Primary invasive aspergillosis of the digestive tract: report of two cases and review of the literature.

BACKGROUND: Disseminated aspergillosis is thought to occur as a result of vascular invasion from the lungs with subsequent bloodstream dissemination, and portals of entry other than sinuses and/or the respiratory tract remain speculative.
METHODS: We report two cases of primary aspergillosis in the digestive tract and present a detailed review of eight of the 23 previously-published cases for which detailed data are available. RESULTS AND
CONCLUSION: These ten cases presented with symptoms suggestive of typhlitis, with further peritonitis requiring laparotomy and small bowel segmental resection. All cases were characterized by the absence of pulmonary disease at the time of histologically-confirmed gastrointestinal involvement with vascular invasion by branched Aspergillus hyphae. These cases suggest that the digestive tract may represent a portal of entry for Aspergillus species in immunocompromised patients.

Introduction

Aspergillus spores are ubiquitous, and once aerosolized, they may colonize the airways and related structures, such as the nose and facial sinuses [1]. Further immunosuppression, such as severe and prolonged neutropenia, markedly increases the risk for invasive disease characterized by tissue invasion and secondary bloodstream dissemination [1]. Aspergillus fumigatus, Aspergillus flavus and Aspergillus niger are responsible for the majority of invasive diseases [2-4]. Invasive aspergillosis is reported to occur in fewer than 1% of patients infected by human immunodeficiency virus (HIV), in 1–5% of liver transplant recipients, in 3–7% of allogenic bone marrow transplant recipients, but in up to 10% of patients with hematological malignancies or lung transplants, and as high as 14% of heart transplant recipients [2-7].

Invasive pulmonary aspergillosis accounts for 90–98% of invasive infections. Extra-pulmonary aspergillosis may be present in 25–60% of cases and is almost universally described in the context of disseminated diseases [2, 8–15]. Although rarely documented before autopsy, these conditions usually result from bloodstream dissemination secondary to vascular invasion at the primary site of infection [16]. Isolated extra-pulmonary aspergillosis located in the central nervous system, the skin, the liver, the urinary tract and the digestive tract has only been mentioned in case reports, but potential portals of entry other than the respiratory tract are speculative [2, 3, 17]. We report two cases of primary invasive aspergillosis of the digestive tract and review the literature on Aspergillus spp. gastrointestinal involvement.

Methods

Our objective was to identify lower digestive tract involvement reported in series of invasive aspergillosis and secondly, to identify previously-published cases with a possible diagnosis of aspergillosis at this site. We searched the English-language literature from 1960 to 2005, December, for reports of aspergillosis with digestive tract involvement through an electronic search of the MEDLINE (National Library of Medicine, Bethesda, MD, USA) database using key words “aspergillosis”, “invasive aspergillosis”, “disseminated disease”, “extra-pulmonary aspergillosis” and “digestive tract aspergillosis” and the reference lists of retrieved articles, including reviews. Cases were included if the diagnosis of primary invasive aspergillosis of the bowel was defined as histologic evidence of Aspergillus hyphae in a segment of the bowel biopsy with mucosal alteration and tissue destruction and/or tissue invasion with microvascular involvement. Cases with isolated involvement of the upper digestive tract were excluded.

Case Reports

Case 1

A 65-year-old man presented with septic shock attributed to Proteus vulgaris primary bacteremia without clinical focus of infection. It occurred on day 6 after admission for transformation of a myelodysplasic syndrome into acute myeloid leukemia for which he received high-dose cytarabine with idarubicin as induction therapy. He responded to empirical broad spectrum antibiotics within 48 h. Fever recurred on day 10 with abdominal pain, and septic shock developed the following day. On day 12, emergency laparotomy showed a necrotic mass of the jejunum which was resected. Direct histologic examination showed branched hyphae with transmural involvement and vascular invasion. After transient improvement for 48 h, multiple organ failure developed. Macroscopic Aspergillus colonies appeared on the surgical stomas at day 14 and the patient died on day 16 despite intensive support and amphotericin B therapy. Autopsy showed disseminated aspergillosis with several new segmental necroses of the small bowel and multiple emboli of fungal material in several organs including the lungs. A detailed examination of the lungs did not show any consolidated aera. A. fumigatus was isolated from peroperative and autopsy cultures.

