Category: Infectious Disease

Distorted Treatment Effects for Steroids for Pneumonia

This is the second “steroids for pneumonia” trial published in the last few weeks.  The last trial, enrolling 785 patients with community-acquired pneumonia, showed a small – but potentially relevant – reduction in inpatient length-of-stay.  No differences were noted with respect to mortality or treatment failure.

This trial, however, is a bit different.  In an effort to maximize the theoretical mortality reduction associated with steroid use in pneumonia, these authors targeted therapy specifically at those in the highest pneumonia severity risk categories and required a CRP >150 mg/L.  Patients were then randomized to 0.5 mg/kg twice daily of intravenous methylprednisolone or placebo.  The primary outcome was “treatment failure”, which was composed of two definitions – one specifically for early deterioration and one for late deterioration.

At face value – the results are excellent.  There was 31% failure rate in the 59 patients in the placebo group, compared with 13% of the 61 patients in the methylprednisolone group.  Deaths were 10% in the methylprednisolone group and 15% for placebo, and few adverse events occurred in either group – these differences, however, did not reach statistical significance due to the small sample size.

But this trial is essentially noise, full of baseline confounders and inconsistencies.  To start, simply, note each center enrolled, on average, one patient every-other month for eight years – only managing to screen 519 total patients with pneumonia for eligibility over the course of the trial.  This does not reflect a well-executed trial infrastructure.  An excess of 11% of placebo patients were admitted to the ICU, reflecting in part a 20% excess of placebo patients with shock as part of their initial presentation.  Shock and multiple organ failure was the major cause of death in the placebo group, compared with disease progression in the steroid cohort.

Furthermore, 40% of the placebo patients presenting with shock did not receive antibiotics within 4 hours of arrival.  Causative organisms were detected for 51% of the steroid cohort, compared with 30% of the placebo group – with 21% of the steroid cohort having a “respiratory virus” compared with 8% in the placebo group.  Antibiotic use was also odd, with the prevailing choice being ceftriaxone plus levofloxacin, rather than the typical ceftriaxone + azithromycin combination used for CAP.

How this managed to get published in one of the supposedly pre-eminent medicine journals is beyond me.  With only 120 patients, all the substantial absolute differences in baseline characteristics and care heavily distort the overall results.  Mostly, unfortunately, it looks like placebo patients were sicker and received less-adequate initial care – and everything measured in this small trial is suspect as a result.

“Effect of Corticosteroids on Treatment Failure Among Hospitalized Patients With Severe Community-Acquired Pneumonia and High Inflammatory Response”
http://www.ncbi.nlm.nih.gov/pubmed/25688779

Which Review of Tamiflu Data Do You Believe?

Ever since its introduction, there have been skeptics regarding the utility of oseltamivir and other neuraminidase inhibitors for the treatment of influenza.  Roche has profited tremendously off strategic stockpiling by many governments as a response to pandemic influenza – yet, nearly all the data comes from Roche-conducted trials, and the data has been persistently cloaked from independent review.  This past year, after much strife and public shaming, the Cochrane Collaboration received some access to clinical trial reports to conduct an independent review.  This review found, on average, adults receiving early treatment with oseltamivir benefited by reduction in symptom duration from 7 days to 6.3 days.  No benefit was found for reduction in respiratory infectious complications or hospitalization, the truly critical need during influenza outbreaks.

However, a second group also conducted an independent review – the “Multiparty Group for Advice on Science”.  Their results, based on an individual-patient meta-analysis, are published in the Lancet and offer similar – yet wildly different – conclusions.  They find, as did the Cochrane group, approximately a 17-hour reduction in symptoms in the intention-to-treat population across the eight Roche trials evaluated.

Similar to the Cochrane review, they perform secondary analyses for “lower respiratory tract infection”(e.g., bronchitis or pneumonia) and hospitalization, stratified by ITT and ITT-infected populations.  Most prominently emphasized are the results for the ITT-infected population, in which the antibiotics for LRTI were provided to 4.2% in the oseltamivir cohort, compared with 8.7% in placebo.  Likewise, 0.9% of patients were hospitalized for any cause compared with 1.7% of placebo.  The authors therefore conclude oseltamivir use decreased infectious complications of influenza.

