When should I suspect invasive pulmonary aspergillosis in my patient with COPD exacerbation?

Think of invasive pulmonary aspergillosis (IPA) in your patient when she or he has a COPD exacerbation that appears refractory to broad-spectrum antibiotics and high doses of steroids. Heighten your suspicion even more in patients with severe-steroid dependent COPD, presence of a new pulmonary infiltrate or isolation of Aspergillus spp from respiratory cultures. 1

It’s worth remembering that although dyspnea and bronchospasm are found in most COPD patients with IPA, in contrast to haematological patients, fever, chest pain and hemoptysis are usually absent in this patient population.1

Diagnosis of IPA in this patient population is challenging for several reasons including: 1. A definitive or “proven” diagnosis requires histopathologic evidence of Aspergillus invasion of lung tissue which is not possible without subjecting an already fragile patient to invasive procedures (eg, lung aspiration or biopsy); 2. In contrast to IPA in highly susceptible immunocompromised patients with cancer and recipients of hematopoietic stem cell transplants, standardized definition of IPA in patients with COPD is lacking; 1,3 and 3. Frequent colonization of the respiratory tract of COPD patients with Aspergillus spp (16.3 per 1000 COPD admission in 1 study) 4,5, makes it difficult to diagnose IPA based on cultures alone.

Aside from respiratory cultures, another non-invasive test, serum galactomannan (GM, a polysaccharide antigen that exists primarily in the cell walls of Aspergillus spp and released into the blood during its growth phase 6) may have some utility in suggesting IPA in COPD patients, albeit with a mediocre sensitivity (~30-60%) but respectable specificity (>80 %). In contrast, bronchoalveolar lavage fluid GM may have better sensitivity  (~75%-90%) with similar specificity as that of serum GM in the diagnosis of IPA in these patients 7-8

Bonus pearl: Did you know that the incidence of IPA appears to be increasing in COPD patients requiring ICU admission, with reported mortality rates of 67% to 100%? 7

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References

  1. Bulpa P, Dive A, Sibille Y. Invasive pulmonary aspergillosis in patients with chronic obstructive pulmonary disease. Eur Res J 2007;30:782-800. https://www.ncbi.nlm.nih.gov/pubmed/17906086
  2. Bulpa P, Bihin B, Dimopoulos G, et al. Which algorithm diagnoses invasive pulmonary aspergillosis best in ICU patietns with COPD? Eur Resir J 2017;50:1700532 https://www.ncbi.nlm.nih.gov/pubmed/28954783
  3. Barberan J, Garcia-Perez FJ, Villena V, et al. Development of aspergillosis in a cohort of non-neutropenic, non-transplant patients colonized by Aspergillus spp. BMC Infect Dis 2017;17:34. https://link.springer.com/article/10.1186/s12879-016-2143-5
  4. Guinea J, Torres-Narbona M, Gijon P, et al. Pulmonary aspergillosis in patients with chronic obstructive pulmonary disease: incidence, risk factors, and outcome. Clin Microbiol Infect 2010; 16:870-77. https://www.sciencedirect.com/science/article/pii/S1198743X14617432
  5. Blot Stijn I, Taccone FS, Van den Abeele A-M, et al. A clinical algorithm to diagnose invasive pulmonary aspergillosis in critically ill patients. Am J Respir Crit Care Med 202;186:56-64. https://www.atsjournals.org/doi/full/10.1164/rccm.201111-1978OC
  6. Pfeiffer CD, Fine JP, Safdar N. Diagnosis of invasive aspergillosis using a galactomannan assay: a meta-analysis. Clin Infect Dis 2006;42:1417-27. https://academic.oup.com/cid/article/42/10/1417/278148
  7. He H, Ding L, Sun B, et al. Role of galactomannan determinations in bronchoalveolar lavage fluid samples from critically ill patients with chronic obstructive pulmonary disease for the diagnosis of invasive pulmonary aspergillosis: a prospective study. Critical Care 2012;16:R138. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5066034/
  8. Zhou W, Li H, Zhang Y, et al. Diagnostic value of galactomannan antigen test in serum and bronchoalveolar lavage fluid samples from patients with nonneutropenic invasive pulmonary aspergillosis. J Clin Microbiol 2017;55:2153-61. https://www.ncbi.nlm.nih.gov/pubmed/28446576
When should I suspect invasive pulmonary aspergillosis in my patient with COPD exacerbation?

Should I routinely treat my patients with acute COPD exacerbation with antibiotics?

The answer is “NO”! With an estimated 20% to 50% of acute chronic obstructive pulmonary disease (COPD) exacerbations attributed to noninfectious factors (1,2), routine inclusion of antibiotics in the treatment of this condition is not only unnecessary but potentially harmful.

 
Although the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommends the use of antibiotics in patients who have dyspnea, increased sputum volume, and increased sputum purulence—or at least 2 of these 3 criteria when sputum purulence is one of them (3)—, these recommendations are not based on robust evidence and have not been widely corroborated (2,4-6).

