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Respiratory infection—fungal 

Respiratory infection—fungal
Respiratory infection—fungal

Stephen Chapman

, Grace Robinson

, John Stradling

, Sophie West

, and John Wrightson

Page of

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date: 16 May 2022

Aspergillus lung disease: classification

Types of disease

Aspergillus fumigatus and other Aspergillus moulds are ubiquitous fungi that can be isolated from the air in most houses, and this increases with increasing indoor humidity. Inhalation of spores (conidia) can produce a range of diseases, some of which are related to each other and some of which are not. The finding of fungal hyphae (rather than just spores) in the sputum should provoke an assessment.


IgE-mediated allergic asthma

from inhaled Aspergillus spores. One of many common antigens provoking airway inflammation and bronchospasm.

Exuberant IgE and IgG reaction

to Aspergillus in the airways of (usually) asthmatics, provoking mucous plugging with distal consolidation that may flit from area to area. This is one of the causes of pulmonary eosinophilia.

Allergic bronchopulmonary aspergillosis (APBA)

A probable evolution and progression of exuberant IgE and IgG reaction to Aspergillus in (usually) asthmatics, with inflammatory damage to the airways and resultant bronchiectasis (but no actual invasion of Aspergillus into the airway walls).

Invasive Aspergillus pneumonia due to invasion of Aspergillus

into lung tissue 2° to immunosuppression. This can be a multi-system disorder with Aspergillus invading almost any part of the body.

Semi-invasive aspergillosis,

a much lower-grade process than invasive Aspergillus pneumonia, usually seen in older individuals with no apparent immunosuppression, but usually some underlying chronic lung disease.


where Aspergillus lives and grows as a separate ball of fungus in a pre-existing lung cavity. There is usually an inflammatory response to limited hyphae invasion into the tissue walls of the cavity.

Hypersensitivity pneumonitis

(or extrinsic allergic alveolitis) due to an immune inflammatory reaction to inhalation of large numbers of spores (see Respiratory infection—fungal pp. [link][link]).

The presentation and clinical setting of these various Aspergillus-related disorders are clearly different and thus are detailed separately.

Atopic allergy to fungal spores

Approximately 10% of asthmatics are skin prick-positive to Aspergillus species, compared with about 70% to house dust mite. It is assumed that this allergy contributes to allergic inflammation in the airways, but, in the few relevant studies, symptoms have not always correlated with exposure. However, in some studies, asthma admissions to hospital correlated better with fungal spore counts than with pollen counts. Fungal spore release may explain an association between thunderstorms and asthma attacks. Particularly high exposure results from working with mouldy vegetable matter, e.g. in compost heaps, during late summer/early autumn.

Asthma and positive IgG precipitins to Aspergillus


Asthmatics with IgE responses to Aspergillus can also develop IgG antibodies (precipitins). Why this happens is not clear. Aspergillus hyphae can sometimes be isolated from the sputum, and it has been suggested that Aspergillus spores are able to germinate and grow in the mucus within the airways. This may explain the mucous plugging and flitting areas of pulmonary consolidation.

Clinical features and investigations

Associated features may include:

  • Serum IgE >1, 000ng/mL

  • Blood eosinophilia >0.5 × 109/L

  • Skin prick +ve to Aspergillus

  • IgG precipitins to Aspergillus (many different allergenic proteins)

  • Long history of asthma, perhaps recently deteriorated.

Therefore, suspect this development in:

A patient with long-term asthma whose control deteriorates, with CXR changes, lgE and lgG to Aspergillus, eosinophilia, and perhaps hyphae in the sputum.


may only require an increase in inhaled steroids. However, there is a suggestion that courses of oral steroids are particularly effective and may prevent progression to bronchiectasis (see next section). Steroids limit the host’s immunological response but do not seem to lead to Aspergillus invasion of the tissues. Poorly documented evidence of improvement with antifungal agents such as itraconazole.

Allergic bronchopulmonary aspergillosis


This condition is probably an extension of exuberant IgE and IgG reaction to Aspergillus where the inflammatory response to the Aspergillus in the airways provokes a more exuberant response, with damage to the bronchial walls and bronchiectasis. Some authors reserve the use of the term ABPA for when bronchiectasis is present; others may include exuberant IgE and IgG reaction to Aspergillus and subdivide into ABPA-S (seropositive only) and ABPA-CB (central bronchiectasis).

The prevalence of ABPA in asthmatic populations has varied considerably between studies and clearly will depend on whether the definition includes bronchiectasis or not. It probably occurs in about 1–2% of asthmatics. A related condition occurs in patients with CF where it appears about 7% have evidence of colonization and potential ongoing damage.


