Advances in Anatomic Pathology:
Fungal Infections of the Gastrointestinal Tract in the Immunocompromised Host: An Update
Lamps, Laura W. MD*; Lai, Keith K. T. MD*; Milner, Danny A. MD, MSc†
*Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR
†Department of Pathology, Brigham and Women’s, Harvard Medical School, Boston, MA
All figures can be viewed online in color at http://www.anatomicpathology.com
D.A.M. is currently receiving grant funds for Malaria research from the NIH.
L.W.L. receives royalties from Amirsys Publishing Company for chapter royalties; D.A.M. has been paid money by Up To Date for malaria and stool diagnostics and has been paid money by Biosciences Solutions Group LLC as a partial owner of laboratory consulting firm. The remaining author has no conflicts of interest to disclose.
Reprints: Laura W. Lamps, MD, Department of Pathology, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Slot 517, Little Rock, AR 72205 (e-mail: firstname.lastname@example.org).
Fungal infections are one of the most significant causes of morbidity and mortality in immunocompromised patients. The incidence of invasive fungal infections, including those of the gastrointestinal tract, has increased significantly as numbers of immunocompromised patients have increased. The diagnosis of fungal infections in immunocompromised patients may be particularly problematic as these patients may present with atypical clinical features. Although Candida and Aspergillus species represent the majority of fungi diagnosed in the immunocompromised patient population, other fungi are emerging as increasingly common pathogens, and this review will focus on several important emerging fungal infections in immunocompromised patients.
Infections are one of the most common complications in immunocompromised patients, and the endemic mycoses are one of the most significant infectious causes of morbidity and mortality in this population.1–3 The incidence of invasive fungal infections, including those of the gastrointestinal tract, has increased significantly over the past 20 years as numbers of immunocompromised patients have increased. Despite advances in laboratory technology, particularly in the areas of serologic and molecular testing, the recognition, diagnosis, and classification of fungal infections in this patient population remains challenging.
Although primary transmural invasion by fungi cause some gastrointestinal infections, disseminated fungal disease (and recognition thereof) is equally important. Signs and symptoms of gastrointestinal fungal infections include diarrhea, vomiting, melena, hemorrhage, abdominal pain, and fever, and are often similar irrespective of the type of fungus involved. The diagnosis of fungal infections in immunocompromised patients may be particularly problematic as these patients may present with atypical clinical features, and it is important to remember that GI signs and symptoms may be the initial and only presenting features of a disseminated illness.
The term “immunocompromised” is primarily associated with underlying disorders such as AIDS, chemotherapy, and solid organ and bone marrow transplantation. However, many other forms of immunocompromise also result in susceptibility to fungal infections, including primary immunodeficiencies (eg, common variable immunodeficiency), patients on chronic immunomodulatory therapy or steroids, very young or very elderly patients, diabetics, patients who are status—postsplenectomy, and those with chronic alcoholism, malnutrition, or any chronic debilitating disease.4–7
Although Candida and Aspergillus species represent the majority of fungi diagnosed in the immunocompromised patient population,5,6 other fungi are emerging as increasingly common serious pathogens. The organism to which any individual patient is susceptible varies with a number of factors, including the underlying disease, the degree of immunocompromise, and environmental factors, such as where the patient lives and types and magnitude of exposure. Furthermore, the host is the sole source of the inflammatory response to the organism, and the specific deficits in the host immune system along with the patient’s environment and exposure history create the differential diagnosis for any given mycosis. This review will focus on several important emerging fungal infections in immunocompromised patients.
