Prophylaxis
Secondary pharmacologic prophylaxis for mucocutaneous infection may be started in patients who have experienced several episodes of thrush (in advanced AIDS) or vaginitis (in pregnancy). Profoundly neutropenic patients with sufficient mucosal breakdown to provide portals of entry for Candida into the bloodstream require primary pharmacologic prophylaxis until the mucosal barriers have recovered their protective function. Examples of such mucosal barrier breakdown include, but are not limited to, mucositis during bone marrow transplant procedures, GI graft versus host disease (GVHD), and viral gastroenteritis. Prophylactic medications can be topical or systemic, depending on the site involved and the patient’s tolerance of individual agents.
The use of antifungal chemotherapy can shift GI yeast flora from C. albicans to fluconazole-resistant species. For that reason, candidal infections that occur during fluconazole prophylaxis require culture and sensitivity testing to determine definitive treatment.
Prognosis
Fortunately, most candidal infections are readily manageable, provided that further diagnostic investigation (e.g., susceptibility testing and radiography) is pursued for poorly responsive infections. Morbidity and mortality remain highest for patients with hematogenous and major-organ candidiasis.
Cryptococcosis
Epidemiology
Cryptococcus neoformans is a yeast that is widely distributed in nature. Environmental sources of C. neoformans include aged pigeon droppings, pigeon nesting areas, dust, and eucalyptus trees.19 However, most persons exposed to environmental sources of C. neoformans do not experience symptomatic disease. Suppressed cell-mediated immunity is the most important risk factor for symptomatic infection; currently, AIDS patients with CD4+ T cell counts below 100/mm3 account for 80% to 90% of cases of clinical cryptococcosis. In the United States, the annual incidence of cryptococcosis in AIDS patients decreased substantially during the 1990s, with more than two thirds of cases occurring in patients who did not receive highly active antiretroviral therapy.20 Person-to-person transmission has not been documented other than through transplanted organs.
Etiology
Cryptococcus infection begins with the inhalation of aerosolized organisms and localized proliferation with pulmonary invasion. In immunocompetent individuals, pulmonary infection may be asymptomatic and resolve spontaneously. Immunocompromised persons may have an acute, symptomatic pulmonary infection, which may disseminate by hematogenous spread—most often to the CNS, but also to the skin, soft tissue, genitourinary tract, bone, or joints. Cryptococ-cal CNS infection may become symptomatic while pulmonary infection clears because cerebrospinal fluid lacks several soluble anticryptococcal factors that are present in serum, such as complement components. Organ transplant recipients who receive calcineurin inhibitors such as tacrolimus as their primary immunosuppressive agent may be protected from cryptococcal infections, because calcineurin is thought to be a potential virulence factor for the yeast. Moreover, only a minority of crypto-coccal infections in organ transplant recipients involve the CNS.21 Rarely, Cryptococcus can be directly inoculated through intact skin as a route of infection.
Pathogenesis
C. neoformans is a round or oval yeastlike structure, 4 to 6 ^m in diameter, that grows well at body temperature. A large protective polysaccharide capsule surrounds each cell. The highly negative surface charge may contribute to resistance to leukocyte phagocytosis.
Diagnosis
Clinical Manifestations
CNS infection Cryptococcosis of the CNS may present as mild and nonspecific complaints, such as persistent headache, nausea, dizziness, ataxia, impaired memory and judgment, irritability, somnolence, clumsiness, confusion, and obtundation. Patients may or may not have fever, and most have minimal or no nuchal rigidity. Papilledema is noted in up to one third of cases and cranial nerve palsies in about one fifth. If the cranial nerves become involved, patients may experience decreased visual acuity, diplopia, facial numbness or weakness, or catastrophic vision loss.22 As the disease progresses, seizures may occur.
Respiratory infection Pulmonary cryptococcosis may present as cough, dyspnea, blood-streaked sputum, and a dull ache in the chest.