The factors promoting the evolution from atopic asthmatic to ABPA are not known. A particular HLA association has been shown, with the suggestion that a CD4/Th2 response to a particular Aspergillus antigen (Asp f 1 antigen), with release of IL4 and IL5, may be critical. Proteolytic enzymes are released by Aspergillus as part of its exophytic feeding strategy, and these enzymes may damage airway mucosa. However, most believe that the damage results from host defence mechanisms. Septated hyphae (rather than just spores) may be visible in the mucus and grown from sputum, but there does not appear to be actual invasion of the bronchial mucosa. This immune inflammatory activity produces mucoid impaction in the airways, eosinophilic pneumonitis, and bronchocentric granuloma formation.

Main criteria for diagnosis

(the first four are the most important)

  • Long history of asthma

  • Skin prick/IgE +ve to Aspergillus fumigatus

  • IgG precipitins to Aspergillus fumigatus

  • Central (proximal) bronchiectasis

  • Blood/sputum eosinophilia

  • Total serum IgE >1, 000ng/mL

  • Lung infiltrates—flitting.

Other clinical features

  • Long-standing asthma, recent deterioration

  • Recurrent episodes of mucous plugging

  • Fever/malaise

  • Expectoration of dark mucous plugs, sometimes as casts of the airways

  • Eosinophilia (sputum and blood)

  • Occasional haemoptysis.

The major complication is poorly controlled asthma that requires repeated courses of oral steroids.


  • Spirometry Degree of airways obstruction

  • Skin prick sensitivity to Aspergillus (IgE)

  • Sputum Aspergillus hyphae and eosinophils

  • Blood

    • IgG precipitins

    • IgE RAST to Aspergillus

    • Total serum IgE

    • Eosinophil count (suppressed if on steroids)

  • CXR

    • Flitting infiltrates

    • Bronchiectasis, mucous impaction (gloved finger shadows)

  • CT Central (proximal) bronchiectasis with upper lobe predominance.


The management is essentially that of severe chronic asthma, but with generous use of courses of oral steroids. Several RCTs have shown courses of itraconazole (200mg bd for 4 months) are well tolerated, reduce steroid requirements, and improve exercise tolerance. There appears to be a sustained effect after the itraconazole is stopped, suggesting at least temporary eradication of the Aspergillus. Response and relapse can be monitored with IgG precipitins to Aspergillus. Itraconazole can cause liver dysfunction, so LFTs need monitoring.

Differential diagnosis

This list revolves mainly around the pulmonary infiltrates and eosinophilia.

  • Acute/chronic eosinophilic pneumonia

  • Churg–Strauss/EGPA syndrome

  • Various parasites (e.g. filariasis, ascaris; Löffler’s syndrome)

  • Drug-induced eosinophilic pneumonia.

Further information

Denning DW et al. The link between fungi and severe asthma: a summary of the evidence. Eur Resp J 2006;27:615–26.Find this resource:

Wark PA et al. Azoles for allergic bronchopulmonary aspergillosis associated with asthma. Cochrane Database Syst Rev 2004;3:CD001108.Find this resource:

Invasive aspergillosis


The term ‘invasive aspergillosis’ is reserved for the situation where Aspergillus hyphae actually invade tissue (hyalohyphomycosis). This usually occurs with severe immune suppression, particularly neutropenia and steroid use. The port of entry is probably the lungs, but spread can be to almost any area of the body. The species most commonly seen are Aspergillus fumigatus, flavus, terreus, and niger. Mortality is very high. The source of Aspergillus is unclear but has been found in hospital water supplies.


Alveolar macrophages probably normally destroy Aspergillus spores. Macrophage failure may allow more spores to germinate, and any subsequent invasion with hyphae seems to be prevented by neutrophils. Inadequate neutrophil function allows invasion across tissue planes and into vessels, with infarction and further spread throughout the body. There is some evidence that CMV may inactivate macrophages, allowing spores to germinate. The fungal digestive proteases do the damage, rather than the host’s limited immunological responses.

Clinical features

Typical setting

Fever, chest pain, cough, haemoptysis, dyspnoea, and pulmonary infiltrate in a neutropenic patient failing to respond to broad-spectrum antibiotics.

Risk factors

  • Following chemotherapy, particularly provoking severe neutropenia (<100 cells/microlitre)

  • Bone marrow suppression for allogeneic stem cell transplants

  • Advanced HIV infection and AIDS

  • Immune suppression following transplant

  • Infliximab (or other anti-TNF-α‎) therapy.


can occur anywhere, with the following well recognized:

  • Sinuses (paranasal) and spread into the brain

  • Endocarditis

  • Eyes

  • Skin (papular, ranging to ulcerative, lesions).

Careful examination and particular investigations may be needed to detect spread to these areas.


