n u a l prevalence of invasive fungal infections related to the n u m b e r of autopsies.

Candida as the leading pathogen in 1 9 7 8 - 8 2 to Aspergillus in the most recent years (Table III, Figure 2). Related to the total number of autopsies, there was a highly significant increase in Aspergillus infections over time, whereas the prevalence of Candida infections was stable and even revealed a declining trend within the last years. Also, a significant increase in mixed as well as unclassified fungal infections could be noted. Only a few cases of cryptococcosis and mucormycosis and none of the endemic mycoses were observed (Table III). The global prevalence of invasive fungal infections in examined patients from affiliated teaching hospitals was

100

~\\\\\\\\\\\\~ 80

Total prevalence of invasive fungal disease and spectrum offungal pathogens Despite considerable annual fluctuations, the total prevalence of invasive fungal infections at autopsy rose steadily from 2.2% in 1 9 7 8 - 8 2 and 3.2% in 1 9 8 3 - 8 7 to 5.1% in 1 9 8 8 - 9 2 with a peak of 7.3% in 1992, and this increase over time was highly significant (Table III and Figure 1). Moreover, it remained significant when the number of infections found at autopsy was related to the total number of patients who have died at the university hospital (1.7, 2.3, and 3.7% for the three time periods, P = 0.0001). The majority of invasive fungal infections was caused by Candida or Aspergillus species with a change from

m

m

"~ ~ 60 ta0

~ 4o 20

o

78-82

83-87

88-92

Time periods Figure 2. Spectrum of fungal pathogens over time. (C]) candida; ([]) aspergillus; (11) cryptococcus; (N) mucor; (k~) mixed infections; (N) unclassified.

Postmortem Epidemiology of Fungal Infections

27

Table IV. Global prevalence of invasive fungal infections related to underlying diseases. Disease group

Cases/autopsies (%)

P value

1978-82 (n = 2956)

1983-87 (n = 2718)

1988-92 (n = 2450)

Aplastic syndromes Haematol. malignancies AML HG-NHL M. Hodgkin CML LG-NHL

3/3 (100) 32/276 ( 1 2 ) 8/58 (14) 8/54 (15) 5/35 (14) 3/35 (09) 8/94 (09)

10/12 (83) 32/188 ( 1 7 ) 16/44 (36) 5/50 (10) 3/24 (13) 3/19 (16) 5/51 (10)

4/10 ( 4 0 ) 43/198 ( 2 2 ) 14/49 ( 2 9 ) 17/70 (24) 2/10 (20) 6/15 ( 4 0 ) 4/54 (07)

0.04267 0.0119" 0.0271" 0.1057 0.8509 0.0264* 0.8967

AIDS Organ transplantation Solid turnouts All other

0/2 (00) 0/6 (00) 15/930 ( 0 2 ) 16/1739 (<1)

11/73 (15) 3/17 (18) 13/825 (02) 17/1603 (01)

49/239 ( 2 1 ) 6/38 (16) 9/601 ( 0 1 ) 15/1364 (01)

0.4622 0.5532 0.9843 0.8677

* Increase over time and ~ Decrease over time significant by 3 x 2 Chi-square test. AML, Acute MyeloblasticLeukaemia: CML,Chronic MyeloblasticLeukaemia; HG-NHL/LG-NHL,HighGrade/Low-GradeNon-Hodgkin'sLymphoma.

0 . 6 . 0 . 5 and 1.0% with no significant increase over time (P = 0.1900), but a similar trend towards Asperftillus as the predominant pathogen. Compared to the university hospital, the overall prevalence was significantly lower (0.7 vs. 3.4%, P = 0 . 0 0 0 1 ) along with a lower rate of cases with high-risk primary diseases (aplastic syndromes, haematologic malignancies, AIDS, transplantation) in this setting (4 vs. 13%, P = 0 . 0 0 0 1 ) .

