Cryptococcus/Cryptococcosis

General Characteristics of Cryptococcus

Features

• Morphology: round or oval-shaped, heavily encapsulated yeast (not dimorphic)
  • 5–10 µm in diameter
  • Variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables capsule thickness: can be > 50% of the yeast diameter
• Characteristics:
  • Obligate aerobe
  • Urease positive
  • Can be visualized on India ink, methenamine silver, and mucicarmine stains

Clinically relevant species

• The Cryptococcus genus contains over 50 species. 
• Only C. neoformans and C. gattii are pathogenic in humans.
• C. neoformans is the primary pathogenic member of the genus.

Forms of disease

• Pulmonary cryptococcosis
• Cryptococcal meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis 
• Cutaneous cryptococcosis
• Other forms (less common):
  • Osteomyelitis Osteomyelitis Osteomyelitis is an infection of the bone that results from the spread of microorganisms from the blood (hematogenous), nearby infected tissue, or open wounds (non-hematogenous). Infections are most commonly caused by Staphylococcus aureus. Osteomyelitis
  • Ocular cryptococcosis 
  • Pyelonephritis Pyelonephritis Pyelonephritis is infection affecting the renal pelvis and the renal parenchyma. This condition arises mostly as a complication of bladder infection that ascends to the upper urinary tract. Pyelonephritis can be acute or chronic (which results from persistent or chronic infections). Typical acute symptoms are flank pain, fever, and nausea with vomiting. T Pyelonephritis and Perinephric Abscess
  • Endocarditis Endocarditis Endocarditis is an inflammatory disease involving the inner lining (endometrium) of the heart, most commonly affecting the cardiac valves. Both infectious and noninfectious etiologies lead to vegetations on the valve leaflets. Patients may present with nonspecific symptoms such as fever and fatigue. Endocarditis
  • Hepatitis
  • Sinusitis Sinusitis Sinusitis refers to inflammation of the mucosal lining of the paranasal sinuses. The condition usually occurs concurrently with inflammation of the nasal mucosa (rhinitis), a condition known as rhinosinusitis. Acute sinusitis is due to an upper respiratory infection caused by a viral, bacterial, or fungal agent. Sinusitis

Epidemiology

Incidence

• The incidence of cryptococcosis notably increased during 1981–1992 due to the AIDS epidemic. 
• The development and use of corticosteroids, along with improved patient survival rates, also contributed to an increased incidence.
• Global incidence rate: 1 million annually
• The majority of cases reported have been in patients with AIDS:
  • Approximately 7%–15% of patients with AIDS develop cryptococcal infections
  • Incidence has declined over the past 20 years due to advances in antiretroviral therapy Antiretroviral therapy Antiretroviral therapy (ART) targets the replication cycle of the human immunodeficiency virus (HIV) and is classified based on the viral enzyme or mechanism that is inhibited. The goal of therapy is to suppress viral replication to reach the outcome of undetected viral load. Anti-HIV Drugs.

Morbidity and mortality

• Approximately 625,000 deaths per year globally
• The use of amphotericin B has dramatically improved patient outcomes.
• 14% mortality rate with amphotericin B + flucytosine Flucytosine Flucytosine is a pyrimidine analog that disrupts fungal DNA and RNA synthesis. Flucytosine is always used in combination with other antifungal agents and is primarily used to treat cryptococcal meningitis. Flucytosine, Griseofulvin, and Terbinafine

Pathogenesis

Infectious process

• Habitat:
  • Largely found in soil contaminated with old bird droppings
  • Also found in decaying wood and tree hollows
• Transmission: Yeast spores are inhaled from contaminated soil.
• Pathogenicity and disease process:
  • Spores are deposited into the pulmonary alveoli → phagocytized by macrophages
  • Cryptococcal polysaccharide capsule prevents recognition within macrophages → prevents leukocyte migration
  • Glucuronoxylomannan and glucuronoxylomannogalactan (known together as GXM): 
    • Components of the capsule
    • Highly immunosuppressive
  • C. neoformans and C. gattii also produce phenol oxidase:
    • ↑ Production of melanin
    • Melanin accumulates in the cell wall and prevents attacks from the host immune system.
• Healthy individuals: Infection is often self-contained.
• Immunocompromised:
  • The initial site is infected and then spreads via hematogenous dissemination
  • If contained, reactivation at the initial site can occur later due to declined immune status.

