A Diagnostic Dilemma: Disseminated Histoplasmosis Presenting as a Small-Bowel Obstruction

Introduction

Histoplasma capsulatum is a dimorphic fungus endemic to the Ohio and Mississippi river valleys in the United States, but also present worldwide, mainly in parts of Central and South America [1]. The fungus is found in soil enriched with bird and bat guano, and infection usually occurs when the soil is disturbed, resulting in conidia becoming airborne and being inhaled [2]. In endemic areas, the incidence of histoplasmosis is estimated to be 6.1 cases per 100 000 population; however, most (approximately 90%) infections are asymptomatic or develop only mild symptoms [1,3]. On the other hand, infections in immunocompromised patients, such as those taking immunosuppressive treatments or those with Human Immunodeficiency Virus (HIV) can often lead to the disseminated form of the disease, spreading from the lungs to other organs such as the gastrointestinal (GI) tract, skin, liver, spleen, bone marrow, and CNS [1].

In cases of disseminated histoplasmosis (DH), autopsies have shown that 70% of patients had GI involvement; however, only 10% of cases have symptomatic manifestations for GI involvement, and those that do rarely present as small-bowel obstructions [4,5]. Even more rare is the manifestation of hypercalcemia secondary to DH, a symptom reported in only 16 other cases [6]. The mortality rate of DH in patients when treated is 25%, while that of those left untreated is 80–100% [1,7]. Delays in diagnosis are a significant cause of high mortality rates and are attributed to a number of factors, including the non-specificity of histoplasmosis symptoms, which can mimic and be confused for other diseases such as inflammatory bowel disease, tuberculosis, sarcoidosis, community-acquired pneumonia, and malignancy [1,8].

This report portrays a rare presentation of DH in a non-HIV immunocompromised patient. The symptoms manifested during the period of infection highlight the wide array of symptoms that can present during cases of DH.

Case Report

A 64-year-old woman with a history of chronic kidney disease stage 3, depression, anemia, rheumatoid arthritis on tumor necrosis factor (TNF)-α inhibitor (infliximab), and long-term cannabis use for joint pain presented as an outpatient to the gastroenterology clinic for evaluation of abdominal pain/bloating and weight loss (50 lbs). Work-up included elevated fecal calprotectin at 365 mc/g (<50mcg/g), and a computed tomography (CT) scan of the abdomen showed inflammation and strictures in the distal ileum, while colonoscopy to the distal ileum was normal (Figure 1). Capsule endoscopy and double-balloon enteroscopy with biopsy led to the consideration of possible Crohn’s disease or infection, due to findings of the stenotic segment of distal ileum with abnormal nodular folds, ulcerated mucosa with inflamed granulation tissue, active and chronic inflammation (Figure 2), and fungal organisms (Figure 3). Unfortunately, culture was not performed on the original histology specimen.

The patient subsequently developed tachycardia and tachypnea and presented to a local hospital for further evaluation. Her symptoms of fever persisted despite broad-spectrum IV antibiotics and antifungals, including vancomycin (loading dose of 1500 mg once, followed by maintenance dose of 1000 mg q24h), micafungin (100 mg IV q24h), and meropenem (1 g q8h), suggesting either resistant bacterial infection, non-Candida spp. fungal infection, or non-infectious causes such as autoimmune disease or malignancy. She was then transferred to a tertiary facility for further work-up, including magnetic resonance cholangiopancreatography (MRCP) and CT enterography, which showed multifocal biliary strictures causing intrahepatic but not extrahepatic dilation, suggesting primary sclerosing cholangitis (PSC). A 6-cm segment of the terminal ileum had moderate wall thickening and mucosal hyperemia with a stricture, further raising suspicion of Crohn’s disease. Chest CT was done to evaluate shortness of breath, which showed extensive bronchiolitis with multifocal bronchopneumonia, and innumerable lower-lung predominant bronchocentric nodules. Shortly thereafter, the patient underwent bronchoscopy with the collection of bronchoalveolar lavage (BAL) that was unrevealing for infection. During this time, all the patient’s immunosuppressive treatments for rheumatoid arthritis, including infliximab (390 mg IV every 30 days), methotrexate (2.5 mg PO once per week), and prednisone (5 mg PO daily), were stopped.