Cutaneous infection Skin lesions may be single or multiple and commonly begin as painless lesions of the face or scalp. Skin lesions may take the form of erythematous or umbilicated papules, pustules, acneiform lesions, indurated plaques, palpable purpura, soft subcutaneous masses, sinus tracts, cellulitis, vesicles, or large ulcers with undermined edges.
Prostatic infection The prostate can provide a sequestered focus of active cryptococcosis after therapy for systemic crypto-coccal infection. These foci may occur even in patients who did not have prostatic involvement initially, and the foci can be a source of recurrent systemic infection. Prostatic cryptococcosis may present as a peripheral prostatic nodule, but patients often have no symptoms. Diagnosis requires culture of urine obtained after prostatic massage.
Laboratory Tests
Routine blood studies remain normal in cryptococcosis. Lumbar puncture is indicated in immunosuppressed patients with CNS abnormalities; characteristic findings include elevated opening pressure, depressed glucose level, increased protein concentration, and lymphocytic pleocytosis. The latex agglutination test detects antigen in CSF or serum in more than 90% of patients with cryptococcal meningitis, whereas India ink smear of CSF detects cryptococci in 25% to 60%.
In cryptococcal CNS infection, CT or MRI scans of the head may be normal or reveal hydrocephalus, cerebral edema or atrophy, or a focal space-occupying mass lesion. Gelatinous crypto-coccal pseudocysts may appear as nonenhancing lesions.
In pulmonary cryptococcosis, chest x-rays most often show one or more circumscribed masses or nodules, often in the upper lobes, without hilar involvement. Less common radiographic patterns include segmental pneumonia, single thick-walled cavities, pleural effusion, and miliary disease.
Antigen titers in either serum or CSF can be used to follow the course of disease, but a lack of standardization among manufacturers of cryptococcal antigen tests means that reliable results can be obtained only if the same kit is used for serial measurements. For definitive diagnosis of cryptococcosis, positive antigen test results must be confirmed by culture. Sputum cultures are often negative, however, and may be falsely positive. Bone lesions appear on radiographic studies as round, lytic lesions.
Differential diagnosis
CNS cryptococcosis may resemble coccidioidomycosis, histo-plasmosis, tuberculosis, brucellosis, syphilis, viral meningoen-cephalitis, meningeal metastases, sarcoidosis, and chronic benign lymphocytic meningitis. Cryptococcomas may resemble pyogenic, nocardial, or mold-associated abscesses; tuberculosis; toxoplasmosis; hemorrhage; or lymphoma or other neoplasms. Pulmonary cryptococcosis may be indistinguishable from tuberculosis, histoplasmosis, pneumocystosis, and neoplasm. Cutaneous cryptococcosis may resemble comedones, acne, lipoma, syphilis, tuberculosis, sarcoidosis, molluscum contagiosum, and basal cell carcinoma. Bone lesions resemble those of other mycoses and tuberculosis.
Treatment
In patients with cryptococcal CNS infection, therapy begins with intravenous amphotericin B plus oral flucytosine [see Table 2].23 Once the patient is clinically stable and afebrile, which usually takes 2 to 6 weeks to achieve, those agents are replaced with fluconazole. After 8 to 10 weeks of maintenance therapy, flu-conazole is continued at a reduced dose for the duration of suppressed cell-mediated immunity, to prevent relapse.24
A condition that resembles immune reconstitution syndrome has been reported in organ transplant recipients with C. neofor-mans infection. Onset of this condition was observed a median of 5.5 weeks after the initiation of antifungal therapy and was marked by worsening of clinical manifestations despite negative cultures for C. neoformans. In some patients, this condition may be misconstrued as a failure of therapy. Immunomodulatory agents may have a role as adjunctive therapy.
Pulmonary disease from C. neoformans can be treated with amphotericin or fluconazole. Secondary prophylaxis for pulmonary disease is often not indicated in patients whose im-munosuppression is not severe.
