Pneumonia

Add-On Clarithromycin Pans Out in Community-Acquired Pneumonia Trial

Posted by

0


A close up photo of a clarithromycin tablet lying on its blisterpack

In a phase III trial, the addition of oral clarithromycin to beta-lactam antibiotic treatment improved the clinical response of people with community-acquired pneumonia who had systemic inflammatory response syndrome, findings that support existing guidelines.

In the study, the proportion of patients meeting the primary composite endpoint after 72 hours of treatment — fulfilling criteria for both respiratory symptom improvement and an early dampening of the inflammatory burden — reached 68% of those randomized to clarithromycin atop standard care and 38% of those receiving beta-lactam antibiotics alone (OR 3.40, 95% CI 2.06-5.63), reported Evangelos Giamarellos-Bourboulis, MD, of the National and Kapodistrian University of Athens, Greece, and coauthors.

Additionally, the combination of antibiotics significantly reduced the risk for subsequent organ dysfunction, prevented development of new sepsis, and shortened the time to hospital discharge, according to the double-blind ACCESS trial published in Lancet Respiratory Medicineopens in a new tab or window.

“Our results suggest that clarithromycin should be added to the management of hospitalized patients with community-acquired pneumonia to alleviate the inflammatory burden and to achieve early clinical benefit,” the group wrote.

Serious treatment-emergent adverse events (TEAEs) out to 90 days occurred in similar numbers between groups (43% vs 53%; OR 1.46, 95% CI 0.89-2.35).

Time-to-event curves suggested most of the benefit of the macrolide occurred in the first 8 days. The investigators added that they had indirect evidence of clarithromycin having a strong effect at the level of immune function — given that the clarithromycin group produced more tumour necrosis factor-α and less interleukin-10 in response to lipopolysaccharide stimulation than patients in the placebo group at day 4 — though cautioned that the antibiotic should still be used with caution to avoid emergence of resistance.

“Perhaps the most intriguing aspect of the study was the attempt to assess how clarithromycin modified immune response,” commented Grant Waterer, MD, PhD, of the University of Western Australia and Royal Perth Hospital.

“If impairment in early downregulation of pro-inflammatory responses is beneficial, this has fundamental implications for our understanding of the pathobiology of severe sepsis. Because most of the trend to benefit in mortality with clarithromycin was observed in the first 6-7 days, primary sepsis was probably driving mortality, not a reduction in secondary infections,” he wrote in an invited commentopens in a new tab or window.

In any case, ACCESS filled the need for a good randomized trial on combining beta-lactam antibiotics and macrolides for community-acquired pneumonia, a practice that has already been recommended by American and European guidelines alike.

ACCESS was conducted at multiple public hospitals within Greece from 2021 to 2023.

Investigators sought adults requiring hospital admission who were experiencing two or more community-acquired pneumonia-related symptoms such as cough, dyspnoea, pleuritic chest pain, or purulent sputum expectoration. Participants were ineligible if they had any history of contact with the hospital environment or with healthcare facilities during the preceding 90 days.

Patients also needed to exhibit two or more criteria for systemic inflammatory response syndrome, have a total Sequential Organ Failure Assessment (SOFA) score of at least 2, and have a procalcitonin concentration of at least 0.25 ng/mL.

A total of 278 patients were enrolled in the trial and randomized to standard care with or without oral clarithromycin (500 mg tablets every 12 hours for a week). Over 60% of the patient population were men, and all of the patients were white.

Individual components of the primary endpoint all favored the clarithromycin group over controls:

  • Decreases in respiratory symptom severity scores of at least 50% from baseline: 72% vs 48% (OR 2.83, 95% CI 1.70-4.70)
  • Decrease of 30% or more in SOFA score: 68% vs 41% (OR 3.10, 95% CI 1.88-5.11)
  • Favorable change in procalcitonin kinetics: 69% vs 54% (OR 1.86, 95% CI 1.12-3.06)

None of the TEAEs were found to be related to the study treatments. The most common events were septic shock, anemia, and SARS-CoV-2 infection, all of which were numerically more frequent among placebo patients.

As for the trial’s limitations, researchers noted that there was a heavy inflammatory burden among the patients enrolled and that the pathogen was ultimately found in 55% of the patient population, distinguishing ACCESS from other studies.

