Blastomycosis, Coccidiodomycosis, and Histoplasmosis Case File

Blastomycosis, Coccidiodomycosis, and Histoplasmosis Case File

Eugene C.Toy, MD, Cynthia Debord, PHD, Audrey Wanger, PHD, Gilbert Castro, PHD, James D. Kettering, PHD, Donald Briscoe, MD

CASE 40

A 52-year-old man presents to the physician’s office for the evaluation of a cough and fever. He has had these symptoms for approximately a week. He has also noted a sharp chest pain that is worse when he coughs or takes a deep breath. He has had some associated fatigue, headaches, achy joints, and sweatiness at night. He has been using an over-the-counter flu medication, which helps to reduce the cough, but he wanted to be checked because his symptoms are lingering. He has no history of pulmonary diseases and has never smoked cigarettes. He has had no exposure to ill contacts. His only recent travel was a weeklong golf vacation to Phoenix, which he took 3 weeks ago. On examination, he is comfortable appearing and in no respiratory distress. His temperature is 37.7°C (99.9°F), and his vital signs are otherwise normal. His pulmonary examination is notable for some faint expiratory wheezing and crackles in the left upper lung field. The remainder of his physical examination is unremarkable. A chest x-ray shows hilar adenopathy. A CBC shows a normal total white blood cell count but with a high percentage of circulating eosinophils. Microscopic examination of a fresh sputum sample treated with KOH reveals numerous spherules.

◆ What organism is the likely cause of this patient’s symptoms?

◆ For this organism, how do spherules form and what is their role in propagating infection?

ANSWERS TO CASE 40: BLASTOMYCOSIS, COCCIDIODOMYCOSIS, AND HISTOPLASMOSIS

Summary: A 52-year-old man who recently traveled to Phoenix complains of a cough, fatigue, and night sweats. A chest x-ray shows hilar adenopathy. The sputum reveals numerous spherules.

◆ Organism most likely to cause his symptoms: Coccidioides immitis.

◆ How do spherules form and what is their role in propagating infection: Inhaled arthroconidia lose their hydrophobic outer wall and remodel into spherical cells, or spherules. Nuclear division and cell multiplication occur and multiple septae develop within the circular cell, dividing it into endospore-containing compartments. The external wall of the spherule thins as growth occurs and then ruptures, releasing multiple spores and propagating the infection.

CLINICAL CORRELATION

Coccidioides immitis is a dimorphic fungus endemic in the western hemisphere. It is typically found in semiarid climates within the north and south 40° latitudes. Common endemic regions in the United States include the San Joaquin Valley, southern Arizona, and southwestern Texas. Transmission occurs by inhalation of the arthroconidia from the soil. The arthroconidia are taken into the bronchioles, where they form a spherule. When symptoms do occur, they usually start 1–3 weeks after exposure and typically include cough, fever, and fatigue. Chest pain, dyspnea, arthralgias, and skin rashes may occur as well. Most infections are self-limited, but it can take several weeks to months for symptomatic resolution. A small percentage of infections result in progressive pulmonary disease or chronic pulmonary complications, and an even smaller percentage may result in dissemination outside of the lung the most common site being the skin. Other areas of dissemination include the bones, joints, and the central nervous system (CNS). Most patients who develop disseminated disease have an underlying risk factor of severe immunosuppression, including those infected with HIV.

APPROACH TO THE SUSPECTED Coccidoides PATIENT

Objectives

1. Know the morphology, growth, and reproductive characteristics of C. immitis.
2. Know the sources of infection, modes of transmission, and clinical diseases associated with C. immitis infection.

Definitions

Dyspnea: Shortness of breath or difficulty breathing.

Dimorphic fungi: Fungi that grow as a mold at room temperature and in the environment and as yeast at 35°C (95°F) or in the body.

Arthroconidia: Barrel-shaped structures that are the mold and infectious form of C. immitis.

