29th July 2023

Fungal Infections

Background

Fungi are eukaryotic organisms found in abundance worldwide. They encompass a vast range of species with widely varying biology. Fungi can be differentiated from other organisms by their chitin-containing cell wall and cell membrane, which contains ergosterol (as opposed to the cholesterol found in animal cells).

Fungi can be morphologically characterised as yeasts or moulds. Yeasts are unicellular organisms which undergo cell division via budding. In contrast, moulds form multicellular structures, which through branching hyphae, form a network termed mycelium. Mould releases spores (conidia), allowing the organism to dispersion and spread. Dimorphic fungi can switch between each growth form, typically growing as moulds at 25ᵒC but yeasts at 37ᵒC (i.e. body temperature).

Fungal infections are an overlooked group of diseases, accounting for more deaths worldwide annually than malaria and tuberculosis. Host immunity to fungi is generally very high, so infection in most hosts will be limited to superficial sites (e.g. mucosal candidiasis). Invasive infection often requires either immunocompromise (e.g. advanced HIV, solid organ transplantation, haematological malignancy) or indwelling prosthetic material (e.g. central venous access devices).

This section focuses on some of the most important fungal infections to be aware of for the MRCP examination. Other sections which feature content on fungal infections include the Antimicrobials, HIV and Infections in Immunocompromised Hosts topics, which should also be referred to.

Antifungal drugs

Numerous antimicrobial drugs active against yeast and moulds exist, which can be used to treat fungal infections. The 3 main classifications of systemic antifungals, their mechanism of action, and their indications are summarised in the table below.

Further information can also be found in the Antimicrobials topic.

Table 1: Summary of antifungal drugs

Candidiasis

Candidiasis refers to the infection caused by yeasts belonging to the genus Candida. Candida albicans causes the majority of candidiasis. However, a range of non-albicans Candida species have been associated with human infection (e.g. Candida glabrata, Candida tropicalis, Candida parapsilosis and Candida krusei).

Candida are commensal organisms of the skin, oropharynx, gastrointestinal tract, and vagina. Overgrowth in these sites (e.g. following antibiotic therapy disrupting the local bacterial microbiota) can cause local or superficial infection. More invasive or disseminated infection typically occurs in cases of severe immunosuppression (e.g. neutropenia, particularly within haematological malignancy), indwelling prosthetic material (e.g. intravascular catheters), or heavy inoculation of a usually sterile site (e.g. following perforation of the gastrointestinal tract).

The major clinical manifestations of candida are discussed below.

Vulvovaginal candidiasis

Also known as genital thrush, vulvovaginal candidiasis presents as localised inflammation of the vagina or vulva. Around 90% of cases are due to Candida albicans. It is a common condition that can affect any person with female genitalia, regardless of age. It is generally due to the overgrowth of commensal candida and is strongly associated with antibiotic therapy leading to disruption to the balance of natural vaginal flora.

Other risk factors for vulvovaginal candidiasis include oestrogen excess (e.g. pregnancy. HRT), use of local irritants such as soaps and douches, and immunocompromise (see below).

Acute infection refers to an isolated infection. Recurrent candida is defined as 4 or more symptomatic episodes in 1 year, and can indicate an underlying disease causing immunosuppression; hence warrants investigation for diabetes mellitus and HIV. Long-term steroid use is also associated with recurrent candida due to immunosuppression.

Diagnosis can generally be made clinically, and if the diagnosis is apparent from the history, an external examination may not be indicated. However, this should be done if the diagnosis is uncertain, and if laboratory confirmation is required, then high-vaginal swabs and cultures are the main diagnostic test. STI screening may also be indicated.

For acute infection, management includes symptomatic measures such as emollients, avoiding irritants like soap, and wearing loose-fitting clothing. The drug treatment of choice is single dose oral fluconazole or single dose clotrimazole, pessary if fluconazole is contraindicated. Vulval disease can be co-treated with topical or intravaginal clotrimazole, which is available over the counter.