“Questions undoubtedly remain over the role of macrolides in community-acquired pneumonia,” Waterer wrote. “The threshold of severity for mandatory use is unclear and further studies are needed at lower thresholds, acknowledging that many patients with mild community-acquired pneumonia will have good outcomes regardless of the therapy chosen.”

Scientific Study of Surfer Butts Reveal Drug-Resistant Bacteria in the Oceans

Posted by

0


Surfers are known to brave bad weather, dangerously sized waves, and even sharks, for the perfect ride. But, it seems another danger of surfing has been lying in plain sight all along: ocean waters are full of drug-resistant bacteria — and surfers are most at risk.

 %E2%80%9CBeach%20Bums%E2%80%9D%20Study%20

In a study published this weekend in the journal Environmental International, a team of researchers from the University of Exeter found that regular surfers and bodyboarders are four times as likely as normal beach-goers to harbor bacteria with high likelihoods of antibiotic resistance. This is because surfers typically swallow ten times more seawater during a surf session than sea swimmers.

The cheekily named Beach Bums study, carried out with the help of UK charity Surfers Against Sewage compared rectal swabs from 300 participants and found that 9 percent of the surfers and bodyboarders (13 of 143) harbored drug-resistant E. coli in their systems, compared to just 3 percent of non-surfers (four of 130).

World Health Organization Anti-Microbial Resistance
The World Health Organization is concerned about drug resistance.

The World Health Organization has warned that widespread drug resistance may render antibiotics useless in the face of otherwise easily treatable bacterial infections, meaning that just as in the age before Penicillin, diseases like tuberculosis, pneumonia, blood poisoning, gonorrhea, food– and water-born illnesses as well as routine medical procedures that can lead to infection, including joint replacements and chemotherapy, could once again be fatal.

 Indeed, a 2016 report commissioned by the British government estimated that, by 2050, infections stemming from antimicrobial resistance could kill one person every three seconds.

Solutions to an impending drug resistance epidemic have largely focused on prescriptions and use, but there is an increasing focus on the role of the environment in transmitting drug-resistant bacteria strains. The Beach Bums study adds important insight into how sewage, run-off, and pollution that makes its way into the oceans spread the drug-resistant bacteria.

“We are not seeking to discourage people from spending time in the sea,” says Dr. Will Gaze of the University of Exeter Medical School, who supervised the research. “We now hope that our results will help policy-makers, beach managers, and water companies to make evidence-based decisions to improve water quality even further for the benefit of public health.”

Though the study’s purpose is not to alarm beachgoers — or surfers — Dr. Anne Leonard, who led the research, tells Inverse that the risk for anti-drug resistance may actually be lower in the United Kingdom, which “has invested a great deal of money in improving water quality at beaches, and 98 percent of English beaches are compliant with the European Bathing Water Directive. The risk of exposure to and colonization by antibiotic resistant bacteria in seawater might be greater in other countries which have fewer resources to spend on treating wastewater to improve water quality.”

For surfers on this side of the pond, check out the free app available for Apple and iOS, Swim Guide, for updated water quality information on 7,000 beaches in Canada and the U.S.

Are Steroids beneficial and safe in Pneumonia?

Posted by

0


https://speciality.medicaldialogues.in/are-steroids-beneficial-and-safe-in-pneumonia/

Bronchitis Versus Pneumonia: How to Tell Them Apart

Posted by

0


Many people often confuse pneumonia with bronchitis, because the symptoms of these two illnesses can be quite similar. In some cases, these two conditions are also mistaken for asthma, bronchiolitis, chronic obstructive pulmonary (COPD), or even a severe bout of the common cold.

bronchitis vs pneumonia

Story at-a-glance

  • Many people often confuse pneumonia with bronchitis, because the symptoms of these two illnesses can be quite similar
  • Bronchitis occurs when the lining of the passages that carry air to and from your lungs, known as your bronchial tubes, becomes infected. On the other hand, pneumonia occurs when the alveoli, or the air sacs in the lungs that transfer oxygen to the bloodstream, are inflamed

Differentiating Bronchitis From Pneumonia

Learning the key differences between bronchitis and pneumonia is crucial to help you come up with an effective treatment plan. Bronchitis occurs when the lining of the passages that carry air to and from your lungs, known as your bronchial tubes, becomes infected.

It usually manifests after a viral illness, such the common cold or flu, or in some cases the infection may develop on its own. Bronchitis is usually a viral infection, meaning antibiotics may not be helpful in treating it.