Complications
Elevated CSF pressure in CNS cryptococcosis is associated with blindness and death. An absolute pressure under 250 to 300 mm H2O can be maintained by removing CSF to decrease pressure by 50%.26 Hydrocephalus can lead to permanent loss of cognitive function even in patients whose infection is considered cured. Relief of hydrocephalus with a shunt is vital to ensure an optimal outcome.
Prognosis
In CNS cryptococcosis, a good prognosis is associated with normal mental status, a CSF leukocyte level of more than 20 cells/mm3, and a CSF cryptococcal antigen titer of less than 1:1,024. Even in patients who respond to therapy initially, up to 40% may have residual neurologic defects and up to 25% of the 40% may experience relapse.
For HIV-negative patients who had cryptococcosis between 1990 and 1996, overall mortality was 30% and attributable mortality 12%. Significant predictors of mortality included age greater than 60 years, hematologic malignancy, and organ fail-ure.28 For solid-organ transplant recipients, renal failure at the time of hospital admission has been identified as an independent predictor of death.
Pneumocystosis
Epidemiology
Common and apparently harmless in the lungs of healthy persons, Pneumocystis jiroveci (formerly known as P. carinii) can cause pneumonia in those with prolonged lymphopenia. AIDS patients remain the single largest group at risk, although prophylaxis has markedly reduced the incidence of the disease in that population.29 The risk of Pneumocystis pneumonia (PCP) is also higher in the setting of primary immune deficiencies, severe malnutrition (which accounted for epidemics in Central Europe during World War II), organ transplantation, and long-term cor-ticosteroid treatment with monthly doses above 20 mg of prednisone or the equivalent. For solid-organ transplant (except lung transplant) recipients, the incidence of P. jiroveci pneumonia is highest during the first year after transplantation.
Figure 1 Cysts of Pneumocystis, which stain black and measure approximately 4 to 5 m, are visible on a methenamine-silver stain of a cytospin preparation from a bronchoscopic alveolar lavage fluid sample.
Etiology
Once P. jiroveci is inhaled, it attaches to lung epithelial cells. Pulmonary infection focuses on the interstitium and the alveoli.
Uncommonly, P. jiroveci infection spreads beyond the lungs. Patients receiving aerosolized pentamidine as prophylaxis are at risk for upper lung lobe and extrapulmonary disease because this is primarily a topical treatment; the aerosol does not penetrate into the less well ventilated portions of the lungs, and the drug is not absorbed into the circulation. Sites of extrapul-monary involvement include lymph nodes, abdominal organs, bone marrow, eyes, and thyroid.31
Pathogenesis
Although Pneumocystis was formerly classified as a protozoan, nucleic acid comparison studies have identified this organism as a fungus. Host immune defects in humoral and cellular immunity allow unchecked replication of the organism. In the absence of CD4+ T cells, alveolar macrophages are unable to contain infection.
Diagnosis
Clinical Manifestations
Most patients with PCP have a fever.Tachypnea and tachycardia are common in acutely ill patients. Clinical manifestations may develop insidiously and may not interfere with the person’s daily routine initially. Consequently, some patients present with several weeks of pulmonary symptoms, including dyspnea, nonproductive cough, hypoxemia, chest pain, and hemoptysis. Nevertheless, lung auscultation may reveal only scant abnormal findings.33
Laboratory Tests
Chest x-rays show bilateral infiltrates in most patients. Patients who have received aerosolized pentamidine as prophylaxis but experienced breakthrough infection are more likely to have disease confined to the apices.31
Methenamine-silver staining of induced sputum or broncho-scopic alveolar lavage specimens can usually confirm the diagnosis [see Figure 1 ]. At 4 ^m in diameter, the cysts of Pneumocystis are similar in size to the 5 ^m cysts of Histoplasma. Pulse oxime-try and arterial blood gases are among the methods for testing the level of oxygenation that are used to evaluate disease severity and monitor progression.
Differential diagnosis
Any immunocompromised patient with respiratory symptoms, fever, and an abnormal chest radiograph should be considered to have PCP. Nevertheless, many other infectious agents and noninfectious diseases can mimic PCP.
