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Abstract
An immunocompetent man in his 60s was treated in the emergency department with prednisone and doxycycline for suspected contact dermatitis and superimposed cellulitis. Two days later, he returned with abdominal pain, scrotal swelling, and progressive rash. Imaging revealed perforated diverticulitis extending into the right testicle. He was managed with broad-spectrum antibiotics and underwent an exploratory laparotomy. An elevated serum galactomannan level was noted but deemed clinically insignificant, as he was not considered a typical host for an invasive mold infection. He required additional surgeries, with pathology eventually showing necrosis and fungal hyphae consistent with Aspergillus species infiltrating the small bowel with associated angioinvasion. He was started on combination antifungal therapy with voriconazole and micafungin, followed by liposomal amphotericin B. The patient ultimately died from invasive gastrointestinal aspergillosis (IGIA). This case report explores the risk factors, clinical course, and treatment of IGIA in an intensive care unit patient who was otherwise immunocompetent.
- Infectious diseases
- Gastrointestinal surgery
- Fungal Infections
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Background
Aspergillus species (spp) are saprophytic, septate, hyaline molds that are ubiquitous in the environment. The clinical spectrum of Aspergillus spp infections ranges from non-invasive forms, such as aspergilloma and allergic bronchopulmonary aspergillosis, to invasive aspergillosis (IA), a life-threatening condition.1 While IA is occasionally described in immunocompetent hosts, it primarily affects immunocompromised patients,1 particularly those with haematologic malignancies or those undergoing organ transplantation, due to compromised neutrophil function and cell-mediated immunity. Although invasive disease is most commonly pulmonary, it can involve the sinuses, gastrointestinal (GI) tract, and central nervous system. Invasive GI aspergillosis (IGIA) is considered the second or third most prevalent form, with the small intestine being the most commonly affected organ.
Positive fungal cultures along with histopathology demonstrating invasive disease are the most definitive methods for diagnosing IA. However, invasive sampling is not always feasible and cultures can be low-yield.2 Thus, the diagnosis of IA typically relies on a combination of host factors, compatible imaging, and positive biomarkers that indicate the presence of Aspergillus spp.3 Key fungal biomarkers include Aspergillus galactomannan (GM), an Aspergillus-specific antigen (Ag) released during infection,4 and beta-D-glucan (BDG), a non-specific fungal cell wall marker. In immunocompetent hosts, interpreting positive fungal markers can be challenging due to a lower pretest probability of infection and the risk of false positives, especially in cases of colonization.5
Voriconazole and, more recently, posaconazole and isavuconazole are considered first-line therapies for IA, while amphotericin B is considered second-line therapy due to lower efficacy and toxicities.6 7 Combination therapy, such as with echinocandins, is not clearly proven to improve survival but is occasionally used in severe cases.6 Early detection, reduction of immunosuppression, and treatment of IA are all critical for patient survival.8
Case presentation
A man in his 60s presented to the emergency department with a 4-day history of a new right thigh and ankle painless, blistering, and non-pruritic rash associated with ankle swelling that developed after gardening. A lower extremity ultrasound (US) did not show any evidence of deep vein thrombosis. He was thought to have contact dermatitis with possible superimposed bacterial infection and was discharged on prednisone 50 mg daily for 5 days and doxycycline 100 mg twice daily for 7 days. The patient presented two days later due to fatigue, diffuse abdominal pain and distention, constipation, nausea, right scrotal pain and swelling, and difficulty urinating. His right lower extremity (RLE) rash persisted, and a similar rash developed over the left hip. The remainder of the review of systems was negative.
The patient’s past medical history included hypertension, hyperlipidaemia, gastro-oesophageal reflux disease, diverticulosis, and follicular thyroid carcinoma status post-thyroidectomy with subsequent hypothyroidism. Surgical history also included a healed right forearm skin graft for a burn sustained years ago, and colonoscopy 4 months prior to presentation that identified and resected a hyperplastic polyp. Noteworthy social history included upbringing on a farm where he raised birds. His hobbies included gardening and fishing. He had a 30-pack-year smoking history but quit smoking 20 years ago. He did not use herbal supplements, alcohol, or other recreational substances. Family history was negative for autoimmune or immunocompromising conditions. He had no drug allergies. His medications included atorvastatin 40 mg daily, diltiazem 360 mg daily, levothyroxine 125 μg daily, omeprazole 20 mg daily, spironolactone 25 mg daily, and valsartan 20 mg daily.
