Characteristic clinical features of Aspergillus appendicitis: Case report and literature review

Table 1 Case reports of isolated Aspergillus appendicitis without other known Aspergillus infection

Age and sex [reference]	Underlying condition	Chemotherapy received prior to appendicitis	Symptom appearance after initiating chemotherapy	Neutropenia at presen- tation	Abdominal imaging	Pathologic findings in resected appendix	Therapy and outcome
8-yr-old male[1]	ALL	Initial therapy: Vincristine, prednisolone, L-asparaginase, intra- thecal methotrexate.Chemotherapy during relapse: not reported	14 mo after therapy restarted for a relapse	Yes	USD: enlarged appendix, cecal wall thickened, and small periappendiceal fluid collection	Necrosis and inflammation in mucosa and nearby muscle consistent with acute appendicitis. Many septated fungal hyphae showing acute-angle branching, characteristic of Aspergillus	Fared poorly for 10 d while treated with conventional antibiotic therapy of ceftazdime and amikacin before undergoing appendectomy. Did well after appendectomy. Discharged in stable condition at postoperative day 10 (not mentioned whether received antifungal therapy after appendectomy)
41-yr-old male[2]	ALL (B-cell type with BCR-ABL trans-location)	Induction therapy: cyclophosphamide, daunorubicin, vincristine, prednisone, L-asparaginase, and dasatinib; Maintenance therapy: 6-mercaptopurine and dasatinib; Received stem cell transplantation	12 d after transplantation; 5 mo after initiation of chemotherapy	Yes	CT: cecal wall thickened, thickened retrocecal appendix, and periappendiceal inflammatory changes; small amount of free fluid present	Full-thickness invasion of appendiceal wall including serosa; fungal angioinvasion with vessels occluded by hyphal forms; positive methenamine-silver stain	Fared extremely poorly for 6 d with conventional antibiotic therapy plus acyclovir and fluconazole. Improved after appendectomy and after receiving liposomal amphotericin B and micafungin (switched on day 3 to voriconazole and micafungin due to acute renal injury). Discharged 46 d after appendectomy. Clinically stable 12 mo after hospitalization, without further aspergillus complications
21-yr-old male[3]	AML- M1	Mitozantrone and cytarabine.Later treatment with daunorubicin and cytarabine	30 d after diagnosis	Yes. WBC = 500/mm3 (no neutrophils seen)	USD: dilated bowel loops and right hydronephrosis.CT scan: right hydroureter extending down into pelvis with loss of fat planes in the region, consistent with inflammatory process around distal ureter	Coagulative necrosis of appendiceal tip with septate fungal hyphae with dichotomous branching pattern, permeating and occluding arterial branches.Immunoperoxidase stain demonstrated Aspergillus flavus	Amphotericin BSecond laparotomy 6 d after first showed 3 small bowel perforations. Died at day 49 from bleeding from Aspergillus invasion of iliac vein
139-yr-old, sex not stated[6]	Not reported	NA	NA	Not reported	Not reported (case published in 1959 before abdominal CT or USD became available)	At surgery: inflamed, enlarged, gangrenous appendix with severe surrounding inflammation. Microscopic pathology not reported	Did poorly postoperatively with high spiking fevers, overwhelming sepsis, and progressive jaundice while receiving streptomycin and 2 other antibacterial antibiotics. On day 9 therapy with antimycotic trichomycin initiated after Aspergillus nidulans isolated from appendiceal culture. Died 3 d later from progressive organ failure
8-yr-old male[Current Case Report]	AML-M5	Daunorubicin, cytarabine, thioguanine, etopiside, and dexamethasone	30 d	Yes. WBC=200/mm3	USD: no evident right lower quadrant abscess or free fluid. CT: inflammatory changes in right lower quadrant with thick-walled appendix and dilated appendiceal lumen	Branched, septate fungal hyphae invading full thickness of appendiceal wall without discrete perforation	Underwent appendectomy: Did poorly initially postoperatively while receiving antibacterial antibiotics. Recovered after receiving amphotericin B and discharged after 21 d of this therapy.No signs of disseminated Aspergillosis during 8 mo of follow up while receiving prophylaxis with itraconazole

¹Case excluded from analysis in this paper because this case report was published in 1959 before modern imaging tests became available and this case report lacks critical clinical details due to its brevity. AML: Acute myelogenous leukemia; ALL: Acute lymphocytic leukemia; CT: Computerized tomography; USD: Ultrasound; DIC: Disseminated intravascular coagulation; WBC: White blood cell; NA: Not available.

