For our Tuesday July 13th morning report, we discussed fungal infections. Whether you are in a subspecialty clinic such as Infectious Diseases or Respirology, or on-call in the Emergency Department, seeing patients in the AACU, ordering a CXR in your family practice, you may get an imaging finding of cavitary lesions. We began our discussion during morning report with a differential diagnosis for cavitating lesions.

We discussed a deidentified, anonymized case of a person with cough and blood-tinged sputum for 8 weeks, right-sided chest pain, constitutional symptoms. There was no history of TB risk factors, no recent travel, no sick contacts, and no COVID-19 contacts. In our morning report case, the person worked as a car mechanic, actively smoked (10-pack-year history). On examination, I showed you the following image as well as a CT scan that demonstrated extensive RLL consolidation with round-low attenuation lesions suggestive of cavities.

1. Cavitating Lesions

Your differential diagnosis to any issue should be developed using a structure similar to below. Use acronyms such as “VINDICATE” to help you – Vascular, Infectious/Inflammatory, Neoplastic, Degenerative/Deficiency/Drugs, Idiopathic/Iatogrenic/Intoxication, Congenital/Cardiac, Anatomic/Auotimmune/Allergic, Traumatic, Endocrine (Metabolic).”

A differential diagnosis for cavitating lesions could include the following:

Infectious	Bacterial infections – necrotizing pneumonias, lung abscesses, septic emboli (Staphylococcus aureus, Strep pneumoniae, Haemophilus influenze, Klebsiella pneumoniae, Streptococcus milieri) Uncommon bacterial infections – Actinomyces, Nocardia, Melioidosis, Rhodococcus Mycobacterial infections – Tuberculosis, Non-tuberculous mycobacterium Fungal – Aspergillosis, Zygomycosis, Histoplasmosis, Blastomycosis, (Para-) Coccidiomyosis, Talaromyces, PJP Parasites – Echinococcus, Paragonimiasis
Malignancies	Squamous cell carcinoma, lung, oropharyngeal (GU > GI), Kaposi’s sarcoma, lymphoma
Rheumatologic disease/Inflammatory	ANCA-vasculitis such as Wegener’s granulomatosis or GPA Sarcoidosis Rheumatoid arthritis
Other resp diagnoses	Pulmonary infarction, cryptogenic organizing pneumonia (COP), pulmonary Langerhan’s cell histiocytosis
Cardiac	Septic embolic from infective endocarditis
Iatrogenic	Foreign body
Congenital	Congenital cystic adenomatoid malformation

Bronchoscopic alveolar lavage (BAL) provided you with more information as it was positive for Blastomyces spp. Acid-fast bacilli (AFB) stains were negative, and culture was negative for bacteria. Now let’s talk a little bit about classification of fungal pathogens. Fungi are more than just what you put on your pizza if you’re a mushroom person! We categorize them into three major categories.

2. Fungi Classification

Yeast	Dimorphic fungi	Moulds
Candida albicans Candida glabrata Candida krusei Candida parapsilosis Candida tropicalis Candida dubliniensis Cryptococcus neoformans Cryptococcus gatti	Blastomycosis Histoplasmosis Coccidiomyocsis Paracoccidiomycosis Talaromyces Sporothrix “Yeast in the heat, mould in the cold”	Aspergillus – septated Mucor – not septated

Yeast are unicellular organisms that typically cause more superficial infection but can cause invasive disease in immunocompromised hosts. The yeast life cycle typically involves asexual reproduction in the way of budding or fission; yeast exist in haploid and diploid state and diploid yeast can undergo sexual reproduction. Diploid yeast will survive in stressful conditions. The two types of yeast that we reviewed were Candida (some species listed above), and Cryptococcus.

3. Yeast

Candida is a ubiquitous organism that is seen in the respiratory, skin, GI and GU tract and therefore only in some settings will it actually produce clinically apparent infection and/or cause invasive disease. We reviewed that Candida in the bloodstream should always be treated.

Risk factors for Candidemia include:

1. Neutropenia
2. Total parenteral nutrition (TPN)
3. Intensive care unit (ICU) admission
4. Abdominal surgery/trauma
5. Broad spectrum antibiotics
6. Intravenous drug use
7. Central venous catheters
8. Necrotizing pancreatitis

Management for Candidemia (or Candida in the blood stream) includes

• Repeat blood cultures
• Change all the lines
• Ophthalmology consult for assessment of Candida endophthalmitis
• Drain collections/source control
• Choosing empiric antifungal will be based on recent exposure to azole therapy, species, immunocompromise. An echinocandin is recommended as initial therapy, fluconazole is an acceptable alternative
• Duration of therapy – 14 days after clearance of cultures. Though in setting of other foci of infection this may differ. For instance in the setting of Candida endophthalmitis, treat for typically 4-6 weeks but usually until lesions resolve on serial dilated ophthalmologic examinations. (Ref: UpToDate) Decisions around surgery in the setting of Candida endophthalmitis to be done in conjunction with Ophthalmology/ID (IDSA guideline)
• If persistently positive blood cultures – look for endovascular source

Check out the Candidiasis guideline here from IDSA: https://academic.oup.com/cid/article/62/4/e1/2462830

Cryptococcus neoformans usually causes CNS infections such as cryptococcoma, or cryotococcal meningitis.