On presentation, he was afebrile and haemodynamically stable. Physical exam was notable for abdominal distention, left lower quadrant tenderness, scrotal swelling, erythema and induration, as well as a purpuric rash with associated bullae on the right medial thigh and ankle and left hip.
Initial labs showed white blood cell count 8.2 K/µL (ref: 4–11 K/µL), absolute neutrophil count 6.8 K/µL (ref: 1.5–7.9 K/µL), haemoglobin 14 g/dL (ref: 13–17.5 g/dL), platelets 129 K/µL (ref: 150–400 K/µL), international normalised ratio 1, sodium 130 mmol/L (ref: 135–146 mmol/L), creatine (Cr) 1.4 mg/dL (ref: 0.5–1.3 mg/dL), urea 37 mg/dL (ref: 6–24 mg/dL), lactic acid 2.8 mmol/L (ref: 0.5–2.2 mmol/L), and albumin 1.2 g/dL (ref: 3.2–5 g/dL). Liver enzymes were within normal limits. Urinalysis was unremarkable. Blood cultures and RLE wound cultures were collected. Nasal SARS-CoV-2 PCR was positive.
A chest computed tomography (CT) with contrast did not show any evidence of pneumonia. CT abdomen and pelvis with contrast showed perforated diverticulitis with extension of bubbles of gas to the right hemi-scrotum and a 7.0 × 2.4 cm left paracolic abscess. A scrotal Doppler US showed right epididymo-orchitis and a complex right hydrocele. The patient was started on intravenous (IV) vancomycin, piperacillin-tazobactam, clindamycin, and fluconazole. Given lack of respiratory symptomatology, no SARS-CoV-2 treatments were given. Surgery and urology were urgently consulted, and the patient was taken to the operating room where he underwent exploratory laparotomy, sigmoid colectomy for necrotic bowel, splenic flexure mobilization, end colostomy, abdominal closure, right hydrocelectomy, and debridement. His postoperative course was complicated by septic shock requiring pressors and initiation of IV hydrocortisone 100 mg every 6 hours, respiratory failure and inability to extubate, acute kidney injury (with peak Cr 2.9 mg/dL) requiring renal replacement therapy, elevated liver function tests, and worsening thrombocytopenia (nadir 11 K/µL). His initial blood cultures grew Escherichia coli, while the intra-operative peritoneal and scrotal cultures grew E. coli, Streptococcus constellatus, Streptococcus anginosus, Proteus mirabilis, and Prevotella oralis for which the infectious diseases team was consulted. On day 3 of hospitalization, dermatology evaluated his now progressed rash and thought it was concerning for purpura fulminans from an infectious (eg, from bacteraemia or an angioinvasive fungal infection) or thrombotic vasculopathy and had sent serum GM and BDG. Rheumatology was consulted and noted the possibility of vasculitis for which he was given IV immunoglobulin (IVIG).
On day 5, he underwent abdominal re-exploration, noting a necrotic descending colon. Pathology confirmed necrosis, and both Grocott-Gomori methenamine silver (GMS) and periodic acid-Schiff stains were negative. On day 6, dermatology performed a punch biopsy of the left hip (figure 1), with pathology revealing thrombotic vasculopathy without immunofluorescence after incubation with antibodies against immunoglobulin (Ig) G, IgM, IgA, complement 3, fibrin, and albumin. Both the left hip tissue culture and GMS staining were negative. Also on day 6, results of serum BDG and GM, collected on day 3, returned positive (149 pg/mL (ref: <80 pg/mL) and 5 (ref: <0.5), respectively); however, these findings were not considered clinically significant, as the patient was not immunocompromised and his clinical picture was not compatible with an invasive mold infection. Repeat fungal markers were ordered due to concern for false-positive results. He required ongoing laparotomy procedures due to progressive bowel necrosis, which eventually extended into the small bowel, with no clear explanation for the cause. Repeat peritoneal cultures grew Citrobacter braakii. Small bowel pathology from his third procedure, done on day 7 of hospitalization, returned on day 13, showing numerous fungal hyphae with focal transmural bowel wall involvement, acute inflammation, necrosis, and transmural arterial involvement by fungal hyphae, concerning for an invasive mold infection (figure 2a, b and c).
Skin, punch biopsy, H&E, 40×. Small dermal vessels with luminal thrombus. There is no significant inflammation. Grocott-Gomori methenamine silver stain was negative.
(a) Small bowel resection, H&E, 2×. Transmural necrosis and haemorrhage. The blue arrow indicates the vessel depicted in figure 2a. (b) Small bowel resection, H&E, 40×. Intramural artery with numerous fungal hyphae penetrating through the tunica intima and muscular tunica media. (c) Small bowel resection, Grocott-Gomori methenamine silver, 100×. The stain highlights fungal elements that show septations and acute angle branching, consistent with Aspergillus species. The yellow arrow notes the septation.
