Typhlitis

Typhlitis (neutropenic enterocolitis) occurs in patients who are severely neutropenic, usually in the setting of chemotherapy. Pathologically, the areas of involvement include the cecum and terminal ileum. Typhlitis is a broad-spectrum disease characterized by bowel wall edema, diffuse or patchy necrosis involving the mucosa alone or the full thickness of the bowel wall, mucosal ulcerations, hemorrhage, inflammatory infiltrates, and infiltration of the bowel wall by bacteria or fungi. Mild cases are self-limiting when treated with bowel rest/antibiotics. Death may occur in severe cases.

Signs and Symptoms

Signs and symptoms of typhlitis can be nonspecific but usually include fever, abdominal pain (typically in the right lower quadrant), and abdominal distention. The patient may have diarrhea (sometimes bloody), nausea, and vomiting or may demonstrate signs and symptoms consistent with those of acute appendicitis.

There may be abdominal guarding and rebound tenderness, diminished bowel sounds, or even a mass in the right lower quadrant of the abdomen.

Diagnosis

Radiographs or CT scans of the abdomen may demonstrate a thickened cecum, mass, or even gas within the colon wall.

Treatment

Mortality from typhlitis is high (> 50%), and therapy is controversial. However, broad-spectrum antibiotics covering both gut aerobes and anaerobes, as well as resection of necrotic bowel, are recommended.

Fungal Infections

Fungal infections are a leading cause of morbidity and mortality in cancer patients. These infections pose a formidable management challenge, in that diagnosis is often difficult to make at an early stage, therefore appropriate treatment may be delayed.

Etiology and Risk Factors

Candida species

The most common fungal infections in cancer patients are caused by Candida species. Of the candidal pathogens found in these patients, C albicans is the most common. However, more recently other Candida species, such as C tropicalis, C glabrata, C parapsilosis, C krusei, and C lusitaniae, have become more prevalent. This finding is significant, as many of these species can be resistant to fluconazole (C krusei, C glabrata, C lusitaniae) and echinocandins (C parapsilosis, C guilliermondii).

Major risk factors for candidal infections include neutropenia, a breakdown in physical defense barriers (such as mucositis induced by chemotherapy and radiation therapy), broad-spectrum antibiotics, immune dysfunction (caused by chemotherapy and steroids), surgery (especially gastrointestinal surgery), long-term indwelling vascular catheters, and poor nutritional status/total parenteral nutrition.

Aspergillus species

Aspergillus species are a less common cause of infection in cancer patients than candidal organisms, although Aspergillus infections have surpassed Candida in HCT recipients. The most common of the Aspergillus species is A fumigatus, followed by A flavus, A niger, and A terreus.

Risk factors for Aspergillus infections include severe immunosuppression (primarily allogeneic HCT), steroid therapy, antitumor necrosis factor therapy, GVHD, and environmental exposure.

Other fungi

Other fungal pathogens in the cancer patient include the Mucorales (Zygomycetes) species, Fusarium, and Scedosporium species; Cryptococcus; and the dematiaceous/pigmented fungi (eg, Bipolaris spicifera, Cladosporium bantianum).

Finally, the endemic fungi, Coccidioides immitis and Histoplasma capsulatum, are often more virulent and aggressive than other fungi in the immunocompromised host.

Signs and Symptoms

Candidiasis

Candidiasis can present as a wide spectrum of diseases, from mucosal infection to disseminated and invasive disease.

Oropharyngeal candidiasis can present as classic thrush with beige plaques. It may be painful, as there may be a concurrent mucositis due to the ablative chemotherapy. Oropharyngeal candidiasis may extend into the esophagus, which may manifest as odynophagia. Epiglottitis may present as odynophagia and laryngeal stridor.

Candidemia may present simply as an asymptomatic fever or may result in a full-blown septic shock syndrome (acute disseminated candidiasis). In contrast, chronic disseminated candidiasis is an indolent infection of different organs, such as the liver, spleen, and kidneys, which may be manifested by fever alone.

Aspergillosis

Invasive aspergillosis most commonly involves the lungs and sinuses. However, it can also disseminate to the brain (and may be the most common cause of brain abscesses in HCT patients). Less commonly, Aspergillus can disseminate to other organs, including the skin.

Signs and symptoms of invasive pulmonary aspergillosis include pleuritic pain, pulmonary hemorrhage, hemoptysis, and cavitation. The chest radiograph or CT scan may demonstrate pulmonary nodular infiltration and/or cavitary lesions.

Patients with sinusitis may have few signs (swelling) or symptoms (pain), especially if they are neutropenic.

Patients with brain abscesses may have headaches and neurologic signs consistent with the specific site of the lesion.

Skin involvement may present as necrotizing skin nodules or ulcers.

Other infections

Mucorales (Zygomycetes) infections cause sinopulmonary disease, similar to aspergillosis, and have recently been rising in incidence.

Scedosporium and Fusarium infections are also similar to those of aspergillosis; pulmonary infiltrates and sinusitis are prominent manifestations. They can be found in the bloodstream; additionally, cutaneous lesions can be seen with Fusarium.