Prevalence of invasive fungal disease related to underlHing conditions The global prevalence was highest in patients with aplastic syndromes (68%), followed by acute myeloblastic leukaemia (AML, 25%), AIDS (19%), high-grade NonHodgkin's Lymphoma (HC-NHL) and chronic myeloblastic leukaemia (CML, 17% each), solid organ transplantation (15%) and Hodgkin's disease (14%). Over time, a significant increase was found in the group of haematologic malignancies as a whole, in AML and CML, and there was an increasing trend for HG-NHL. A significant decrease occurred in aplastic syndromes within the most recent years (Table IV). In Candida infections, the highest prevalence rates were found in aplastic syndromes (40%), AML (14%), HG-NHL (11%), Hodgkins disease (10%) and CML (9%). Over time, the prevalence was stable or revealing a negative trend with a significant decrease in aplastic syndromes, AML and solid tumours (Table V). In contrast, Aspergillus infections showed a significant increase in haematologic malignancies as a whole, HG-NHL, M. Hodgkin and CML and an increasing trend in all other entities. Altogether,

the prevalence was highest in aplastic syndromes (24%), followed by AIDS (12%), transplantation (8%), AML and HG-NHL (7 and 6%, respectively) (Table VI). Between Candida and Asper~illus infections, no significant differences could be observed regarding the prevalence of underlying endstage disease, remission status in neoplastic disease, bone m a r r o w and lymphatic tissue compromise and other pathologic findings within the central nervous system (CNS). However, in Aspergillus infections, a significantly higher rate was noted in the frequency of concurrent pulmonary diseases (P = 0.003 9) and concurrent infectious complications (P = 0.000 7) as well as a significantly longer hospitalization prior to death (P = 0.0012). Mucor infection ( n = 5 ) was associated with haematologic malignancies (3), type I diabetes mellitus, and AIDS; cryptococcal infection ( n = 8) with AIDS (5), solid turnout, sarcoidosis and no defined underlying condition; chronic cerebral cryptococcosis along with pulmonary aspergillus with AIDS; concurrent Candida and Aspergillus infections ( n = 6 ) with haematologic malignancies (3) and AIDS; and unclassified fungal infection (n = 10) with haematologic malignancies (5), solid tumours (3), aplastic syndrome and chronic renal failure.

Prevalence of invasive fungal infections, AIDS excluded In order to address the issue whether the increase in invasive fungal infections and in particular in invasive aspergillosis was not merely due to the occurrence of AIDS associated with a high rate of Aspet~illus infections, all AIDS cases were excluded from the analysis. However,

A . H . Groll et al.

28

Table V. Prevalence of invasive Candidainfections related to underlying diseases. Disease group 1978-82 (n = 2956) Aplastic syndromes Haematol. malignancies AML HG-NHL M. Hodgkin CML LG-NHL AIDS Transplantation Solid tumours All other

P value

Case/autopsies (%) 1983-87 (n = 2718)

1988-92 (n = 2450)

3/3 (100)

6/12 (50)

1/10 (10)

0.0126"

27/276 ( 1 0 )

22/188 ( 1 2 ) 11/44 (25) 3/50 (06) 2/24 (08) 3/19 (16) 3/51 (06)

13/198 (07) 4/49 (08) 8/70 (11) 0/10 (00) 1/15 (07) 0/54 (00)

0.2128 0.0390* 0.3491 0.3918 0.4330 0.1712

3/73 (04) 2/17 (12)

10/239 (04) 2/38 (05)

0.9571 0.5280

6/58 8/54 5/35 2/35 6/94

(10) (15) (14) (06) (06)

0/2 (00) 0/6 (00) 11/930 (01) 10/1739 ( < 1 )

6/825 (<1) 8/1603 ( < 1 )

0/601 (00) 5/1364 (<1)

0.0283* 0.7088

* Decrease over time significant by 3 x 2 Chi-square test.

