See also separate record on Systemic Mycoses.

Fungi may cause lung disease through direct infection of pulmonary tissue, through infection of pulmonary air spaces/lung cavities, or through their ability to trigger an immunological reaction when fungal material is inhaled. The latter mechanism is involved in cases of allergic bronchopulmonary aspergillosis, aspergillus-induced asthma and extrinsic allergic alveolitis due to fungi (e.g. maltworker's lung, farmer's lung). This article will concentrate on those diseases caused by direct fungal infection of the lung (fungal pneumonias).

With the exception of aspergillosis, these infections are usually not present to any significant degree in immunocompetent residents of the UK. They are more likely to affect those who have travelled abroad to areas where they are endemic, or arise as opportunistic infections in patients who are immunocompromised as a result of oncological treatment, due to immunomodulation following solid organ transplantation, or HIV infection. Pulmonary infection occurs after inhalation of spores/conidia, or by the reactivation of latent infection. Haematogenous dissemination of fungal infection leading to a systemic mycosis tends to occur chiefly in immunocompromised patients.¹

Epidemiology and distribution

In the UK the endemic fungi are exceedingly rare and occur only in returning travellers. The endemic fungi are distributed in the Americas in the valleys of the Mississippi and Ohio rivers (histoplasmosis and blastomycosis), the Southwestern United States and Northern Mexico (coccidioidomycosis) and Central and South America (paracoccidioidomycosis). In Africa histoplasmosis is found in the equatorial regions.

The opportunistic pathogens are ubiquitously distributed and may cause disease in those with immunosuppression. There are few figures for their incidence in the population at large in the UK. A recent review estimates that 15–18.3% of HIV-infected patients admitted to hospital will suffer a nosocomial pulmonary infection. Of these, a small but significant proportion (around 5–10%) will be due to opportunistic fungal pneumonias.²

Risk factors

• Travel to an area where fungal pneumonia pathogens are endemic (see above).
• Regular exposure to bird, bat or rodent droppings in endemic areas.
• Any cause of immunocompromise, for opportunistic infections.
• Endemic fungal infections seem to be more common in men than women as oestrogen is thought to exert an inhibitory effect on the growth cycle of fungi.¹

Presentation

Symptoms

• Fever – persistent fever in the immunocompromised should always raise the suspicion of opportunistic pulmonary or systemic fungal infection.
• Cough which is usually dry.
• Chest discomfort (dull and poorly localised or focal and pleuritic).
• Progressive dyspnoea, particularly on exertion.
• Haemoptysis is a relatively common symptom of invasive aspergillosis/mucormycosis.
• Endemic mycoses may cause lymphadenopathy and obstruction of large airways through pressure effects.
• Endemic mycoses have a predilection for causing symptoms of 'rheumatological' syndromes, e.g. arthritis/arthralgia, erythema multiforme, erythema nodosum, pericarditis.
• Endemic mycoses may also cause symptoms by haematogenous dissemination to skin, brain/meninges, bone and joints and full-blown septicaemia.
• Aspergillus and Candida infections and other opportunistic fungi may cause symptoms of hypersensitivity reactions, e.g. allergic asthma, allergic bronchopulmonary aspergillosis, extrinsic allergic alveolitides.
• Symptoms due to other sites of extra-pulmonary involvement (particularly in the immunocompromised), e.g. meningoencephalitis/brain abscess, skin lesions, kidneys, liver, muscles, endophthalmitis, nasal passages and sinuses, systemic sepsis affecting blood and bone marrow.

Signs

• Fever
• Tachycardia
• Tachypnoea
• Wheeze
• Signs of focal pulmonary consolidation, e.g. reduced expansion, dullness to percussion and bronchial breathing
• Signs of bronchial obstruction if thoracic lymphadenopathy is significant
• Signs of pleural effusion
• Seek signs of extra-pulmonary involvement, e.g. skin lesions, signs of meningism, joint pain or swelling, retinal lesions on ophthalmoscopy.

Differential diagnosis

• Bacterial, atypical or viral pneumonia
• Aspiration pneumonia
• Pneumocystis jiroveci (carinii) pneumonia
• Eosinophilic pneumonia
• Hypersensitivity reaction caused by fungal antigen, e.g. allergic asthma, allergic bronchopulmonary aspergillosis, extrinsic allergic alveolitis
• Chemical pneumonitides, e.g. chemical worker's lung
• Coal worker's pneumoconiosis
• Löffler's syndrome or disease (marked eosinophilia and benign, transient, migratory or recurrent pulmonary infiltrates with minimal constitutional upset)
• Adult respiratory distress syndrome
• Causes of pulmonary fibrosis
• Tuberculosis (TB)
• Pulmonary oedema
• Helminthic infections