DISCUSSION

Characteristics of Coccidioides Species

Coccidioides is one of several systemic and dimorphic fungi. Histoplasma capsulatum, Blastomyces dermatitidis, and Paracoccidioides braziliensis are the others. Cryptococcus neoformans is also a systemic fungus but is not dimorphic. Sporothrix schenckii is dimorphic but not usually systemic. These fungi are commonly found in the environment in differing parts of the world and are transmitted by the aerosol route. In the majority of cases, fungi are inhaled into the lungs, and disease is unrecognized because patients remain asymptomatic.

Coccidioides immitis grows in the soil as mycelia by apical extension. Maturation results in the development of arthroconidia, which have a hydrophobic outer layer and can remain viable for a long period of time. They form fragile attachments to adjacent cells that are easily broken. Physical trauma, even a mild wind, can break these attachments and result in airborne dissemination of arthroconidia. If inhaled, the arthroconidia can deposit in the lung, where they lose their hydrophobic outer wall. The cell remodels into a spherical form known as a spherule. Within the spherule, cells multiply and septae form that divide the spherule into multiple compartments. These compartments contain endospores that are released as the spherule grows and eventually ruptures. The endospores are capable of generating new spherules or reverting to mycelial growth if removed from the site of an infection.

Spherule growth and rupture result in a host inflammatory response that includes the action of neutrophils and eosinophils. T lymphocytes also play an important role in the control of C. immitis infection. Most infections with this organism are asymptomatic or cause mild, nonspecific upper respiratory symptoms that are not diagnosed.

Diagnosis

Initial preliminary diagnosis is made by consistent clinical symptoms in a patient with recent travel to a Coccidioides endemic area of the country. Definitive diagnosis is made by direct observation of spherules with subsequent culture of the organism in a specimen, usually of respiratory origin. Direct examination can be made using either KOH or calcofluor white stains.

Coccidioides immitis is a dimorphic fungus that forms spherules in the patient (35°C [95°F]) and arthroconidia in the environment (room temperature). The arthroconidia are the infectious form and can be transmitted in the laboratory if proper biosafety precautions are not adhered to. Coccidioides immitis grows rapidly (within 1 week) on routine laboratory media. Colonies appear as a white fluffy mold, whose appearance is indistinguishable from the other dimorphic fungi, including Histoplasma capsulatum and Blastomyces dermatitidis. Coccidioides immitis can be specifically identified by immunodiffusion of extracted C. immitis antigen and commercially prepared antibody or by DNA probes specific for C. immitis RNA.

In cases in which culture is not possible, or negative, serology or skin testing may be helpful for diagnosis. The disadvantage of both is that a positive conversion may last for life and make diagnosis of a current infection difficult.

Treatment and Prevention

Treatment is not usually provided to patients with uncomplicated respiratory disease without risk factors for dissemination. Patients with complicated disease are treated with either an azole or amphotericin B.

COMPREHENSION QUESTIONS

[40.1] A 35-year-old man is HIV antibody-positive and has a CD4 count of 50 cells/mm3 (normal: 500–1000 cells/mm3). He has had a fever of 38.3°C (101ºF) for a few weeks and “feels tired all the time.” He has no other symptoms, and findings on physical examination are normal. Complete blood count, urinalysis, and chest x-ray are normal. A bone marrow biopsy reveals granulomas, and a culture grows an organism that is a budding yeast at 37ºC (98.6ºF), but produces hyphae and tuberculated chlamydospores at 25ºC (77ºF). Of the following, which is the most likely cause?

A. Aspergillus fumigatus

B. Coccidioides immitis

C. Cryptococcus neoformans

D. Histoplasma capsulatum

E. Mucor species

[40.2] A 4-year-old girl who lives in Bakersfield, CA, has had a low-grade fever. Skin tests performed for the first time give the following results:

Tuberculin (PPD)	Positive (10 mm induration)
Coccidioidin test	Positive (15 mm induration)
Dick test	Positive (with erythema)
Dick control test (heated toxin)	Negative (no erythema)
Schick test	Negative (no erythema)
Schick control test (heated toxin)	Negative (no erythema)

The test results suggest which of the following?

