European societies issue aspergillosis diagnosis, management guidelines

European respiratory disease and infectious disease specialists have banded together to issue new clinical guidelines on the diagnosis and management of an uncommon but serious problem: chronic pulmonary aspergillosis (CPA).

Pulmonary infections with Aspergillus species, although uncommon, are a complicating factor in several lung diseases, especially tuberculosis, and aspergillosis is a serious, often fatal opportunistic infection in transplant recipients who are on chronic immunosuppression or patients who are immunocompromised from disease or cytotoxic chemotherapy.

Approximately 240,000 people in Europe and 3 million people worldwide have chronic pulmonary aspergillosis (CPA). The Centers for Disease Control and Prevention notes that because aspergillosis is not classified as a reportable disease, data on the actual incidence of infections in the United States are hard to come by.

“You don’t see this every day, whether you’re an infectious disease specialist or pulmonologist, so you really can’t rely on your experience to guide you in managing these cases, which is why guidelines such as this can be very helpful,” commented Dr. Norman Edelman, a pulmonologist and senior consultant for scientific affairs for the American Lung Association.

The guidelines, issued by the European Society for Clinical Microbiology and Infectious Diseases in cooperation with the European Confederation of Medical Mycology and the European Respiratory Society, are an attempt to provide clinicians with the best possible evidence-based guidance on managing patients with aspergillosis, primarily those with CPA (Eur Respir J. 2015. doi: 10.1183/13993003.00583-2015).

Dr. Edelman noted that the most frequent presentation he sees – and that very infrequently – is allergic bronchopulmonary aspergillosis in patients with asthma.

The most recent U.S. guidelines, issued under the aegis of the Infectious Diseases Society of America (IDSA) in 2000 and revised in 2008 (CID 2008;46:327-360), differ from the European recommendations in their level of detail, explained Prof. David W. Denning, professor of infectious diseases in global health at the University of Manchester (England) and lead author of the European guidelines.

“The IDSA guidelines assume that you know how to make the diagnosis, but actually for chronic pulmonary aspergillosis that’s not so easy with some patients,” he said in an interview.

“The European ones go into in great detail the diagnosis, the radiology, whether this test is better than that test, how they all add up, and all that sort of stuff,” he said,

The European guidelines also make recommendations for duration of therapy and comment on the use of steroids and immunotherapy with interferon-gamma, Dr. Denning noted.

Diagnostic criteria

The European guidelines categorize Aspergillus infections according to differences in clinical management:

• Simple aspergilloma. A single pulmonary cavity containing a fungal ball, supported by serologic or microbiologic evidence of infections with Aspergillus species in patients who are not immunocompromised and are asymptomatic or have only minor symptoms and no radiographic evidence of progression for at least 3 months.

• Chronic cavitary pulmonary aspergillosis (CCPA). The presence of one or more pulmonary cavities that may contain one or more aspergillomas or irregular intraluminal material, evidence of Aspergillus species, significant pulmonary/systemic symptoms, and overt progression on radiography over 3 or more months of observations.

• Chronic fibrosing pulmonary aspergillosis (CFPA). Severe, fibrotic destruction of at least two lung lobes as a complication of CCPA, causing a major loss of lung function. The guidelines note that destruction of a single lobe is designated as CCPA of that lobe.

• Aspergillus nodules. This unusual presentation is marked by the presence of one or more nodules that may or may not cavitate. The nodules may resemble tuberculoma, carcinoma of the lung, or coccidioidomycosis; histology is required to make an accurate diagnosis.

• Subacute invasive aspergillosis (SAIA). This can occur over the course of 1-3 months in patients who are mildly immunocompromised. Radiologic features can vary, and may include cavitation, the presence of nodules, and progressive consolidation with the appearance of abscess formation. Fungal hyphae (filaments) can be seen in biopsied lung tissues, and there may be evidence of Aspergillus galactomannan antigen in respiratory fluids or blood.

Treatment

The guidelines note that most of the evidence for managing CPA are based on cohort studies and case reports rather than randomized clinical trials, and that there have been no head-to-head trials comparing oral triazole agents.