Table VL Prevalence of invasive Aspergillus infections related to underlying diseases. Disease group

Cases/autopsies (%)

P value

1978-82 (n = 2956)

1983-87 (n = 2718)

1988-92 (n = 2450)

Aplastic syndromes

0/3 (00)

4/12 (33)

2/10 (2o)

0.4475

Haematoi. malignancies AML HG-NHL M. Hodgkin CML LG-NHL

2/276 (<1) 1/58 (02) 0/54 (00) 0/35 (00) 0/35 (00) 1/94 (01)

9/188 (05) 4/44 (09) 2/50 (04) 1/24 (04) 0/19 (00) 2/51 (04)

23/198 (12) 6/49 (12) 8/70 (11) 2/10 (20) 3/15 (20) 4/54 (07)

0.0001"

AIDS Transplantation

0/2 (00) 0/6 (00)

5/73 (07) 1/17 (06)

32/239 (13) 4/38 (11)

0.2767 0.6279

Solid tumours All other

4/930 (<1) 5/1739 ( < 1 )

6/825 (<1) 7/1603 (<1)

6/601 (01) 9/1364 (<1)

0.0977 0.0208* 0.0237* 0.0035* 0.1288

0.4084 0.3027

* Increase over time significant by 3 x 2 Chi-square test.

the overall increase in invasive f u n g a l infections over time r e m a i n e d significant ( P = 0 . 0 2 6 1 ) a n d the same was also true for Aspergillus infections ( P = 0 . 0 0 0 1 ) . I n the case of Candida, indeed, a significant decrease could be n o t e d (P = 0 . 0 4 7 8 ) .

Pattern of fungaI disease Invasive f u n g a l disease most c o m m o n l y affected the gastrointestinal tract i n c l u d i n g the oesophagus a n d the l u n g

in Candida infection a n d the l u n g a n d the CNS in Aspergillus infection (Table VII). I n Candida infection, disease was limited to the gastrointestinal tract in 22% a n d to the lungs in 17%. Diss e m i n a t e d disease occurred in 51%, with the gastrointestinal tract, lung, kidney, liver, heart, spleen a n d CNS as the most c o m m o n l y involved sites. Oesophagitis was noted altogether in 38%; in 36 of the 49 cases with oesophagitis, however, there was c o n c o m i t a n t involvem e n t of lower parts of the gastrointestinal tract. I n

Postmortem Epidemiology of Fungal Infections

29

Table VII. Organ involvement in invasive Candidaand Aspergillusinfections. No. of patients (%)

Candida (n = 129) GIT only Lung only Kidney only Lower airways only Heart only Liver/Spleen only

Aspergillus (n = 119) 291 22 04 03 03 02

(22) (17) (03) (02) (02) (02)

Lung only Lower airways only CNS only

49 (41) os (04) 02 (02)

Disseminated

66 (51)

Disseminated

63 (53)

--GIT lung --lddney --liver ~eart --spleen --CNS

442 40 28 22 20 13 11

--lung --CNS --kidney --heart --GIT --spleen --liver

58 (92)* 26 (41) 22 (35) 18 (29) 11 (17) 6 (10) 4 (06)

(67)* (61) (42) (33) (30) (20) (17)

* Percentage of cases with disseminated disease. 10esophageal invoIvement, n = 25 (oesophagus only: 9/25). 20esophageal involvement, n = 24 (oesophagus only: 4/24). GIT, gastrointestinal tract including oesophagus; CNS, central nervous system.

