Blastomyces/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 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. Extrapulmonary disease, such as 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 lesions, 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, genitourinary infections, and 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 can occur. The diagnosis is made by identifying the organism in sputum or tissue samples using culture, PCR, or antigen testing. Antifungals are used for treatment.

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General Characteristics and Epidemiology

Basic features of Blastomyces

  • Taxonomy:
    • Order: Onygenales
    • Family: Ajellomycetaceae
  • Dimorphic microfungus:
    • Mycelial phase:
      • Present at room temperature
      • White mold → trunks that are light brown
      • Branching hyphae
      • Right angle conidiophores with single conidium
      • Form conidia (spores)
    • Yeast phase:
      • Occurs at 37°C (98.6°F)
      • Cream or tan color
      • Thick cell wall
      • Multinucleate
      • Asexual reproduction: budding
Blastomyces dermatitidis yeast form

Blastomyces dermatitidis yeast form at 37°C

Image: “Blastomyces dermatitidis yeast form” by Medmyco. License: CC0 1.0

Clinically relevant species

Blastomycosis is caused by Blastomyces dermatitidis.

Epidemiology

  • Endemic in the soils of:
    • Ohio and Mississippi River valleys
    • Great Lakes region
    • Southeastern United States
  • Annual incidence rates in endemic regions: < 1 case per 100,000 people

Pathogenesis

Reservoir

  • Moist soil
  • Decomposing material

Transmission

The conidia form of B. dermatitidis can be aerosolized by disturbing the fungal colony followed by inhalation.

Host risk factors

Blastomycosis is more common in individuals who are immunocompromised, but can occur in immunocompetent individuals too.

Virulence factors

  • Thick cell walls provide resistance to phagocytosis. 
  • Blastomyces adhesin (BAD)-1: 
    • Glycoprotein adhesin
    • Allows attachment to host cells
    • Impairs proinflammatory response
  • DPP-IVA:
    • Serine protease
    • Blunts cytokine release

Pathophysiology

  • Conidia are inhaled → phagocytosed by neutrophils and macrophages in alveoli → infection cleared
  • Some fungi Fungi Fungi belong to the eukaryote domain and, like plants, have cell walls and vacuoles, exhibit cytoplasmic streaming, and are immobile. Almost all fungi, however, have cell walls composed of chitin and not cellulose. Fungi do not carry out photosynthesis but obtain their substrates for metabolism as saprophytes (obtain their food from dead matter). Mycosis is an infection caused by fungi. Mycology: Overview evade phagocytosis → rapidly move into the yeast phase → resistant to phagocytosis
  • Yeast multiplies in lung tissues → spreads through blood or lymphatics to other tissues: 
    • Skin
    • Bone
    • Genitourinary tract
    • Brain 

Clinical Presentation

Severity of the infection depends on a person’s immune system.

Pulmonary disease

  • Acute 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:
    • Fever
    • Cough:
      • Initially nonproductive
      • Often becomes productive (purulent sputum)
    • Chest pain Chest Pain Chest pain is one of the most common and challenging complaints that may present in an inpatient and outpatient setting. The differential diagnosis of chest pain is large and includes cardiac, gastrointestinal, pulmonary, musculoskeletal, and psychiatric etiologies. Chest Pain
    • Dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea
    • 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
    • Myalgia
  • Chronic 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:
    • Presents similar to 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
    • Low-grade fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
    • Cough
    • Night sweats
    • Weight loss
  • 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:
    • Rare
    • Diffuse pneumonitis
    • Rapidly progressive
    • High mortality

Extrapulmonary disease

  • Cutaneous:
    • Verrucous (wart-like)
    • Ulcerated with small pustules at the margins
  • Bone and joint:
    • Osteomyelitis:
      • Lytic lesions can cause bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones or joint pain.
      • Soft tissue swelling
      • Draining sinus tract
    • Arthritis
  • Genital:
    • Asymptomatic pyuria
    • Prostatitis Prostatitis Prostatitis is inflammation or an irritative condition of the prostate that presents as different syndromes: acute bacterial, chronic bacterial, chronic prostatitis/chronic pelvic pain, and asymptomatic. Bacterial prostatitis is easier to identify clinically and the management (antibiotics) is better established. Prostatitis
    • Epididymo- orchitis Orchitis Epididymitis and orchitis are characterized by acute inflammation of the epididymis and the testicle, respectively, due to viral or bacterial infections. Patients typically present with gradually worsening testicular pain and scrotal swelling along with systemic symptoms such as fever, depending on severity. Epididymitis and Orchitis
    • Endometritis Endometritis Endometritis is an inflammation of the endometrium, the inner layer of the uterus. The most common subtype is postpartum endometritis, resulting from the ascension of normal vaginal flora to the previously aseptic uterus. Endometritis
    • Tubo-ovarian abscess
  • Nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System:
    • Meningitis
    • Intracranial abscess
    • Epidural abscess

