CME INDIA Presentation by Dr. Sangram S. Biradar, MD, FICP, FACP, FRCP, FCSI, FACC. Professor Medicine MRMC Gulbarga-Karnataka, Associate Editor API Karnataka Journal. Governing Body Member National API.

Based on the presentation at APICON-2022, Jaipur.

Pulmonary Aspergillosis

Quick Take Away

• The classification, diagnosis, and treatment of different forms of pulmonary aspergillosis has dramatically changed.
• It is a semi-continuous spectrum.
• It starts from an allergic, non-invasive form to a more aggressive invasive disease.
• Clinicians should maintain a high index of suspicion for pulmonary aspergillosis because early diagnosis and treatment are associated with a favorable outcome.
• IPA (Invasive Pulmonary aspergillosis) remains the most serious entity of this spectrum, with a high mortality rate despite optimal therapy.

What is this?

• Aspergillus is a mold which may lead to a variety of infectious, allergic diseases depending on the host’s immune status or pulmonary structure.
• Invasive pulmonary aspergillosis occurs primarily in patients with severe immunodeficiency.
• The significance of this infection has dramatically increased with growing numbers of patients with impaired immune state associated with the management of malignancy, organ transplantation, autoimmune and inflammatory conditions; critically ill patients and those with chronic obstructive pulmonary disease appear to be at an increased risk.

Risk Factors

• Prolonged neutropenia.
• Transplantation (highest risk with lung transplantation and HSCT).
• Prolonged (>3 weeks) and high dose corticosteroid therapy.
• Hematological malignancy (risk is higher with leukemia).
• Chemotherapy.
• Advanced AIDS.
• Chronic granulomatous disease.

Risk Factors for IPA

Symptoms of Pulmonary Aspergillosis

• Wheezing.
• Shortness of breath.
• Cough.
• Fever (in rare cases).

Spectrum of Pulmonary Aspergillosis

Credit: M. KOUSHA ET AL. European Respiratory Review Print ISSN 0905-9180 Online ISSN 1600-0617

Credit: Russo, A., Tiseo, G., Falcone, M. et al.  Infect Dis Ther 9, 511–524 (2020).

Clinical Manifestations

• Pulmonary aspergillosis is the most common presentation.
• Invasive pulmonary aspergillosis associated with fever, cough, dyspnea, pleuritic pain.
• Additional manifestations include necrotizing tracheobronchitis, pseudomembranous tracheobronchitis, CNS involvement, cutaneous, sinus, middle ear and mastoid infection.

Diagnostic Criteria

Diagnosis

• A high index of suspicion for IPA is required in patients with well-known risk factors.
• Histopathological examination of lung tissue obtained by thoracoscopic or open lung biopsy remains the gold standard for the diagnosis of IPA.
• For a better yield, specimen collection should be guided by CT scan findings, and large quantities of samples should be gathered.
• Thin, septated, hyphae with dichotomous acute angle branching are typically seen under the microscope.
• Surgical lung biopsy is commonly not possible in patients with suspected IPA due to their compromised respiratory status and bleeding tendencies.

A). chest computed tomography image showing left upper lobe cavitary lesion consistent with invasive pulmonary aspergillosis (IPA) in an allogeneic  haematopoietic stem-cell transplantation recipient.

B). brain magnetic resonance image from the same patient showing left parietal ring enhancing lesion due to disseminated IPA

Credit: M. KOUSHA ET AL. European Respiratory Review Print ISSN 0905-9180 Online ISSN 1600-0617

Criteria for IPA

Clinical scenarios of Aspergillus overlap syndromes in the lungs. ABPA: allergic bronchopulmonary aspergillosis; IPA: invasive pulmonary aspergillosis; CNA: chronic necrotising aspergillosis.

Credit: M. KOUSHA ET AL. European Respiratory Review Print ISSN 0905-9180 Online ISSN 1600-0617

Treatment Recommendation

Treatment Pearls

• Initiate promptly as the patient’s condition can decline quickly over 1 to 2 weeks from onset to death.
• Intravenous therapy for critically ill patients can include voriconazole (4 mg/kg, twice daily), posaconazole (300 mg IV, daily), micafungin (150 mg IV, daily), or amphotericin B (1 mg/kg, daily) for a 6 to the 12-week course.
• Voriconazole is considered the first-line treatment.
• While amphotericin is considered effective, it is deemed a second-line agent due to its adverse effect profile.
• Treatment of patients with chronic pulmonary: Start with oral therapy of itraconazole (200 mg, twice daily) or voriconazole (200 mg, twice daily).
• Treatment of chronic pulmonary aspergillosis with 12 months of oral itraconazole has been found superior to 6 months of oral itraconazole in reducing relapses at 2 years. Itraconazole should be given for at least 12 months for treating chronic pulmonary aspergillosis. (Lancet 2022)
• A minimum of 6 months of therapy for all patients is recommended, though lifelong therapy for patients with chronic progressive disease may be necessary.
• If failure of outpatient therapy it requires hospital admission for intravenous (IV) therapy.
• Repeat imaging should be done after a minimum of 2 weeks of therapy is completed.
• Surgery along with antifungal therapy may be required to remove an aspergilloma.
• This approach is most effective in patients who have a single lesion and not diffuse disease.
• Antifungal prophylaxis with voriconazole or posaconazole is recommended for patients with prolonged periods of neutropenia from chemotherapy, lengthy radiation treatments, allogeneic stem cell transplant recipients, severe or prolonged graft-versus-host disease, and solid organ transplant recipients.
• Allergic bronchopulmonary aspergillosis exacerbations are typically treated with a 3 to 6-week course of oral corticosteroids in addition to itraconazole.

