Opportunistic Mycoses

Question 1

Opportunistic Infections

Answer 1

• Opportunistic infections are those that do not usually occur in the immunocompetent host.
• The immunodeficiencies that place patients at increased risk vary based on the particular fungal infection.
• It could be a defect in innate immune function, such as hyperglycemia, loss of skin or mucosal integrity, or neutropenia.
• It may also be a loss of cellular immune function, such as occurs during late HIV infection, long-term corticosteroid therapy, allogeneic transplantation, and in certain lymphomas, such as Hodgkin’s disease.

Question 2

Common Opportunistic Mycoses

Answer 2

•The opportunistic mycoses to be discussed will include the hyalohyphomycoses, which are due to non-pigmented, soil-dwelling molds; mucormycosis; pneumocystosis; and infections due to the yeasts Cryptococcus and Candida.

Question 3

Hyalohphomycoses

Answer 3

• These are infections due to fungi that are non-pigmented septated molds that live in the soil.
• The most common of these are due to Aspergillus, Fusarium, and Scedosporium

Question 4

Aspergillus Species

Answer 4

• Aspergillus spp. are ubiquitous in the soil, air and water as well as in decaying vegetation.
• A. fumigatus is the cause of infection in 90% of cases of aspergillosis. A. flavus, A. terreus, and A. niger are other causes. Infection is usually acquired through inhalation.

Question 5

Aspergillus and Neutrophils

Answer 5

•Neutrophil function is important in defense against aspergillosis and neutropenia is a major risk factor

Question 6

Aspergillus Clinical Syndromes

Answer 6

• There are several clinical syndromes and these can be divided into invasive and non-invasive forms that relate to the degree of immunodeficiency of the patient.
• As immune function wanes, invasive disease becomes more prominent

Question 7

Non-invasive Aspergillus - ABPA

Answer 7

• One form of non-invasive aspergillosis is allergic bronchopulmonary aspergillosis (ABPA).
• This is a hypersensitivity syndrome associated with colonization of the airways with Aspergillus spp., usually A. fumigatus, and is not a true infection.

-It usually occurs in patients with severe asthma and in approximately 10% of patients with cystic fibrosis.

• It is associated with pulmonary infiltrates, marked peripheral blood eosinophilia and an elevated serum IgE.
• Treatment is corticosteroid therapy. The role of antifungal therapy is not established but voriconazole has been used in some cases.

Question 8

Non-invasive Aspergillus - Aspergilloma

Answer 8

• An aspergilloma is another form of non-invasive disease.
• It usually develops in a pre-existing lung cavity such as caused by tuberculosis or coccidioidomycosis.
• A. fumigatus is the most common etiology.

-Pathologically, it consists of a fungus ball – a mass of mycelia, fibrin, mucus and tissue debrís – within the pulmonary cavity.

• Hemoptysis is the most common symptom.
• Radiographically, a radiodense or white mass is seen within the cavity.
• Most cases do not require any therapy. If they do, surgical extirpation is the treatment of choice but has significant morbidity. The role of antifungal therapy is not clear.

Question 9

Invasive Aspergillus - CNA

Answer 9

• Chronic necrotizing aspergillosis (CNA) invades pulmonary tissue but not vasculature; hence, it is not “angioinvasive.”
• It usually occurs in middle-aged men with underlying chronic lung disease.

-These patients frequently have some degree of immunosuppression, usually from chronic corticosteroid use.

• Symptoms include fever, cough, and weight loss over months.
• There are persistent infiltrates on chest radiography.
• Diagnosis involves growing Aspergillus from respiratory specimens and histological evidence of tissue invasion by the fungus.
• Antifungal therapy is now most commonly voriconazole, but itraconazole, posaconazole, amphotericin B, and echinocandins are other options.