Treatment
Active Infection
The treatment of choice for P. jiroveci infection is high-dose intravenous trimethoprim-sulfamethoxazole (TMP-SMX). Severely hypoxemic patients should receive adjunctive corticosteroid therapy.34 Approximately 25% of patients receiving high-dose TMP-SMX have a poor therapeutic response or hypersensitivity reactions. Alternative treatment regimens include pentamidine, trimethoprim-dapsone, clindamycin-primaquine, trimetrexate-leucovorin, and atovaquone [see Table 3].
Prophylaxis
Primary prophylaxis is indicated for HIV and organ transplant patients whose CD4+ T cell count is below 200/mm3, and secondary prophylaxis is indicated for those with a history of PCP. In HIV-infected patients who respond to highly active anti-retroviral therapy, primary and secondary Pneumocystis prophylaxis can be safely discontinued once the CD4+ T cell count has remained above 200/mm3 for more than 3 months.
TMP-SMX is the first choice for pharmacologic prophylaxis. Along with helping prevent PCP, TMP-SMX has the added benefit of providing protection against toxoplasmosis, salmonel-losis, Haemophilus infection, and staphylococcal infection.36 The dosage for TMP-SMX prophylaxis is specific to different im-munocompromised patient populations.
There is a significant incidence of adverse reactions to TMP-SMX (rash, nausea, and, in rare cases, myelosuppression or cholestasis). However, because of its superior efficacy and low cost, desensitization should be attempted before switching to a second-choice agent in patients who experience side effects from TMP-SMX [see Table 4]. Other options for prophylaxis include dapsone, aerosolized pentamidine, atovaquone, and trimetrex-ate37 [see Table 3]. Breakthrough infection with P. jiroveci may occur despite prophylaxis, especially in patients who have unrecognized poor compliance with a regimen of TMP-SMX or high-dose dapsone (100 mg daily).
Prognosis
Prognosis is related to the degree of hypoxemia at presentation, degree of infiltrates on chest radiographs, elevated lactate dehydrogenase level, the presence of copathogens, prior lung damage, severity of the underlying disease, and general markers of debility. Spontaneous pneumothorax is associated with a poor prognosis.
Aspergillosis
Aspergillus is an environmental saprobe whose spores (conidia) readily become airborne. Conidia of A. fumigatus, the principal Aspergillus species involved in human infection, are the ideal size for deposition into lungs and sinuses, with a diameter of 2 to 5 ^.m. Aspergillus thrives in wet areas such as crawl spaces, basements, and water-treatment facilities. Renovations may result in the release of spore-bearing dust. Potted plants and marijuana have been suggested as sources of spores.
After it is inhaled, Aspergillus can cause a localized infection that may result in allergic or invasive disease. Allergic bron-chopulmonary aspergillosis (ABPA) and invasive aspergillosis are the two major clinical variants.
Allergic bronchopulmonary aspergillosis
Epidemiology
ABPA affects patients with a hypersensitive immune status, such as those with atopy, asthma, extrinsic alveolitis, and cystic fi-brosis.38 Genetic determinants of immune response are thought to help explain why ABPA develops in only some patients with those conditions. ABPA is equally distributed between males and females with asthma and probably also in those with cystic fibrosis. Diagnosis is usually made in the late teenage years or in the 20s.
Etiology
In susceptible individuals, exposure to Aspergillus antigens causes the formation of IgE antibodies directed at the antigen. Reexposure will then result in mast cell degranulation and eosinophilic infiltration, with wheezing and fleeting pulmonary infiltrates.
Pathogenesis
Aspergillus does not invade tissue in ABPA; rather, it colonizes pulmonary secretions. The severity of ABPA probably varies with the intensity of exposure to spores, the species of Aspergillus involved, and the immune status of the host. Initially, fungal spores are trapped within thick bronchial mucus. As the fungus proliferates, the bronchi fill with mucus and become dilated; fungal hyphae can be identified in mucoid impactions. ABPA has been divided into five stages [see Table 5]. Patients do not necessarily progress through these stages in linear fashion.
