Fungal Diseases of the Respiratory System

Histoplasmosis

Histoplasmosis is a disease caused by the fungus Histoplasma capsulatum.

Learning Objectives

Describe the traits associated with and mode of transmission for Histoplasma capsulatum

Key Takeaways

Key Points

  • Histoplasmosis is s a disease caused by the fungus Histoplasma capsulatum, which is usually found in soil, and often associated with decaying bat guano or bird droppings.
  • Cases of histoplasmosis have declined acutely since the Industrial Revolution as quality of life improved dramatically and humans were no longer living in their own squalor.
  • Symptoms of this infection vary greatly, but the disease affects primarily the lungs. Occasionally, other organs are affected, and it can be fatal if left untreated.

Key Terms

  • Histoplasmosis: Histoplasmosis is a disease caused by the fungus Histoplasma capsulatum. Symptoms of this infection vary greatly, but the disease primarily affects the lungs. Other organs are occassionally affected; this is called disseminated histoplasmosis and can be fatal if left untreated.
  • fungus: Any member of the kingdom Fungi; a eukaryotic organism typically having chitin cell walls but no chlorophyll or plastids. Fungi may be unicellular or multicellular.

Histoplasmosis (also known as “Cave disease,” “Darling’s disease,” “Ohio valley disease,” “Reticuloendotheliosis,” “Spelunker’s Lung,” and “Caver’s disease”) is a disease caused by the fungus Histoplasma capsulatum. Symptoms of this infection vary greatly, but the disease primarily affects the lungs. Other organs are occasionally affected; this is called disseminated histoplasmosis and can be fatal if left untreated. Histoplasmosis is common among AIDS patients due to their suppressed immune system.

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Histoplasmosis: This is a Methenamine silver strain of Histoplasma capsulatum that shows histopathologic changes in the histoplasmosis.

If symptoms of histoplasmosis infection occur, they will start within 3 to 17 days after exposure, with the average being 12 to 14 days. Most affected individuals have clinically silent manifestations and show no apparent ill effects. The acute phase of histoplasmosis is characterized by non-specific respiratory symptoms, often cough or flu-like. Chest X-ray findings are normal in 40 to 70% of cases. Chronic histoplasmosis cases can resemble tuberculosis, and disseminated histoplasmosis affects multiple organ systems and is fatal unless treated.

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Acute pulmonary histoplasmosis: This is a chest X-ray of a patient with acute pulmonary histoplasmosis.

Histoplasmosis may be divided into the following types: primary pulmonary histoplasmosis, progressive disseminated histoplasmosis, primary cutaneous histoplasmosis, and African histoplasmosis.

Histoplasma capsulatum is found throughout the world. It is endemic in certain areas of the United States, particularly in states bordering the Ohio River valley and the lower Mississippi River. It is also common in caves in southern and East Africa. Positive histoplasmin skin tests occur in as many as 90% of the people living in areas where Histoplasma capsulatum is common, such as the eastern and central United States.

Histoplasma capsulatum grows in soil and material contaminated with bird or bat droppings (guano). The fungus has been found in poultry house litter, caves, areas harboring bats, and in bird roosts (particularly those of starlings). The fungus is thermally dimorphic: in the environment it grows as a brownish mycelium, and at body temperature (37 °C in humans) it morphs into a yeast. The inoculum is represented principally by microconidia that, once inhaled into the alveolar spaces, germinate and then transform into budding yeast cells. Histoplasmosis is not contagious, but is contracted by inhalation of the spores from disturbed soil or guano.

Histoplasmosis can be diagnosed by samples containing the fungusken from sputum, blood, or infected organs. It can also be diagnosed by detection of antigens in blood or urine samples by ELISA or PCR. It can also be diagnosed by a test for antibodies against Histoplasma in the blood. Histoplasma skin tests indicate whether a person has been exposed, but do not indicate whether they have the disease. Formal histoplasmosis diagnoses are often confirmed only by culturing the fungus directly. Cutaneous manifestations of disseminated disease are diverse and often present as a nondescript rash with systemic complaints. Diagnosis is best established by urine antigen testing. Blood cultures may take up to 6 weeks for diagnostic growth to occur and serum antigen testing often comes back with a false negative before 4 weeks of disseminated infection.

It is not practical to test or decontaminate most sites that may be contaminated with Histoplasma capsulatum, so precautions to reduce a person’s risk of exposure are important. Precautions common to all geographical locations would be to avoid accumulations of bird or bat droppings.