For treatment of CPA, the European guidelines recommend:

• Itraconazole 200 mg twice daily, with therapeutic drug monitoring and dose adjustment as necessary (Grade A [strong] recommendation).

• Voriconazole 150-200 mg twice daily, with monitoring and dose adjustment. The guidelines recommend lower doses for patients older than 70 years, those with low body weight, significant liver disease, and/or those of Northeast Asian descent, who may be genetically inclined to slow drug metabolism (Grade A).

• Posaconazole liquid 400 mg twice daily, or tablets 300 mg once daily (Grade B [moderate] recommendation].

In general, the recommended duration of therapy for control of infection in patients with CPA or curative intent for patients with SAIA or chronic necrotizing pulmonary aspergillosis is 6 months or more, depending on patient status and drug tolerance.

For patients with CPA with progressive disease, those whom therapy has failed, or those who are intolerant of or have disease resistant to triazoles, intravenous therapy with micafungin, 150 mg day (Grade B); amphotericin B deoxycholate, 0.7-1.0 mg/kg per day (Grade C [marginal] recommendation); liposomal amphotericin B, 3 mg/kg per day (Grade B); or caspofungin, 50-70 mg/day (Grade C) are recommended.

The guidelines also recommend surgical excision of simple aspergilloma, preferably by a video-assisted thoracic surgery technique, if technically feasible.

“In my own experience, we resort to surgery very infrequently,” Dr. Edelman said.

He noted that it would be helpful if the guidelines had also allergic bronchopulmonary aspergillosis as a separate entity.

Ideal not always achievable

Prof. Denning points out that the optimum therapies and practices described in the guidelines can’t always be implemented. Worldwide, he said, antifungal therapy is not widely available, with the exception of fluconazole, which has no activity against Aspergillus, and is inferior to itraconazole and other extended azoles for other fungal diseases such as histoplasmosis, blastomycosis, and paracoccidioidomycosis.

The price of antifungal therapies can also be a barrier to effective treatment in many parts of the world.

“If you’re having to pay for your medicines and you’re living on $5 or $10 a day in Kenya, say, you can’t afford to buy them. So even if the drugs are physically there, it may not be really affordable for a course of therapy for these patients, and there’s some advocacy to be done around that for the whole world,” he said.

The guidelines were funded primarily by grants from ESCMID and ERS with additional support from ECMM. Authors’ travel expenses were funded jointly by ESCMID and ERS. Dr. Denning has received grant support and founder shares in F2G, and has received grants from the Fungal Research Trust, Wellcome Trust, Moulton Trust, Medical Research Council, Chronic Granulomatous Disease Research Trust, National Institute of Allergy and Infectious Diseases, National Institute of Health Research and the European Union, and AstraZeneca. Dr. Edelman reported no relevant disclosures.

[email protected]

European respiratory disease and infectious disease specialists have banded together to issue new clinical guidelines on the diagnosis and management of an uncommon but serious problem: chronic pulmonary aspergillosis (CPA).

Pulmonary infections with Aspergillus species, although uncommon, are a complicating factor in several lung diseases, especially tuberculosis, and aspergillosis is a serious, often fatal opportunistic infection in transplant recipients who are on chronic immunosuppression or patients who are immunocompromised from disease or cytotoxic chemotherapy.

Approximately 240,000 people in Europe and 3 million people worldwide have chronic pulmonary aspergillosis (CPA). The Centers for Disease Control and Prevention notes that because aspergillosis is not classified as a reportable disease, data on the actual incidence of infections in the United States are hard to come by.

“You don’t see this every day, whether you’re an infectious disease specialist or pulmonologist, so you really can’t rely on your experience to guide you in managing these cases, which is why guidelines such as this can be very helpful,” commented Dr. Norman Edelman, a pulmonologist and senior consultant for scientific affairs for the American Lung Association.

The guidelines, issued by the European Society for Clinical Microbiology and Infectious Diseases in cooperation with the European Confederation of Medical Mycology and the European Respiratory Society, are an attempt to provide clinicians with the best possible evidence-based guidance on managing patients with aspergillosis, primarily those with CPA (Eur Respir J. 2015. doi: 10.1183/13993003.00583-2015).