There are two types of bronchitis: acute and chronic. Acute bronchitis may last for only a week or so, although some of the symptoms (such as coughing) may still be felt several weeks after the condition has cleared up.

Meanwhile, chronic bronchitis may last for a few months, and the symptoms may come with sputum (a mix of mucus and saliva) on a daily basis. This can become quite serious, as it can increase your risk of lung cancer, or the infection may spread to your lungs.1

On the other hand, pneumonia occurs when the alveoli, or the air sacs in the lungs that transfer oxygen to the bloodstream, are inflamed. Generally, people with pneumonia feel much worse than those with bronchitis.2

It is also more dangerous than bronchitis, as it affects your oxygen supply, meaning all the organs and tissues in your body can be severely compromised. While bronchitis is usually viral in nature, pneumonia may be viral, fungal, or bacterial in nature, or may occur because of other harmful organisms.

There are similarities between the symptoms of these two illnesses. Mainly, they come with a persistent wet or dry cough, chest pain, chills, and shortness of breath. However, pneumonia usually comes with fever, headache, and fatigue as well.

What Is Bronchopneumonia?

In some instances, bronchitis and pneumonia may occur at the same time. This condition is known as bronchopneumonia. This means that both your bronchial tubes and alveoli sacs are infected. Bronchopneumonia may be caused by either a virus or bacteria.3 Whether you have bronchitis, pneumonia, or bronchopneumonia, learning the correct diagnosis is crucial in order for you to reach an effective treatment plan.

For example, if you are mistakenly diagnosed with pneumonia when you actually have bronchitis, and your physician recommends taking antibiotics, this will not treat the disease. Antibiotics only work on bacterial infections, and not viruses, and may only lead to antibiotic resistance – spelling more danger for your health.

Less antibiotic prescription does not increase risks of RTIs, except pneumonia, quinsy

Posted by

0


Less antibiotic prescription does not increase risks of RTIs, except pneumonia, quinsy

Reduced antibiotic prescription for respiratory tract infections (RTIs) in primary care settings was associated with a slight increase in the risks of pneumonia and peritonsillar abscess (quinsy), but not other RTIs, implying a need to review current antibiotic prescribing practice in view of increased drug resistance in bacteria, a new study suggested.

“Many RTIs are largely self-limiting, but antibiotics continue to be prescribed for about 50 percent of consultations for RTIs in primary care,” said the researchers, noting that widespread unnecessary use of antibiotics have led to increased antimicrobial drug resistance.

The study analysed the incidence of RTIs from 610 general practices in the UK using 411,226 patient records over 10 years (2005-2014), equivalent to 45.5 million person-years of patient follow-up. [BMJ2016;doi:10.1136/bmj.i3410]

In general, the proportion of RTI consultations requiring antibiotic prescriptions decreased for both men and women over the 10 years (from 53.9 to 50.5 percent for men, and from 54.5 to 51.5 percent for women).

New incidence of meningitis, middle ear infections (mastoiditis), and peritonsillar abscess saw a yearly decrease of 5.3, 4.6, and 1.0 percent, respectively during the period, while pneumonia incidence increased by 0.4 percent yearly.

A 10-percent reduction in antibiotic prescription increased the relative risk for pneumonia by 12.8 percent and 9.9 percent for peritonsillar abscess (p<0.001 for all), after adjusting for age and sex.

Put differently, if 10 percent fewer antibiotics were prescribed for RTIs in a general practice (GP) with an average size of 7,000 patients listed over 10 years, equivalent to 2,030 fewer antibiotic prescriptions, one additional case of pneumonia could be expected each year and an additional case of peritonsillar abscess could be expected each decade.

However, no increase in the risk of intracranial abscess, meningitis, mastoiditis, empyema, and Lemierre’s syndrome was observed with reduced antibiotic prescriptions.

“Even a substantial reduction in antibiotic prescribing may be associated with only a small increase in the numbers of [pneumonia and peritonsillar abscess] cases observed,” said lead author Professor Martin Gulliford of the Department of Primary Care and Public Health Sciences at King’s College London in London, UK, noting that both the complications can be readily treated when identified.

“Our results suggest that, if antibiotics are not taken, this should carry no increased risk of more serious complications,” he added.