  • Isolate Aspergillus branching septate hyphae from respiratory tract by:

    • Sputum

    • Expressed sputum (3% saline via nebulizer)

    • BAL

    • TBB.

(Hyphae may be present when not the 1° cause of the infiltrate.)

  • Biopsies from other sites (most convincing when acute-angle branching, septated non-pigmented hyphae are seen)

  • Circulating levels of galactomannan, an exoantigen of Aspergillus (commercial EIA kit available; sensitivity for invasive aspergillosis 71%, specificity 89%; false positives due to some antibiotics, e.g. co-amoxiclav and piperacillin-tazobactam). Serial sampling is recommended. May also have a role in examining BAL fluid

  • Presence of β‎-glucan in serum represents fungal invasion but is not Aspergillus-specific; false positives due to blood processing and some antibiotics may affect results

  • CXR/CT CXR changes are usually non-specific. CT may show a halo of low attenuation surrounding a nodular lesion early on. An ‘air crescent’ sign may develop on CXR, with air appearing at the edge of an area of consolidation. Usually occurs when neutrophil count rising and probably represents gradual containment of the infection into a cavity, not unlike an aspergilloma. Radiological findings may also be seen with other angioinvasive filamentous fungi, Nocardia spp., and Pseudomonas aeruginosa.

Ultimately, it is the clinical picture that dominates the diagnosis.


Reduction of immunosuppression when possible; consider colony-stimulating factors. Prompt use of antifungals is essential, for a minimum of 6–12 weeks

  • IV voriconazole is the treatment of choice (may cause visual disturbances, deranged LFTs, skin rash)

  • Liposomal amphotericin B is an alternative first-line treatment

  • Patients who are intolerant of voriconazole/liposomal amphotericin or who have refractory disease can be treated with lipid-based amphotericin posaconazole, itraconazole, caspofungin, or micafungin

Some centres use oral posaconazole as prophylaxis when commencing substantial immune suppression.

Surgical resection of the infected focus should be considered in some (e.g. lung lesions contiguous with the heart or great vessels, chest wall invasion, osteomyelitis, pericardial infection, and endocarditis).

Differential diagnosis

The differential will be the large number of other opportunistic infections seen in immunosuppressed patients. Another invasive mycosis Candida albicans is now less common due to its susceptibility to fluconazole.

Further information

Walsh TJ et al. Treatment of aspergillosis: Clinical Practice Guidelines of the Infectious Diseases Society of America. Clin Infect Dis 2008;46:327–60.Find this resource:

Upton A et al. Invasive aspergillosis following hematopoietic cell transplantation. Clin Infect Dis 2007;44:531–40.Find this resource:

Patterson TF. Advances and challenges in the management of invasive mycoses. Lancet 2005;366:1013–25.Find this resource:

Semi-invasive aspergillosis

(also known as chronic necrotizing aspergillosis, chronic pulmonary aspergillosis, or subacute invasive pulmonary aspergillosis)


This entity is poorly defined, but it is clear that a low-grade chronic invasion of Aspergillus into airway walls and surrounding lung can occur. In the original descriptions, some cause of mild immuno-incompetence was present such as diabetes, steroid therapy, chronic lung disease, poor nutrition, etc. Previous asthma is not usually present, unlike ABPA.


It is assumed that this form of aspergillosis results from lowered immunity in those with a tendency to make Th2 eosinophilic responses to antigens. There is infiltration of hyphae into lung tissue, ranging from minor patchy consolidation to multiple cavities. There is little, if any, angioinvasion. It is assumed that the fungal digestive proteases gradually do the damage, rather than the host’s immunological response.

Clinical features

Suspect semi-invasive aspergillosis when:

  • Middle-aged

  • Reason for mild immunosuppression, e.g. diabetes, alcoholism, and steroid usage

  • A pre-existing chronic lung disease

  • Fever

  • Productive cough

  • Patchy indolent CXR changes.


  • Sputum samples may allow isolation of hyphae

  • CT will show an airway-centred type of picture with ‘tree-in-bud’ appearance. With increasing severity, this gives way to denser areas and small cavities that occasionally may contain a fungus ball

  • Likely to have IgG precipitins to Aspergillus, but not always.


On the assumption that mild immune suppression is the dominant cause, steroids are not usually recommended for fear of further immune suppression. This is in contrast to ABPA where the damage is due to the host’s immune defence mechanisms. Oral treatment with voriconazole is usually appropriate, but IV therapy is required for severely ill patients. Alternative treatment options are as for invasive aspergillosis.


(known as chronic cavitary pulmonary aspergillosis when there are multiple cavities)


The term aspergilloma is used to describe a ball of fungal hyphae within a cavity in the lung. It is assumed that this is colonization of a prior cavity (‘saphrophytic infection’), rather than arrested invasion. Aspergillomas can occur in other organs, including the pleural space.

