Chris Kosmidis

The clinical spectrum of pulmonary aspergillosis

The clinical presentation of Aspergillus lung disease is determined by the interaction between fungus and host. Invasive aspergillosis develops in severely immunocompromised patients, including those with neutropenia, and increasingly in the non-neutropenic host, including lung transplant recipients, the critically ill patients and patients on steroids. A high index of suspicion is required in patients without the classical risk factors as early presentation is usually silent and non-specific, pyrexia uncommon and timely treatment is crucial for survival. Invasive aspergillosis has also been diagnosed in normal hosts after massive exposure to fungal spores. Chronic pulmonary aspergillosis affects patients without obvious immune compromise, but with an underlying lung condition such as COPD or sarcoidosis, prior or concurrent TB or non-tuberculous mycobacterial disease. Aspergillus bronchitis may be responsible for persistent respiratory symptoms in patients with Aspergillus detected repeatedly in sputum without evidence of parenchymal Aspergillus disease, especially in patients with bronchiectasis and cystic fibrosis. Allergic bronchopulmonary aspergillosis affects patients with asthma and cystic fibrosis, and is important to recognise as permanent lung or airways damage may accrue if untreated. Changes in the classification of Aspergillus allergic lung disease have been proposed recently. Cases of extrinsic allergic alveolitis and chronic pulmonary aspergillosis have been observed after Aspergillus exposure. Asymptomatic colonisation of the respiratory tract needs close monitoring as it can lead to clinical disease especially with ongoing immunosuppression. The various syndromes should be viewed as a semicontinuous spectrum of disease and one form may evolve into another depending on the degree of ongoing immunosuppression.

Republished: The clinical spectrum of pulmonary aspergillosis

The clinical presentation of Aspergillus lung disease is determined by the interaction between fungus and host. Invasive aspergillosis develops in severely immunocompromised patients, including those with neutropenia, and increasingly in the non-neutropenic host, including lung transplant recipients, the critically ill patients and patients on steroids. A high index of suspicion is required in patients without the classical risk factors as early presentation is usually silent and non-specific, pyrexia uncommon and timely treatment is crucial for survival. Invasive aspergillosis has also been diagnosed in normal hosts after massive exposure to fungal spores. Chronic pulmonary aspergillosis affects patients without obvious immune compromise, but with an underlying lung condition such as COPD or sarcoidosis, prior or concurrent TB or non-tuberculous mycobacterial disease. Aspergillus bronchitis may be responsible for persistent respiratory symptoms in patients with Aspergillus detected repeatedly in sputum without evidence of parenchymal Aspergillus disease, especially in patients with bronchiectasis and cystic fibrosis. Allergic bronchopulmonary aspergillosis affects patients with asthma and cystic fibrosis, and is important to recognise as permanent lung or airways damage may accrue if untreated. Changes in the classification of Aspergillus allergic lung disease have been proposed recently. Cases of extrinsic allergic alveolitis and chronic pulmonary aspergillosis have been observed after Aspergillus exposure. Asymptomatic colonisation of the respiratory tract needs close monitoring as it can lead to clinical disease especially with ongoing immunosuppression. The various syndromes should be viewed as a semicontinuous spectrum of disease and one form may evolve into another depending on the degree of ongoing immunosuppression.

Response to pneumococcal polysaccharide vaccination in patients with chronic and allergic aspergillosis