Diagnosis and Management

Diagnosis

  • Confirmed by the identification of organisms in sputum or tissues using:
    • KOH prep
    • Histology (tissue biopsy) 
  • PCR for B. dermatitidis DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure
  • Urine antigen testing
  • Culture of the organism

Management

Spontaneous remission can occur, but patients should be indicated antifungal therapy to reduce the chances of dissemination or recurrence.

  • Itraconazole (treatment of choice for most forms of the disease)
  • Amphotericin B:
    • More toxic alternative
    • Reserved for critically ill patients and those with CNS infections
  • Azoles Azoles Azoles are a widely used class of antifungal medications inhibiting the production of ergosterol, a critical component in the fungal cell membrane. The 2 primary subclasses of azoles are the imidazoles, older agents typically only used for topical applications, and the triazoles, newer agents with a wide spectrum of uses. Azoles:
    • Used as step-down therapy for patients with CNS disease
    • Good CNS penetration
    • Options:
      • Itraconazole
      • Voriconazole
      • Fluconazole

Prognosis

  • Recurrence is rare.
  • 80%–95% of immunocompetent individuals are successfully treated.
  • Prognosis is poor in patients who are immunocompromised.

Differential Diagnosis

  • 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: an infectious disease caused by 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 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. Pulmonary disease presents with fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, night sweats, cough, hemoptysis, fatigue, and weight loss. Extrapulmonary manifestations can include pleurisy, 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, Pott’s disease, pericarditis Pericarditis Pericarditis is an inflammation of the pericardium, often with fluid accumulation. It can be caused by infection (often viral), myocardial infarction, drugs, malignancies, metabolic disorders, autoimmune disorders, or trauma. Acute, subacute, and chronic forms exist. Pericarditis, and miliary disease. The diagnosis is established using 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, sputum culture, and lung imaging. The mainstay of management is antimycobacterial drugs.
  • Atypical 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: a form of pulmonary infection that typically has a slow onset and progression and presents with a nonproductive, dry cough and extrapulmonary symptoms such as fatigue, malaise, and headaches. Diagnosis is made based on history, physical exam, and chest imaging. Atypical 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 is usually treated with antibiotics.
  • Lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer: the malignant transformation of lung tissue and the leading cause of cancer-related deaths. Lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Definitive diagnosis and staging Staging Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. Grading, Staging, and Metastasis are made by biopsy, genetic mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations with biomarker testing, and imaging. Management is guided by the cancer stage and associated molecular profile.
  • Tularemia: a rare infection caused by Francisella tularensis, acquired by contact with animal tissue, ticks, or biting flies. The infection manifests as a papule, followed by fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, headache, and suppurative lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy. Tularemia may have multiorgan involvement. Diagnosis is based on the culture of blood and infected tissues. Treatment is with antibiotics.
  • Squamous cell carcinoma Squamous cell carcinoma Cutaneous squamous cell carcinoma (cSCC) is caused by malignant proliferation of atypical keratinocytes. This condition is the 2nd most common skin malignancy and usually affects sun-exposed areas of fair-skinned patients. The cancer presents as a firm, erythematous, keratotic plaque or papule. Squamous Cell Carcinoma (SCC): the malignant proliferation of atypical keratinocytes. The cancer presents as a firm, erythematous, keratotic plaque or papule. Histopathologic examination should be performed for all suspected cases, as many lesions, such as actinic keratosis Actinic keratosis Actinic keratosis (AK) is a precancerous skin lesion that affects sun-exposed areas. The condition presents as small, non-tender macules/papules with a characteristic sandpaper-like texture that can become erythematous scaly plaques. Actinic Keratosis (AK), mimic the appearance of SCC. Surgical excision is the mainstay of treatment. 
  • Pyoderma gangrenosum: a chronic, progressive, neutrophilic 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 necrosis. The etiology of pyoderma gangrenosum is unknown but often associated with systemic illnesses. Patients can have varying presentations, with 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 lesions progressing from a papule or nodule to ulcers with a necrotic base and violaceous border. Fever and malaise may accompany these presentations. The diagnosis is clinical. Management includes wound care, and treatment with anti-inflammatory medications and immunosuppressants Immunosuppressants Immunosuppressants are a class of drugs widely used in the management of autoimmune conditions and organ transplant rejection. The general effect is dampening of the immune response. Immunosuppressants.