Chronic cavitary pulmonary aspergillosis (CCPA) demonstrates multiple cavities, often with aspergillomas, in association with pulmonary and systemic symptoms and raised inflammatory markers. Usually associated with prolonged symptoms and defects in innate immunity.


Cavities can occur in the lung following a variety of insults such as TB, sarcoid, ordinary pneumonia/lung abscess, treated tumours, and CF. Fungal spores entering the cavity germinate and survive in a relatively protected environment. The ball consists of hyphae, inflammatory cells, fibrin, and debris. Around the cavity is an intense inflammatory response, often with considerable extra vascularization from bronchial arteries and occasional fungal hyphae.

Clinical features

Aspergillomas are often asymptomatic. Up to 75% will present with haemoptysis, assumed to come from damaged vessels on the inner surface of the cavity wall, via a communication with a bronchus. Sometimes, there are systemic symptoms, malaise, and fever, as well as chest pain. Superadded infection may provoke exacerbations.


  • CXR Apical cavity with ball within that changes position if CXR is performed decubitus

  • CT Obvious cavity with fungus ball and possible invasion into surrounding lung (uncommon)

  • Sputum culture

  • Aspergillus IgG precipitins Often higher levels than seen in other Aspergillus diseases.


  • Single aspergilloma:

    • May not require treatment

    • Consideration of surgical resection

    • Systemic symptoms of fever and malaise may be hard to ascribe to a mycetoma and require a therapeutic trial of voriconazole/itraconazole

    • The most significant complication is life-threatening haemoptysis. The emergency management of haemoptysis is described on Respiratory infection—fungal p. [link]

    • Itraconazole or voriconazole will not eradicate the fungus but seem to reduce cavity size and lessen the tendency to haemoptysis. It is assumed that they kill any fungus in the walls and inhibit growth in the cavity

  • CCPA:

    • Treat with itraconazole or voriconazole

    • Avoid surgery (associated with high morbidity and mortality, with complications, including haemorrhage, bronchopleural fistulae, and soiling of the pleural space).


  • Bronchial arteriograms should reveal a leash of vessels supplying part of the cavity wall that can be embolized, even if not actively bleeding. Short-term success rate is good; long term, less good

  • Surgery can be difficult, as mycetomas may be stuck to the chest wall. Problems of seeding the pleural space are seen less often than in the past, probably due to better antifungal agents

  • A few case reports exist of successful reduction of haemoptysis with radiotherapy

  • Older approaches involving intracavity injections of amphotericin are rarely used now, although a recent case series of 40 patients seemed promising.

Overview of Aspergillus lung disease

The essential differences between the Aspergillus lung diseases depends on whether the damage to the lung is mediated by host defence mechanisms (atopic asthma, flitting consolidation, ABPA, possibly aspergilloma) or by the fungus’ own digestive proteolytic enzymes (invasive aspergillosis, semi-invasive, aspergilloma). These two disease states are clearly different, but there probably exists a continuum between each of the subdivisions within each group, and the dominant mechanism in aspergilloma is not entirely clear. Therefore, it is likely that patients with mixed and transitional features will be encountered.

Future developments

  • Evaluation of combination antifungal therapies

  • Antifungal action of older drugs—flucytosine, rifampicin

  • Place of early surgery

  • Place of prophylaxis

  • Further evaluation of the role of galactomannan and β‎-glucan levels in blood and BAL fluid for diagnosis.

Further information

Aspergillus/Fungal Research Trust website. Respiratory infection—fungal

Soubani A et al. The clinical spectrum of pulmonary aspergillosis. Chest 2002;121:1988–99.Find this resource:

General approach to chronic haemoptysis

  • Tranexamic acid (must be taken during clot formation, as binds to fibrin to prevent action of endogenous fibrinolytics)

  • Treat associated bacterial infections.

Specific to aspergilloma

  • Itraconazole/voriconazole

  • Arterial embolization (usually bronchial circulation)

  • Surgical resection.

Pneumocystis pneumonia (PCP): diagnosis


PCP is the clinical syndrome of pneumonia resulting from infection with the fungus Pneumocystis jirovecii (previously termed Pneumocystis carinii). Pneumocystis jirovecii is widespread in the environment, and most people are infected by the age of 2y; PCP is thought, however, to follow new infection, rather than reactivation of latent infection. Most cases of infection are likely to be person-to-person airborne transmission, rather than environmental.