Investigations
Infectious workup
Fungal abdominal tissue culture was negative. Fungal blood culture was negative. Serum cryptococcal Ag, HIV Ag/antibody (Ag/Ab), hepatitis B surface Ag and core Ab, and hepatitis C Ab were negative. Repeat BDG and GM were above assay (>500 pg/mL and >6.8, respectively). Tick panel, thin smear, and buffy coat were negative.
Immune and rheumatology workup
Haemoglobin A1c 6.7% (<5.6%) consistent with diabetes mellitus (DM). Serum IgG was elevated at 1821 mg/dL (ref: 700–1600 mg/dL), though this was measured after administration of IVIG. Rheumatoid factor, antinuclear antibody, antineutrophilic cytoplasmic antibody panel, cardiolipin Ab, beta-2 glycoprotein Ab, and cryoglobulin were all negative.
Haematologic workup
Haptoglobin 342 mg/dL (ref: 26–240 mg/dL), lactate dehydrogenase 523 U/L (ref: 110–250 U/L), von Willebrand factor-cleaving protease activity 0.1 IU/mL (ref: 0.6–1.63 IU/mL)—low, likely due to sepsis. Serotonin release assay and platelet factor 4 Ab were negative. Blood smear showed no schistocytes or other evidence of haemolysis.
Differential diagnosis
In this patient with progressive bowel necrosis despite antibiotic therapy and bowel resection, the differential diagnosis was broad. Given the patient’s critical condition and pressor requirement, mesenteric ischaemia was considered. The presence of a rash raised the possibility of vasculitis, such as polyarteritis nodosa, or a haematologic disorder like thrombotic thrombocytopenic purpura. A secondary vasculopathy due to bacteraemia was also considered. However, bowel pathology revealed distinct fungal elements with angioinvasion, indicating a fungal infection. This infection could have been introduced through ingestion or intraoperative inoculation and may have developed due to the patient’s critical illness and impaired defences. Alternatively, it might have preexisted from prior ingestion, causing the initial perforation, and worsened as the patient’s condition deteriorated. Dissemination from another source was less likely due to the lack of evidence of fungal skin infection, pneumonia, or fungemia.
Potential pathogens included Candida, Cryptococcus, Aspergillus, Mucorales, Fusarium, or endemic mycoses. Candida, typically appearing as budding yeast with occasional pseudohyphae, was deemed improbable based on the observed narrow septate hyphae, the absence of yeast forms, and elevated serum GM levels. Cryptococcus was ruled out due to the absence of encapsulated yeast forms and a negative serum cryptococcal Ag. Mucorales were considered unlikely, as they typically appear ribbonlike, wide and aseptate; positive fungal biomarkers are also not characteristic of Mucorales. Fusarium, which can also show narrow septate hyphae and may cause elevated serum GM level due to occasional cross-reactivity, did not fit the clinical picture, as it often presents with fungemia and disseminated discrete skin lesions, neither of which were evident in this case. Endemic mycoses were unlikely due to the absence of relevant exposures. The presence of characteristic septate, acute-angle branching hyphae along with a very elevated serum GM level, suggested Aspergillus as the most probable pathogen.
Treatment
The patient’s blood cultures cleared on day 5 of admission. He underwent six additional exploratory laparotomies over 2 weeks for removal of necrotic bowel. During the final procedure, gross mold was noted on the stomach and liver. His surgical treatments were as follows: exploratory laparotomy with sigmoidectomy, end colostomy, exploration, and debridement of scrotum, exploratory laparotomy with sigmoid resection and temporary abdominal closure, exploratory laparotomy with completion colectomy, small bowel resection, and temporary abdominal closure, exploratory laparotomy with small bowel resection and temporary abdominal closure, bedside exploratory laparotomy with temporary abdominal dressing, exploratory laparotomy with washout, packing, and temporary abdominal closure, exploratory laparotomy with washout, exploratory laparotomy with bowel resection and Witman patch placement, exploratory laparotomy with washout, exploratory laparotomy with jejunostomy, ileostomy, and gastrostomy.
On return of the pathology report that was suggestive of IA, he was started on IV voriconazole 4 mg/kg every 12 hours and IV micafungin 150 mg daily dosed renally. IV liposomal amphotericin B 420 mg daily was added to the antifungal regimen 3 days later.