Antifungal medications are used to treat severe cases of acute histoplasmosis and all cases of chronic and disseminated disease. Typical treatment of severe disease first involves treatment with amphotericin B, followed by oral itraconazole. Treatment with itraconazole will need to continue for at least a year in severe cases.

In many milder cases, oral itraconazole or ketoconazole is sufficient. Asymptomatic disease is typically not treated. Past infection results in partial protection against ill effects if reinfected.

Coccidiomycosis

Coccidioidomycosis is a fungal disease caused by Coccidioides immitis or C. posadasii.

Learning Objectives

Describe the mode of transmission, symptoms and diagnostic test associated with Coccidioidomycosis immitis

Key Takeaways

Key Points

  • C. immitis resides in the soil in certain parts of the southwestern United States, northern Mexico, and parts of Central and South America.
  • Infection is caused by inhalation of the particles.
  • The disease is usually mild, with flu-like symptoms and rashes.

Key Terms

  • Coccidioidomycosis: Coccidioidomycosis is a fungal disease caused by Coccidioides immitis or C. posadasii. It is endemic in certain parts of Arizona, California, Nevada, New Mexico, Texas, Utah and northwestern Mexico.
  • fungal: Of or pertaining to a fungus or fungi
  • inhalation: The substance (medicament) which is inhaled.

Coccidioidomycosis (commonly known as “Valley fever”, as well as “California fever”, “Desert rheumatism”, and “San Joaquin Valley fever”) is a fungal disease caused by Coccidioides immitis or C. posadasii. It is endemic in certain parts of Arizona, California, Nevada, New Mexico, Texas, Utah and northwestern Mexico.

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Coccidioidomycosis: Histopathological changes in a case of coccidioidomycosis of the lung showing a large fibrocaseous nodule.

C. immitis resides in the soil in certain parts of the southwestern United States, northern Mexico, and parts of Central and South America. It is dormant during long dry spells, then develops as a mold with long filaments that break off into airborne spores when the rains come. The spores, known as arthroconidia, are swept into the air by disruption of the soil, such as occurs during construction, farming, or an earthquake.

Infection is caused by inhalation of the particles. The disease is not transmitted from person to person. The infection ordinarily resolves leaving the patient with a specific immunity to re-infection. C. immitis is a dimorphic saprophytic organism that grows as a mycelium in the soil and produces a spherule form in the host organism.

The disease is usually mild, with flu-like symptoms and rashes. The Mayo Clinic estimates that half the population in some affected areas have suffered from the disease. On occasion, those particularly susceptible may develop a serious or even fatal illness. Serious complications include severe pneumonia, lung nodules, and disseminated disease, where the fungus spreads throughout the body. The disseminated form of Valley Fever can devastate the body, causing skin ulcers, abscesses, bone lesions, severe joint pain, heart inflammation, urinary tract problems, meningitis, and often death. In order of decreasing risk, people of Filipino, African, Native American, Hispanic, and Asian descent are susceptible to the disseminated form of the disease. Men and pregnant women, and people with weakened immune systems (such as from AIDS), are more susceptible than non-pregnant women.

It has been known to infect humans, cattle, deer, dogs, elk, fish, mules, livestock, apes, kangaroos, wallabies, tigers, bears, badgers, otters and marine mammals.

Symptomatic infection (40% of cases) usually presents as an influenza-like illness with fever, cough, headaches, rash, and myalgia (muscle pain). Some patients fail to recover and develop chronic pulmonary infection or widespread disseminated infection (affecting meninges, soft tissues, joints, and bone). Severe pulmonary disease may develop in HIV-infected persons.

An additional risk is that health care providers who are unfamiliar with it or are unaware that the patient has been exposed to it may misdiagnose it as cancer and subject the patient to unnecessary surgery.

Coccidioidomycosis may be divided into the following types: Primary pulmonary coccidioidomycosis; Disseminated coccidioidomycosis; and Primary cutaneous coccidioidomycosis.

The fungal infection can be demonstrated by microscopic detection of diagnostic cells in body fluids, exudates, sputum and biopsy-tissue. With specific nucleotide primers, C.immitis DNA can be amplified by PCR. It can also be detected in cultures by morphological identification, or by using molecular probes that hybridize with C.immitis RNA. An indirect demonstration of fungal infection can be achieved also by serologic analysis detecting fungal antigen or host antibody produced against the fungus.