For recurrent infection, an induction dose of 3 doses of oral fluconazole is given, followed by a 6 month course of once-weekly doses, with appropriate follow up arranged.

Oral fluconazole is not recommended in pregnancy – topical or intravaginal formulations are used instead.

Oropharyngeal candidiasis

‘Oral thrush’ is another common form of candidiasis. In addition to the general risk factors for candidiasis, poor dental hygiene, smoking, malnutrition, and those with dental prostheses are an additional risk.

The most common form is pseudomembranous oral candidiasis, which presents with distinctive white-yellow plaques in the oral cavity. Unlike diseases like leukoplakia, these can be easily removed, which is an important distinguishing factor. Diagnosis is generally clinical, and swabs are not required.

In a non-immunocompromised individual, 2 weeks of treatment with a topical antifungal, such as miconazole gel or Nystatin, is recommended. Oral fluconazole can be used in severe cases.

In immunocompromised patients, the first line treatment is the same, but there is a higher risk of recurrent infection, spread to the oesophagus, or systemic infection, so the patient should be closely monitored for these complications.

Oesophageal candidiasis

A more serious manifestation, which may occur as a complication of oropharyngeal candidiasis, is generally only seen in immunocompromised patients, especially those with HIV and on chemotherapy.

Clinical features include dysphagia, pain on swallowing (odynophagia), and retrosternal pain; although it may be asymptomatic. Odynophagia is considered the hallmark feature, and oesophageal candidiasis should be considered in any immunosuppressed patient reporting this symptom.

The characteristic plaques generally cannot be visualised; hence, endoscopy is required, from which histological samples may be sent.

Systemic treatment should be given – oral fluconazole for a minimum of 2 weeks is first line, although it may need to be given IV if this cannot be tolerated. Itraconazole and voriconazole can be used as second line options.

Candidaemia

This refers to the presence of Candida in the bloodstream as septicaemia and is associated with severe disseminated illness. It may occur as a complication of localised infection and is generally only seen in immunocompromised patients. Invasive candidiasis refers to systemic infection but may or may not be associated with candidemia. Sites that may be affected by invasive candidiasis include the CNS, heart (i.e. endocarditis), bones, joints, abdomen, renal tract, and eyes.

This is a severe life-threatening illness that necessitates hospital management and parental treatment. The echinocandin caspofungin given IV is the first line, and IV fluconazole may also be used. Liposomal amphotericin B can be used in refractory cases.

Aspergillosis

Aspergillosis refers to the infection caused by moulds belonging to the genus Aspergillus. Hundreds of species of Aspergillus exist in nature, and many can cause disease in humans, but over half of all cases of invasive aspergillosis are caused by Aspergillus fumigatus.

Aspergillus is found worldwide and is particularly associated with decomposing vegetable material (e.g. mulch). Humans inhale aspergillus spores frequently without disease occurring. In general, there needs to be a background of immunosuppression or chronic lung disease (e.g. asthma) for aspergillosis to occur.

Aspergillosis is not contagious, and spores cannot be passed from one person to another.

A range of disease syndromes caused by aspergillus can occur; the most clinically important include:

• Allergic bronchopulmonary aspergillosis (ABPA)
• Chronic pulmonary aspergillosis (including aspergilloma)
• Invasive aspergillosis

Allergic bronchopulmonary aspergillosis (ABPA)

ABPA occurs most often in individuals with underlying asthma or cystic fibrosis due to a hypersensitivity reaction to inhaling Aspergillus spores.

The clinical presentation is similar to an acute exacerbation of asthma or a severe allergic reaction – characterised by wheezing, cough and shortness of breath.

It is associated with bronchiectasis, which is a potential chest X-ray finding. Characteristically, patients will demonstrate marked eosinophilia on blood tests. Radioallergosorbent (RAST) tests and Aspergillus-specific IgE serum tests can also be done to confirm the diagnosis.