Outcome and follow-up
Despite antifungal therapy, multiple exploratory laparotomies with removal of necrotic and infected tissues, and washouts, the patient showed no improvement and his need for pressors persisted. Following a goals of care discussion with the patient’s family, he was transitioned to comfort measures only on day 20 of hospitalization.
Discussion
Aspergillus spp are filamentous, hyaline hyphomycetes that produce spores known as conidia. These fungi are ubiquitous and can be found in various environments, including soil, decomposing plant matter, household dust, building materials, plants, food, and water.9 IA is characterized by the presence of hyphal elements invading tissues, as observed in biopsies from any affected site.10 The lungs are involved in 90%–98% of cases.11 Extrapulmonary IA may manifest either as part of a disseminated infection or in isolation with single-organ involvement. IGIA is thought to be the second or third most prevalent form, with the small intestine being the most commonly affected organ.12–14 Other potential sites of involvement include the central nervous system, sinuses, eyes, heart, skin, liver, and kidneys.
Risk factors predisposing individuals to IA include cytotoxic chemotherapy, prolonged neutropenia, corticosteroid therapy, organ or bone marrow transplantation, and aquired immunodeficiency syndrome. In the intensive care unit (ICU) setting, additional risk factors include corticosteroid therapy before ICU admission, chronic obstructive pulmonary disease (COPD), liver cirrhosis with an ICU stay more than 7 days, solid malignancies, severe burns, and ICU stays more than 21 days.15–17 Other potential risk factors include prematurity, near-drowning incidents, sepsis, influenza, SARS-CoV-2 infection, non-fungal pneumonia, antibiotic exposure, liver dysfunction, alcoholism, haemodialysis (HD), mechanical ventilation (MV), DM, chronic granulomatous disease, and surgical interventions.11 Specifically concerning IGIA, risk factors include a history of transplantation, haematologic malignancies (particularly acute myeloid leukaemia), pancytopenia, appendicitis, ulcerative colitis, necrotizing enterocolitis, neuroectodermal tumors, and lung malignancies.13 In this patient’s case, risk factors for IA included sepsis, prolonged ICU admission, corticosteroid therapy before and after ICU admission, antibiotic exposure, HD, MV, and recent DM diagnosis. The patient also had findings of tissue necrosis and required repeated laparotomies, some of which were performed in the surgical ICU rather than in a sterile operating room. It remains unclear whether the initial intra-abdominal insult was caused by IGIA.
For IGIA to develop, the fungus must directly infiltrate a compromised digestive tract, either through ingestion or direct inoculation from ubiquitous spores or contaminated sources like sutures. The fungus must then evade host protective mechanisms, which may be compromised due to factors such as acid suppression by proton pump inhibitors or breaches in the mucosal barrier as observed in ulcerative colitis, necrosis, or chemotherapy-induced mucositis. Alternatively, spores may enter the human body through other routes such as inhalation or through the skin via inoculation, and subsequently disseminate haematogenously to the GI tract.11 13 18 Potential routes for our patient’s infection include ingestion or direct inoculation from the environment, or dissemination from the skin considering his gardening activities and recent rash history. His skin biopsy did not demonstrate histopathological evidence of cutaneous aspergillosis and GMS stain was negative. Despite testing positive for SARS-CoV-2 and requiring MV, his lung imaging was not concerning for invasive pulmonary aspergillosis (IPA) and his oxygen requirements were minimal and stable. While most cases of SARS-CoV-2 infection-related aspergillosis, including cases involving the GI tract, are due to an initial pulmonary insult,19 it is plausible that SARS-CoV-2 infection resulted in some immune modulation, predisposing this patient to IGIA. We hypothesise that IGIA in our patient likely resulted from ingested spores and either directly led to bowel necrosis or successfully evaded the immune system due to already necrotic bowel and critical illness, given the elevated GM on the third day of hospitalization.
