Cough Case 5

A 14-year-old girl receives a bone marrow transplant as part of her treatment for acute lymphoblastic lymphoma. During the period of profound immunosuppression before the marrow engrafts, she develops nonproductive cough, fever, mild hemoptysis, and pleuritic chest pain. A plain chest x-ray film shows a pleuraI-based wedge-shaped lesion with focal cavitation. Open chest lung biopsy reveals necrosis and hemorrhage.
Septate fungal forms with dichotomous 45-degree branching are seen in the necrotic areas and involving the walls of several blood vessels.
When the fungus is cultured, it is found to be a monomorphic fungus.

Q 1

Which of the following is a monomorphic filamentous fungus?

/ A. Aspergillus
/ B. Blastomyces
/ C. Coccidides
/ D. Histoplasma
/ E. Sporothrix

Q 2
Two commonly encountered invasive fungi are Aspergillus and Candidia. In tissue specimens, which of the following features is often helpful in distinguishing these organisms?

/ A. Aspergillus has both hyphae and pseudohyphae
/ B. Aspergillus has budding yeasts
/ C. Aspergillus has germ tubes
/ D. Aspergillus shows dichotomous branching
/ E. Aspergillus shows generally obtuse angles of branching

Q 3

Involvement by this patient's infection of which of the following is considered to have the worst prognosis?
/ A. Brain
/ B. Lung
/ C. Middle ear
/ D. Sinus
/ E. Skin

Q 4
Which of the following is the most appropriate pharmacotherapy for this patient?
/ A. Amphotericin B
/ B. Clotrimazole
/ C. Fluconazole
/ D. Flucytosine
/ E. Griseofulvin

Q 5

Which of the following best describes the mechanism of action of the most appropriate medication for this patient's disease?
/ A. Forms pores in fungal membranes
/ B. Inhibits the demethylation of lanosterol
/ C. Inhibits squalene epoxidase
/ D. Inhibits thymidylate synthase
/ E. Interferes with the synthesis of ergosterol

Q 6

Toxicity to which of the following organs is most likely to limit the administration of the most appropriate medication for this patient's disease?
/ A. Brain
/ B. Heart
/ C. Kidney
/ D. Liver
/ E. Lung

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Cough Case 5 Answers
A1
The correct answer is A. The fungi that cause "deep infections" in humans are subdivided into the dimorphic forms (which, depending upon temperature, can be either yeast forms or hyphal forms) and the monomorphic forms (which grow in the same general form at different temperatures). Of the fungi listed, only Aspergillus is monomorphic. Aspergillus is a common saprophytic mold found on decaying material in the environment throughout the world. It can cause human diseases, including allergic bronchopulmonary aspergillosis (which is essentially an allergic reaction to inhaled Aspergillus conidia or spores), fungus ball (in which the Aspergillus grows without invading in a preexisting cavitary lesion of the lung), invasive aspergillosis (including pneumonia, meningitis, and other systemic infections), and cellulitis. Invasive aspergillosis is most often seen in severely immunocompromised patients with severe neutropenia, notably including those with a history of transplantation, chronic granulomatous disease, and leukemia. This patient's presentation is typical for invasive pulmonary aspergillosis. The other fungi listed (choices B, C, D, and E) are all dimorphic.

A2
The correct answer is D. Aspergillus has hyphae, but not pseudohyphae, budding yeasts, or germ tubes. The branching is dichotomous and at an acute (often about 45 degrees) angle (opposite of choice E).
Characteristics to look for with Candida include both pseudohyphae and true hyphae (choice A), budding yeasts (choice B), and occasionally germ tubes (choice C, better seen with some culture methods).

A3
The correct answer is A. Cerebral aspergillosis is a feared complication of other forms of aspergillosis because most patients die despite appropriate antifungal therapy. Of the other sites listed in the question choices, true invasive infection of the lung (choice B), as opposed to a fungus ball, is considered the most serious site of infection, though less so than infection of the brain.
Middle ear and sinus involvement (choices C and D) become clinically worrisome when dissemination or extension to the brain occurs.
Skin involvement (choice E) is worrisome if dissemination occurs.

A4
The correct answer is A. Amphotericin B is the mainstay of therapy of invasive aspergillosis. This medication has a wide fungicidal spectrum and remains either the drug of choice or the co-drug of choice for severe infections caused by Aspergillus, Candida, Cryptococcus, Histoplasma, Mucor, and Sporothrix. Alternative antifungal agents that are not the preferred therapy but do have some activity against aspergillus include itraconazole, flucytosine (choice D), and voriconazole.
Clotrimazole (choice B) is used topically for candidal and dermatophytic infections.
Fluconazole (choice C) is the drug of choice for esophageal and invasive candidiasis and coccidioidomycosis, and is used for prophylaxis and suppression in cryptococcal meningitis.
Flucytosine (choice D) is also synergistic with amphotericin B in candidiasis and cryptococcosis.
Griseofulvin (choice E) is given orally, but is active only against dermatophytes.

A5
The correct answer is A. The polyene anti-fungal amphotericin B is an amphoteric compound, with both polar and non-polar structural elements, that interacts with ergosterol in fungal membranes to form artificial "pores," which disrupt membrane permeability. Resistant fungal strains are those that appear to have low ergosterol content in their cell membranes. Amphotericin B is given by slow IV infusion and penetrates poorly into the central nervous system (intrathecal injections can be used). It has a half-life of more than 2 weeks and is removed by both metabolism and renal elimination.
Antifungal agents in the azole class (including ketoconazole, fluconazole, and itraconazole) interfere with the synthesis of ergosterol (choice E) by inhibiting the P450-dependent 14-alpha-demethylation of its precursor molecule, lanosterol (choice B).
Flucytosine is activated by fungal cytosine deaminase to 5-fluorouracil (5-FU), which can be incorporated into fungal RNA and can be also used to form 5-fluorodeoxyuridine monophosphate, which in turn inhibits thymidylate synthase (choice D) and the synthesis of thymine.
The anti-dermatophytic drug terbinafine inhibits squalene epoxidase (choice C) and thus decreases ergosterol synthesis (choice E).

A6
The correct answer is C. Nephrotoxicity is most likely to be dose-limiting, and may force amphotericin treatment to end prematurely. This is an important problem, since we have so few drugs with wide spectrum activity against invasive fungal organisms. An amphotericin B lipid complex (ABLC, Abelcet) that may be less nephrotoxic in those patients who cannot tolerate conventional amphotericin is available. Amphotericin B also causes infusion-related reactions including fever, chills, nausea, vomiting, headache, generalized malaise, hypotension, and arrhythmias.
Major problems encountered less commonly than renal toxicity include anaphylaxis, generalized pain, bone marrow toxicity, rash, a variety of cardiac problems including cardiac arrest (choice B), liver failure (choice D), pulmonary edema (choice E), and convulsions (choice A).