Risk factors for PCP include HIV infection (particularly with CD4 count <200 × 106/L), treatment with chemotherapy (especially fludarabine), corticosteroids or other immunosuppressive agents, and malnutrition in children. Neutropenia does not appear to be a particular risk factor. PCP occurring in the setting of AIDS is associated with both a greater number of organisms and fewer inflammatory cells in the lungs when compared with infection associated with other causes of immunocompromise. PCP is much less common following the routine use of co-trimoxazole prophylaxis in HIV and post-transplantation, although cases still occur, e.g. in patients presenting with advanced HIV or in those non-compliant with prophylaxis. The threshold steroid dose for predisposition to PCP is unclear, although a dose equivalent to 16mg prednisolone or greater for 8 weeks appears to significantly increase risk; the risk is likely also to reflect the underlying condition, e.g. PCP may develop in patients with haematological malignancy taking as little as 5mg prednisolone daily. PCP often appears to present as immunosuppressant drug doses are tapered or increased.

Clinical features

Gradual onset of dry cough and exertional breathlessness, sometimes with retrosternal tightness. Fever and tachypnoea may occur; chest examination is typically normal. May present with pneumothorax. Extrapulmonary disease is very rare.


  • CXR Pattern is classically of bilateral perihilar infiltrates that progress to alveolar shadowing. Less common patterns include small nodular infiltrates or focal consolidation. CXR is normal in about 10%. Pleural effusions are very rare. CT is not routinely required, except in cases of a normal CXR when it may demonstrate a bilateral ground-glass pattern or cystic lesions

  • Hypoxia is common. Desaturation on exercise may suggest the diagnosis in at-risk individuals with normal saturations at rest

  • White blood count is usually normal. Serum LDH is typically raised (sensitive but non-specific)

  • Induced sputum (see Respiratory infection—fungal p. [link]) has a diagnostic yield of about 60% in HIV infection but is much less sensitive when performed in the setting of non-HIV immunocompromise where the organism burden is lower. It should not be performed on the open ward or outpatient department

  • Bronchoscopy with BAL is the diagnostic investigation of choice in non-HIV-infected patients and in patients with HIV in whom induced sputum analysis is non-diagnostic. BAL with silver or immunofluorescent staining has a specificity of nearly 100% and sensitivity of 80–90%. This sensitivity is lower in non-HIV-infected immunocompromised patients, reflecting their lower pathogen loads

  • Transbronchial lung biopsy has a slightly higher sensitivity (around 95%) but is associated with an increased risk of complications so is reserved for cases where BAL is non-diagnostic. Surgical lung biopsy may be required for diagnosis in a minority of HIV-negative patients.

PCP: treatment


  • Liaise with infectious diseases or HIV specialist

  • High-dose co-trimoxazole (trimethoprim and sulfamethoxazole) remains the drug of choice. Administer 120mg/kg daily in four divided doses PO or IV (dilute 480mg ampoules in at least 75mL 5% glucose; infuse over 60min). Use IV route initially and then PO during clinical improvement; PO may be used initially in mild cases. Side effects (e.g. rash, nausea, vomiting, blood disorders) are common, particularly in HIV-infected patients. Consider routine use of antiemetics

  • Second-line choices, if intolerant or unresponsive to co-trimoxazole, include IV pentamidine, clindamycin and primaquine, dapsone and trimethoprim, atovaquone

  • All treatments should be for 2–3 weeks

  • If PCP is strongly suspected and the patient is unwell, treatment can be started immediately, as BAL pneumocystis stains remain positive for up to 2 weeks. Empirical treatment is also required in the occasional situation where the diagnosis is suspected but bronchoscopy is non-diagnostic or not tolerated

  • In cases of HIV presenting with PCP, early introduction of highly active antiretroviral therapy (HAART) has been contentious, with theoretical risks of drug interactions, increasing toxicities, and the potential for IRIS. However, a randomized trial and a retrospective analysis both demonstrated a 50% reduction in mortality when HAART was started within 2 weeks of PCP treatment. Suspected IRIS should be treated with corticosteroids ± reintroduction of PCP therapy.


  • High-dose steroids (prednisolone 40mg bd PO or IV hydrocortisone) are recommended for all patients in respiratory failure. Treat at high dose for 5 days; taper dose over 1–3 weeks (e.g. prednisolone 40mg daily for days 6–11, then 20mg daily for days 12–21).

Supportive therapy

  • Hypoxia is common; administer supplementary high-flow O2, and consider use of CPAP. Mechanical ventilation, if considered appropriate, may be required; make this decision prior to initiating CPAP.


  • Mortality 10–20% in the setting of AIDS, but 35–50% in patients with other forms of immunocompromise, probably reflecting the adverse consequences of the greater pulmonary inflammatory response to pneumocystis which is observed in non-HIV immunocompromise. Mortality from PCP requiring mechanical ventilation in HIV-infected patients is about 60% although may be significantly higher in patients with low CD4 counts.