Nonetheless, current guidelines for managing RTIs recommend that specific patient subgroups who have a higher risk of pneumonia, such as those with comorbidities or clinical presentation of serious complications, the very young, or the very old should be considered for immediate antibiotic prescription. [Med Decis Making 1981;1:239-246]

Antibiotic treatment of RTIs, in which most of the cases are caused by viruses and are often self-limiting, offers negligible benefit to patients, said the authors, suggesting that reduced antibiotic prescriptions for RTIs could minimize side effects such as vomiting, rashes, and diarrhoea.

Still, general practitioners might feel obliged to prescribe antibiotics for RTIs due to patients’ expectations and concerns about the safety of not prescribing antibiotics that could lead to missed opportunities for treatment. [Scand J Prim Health Care 2015;33:11-20]

A delayed antibiotic prescribing strategy, whereby a prescription is issued but not used until symptoms were deemed to have failed to improve, might help reduce antibiotic use in managing RTIs. [Cochrane Database Syst Rev 2013;4:CD004417]

“This would be expected to reduce the risks of antibiotic resistance, the side effects of antibiotics, and the medicalization of largely self-limiting illnesses,” said the researchers.

Further studies are required to evaluate the associations in different age groups, especially in children and older adults, as well as the severity of complications and mortality outcomes, they suggested.

Fluoroquinolone prescriptions for pneumonia are associated with longer delays in diagnosis and treatment of pulmonary TB and a higher risk of developing fluoroquinolone-resistant M. tuberculosis.

Posted by

0


Abstract:

BACKGROUND: Current guidelines for treating community-acquired pneumonia recommend the use of fluoroquinolones for high-risk patients. Previous studies have reported controversial results as to whether fluoroquinolones are associated with delayed diagnosis and treatment of pulmonary tuberculosis (TB) and the development of fluoroquinolone-resistant Mycobacterium tuberculosis. We performed a systematic review and meta-analysis to clarify these issues.

METHODS: The following databases were searched through September 30, 2010: PubMed, EMBASE, CINAHL, Cochrane Library, Web of Science, BIOSIS Previews, and the ACP Journal Club. We considered studies that addressed the issues of delay in diagnosis and treatment of TB and the development of resistance.

RESULTS: Nine eligible studies (four for delays and five for resistance issues) were included in the meta-analysis from the 770 articles originally identified in the database search. The mean duration of delayed diagnosis and treatment of pulmonary TB in the fluoroquinolone prescription group was 19.03 days, significantly longer than that in the non-fluoroquinolone group (95% confidence interval (CI) 10.87 to 27.18, p<0.001). The pooled odds ratio of developing a fluoroquinolone-resistant M. tuberculosis strain was 2.70 (95% CI 1.30 to 5.60, p=0.008). No significant heterogeneity was found among studies in the meta-analysis.

CONCLUSIONS: Empirical fluoroquinolone prescriptions for pneumonia are associated with longer delays in diagnosis and treatment of pulmonary TB and a higher risk of developing fluoroquinolone-resistant M. tuberculosis.

Liver plays role in pneumonia, sepsis susceptibility

Posted by

0


New evidence highlights the importance of the liver in immunity against bacterial pneumonia. The study is the first of its kind to directly show such a link between liver-produced molecules and pneumonia susceptibility during sepsis.

Led by researchers at Boston University School of Medicine (BUSM), the study appears in the journal Infection and Immunity.

Pneumonia, according to the World Health Organization, is the leading infectious cause of death in children worldwide, taking more than 900,000 lives of children under the age of 5 in 2013 alone. Pneumonia, in both children and adults, is frequently associated with , which is the body’s own inflammatory reaction to becoming infected.

In order to model the common clinical scenario of sepsis followed by , models were systemically treated with a bacterial product (eliciting a sepsis-like response) followed hours later by a live bacterial challenge in the lungs. One group had completely normal livers, and the other lacked a gene in their livers that prevented maximal activation. The researcher found the group lacking a complete liver response was more likely to succumb to pneumonia, exhibiting a significantly compromised immune response in both the lungs and blood, where more bacteria survived.

According to the researchers there is a well-established link between pneumonia and sepsis, such that both increase the likelihood of the other. Both also activate the liver to initiate what is known as the acute phase response, an event leading to the liver’s production of acute phase proteins that change in the blood “These proteins are frequently used as clinical biomarkers, but their combined biological significance is mostly speculative. However, the results of this study directly suggest that liver activation is required to maintain adequate immune responses in the lungs,” explained corresponding author Lee J. Quinton, PhD, associate professor of medicine and pathology at BUSM.