Table 2 Reported cases of Aspergillus appendicitis with additional gastrointestinal involvement

Age and sex. areas of aspergillus infection [reference]	Underlying condition	Chemotherapy received prior to appendicitis	Presentation with symptoms after initiation of chemotherapy	Neutropenia at time of developing symptoms	Abdominal imaging	Pathologic findings in resected appendix	Antifungal therapy: Outcome
11-yr-old male.Extensive GI involvement including appendix and cecum (typhlitis)[28]	AML	Cytarabine, daunorubicin, and etoposide	Day 12 after initiating chemotherapy	Yes	USD: thickened intestinal walls with indistinct hypoechogenic area reaching from cecal pole to mesenteric root	Performed cecal resection and appendectomy. Chronic, partially hemorrhagic inflammation of intestine infiltrated by Aspergillus. Fungal hyphae also demonstrated within blood vessels	Amphotericin B and fluoro-cytosine: Patient succumbed to septic shock while on persistent antifungal therapy 6 wk after admission. Autopsy demonstrated disseminated Aspergillosis
38-yr-old male. Only appendix and cecum infected[26]	ALL	Vincristine and prednisone and intrathecal methotrexate. Later changed to cytoxan and adriamycin	Hospital day 7	Yes, WBC = 100/mm3	Gallium scan: increased uptake in midabdomen and pelvis consistent with infectious process.CT: increased density in right lower quadrant consistent with an abscess or fluid-filled cecum	Laparotomy: appendix not found (apparently due to destruction), but cecal perforation with surrounding abscess with multiple coloenteric fistulas found. Resected specimen showed Aspergillus hyphae in necrotic area of bowel wall invading peritoneal surfaces	Amphotericin B: Stable at 6 mo follow-up, with right lung infiltrate that identified on previous X-ray, being stable in size
62-yr-old female.Appendix, cecum, ascending colon and ileum infected[27]	AML M6	Induction therapy: cytarabine for 7 d and idarubicin for 3 d	Day 16 after initiating chemotherapy	Yes, WBC = 600/mm3, no neutrophils	CT: inflammatory changes and fat stranding surrounding dilated appendix. Small amount of adjacent free fluid in pelvis	Resected 2.5 cm segment of small bowel and 60 cm segment of cecum and ascending colon. Microscopic evaluation of sections of bowel and appendix showed transmural intestinal infarction with hemorrhagic plugs within intestine blood vessels and fungal hyphae with septation and acute branching angles. Fungal stain revealed morphology consistent with Aspergillus	Voriconazole started empirically 20 d after admission, before surgery: Patient expired from cardiac arrest 26 d after admission
5-yr-old female. Appendix involved with widespread GI infection[29]	AML and diffuse large B-cell lymphoma	6 cycles of ThaiPOG protocol	Not specified	Yes	CT: early abscess formation in distal ileum and appendix	Pathological confirmation of appendicitis caused by invasive aspergillosis	Amphotericin B, metronidazole and piperacillin with tazobactam: Died 1 d later from septicemia with DIC; Autopsy disclosed fungal infection disseminated throughout body

GI: Gastrointestinal; AML: Acute myelogenous leukemia; ALL: Acute lymphocytic leukemia; NA: Not applicable; WBC: White blood cell; CT: Computerized tomography; USD: Ultrasound; DIC: Disseminated intravascular coagulation. ThaiPOG protocol: Thailand Pediatric Oncology Group protocol as described in: Seksarn P, Wiangnon S, Veerakul G, Chotsampancharoen T, Kanjanapongkul S, Chainansamit SO. Outcome of childhood acute lymphoblastic leukemia treated using the Thai National Protocols. Asian Pac J Cancer Prev 2015; 16 (11): 4609-4614.