Manifestations and complications of IGIA include tissue necrosis, ulceration, haemorrhage, bowel perforation, obstruction due to aspergillomas with possible secondary appendicitis, and mesenteric invasion leading to septic thromboembolism.13
Due to the absence of typical risk factors in atypical hosts and the rarity of the condition, IGIA often escapes routine consideration in the differential diagnosis process, posing a significant risk of delayed diagnosis and treatment initiation. The diagnosis necessitates histopathological evidence indicating hyphal infiltration of the intestinal wall, arteritis, and/or thrombus formation within intramural vessels. Alternatively, tissue culture from the affected site showing growth of Aspergillus spp can confirm the diagnosis.13 Serum GM and BDG can be used as adjunctive tests to establish an early diagnosis. However, it is crucial to note their limitations. False-positive BDG assays have been documented with the use of certain gauze products, dialysis membranes, albumin, IVIG, blood products, and GI translocation of candida.20 False-positive GM may be seen with breakdown of GI mucosal barriers, certain foods, glucose-containing IV products,21 and in cases of other invasive mycoses besides IA. The reported performance of GM and BDG varies across studies, contingent on the cut-off value for positivity, type of invasive fungal infection, and the characteristics of the patient population. For instance, a meta-analysis conducted by Huang et al assessed the diagnostic accuracy of serum GM and BDG in patients suspected of having IA, predominantly comprising individuals with severe immunocompromising conditions and/or haematological malignancies. They found that the pooled sensitivity and specificity of GM were 0.53 (95% CI 0.40 to 0.66) and 0.94 (95% CI 0.91 to 0.97), respectively, whereas for BDG, the pooled sensitivity and specificity were 0.72 (95% CI 0.61 to 0.81) and 0.82 (95% CI 0.73 to 0.88), respectively.22 In non-neutropenic patients with IPA, Wu et al found that serum GM had a sensitivity of 16.7% and a specificity of 98.5% with a cut-off value of 1.23 In ICU patients with IPA who did not have haematological malignancies or neutropenia, Acosta et al reported a sensitivity of 50% and a specificity of 90% for serum GM with a cut-off value of 0.5. However, only a limited number of patients with probable or proven aspergillosis were included (n=9).24 Of note, since IPA is the most common manifestation of IA, there is more extensive, although limited, literature documenting the utility and performance of bronchoalveolar lavage GM in ICU patients, though there is debate regarding the optimal cut-offs.25–27 In general, the performance characteristics of serum GM outside the haematological malignancy population are not well characterised. The pretest probability of IA must be considered when interpreting any positive result.
IGIA has been reported to have a mortality rate of 39%13 with improved survival rates observed with combination antifungal and surgical therapy. Consequently, the management of IGIA often involves a combination of medical and surgical intervention, guided by the severity of the infection. Rapid identification of this process is required to allow for timely surgical intervention and appropriate medical management.18 28 However, to date, no optimal therapy protocol has been clearly defined.29 Among antifungals, triazoles are typically preferred, with voriconazole being recommended as the first-line agent. Additionally, amphotericin B, echinocandins and possibly flucytosine are recognised as effective antifungal agents. Echinocandins are not recommended for use as monotherapy for the primary treatment of IA. Combinations of polyenes or azoles with echinocandins have shown additive or synergistic effects in some preclinical studies.30 Although robust clinical data demonstrating the efficacy of combination therapy are lacking, it is sometimes used for salvage therapy. For refractory or progressive IA, management may involve switching antifungal class, tapering or reversing underlying immunosuppression when feasible, and surgical intervention. There are very few reported cases of IGIA in immunocompetent hosts in the literature. For instance, in one case with colonic disease, treatment involved surgical resection followed by administration of amphotericin and subsequent voriconazole therapy,18 and another case of gastric aspergillosis was managed solely with surgical resection.31 A high index of suspicion is required in patients with extensive, progressive bowel necrosis of unclear aetiology, in the absence of a known vasculitis. Fungal markers must be interpreted with caution in immunocompetent hosts.
Learning points
Invasive aspergillosis (IA) primarily affects severely immunocompromised patients, but it can also occur in those with critical illness, COPD, steroid use, liver disease, and recent viral infections.
Invasive gastrointestinal aspergillosis (IGIA) should be considered in patients with extensive, progressive bowel necrosis of unclear aetiology, especially in the absence of a known vasculitis.
IA diagnosis requires a combination of host factors, biomarkers, imaging, and tissue sample analysis. While serum BDG and GM are useful biomarkers, their performance in ICU patients is not well characterized. One study noted a relatively high specificity of GM in ICU patients with IPA. Elevated levels should be cautiously interpreted in immunocompetent hosts.
The presence of fungal hyphae with tissue and vessel involvement, along with inflammation and necrosis, is highly suggestive of IA.
Management of IGIA typically involves both medical and surgical interventions. First-line antifungal agents include triazoles such as voriconazole. Amphotericin B may be used as a second-line option. Combination therapies with echinocandins can be used as salvage therapy.
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References
Footnotes
Contributors The following authors were responsible for drafting of the text, sourcing and editing of clinical images, investigation results, drawing original diagrams and algorithms and critical revision for important intellectual content: AH, TH, FR and ZW. The following authors gave final approval of the manuscript: AH, TH, FR and ZW. The guarantor is AH.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.