While it may be too early to immediately speculate on the applications of these findings, the authors believe that liver activity may serve as a previously unappreciated window into pneumonia defense/susceptibility. “A better understanding of how these distinct organs collaborate to mount immune responses has important clinical implications for patients with or at risk for pneumonia and sepsis. The idea that non-lung tissue could be targeted for treatments of lung disease is compelling,” added Quinton.

ACE inhibitors may not protect against pneumonia in older tube-fed patients

Posted by

0


Angiotensin-converting enzyme (ACE) inhibitors have no protective effect against pneumonia in older tube-fed patients, a Hong Kong randomized controlled trial (RCT) has shown.

The trial results have refuted evidence from previous studies and meta-analyses, which linked the use of ACE inhibitors to improvement of swallowing reflex as well as reduction of silent aspirations and pneumonia incidence in older patients with dysphagia.

“To our knowledge, this is the first RCT to examine the effect of ACE inhibitors on pneumonia in older patients on tube-feeding, with pneumonia as the primary outcome,” wrote investigators from the Chinese University of Hong Kong, Alice Ho Mui Ming Nethersole Hospital, Shatin Hospital, Tai Po Hospital, Prince of Wales Hospital, Pok Oi Hospital, Ruttonjee Hospital, Buddhist Hospital and Princess Margaret Hospital.

They recruited 71 patients aged ≥60 years who had been on tube-feeding for more than 2 weeks due to neurologic dysphagia secondary to cerebrovascular diseases. The patients were randomized to receive the ACE inhibitor lisinopril 2.5 mg once daily or placebo.

“We hypothesized that ACE inhibitors may reduce the incidence of pneumonia in these patients,” wrote the investigators. To their surprise, however, the rates of pneumonia were comparable between the two groups at 6 months after randomization (57.6 percent in the treatment group vs 47.4 percent in the placebo group; p=0.39).

The study was terminated prematurely due to the unexpectedly high overall mortality rate of 40.8 percent at 6 months. Notably, patients receiving lisinopril had significantly higher risks of 6-month mortality (adjusted odds ratio [OR], 7.79; p=0.018) and the composite endpoint of pneumonia or death (adjusted OR, 7.16; p=0.025).

“The higher mortality rate observed in the treatment group appeared to be attributed to its greater pneumonia-related deaths [14 cases vs 7 cases in the placebo group],” noted the investigators. “However, this might have been a chance finding, because the proportion of deaths due to pneumonia [relative to non-pneumonia causes] was similar between both groups [73 percent in the treatment group vs 70 percent in the placebo group]. In addition, pneumonia-related deaths between the two groups were not significantly different in the multiple logistic regression analysis.”

“Although observational studies in community-based populations suggested a protective or non-significant effect of ACE inhibitors in pneumonia, our results showed that whatever immune-modulating effects ACE inhibitors might have did not benefit these very frail patients,” they concluded.

On a positive note, the investigators observed a trend towards better swallowing function in patients treated with lisinopril (p=0.052). Further studies are warranted to examine this potential effect of ACE inhibitors.

IPD, pneumonia rates remain high among children with chronic conditions .

Posted by

0


Despite widespread use of 7-valent pneumococcal conjugate vaccine and an overall decline in rates of invasive pneumococcal disease, pneumonia, and pneumococcal pneumonia among children, disease rates remain high among children with chronic conditions, according to study findings in Clinical Infectious Diseases.

Stephen I. Pelton, MD, of Boston University Schools of Medicine and Public Health, and colleagues analyzed health care claims data from 2007 to 2010 to compare rates of pneumococcal disease among children with high-risk and at-risk conditions with rates among children without risk factors. Study participants were categorized into age groups (younger than 5 years or aged 5 to 17 years) and considered high-risk, at-risk, or have no at-risk/high conditions based on Advisory Committee in Immunization Practices (ACIP) and AAP recommendations.

Stephen I. Pelton, MD

Stephen I. Pelton

Most children had no chronic or immunocompromising conditions. About 7% of children in each age group had one or more at-risk conditions; less than 1% of each age group had a high-risk condition.

Among children aged younger than 5 years with at-risk conditions, 46% were premature or had low birth weight; 36% had asthma; 13% had chronic heart disease; and 12% had chronic lung disease. Thirteen percent of younger children had more than one at-risk condition. Among older children with at-risk conditions, 72% had asthma; 11% had neuromuscular or seizure disorders; and 5% had more than one at-risk condition.