These numbers, however, are entirely different from the Cochrane review.  The Cochrane review found a 1.4% hospital admission rate in the oseltamivir cohort and 1.8% in the placebo cohort.  Broken down by trial, the admit rates for the oseltamivir cohort in the MUGAS analysis compared with the Cochrane review:

  • M76001: 7/965 vs. 9/965
  • WV15670: 1/241 vs. 1/484
  • WV15671: 1/210 vs. 6/411
  • WV15707: 2/17 vs. 2/17
  • WV15812+: 6/199 vs. 9/199
  • WV15819+: 6/360 vs. 9/362
  • WV16277: 2/226 vs. 2/225

The differences in WV15670 and WV15671 appear to stem, at least in part, due to the MUGAS analysis being restricted to only trial patients taking 75mg twice daily, and not 150mg twice daily.  However, it is otherwise entirely unclear how the Cochrane group found extra hospitalizations in the other trials the MUGAS group did not – particularly considering the hospitalization numbers in the placebo cohorts were essentially identical.  Might it be partly a result of the MUGAS group receiving their data directly from a Roche web portal, while the Cochrane group reviewed the individual clinical study reports?

Rather, might it be revealing to pry into the genesis of the “Multiparty Group for Advice on Science”?  Is it an unbiased, independent clearinghouse for re-analysis of trial data?  Do they have a long track record of respected publications in multiple disciplines?  Unfortunately, neither of these conjectures are true – making it increasingly likely they are a puppet foundation fraught with conflict-of-interest.  MUGAS and the present work were funded by an unrestricted grant from Roche.  Furthermore, MUGAS, along with the European Scientific Working group on Influenza (ESWI), are projects of Semiotics, a scientific branding and communication company specializing in influenza.  The stated goal of Semiotics is promoting corporate science and ensuring its place on top of the policy agenda – and MUGAS is one of their “brands”.  This ought to very clearly demonstrate MUGAS is not a scientific enterprise, and rather an organization tasked with the sort of advocacy as best represents the needs of its sponsors.

Any bias might also be clear just in the style used to present results.  These authors present the tiny absolute differences in hospitalization and infectious complications in forest plot figures using only relative risk, rather than absolute risk.  This serves to inflate the apparent effect size.  Conversely, they present the increased incidence of adverse effects in a table culminating in adjusted absolute risk, with the opposite effect.  This manner of presentation persists in their Discussion, highlighting a “significant 63% reduction in risk of hospitalization”, compared with “absolute increases of 3.7% for nausea and 4.7% for vomiting.”

So – the results of an analysis performed by a “brand”, highlighting results discordant with a prior unbiased analysis.  Where is the peer review vetting such discrepancies?  With so many professional reputations and so much revenue at stake – which report do you believe?

“Oseltamivir treatment for influenza in adults: a meta-analysis of randomised controlled trials”
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)62449-1/abstract

Additional editorial content:
“The BMJ Today: The FDA and CDC’s disagreement over Tamiflu, and the spy who isn’t”
http://blogs.bmj.com/bmj/2015/02/05/the-bmj-today-the-fda-and-cdcs-disagreement-over-tamiflu-and-the-spy-who-isnt/

Prednisone … for Pneumonia?

The utility of antibiotics for eradication of bacterial pathogens from the lower respiratory tract is a given.  Use of steroids – also known for their immunosuppressive properties – not so much.

But, one can imagine clinical utility for steroids in acute infection.  Not every function of the immune system results in desirable patient-oriented effects.  Immunologic host responses include release of many inflammatory cytokines responsible for organ dysfunction, and steroids are already part of accepted therapy for several specific manifestations of pneumonia.  Based on prior results in smaller trials, these authors suspected use of steroids might be of benefit – both in mortality and in time to symptom resolution.

With 785 patients allocated in blinded fashion to 50 mg of prednisone daily or placebo, patients receiving prednisone reached “clinical stability” in a median of 3 days, compared to 4.4 days for the placebo cohort.  Hospital length-of-stay was reduced to 6 days from 7, and intravenous antibiotic use was cut by a day.  There were few important adverse effects overall, and the only consistent harm apparent in these data was increased hyperglycemia associated with corticosteroid use.

The accompanying editorial in The Lancet states adjunctive therapy with steroids is a therapy whose time has come, based on healthcare savings due to resource utilization.  In the context of other published studies, this observed reduction in time to vital sign normalization is valid.  However, whether the effect of steroids is truly beneficial or akin to simply masking the underlying clinical state by suppression of pro-inflammatory cytokine release is less certain.  Use of anti-pyretics blunts outward signs of systemic inflammatory response syndrome, and beta-blockers likewise reduce the tachycardia resulting from physiologic stress without specifically treating the underlying process.  It is hard to associate the outcomes measured in this trial with actual expedited clinical cure.