INTRODUCTION Pneumococcal infection causes significant morbidity in patients with underlying lung disease, and vaccination has been associated with reduced disease rates. Response to vaccination has not been studied in chronic lung conditions characterised by ongoing infection or inflammation like chronic pulmonary aspergillosis (CPA). METHODS In a prospective observational study, consecutive patients with CPA, allergic aspergillosis and bronchiectasis attending a national referral centre received pneumococcal 23-valent polysaccharide vaccine (PPV-23) and had pre- and post-vaccination antibody concentrations quantified as part of routine clinical care. Serotype-specific pneumococcal IgG antibodies were quantified for 12 serotypes using a multiplex microsphere assay. A protective response was defined as a level of >1.3μg/mL or a ≥ fourfold rise in concentration for ≥70% of serotypes, pre to post-vaccination. C-reactive protein, Immunoglobulins and mannose binding lectin (MBL) levels were measured and correlated to vaccine response. RESULTS A total of 318 patients were enrolled. In vaccine-naïve patients (n=127), the lowest pre-vaccination levels were seen with serotypes 1 and 4 and the highest with serotype 19A. A protective response post-vaccination was seen in 50% of patients. The poorest responses were observed with serotypes 1, 3 and 4. Levels of C-reactive protein did not affect efficacy. Profound MBL deficiency was found in 28.8%; there were no significant differences in response to vaccination in patients with or without MBL deficiency. Post-vaccination serotype-specific concentrations waned gradually, however they were still elevated compared to pre-vaccination after 2-5 years. CONCLUSIONS Patients with chronic and allergic aspergillosis exhibited a poor response to PPV-23 vaccination compared to healthy adults. An alternative vaccination strategy or delay of vaccination until their underlying condition is better controlled, e.g. after treatment with antifungals may result in better response.

Innate and Adaptive Immune Defects in Chronic Pulmonary Aspergillosis

We evaluated the expression of biomarkers of innate and adaptive immune response in correlation with underlying conditions in 144 patients with chronic pulmonary aspergillosis (CPA). Patients with complete medical and radiological records, white cell counts, and a complete panel of CD3, CD4, CD8, CD19, and CD56 lymphocyte subsets were included. Eighty-four (58%) patients had lymphopenia. Six (4%) patients had lymphopenia in all five CD variables. There were 62 (43%) patients with low CD56 and 62 (43%) patients with low CD19. Ten (7%) patients had isolated CD19 lymphopenia, 18 (13%) had isolated CD56 lymphopenia, and 15 (10%) had combined CD19 and CD56 lymphopenia only. Forty-eight (33%) patients had low CD3 and 46 (32%) had low CD8 counts. Twenty-five (17%) patients had low CD4, 15 (10%) of whom had absolute CD4 counts <200/μL. Multivariable logistic regression showed associations between: low CD19 and pulmonary sarcoidosis (Odds Ratio (OR), 5.53; 95% Confidence Interval (CI), 1.43–21.33; p = 0.013), and emphysema (OR, 4.58; 95% CI; 1.36–15.38; p = 0.014), low CD56 and no bronchiectasis (OR, 0.27; 95% CI, 0.10–0.77; p = 0.014), low CD3 and both multicavitary CPA disease (OR, 2.95; 95% CI, 1.30–6.72; p = 0.010) and pulmonary sarcoidosis (OR, 4.94; 95% CI, 1.39–17.57; p = 0.014). Several subtle immune defects are found in CPA.

Chronic fibrosing pulmonary aspergillosis: a cause of ‘destroyed lung’ syndrome

Abstract Background: Chronic pulmonary aspergillosis (CPA) has substantial impact on quality of life. A subset of patients develops significant pulmonary fibrosis, identified either on biopsy or radiologically. The term chronic fibrosing pulmonary aspergillosis (CFPA) has been suggested. Methods: We describe 11 patients with CFPA referred to our centre. Results: Mean age was 58.5 years and five were male. In nine, fibrosis was already evident on presentation, while in two it developed 3 and 6 years later. The predominant radiological feature was extensive or complete involvement of the entire lung, with minimal contralateral involvement. All patients received prolonged antifungal treatment. Two patients had surgical treatment; both developed post-operative complications. The contralateral lung remained free of significant disease in all but three patients. Conclusions: CFPA is a rare complication of CPA that is usually evident on presentation, but may develop after years in patients not on antifungals. Fibrosis resembles the ‘destroyed lung’ syndrome described after treated tuberculosis.