Rates of invasive pneumococcal disease (IPD) were 11.2 and 40.1 times higher among younger and older high-risk children than children with no risk factors. Among children with at-risk conditions, rates for IPD were 1.8 and 3.3 times higher for each age group than rates for children with no risk.

Rates of pneumococcal pneumonia were also higher among high-risk children, by 6.8 and 8.9 for the younger and older age group; and by 2.6 and 2.9 for at-risk children of each age group.

Among children with asthma, rates and rate ratios for IPD and pneumococcal pneumonia increased more rapidly than rates for children with high-risk or at-risk conditions.

IPD rate ratios increased from 1.7 for younger, at-risk children with one condition to 4 for those with three or more conditions. Rate ratios for pneumococcal pneumonia increased from 2.1 among younger, at-risk children with one condition to 13.4 among those with three or more conditions.

Regarding older, at-risk children, IPD rate ratios increased from 3 to 32.1 as the number of conditions increased from one to three or more. Pneumococcal pneumonia rate ratios increased from 2.4 to 33.1 as the number of conditions increased from one to three or more.

Rates and rate ratios for all-cause pneumonia were similar to those for IPD and pneumococcal pneumonia.

These data demonstrate disease rates remain disproportionately high in children with high-risk and at-risk conditions, according to the researchers. In addition, they wrote, the increased risk of disease in high-risk and at-risk children is likely due to serotypes not covered in the 7-valent conjugate vaccine (Prevnar, Pfizer) rather than vaccine failure.

“We have identified a group of children who are at an increased risk for pneumococcal disease due to having medical conditions not currently included within the ACIP and AAP recommendations for prevention. These include children with asthma, especially those with moderate or severe disease, as well as children with asthma and concurrent morbidities such as lung or heart disease, diabetes, or neuromuscular disorders,” the researchers concluded.

 

Perspective

  • These data demonstrate that despite widespread use of PCV7 and an overall decline in IPD and pneumonia rates, disease rates remain disproportionately high in children <17 years old with high-risk conditions. The fold risk increased with the severity of the conditions, especially with asthma, the number of risk factors and the increasing age. Vaccine failure is an unlikely explanation for these findings. A more likely reason is increased risk of disease due to non-PCV7 serotypes. The introduction of PCV13 in all children <6 years old with selected chronic medical conditions and recommendations for its use in naïve children 6-18 years with HIV or asplenia, is likely to further decrease disease in high-risk children. However it is also likely that high-risk children will continue to suffer considerably form IPD and pneumonia caused by no-PCV13 pneumococcal serotypes, capable to cause disease mainly in compromised children, resulting in serotype replacement disease in these children. The role of additional dose of the 23-valent polysaccharide vaccine is questionable.

    The authors have identified medical conditions, not currently included within the ACIP and AAP recommendations for prevention by PCVs. These include children with asthma (especially moderate and severe), neuromuscular disorders, prematurity/low birth weight, and the combination of two or three or more of these conditions.

    What are the implications of this study? In the near future we may want to expand recommendation of PCV13 administration to the additional high-risk conditions pointed in the current study. In the future we may be able to expand PCV spectrum to include more than 13 serotypes. It is important also to study the potential role of influenza vaccines and maybe in the future RSV vaccines in prevention of secondary pneumococcal pneumonia in these high-risk children.

    • Ron Dagan, MD
    • Director, Pediatric Infectious Disease Unit
      Soroka University Medical Center

Inhaled corticosteroids in COPD and the risk of serious pneumonia

Posted by

0


Abstract

Background Inhaled corticosteroids (ICS) are known to increase the risk of pneumonia in patients with chronic obstructive pulmonary disease (COPD). It is unclear whether the risk of pneumonia varies for different inhaled agents, particularly fluticasone and budesonide, and increases with the dose and long-term duration of use.

Methods We formed a new-user cohort of patients with COPD treated during 1990–2005. Subjects were identified using the Quebec health insurance databases and followed through 2007 or until a serious pneumonia event, defined as a first hospitalisation for or death from pneumonia. A nested case–control analysis was used to estimate the rate ratio (RR) of serious pneumonia associated with current ICS use, adjusted for age, sex, respiratory disease severity and comorbidity.