First line treatment is with oral corticosteroids, with itraconazole used as the second line for cases which fail to respond to initial treatment.

Chronic pulmonary aspergillosis (and aspergilloma)

In which aspergillosis leads to fibrosis of the lungs, cavitation, and pleural thickening. Chronic pulmonary aspergillosis encompasses several diseases, such as aspergilloma, chronic cavitary pulmonary aspergillosis, chronic fibrosing pulmonary aspergillosis, and subacute invasive pulmonary aspergillosis. Aspergilloma is explored in greater detail below and is a frequent MRCP question.

Patients typically present with a chronic respiratory illness similar to bronchiectasis or COPD – chronic productive cough, wheeze, dyspnea – with intermittent episodic flare-ups marked by more acute symptoms and systemic upset. The condition may also be asymptomatic for long periods.

If asymptomatic, many cases can be managed with watchful-waiting, and vigilance for developing any complications. Steroids and antifungals may be used if a patient presents with acute symptoms. Chronic pulmonary aspergillosis is also associated with secondary bacterial chest infections, which are appropriately treated with antibiotics.

The condition can recur after treatment, so long-term monitoring and follow-up are essential.

Aspergilloma

An aspergilloma is a type of mycetoma – a ball of fungal material which forms a mass. They typically form in pre-existing lung cavities and are associated with a previous history of emphysema, tuberculosis and other cavitating lung diseases.

Most people with aspergillomas are asymptomatic, but they can cause a respiratory illness of wheezing, chronic cough, chest pain, haemoptysis and malaise. It is, therefore, an important differential diagnosis for this collection of symptoms.

Diagnosis is through chest x-ray, which will demonstrate the aspergilloma. The serum testing mentioned previously can be used to screen for Aspergillus. A definitive diagnosis can be made with a biopsy and fungal culture to confirm the aetiology.

Management is of chronic pulmonary aspergillosis, as outlined above.

Invasive aspergillosis

The most severe form of the disease will typically only infect immunocompromised patients. Infection typically begins with pulmonary manifestations and may disseminate to various organ systems, such as the kidneys, heart, skin and CNS, where it can cause a meningitic illness. It is also a cause of endocarditis, and haematogenous spread is associated with endophthalmitis of the eye (inflammation of the intraocular fluids).

Regardless of the site affected, the patient will present with a systemic illness of fever, malaise, and sometimes rigors. Life-threatening complications such as sepsis, mass haemoptysis, kidney and liver failure, and airway obstruction may occur.

Diagnosis is confirmed with serological testing for Aspergillus.

Management is with high dose IV antifungals, such as voriconazole. Second line options include caspofungin and amphotericin B for cases which do not respond to initial treatment. Evidence increasingly suggests better outcomes with a combination of voriconazole and caspofungin, which is now generally first line management.

Pulmonary artery embolisation – and even surgery – may be required to manage severe or persistent haemoptysis.

Cryptococcosis

The most clinically relevant form of this yeast is Cryptococcus neoformans, which can cause disease in both immunocompetent and immunosuppressed individuals. However, most fungal infections are more likely to cause serious and invasive diseases in the latter group. Patients with HIV/AIDs are particularly at risk, and mortality is as high as 12% in this demographic.

The yeast is surrounded by a gelatinous cell wall, which makes it resistant to conventional Gram staining techniques. Instead, the Indian ink stain is used to visualise the organisms. Cryptococcus is ubiquitous globally and particularly associated with soil and bird droppings.

Initial infection is generally asymptomatic and often remains so in healthy individuals. The disease manifests typically through haematogenous spread to other sites, or via reactivation of previously dormant infections, in immunosuppressed patients. When the infection causes a disease, it is known as cryptococcosis. The two most commonly affected body systems are the CNS and lungs, which are the focus of this topic.

Pulmonary cryptococcosis

Lung disease can be seen in both immunocompetent and immunosuppressed people but is more likely to cause serious disease in the latter.