p u h n o n a r y infections, a p o t e n t i a l h a e m a t o g e n o u s origin (microscopic association of the o r g a n i s m w i t h blood vessels) was obvious in 15% a n d only f o u n d in the presence of d i s s e m i n a t e d disease. Infectious endocarditis was diagnosed in six cases, t h r e e of t h e m in c o n j u n c t i o n w i t h d i s s e m i n a t e d disease. CNS-disease involved the pare n c h y m a in nine a n d t h e m e n i n g e s in four cases. 4:1% of Aspel#illus infections were confined to the l u n g and d i s s e m i n a t e d disease w a s found in 53% of t h e cases w i t h the lung, CNS, kidney, h e a r t a n d the g a s t r o i n t e s t i n a l t r a c t as the m o s t c o m m o n l y affected sites. Infectious endocarditis was found in one case, a n d CNS-disease involved the p a r e n c h y m a in 28 cases w i t h f u n g u s found o n the m e n i n g e s in eight of these cases. Mucor infection (n = 5) was p u l m o n a r y , sinoorbital a n d c e r e b r a l in one case e a c h a n d d i s s e m i n a t e d disease was observed in two cases (lung, CNS, liver, spleen; lung, liver, spleen). Cryptococcal infection (n = 8) w a s confined to the lung, CNS, a n d l u n g plus CNS in one case e a c h a n d a sepsis-like d i s s e m i n a t i o n w a s found in five cases, all of t h e m w i t h CNS- a n d two of t h e m w i t h l u n g i n v o l v e m e n t . Mixed infections ( n = 6) consisted of pulm o n a r y aspergillosis associated w i t h invasive gast r o i n t e s t i n a l candidiasis. H a e m a t o g e n o u s spread to v a r i o u s o r g a n s o c c u r r e d in two cases (one Candida only, one Candida a n d Aspergillus). There was one case of invasive p u l m o n a r y aspergillosis associated w i t h c h r o n i c c r y p t o c o c c a l m e n i n g o e n c e p h a l i t i s . In unclassified infection (n = 10), the l u n g w a s affected in all cases. Disease

was confined to the l u n g in six cases, to the gastrointestinal t r a c t a n d l u n g in two a n d to the lung a n d various organs in two cases.

Clinical diagnosis and impact on outcome F u n g a l infection h a d been suspected or confirmed antem o r t e m in 22% of all cases w i t h a significant imp r o v e m e n t over time from 11% in 1 9 7 8 - 8 2 to 30% w i t h i n the most r e c e n t y e a r s (Candida- a n d Aspergillus infections: from 8 a n d 9% to 32% each; total: 16 vs. 24%, P = 0 . 1 1 2 6 ) (Table VIII). I n cryptococcosis, six out of eight infections h a d been d i a g n o s e d at lifetime. Mucor infection was clinically k n o w n in two cases a n d fungal infection h a d been suspected in one o u t of 10 cases of unclassified infections. Mixed infections were only detected at a u t o p s y except the case of c o m b i n e d cryptococcal a n d Aspergillus infection, in w h o m c r y p t o c o c c a l disease h a d been established antemortem. In 211 cases or 76%, fnngal disease was j u d g e d to be the i m m e d i a t e or significantly c o n t r i b u t o r y cause of d e a t h (Candid& 77%; Aspergillus, 85%; Mucor, 80%; Cryptococcus, 86%; mixed infections, 100%; a n d unclassified infections, 60%) (Table VIII). W h e r e a s no t r e n d over time w a s observed in fungal disease as a w h o l e a n d in Aspergillus infections (P = O. 7173), Candida infections were i n c r e a s i n g l y found as incidental finding at a u t o p s y

A. H. Groll et al,

30

Table VIII. Clinical diagnosis and impact of invasive fungal infections on outcome. FungaI infection

P value

No. of cases (%) 1978-82 (n=66)

1983-87 (n=86)

1988-92 (n= 126)

7 (11)

15 (17)

38 (30)

0.0004*

Incidental finding at death

16 (24)

20 (23)

31 (25)

0.9745

Related to the cause of death

50 (76)

66 (77)

95 (75)

0.9745

27 (41) 23 (35)

38 (44) 28 (33)

73 (58) 22 (17)

0.0387* 0.0095~

Clinically suspected/confirmed

Endstage underlying condition No endstage underlying condition

* Increase over time and 1 decrease over time significant by 3 x 2 Chi-square test.

(from 29% and 26% to 52% in 1 9 8 8 - 9 2 , P = 0 . 0 4 2 8 ) . Most patients, in w h o m fungal infection was related to the cause of death, had primary diseases in their endstages with a significantly increasing trend over time (Table VIII) and the overall proportion of patients, who were not considered terminally ill but had died from fungal infection (excess mortality) decreased significantly from 35% i n 1 9 7 8 - 8 2 to 17% of all cases within the most recent years (Candida, from 33 % to 16%, P = 0.2269; Aspergillus, from 36% to 17%, P = 0 . 0 4 9 1 ; Mucor, 40%; Cryptococcus, 25%; mixed infections, 14%; and unclassified infections, 30%).