In the case of cryptococcal meningitis, patients have elevated opening pressure when performing a lumbar puncture. The cryptococcal antigen which is > 90% sensitive can be elevated in CSF and serum in these cases. Cerebrospinal fluid in the setting of cryptococcal meningitis will demonstrate lymphocytic pleocytosis, low glucose, high protein and stain positive for yeast on India ink stain. The treatment involves amphotericin B + flucytosine for 2 week induction then 1 year of fluconazole. Therapeutic lumbar punctures are part of the management to relieve the high intracranial pressure (until opening pressure < 20 mmHg).

Cryptococcus gatti is an organism typically thought of being implicated in pneumonia.

4. Endemic Fungi

A thorough exposure and travel history can help ascertain risk factors for endemic fungal infection. The table below summarizes typical geographical locations, risk factors for acquisition, and clinical manifestations.

Blastomyces	Histoplasmosis	Cocciodimycoses	Sporotrichosis	Talaromyces marneffei
Regions surrounding the Great Lakes and St. Lawrence River in Ontario, Ohio and Mississippi river valleys Kenora, ON and Vilas County, Wisconsin	North America, Latin America, Ohio and Mississippi river valleys	Southwestern U.S., Puerto Rico, and other parts of the world	Brazil, reported in United States, India, Malaysia, Argentina, Mexico, and Panama	Endemic to southeast Asia, northern India, southern China
Inhaling spores that reside in soil and decomposing organic matter. Working, planting, hunting in woods.	Also found in the soil, exposure to chicken coops, barns, caves, and soil containing bat and bird droppings.	Working in dusty areas, digging, truck driving, construction workers. Found in soil.	Rosethorn nodulesand called “rose gardener’s disease”. Soil, sphagnum moss, rose bushes, hay	Inhalation of T. marneffei conidia from soil or plants where bamboo rat feces may be present.
Pulmonary manifestations can be consolidation, LN, effusions, less commonly military pattern. Soft tissue “dermatitidis”, CNS, prostatitis orchitis	Flu-like symptoms, may resemble atypical PNA or TB. Disseminated infection lymph nodes, liver, bone marrow, skin involvement, spleen.	Flu like symptoms (fungus flu), Fever (Valley Fever), Disseminates to the skin, bones, and lungs.	Lesions distal to proximal on the skin. Pulmonary manifestations rare but possible and can disseminate to bones, joints, CNS.	Clinical features of disseminated Talaromyces are fever, LN, HSM, resp GI symptoms.

Resources for reference:

• Clinical Practice Guideline for the management of Blastomycosis – https://academic.oup.com/cid/article/46/12/1801/296953
• Clinical Practice Guideline for the management of Histoplasmosis – https://academic.oup.com/cid/article/45/7/807/541502
• Talaromyces marneffei – https://www.cmaj.ca/content/192/4/E92

5. Moulds

The first mould that we spoke about Mucormycosis (a fungal infection of the class Zygomycetes), which typically causes rhino-orbital-cerebral and pulmonary infections. There is a disease association between Mucormycosis and diabetic ketoacidosis. In the setting of beta-hydroxybutyrate (BHB) and low pH in cases of hyperglyemia and ketoacidosis, there is reduced iron chelation by transferrin. The available iron, glucose, and BHB allow for expression of specific proteins that results in fungal growth. Rhizopus species (also within this class) have ketone reductase which allows the organisms to grow in environments with high sugar and low pH. The physical examination finding to look for is an eschar in nasal mucosa or palate.

Treatment involves source control with surgical debridement and antifungal therapy with IV amphotericin B upfront then can transition to other anti-fungal therapy.

References:

• http://website60s.com/upload/files/2-mucormycosis-pathogenesis-and-pathology.pdf
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3286196/

Aspergillus spp. is the second mould that we reviewed. You may have heard of a wide array of clinical syndromes related to Aspergillus. They are summarized below with images and clinical features related to each:

1. Allergic bronchopulmonary aspergillus (ABPA)
   1. Hypersensitivity response to Aspergillus allergens
   2. Elevated IgE, eosinophils, can have elevated Aspergillus-specific IgG levels
   1. Bronchodilators and postural drainage may help to reduce mucus plugging
   2. Management of exacerbations of disease is glucorticoids. Antifungal therapy gives a steroid-sparing therapeutic option. May use anti-IgE therapy.
2. Chronic pulmonary aspergillus includes various clinical entities, two of which are summarized below:
   1. Aspergilloma – Mycetoma that forms in an existing cavity. In some cases no treatment, other cases will lead to surgery depending on lung function and symptomatic +/- anti-fungal therapy
   2. Chronic cavitary pulmonary aspergillosis (CCPA) – Pre-existing risk factor is lung disease; treat with anti-fungals.
3. Invasive aspergillosis
   1. Opportunistic infection seen in the setting of immunocompromise
   2. Serum and BAL galactomannan can aid in diagnosis
   3. Treat with voriconazole

Resource for your reference:

• https://www.resmedjournal.com/action/showPdf?pii=S0954-6111%2818%2930227-0
• https://thorax.bmj.com/content/70/3/270

Case Wrap Up:

In the setting of moderate to severe Blastomycosis infection, treat with IV amphotericin B for 2 weeks and then subsequently with oral itraconazole. Remember that while patients are being treated with amphotericin B, you should monitor for infusion-related reactions, monitor renal function (daily initially then weekly thereafter if stable). Serum electrolytes, namely potassium and magnesium, should be monitored at baseline and then at least twice weekly throughout therapy (more frequent if abnormalities). Complete blood counts should be monitored weekly during therapy.

I hope that you found this review of the cavitating lesions and summary of fungal infections helpful! Please email any questions or feedback to cmr@wchospital.ca.