Dr. Edelman noted that the most frequent presentation he sees – and that very infrequently – is allergic bronchopulmonary aspergillosis in patients with asthma.

The most recent U.S. guidelines, issued under the aegis of the Infectious Diseases Society of America (IDSA) in 2000 and revised in 2008 (CID 2008;46:327-360), differ from the European recommendations in their level of detail, explained Prof. David W. Denning, professor of infectious diseases in global health at the University of Manchester (England) and lead author of the European guidelines.

“The IDSA guidelines assume that you know how to make the diagnosis, but actually for chronic pulmonary aspergillosis that’s not so easy with some patients,” he said in an interview.

“The European ones go into in great detail the diagnosis, the radiology, whether this test is better than that test, how they all add up, and all that sort of stuff,” he said,

The European guidelines also make recommendations for duration of therapy and comment on the use of steroids and immunotherapy with interferon-gamma, Dr. Denning noted.

Diagnostic criteria

The European guidelines categorize Aspergillus infections according to differences in clinical management:

• Simple aspergilloma. A single pulmonary cavity containing a fungal ball, supported by serologic or microbiologic evidence of infections with Aspergillus species in patients who are not immunocompromised and are asymptomatic or have only minor symptoms and no radiographic evidence of progression for at least 3 months.

• Chronic cavitary pulmonary aspergillosis (CCPA). The presence of one or more pulmonary cavities that may contain one or more aspergillomas or irregular intraluminal material, evidence of Aspergillus species, significant pulmonary/systemic symptoms, and overt progression on radiography over 3 or more months of observations.

• Chronic fibrosing pulmonary aspergillosis (CFPA). Severe, fibrotic destruction of at least two lung lobes as a complication of CCPA, causing a major loss of lung function. The guidelines note that destruction of a single lobe is designated as CCPA of that lobe.

• Aspergillus nodules. This unusual presentation is marked by the presence of one or more nodules that may or may not cavitate. The nodules may resemble tuberculoma, carcinoma of the lung, or coccidioidomycosis; histology is required to make an accurate diagnosis.

• Subacute invasive aspergillosis (SAIA). This can occur over the course of 1-3 months in patients who are mildly immunocompromised. Radiologic features can vary, and may include cavitation, the presence of nodules, and progressive consolidation with the appearance of abscess formation. Fungal hyphae (filaments) can be seen in biopsied lung tissues, and there may be evidence of Aspergillus galactomannan antigen in respiratory fluids or blood.

Treatment

The guidelines note that most of the evidence for managing CPA are based on cohort studies and case reports rather than randomized clinical trials, and that there have been no head-to-head trials comparing oral triazole agents.

For treatment of CPA, the European guidelines recommend:

• Itraconazole 200 mg twice daily, with therapeutic drug monitoring and dose adjustment as necessary (Grade A [strong] recommendation).

• Voriconazole 150-200 mg twice daily, with monitoring and dose adjustment. The guidelines recommend lower doses for patients older than 70 years, those with low body weight, significant liver disease, and/or those of Northeast Asian descent, who may be genetically inclined to slow drug metabolism (Grade A).

• Posaconazole liquid 400 mg twice daily, or tablets 300 mg once daily (Grade B [moderate] recommendation].

In general, the recommended duration of therapy for control of infection in patients with CPA or curative intent for patients with SAIA or chronic necrotizing pulmonary aspergillosis is 6 months or more, depending on patient status and drug tolerance.

For patients with CPA with progressive disease, those whom therapy has failed, or those who are intolerant of or have disease resistant to triazoles, intravenous therapy with micafungin, 150 mg day (Grade B); amphotericin B deoxycholate, 0.7-1.0 mg/kg per day (Grade C [marginal] recommendation); liposomal amphotericin B, 3 mg/kg per day (Grade B); or caspofungin, 50-70 mg/day (Grade C) are recommended.

The guidelines also recommend surgical excision of simple aspergilloma, preferably by a video-assisted thoracic surgery technique, if technically feasible.

“In my own experience, we resort to surgery very infrequently,” Dr. Edelman said.