Case 2

A 52-year-old man presented with septic shock due to Pseudomonas aeruginosa primary bacteremia without clinical focus of infection. The symptoms occurred on day 14 after admission for transformation of a myelodysplasic syndrome into acute myelocytic leukemia for which he received high-dose cytarabine with idarubicin as induction therapy. He responded to empirical broad spectrum antibiotics within 48 h. Fever relapsed on day 25 with abdominal pain. A CT scan excluded lung infiltrates and confirmed the diagnostic of typhlitis. On day 30, a laparotomy performed for acute peritonitis revealed four masses in the ileon. Histology showed branched hyphae (A. fumigatus by culture) with transmural involvement and vascular invasion (Figure 1). A second CT scan excluded lung involvement. Therapy with amphotericin B (2 g over 28 days) was initiated and the patient made a full recovery on day 45. Two months later he died from hemorrhage during induction therapy for autologous bone marrow transplantation. Autopsy showed no recurrence of aspergillosis.

Figure 1

Giemsa-Silver coloration (original magnification, ×200). Diffuse hemorrhagic necrosis surrounding an ulceration of the wall of a surgically-resected segment of jejuna with loss of the architectural organization of the layers. Vascular occlusion by branched A. fumigatus hyphae (black structures).

Results

Of 23 cases of possible primary invasive aspergillosis of the digestive tract identified in the literature [5, 12–14, 18–22], details were available for only eight of them [23-30] (Table 1).

Table 1

Selected characteristics of ten patients with primary digestive invasive aspergillosis.

	Case report	Case report	Case 37-1976 [23]	Weingard [24]	Cohén [25]	Marterre [26]	Catalano [27]	Shah [28]	Sousa [29]	Trésallet [30]
Age (years)	63	52	4 weeks	38	33	8	58	68	21	57
Underlying disease	AML	AML	AML	ALL	AML	AML	AML	AML	Aplastic anemia	Lymphoma
Documentation	Histology + culture	Histology + culture	Histology + culture	Histology + culture	Histology + culture	Histology + culture	Histology + culture	Histology + culture	Histology + culture	Histology + culture
Previous infection	Bacteremia	Bacteremia	Bacteremia	Bacteremia	Fever of unknown origin	Bacteremia	Fever of unknown origin	Suspected line infection	Fever of unknown origin	Fever of unknown origin
Microorganisms	Proteus vulgaris	Pseudomonas aeruginosa	Staphylococcus aureus	Klebsiella oxytoca; Enterococcus faecatis	—	Pseudomonas aeruginosa	—	—	—	—
Chemotherapy	Cytarabine, idarubicin	Cytarabine, idarubicin	Cytarabine, daunorubicin	Cytarabine, adriamicin	Cytarabine, daunorubicin	Vincristin	Cytarabine, daunorubicin	Cytarabine, idarubicin	Cyclosporin A	Cytarabine, etoposide
Days after chemotherapy	13	14	8 (second cycle)	19 (second cycle)	24	23	15	11	28	Not specified (induction)
Neutropenia at diagnosis	Yes	Yes	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes
Antifungal prophylaxis	No	No	No	Not specified	Not specified	Not specified	Yes	Not specified	Not specified	Not specified
Number of previous antibiotics	3	3	3	2	5	3	Several	4	Several	3
Antimicrobial agents	Ciprofloxacin, gentamicin, metronidazole	Meropenem, amikacin, teicoplanin	Carbenicillin, gentamicin, oxacillin	Ceftazidime, amikacin	Ceftazidime, amikacin	Ceftazidime, tobramycin, ticarcillin	Not specified	Cefepime, metronidazole, gentamicin, vancomycin	Not specified	Imipenem, gentamicin, metronidazole
Prior exposure to amphotrericin B	No	Yes	No	No	Yes	No	No	No	No	No
Clinical presentation	Relapsing fever, ileus, peritonitis	Relapsing fever, ileus, bloody diarrhea, peritonitis	Relapsing fever, peritonitis	Relapsing fever, ileus, bloody diarrhea, peritonitis	Relapsing fever, watery diarrhea, peritonitis	Relapsing fever, ileus, peritonitis	Relapsing fever, digestive hemorrhage, peritonitis	Persisting fever, peritonitis	Persisting fever, peritonitis	Persisting fever, peritonitis
Serology	—	—	—	—	—	—	—	—	—	—
Antigenemia	—	—	—	—	—	—	—	—	—	6.2 ng/ml (ELISA)
Secondary dissemination	Lung	No	Lung, liver	Lung	Lung, liver	No	Not specified	Not specified	Not specified	No
No. of surgical interventions	1	2	1	1	2	5	1	1	1	1
Days after chemotherapy	12	13	8	19	24	23	15	14	28	Not specified
Bowel excision	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Antifungal treatment	Amphotericin B	Amphotericin B	—	—	—	—	Not specified	Not specified	Not specified	Voriconazole
Outcome at 28 days	Death	Survival	Death	Survival	Death	Survival	Death	Death	Death	Survival