C immitis and H capsulatum also target the lungs but can disseminate to other organs.

Cryptococcus infections can cause pneumonia, meningitis, and cellulitis/skin lesions.

Diagnosis

Diagnosis of fungal infection in the cancer patient requires documentation by culture, serology, or histologic examination.

Candidiasis

Although the diagnosis of oropharyngeal candidiasis often is made on clinical grounds, the lesions should be scraped for microscopic examination and culture. Biopsy of esophageal lesions via endoscopy should be performed to confirm Candida (as opposed to HSV or CMV) as the etiology of the infection.

A positive blood culture for Candida (especially a species other than C albicans) should never be considered a “contaminant” and often implies a right atrial catheter infection. A glucan assay [(1,3)-β-D glucan] may be positive in a patient with disseminated candidiasis. Less likely to result in positive blood cultures are chronic, deep-seated infections, such as hepatosplenic candidiasis. Such infections require biopsy for confirmation. New tests may include rapid diagnostics, such as T2 Biosystems’s T2Candida Panel.

Aspergillus species

Aspergillus species, like other fungal species, such as those of the Mucorales order (Zygomycetes) and dematiaceous fungi, are rarely found in the bloodstream and tissue sampling is required for diagnosis. Occasionally, bronchoalveolar lavage fluid or sinus drainage will yield Aspergillus, but often a lung biopsy is required. A galactomannan enzyme immunoassay test has become available for the diagnosis of invasive aspergillosis. Unfortunately, it is not clear that it is a sufficiently sensitive test (especially in patients receiving antifungal agents) or a predictive test for the disease. It can be performed on serum or bronchoalveolar lavage fluid. There are also two other diagnostic tests now available: the glucan assay and the Aspergillus DNA PCR test. The glucan assay suffers from a high incidence of false positives, and the PCR test for Aspergillus has not been standardized among laboratories.

Fusarium and Scedosporium

Fusarium and Scedosporium, in contrast to Aspergillus species, are often isolated from the bloodstream.

Skin lesions

Any skin lesion suspicious for fungal infection should be biopsied, cultured, and examined histologically.

Search for sites of infection

When a fungal infection is suspected or documented, a search for possible sites of infection should ensue. For a blood culture that grows a Candida species, the intravascular catheter should, in most cases, be removed for diagnostic as well as therapeutic reasons, and the catheter tip should be cultured. A CT scan of the abdomen should be obtained. In cases of suspected Aspergillus infection, in addition to a CT scan of the chest, a CT scan of the brain and sinuses should be performed.

Treatment

Antifungal agents

There are now three major groups of antifungal agents: (1) the polyenes (amphotericin B deoxycholate and its lipid formulations [amphotericin B lipid complex, liposomal amphotericin B, amphotericin B cholesteryl sulfate]); (2) the azoles (fluconazole, itraconzaole, voriconazole, posaconazole); and (3) the echinocandins (caspofungin, micafungin, anidulafungin [Eraxis]).

Amphotericin B deoxycholate has been the standard therapy for invasive fungal infection for 50 years. It is fungicidal and has a broad spectrum of activity against yeasts and molds, including the Mucorales (Zygomycetes). It is thought to be less active against A terreus, Scedosporium, C guilliermondii, and C lusitaniae. However, it is limited by its nephrotoxicity and infusional toxicity. The lipid formulations are less nephrotoxic but much more expensive than the other formulations.

The azoles are not nephrotoxic. The first-generation azoles (fluconazole and itraconazole) are considered fungistatic, whereas the extended-spectrum azoles (voriconazole and posaconazole) are considered more fungicidal. Fluconazole is well absorbed orally and can be administered orally or intravenously but is not active against molds and certain Candida species (C krusei). Itraconazole is hepatotoxic and is not well absorbed when orally administered. Voriconazole is well absorbed orally and can also be administered intravenously. It is broadly active against most Candida species and most molds, with the exception of the Mucorales (Zygomycetes). Posaconazole can only be orally administered. The suspension requires ingestion of a high-fat meal and is pH-dependent. The new oral tablet is not pH-dependent. It is broadly active against most Candida species and most molds, including the Mucorales (Zygomycetes). Drawing azole levels should be obtained for itraconazole, voriconazole, and posaconazole. Trough levels are recommended to ensure adequate drug concentrations, and there are increasing data indicating correlation to efficacy.

The echinocandins are the least toxic of the antifungal agents. They can only be administered intravenously. They are said to be fungicidal against yeasts but fungistatic against molds.

An intravenous formulation of posaconazole was approved in March 2014. Isavuconazole is also available, having been approved for both invasive aspergillosis and mucormycosis in March 2015.

Candidiasis.

• Mucosal candidiasis—In patients with local mucosal candidiasis (including esophagitis), oral fluconazole or itraconazole can be used. If the patient has difficulty in taking oral medication, IV fluconazole should be used. If the patient was receiving prophylactic fluconazole when candidiasis developed, there is a high likelihood that the causative Candida species may be azole-resistant, and either an echinocandin or a lipid formulation of amphotericin B should be used.