Discussion This study offers the unique opportunity to assess the postmortem epidemiology of invasive fungal infections over an extended period at a single large institution with all major specialties and a relatively high autopsy rate. A limitation is the lack of cultural confirmation, which was unavoidable, mostly because cultures were not routinely performed and fungal infection had not been suspected from the examination of fresh tissue. However, accounting the fact that fungi m a y not be cultured from tissue known to be infected on histological examination in 4 0 - - 6 0 % , 13'14 identification of fungi by morphologic means remains valuable in the recognition of invasive fungal infections, l°'n Diagnosis of endemic mycoses, cryptococcosis, mucormycosis and infections by most Candida spp. can be made histologically with some confidence, m Although it is nearly impossible to differentiate Aspergillus hyphae from those of rare is pathogenic molds such as Fusarium, Penicillum or Pseudallescheria boydii, we consider that the overwhelming majority of these cases did indeed represent Aspergillus spp. There was a significant relative and absolute increase in invasive fungal infections at autopsy over time up to an incidence of more than 7% in 1992. Besides the

emergence of mixed and unclassified infections, this was mainly due to a significant increase in Aspelgillus infections. In contrast, the incidence of Candida infections was stable and even showed a declining trend within the most recent years along with a shift towards non lifethreatening manifestations. This tendency was noted in all underlying conditions, either as a trend or statistically significant, and was not related to the occurrence of AIDS associated with a high rate of invasive aspergillosis. Cryptococcosis became more common with AIDS, and mucormycosis was only sporadically observed. An increasing incidence of invasive aspergillosis over the last decades is well documented in autopsy studies on patients with haematologic malignancies, 16 and it is clinically recognized as most significant fungal infection in patients undergoing bone m a r r o w 17'18 or solid organ transplantation 19 and in aplastic anaemia, a° However, in general, Candida is still considered as the predominant fungal pathogen in immunocompromised patients, s' 7.16,18 Moreover, in a recent clinical survey on the epidemiology of nosocomial fungal infections in the United States, Candida spp. accounted for 78% of nosocomial fungal infections and AspeNillus spp. for only 1.3% 2 and Candida spp. are currently responsible for 6 - 1 0 % of nosocomial bloodstream infections in the U.S. and Europe.21, 22 Although our data can not provide direct evidence, the decreasing incidence and prognostic significance of invasive Candida infections at autopsy might be explained by an overall increased awareness among physicians, the widespread use of nonresorbable polyenes and systemic fluconazole for prophylaxis and the more aggressive use of amphotericin B in high risk groups ~ as well as by advances in blood culture techniques 23 and a n improved prognosis of primary bloodstream infections in more recent times. 2' 23.24 In contrast, even in extensive organ involvement, Aspergillus spp. are infrequently recovered from the