AML: acute myeloid leukemia; ALL: acute lymphoid leukemia

Nine of ten patients presented with acute hematologic malignancy, and eight received high-dose cytarabine known to be associated with diffuse mucositis. Six presented a prior episode of bacteremia during neutropenia. All ten received a combination of antibiotics with broad spectrum coverage within the 2 weeks before the onset of the abdominal complication, and all presented with abdominal symptoms suggestive of typhlitis, with digestive hemorrhage in three. Laparotomy was performed for acute peritonitis and showed transmural necrosis of the small bowel requiring segmental resection in all cases. Histology consisted in multiple lesions from superficial ulceration to transmural necrosis and vascular thrombosis with tissue invasion by branched hyphae of Aspergillus spp. were present in all cases (Figure 1). All cases were characterized by the absence of pulmonary disease at time of histologically-confirmed digestive aspergillosis. Serology and antigenemia was either not available or not performed in all but one cases and death occurred in six of ten patients (60%).

Of 155 clinical studies retrieved from our review of the literature, 25 included more than 25 cases of invasive aspergillosis in non-HIV infected adult patients with details on the distribution of organs involved (Table 2). There were 6 autopsy series [11–13, 18, 31, 32], 11 retrospective series [5, 14, 15, 19, 33–39] and 8 prospective series [20–22, 40–44].

Table 2

Invasive aspergillosis: organ distribution and mortality; 1960–2005. Studies including more than 25 adult patients.

					Organ distribution
Authors	N	Mortality	Lung	Disseminated	CNS	Digestive	Primary digestive
Autopsy
Young et al. [12]	98	100%	92 (94%)	34 (35%)	13 (13%)	21 (21%)	3 (3%)
Meyer et al. [13]	93	100%	90 (98%)	23 (35%)	9 (10%)	9 (10%)	1 (1%)
Boon et al. [11]	32	100%	32 (100%)	20 (63%)	16 (50%)	15 (53%)	0
Vogeser et al. [18]	27	100%	23 (85%)	16 (59%)	12 (44%)	7 (26%)	1 (4%)
Vogeser et al. [31]	48	100%	41 (85%)	28 (58%)	21 (44%)	1 (2%)	0
Hori et al. [56]	107	100%	105 (98%)	52 (52%)	22 (21%)	12 (11%)	0
Total	405	100%	383 (95%)	176 (43%)	93 (23%)	67 (17%)	5 (1%)
Retrospectiva
Fisher et al. [14]	91	88%	83 (91%)	20 (22%)	13 (14%)	5 (5%)	1 (1%)
Albelda et al. [15]	26	62%	26 (100%)	NS	NS	NS	NS
Morrison et al. [5]	93	62%	87 (95%)	43 (47%)	21 (23%)	NS	1 (1%)
Horvath and	69	52%	49 (71%)	NS	NS	NS	NS
Dummer [33]
Janssen et al. [34]	25	92%	25 (100%)	8 (32%)	3 (12%)	4 (28%)	0
Caillot et al. [35]	37	27%	37 (100%)	8 (22%)	0	0	0
Kaiser et al. [36]	35	97%	33 (94%)	8 (23%)	1 (3%)	0	0
Abbasi et al. [37]	66	85%	46 (70%)	23 (35%)	9 (14%)	0	0
Lortholary et al. [38]	31	45%	28 (90%)	7 (23%)	4 (13%)	0	0
Nosari et al. [39]	61	48%	56 (92%)	20 (33%)	5 (8%)	0	0
Pagano et al. [19]	391	51%	332 (85%)	NS	37 ( 9%)	9 (2%)	4 (1%)
Total	925	60% 555/925	802 (87%)	137/438 (31%)	92/829 (11%)	18/737 (2%)	6/829 (0.7%)
Prospective
Ringden et al. [40]	32	34%	29 (91%)	NS	NS	0	NS
Denning et al. [20]	76	32%	51 (67%)	NS	8 (11%)	NS	1 (1.3%)
Stevens et al. [21]	125	34%	90 (72%)	24 (19%)	8 (6%)	0	1 (0.8%)
Denning et al. [22]	123	64%	106 (87%)	33 (27%)	10 (8%)	0	1 (0.8%)
Patterson et al. [41]	595	51%	330 (56%)	148 (25%)	34 (6%)	NS	NS
Denning et al. [42]	116	58%	81 (70%)	6 (5%)	19 (16%)	0	0
Bowden et al. [44]	174	53%	107 (62%)	NS	12 (7%)	NS	NS
Herbrecht et al. [43]	277	35%	240 (87%)	15 (5%)	10 (4%)	NS	NS
Total	1,518	47%	1,034 (64%)	226/1,236 (18%)	101/1,486 (7%)	0/396 (0%)	3/440 (0.7%)
		716/1518
All studies	2,848	59%	2,219 (78%)	539/2,079 (26%)	296/2,720 (11%)	85/1,538 (5.5%)	14/1,674 (0.8%)
		1676/2848