Upon further investigation of the patient’s social history, she had recently traveled to Indiana, raising concern for possible fungal sources. Serum histoplasmosis antigen was positive, but urine antigen testing was negative. There was concern about false positives due to cross-reactivity, and multiple negative urine confirmatory tests resulted in the decision to not start antifungal treatment. The patient was therefore discharged with levofloxacin (750 mg PO once daily to complete a 7-day course) for pneumonia with a follow-up appointment with the GI Clinic for a possible diagnosis of Crohn’s disease. A complete investigation of possible Histoplasma diagnosis is represented in Table 1.

Prior to outpatient follow-up, she was re-admitted via the hospital’s emergency room with hypercalcemia at 13.9 mg/dL (8.8–10.29 mg/dL) with altered mental status, hallucinations, lethargy, and disorientation. Hypercalcemia was improved with IV fluids (2 L bolus IV normal saline plus maintenance normal saline at 100 cc and 1 dose of zoledronic acid 4 mg IV). With the evidence of hypercalcemia, a granulomatous disease such as histoplasmosis was higher on the differential with continued positive serum antigen, previously thought to be a false positive. The patient was therefore started on itraconazole (100 mg PO twice daily for 1 year) due to suspected histoplasmosis infection and discharged.

Despite itraconazole, the patient presented to the Emergency Department 1 week later with abdominal pain and obstructive symptoms due to high-grade obstruction related to a 3-cm-long stricture in her terminal ileum, as shown by CT (Figure 4). She was switched off itraconazole and placed on intravenous (IV) liposomal amphotericin B (5 mg/Kg q24) for 2 days. Due to the severity of intestinal obstruction, she underwent a laparoscopic ileocolic excision, excision of the mesenteric nodule, and diverting loop ileostomy. Grocott Methenamine Silver (GMS) staining (Figure 5) and broad-range bacteria PCR with sequencing run on terminal ileal tissue biopsy (Figure 6) taken during surgery confirmed the diagnosis of DH with GI involvement. On discharge, the patient was transitioned back to itraconazole (100 mg PO twice daily for 1 year). Two months after surgery, she was restarted on infliximab (390 mg IV every 30 days) immunosuppressive treatment for her rheumatoid arthritis. The full timeline of case development is shown in Figure 1.

Discussion

In this case report, we present an immunocompromised patient diagnosed with DH with GI involvement, 3 months after the initial onset of symptoms. The non-specificity and large variety of symptoms that can be manifested by DH commonly result in delayed or misdiagnosis [8].

Given the initial presentation of abdominal pain, bloating, weight loss, and imaging findings, Crohn’s disease was high on the differential in a patient with co-morbid rheumatoid arthritis. Further diagnostic findings, including capsule endoscopy and double-balloon enteroscopy with chronic ileitis on pathology, further confirmed Crohn’s disease as a diagnostic consideration. The subsequent development of PSC, which is also associated with inflammatory bowel disease, also created a clearer diagnosis [9]. However, several features brought this into question as the sole etiology for the patient’s presentation, including the development of inflammation and stricturing despite treatment with itraconazole, the presence of lung nodules, and severe hypercalcemia. In an immunocompromised patient, it is always imperative to consider infection as a top differential diagnosis. Ultimately, the histopathology findings permit differentiation of this fungal disease versus Crohn’s, especially when GI symptoms and endoscopy findings are characteristic of both conditions.

Patients with DH usually have a history of HIV/AIDS or immunosuppressive treatments [1]. The immunosuppressant culprit in this case, infliximab, acts as an antibody to TNF-α and is commonly used in autoimmune conditions, leading to an immunocompromised state [14]. The mechanism for defense through lymphocyte exposure to Histoplasma capsulatum is the secretion of TNF-α granulomas; however, in infliximab patients these are neutralized, leading to increased intracellular growth of opportunistic infections such as Histoplasma capsulatum [14]. In DH patients, the infection usually starts in the lungs after inhalation of fungal spores, forming pulmonary nodules and, in 90.7% of cases, pneumonia [15]. Histoplasma capsulatum can then disseminate into other tissues via macrophage transport [16]. Given our patient’s rheumatoid arthritis and immunosuppressive therapy, there was a significant risk that this treatment could exacerbate a fungal infection such as histoplasmosis. To manage this treatment contradiction, we can consider the following strategies such as risk assessment, adjusting medication, and antifungal prophylaxis. Regular evaluation of the patient’s risk for fungal infections and early detection are crucial for effective management. In each patient, if possible, the dose of the immunosuppressive medications may be adjusted or switched to lower the risk of fungal infection without exacerbating the underlying autoimmune condition.