  • Relapse rate in AIDS is high (60% in 1y), so 2° prophylaxis with co-trimoxazole is recommended. 1° prophylaxis is offered to HIV-positive patients with CD4 count <200 × 106/L. The indications for prophylaxis in non-HIV patients are less well defined; consider prophylaxis for patients who are likely to receive high doses of prednisolone for prolonged periods.

Future developments

  • The effect of co-infection with CMV on the outcome of PCP in HIV-infected patients is unclear. In patients with severe PCP treated with steroids, the presence of CMV in BAL fluid is associated with a worse outcome; the role of anti-CMV therapy, such as ganciclovir, in such cases is unknown

  • The use of PCR to detect pneumocystis may further increase diagnostic sensitivity, although, in a proportion of cases, detection using PCR is not accompanied by evidence of clinical infection and appears to represent colonization. It is unclear if asymptomatic carriage precedes infection in such patients, and the consequences of carriage in immunocompetent individuals are also unknown

  • Pneumocystis is one of only a handful of cells known to be unable to synthesize the metabolic intermediate molecule S-adenosylmethionine (AdoMet) and, as a result, must scavenge this molecule from its host. In a small study, lower plasma levels of AdoMet were demonstrated in PCP when compared with healthy controls and individuals with other pulmonary infections, suggesting a possible role for AdoMet in diagnosis. This finding has not yet been replicated in a larger study, however.

Further information

Kovacs JA et al. New insights into transmission, diagnosis, and drug treatment of Pneumocystis carinii pneumonia. JAMA 2001;286:2450–60.Find this resource:

Thomas CF, Limper AH. Pneumocystis pneumonia. N Engl J Med 2004;350:2487–98.Find this resource:



  • Cryptococcus neoformans is found worldwide in bird droppings. Following inhalation, yeasts propagate within the alveoli, without usually causing symptoms. Migration to the CNS may then occur, and meningoencephalitis is the most common clinical manifestation of infection

  • Patients with impaired cell-mediated immunity (e.g. AIDS, steroid use, lymphoma) are particularly vulnerable to cryptococcal infection.

Clinical features

  • Clinically evident cryptococcal lung disease is rare, but well described, even in HIV-negative patients. Symptoms are non-specific, including fever and cough, and presentations may be acute or chronic. The CXR may show non-calcified nodules, lymphadenopathy, lobar infiltrates, or pleural involvement

  • Pulmonary involvement is associated with meningoencephalitis in those with underlying immunosuppression, and clinical signs of meningism are characteristically absent. CT head (to exclude a space-occupying lesion), followed by lumbar puncture, should therefore be considered in all patients with pulmonary cryptococcal disease who have any condition predisposing to dissemination or neurological signs.


Diagnostic techniques include:

  • India ink stain on CSF, or latex agglutination test for capsular antigen in BAL or pleural fluid, blood, or CSF. Serum cryptococcal antigen test is extremely sensitive and specific for the diagnosis

  • Stains and culture of sputum, blood, urine, or BAL fluid. Positive culture from sputum may indicate colonization, rather than active disease, and should be interpreted in the clinical context.


of cryptococcal infection in the immunocompromised is with amphotericin B IV and flucytosine IV for 2–3 weeks, followed by fluconazole. The natural history of disease in immunocompetent patients is poorly understood, and observation alone is often recommended; disseminated disease may occur, however, and some experts advise treatment with fluconazole.

Candidal pneumonia

  • Candida occurs as part of the normal human flora and is found in the GI tract and on the skin. Invasive disease may occur in the immunocompromised, particularly in neutropenic patients. Prophylaxis with fluconazole is used following bone marrow transplantation

  • Candida is often isolated from respiratory secretions but very rarely causes respiratory disease. Haematogenous seeding to the lungs causing infiltrates or enlarging nodules may occur with disseminated candidal infection

  • Risk factors for candidaemia include immunocompromise, central venous lines, parenteral nutrition, and GI surgery. In lung transplant recipients, a positive donor tracheal culture for Candida is a marker for post-transplant candidal infection

  • The clinical and radiological features of pulmonary involvement are non-specific. Extrapulmonary manifestations of infection are common, e.g. skin, eye, hepatic, or CNS involvement. Candidaemia is typically associated with a high fever

  • Definitive diagnosis of pulmonary disease requires identification of tissue invasion by Candida on TBB or surgical lung biopsy

  • Treat with an echinocandin (e.g. caspofungin, micafungin), amphotericin B, or fluconazole, and remove any central lines

  • Candidaemia carries a mortality of 30–40%.