Mucormycosis is a life-threatening infection caused by fungi of the order Mucorales.8–12 As noted above, Aspergillus species have long been recognized as the most commonly encountered filamentous fungus in the immunocompromised patient population. For reasons that remain poorly understood, however, the incidence of mucormycosis is increasing, particularly in patients with diabetes, hematologic malignancies, and bone marrow transplants.8 Recent reclassification abolished the order known as the Zygomycetes and placed the order Mucorales in the subphylum Mucoromycotina.13 Therefore, infection by these organisms is now referred to as “mucormycosis” rather than “zygomycosis.” Mucormycosis is associated with diabetes and other causes of metabolic acidosis, deferoxamine therapy, organ or bone marrow transplant, neutropenia, skin and soft tissue breakdown, intravenous drug use, neonatal prematurity, and malnourishment. Interestingly, HIV/AIDS does not appear to be a risk factor for this infection. The incidence appears to be increasing, especially in cancer patients. The mortality rate is quite high (over 40% in general) and even higher in patients with hematologic malignancies and those status—post-bone marrow transplant.9–12
The major categories of disease caused by the Mucorales are sinonasal/rhinocerebral, pulmonary, cutaneous/subcutaneous, gastrointestinal, and disseminated infection.9–12 Sinonasal/rhinocerebral disease represents one third to one half of all cases and is most often associated with diabetic ketoacidosis. Pulmonary disease is also common. Gastrointestinal zygomycosis14–16 is relatively uncommon, but often fatal, with mortality reportedly approaching 40% to 50%. Although any portion of the alimentary tract can be affected, gastric and colonic involvement are the most frequent. Ulcers are the most common gross manifestation, often large, with rolled, irregular edges that may mimic malignancy. These fungi may also superinfect previously ulcerated tissues, and disseminated disease may arise from primary gastrointestinal infection.
The lesions caused by Mucor and related species are histologically very similar to those seen in aspergillosis.17,18 Both Mucor and Aspergillus are angioinvasive (Fig. 1B), leading to thrombosis and areas of infarction and necrosis. The inflammatory response is variable, but neutrophils are usually prominent (Fig. 1C). Mucor produces broad, ribbon-like pauciseptate hyphae with irregular walls, which branch randomly at any angle (Figs. 1D, F). When cut at cross-section, they may appear optically clear. They do not produce spores. Segmented atypical forms can rarely be seen, which have a variable large, round to oval appearance and bear internal structures (Fig. 1E).
The differential diagnosis of mucormycosis primarily includes other fungal infections (Table 1). As above, aspergillosis and mucormycosis can closely mimic each other both clinically and morphologically (Figs. 1A, 2A).17,18 However, in contrast to Mucor, Aspergillus has septate hyphae of uniform width that branch at acute angles (Fig. 2B). Fusarium, an emerging filamentous fungal pathogen, that is also associated with neutropenia, closely mimics aspergillosis both clinically and radiographically and is indistinguishable from Aspergillus on morphologic grounds alone.19
Basidiobolomycosis is another fungus in the differential diagnosis of mucormycosis that has recently gained attention as a gastrointestinal pathogen.20–27 The causative organism, Basidiobolus ranarum, is a zygomycete of the order Entomophthorales and a worldwide soil saprophyte. This infection was originally described in Africa, Saudi Arabia, and Southeast Asia but has recently gained attention in the United States, primarily in Arizona.24–26 Risk factors include pediatric age group, peptic ulcer disease, diabetes, pica, ranitidine use, and living in an endemic area. Of note, unlike many of the other filamentous fungi, typical causes of immunocompromise such as neutropenia, HIV/AIDS, and organ transplantation are not risk factors for this infection. Gastrointestinal infections may mimic malignancy or chronic idiopathic inflammatory bowel disease clinically, and pericolonic masses that are worrisome for colon cancer are common in this disease.27
Although the fungi themselves are morphologically similar to Mucor, there are typically fewer of them on a given tissue section, and the fungi may have a “cellophane-ball” or crumpled appearance (Figs. 3A, B). In addition, Basidiobolus is not angioinvasive. The inflammatory response is also quite different from that of mucormycosis, featuring prominent eosinophilia, granulomas, and a Splendore-Hoeppli reaction to organisms (Figs. 4A–C).
Phaeohyphomycosis refers to infections caused by various (over 70 recognized species) dematiaceous or naturally pigmented fungi that develop as black molds in culture and are visible as pigmented brown organisms in tissue sections. These fungi are worldwide saprophytes present in soil, wood, and compost. Infections typically occur in immunocompromised hosts, and risk factors include neutropenia, bone marrow or solid organ transplantation, and exposure to dirt/soil through farming, gardening, or other outdoor work.28–34 Infections are most often subcutaneous, but gastrointestinal infections rarely occur, probably through colonization of preexisting ulcers.35 The inflammatory reaction is mixed and may consist of neutrophils, granulomas, or both. The organisms appear as variable sized, often branched fungi that are pigmented (Figs. 5A, B), although the pigment may be difficult to detect on hematoxylin and eosin (H&E) staining in some cases.17 Fontana-Masson stains may be useful in accentuating the melanin pigment (Table 1).