Question 10

Invasive Aspergillus - IPA

Answer 10

•Invasive pulmonary aspergillosis (IPA) is seen in patients with prolonged neutropenia of fewer than 500 polymorphonuclear leukocytes (PMN)/µl for >3 weeks, usually due to cancer chemotherapy.

• It also is commonly seen in patients undergoing hematopoietic stem cell transplantation (HSCT), with a higher risk if it is allogeneic compared to autologous.
• Solid organ transplantation recipients, particular lung and heart-lung, are also at significant risk.
• Finally, in patients with very late HIV infection, there appears to be a risk, but this is often associated with other factors, such as corticosteroid use or neutropenia.
• It is frequently angioinvasive.
• There are a variety of pulmonary radiographic manifestations of IPA, including nodular infiltrates, “halo,” and “air crescent” signs.
• Definitive diagnosis is based on identifying Aspergillus hyphae invading blood vessels on lung biopsy. Aspergillus are septate and hyphae branch at 45° angles. A probable diagnosis of IPA is based on growing Aspergillus from a respiratory sample with the finding of an elevated serum level of galactomannan.
• Voriconazole has become the therapy of choice. Other options include amphotericin B, the triazoles itraconazole and posaconazole, and the echinocandins. However, mortality is frequently very high despite appropriate therapy.

Question 11

Fusariosis

Answer 11

•Voriconazole has become the therapy of choice. Other options include amphotericin B, the triazoles itraconazole and posaconazole, and the echinocandins. However, mortality is frequently very high despite appropriate therapy.

Question 12

Fusariosis Infection - Non compromised hosts

Answer 12

•In non-compromised hosts, infection may occur as a result of direct inoculation. Recently, fusarium keratitis was reported in contact lens users. Patients presented with redness, pain, tearing and discharge of the eye. It was associated with use of a particular type of contact lens cleaning solution. Other manifestations of direct inoculation include skin infections after burns as well as bone, joint and nail-bed infections

Question 13

Fusariosis Infection - Immunocompromised hosts

Answer 13

•In immunocompromised hosts, such as those with prolonged neutropenia or allogeneic transplants, there has been an increase in the number of infections due to Fusarium spp. These present as disseminated infection with fungemia and multiorgan involvement. Amphotericin B and voriconazole have been used for therapy but there are limited data on the efficacy of these treatments

Question 14

Scedosporiosis

Answer 14

• Two species, Scedosporium apiospermum and S. prolificans, are associated with human disease.
• Like fusariosis, scedosporiosis may occur by direct inoculation and be associated with keratitis, skin and soft tissue infection and bone and joint infections. In compromised patients, such as those with prolonged neutropenia, hematologic malignancies, transplantation recipients and those with diabetes, severe disease may occur.

Question 15

S. apiospermum

Answer 15

•S. apiospermum is non-pigmented and is the anamorph of Pseudallescheria boydii. This is an instance where both the anamorphic (asexual) and the teleomorphoc (sexual) stages of a single fungus are both associated with disease

Question 16

S. prolificans

Answer 16

•S. prolificans is encountered less frequently than S. apiospermum and has been associated with fungemia. Although categorized here as part of the hyalohyphomycoses, it is actually dematiaceous (darkly pigmented) when grown on artificial media.

Question 17

Scedosporiosis Diagnosis

Answer 17

•The diagnosis is usually established when the fungus is grown from a sterile site. Visible growth is usually seen in 48 to 72 hr at incubation temperatures between 30 and 37°C. S. apiospermum forms pale gray to brown colonies. Hyphae are septate and branching with terminal conidia. The teleomorphic or sexual stage, P. boydii, forms large spherical structures called cleistothecia. S. prolifican colonies are green to black. There are flask-shaped conidiogenous cells.