Further information

Pappas PG et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 2009;48:503–35.Find this resource:

Endemic mycoses: introduction

Several types of dimorphic fungi are known to commonly cause pulmonary disease in endemic regions, particularly in North America: histoplasmosis, blastomycosis, coccidioidomycosis, and paracoccidioidomycosis. Endemic fungi can rarely present in non-endemic areas, and diagnosis is often delayed because of their non-specific and varied clinical features and the failure to obtain a detailed travel history. Fungal infection may mimic other diseases, such as TB and lung cancer, often leading to inappropriate investigations and treatment. Fungal infections can also cause granulomata on lung biopsy, which sometimes results in diagnostic confusion (e.g. with sarcoidosis).

Infection in immunocompetent individuals is usually either asymptomatic or mild and self-limiting, although severe infection may rarely occur in apparently immunocompetent individuals. Outbreaks of disease may occur, as well as sporadic cases. Unlike invasive candidiasis and aspergillosis, where neutrophils are the key host defence mechanism, T-cell-mediated immunity is essential for defence against the endemic mycoses. Patients with impaired T-cell-mediated immunity (e.g. AIDS, lymphoma, steroid use) are therefore at particular risk of developing severe or disseminated infection.

Endemic mycoses: histoplasmosis


Histoplasma capsulatum is found in bird and bat dropping-contaminated soil in the Midwest and south-east USA, particularly the Ohio and Mississippi valleys, as well as in Mexico and parts of South America. The mycelial form is inhaled and subsequently develops into the yeast form (‘dimorphism’) within the lung before spread via the lymphatics and the activation of T-cell-mediated immunity with granuloma development.

Clinical features

Manifestations of infection are highly variable.

  • Asymptomatic infection occurs in the majority of cases. CXR may be normal or demonstrate single or multiple nodules, which may calcify in a characteristic ‘target lesion’ pattern. Lymphadenopathy may occur with eggshell calcification

  • Acute symptoms may follow heavy or recurrent exposure (e.g. pigeon fanciers, cavers). Range from a self-limiting flu-like illness of fever, cough, and malaise to fulminant disease with respiratory failure. CXR may be normal or show consolidation, bilateral alveolar shadowing, multiple small nodules, and sometimes lymphadenopathy

  • Chronic progressive lung disease occurs particularly in patients with underlying COPD; lung cavitation is common, sometimes leading to an incorrect diagnosis of TB or cancer

  • Disseminated disease may affect the immunocompromised (particularly AIDS) and the elderly. Presentation may be acute or chronic, and manifestations include fever, weight loss, and diffuse lung involvement, although almost any organ system may be affected; other features may include hepatosplenomegaly, GI symptoms, headache and meningism, cytopenias, endocarditis, and adrenal failure

  • Other unusual manifestations include broncholithiasis, mediastinal fibrosis (with compression of large airways, oesophagus, or SVC), or isolated extrapulmonary disease (e.g. arthritis, pericarditis, erythema nodosum, erythema multiforme).


  • Smears or culture of infected material, e.g. sputum or BAL fluid (for chronic pulmonary disease, insensitive for acute disease), blood, urine, or bone marrow (for disseminated disease). May take several weeks

  • Serology in acute disease—typically negative at presentation and becomes positive after several weeks. A variety of serological tests are in use, including:

    • Complement fixation, designed to detect antibodies to Histoplasma mycelial antigen or Histoplasma yeast antigen. A positive result (serum titre ≥1:16 for mycelial antigen, ≥1:32 for yeast antigen) for either antigen, in a compatible clinical setting, is considered diagnostic of active disease

    • Immunodiffusion may distinguish active disease from previous exposure but is less sensitive than complement fixation, and a negative result does not exclude the diagnosis

  • Serum, urine, or BAL fluid Histoplasma polysaccharide antigen test—useful for diagnosis of disseminated disease and also pulmonary disease. Positive in 85–95% cases in AIDS patients. Antigenuria is seen in 90%, and antigenaemia in <50% of non-AIDS patients.


  • Infection in immunocompetent individuals is typically self-limiting, and symptoms usually resolve within 2–4 weeks without treatment

  • Indications for antifungal treatment are:

    • Persistent symptoms (usually lasting >1 month)

    • Progressive disseminated disease

    • Heavy exposure leading to ARDS

    • Infection in the setting of immunocompromise

  • Oral itraconazole is appropriate for persistent symptoms in mild to moderate disease and for disseminated disease, including patients with AIDS who have mild disease. Treat for 6–12 weeks in acute histoplasmosis, and for 1–2y in chronic disease. In the setting of AIDS, treatment should be lifelong or until CD4 count >200 for at least 6 months after starting HAART. Check itraconazole drug interactions, and monitor liver function (ideally monthly) if taking for >1 month. Hypokalaemia may be associated with long-term use

  • IV lipid formulations of amphotericin B should be used to treat severe infection in the setting of ARDS or immunocompromise.