 
That’s why the findings of a 2019 New England Journal of Medicine study (PACE) supporting the use of serum C-reactive protein (CRP) as an adjunctive test in COPD exacerbation is particularly welcome (1). In this multicenter randomized controlled trial performed in the U.K., the following CRP guidelines (arrived from prior studies) were provided to primary care clinicians to be used as part of their decision making in determining which patients with COPD exacerbation may not need antibiotic therapy:

 
• CRP less than 20 mg/L: Antibiotics unlikely to be beneficial
• CRP 20-40 mg/L: Antibiotics may be beneficial, mainly if purulent sputum is present
• CRP greater than 40 mg/L: Antibiotics likely to be beneficial

 
Adoption of these guidelines resulted in significantlly fewer patients being placed on antibiotics without evidence of harm over a 4-week follow-up period (1).  Despite its inherent limitations (eg, single country, outpatient setting), CRP testing may be a step in the right direction in curbing unnecessary use of antibiotics in COPD exacerbation.  

 

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References

 
1. Butler CC, Gillespie D, White P, et al. C-reactive protein testing to guide antibiotic prescribing for COPD exacerbations. N Engl J Med 2019;381:111-20. https://www.ncbi.nlm.nih.gov/pubmed/31291514
2. Llor C, Moragas A, Hernandez S, et al. Efficacy of antibiotic therapy for acute exacerbations of mild to moderate chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012;186:716-23. https://www.ncbi.nlm.nih.gov/pubmed/22923662
3. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. GOLD, 2019 (http://www.goldcopd.org).
4. Brett AS, Al-Hasan MN. COPD exacerbations—A target for antibiotic stewardship. N Engl J Med 2018;381:174-75. https://www.ncbi.nlm.nih.gov/pubmed/31291521
5. Miravitlles M, Moragas A, Hernandez S, et al. Is it possible to identify exacerbations of mild to moderate COPD that do not require antibiotic treatment? Chest 2013;144:1571-7. https://www.ncbi.nlm.nih.gov/pubmed/23807094
6. Van Vezen P, Ter Riet G, Bresser P, et al. Doxycycline for outpatient-treated acute exacerbations of COPD: a randomized double-blind placebo-controlled trial. Lancet Respir Med 2017;5:492-9. https://www.ncbi.nlm.nih.gov/pubmed/28483402

Should I routinely treat my patients with acute COPD exacerbation with antibiotics?

When should I consider Pseudomonas aeruginosa as a cause of respiratory tract infection in my hospitalized patient with COPD exacerbation?

The most consistent risk factor for isolation of P. aeruginosa from sputum of adults with COPD is the presence of more advanced pulmonary disease (eg, FEV-1 <35%-50% of predicted value) or functional impairment (1-5).

 

Chronic corticosteroid use is also frequently cited as an important predictor of respiratory tract colonization/infection due to P. aeruginosa in patients with COPD, while the data on antibiotic use during the previous months have been conflicting (2,4). Other risk factors may include prior isolation of P. aeruginosa and hospital admission during the previous year (1).

 
A prospective study of patients hospitalized for COPD exacerbation found P. aeruginosa to be the most frequently isolated organism, growing from 26% of validated sputum samples at initial admission, followed by Streptococcus pneumoniae and Hemophilus influenzae. In the same study, bronchiectasis (present in up to 50% of patients with COPD) was not shown to be independently associated with the isolation of P. aeruginosa (1).

 
Of interest, compared to the patients without P. aeruginosa, patients hospitalized for acute exacerbation of COPD and isolation of P. aeruginosa from sputum have significantly higher mortality: 33% at 1 year, 48% at 2 years and 59% at 3 years (5).

 

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References
1. Garcia-Vidal C, Almagro P, Romani V, et al. Pseudomonas aeruginosa in patients hospitalized for COPD exacerbation: a prospective study. Eur Respir J 2009;34:1072-78. https://www.ncbi.nlm.nih.gov/pubmed/19386694
2. Murphy TF. Pseudomonas aeruginosa in adults with chronic obstructive pulmonary disease. Curr Opin Pulm Med 2009;15:138-42. https://www.ncbi.nlm.nih.gov/pubmed/19532029
3. Miravitlles M, Espinosa C, Fernandez-Laso E, et al. Relationship between bacterial flora in sputum and functional impairment in patients with acute exacerbations of COPD. Chest 1999;116:40-6. https://www.ncbi.nlm.nih.gov/pubmed/10424501
4. Murphy TF, Brauer AL, Eschberger K, et al. Pseudomonas aeruginosa in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2008;177:853-60. https://www.ncbi.nlm.nih.gov/pubmed/18202344
5. Almagro P, Silvado M, Garcia-Vidal C, et al. Pseudomonas aeruginosa and mortality after hospital admission for chronic obstructive pulmonary disease. Respiration 2012;84:36-43. https://www.karger.com/Article/FullText/331224

 

 

When should I consider Pseudomonas aeruginosa as a cause of respiratory tract infection in my hospitalized patient with COPD exacerbation?