Primary systemic fungal infection lecture NO -15- Dalia Kamal Eldien Mohammed

INTRODUCTION Systemic mycoses due to primary pathogens originate primarily in the lungs and may spread to many organ systems. Organisms that cause systemic mycoses are inherently virulent. In general primary pathogens that cause systemic mycoses are dimorphic. These infections usually result from inhalation of fungal spores, which can cause a localized pneumonia as the primary manifestation of infection. In immunocompetent patients, systemic mycoses typically have a chronic course; disseminated mycoses with pneumonia and septicemia are rare . Symptoms include fever, chills, night sweats, anorexia, weight loss, malaise, and depression may occur. Various organs may be infected, causing symptoms and dysfunction.

Common systemic infections are: Histoplasmosis ; Generalized involvement of the reticuloendothelial system (liver, spleen, bone marrow) Blastomycosis; Single or multiple skin lesions or involvement of the prostate Coccidioidomycosis:  Bone and joint infections, skin lesions, and meningitis Paracoccidioidomycosis

Histoplasmosis Histoplasmosis is an infection caused by the fungus Histoplasma capsulatum.  The fungus lives in the environment, particularly in soil People can get histoplasmosis after breathing the spores from the air. Although most people who breathe in the spores don’t get sick, those who do may have a fever, cough, and fatigue. Many people who get sick will get better on their own without medication. In some people, such as those who have weakened immune systems, the infection can become severe, especially if it spreads from the lungs to other organs. Histoplasmosis can’t spread from the lungs between people or between people and animals.

Symptoms Symptoms of histoplasmosis are similar to those of pneumonia include: Fever Cough Fatigue (extreme tiredness) Chills Headache Chest pain Body aches

Diagnosis The symptoms and signs of histoplasmosis are not specific enough to establish the diagnosis. Some of the many diagnostic laboratory tests available include the following: Microscopic examination of samples of infected tissues Cultures of body fluids or tissues to identify the fungus Detection of surface markers of Histoplasma in a urine test Blood tests to measure antibody response to Histoplasma

Specimen; bone marrow aspirate or biopsy material, bronchoalveolar lavage fluid or biopsy material from lung, sputum, urine or skin lesions Direct microscopy: using 10% KOH and Parker ink or calcofluor white mounts. Microscopically, they are composed of hyaline septated hyphaes with micro and macroconidias in various developmental stages. Tissue sections should be stained using PAS (Periodic Acid Schiff) digest, Grocott’s methenamine silver (GMS) or Gram stain Culture:  Sabouraud agar, following incubation at 25°C for 6 to 12 weeks. Under these conditions, the fungal colonies are initially smooth, but become filamentous, cottony, and brownish with the age

The conversion from the mold phase to the yeast phase is necessary for accurate diagnosis of H. capsulatum. Conversion is achieved using enriched media such as blood agar or Brain-heart infusion agar (BHI) with cystein incubated at 35–37°C. After conversion, smooth white to brown colonies can be observed that are yeast by microscopic examination.

Histoplasma capsulatum macro& microconidias with septated hyphae

A PAS stain highlights H.capsulatum infection in the liver

Treatment Mild cases of histoplasmosis that are limited to the lungs will resolve without specific treatment in about a month. Severe or disseminated cases of histoplasmosis require treatment with antifungal medications. Itraconazole (Sporanox, Onmel), fluconazole (Diflucan), and amphotericin B

Blastomycosis Blastomycosis is a systemic mycotic disease caused by the dimorphic fungus Blastomyces dermatitidis. The disease primarily affects dogs and humans, but has been reported in cats, horses, sea lions, lions, wolves. Blastomycosis cannot be spread from person to person or from animals to people. The fungus lives in moist soil and in association with decomposing organic matter such as wood and leaves. Lung infection can occur after a person inhales airborne, fungal spores from the environment; however, many people who inhale the spores do not get sick. The symptoms of blastomycosis are similar to flu symptoms include fever, chills, cough, muscle aches, joint pain, and chest pain., and the infection can sometimes become serious if it is not treated.

Diagnosis tissues or body fluids, such as blood, sputum, bone marrow, liver, or skin and see if the fungus will grow from these samples in a laboratory. Blastomycosis can also be diagnosed by looking at a small sample of infected tissue under a microscope, to examine the yeast cell. An antigen test can detect the presence of the fungus in a urine or serum sample, and a blood test can measure prior exposure to the fungus by detecting Blastomyces antibodies

Yeast of Blastomyces dermatitidis

Coccidioidomycosis Valley fever, also called coccidioidomycosis, is an infection caused by the fungus Coccidioides immitis or Coccidioides posadasii. People can get valley fever by breathing in the microscopic fungal spores from the air, although most people who breathe in the spores don’t get sick. Usually, people who get sick with valley fever will get better on their own within weeks to months, but some people will need antifungal medication. C. immitis is a dimorphic saprophytic fungus that grows as a mycelium in the soil and produces a spherule form in the host organism. 