Investigations

• FBC:
  • Raised WCC in immunocompetent patients
  • Eosinophilia may predominate
  • Progressive neutropenia or leucopenia in an unwell immunocompromised host suggests systemic candidiasis/aspergillosis.
• CXR:
  • May show patchy infiltration, nodules, consolidation, cavitation or pleural effusion
  • Pronounced mediastinal lymphadenopathy – some endemic fungal pneumonias
  • Miliary pattern pulmonary infiltration in extensive disease
• Blood cultures (may require specific fungal culture bottles)
• Urine/sputum/invasive catheter cultures (KOH staining can be used for sputum but may detect colonising rather than invasive species)
• CT/MRI of thorax – to detect early signs of opportunistic fungal pneumonia in the immunocompromised
• Bronchoscopy – to obtain bronchoalveolar lavage/trans-bronchial biopsy specimens for fungal staining and culture
• Transthoracic fine needle biopsy – usually radiologically guided to biopsy nodules for staining/histology/culture
• Open lung biopsy – used occasionally
• Lumbar puncture in cases of suspected meningeal involvement
• Bone marrow aspiration/biopsy in immunocompromised patients with suspected disseminated disease
• Biopsy of any skin lesions
• Joint aspiration if joint effusion
• There are specific antigen-detection tests, PCR techniques and ELISA assays and serial serology available to detect specific pathogens – seek microbiological advice on the most appropriate test in the clinical context.

It is also important to think of why the patient might be immunosuppressed. There are other illnesses that may explain the reason for immunosuppression, e.g. previously unknown TB, diabetes and HIV. Thus history, examination and investigations also need to be tailored to try to determine the cause of immunosuppression. TB should be particularly sought after as it is an important differential diagnosis.

Management¹

• In immunocompromised patients, factors that are contributing to the illness, such as chemotherapy, steroids, indwelling venous catheters, etc. need to be addressed.
• Immunocompromised patients may benefit from the use of colony stimulating factors to boost immune cell production.
• Fluconazole has shown some benefits as prophylaxis against invasive fungal infections in transplant patients.³
• Intravenous amphotericin B in standard, cholesteryl sulfate complex, lipid complex or lysosomal formulation is the mainstay of treatment; each of the formulations has its advantages and disadvantages and expert input is needed to decide on the appropriate dose and type of amphotericin to be given.
• In milder cases of endemic fungal pneumonia then azoles and triazoles (e.g. fluconazole, itraconazole, ketoconazole, voriconazole) may be used; these agents may also be used synergistically with amphotericin B in opportunistic fungal pneumonias and advanced endemic disease.
• Rifampicin may be used as an additional agent in advanced cases.
• Flucytosine with amphotericin B has been used to treat cases of advanced systemic candidiasis.
• NSAIDs are useful to treat rheumatological manifestations of the endemic fungal pneumonias.
• Cardiothoracic surgery may be needed to resect infiltrated/necrotic pulmonary tissue as an adjunct to antifungal therapy, or to treat some complications such as massive haemoptysis and pulmonary abscesses.

Complications

• Dissemination of fungal infection to other sites such as brain, meninges, skin, liver, kidneys, adrenal glands, heart, eyes, spleen
• Progressive respiratory failure
• Systemic fungaemia and septic shock
• Blood vessel invasion causing massive haemoptysis, pulmonary infarction, MI, cerebral infarction/embolism
• Associated rheumatological complex/pericarditis with endemic fungal pneumonias
• Lung cavitation
• Development of mycetoma in a lung cavity
• Local pulmonary damage causing bronchopleural or tracheoesophageal fistulas, mediastinal fibrosis, calcification in pulmonary tree, chronic pulmonary symptoms
• Immunological reaction to fungal antigens
• Fungal endocarditis

Prognosis

• This is highly variable in cases of opportunistic infection depending on the cause and degree of immunocompromise, comorbidities and speed of recognition of pulmonary fungal infection.
• Overall mortality is relatively high (probably >50% in immunocompromised patients).
• Mortality for untreated disseminated histoplasmosis is ~80%, reduced to ~25% with treatment.¹
• Aspergillosis and mucormycosis have mortality rates of 50–85% in transplant recipients, especially after bone marrow transplantation.¹
• Coccidioidomycosis has a mortality rate as high as 70% in patients with AIDS.¹

Prevention

• HIV patients are routinely treated with prophylactic anti-fungal drugs to try and avoid infection with opportunistic fungal pathogens, particularly Cryptococcus neoformans.
• Transplant patients may also benefit from prophylactic anti-fungal agents.³
• Patients likely to have prolonged neutropenia should avoid activities that increase exposure to environmental fungal spores, such as gardening or working with potted plants and fresh flowers, cleaning, building work and handling uncooked vegetables.