Treatment of Pulmonary Aspergillus

• A new broad-spectrum triazole, voriconazole, has been approved as the initial treatment of invasive aspergillosis and is currently considered the treatment of choice in many patients with IPA.
• In a large prospective, randomized, multicenter trial, voriconazole was compared to amphotericin B as the primary therapy for IPA.
• Patients receiving voriconazole had a higher favorable response rate at week 12 (53% versus 32% in patients receiving amphotericin B) and a higher 12-week survival (71% versus 58%).
• Voriconazole is available in both intravenous and oral formulations.
• Voriconazole is available in both intravenous and oral formulations. The recommended dose is 6 mgkg-1 twice daily intravenously on day 1, followed by 4 mg kg-1day-1. After 7 days, switching to 200 mg p.o. twice daily may be considered.

Other Options for treatment

• Another broad-spectrum triazole, posaconazole, is effective and safe as salvage therapy in patients with IPA refractory to standard antifungal therapy.
• Echinocandin derivatives such as caspofungin, micafungin and anidulafungin are also effective agents in the treatment of IPA refractory to standard treatment, or if the patient cannot tolerate first-line agents.
• While polyenes and azoles target the fungal cell membrane, echinocandins inhibit the (13)-b-D-glucan constituent of the fungal cell wall.
• The combination of caspofungin and liposomal amphotericin B as a salvage therapy showed an overall response rate of 42%, although in patients with documented progressive IPA, the response rate was only 18%.

Points to Be Considered While Assigning Treatment

• According to the recent statement of the American Thoracic Society for treating fungal infections in adults, the duration of IPA therapy should be individualized to the patient’s clinical and radiological response.
• The treatment is often prolonged, lasting several months to >1 yr. Prerequisites for discontinuing treatment include clinical and radiographic resolution, microbiological clearance and reversal of immunosuppression.
• Reinstating therapy in patients who have responded should be considered if immunosuppression is resumed, or if the patient requires additional cytotoxic therapy or another HSCT.

Surgical Intervention

• Surgical resection has generally a limited role in the management of patients with IPA, but it becomes important in cases with invasion of bone, burn wounds, epidural abscesses and vitreal disease.
• It should also be considered in cases of massive haemoptysis, pulmonary lesions close to the great blood vessels or pericardium, or residual localised pulmonary lesions in patients with continuing immunosuppression or those who are expected to have immunosuppressive therapy in the future.
• Several reports have shown the relative efficacy and safety of surgical intervention, in addition to antifungal therapy, in these situations.

Immunotherapy

• Immunomodulatory therapy could be used to decrease the degree of immunosuppression and as an adjunct to antifungal therapy for the treatment of IPA.
• This includes colony stimulating factors, like granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-c.
• Colony-stimulating factors stimulate the bone marrow to produce more neutrophils, and have been shown to augment the phagocytic activity of neutrophils against fungi, including Aspergillus spp.
• There is a theoretical advantage to adding these agents to the treatment of neutropenic patients suspected to have IPA.

Prevention Pearls

• Consider excluding plants and flowers from rooms and avoiding food items such as nuts and spices.
• Erect suitable barriers between patient care and construction sites, clean shower heads routinely as well as hot-water faucets and air-handling systems.

Final Points

References:

1. M. Kousha, RPulmonary aspergillosis: a clinical review. Eur Respir Rev 2011; 20: 121, 156–174
2. Researchgate.net/figure/Different-stages-of-invasive-pulmonary-aspergillosis-IPA-and-the-potential-therapeutic_fig8_259608531
3. Fosses Vuong M, Waymack JR. Aspergillosis. [Updated 2022 Jan 28]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482241/
4. Sehgal IS Dhooria S Muthu V et al.Efficacy of 12-months oral itraconazole versus 6-months oral itraconazole to prevent relapses of chronic pulmonary aspergillosis: an open-label, randomised controlled trial in India.Lancet Infect Dis. 2022; (published online April 13.)https://doi.org/10.1016/S1473-3099(22)00057-3
5. Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline.Clin Microbiol Infect. 2018; 24: e1-38.
6. Russo, A., Tiseo, G., Falcone, M. et al. Pulmonary Aspergillosis: An Evolving Challenge for Diagnosis and Treatment. Infect Dis Ther 9, 511–524 (2020). https://doi.org/10.1007/s40121-020-00315-4
7. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(22)00126-8/fulltext April 13, 2022DOI:https://doi.org/10.1016/S1473-3099(22)00126-8

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