Postmortem Epidemiology of Fungal Infections respiratory tract and only exceptionally from blood cultures. 1 They are not susceptible to prophylaxis with fluconazole and oral polyenes and the effects of amphothericin B aerosols and itraconazole have not yet been proven4; reducing environmental exposure through high efficiency particulate air (HEPA)-filters is not feasible for all patients at risk. 25 Furthermore, invasive infections with Aspagillus spp. and other more resistant organisms have been reported in patients receiving low-dose (0.5-0.6 mg/kg/day) amphotericin B for empirical antifungal therapy 4 and there is general consensus that higher doses of amphotericin B (1.0-1.5 mg/kg/day) are reqt~ired to provide a chance for survival in these infections. 26-2~ Invasive aspergillosis has recently been reported as an emerging problem in advanced stages of AIDS 29-3~ but has not yet been well recognized as an AIDS-associated complication. The reported overall prevalence of 4% in autopsy studies 32 stands markedly in contrast to the 13% prevalence rate within the last 5 years of this survey. Besides the impact of the high autopsy rate at our hospital, this is most probably related to the prolonged survival of patients with AIDS and deserves further analysis. However, quantitative and qualitative disorders of neutrophils and macrophages by either the H u m a n Immunodeficiency Virus (HW) itself or by drug therapy are characteristic for advanced stages of HIV-infection and other, potentially predisposing pulmonary affections are a hallmark of AIDS. ~2 33 The pattern of fungal disease in Candida and AspeNillus infections reflects the different modes of acquisition and is in agreement with the literature.16 In Candida infections, t h e gastrointestinal tract including the oesophagus and the lung were the most frequently involved sites. Primary Candida pneumonia (no distant focus of infection and no microscopic evidence for haematogenous origin) was common (1 7%); its prognostic significance has recently been re-emphasized) 4 In Aspe~gillus infections, pulmonary disease was found in more than 90% of the cases and the brain was the second most frequently involved organ. Reflecting the progressive nature of the disease, dissemination was present at the time of death in the majority of both Candida and Aspergillus infections. Fungal infections that could not be classified by morphologic methods possibly represented uncommon fungi, such as rrichosporon spp., dematiaceous "fungi, Fusarium spp. and other molds, which are increasingly observed in cancer patients with granulocytopenia or receiving corticosteroids. ~5'3s They are relatively refractory or resistant to amphotericin B, and their occurrence might in part be due to more aggressive immunosuppressive therapies and a selection of resistant organisms by the increasing use of empirical amphotericin B. 3~

31

Most cases of cryptococcosis were found in AIDS, the remaining were associated with solid tumour, sarcoidosis, and no overt predisposition. Neoplastic disease and steroid therapy are well known predisposing factors, but, before AIDS, in 20-30%, no apparent underlying condition could be found. Since 1980, AIDS has become the most frequent predisposing condition. 36 The CNS was involved in all but one case, and the lung was the second most common involved site. As the usual site of entry is the lung, progressive and severe pulmonary involvement is not infrequently observed in immunocompromised patients. 1(~'36 The low prevalence of mucormycosis, its disease pattern and underlying conditions are compatible to the common experience. ~637 However, the low infection rate in severely immunocompromised patients by the ubiquitous organisms is yet not well elucidated. 37 All but one patient in the present series had at least one of the well established 3s predisposing conditions, and the majority (>70%) was severely immunocompromised in terms of their primary disease and its treatment. Bone marrow insufficiency was present in altogether 77% and cellular depletion of lymphatic tissues in 68% with a significant increase over time. The highest infection rates were found in aptastic syndromes, followed by AML, AIDS, other haematologic malignancies and solid organ transplantation. The prevalence was low in solid tumours (2%) and all other entities (1%). Most notable, AIDS has emerged as the major underlying condition in fungal infections within the most recent years. There was a significantly increasing, high overall morbidity, as assessed by the proportion of patients with endstage disease, length of hospitalization, significant other pathologic findings in strategic organs and the prevalence of documented other infectious processes at death. In more than 75% of all cases, invasive fungal disease was judged to be the immediate or significantly contributory cause of death, which emphasizes the high lethal potential of these infections. For several reasons, however, the mortality directly attributable to invasive fungal infections in the setting of impaired host defenses is not truly known. The severity of the underlying disease process is the predominant factor in influencing outcome and restoration of host defenses, if at all feasible, is a prerequisite for successful management.i, s-7 Accordingly, in most patients, in whom fungal infection was related to the cause of death, the final outcome was primarily determined by the underlying disease process and its complications and not by fungal infection. The proportion of patients who were not considered terminally ill but died from fungal infection (excess mortality) was low and decreased significantly over time to 17% of all cases within the most recent years.

32

A . H . Groll e t al.

In conclusion, the postmortem findings document an increasing prevalence of invasive fnngal infections among hospitalized patients along with significant changes in aetiology and underlying disease processes. Although limited by the exclusion of patients who survived their infection or died and did not undergo examination, this survey emphasizes the value of the autopsy as essential feedback for the clinician in particular in the setting of a severely immunocompromised population 39 and underscores the continuous, urgent need for more effective prevention, diagnosis, and treatment.

17 18 19 20 21

22

References

23

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