He noted that it would be helpful if the guidelines had also allergic bronchopulmonary aspergillosis as a separate entity.

Ideal not always achievable

Prof. Denning points out that the optimum therapies and practices described in the guidelines can’t always be implemented. Worldwide, he said, antifungal therapy is not widely available, with the exception of fluconazole, which has no activity against Aspergillus, and is inferior to itraconazole and other extended azoles for other fungal diseases such as histoplasmosis, blastomycosis, and paracoccidioidomycosis.

The price of antifungal therapies can also be a barrier to effective treatment in many parts of the world.

“If you’re having to pay for your medicines and you’re living on $5 or $10 a day in Kenya, say, you can’t afford to buy them. So even if the drugs are physically there, it may not be really affordable for a course of therapy for these patients, and there’s some advocacy to be done around that for the whole world,” he said.

The guidelines were funded primarily by grants from ESCMID and ERS with additional support from ECMM. Authors’ travel expenses were funded jointly by ESCMID and ERS. Dr. Denning has received grant support and founder shares in F2G, and has received grants from the Fungal Research Trust, Wellcome Trust, Moulton Trust, Medical Research Council, Chronic Granulomatous Disease Research Trust, National Institute of Allergy and Infectious Diseases, National Institute of Health Research and the European Union, and AstraZeneca. Dr. Edelman reported no relevant disclosures.

[email protected]

European respiratory disease and infectious disease specialists have banded together to issue new clinical guidelines on the diagnosis and management of an uncommon but serious problem: chronic pulmonary aspergillosis (CPA).

Pulmonary infections with Aspergillus species, although uncommon, are a complicating factor in several lung diseases, especially tuberculosis, and aspergillosis is a serious, often fatal opportunistic infection in transplant recipients who are on chronic immunosuppression or patients who are immunocompromised from disease or cytotoxic chemotherapy.

Approximately 240,000 people in Europe and 3 million people worldwide have chronic pulmonary aspergillosis (CPA). The Centers for Disease Control and Prevention notes that because aspergillosis is not classified as a reportable disease, data on the actual incidence of infections in the United States are hard to come by.

“You don’t see this every day, whether you’re an infectious disease specialist or pulmonologist, so you really can’t rely on your experience to guide you in managing these cases, which is why guidelines such as this can be very helpful,” commented Dr. Norman Edelman, a pulmonologist and senior consultant for scientific affairs for the American Lung Association.

The guidelines, issued by the European Society for Clinical Microbiology and Infectious Diseases in cooperation with the European Confederation of Medical Mycology and the European Respiratory Society, are an attempt to provide clinicians with the best possible evidence-based guidance on managing patients with aspergillosis, primarily those with CPA (Eur Respir J. 2015. doi: 10.1183/13993003.00583-2015).

Dr. Edelman noted that the most frequent presentation he sees – and that very infrequently – is allergic bronchopulmonary aspergillosis in patients with asthma.

The most recent U.S. guidelines, issued under the aegis of the Infectious Diseases Society of America (IDSA) in 2000 and revised in 2008 (CID 2008;46:327-360), differ from the European recommendations in their level of detail, explained Prof. David W. Denning, professor of infectious diseases in global health at the University of Manchester (England) and lead author of the European guidelines.

“The IDSA guidelines assume that you know how to make the diagnosis, but actually for chronic pulmonary aspergillosis that’s not so easy with some patients,” he said in an interview.

“The European ones go into in great detail the diagnosis, the radiology, whether this test is better than that test, how they all add up, and all that sort of stuff,” he said,

The European guidelines also make recommendations for duration of therapy and comment on the use of steroids and immunotherapy with interferon-gamma, Dr. Denning noted.

Diagnostic criteria

The European guidelines categorize Aspergillus infections according to differences in clinical management:

• Simple aspergilloma. A single pulmonary cavity containing a fungal ball, supported by serologic or microbiologic evidence of infections with Aspergillus species in patients who are not immunocompromised and are asymptomatic or have only minor symptoms and no radiographic evidence of progression for at least 3 months.