• Candidemia—If candidemia is documented, the intravascular catheter should be removed. This step should be followed by the administration of an antifungal for at least 2 weeks after the last positive blood culture is obtained and all signs and symptoms have resolved. Although fluconazole has been shown to be an effective and safe agent in the treatment of candidemia, there are certain circumstances in which an alternative (an echinocandin or a lipid formulation of amphotericin B) might be preferable. These situations would include hemodynamic instability, neutropenia, or high suspicion of azole resistance (eg, a patient who is colonized with a resistant Candida species or has been on recent fluconazole prophylaxis or treatment).

• Disseminated, deep-seated candidiasis (eg, hepatosplenic infection)—Although the standard of therapy for deep-seated candidiasis has been long-term therapy with amphotericin deoxycholate, it has been limited by nephrotoxicity. Thus, the lipid formulations of amphotericin B have allowed higher cumulative doses with a lower nephrotoxic potential. The azoles (fluconazole, voriconazole) have the advantage of convenient (ie, oral) administration and good absorption, with little toxicity. The echinocandins also have been shown to be effective against this infection.

Aspergillosis.

• Antifungal therapy—Amphotericin B deoxycholate (1 to 1.5 mg/kg/d) had long been the standard therapy for invasive aspergillosis. However, voriconazole has led to better responses, improved survival, and fewer adverse events compared with amphotericin B when used as initial therapy in patients with invasive aspergillosis. Thus, voriconazole is now the standard therapy for invasive aspergillosis. However, amphotericin B lipid complex, amphotericin B cholesteryl sulfate, liposomal amphotericin B, posaconazole, and caspofungin can be used. All of these formulations are less nephrotoxic than amphotericin B deoxycholate. Although combination therapy with voriconazole and an echinocandin in a double-blind randomized trial did not definitively demonstrate superiority over monotherapy voriconazole, this combination may still be used in some cases.

• Surgical removal of infected sites—In addition to antifungal therapy, it is important to attempt surgical removal of infected sites, if at all feasible. Sinus surgery should be performed. Resection of pulmonary lesions should be attempted if there are only one or two limited, discrete lesions.

Infections with other fungi. Although amphotericin B is the drug of choice for most invasive fungal infections, there are exceptions. Scedosporium and Fusarium species are often resistant to amphotericin B, and voriconazole may be the drug of choice for these infections. Voriconazole, however, is not active against Mucorales (Zygomycetes) species, and if an infection with this organism is suspected, documented, or cannot be ruled out, amphotericin B deoxycholate, an amphotericin B lipid formulation, or posaconazole (only if a polyene cannot be tolerated) should be used. The dematiaceous/pigmented fungi also may be better treated with itraconazole. For Trichosporon infections, voriconazole may be more effective than amphotericin B.

Prevention

Because invasive fungal infection occurs with high frequency in the setting of HCT, most prophylactic studies have been performed in HCT recipients. Thus, the following recommendations apply mainly to this group, although prophylaxis can be justified when the incidence of these infections in any population is high enough.

Fluconazole

Two randomized, placebo-controlled studies using prophylactic fluconazole (400 mg/d) have demonstrated a decrease in invasive and superficial C albicans infections. One study showed a reduction in mortality. As fluconazole is not active against C krusei, C glabrata, or molds such as Aspergillus species, there is concern that its prophylactic use will increase the incidence of these resistant fungi. Some authors have reported such an occurrence.

Micafungin

Micafungin has been approved for use as an antifungal (candidiasis) prophylactic agent in HCT. There was also a trend toward protection against Aspergillus infection with micafungin, although it was not significant.

Itraconazole

Itraconazole has been shown to be an effective antifungal prophylactic agent in HCT, but no survival benefit has been demonstrated, possibly because of the toxic GI effects and hepatotoxicity associated with this agent.

Low-dose amphotericin B

Low-dose amphotericin B was observed, in a retrospective study, to decrease the incidence of Candida infection. However, this regimen only delayed the onset of Aspergillus infections.

Posaconazole

Posaconazole has been shown to be effective antifungal prophylaxis in two settings: (1) patients with neutropenic AML (acute myelogenous leukemia) and MDS (myelodysplastic syndrome); and (2) allogeneic HCT recipients with GVHD.

Voriconazole

Voriconazole has been shown to be as efficacious as fluconazole. However, it has not resulted in a significant prevention of aspergillosis or demonstrated a survival benefit.

Other prophylactic regimens

Other prophylactic regimens have been used in small numbers of patients, with various degrees of success. They include aerosolized amphotericin B, intranasal amphotericin B, and amphotericin B lipid complex.

The prophylactic regimen

The prophylactic regimen of choice in HCT might be an echinocandin (eg, micafungin) initially (while the patient is neutropenic and hospitalized) followed by an oral azole (eg, posaconazole) administered to outpatients who remain at high risk for mold infections.

HEPA filtration

Other than using prophylactic antifungals, there is little that can be done to prevent fungal infections in cancer patients. The one possible exception is the use of HEPA filtration, which can eliminate Aspergillus spores from the environment. However, most patients emerge from this environment still possessing the same risk factors (treatment with steroids, GVHD) for aspergillosis.