References

  1. Centers for Disease Control and Prevention (2020). Fungal Diseases: Blastomycosis. Retrieved June 10, 2021, from https://www.cdc.gov/fungal/diseases/blastomycosis/index.html
  2. Castillo, C.G., Kauffman, C.A., Miceli, M.H. (2016). Blastomycosis. Infectious Disease Clinics of North America. https://pubmed.ncbi.nlm.nih.gov/26739607
  3. Cano, M.V., Ponce-de-Leon, G.F.; Tippen, S., Lindsley, M.D.; Warwick, M., Hajjeh, R.A. (2003). Blastomycosis in Missouri: Epidemiology and Risk Factors for Endemic Disease. Epidemiology and Infection. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2870035
  4. Smith, J.A., Riddell, J., Kauffman, C.A. (2013). Cutaneous manifestations of endemic mycoses. Curr Infect Dis Rep. https://www.ncbi.nlm.nih.gov/pubmed/23917880
  5. Gray, N.A., Baddour, L.M. (2002). Cutaneous inoculation blastomycosis. Clin Infect Dis. https://www.ncbi.nlm.nih.gov/pubmed/11981746
  6. Saccente, M., Woods, G.L. (2010). Clinical and laboratory update on blastomycosis. Clin Microbiol Rev. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2863359/
  7. Lohrenz, S., Minion, J., Pandey, M., Karunakaran, K. (2018). Blastomycosis in Southern Saskatchewan 2000-2015: Unique presentations and disease characteristics. https://www.ncbi.nlm.nih.gov/pubmed/29924358
  8. Patel, A.J., Gattuso, P., Reddy, V.B. (2010). Diagnosis of blastomycosis in surgical pathology and cytopathology: Correlation with microbiologic culture. Am J Surg Pathol. https://www.ncbi.nlm.nih.gov/pubmed/20090507
  9. Goughenour, K.D., Rappleye, C.A. (2017). Antifungal therapeutics for dimorphic fungal pathogens. Virulence. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5354166/
  10. Lestner, J., Hope, W.W. (2013). Itraconazole: An update on pharmacology and clinical use for the treatment of invasive and allergic fungal infections. Expert Opin Drug Metab Toxicol. https://www.ncbi.nlm.nih.gov/pubmed/23641752
  11. Baker, T., Patel, A., Halteh, P., Toussi, S.S., DeLaMora, P., Lipner, S., Schuetz, A.N., Hartman, B. (2017). Blastomycosis during pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care: A case report and review of the literature. Diagn Microbiol Infect Dis. https://www.ncbi.nlm.nih.gov/pubmed/28291633
  12. Schwartz, I.S., Embil, J.M., Sharma, A., Goulet, S., Light, R.B. (2016). Management and Outcomes of Acute Respiratory Distress Syndrome Acute Respiratory Distress Syndrome 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 Caused by Blastomycosis: A Retrospective Case Series. Medicine (Baltimore). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863776/
  13. Bradsher, Jr., R.W. (2020). Mycology Mycology Fungi belong to the eukaryote domain and, like plants, have cell walls and vacuoles, exhibit cytoplasmic streaming, and are immobile. Almost all fungi, however, have cell walls composed of chitin and not cellulose. Fungi do not carry out photosynthesis but obtain their substrates for metabolism as saprophytes (obtain their food from dead matter). Mycosis is an infection caused by fungi. Mycology: Overview, pathogenesis, and epidemiology of blastomycosis. In Mitty, J. (Ed.), UpToDate. Retrieved June 10, 2021, from https://www.uptodate.com/contents/mycology-pathogenesis-and-epidemiology-of-blastomycosis
  14. Bradsher, Jr., R.W. (2020). Clinical manifestations and diagnosis of blastomycosis. In Mitty, J. (Ed.), UpToDate. Retrieved June 10, 2021, from https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-blastomycosis
  15. Bradsher, Jr., R.W. (2020). Treatment of blastomycosis. In Mitty, J. (Ed.), UpToDate. Retrieved June 10, 2021, from https://www.uptodate.com/contents/treatment-of-blastomycosis
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