The lungs are the initial site of any Cryptococcus infection, as the yeast enters the body through inhalation. Infection presents as a pneumonia-like illness, with cough, dyspnoea, chest pain, and fever the predominant symptoms. In patients with an intact immune system, this may be asymptomatic. Though the disease can become dormant, and for individuals carrying Cryptococcus, there is a risk of reactivation if they undergo an immunosuppressive insult.

Diagnosis can be made through chest x-ray or CT scan to demonstrate pneumonia, and then cultures confirming the presence of Cryptococcus, using the Indian ink stain. Serum assays include the ELISA technique. Blood cultures are used to assess for the presence of disseminated disease.

First line treatment is with fluconazole for an extended treatment course of 6-12 months. Severe or untreated pulmonary cryptococcosis can cause ARDS, which may be life-threatening.

Cryptococcal meningitis

This is the primary manifestation of cryptococcosis in patients with HIV/AIDS, and is an AIDS-defining illness associated with high mortality. It can occur in other immunocompromised people, too. The yeast reaches the meninges through haematogenous spread from the lungs, where it causes an insidious onset of subacute meningitis or meningoencephalitis.

The onset is generally over 1-2 weeks, with the predominant symptoms of headache, fever, and malaise. Neck stiffness, photophobia, and other focal neurological deficits are rare but may occur. Cryptococcal meningitis is fatal if untreated.

Diagnosis is made through CSF analysis following lumbar puncture. The characteristic profile is of lymphopaenia, high protein, and low glucose, but it may also be normal. CSF fluid can then be stained with Indian ink to demonstrate the organisms.

Treatment with antifungals consists of an induction, consolidation, and maintenance phase. Induction is with IV amphotericin B, of which the liposomal forms are now generally preferred, alongside oral flucytosine. Induction is successful when no Cryptococcus organisms are detected on repeat LP and the patient is clinically improving. Following this, fluconazole is given at a high dose for 8 weeks as consolidation. If the patient remains clinically stable, a lower dose is maintained for at least one year.

If a patient has comorbid HIV/AIDS, then appropriate antiretroviral treatment is also essential to prevent relapse.

Histoplasmosis

Histoplasmosis is caused by Histoplasma capsulatum, a dimorphic fungus, which operates either as a yeast or a mould, depending on the temperature conditions. It is acquired through inhalation of spores and associated with soil, bird and bat droppings. It is not directly spread from person to person.

Although found worldwide, it is endemic in the US’s Ohio and Mississippi river valleys. The general route of infection is the inhalation of spores after disturbance of soil associated with riverbeds, and it is also known as ‘Ohio River Valley Fever’ due to its epidemiology.

Most often asymptomatic, or it causes only a mild flu-like illness. However, in immunocompromised people, it can cause a respiratory illness similar to tuberculosis or pneumonia. Pathophysiologically it is characterised by granulomatous inflammation, which creates either caseating or non-caseating granulomas that are visible on chest x-rays. The typical incubation period is 7-21 days, and the predominant symptoms are a non-productive cough, headache, fever and malaise. Extrapulmonary manifestations are primarily dermatological or rheumatological, including arthralgia, erythema nodosum and erythema multiforme – more common in women.

Diagnosis can be confirmed by combining serum and urinary antigen detection, bronchoalveolar lavage, and blood cultures. Bronchoalveolar lavage is rarely positive but is also used to screen for other diseases. Blood cultures are used to assess for disseminated disease, which is associated with hepatosplenomegaly and haematological complications.

Treatment is only recommended if symptoms persist beyond 4 weeks. The first line treatment for acute infection is 3 months of itraconazole. If the disease develops into its chronic form, then 6 months of treatment is indicated, extending to a year if associated with cavitation.

Disseminated illness requires treatment with liposomal amphotericin B as induction therapy for approximately 4 weeks, followed by a minimum of 1 year of itraconazole as maintenance therapy.