Results The cohort included 163 514 patients, of which 20 344 had a serious pneumonia event during the 5.4 years of follow-up (incidence rate 2.4/100/year). Current use of ICS was associated with a 69% increase in the rate of serious pneumonia (RR 1.69; 95% CI 1.63 to 1.75). The risk was sustained with long-term use and declined gradually after stopping ICS use, disappearing after 6 months (RR 1.08; 95% CI 0.99 to 1.17). The rate of serious pneumonia was higher with fluticasone (RR 2.01; 95% CI 1.93 to 2.10), increasing with the daily dose, but was much lower with budesonide (RR 1.17; 95% CI 1.09 to 1.26).

Conclusions ICS use by patients with COPD increases the risk of serious pneumonia. The risk is particularly elevated and dose related with fluticasone. While residual confounding cannot be ruled out, the results are consistent with those from recent randomised trials.

Discussion

Using a large population-based cohort of over 160 000 patients with COPD followed for up to 18 years, we found that ICS use is associated with a significant 69% increase in the risk of serious pneumonia, requiring hospitalisation or fatal. This risk was particularly increased with fluticasone, with a doubling of the rate, and dose dependent with doses of 1000 μg of fluticasone per day associated with a 122% increase. The risk with budesonide was comparatively much lower with an increase of 17% and no dose–response effect. These elevated risks disappeared within a few months of stopping the use of ICS.

Systemic corticosteroids have been associated with increased risks of pneumonia in patients with rheumatoid arthritis.26 ,27 In these patients, a dose–response increase in the risk of pneumonia was seen with doses of prednisone as low as ≤5 mg/day (RR 1.4; 95% CI 1.1 to 1.6),26 and as low as 7.5 mg or less (RR 2.3; 95% CI 1.2 to 4.4).27 It is then not unexpected that high doses of ICS have similar effects on the incidence of pneumonia, as 1000 μg of inhaled fluticasone is estimated to be equivalent to 10 mg per day of prednisone with systemic effects evaluated by suppression of serum cortisol.7

Our findings confirm the observations of several randomised trials of varying durations and doses. The 2-year INSPIRE and 3-year TORCH trials both studied high doses of fluticasone (1000 μg per day) and found HRs of pneumonia of 1.94 (95% CI 1.19 to 3.17) and 1.64 (95% CI 1.33 to 2.02), respectively,3 ,4 ,13 ,14 A 1-year trial of fluticasone 1000 μg/day found a higher increase in the risk (RR 3.1; 95% CI 1.3 to 7.3; our calculation),15 which is consistent with our findings of a somewhat higher early risk. Our results confirm the subgroup analyses of the meta-analysis, suggesting that the risk is particularly elevated with high doses and start at short durations of use.12 With respect to the effect of dose, the two trials that evaluated a lower dose of fluticasone (500 μg per day) for 1 year also found a close to twofold higher incidence of pneumonia at 1 year with fluticasone.16–18This is also consistent with the dose–response curve from our study, which shows an increase in risk with lower doses and a RR of 1.6 at 500 μg/day of fluticasone.

The findings for budesonide confirm the pooled analysis of several trials of budesonide that found no increased risk of pneumonia over 1 year (RR 1.05; 95% CI 0·81 to 1·37),19 and a meta-analysis that suggests a lower risk with budesonide compared with fluticasone.20 Our finding of a more moderate 17% increase in the rate of serious pneumonia is concordant with these trial data. Moreover, the risk of pneumonia did not increase with the dose of budesonide. Nevertheless, a concern remains with budesonide as a recent 1-year trial in COPD found increases in pneumonia adverse events with daily doses of 640 μg (RR 2.3; 95% CI 1.2 to 4.7) and 320 μg (RR 1.7; 95% CI 0.8 to 3.6), equivalent to 400 μg and 200 μg of fluticasone, respectively.28 Since the fluticasone–salmeterol combination was approved and therefore promoted for COPD during the time period under study while the budesonide–formoterol combination was not, it remains possible that those receiving the budesonide combination were more likely to have asthma rather than COPD and be at lower risk of pneumonia compared with subjects receiving the fluticasone–salmeterol combination. Furthermore, since a higher dose formulation was only available for the fluticasone–salmeterol combination, patients with more severe disease may have been more likely to have received a combination therapy containing fluticasone rather than budesonide. Therefore, data on this question from countries where budesonide has a greater market share would be a valuable addition to this evidence.