There are no published prospective studies that examine optimal antifungal therapy for coccidioidomycosis. Mild cases often do not require treatment. Oral Fluconazole and intravenous Amphotericin B are used in progressive or disseminated disease, or in which patients are immunocompromised. Alternatively, itraconazole or ketoconazole may be used. Posaconazole and voriconazole have also been used. There is currently no practical preventative measures available for people who live or travel through Valley Fever endemic areas. It is recommended to avoid airborne dust or dirt, though this is not a guaranteed manner of prevention. People in certain occupations may be advised to wear face masks.

Pneumocystis Pneumonia

Pneumocystis pneumonia (PCP) or pneumocystosis is a form of pneumonia, caused by the yeast-like fungus Pneumocystis jirovecii.

Learning Objectives

Review the symptoms associated with pneumocystis pneumonia and the methods of diagnosis

Key Takeaways

Key Points

  • Pneumocystis jirovecii is a pathogen that is specific to humans.
  • Pneumocystis is commonly found in the lungs of healthy people, but, being a source of opportunistic infection, it can cause a lung infection in people with a weak immune system.
  • Symptoms of PCP include fever, non-productive cough, shortness of breath, weight loss, and night sweats.

Key Terms

  • Pneumocystis pneumonia: Pneumocystis pneumonia (PCP) or pneumocystosis is a form of pneumonia, caused by the yeast-like fungus Pneumocystis jirovecii. This pathogen is specific to humans; it has not been shown to infect other animals.
  • Opportunistic: An opportunistic infection is an infection caused by pathogens, particularly opportunistic pathogens—those that take advantage of certain situations—such as bacterial, viral, fungal or protozoan infections that usually do not cause disease in a healthy host, one with a healthy immune system. A compromised immune system, however, presents an “opportunity” for the pathogen to infect.
  • Symptoms: A symptom is a departure from normal function or feeling which is noticed by a patient, indicating the presence of disease or abnormality. A symptom is subjective, observed by the patient, and cannot be measured directly.

Pneumocystis pneumonia (PCP) or pneumocystosis is a form of pneumonia, caused by the yeast-like fungus (which had previously been erroneously classified as a protozoan) Pneumocystis jirovecii. This pathogen is specific to humans; it has not been shown to infect other animals. Other species of Pneumocystis that parasitize other animals have not been shown to infect humans.

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Pneumocystis jirovecii pneumonia: Pneumocystis jirovecii cysts from bronchoalveolar lavage, stained with Toluidin blue O stain

Pneumocystis is commonly found in the lungs of healthy people, but being a source of opportunistic infection, it can cause a lung infection in people with a weak immune system. Pneumocystis pneumonia is especially seen in people with cancer, HIV/AIDS and the use of medications that affect the immune system.

Nomenclature of Pneumocystis Pneumonia

The older name Pneumocystis carinii (which now only applies to the Pneumocystis species that is found in rats), is still in common usage. As a result, Pneumocystis pneumonia (PCP) is also known as Pneumocystis jiroveci[i] pneumonia and (incorrectly) as Pneumocystis carinii pneumonia.

Regarding nomenclature, when the name of Pneumocystis pneumonia changed from P. carinii pneumonia to P. jirovecii pneumonia, it was at first felt that it could no longer be referred to as “PCP”. However, because the term PCP was already in common usage, it was rationalized that the term PCP could continue to be used, as it stood for PneumoCystis (jirovecii) Pneumonia.

Symptoms of Pneumocystis Pneumonia

Symptoms of PCP include fever, non-productive cough (because sputum is too viscous to become productive), shortness of breath (especially on exertion), weight loss, and night sweats. There is usually not a large amount of sputum with PCP unless the patient has an additional bacterial infection. The fungus can invade other visceral organs (such as the liver, spleen, and kidney), but only in a minority of cases.

Pneumothorax is a well-known complication of PCP. An acute history of chest pain with breathlessness and diminished breath sounds is typical of pneumothorax.

The risk of pneumonia due to Pneumocystis jirovecii increases when CD4 positive cell levels are less than 200 cells/μl. In these immunosuppressed individuals the manifestations of the infection are highly variable. The disease attacks the interstitial, fibrous tissue of the lungs, with marked thickening of the alveolar septa and alveoli, leading to significant hypoxia which can be fatal if not treated aggressively. In this situation LDH levels increase and gas exchange is compromised. Oxygen is less able to diffuse into the blood, leading to hypoxia. Hypoxia, along with high arterial carbon dioxide (CO2) levels, stimulates hyper-ventilatory effort, thereby causing dyspnea (breathlessness).