Host risk factors

The most significant risk factor for infection is an immunocompromised state. In decreasing frequency, the following conditions are most frequently associated with infection:

• HIV and AIDS
• Chronic steroid use
• Organ transplant
• Malignancy
• Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver disease
• Sarcoidosis Sarcoidosis Sarcoidosis is a multisystem inflammatory disease that causes noncaseating granulomas. The exact etiology is unknown. Sarcoidosis usually affects the lungs and thoracic lymph nodes, but it can also affect almost every system in the body, including the skin, heart, and eyes, most commonly. Sarcoidosis

Clinical Presentation

General findings

Clinical presentation varies depending on the affected area and immune status of the host: 

• In immunocompetent individuals, infection is often asymptomatic and self-resolving. 
• The lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs are most often infected, followed by the CNS. 
• Other parts of the body can also be affected by disseminated infection.

Pulmonary cryptococcosis

• The pattern can be highly variable: Up to 30% of immunocompetent individuals are asymptomatic.
• Mild-to-moderate symptoms:
  • Fever
  • Malaise
  • Cough with scant sputum
  • Pleuritic pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
  • Hemoptysis Hemoptysis Hemoptysis is defined as the expectoration of blood originating in the lower respiratory tract. Hemoptysis is a consequence of another disease process and can be classified as either life threatening or non-life threatening. Hemoptysis can result in significant morbidity and mortality due to both drowning (reduced gas exchange as the lungs fill with blood) and hemorrhagic shock. Hemoptysis (rare)
• Frequent radiological findings: single or multiple nodular lesions
  • Well defined
  • Noncalcified
• ARDS ARDS Acute respiratory distress syndrome is characterized by the sudden onset of hypoxemia and bilateral pulmonary edema without cardiac failure. Sepsis is the most common cause of ARDS. The underlying mechanism and histologic correlate is diffuse alveolar damage (DAD). Acute Respiratory Distress Syndrome can occur in severe cases.

Cryptococcal meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis/meningoencephalitis

• Major clinical manifestation of cryptococcal infection and the most common site of dissemination from the lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs
• Most common CNS mycosis Mycosis Fungi belong to the eukaryote domain and, like plants, have cell walls and vacuoles, exhibit cytoplasmic streaming, and are immobile. Mycosis is an infection caused by fungi. Mycology: Overview in immunocompromised patients:
  • 90% of cases seen in patients with AIDS 
  • AIDS-defining condition: CD4 count < 100 cells/µL
• Gradual onset of symptoms:
  • Develops over the course of weeks to months from initial infection
  • Headache: most common presenting symptom
  • Altered mental status
  • Photophobia
  • Behavioral changes
  • Nausea and/or vomiting
  • Neck stiffness
  • Focal neurological deficits 
    • Typically ocular or facial
    • Tend to develop in later stage
• Immunocompromised patients:
  • May have minimal or nonspecific symptoms
  • Fever is often absent or low grade.

Cutaneous cryptococcosis

• Occurs in about 10%–15% of cases
• Skin findings can be variable:
  • Papules
  • Pustules
  • Nodules
  • Ulcers
  • Draining sinuses
• Cellulitis Cellulitis Cellulitis is a common infection caused by bacteria that affects the dermis and subcutaneous tissue of the skin. It is frequently caused by Staphylococcus aureus and Streptococcus pyogenes. The skin infection presents as an erythematous and edematous area with warmth and tenderness. Cellulitis complicated with necrotizing vasculitis has been reported in organ-transplant patients.

Management

Principles

• Because most infections affect the CNS (meningeal infection) and the lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs (pulmonary infection), most evaluated regimens focus on these sites.
• Cryptococcal infections not affecting the CNS or lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs generally represent disseminated infection (although single-site infection is possible).
• Options differ depending on the immune status of the host and site of infection:
  • CNS infection regimen:
    • Induction: flucytosine Flucytosine Flucytosine is a pyrimidine analog that disrupts fungal DNA and RNA synthesis. Flucytosine is always used in combination with other antifungal agents and is primarily used to treat cryptococcal meningitis. Flucytosine, Griseofulvin, and Terbinafine + IV amphotericin B for at least 2 weeks
    • Consolidation: fluconazole for 8 weeks
    • Maintenance: fluconazole (lower dose) for 12 months after diagnosis
  • Fluconazole: 6–12 months
  • Alternatives are available in certain populations or situations.
• Fungal growth is monitored with CSF analysis during the treatment of CNS infection.

Treatment approach

• Immunocompetent:
  • Pulmonary (no CNS infection):
    • Mild pulmonary symptoms or focal infection (no diffuse infiltrates): fluconazole for 6–12 months
    • Severe pulmonary symptoms (diffuse pulmonary infiltrates): CNS infection regimen
  • CNS infection or disseminated infection (≥ 2 noncontiguous sites): CNS infection regimen
• Immunocompromised: 
  • Treatment is indicated in all patients with AIDS.
  • Antiretroviral therapy is delayed until initial cryptococcal treatment (possible immune reconstitution inflammatory syndrome (IRIS)).
  • Mild pulmonary infection: fluconazole 6–12 months
  • CNS infection, severe pulmonary disease, or disseminated infection: CNS infection regimen
• Reduce intracranial pressure:
  • Daily lumbar puncture until asymptomatic
  • Lumbar or ventricular drains