A. The patient has been exposed to Coccidioides immitis.

B. The patient has been immunized against Coccidioides immitis.

C. The patient has had scarlet fever.

D. The patient has IgG antibody to Mycobacterium tuberculosis.

E. The patient lacks immunity to Corynebacterium diphtheriae.

[40.3] A 50-year-old immunocompromised woman is diagnosed as having meningitis. A latex agglutination test on the spinal fluid for capsular polysaccharide antigen is positive. Of the following organisms, which one is the most likely cause?

A. Aspergillus fumigatus

B. Cryptococcus neoformans

C. Histoplasma capsulatum

D. Nocardia asteroides

E. Toxoplasma gondii

[40.4] Which of the following is the most common portal of entry in Blastomyces dermatitidis infection?

A. Genitourinary tract

B. Lymphatic system

C. Mouth

D. Respiratory tract

E. Skin

Answers

[40.1] D. An HIV-positive individual may have normal immune capacity as measured by laboratory parameters, but still be more at risk for opportunistic organisms. Respiratory infections may be caused by fungi, bacteria, or viruses. As a result, laboratory results may be crucial in determining the exact organism causing an infection. In this case, the bone marrow biopsy revealed a budding yeast form at 37ºC (98.6ºF), but hyphae and tuberculated chlamydospores at room temperature (25ºC [77ºF]). In disseminated histoplasmosis, bone marrow cultures are often positive. Tuberculate macroconidia are characteristic for H. capsulatum’s mycelial form.

[40.2] A. The Dick and Schick tests are related to streptococcal infections, specifically scarlet fever. The young girl has been exposed to a Mycobacterium, most likely M. tuberculosis, but the positive reaction observed is based on a cellular immune reaction, not one mediated by antibodies. The location is a region where Coccidioides is endemic and should be one of the suspected pathogens to be considered. No vaccine is available for C. immitis. Therefore, a positive coccidioidin test indicates that the young girl has been exposed to the agent and has developed a cellular immune reaction in response.

[40.3] B. Cryptococcus neoformans is a yeast characterized by a thick polysaccharide capsule. It occurs worldwide in nature and in very large numbers in pigeon feces. Cryptococcus infection is usually associated with immunosuppression. Tests for capsular antigen can be performed on cerebrospinal fluid and serum. The latex agglutination test for cryptococcal antigen is positive in 90 percent of patients with cryptococcal meningitis. With effective treatment (amphotericin B and possibly flucytosine), the antigen titer usually drops except for AIDS patients.

[40.4] D. Blastomyces dermatitidis grows as a mold culture, producing septate hyphae and conidia. In a host, it converts to a large, singly budding yeast cell. It is endemic in North America. Human infection is initiated in the lungs. Diagnosis may be difficult because no skin or serologic tests exist. Chronic pneumonia is a common presentation. Sputum, pus, exudates, urine, and lung biopsy material can be examined microscopically, looking for thick walled yeast cells with broadly attached buds. It may also be cultured.

MICROBIOLOGY PEARLS ❖ Coccidioides immitis is a dimorphic, systemic fungus, commonly found in the soil of arid areas. ❖ Most patients exposed to the arthroconidia of C. immitis develop an asymptomatic or respiratory infection. Disseminated disease occurs rarely in severely immunosuppressed patients. ❖ Person-to-person transmission of C. immitis is not known to occur.

REFERENCES

Galgiani J. Coccidioides immitis. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases, 6th ed. Philadelphia, PA: Churchill Livingstone, 2005:3040–51. 

Murray PR, Rosenthal KS, Pfaller MA. Systemic mycoses In: Murray PR, Rosenthal KS, Pfaller MA. Medical Microbiology, 5th ed. St. Louis, MO: Mosby, 2005:765–78.

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