Endemic mycoses: blastomycosis


Infection with Blastomyces dermatitidis follows the inhalation of spores from contaminated soil, and clinical infection may follow outdoor activities. Blastomycosis is endemic in a distribution similar to that of histoplasmosis in the USA, although extending further north; it is endemic in the south-east USA and the Mississippi, Ohio, and St Lawrence river valleys. Blastomycosis also occurs in Africa, India, and the Middle East. It is significantly less common than histoplasmosis.

Clinical features

Clinical presentation is variable and may mimic other diseases such as bacterial pneumonia, TB, and lung cancer. Clinical manifestations include:

  • Asymptomatic in at least 50% of those infected

  • Acute presentation is typically with fever, cough, productive of mucopurulent sputum, and sometimes pleuritic chest pain; misdiagnosis as bacterial pneumonia is common. Acute presentation of fulminant respiratory disease with ARDS may occur. Other acute presentations include a flu-like illness with fever, myalgia, arthralgia, and erythema nodosum

  • Chronic presentation with fever, productive cough, and weight loss

  • Disseminated disease occurs in a minority of patients (especially in the immunocompromised) and most commonly involves the lungs, skin, bone, joints, and CNS.


Airspace infiltrates are the most common finding, but a very wide range of appearances are seen, including nodular pattern, lobar consolidation, diffuse infiltrates, or large peripheral masses (often with air bronchograms). Lymphadenopathy and pleural effusions may rarely occur.


  • Diagnosis is by the staining or culture of infected material. A pyogenic inflammatory response to the fungus is common (unlike in histoplasmosis) and facilitates diagnosis

  • Culture of sputum has a high yield and is diagnostic in most cases of acute pulmonary disease. Multiple specimens may be required, however. A drawback of sputum culture is that several weeks may be required before the fungus is identified. Cytological examination of sputum may provide a rapid diagnosis if the examiner is trained appropriately and alerted to the possible diagnosis

  • Bronchoscopy has a similar diagnostic yield to sputum culture (92% in one study) and is recommended for patients with negative sputum results; note that lidocaine may inhibit the fungal growth, and minimal concentrations should be used

  • More invasive procedures, such as surgical lung biopsy or thoracoscopy, are only rarely needed. Histological specimens require particular stains (e.g. silver stain) to facilitate identification of the fungus

  • Currently available serological tests lack sensitivity and are rarely helpful.


is usually with itraconazole for at least 6 months. Observation without treatment is not generally recommended, although this is controversial, and symptoms are usually self-limiting in immunocompetent individuals. Lipid formulations of amphotericin B should be used to treat very ill patients.

Endemic mycoses: coccidioidomycosis

Coccidioidomycosis is endemic in parts of south-west USA (Arizona, California, Texas, New Mexico, Utah, Nevada), northern Mexico, and Central and South America. Infection follows inhalation of Coccidioides immitis or C. posadasii spores from soil. Manifestations of infection are variable, including:

  • Asymptomatic infection, which appears to be common in endemic regions

  • Acute pulmonary disease. Presents in a similar manner to bacterial pneumonia, with fever, cough, pleuritic chest pain, and often skin rash (e.g. erythema nodosum or erythema multiforme). Eosinophilia may be present. CXR appearance is variable and may show areas of consolidation, lymphadenopathy, and pleural effusion, or be normal. The disease is self-limiting in most cases (Valley Fever); a minority progress to ARDS or chronic disease

  • Chronic pulmonary disease. Uncommon, may be asymptomatic. CXR typically shows single or multiple nodules that may cavitate; upper lobe infiltrates, similar to those seen in TB, may develop

  • Disseminated disease. Rare, occurs particularly in the immunocompromised. Presentation may be acute or chronic. Pulmonary disease occurs in association with involvement of the skin, bones, joints, genitourinary system, or CNS.


is with stains or culture of infected tissues. Sputum cultures are often positive in cavitating disease. BAL fluid culture and lung biopsies may also be diagnostic. Serological tests are also available.


is not required in the majority of patients who have mild self-limiting disease. Fluconazole is the antifungal of choice, when required.

Endemic mycoses: paracoccidioidomycosis

  • Paracoccidioidomycosis is endemic in parts of Central and South America and Mexico

  • Caused by the dimorphic fungus Paracoccidioides brasiliensis

  • Typically presents as chronic pulmonary disease, although acute disseminated disease may occur in the immunocompromised

  • Diagnosis is made on culture of sputum or BAL fluid, or following staining of lung biopsy samples

  • Treatment is with itraconazole, and long courses of up to 6 months may be needed. Severe disease is treated with amphotericin B.