Prevention

• Antiretroviral therapy for patients with AIDS
• Routine testing for CrAg in newly diagnosed HIV-infected persons (CD4 counts ≤ 100 cells/µL) without signs of meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis:
  • Positive test → CSF evaluation
  • Treat isolated, positive-serum cryptococcal antigenemia without meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis like a focal pulmonary infection.
  • Routine primary antifungal prophylaxis in CrAg-negative patients is generally not recommended, despite CD4 count:
    • Unclear survival benefit with prophylaxis
    • Possible drug interactions
    • Potential for drug resistance

Differential Diagnosis

• Opportunistic fungal infections: a group of infections occurring in patients with weakened immune systems (especially CD4 counts < 200 cells/μL). The infections typically do not cause disease in healthy patients with a normal immune system. General signs and symptoms can be similar to cryptococcosis. Microscopy and culture of sputum or bronchoalveolar lavage with identification of specific organisms can help to differentiate.
• Tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis ( TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis): an infectious disease caused by bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview of the Mycobacterium Mycobacterium Mycobacterium is a genus of the family Mycobacteriaceae in the phylum Actinobacteria. Mycobacteria comprise more than 150 species of facultative intracellular bacilli that are mostly obligate aerobes. Mycobacteria are responsible for multiple human infections including serious diseases, such as tuberculosis (M. tuberculosis), leprosy (M. leprae), and M. avium complex infections. Mycobacterium tuberculosis complex. Like Cryptococcus, the bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview usually infects the lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs, but can also spread to other parts of the body. Both are associated with a period of latency and can present with similar signs and symptoms. Look for a history of exposure to an environment with TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis prevalence (e.g., healthcare setting, homeless shelter). A CD4 count of < 300 cells/μL is typically associated with TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis versus < 200 cells/μL for cryptococcosis. The diagnosis is established with a tuberculin skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin test, blood tests, sputum culture, and lung imaging.
• Histoplasmosis Histoplasmosis Histoplasmosis is an infection caused by Histoplasma capsulatum, a dimorphic fungus. Transmission is through inhalation, and exposure to soils containing bird or bat droppings increases the risk of infection. Most infections are asymptomatic; however, immunocompromised individuals generally develop acute pulmonary infection, chronic infection, or even disseminated disease. Histoplasma/Histoplasmosis: an infection caused by Histoplasma Histoplasma Histoplasmosis is an infection caused by Histoplasma capsulatum, a dimorphic fungus. The fungus exists as a mold at low temperatures and as yeast at high temperatures. H. capsulatum is the most common endemic fungal infection in the US and is most prevalent in the midwestern and central states along the Ohio and Mississippi River valleys. Histoplasma/Histoplasmosis capsulatum. Like cryptococcosis, histoplasmosis is a fungal infection acquired by inhalation and associated with contaminated soil and immunocompromised individuals. Unlike cryptococcosis, histoplasmosis is associated with bat droppings (in addition to bird droppings). Symptoms may be nonspecific, or consistent with pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia. The skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin may be affected as well. Diagnosis can be made by fungal cultures or urine/serum antigen testing. If present, a biopsy of a skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin lesion with culture and histology can help to differentiate.
• Blastomycosis Blastomycosis Blastomycosis is an infection caused by inhalation of the spores of the fungus, Blastomyces. Blastomyces species thrive in moist soil and decaying material and are common in the Ohio and Mississippi River valleys and the Great Lakes regions of the United States and Canada. Although most patients are asymptomatic, some can develop pneumonia. Blastomyces/Blastomycosis: a pulmonary disease caused by inhaling the spores of Blastomyces Blastomyces Blastomycosis is an infection caused by inhalation of the spores of the fungus, Blastomyces. Blastomyces species thrive in moist soil and decaying material and are common in the Ohio and Mississippi River valleys and the Great Lakes regions of the United States and Canada. Although most patients are asymptomatic, some can develop pneumonia. Blastomyces/Blastomycosis. Patients can develop pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia or disseminated-extrapulmonary disease. Unlike cryptococcosis, skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin involvement is the most common site of dissemination. History of exposure to the Great Lakes, the Ohio River Valley, and the Mississippi River Valley regions may be present as Blastomyces Blastomyces Blastomycosis is an infection caused by inhalation of the spores of the fungus, Blastomyces. Blastomyces species thrive in moist soil and decaying material and are common in the Ohio and Mississippi River valleys and the Great Lakes regions of the United States and Canada. Although most patients are asymptomatic, some can develop pneumonia. Blastomyces/Blastomycosis is endemic to the regions. Diagnosis is made by cultures and imaging.