Question 18

Scedosporiosis Treatment

Answer 18

• Voriconazole and amphotericin B have been used for therapy of S. apiospermum and P. boydii infections.
• There is no established antifungal therapy for infections due to S. prolificans

Question 19

Mucormycosis

Answer 19

• This infection, previously called zygomycosis, is most commonly caused by organisms that are in the order Mucorales. Absidia and Rhizopus spp. are the most frequently associated genera.
• Mucormycosis is an uncommon infection that almost always occurs in persons with compromised immune systems. Poorly controlled diabetes with acidemia is one frequent association, as are corticosteroids, leukopenia, malnutrition, and burns. Recently, an outbreak of necrotizing skin-tissue infection associated with mucormycosis was observed due to penetrating trauma and inoculation of fungi from contaminated plant material hurled by the high winds of a tornado

Question 20

Mucormycosis Presentation

Answer 20

• The most common presentation is infection of the rhino-facial-cranial area with involvement of the maxillary sinuses and extension back into the orbit and brain.
• Occasionally, lung, skin and gastrointestinal infection occur. Infection is associated with vascular invasion and tissue infarction with necrosis. The organisms are easily seen on pathological examination as non-septate, irregular, branching hyphae.
• The presentation can be dramatic and rapid with unilateral facial pain, swelling and proptosis. Despite surgical and antifungal therapy, prognosis is generally poor, with survival in only 20- 50% of cases. Amphotericin B has been the mainstay of antifungal therapy but recently the triazole antifungal posaconazole has been demonstrated to have at least in vitro activity. Four factors are associated with improved outcome: 1) rapid diagnosis; 2) reversal of immunosuppression; 3) surgical debridement that is extensive; and 4) providing prompt antifungal therapy.

Question 21

Pneumocystosis

Answer 21

•The ecological niche of Pneumocystis spp. has not been delineated and the organism has never been cultured in vitro. Airborne transmission appears most likely and there is evidence that most individuals are infected at an early age. Whether cases in patients with AIDS are due to reactivation of an earlier infection or to reinfection is not completely established, but the latter seems most likely because person-to-person spread has been noted. Pneumocystosis is the most common AIDS-defining opportunistic infection in those with HIV-1 infection. Other patient groups with depressed cellular immunity are also at risk, including those on high-dose corticosteroids and those with solid organ transplants. Recently, cases have occurred in patients receiving infliximab, a monoclonal antibody directed against TNF-α, as well as rituximab, a monoclonal antibody directed against B lymphocytes.

Question 22

Pneumocystosis Presentation

Answer 22

•Patients present with progressive dyspnea over weeks with fevers and dry cough. The chest radiograph demonstrates diffuse, bilateral interstitial infiltrates and arterial blood gases show hypoxemia with hypocarbia

Question 23

Pneumocystosis - Diagnosis

Answer 23

•Diagnosis is usually established by finding trophozoites or cysts in respiratory fluid, usually obtained by bronchoalveolar lavage (BAL).

Question 24

Pneumocystosis - Treatment

Answer 24

•The most common therapy is the use of high-dose trimethoprim-sulfamethoxazole (TMP-SMX). In HIV-1 infected persons whose peripheral blood CD4 T-lymphocyte

Question 25

Cryptococcus

Answer 25

•Cryptococcus spp. are encapsulated yeast found in soil, decaying matter, and bird excrement. While there are at least 19 species, C. neoformans and C. gattii are presently the only human pathogens.

Question 26

C. neoformans

Answer 26

•For C. neoformans infection, clinical illness occurs almost exclusively in persons with profoundly depressed cellular immunity and most cases are reported in individuals with HIV-1 infection with peripheral blood CD4 T-lymphocyte counts <100/µl. Although infection is acquired by inhalation, meningitis is the most common presentation. Cryptococcosis can occasionally present without meningitis. Pulmonary nodules, skin lesions and osteomyelitis may occur. Biopsy is required to establish the diagnosis.