Accurate speciation of fungal infections is critical, because it significantly affects antifungal therapy. Culture remains the gold standard of diagnosis and speciation for fungal infections, but it may require a substantial amount of time for cultures to grow and to achieve speciation. More importantly, because of the clinical setting, culture material is not always available. The use of 18S rRNA sequence to identify fungus directly by polymerase chain reaction and sequencing is increasingly available as well and can be performed directly from either culture material or the paraffin tissue block. The phaeohyphomycoses cannot be speciated morphologically with certainty, and culture or molecular studies are required for definite classification. If no material is available for culture, then molecular assays should be attempted or the patient should be rebiopsied so that cultures can be performed.
In addition to molecular testing, there are 2 serological laboratory tests36 that are helpful for distinguishing between the various filamentous fungi that may be encountered on a slide. Galactomannan is a component of the Aspergillus cell wall that is released during growth. The galactomannan assay is a serologic test that is helpful in diagnosing invasive aspergillosis, as it is positive in invasive aspergillosis but negative in other invasive fungal infections. However, the galactomannan assay will cross-react with Penicillium marneffei (see below). The β(1.3)-d-glucan assay is also helpful as it is positive in virtually all disseminated fungal infections including Pneumocystis infection but is negative in mucormycosis.
THE DIFFERENTIAL DIAGNOSIS OF YEAST
Candida species are what most often comes to mind when considering gastrointestinal infections with yeast forms, and Cryptococcus remains the most common cause of mortality due to fungal infection in the HIV population.37 However, many other less common but important yeasts are emerging as important pathogens in the immunocompromised patient population.
P. marneffei is a dimorphic fungus that is endemic in Thailand, China, Hong Kong, Vietnam, and Indonesia. Patients with this infection who are encountered in the United States have almost always either traveled in these areas or lived there.38–42 Penicilliosis is emerging as one of the most common opportunistic infections in Asian patients with AIDS.39–42 Patients with this infection who are HIV-negative often have other immunocompromising conditions such as hematologic malignancies, autoimmune diseases, malnutrition, or other debilitating infections, and this infection has rarely been described in immunocompetent persons. P. marneffei most commonly involves the lungs and liver, followed by the gastrointestinal tract. Dissemination can occur in a matter of a few weeks and be quickly fatal, especially in immunocompromised patients.
The organism infects the mononuclear phagocyte system, and multiplies within histiocytes that enlarge to accommodate increasing numbers of organisms. The inflammatory response may be granulomatous, suppurative, or mixed (Figs. 5C, D). The organisms themselves are spherical to ovoid and pack and distend the involved macrophages. As the lesions expand, necrosis predominates, and the macrophages may lyse and release free organisms (Fig. 5F). The fungi are typically small (2 to 5 µm) and resemble histoplasma; however, occasional elongated and/or curved forms with a central septum and rounded ends (“pill capsule” form) may be present (Fig. 5E), and these may measure up to 20 µm. In addition, P. marneffei do not bud, as they divide at their central septum by fission.
The major organism in the morphologic differential diagnosis is Histoplasma capsulatum, as both may be intracellular and are of similar size.43,44Histoplasma capsulatum is endemic to the central United States but has been described in many nonendemic areas as well. Gastrointestinal involvement occurs in >80% of patients with disseminated infection. Histologic findings include diffuse lymphohistiocytic infiltrates and nodules, usually involving the mucosa and submucosa, with associated ulceration (Figs. 6A, B, and 7A). These lesions are often located over lymphoid aggregates. Discrete granulomas and giant cells are present in only a minority of cases. In immunocompromised patients, large number of organisms may be seen with virtually no tissue reaction. Although Histoplasma have easily identified buds at their pointed pole (Fig. 7B), P. marneffei does not bud and has a transverse septum. On H&E staining, Histoplasma within macrophages also have a surrounding small “halo,” reflecting the thin, poorly stained cell wall in contrast to the basophilic cytoplasm (Fig. 6C). In addition, the areas in which these 2 yeasts are endemic are very distinct.