DH to the GI tract is quite common in patients (70% of disseminated cases), but it is usually asymptomatic and only revealed during autopsy [4]. When patients are symptomatic (10%), manifestations of the disease usually occur in the colon and ileum due to their abundance of lymphoid tissues [17,18]. Symptoms such as abdominal pain, diarrhea, weight loss, and GI bleeding are often non-specific and mimic those of other GI conditions such as hepatitis (15.4%), intestinal obstruction (12.2%), inflammatory bowel disease (7.3%), abdominal malignancy (7.3%), and cholecystitis (5.7%), and abdominal tuberculosis (2.4%) [15]. Although ileal or colonic strictures secondary to GH are rare, they have been reported and often manifest with mucosal ulceration, inflammation, granulomatous tissue inflammation, and caseating or non-caseating mucosal granulomas [5,19–21]. Symptoms and pathology of biopsy tissue from GI tracts infected with histoplasmosis often result in the misdiagnosis of Crohn’s disease, as in our case. Hypercalcemia is an even rarer manifestation of histoplasmosis, caused by expression of 1-α-hydrolase enzyme, with only 16 other known cases being reported, of which none had symptoms indicative of GH. Pancreatic involvement in cases of DH has also been reported, manifesting as pancreatitis, pancreatic masses, cystic lesions, granulomas, and microcalcifications [12,13], but these are very rare.

The criterion standard diagnostic tool for histoplasmosis is widely considered to be demonstration of yeast on pathological stains and fungal culture of clinical specimens; however, Histoplasma antigen assays are also used because they can provide quick results. Additionally, molecular methods of Histoplasma detection, mainly consisting of PCR assays, although not presently FDA-approved, are a very promising diagnostic tool [22]. Serologic antibody detection tests exist as well, but the low sensitivity in immunocompromised patients reduces their effectiveness in cases of DH [23]. In patients without DH without HIV/AIDS, the percentages of positive histoplasmosis results for culture, pathology, antigen, and serology are 74.2%, 76.3%, 91.8%, and 75%, respectively, while molecular assay studies are estimated to have 33–87% sensitivity in clinical settings [22]. Due to the low sensitivities of these tests resulting in false negatives, diagnosis of histoplasmosis is often impaired (Table 2). In our case, false negatives with Gram stains, urine antigen, and PCR testing resulted in substantial delays in diagnosis and treatment. Although Histoplasma antigen sensitivities are certainly the highest, the concern for cross-reactivities with other fungal antigens limits their usefulness [22].

The complexity/rarity of DH symptoms presented a diagnostic dilemma, which ultimately led to bowel resection and diagnosis. A review of potential clinical misjudgments for clinicians who may encounter disguised cases of histoplasmosis provides a learning opportunity and may thus improve patient care. In immunocompromised patients, prompt collection of fungal culture with biopsy is crucial, especially after observation of fungal organisms, as seen on double-balloon enteroscopy in this case. Additionally, protocols to increase sensitivities of Histoplasma antigen tests exist and should be recommended when suspicion is high; these include ultrafiltration of urine, a method which has shown the ability to detect Histoplasma in 73.8% of (standard urine antigen) false-negative specimens, or ethylenediaminetetraacetic acid (EDTA) and heat denaturation of serum proteins [24,25]. Furthermore, BAL has been shown to be a superior source for Histoplasma antigen detection, with a sensitivity of 93%, compared to that of urine (79%) and serum (65%) in infected patients [22].

Conclusions

In conclusion, this case demonstrates diagnostic challenges and complexities associated with diagnosing DH in an immunocompromised patient. The initial presentation of non-specific GI symptoms, coupled with imaging findings suggestive of Crohn’s disease, highlights the potential for misdiagnosis in such cases. The patient’s co-morbid rheumatoid arthritis and treatment with infliximab further complicated the clinical picture, as this immunosuppressive therapy can increase susceptibility to opportunistic infections like Histoplasma capsulatum. The dissemination of histoplasmosis to the GI tract is often asymptomatic, yet when symptoms do manifest, they can mimic those of various other GI disorders, leading to diagnostic dilemmas. This case emphasizes the importance of high suspicion for infectious etiologies in immunocompromised patients presenting with GI symptoms. Additionally, it underscores the need for clinicians to utilize the most suitable and sensitive diagnostic tests to accurately detect the presence of such infections. Clinicians should review suspected Crohn’s disease in patients with a clouded clinical picture who are at risk for opportunistic infections.