Question 27

Cryptococcal Meningitis

Answer 27

•Patients with cryptococcal meningitis present with subacute headache and decreased mental status. Nuchal rigidity is uncommon. The CSF profile demonstrates a mild lymphocytic pleocytosis, usually of fewer than 100 cells. The glucose is frequently mildly depressed and the protein mildly increased. The diagnosis can be established either by the finding of encapsulated yeast on an India ink preparation of the CSF, or more commonly, by the finding of a high titer of cryptococcal antigen in the CSF.

Question 28

Cryptococcal Meningitis - Treatment

Answer 28

•Treatment consists of amphotericin B followed by fluconazole. Combining amphotericin B with flucytosine leads to an improved outcome but is associated with increased risk of neutropenia. Some patients develop hydrocephalus, identified by an opening pressure of >20 cm H20 on lumbar puncture. Treatment of this requires either repeated drainage of CSF by lumbar puncture or a CSF shunt.

Question 29

Candidiasis

Answer 29

•Candida spp are commensals of the GI tract and female genital tract. Disruption of immune function can result in either superficial or invasive disease. There are over 200 species of Candida but C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, C. lusitanaie, and C. dubliniensis are the most common causes of disease.

Question 31

Superficial Candidiasis

Answer 31

•Superficial candidiasis presents in several ways. Oropharyngeal disease may present as angular cheilitis, erythematous candidiasis, or pseudomembranous candidiasis, commonly known as thrush. The latter consists of an easily removed white plaque on an erythematous base on the oral mucosa. These manifestations may occur in patients on antibiotic therapy, on inhaled or systemic corticosteroids, or in patients with suppressed cellular immune function due to HIV-1 infection or other causes.

Question 32

Esophageal Candidiasis

Answer 32

•Esophageal candidiasis is seen principally in individuals with suppressed cellular immunity, such as patients with HIV-1 infection and a peripheral CD4 T-lymphocyte count <100/µl. Patients present with dysphagia and odynophagia. Diagnosis requires visualization and culture.

Question 33

Vulvovaginal Candidiasis

Answer 33

•Vulvovaginal candidiasis may occur in women with normal immune systems but is seen more frequently in those with suppressed cellular immunity. It is a common presentation in women with HIV-1 infection. On examination, there is erythema of the vaginal mucosa with an adherent white discharge.

Question 34

Candida funguria

Answer 34

•Candida funguria is associated with indwelling urethral catheters, antibiotic therapy and diabetes. Treatment is generally to remove or control the risk factor. Azole antifungals are indicated in symptomatic cases. Echinocandins do not reach high levels in the urine and are not recommended. Occasionally, therapy consists of direct installation of amphotericin B into the urinary collecting system. Rarely, oral 5-fluorocytosine may be tried but the risk of bone marrow toxicity and the development of resistance are significant.

Question 35

Chronic Mucocutaneous Candido=iasis

Answer 35

•Chronic mucocutaneous candidiasis is a rare disease associated with several immunological defects. It usually manifests during the first decade of life and is associated with progressively worsening superficial candidiasis and endocrinopathies.

Question 36

Fungemia

Answer 36

•Fungemia is the hallmark of invasive candidiasis. In the intensive care unit (ICU), risk factors include intravascular catheters, especially when used for total parenteral nutrition, prolonged antibiotic therapy, and abdominal surgery. Among immunocompromised patients, risks include chronic corticosteroid therapy, neutropenia and transplantation. Fungemia generally presents as fever, tachycardia and hypotension and mimics bacterial sepsis. Hematogenous spread may result in endophthalmitis, skin lesions, and muscle abscesses. In patients recovering from neutropenia, hepatosplenic candidiasis may occur.

Question 37

Fungemia Treatment

Answer 37

• reatment includes removal of intravascular catheters and reduction of other risk factors and antifungal therapy. Amphotericin B, triazole antifungals and echinocandins are generally used.
• Candida has been increasingly associated with triazole antifungal resistance. Several mechanisms have been reported but increased efflux associated with calcium-dependent channels is most common. Resistance is species associated and most C. albicans remain susceptible to fluconazole while C. krusei is resistant.