NS: not specified

The proportion of cases with a definite diagnosis was 100% in autopsy series and 73% (60–92%) and 65% (31–88%) in retrospective, and prospective series, respectively. The number of cases where the diagnosis was made before death increased from 23% (14–56%) in autopsy series, 76% (28–100%) in retrospective and 99.9% (99–100%) in prospective series. Mortality averaged 60% (27–88%) in retrospective and 47% (32–64%) in prospective series. This may indicate that patients included in prospective studies were less critically ill, or may have benefited from early presumptive antifungal therapy. Case-fatality rate was recently confirmed to be highest in bone marrow transplant recipients (87%) and among patients with central nervous system involvement (88%) [45]. A large number of patients with solid organ transplant may have contributed to the higher survival rate reported in prospective series.

Invasive pulmonary aspergillosis accounted for a majority of cases. Bowel involvement during disseminated disease was not reported in prospective series and in only 2% of cases in retrospective series (0–28%). However, it was reported in 17% (2–53%) of cases included in the autopsy series. Apart from 14 cases for which no details were available, invasion of the digestive tract was always reported in the context of disseminated disease [11–14, 18, 20, 21, 34, 40, 46]. A mixed infection with Candida species was reported in series where more details were available [12, 47]. A digestive hemorrhage was reported in most cases, but was not considered specific.

Comment

Invasive aspergillosis is almost exclusively considered as a pulmonary disease with secondary hematogenous dissemination [1, 5]. Fungal infections of the small and large intestine are rare [47]. However, Aspergillus spores are not only inhaled but also ingested, and isolated aspergillosis of the upper digestive tract has been described [48]. In two reviews covering more than 3,000 cases collected from several hundreds of articles over three decades, Denning suggested that, although never demonstrated, the gastrointestinal tract may be considered as a potential portal of entry for Aspergillus spp. [2, 3].

In contrast to Candida spp., Aspergillus spores may not survive or meet favorable conditions to develop on the mucosal surfaces of the digestive tract. However, large ulcers, such as those described as occurring after high-dose cytarabine-related mucositis, may be colonized by Aspergillus spores [48]. This may also be the case for patients developing a neutropenic or necrotizing enterocolitis, also referred to as typhlitis. This defines an abdominal complication occurring in neutropenia and induced by chemotherapy [49]. It complicates 5–30% of treatments, including those with high-dose cytarabine, with variable clinical manifestations ranging from mild gastrointestinal symptoms to life-threatening intestinal necrosis with perforation and secondary peritonitis [50, 51]. The latter condition mandates a surgical approach and has been associated with mortality rates of over 50% [52, 53]. Although not specific, abdominal CT scan may be suggestive. The eventual value of Aspergillus serology and antigenemia has not been studied in this context. Diffuse dilatation with edema of the bowel walls, predominantly located in the caecum, with some degree of hemorrhage and necrosis are common pathological findings [54]. As described in the ten above-mentioned cases, bowel necrosis is associated with the invasion of a poorly vascularized wall by gram-negative bacilli and yeast after breakdown of the normal flora [52, 55].

In conclusion, we report two cases of possible primary digestive aspergillosis. These two cases and the eight previously published suggest that the digestive tract may represent a portal of entry for Aspergillus species in immunocompromised patients.