Twelve-month clinical outcomes of 206 patients with chronic pulmonary aspergillosis

There is a paucity of evidence surrounding the optimal antifungal therapy for use in chronic pulmonary aspergillosis (CPA) and the duration of therapy remains unclear. We retrospectively evaluated treatment outcomes, including change in quality of life scores (St George’s Respiratory Questionnaire (QoL)), weight and Aspergillus IgG at 6 and 12 months following initiation of therapy in a cohort of 206 CPA patients referred to the UK National Aspergillosis Centre (NAC), Manchester between April 2013 and March 2015. One hundred and forty-two patients (69%) were azole naïve at presentation and 105 (74%) (Group A) were commenced on itraconazole, 27 (19%) on voriconazole, and 10 (7%) were not treated medically. The remainder (64 patients, 31%) had previously trialled, or remained on, azole therapy at inclusion (Group B) of whom 46 (72%) received itraconazole, 16 (25%) voriconazole, and 2 (3%) posaconazole. Initial therapy was continued for 12 months in 78 patients (48%) of those treated; the azole was changed in 62 (32%) patients and discontinued in 56 (29%) patients for adverse reactions (32, 57%), azole resistance (11, 20%), clinical failure (8, 14%) or clinical stability (5, 9%). Azole discontinuation rates were higher in Group B than in Group A (42% vs. 22%, p = 0.003). For all patients who survived, weight increased (median of 62.2Kg at baseline, to 64.8 at 12 months), mean Aspergillus IgG declined from 260 (baseline) to 154 (12 months) and QoL improved from 62.2/100 (baseline) to 57.2/100 (12 months). At 12 months, there was no difference in median survival between Groups A and B (95% vs. 91%, p = 0.173). The rate of emergence of resistance during therapy was 13% for itraconazole compared to 5% for voriconazole. Bronchial artery embolization was done in 9 (4.4%) patients and lobectomy in 7 (3.2%). The optimal duration of azole therapy in CPA is undetermined due to the absence of evidenced based endpoints allowing clinical trials to be undertaken. However we have demonstrated itraconazole and voriconazole are modestly effective for CPA, especially if given for 12 months, but fewer than 50% of patients manage this duration. This suggests extended therapy may be required for demonstrable clinical improvement.

Micafungin may be safely administered as outpatient parenteral antimicrobial therapy for chronic pulmonary aspergillosis

Intravenous micafungin has been reported as a treatment alternative in patients with chronic pulmonary aspergillosis (CPA) where long‐term oral triazole therapy is unfeasible.

Assessment of posaconazole salvage therapy in chronic pulmonary aspergillosis using predefined response criteria

OBJECTIVES Chronic pulmonary aspergillosis (CPA) is a progressive infection that destroys lung tissue in non-immunocompromised patients. First-line therapies for CPA (itraconazole and/or voriconazole) are often curtailed due to toxicity or the development of drug resistance. Posaconazole is a potential alternative for these patients. METHODS Use of posaconazole was funded by the National Health Service Highly Specialised National Commissioners on an individual basis for patients who failed or did not tolerate first-line therapy; those who met predefined criteria for improvement at 4 and 6 months (weight gain and/or improvement in St Georges Respiratory Questionnaire) continued posaconazole long-term. We recorded response, failure, discontinuation rates, and adverse events. RESULTS Seventy-eight patients received posaconazole as salvage therapy. Thirty-four (44%) achieved targets for continuation of therapy. Fourteen (18%) failed therapy; five (36%) patients did not achieve clinical targets at 4 or 6 months of assessment and nine (64%) developed clinical and/or radiological failure. Twenty-eight (36%) discontinued their trial early; 8 (29%) died and 20 (71%) had significant side effects. One patient was non-compliant and another was lost to follow up. CONCLUSIONS Establishing criteria for therapeutic success offered a clear, safe and sustainable method of identifying patients who benefit from additional therapy, and minimised continuation of ineffective therapy in those who did not.

Use of voriconazole in non-meningeal cryptococcosis

Use of voriconazole in non-meningeal cryptococcosis Bhagteshwar Singh, Ahmad Lodhi, Cameron Choi, Alec Bonington & Chris Kosmidis To cite this article: Bhagteshwar Singh, Ahmad Lodhi, Cameron Choi, Alec Bonington & Chris Kosmidis (2017): Use of voriconazole in non-meningeal cryptococcosis, Infectious Diseases, DOI: 10.1080/23744235.2017.1308548 To link to this article: http://dx.doi.org/10.1080/23744235.2017.1308548