Diagnosis and Treatment of Pneumocystis Pneumonia

The diagnosis can be confirmed by the characteristic appearance of the chest x-ray, which shows widespread pulmonary infiltrates, and an arterial oxygen level (PaO2) that is strikingly lower than would be expected from symptoms. Gallium 67 scans are also use in the diagnosis. They are abnormal in approximately 90% of cases and are often positive before the chest x-ray becomes abnormal. The diagnosis can be definitively confirmed by histological identification of the causative organism in sputum or bronchio-alveolar lavage (lung rinse). Staining with toluidine blue, silver stain, periodic-acid schiff stain, or an immunofluorescence assay will show the characteristic cysts. The cysts resemble crushed ping-pong balls and are present in aggregates of 2 to 8 (and not to be confused with Histoplasma or Cryptococcus, which typically do not form aggregates of spores or cells). A lung biopsy would show thickened alveolar septa with fluffy eosinophilic exudate in the alveoli. Both the thickened septa and the fluffy exudate contribute to dysfunctional diffusion capacity which is characteristic of this pneumonia.

Pneumocystis infection can also be diagnosed by immunofluorescent or histochemical staining of the specimen, and more recently by molecular analysis of polymerase chain reaction products comparing DNA samples. Notably, simple molecular detection of Pneumocystis jirovecii in lung fluids does not mean that a person has Pneumocystis pneumonia or infection by HIV. The fungus appears to be present in healthy individuals in the general population.

Antipneumocystic medication is used with concomitant steroids in order to avoid inflammation, which causes an exacerbation of symptoms about four days after treatment begins if steroids are not used. By far the most commonly used medication is trimethoprim-sulfamethoxazole, but some patients are unable to tolerate this treatment due to allergies. Other medications that are used, alone or in combination, include pentamidine, trimetrexate, dapsone, atovaquone, primaquine, pafuramidine maleate (under investigation), and clindamycin. Treatment is usually for a period of about 21 days. However, pneumocystis pneumonia can be prevented by the drug TMP-SMX.

Pentamidine is less often used as its major limitation is the high frequency of side effects. These include acute pancreatitis, renal failure, hepatotoxicity, leukopenia, rash, fever, and hypoglycemia.

Blastomycosis

Blastomycosis is a fungal infection caused by the organism Blastomyces dermatitidis.

Learning Objectives

Describe the causes and symptoms of blastomycosis

Key Takeaways

Key Points

  • Infection occurs by inhalation of the fungus from its natural soil habitat.
  • Once suspected, the diagnosis of blastomycosis can usually be confirmed by demonstration of the characteristic, broad-based budding organisms in sputum or tissues by KOH prep, cytology, or histology.
  • Once inhaled in the lungs, Blastomycosis multiply and may disseminate through the blood and lymphatics to other organs, including the skin, bone, genitourinary tract, and brain.

Key Terms

  • fungal: Of or pertaining to a fungus or fungi
  • Blastomycosis: Blastomycosis is a fungal infection caused by the organism Blastomyces dermatitidis. Endemic to portions of North America, blastomycosis causes clinical symptoms similar to histoplasmosis.
  • inhalation: The substance (medicament) which is inhaled.

Blastomycosis (also known as “North American blastomycosis,” “Blastomycetic dermatitis,” and “Gilchrist’s disease”) is a fungal infection caused by the organism Blastomyces dermatitidis. Endemic to portions of North America, blastomycosis causes clinical symptoms similar to histoplasmosis.

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Blastomycosis: Blastomyces dermatitidis, the causative agent of blastomycosis.

Symptoms

Blastomycosis can present in one of the following ways:

  • A flu-like illness with fever, chills, myalgia, headache, and a nonproductive cough which resolves within days
  • An acute illness resembling bacterial pneumonia, with symptoms of high fever, chills, a productive cough, and pleuritic chest pain
  • A chronic illness that mimics tuberculosis or lung cancer, with symptoms of low-grade fever, a productive cough, night sweats, and weight loss
  • A fast, progressive, and severe disease that manifests as ARDS, with fever, shortness of breath, tachypnea, hypoxemia, and diffuse pulmonary infiltrates
  • Skin lesions, usually asymptomatic, that appear as ulcerated lesions with small pustules at the margins
  • Bone lytic lesions that can cause bone or joint pain.
  • Prostatitis may be asymptomatic or may cause pain on urinating. Laryngeal involvement causes hoarseness.

Infection occurs by inhalation of the fungus from its natural soil habitat. Once inhaled in the lungs, Blastomycosis multiply and may disseminate through the blood and lymphatics to other organs, including the skin, bone, genitourinary tract, and brain. The incubation period is 30 to 100 days, although infection can be asymptomatic.