Cryptococcus neoformans is a very commonly encountered yeast in the immunocompromised patient population that is an unusual but an important cause of GI infection.45,46 Virtually all patients with GI cryptococcosis have hematogenously disseminated disease with multisystem organ involvement, and most have associated pulmonary and meningeal disease. The inflammatory reaction is variable and depends on the immune status of the host, ranging from a suppurative, necrotizing inflammatory reaction, often with granulomatous features, to virtually no reaction such as in anergic hosts. Cryptococcus (measuring 4 to 7 µm) is larger than P. marneffei and typically shows considerable variation in size (Fig. 7D). Cryptococcus is round to oval and often has a “soap-bubble” area of clearing around the organism representing the poorly stained capsule on H&E sections (Fig. 7C). It also has frequent budding and lacks the transverse septum of P. marneffei. Cryptococcus stains with Fontana-Masson and often with mucicarmine. Of note, capsule-deficient C. neoformans and C. gattii (an emerging variant of Cryptococcus that is particularly prominent in the Pacific Northwest47,48 will often be negative with mucicarmine staining and require Fontana-Masson or other diagnostic methods for diagnosis (Figs. 7E, F).
Pneumocystis jiroveci (formerly carinii) is also an important entity in this patient population. Although the life cycle of this organism more closely resembles that of a protozoan, there is convincing molecular evidence indicating that P. jiroveci has greater homology with fungi. Extrapulmonary (including GI) involvement is not uncommon in the immunocompromised population,49,50 and in addition to patients with AIDS, Pneumocystis infection rarely has been reported in the context of organ transplant, hematologic malignancy, other immunodeficiency states, and steroid therapy. Pneumocystis infection has also been reported in association with infliximab therapy, an immunosuppressive treatment for Crohn disease and rheumatoid arthritis.50 Microscopically, granular, foamy eosinophilic casts similar to those seen in pulmonary Pneumocystis infection may be seen in mucosal vessels or in the lamina propria, which helps differentiate this from other types of infection (Figs. 8A, B). As in the lung, a wide variety of inflammatory responses may occur, including granulomatous inflammation, prominent macrophage infiltrates, and necrosis. The organisms are 5 to 7 µm spherules that have cup or crescent shapes when collapsed (Fig. 8C) but lack the transverse septum of P. marneffei and do not pack and distend macrophages. Many contain characteristic single or paired comma-shaped internal structures. Organisms stain with GMS and Toluidine blue. Moreover, Pneumocystis does not bud, which helps differentiate them from other similarly sized yeast.
Other entities in the differential diagnosis include Candida glabrata, which features tiny budding yeast forms of similar size to Histoplasma and P. marneffei but does not produce hyphae or pseudohyphae (Fig. 8D).17C. glabrata also have more frequent buds than Histoplasma, are often extracellular, and lack the “halo” that Histoplasma have in tissue sections. C. glabrata does not typically pack and distend macrophages and lacks the transverse septum of P. marneffei. Candida species yeast forms will also stain gram-positive on Gram stain.
Occasionally, other types of organisms such as Leishmania or Toxoplasma may enter the differential diagnosis of the smaller yeasts. Leishmania have a characteristic kinetoplast, are GMS-negative, and stain with Giemsa stain (Figs. 8E, F). Toxoplasma is also GMS-negative and stains with Giemsa (Fig. 9).
As with the filamentous fungi, accurate speciation of these invasive yeasts is critical, because it significantly affects therapy. When material is available, cultures are extremely helpful, although diagnostic features may be present on tissue sections that allow institution of therapy without waiting for mycological culture results. Molecular assays for many of these yeasts are increasingly widely available as well and can often be performed directly from the paraffin block. Immunohistochemical analysis and in situ hybridization assays are available for some of these entities but are not widely available.
As mentioned above, serologic tests36 may be helpful in this category of fungal infections as well. The galactomannan assay for detection of Aspergillus infection will cross-react with P. marneffei,51 which may have utility as the organisms appear quite different in tissue. The β(1.3)-d-glucan assay is also helpful, as it is positive in Pneumocystis infection (Table 2).
The authors gratefully acknowledge Dr George F. Gray, Jr, MD (Nashville, TN); Dr A. Brian West, MD (Yale School of Medicine, New Haven, Connecticut); Dr Matthew R. Lindberg (UAMS, Little Rock, AR); Dr Henry Appelman (University of Michigan, Ann Arbor, MI); Dr Rhonda Yantiss (Weill-Cornell School of Medicine, NY, NY); and Dr Becky Wheeler (Jefferson Regional Medical Center, Pine Bluff, AR) for their assistance with cases and photographs.
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invasive fungal infection; immunocompromised; mycoses; fungus; medically important fungi; filamentous fungi; yeast
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