After Coccidioides infection, Coccidioidomycosis begins with Valley fever, which is its initial acute form. If left untreated, it can progress to the chronic form and then to disseminated Coccidioidomycosis. Therefore may be divided into the following types: Acute coccidioidomycosis Chronic coccidioidomycosis Disseminated Coccidioidomycosis, which includes primary cutaneous coccidioidomycosis significantly higher in individuals with altered cellular immunity due to disease ( HIV infection, lymphoma), medical treatment (corticosteroid therapy), or pregnancy

Primary coccidioidomycosis:  Most patients are asymptomatic, but nonspecific respiratory symptoms resembling those of influenza, acute bronchitis, or, less often, acute pneumonia or pleural effusion sometimes occur. Symptoms, in decreasing order of frequency, include fever, cough, chest pain, chills, sputum production (hemoptysis), and sore throat.  Progressive coccidioidomycosis:  Nonspecific symptoms develop a few weeks, months, or occasionally years after primary infection; they include low-grade fever, anorexia, weight loss, and weakness.  

Diagnosis Specimen include sputum, pleural fluid, CSF, exudate from draining lesions, or biopsy specimens. Eosinophilia may be an important clue in identifying coccidioidomycosis. The diagnosis is suspected based on history and typical physical findings, when apparent; chest x-ray findings can help confirm the diagnosis, which can be established by fungal culture & microscopy Microscopic examination of specimens to check for C. immitis spherules are usually 20 to 80 μm in diameter, thick-walled, and filled with small (2 to 4 μm) endospores. Endospores released into tissues from ruptured spherules may be mistaken for non budding yeasts.  Cultures (routine on fungal media) Serologic testing using an immuno diffusion kit (for IgG and IgM antibodies) and complement fixation (for IgG antibodies) are the most useful tests. 

Coccidioidomycosis Spherules with endospores

Lactophenol analine blue preparation of C. immitis

Paracoccidioidomycosis Paracoccidioidomycosis (also known as "Brazilian blastomycosis,""South American blastomycosis and "paracoccidioidal granuloma") is a fungal infection caused by the fungus Paracoccidioides brasiliensis.  The only etiological agent, Paracoccidioides brasiliensis is geographically restricted to areas of South and Central America. P. brasiliensis is a thermally dimorphic fungus  The habitat of the infectious agent is not known, but appears to be aquatic In biopsies, the fungus appears as a poly gemulating yeast with a pilot's wheel-like appearance.

Paracoccidioidomycosis is a chronic granulomatous disease that characteristically produces a primary pulmonary infection, and then disseminates to form ulcerative granulomata of the buccal, nasal and occasionally the gastrointestinal mucosa. The disease in its inception and development is similar to blastomycosis and coccidioidomycosis.

pathogenicity Paracoccidioidomycosis is a systemic mycosis, Strong evidence indicates this fungus infects the host through the respiratory tract. It frequently involves mucous membranes, lymph nodes, bone, and lungs. like other systemic mycoses, it can cause disease in immunocompetent & immunosuppression patients. Also uniquely, it rarely causes disease in fertile-age women, probably due to a protective effect of Estrogen Primary infection is thought to be auto limited . In young people, a progressive form of the disease occurs with high fever, generalized lymphadenopathy, and pulmonary involvement with milliary lesions. 

Symptoms Infected lymph nodes become swollen and may drain pus, but there is little pain. The lymph nodes most commonly infected are those in the neck and under the arms. Painful ulcers may form in the mouth. If the lungs are affected, people may have a cough and difficulty breathing. The liver and spleen may enlarge. Symptoms last a long time but are rarely fatal. The 2 general clinical categories of paracoccidioidomycosis are: (1) acute/sub-acute (juvenile paracoccidioidomycosis) (2) chronic form (adult paracoccidioidomycosis).

Diagnosis Clinical material: Skin scrapings, sputum and bronchial washings, cerebrospinal fluid, pleural fluid and blood, bone marrow, and tissue biopsies from various visceral organs. Direct Microscopy:  (a) Skin scrapings should be examined using 10% KOH and Parker ink or calcofluor white mounts (b) Exudates and body fluids should be centrifuged and the sediment examined using either 10% KOH and Parker ink or calcofluor white mounts (c) Tissue sections should be stained using PAS digest, Grocott's methenamine silver (GMS) or Gram stain. interpretation: demonstrating the presence of large, 20-60 um, round, narrow base budding yeast cells with multiple budding "steering wheels" from any specimen should be considered significant.

Culture: Clinical specimens should be inoculated onto primary isolation media, like Sabouraud's dextrose agar and Brain heart infusion agar supplemented with 5% sheep blood. Interpretation: A positive culture from any of the above specimens should be considered significant. Serology: Identification: Clinical history, tissue pathology, culture identification with conversion to the yeast phase at 37C are important characters.

Paracoccidioidomycosis Captains Wheel Ships wheel

Paracoccidioidomycosis Captains Wheel Ships wheel

Treatment The antifungal drug itraconazole is the treatment of choice  Amphotericin B  is also effective, but because of its side effects, it is reserved for very severe cases.

This is the last lecture in mycology, I wish all of you luck and success