Diagnosis

Once suspected, the diagnosis of blastomycosis can usually be confirmed by demonstration of the characteristic, broad-based budding organisms in sputum or tissues by KOH prep, cytology, or histology. Tissue biopsy of skin or other organs may be required in order to diagnose extra-pulmonary disease. Blastomycosis is histologically associated with granulomatous nodules. Commercially available urine antigen testing appears to be quite sensitive in suggesting the diagnosis in cases where the organism is not readily detected. While culture of the organism remains the definitive diagnostic standard, its slow growing nature can lead to delays in treatment of up to several weeks.

Treatment

Itraconazole given orally is the treatment of choice for most forms of the disease. Ketoconazole may also be used. Cure rates are high, and the treatment over a period of months is usually well tolerated. Amphotericin B is considerably more toxic, and is usually reserved for immunocompromised patients who are critically ill and those with central nervous system disease. Fluconazole has also been tested on patients in Canada.

Other Fungi Involved in Respiratory Disease

Sporotrichosis is a disease caused by the fungus Sporothrix schenckii.

Learning Objectives

Compare and contrast the various forms of sporotrichosis: cutaneous/skin, pulmonary and disseminated sporotrichosis

Key Takeaways

Key Points

  • In cases of sporotrichosis affecting the lungs, the fungal spores enter through the respiratory pathways.
  • Sporotrichosis progresses slowly – the first symptoms may appear from one to 12 weeks (average three weeks) after the initial exposure to the fungus.
  • Forms and symptoms of sporotrichosis include: cutaneous or skin sporotrichosis; pulmonary sporotrichosis; and disseminated sporotrichosis.

Key Terms

  • fungus: Any member of the kingdom Fungi; a eukaryotic organism typically having chitin cell walls but no chlorophyll or plastids. Fungi may be unicellular or multicellular.
  • Sporotrichosis: A disease caused by the infection of the fungus Sporothrix schenckii, usually affecting the skin, although other rare forms can affect the lungs, joints, bones, and even the brain. Because roses can spread the disease, it is often referred to as rose-thorn or rose-gardeners’ disease.

Sporotrichosis (also known as “Rose gardener’s disease”) is caused by the infection of the fungus Sporothrix schenckii . This fungal disease usually affects the skin, although other rare forms can affect the lungs, joints, bones, and even the brain. Because roses can spread the disease, it is one of a few diseases referred to as rose-thorn or rose-gardeners’ disease.

Because S. schenckii is naturally found in soil, hay, sphagnum moss, and plants, it usually affects farmers, gardeners, and agricultural workers. It enters through small cuts and abrasions in the skin to cause the infection. In cases of sporotrichosis affecting the lungs, the fungal spores enter through the respiratory pathways. Sporotrichosis can also be acquired from handling cats with the disease; it is an occupational hazard for veterinarians.

Sporotrichosis progresses slowly – the first symptoms may appear from one to 12 weeks (average three weeks) after the initial exposure to the fungus. Serious complications can also develop in patients who have a compromised immune system.

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Sporotrichosis: Cytologic preparation from a case of feline sporotrichosis; phagocytic cells show numerous variably-shaped yeast forms within.

Forms and symptoms of sporotrichosis include: cutaneous or skin sporotrichosis; pulmonary sporotrichosis; and disseminated sporotrichosis.

Cutaneous or skin sporotrichosis: This is the most common form of the disease. Symptoms include nodular lesions or bumps in the skin at the point of entry and also along lymph nodes and vessels. The lesion starts off small and painless, and ranges in color from pink to purple. Left untreated, the lesion becomes larger and looks similar to a boil. More lesions will appear, until a chronic ulcer develops. Usually, cutaneous sporotrichosis lesions occur in the finger, hand, and arm.

Pulmonary sporotrichosis: This rare form of the disease occurs when S. schenckii spores are inhaled. Symptoms include productive coughing, nodules and cavitations of the lungs, fibrosis, and swollen hilar lymph nodes. Patients with this form of sporotrichosis are susceptible to developing tuberculosis and pneumonia.

Disseminated sporotrichosis: this occurs when the infection spreads from the primary site to secondary sites in the body and develops into a rare and critical form. The infection can spread to joints and bones (called osteoarticular sporotrichosis) as well as the central nervous system and the brain (called sporotrichosis meningitis). The symptoms include weight loss, anorexia, and the appearance of bony lesions.