There is good evidence supporting the effect of ICS on human pulmonary host defence, acting through several biological pathways, such as an inhibitory action on macrophage functions, a decrease in cytokine production and nitric oxide expression, which may lead to a failure to control infection.29 ,30 Although there have been no studies directly comparing the effects of fluticasone and budesonide on host defence, differences are likely related to their contrasting pharmacokinetic and pharmacodynamic properties. Fluticasone is known to be more potent (ie, greater effect on intracellular steroid receptors), more lipophilic and has a longer half life than budesonide.29Accordingly, fluticasone has a better penetration at the site of action and a more prolonged effect. It is therefore not surprising that a greater risk of oropharyngeal side effects is found with fluticasone compared with budesonide.31 While high potency and lipophilicity can be positive features allowing a lower dose to exert the desired effect, these characteristics may adversely affect drug safety. Indeed, a more prolonged corticosteroid effect in the lungs and greater pulmonary retention will facilitate the local immunosuppressive action.32 ,33 Budesonide enters the lungs with a lower lipophilicity, dissolves more quickly into pulmonary fluids, leading to a reduced local effect because of a more rapid cleavage and passage into the systemic circulation.30

This study has strengths and some limitations. The size of the population-based cohort of over 160 000 patients observed over 18 years permitted the identification of over 20 000 cases of serious pneumonia, allowing precise estimates of the risk associated with the different ICS at several doses. In this study, we defined serious pneumonia as a hospitalisation with a primary diagnosis of pneumonia or death from pneumonia, but did not have proof that the diagnosis was based on radiographic findings as these are not recorded in the RAMQ databases. However, it is most likely that as a primary inpatient diagnosis, it was in fact supported by a radiographic finding. To address confounding by COPD severity, we adjusted for the number of prescriptions for respiratory medications other than ICS, and for exacerbations as measured by prescriptions for oral corticosteroids, antibiotics, as well as prior hospitalisations for pneumonia and COPD exacerbation. Yet, residual confounding arising from unmeasured covariates can still be present. Of most concern is the possibility that budesonide may have been preferentially prescribed to patients with a lower risk of pneumonia, such as those with asthma or less severe COPD. In this specific study, however, our main results, adjusted for differences in severity, are consistent with those of several randomised trials which are inherently free of confounding, albeit less powerful with smaller study populations. Exposure to ICS was measured from dispensed prescriptions so that one must assume that the drugs were actually taken. However, not taking these medications would actually tend to underestimate the true risk increase. The definition of COPD used to identify the patients in our cohort was not based on a physician diagnosis of COPD or objective criteria for the diagnosis of COPD, but rather on including only subjects who started using respiratory medications at the age of 55 years or later and excluding subjects with a prior asthma hospitalisation or who used asthma-specific medications such as nedocromil, ketotifen, cromolyn or antileukotrienes. Nevertheless, our definition likely captured some patients with asthma. One can expect that this would reduce the estimate of risk of ICS since ICS do not appear to increase the risk of pneumonia in patients with asthma.34 Our sensitivity analysis within subjects previously hospitalised for COPD found practically the same differences in estimates of risk for fluticasone and budesonide.

The dose–response effect with fluticasone that we found on the incidence of serious pneumonia, sustained over a long time, is important in the risk–benefit balance for patients with COPD. While ICS are clearly effective for the treatment of asthma, their effectiveness in treating COPD is still controversial.1 ,2 The fact that ICS are now commonly combined in a single device with a long-acting bronchodilator, the latter recommended earlier in COPD, has resulted in ICS now being used by over 70% of patients with COPD.2 Moreover, these combined medications most often contain high doses of ICS, as high as 1000 μg of fluticasone per day.3 ,4 Consequently, the widespread use of ICS at higher doses in patients with COPD, along with the elevated incidence of pneumonia in this age group and their uncertain effectiveness, impact on the risk–benefit profile of ICS in COPD.

In conclusion, high and low doses of fluticasone in patients with COPD are associated with an important increase in the risk of serious pneumonia, while the risk with budesonide is comparatively low, even at high doses, though it needs further examination in light of recent data and the possibility that patients receiving budesonide are inherently at lower risk of pneumonia than those prescribed fluticasone. Further investigations into why the two popular ICS fluticasone and budesonide have such different effects on the risk of pneumonia are warranted.

Source: BMJ Thorax.