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 and, 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(Drug information on 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 GI 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 Zygomycetes, 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
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; additionaly, 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 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.
Aspergillus species
Aspergillus species, like other fungal species, such as 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. An Aspergillus galactomannan enzyme immunoassay test has become available for the diagnosis of invasive aspergillosis. Unfortunately, it is not clear that it is a sufficiently sensitive (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. 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 should be suspected of being of fungal origin and 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(Drug information on amphotericin b), amphotericin B cholesteryl sulfate]); 2) the azoles (fluconazole, itraconzaole, voriconazole(Drug information on voriconazole), posaconazole); and 3) the echinocandins (caspofungin, micafungin(Drug information on 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 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(Drug information on 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 Zygomycetes. Posaconazole can only be orally administered and is well absorbed. It is broadly active against most Candida species and most molds, including the Zygomycetes. Drawing azole levels should be considered for itraconazole, voriconazole, and posaconazole.
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.
Candidiasis
Local 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 (1.0 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(Drug information on caspofungin) can be used. All of these formulations are less nephrotoxic than amphotericin B deoxycholate.
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 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) neutropenic AML (acute myelogenous leukemia) and MDS (myelodysplastic syndrome) patients; 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 (steroids, GVHD) for aspergillosis.
Suggested reading on fungal infections
Pappas PG, Kauffman CA, Andes D, et al: Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 48:503–535, 2009.
Walsh TJ, Anaissie EJ, Denning DW, et al: Treatment of aspergillosis: Clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 46:327–360, 2008.
Ito IJ, Kriengkauykiat J, Dadwal SS, et al: Approaches to the early treatment of invasive fungal infection. Leuk Lymphoma 51:1623-1631, 2010.