• Chronic cavitary pulmonary aspergillosis (CCPA). The presence of one or more pulmonary cavities that may contain one or more aspergillomas or irregular intraluminal material, evidence of Aspergillus species, significant pulmonary/systemic symptoms, and overt progression on radiography over 3 or more months of observations.

• Chronic fibrosing pulmonary aspergillosis (CFPA). Severe, fibrotic destruction of at least two lung lobes as a complication of CCPA, causing a major loss of lung function. The guidelines note that destruction of a single lobe is designated as CCPA of that lobe.

• Aspergillus nodules. This unusual presentation is marked by the presence of one or more nodules that may or may not cavitate. The nodules may resemble tuberculoma, carcinoma of the lung, or coccidioidomycosis; histology is required to make an accurate diagnosis.

• Subacute invasive aspergillosis (SAIA). This can occur over the course of 1-3 months in patients who are mildly immunocompromised. Radiologic features can vary, and may include cavitation, the presence of nodules, and progressive consolidation with the appearance of abscess formation. Fungal hyphae (filaments) can be seen in biopsied lung tissues, and there may be evidence of Aspergillus galactomannan antigen in respiratory fluids or blood.

Treatment

The guidelines note that most of the evidence for managing CPA are based on cohort studies and case reports rather than randomized clinical trials, and that there have been no head-to-head trials comparing oral triazole agents.

For treatment of CPA, the European guidelines recommend:

• Itraconazole 200 mg twice daily, with therapeutic drug monitoring and dose adjustment as necessary (Grade A [strong] recommendation).

• Voriconazole 150-200 mg twice daily, with monitoring and dose adjustment. The guidelines recommend lower doses for patients older than 70 years, those with low body weight, significant liver disease, and/or those of Northeast Asian descent, who may be genetically inclined to slow drug metabolism (Grade A).

• Posaconazole liquid 400 mg twice daily, or tablets 300 mg once daily (Grade B [moderate] recommendation].

In general, the recommended duration of therapy for control of infection in patients with CPA or curative intent for patients with SAIA or chronic necrotizing pulmonary aspergillosis is 6 months or more, depending on patient status and drug tolerance.

For patients with CPA with progressive disease, those whom therapy has failed, or those who are intolerant of or have disease resistant to triazoles, intravenous therapy with micafungin, 150 mg day (Grade B); amphotericin B deoxycholate, 0.7-1.0 mg/kg per day (Grade C [marginal] recommendation); liposomal amphotericin B, 3 mg/kg per day (Grade B); or caspofungin, 50-70 mg/day (Grade C) are recommended.

The guidelines also recommend surgical excision of simple aspergilloma, preferably by a video-assisted thoracic surgery technique, if technically feasible.

“In my own experience, we resort to surgery very infrequently,” Dr. Edelman said.

He noted that it would be helpful if the guidelines had also allergic bronchopulmonary aspergillosis as a separate entity.

Ideal not always achievable

Prof. Denning points out that the optimum therapies and practices described in the guidelines can’t always be implemented. Worldwide, he said, antifungal therapy is not widely available, with the exception of fluconazole, which has no activity against Aspergillus, and is inferior to itraconazole and other extended azoles for other fungal diseases such as histoplasmosis, blastomycosis, and paracoccidioidomycosis.

The price of antifungal therapies can also be a barrier to effective treatment in many parts of the world.

“If you’re having to pay for your medicines and you’re living on $5 or $10 a day in Kenya, say, you can’t afford to buy them. So even if the drugs are physically there, it may not be really affordable for a course of therapy for these patients, and there’s some advocacy to be done around that for the whole world,” he said.

The guidelines were funded primarily by grants from ESCMID and ERS with additional support from ECMM. Authors’ travel expenses were funded jointly by ESCMID and ERS. Dr. Denning has received grant support and founder shares in F2G, and has received grants from the Fungal Research Trust, Wellcome Trust, Moulton Trust, Medical Research Council, Chronic Granulomatous Disease Research Trust, National Institute of Allergy and Infectious Diseases, National Institute of Health Research and the European Union, and AstraZeneca. Dr. Edelman reported no relevant disclosures.

[email protected]