Reductions in length-of-stay and IV antibiotic use are reasonable patient-oriented and system-oriented outcomes, however, so the decision ultimately rests with the magnitude of harms – and the harms are certainly real.  Previous studies have suggested increased early recurrence or persistence of pneumonia, in addition to uncontrolled hyperglycemia.  These authors hoped to measure a 25% reduction in mortality – which was a bit of an odd expectation, given the ~2-4% expected absolute mortality – and no such suggestion of benefit was observed.

Simply put, this is not ready for prime-time or guideline-level adoption.  It is certainly worthy of further study, but steroids should not be used routinely outside the scope of prospective monitoring.

“Adjunct prednisone therapy for patients with community- acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial”
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)62447-8/abstract

Not Osletamivir, But Peramivir

Because the CDC is still pounding the pavement hawking neuraminidase inhibitors, the market is ripe for profit.  Not content to allow Roche all the fun, BioCryst Pharmaceuticals is trying to edge its way into the game.

BioCryst, as you now know, is the manufacturer of peramivir, a neuraminidase inhibotir whose initial claim to fame was emergency approval for intravenous use during the initial H1N1 pandemic.  They were in the news a few months back when they presented results for combined trials highlighting its use as a single intramuscular dose in the outpatient setting.  Now, the results of said trial are fully published, comprising combined populations of a phase 2 and under-enrolled phase 3 trial.

What net benefit, in these sponsored trials, in the lab-confirmed influenza population?

About an 18-hour reduction in symptoms, from a mean of 148 hours down to a mean of 130 hours with the 300mg IM injection.  The number of days until resumption of usual activities was nearly identical, from a mean of 9.4 in the 300mg cohort to 10.2 days in the placebo cohort.

And, what’s interesting, if you go back to some of the earlier studies, you might find nearly all the observed benefit associated with antiviral treatment was observed in the cohort treated within 24-hours, with no clinically relevant benefit between 24-48 hours.  However, you’ll only rarely see such detail presented, as it diminishes the viability of the product.

And, finally, just to add to your peramivir update – a clinical trial regarding the value of intravenous peramivir in hospitalized patients with influenza.  In a rather complicated and confounded design with only a few hundred patients, no benefit was demonstrated by use of peramivir whether as NAI monotherapy or adjunctive therapy to other neuraminidase inhibitors.  In the 121 patients who received peramivir monotherapy as part of the standard of care, there was no difference in any secondary infection or mortality.

But, I’m sure peramivir will rapidly be added to our antiviral armamentarium as a lovely money-wasting enterprise, regardless.

“Single dose peramivir for the treatment of acute seasonal influenza: integrated analysis of efficacy and safety from two placebo-controlled trials.”
http://www.ncbi.nlm.nih.gov/pubmed/25318121

“Efficacy and Safety of Intravenous Peramivir for Treatment of Seasonal Influenza Virus Infection”
http://www.ncbi.nlm.nih.gov/pubmed/20713668

“Evaluation of Intravenous Peramivir for Treatment of Influenza in Hospitalized Patients”
http://www.ncbi.nlm.nih.gov/pubmed/25115871

Bronchiolitis, Simplified

There are new guidelines from the American Academy of Pediatrics, just in time for the 2014-15 bronchiolitis season looming on the horizon – as if we don’t have enough to worry about with influenza and various West African hemorrhagic fevers.

But, the good news – these guidelines substantially reduce the things you have to remember to do for bronchiolitis.  Specifically, the only evidence-supported intervention you have is:  supportive care.

Ineffective, or of inadequate risk/benefit, treatments:

  • A trial of bronchodilators, such as albuterol or salbutamol.
  • Nebulized epinephrine.
  • Nebulized hypertonic saline, except possibly those requiring hospitalization.
  • Systemic or inhaled corticosteroids.
  • Chest physiotherapy.

… which basically covers everything.

And, not inconsistent with a recent trial regarding the misleading clinical weight of pulse oximetry, the guidelines state it is reasonable not to perform continuous oximetry on infants and children with bronchiolitis, and set 90% as an acceptable oxygen saturation.  Finally, the authors also state routine chest radiography should be avoided, as abnormalities are common in bronchiolitis – thus leading to ineffective, and harmful, antibiotic administration.

Simply put – do no harm!

“Clinical Practice Guideline: The Diagnosis, Management, and Prevention of Bronchiolitis”
http://pediatrics.aappublications.org/content/early/2014/10/21/peds.2014-2742.full.pdf+html

Who Loves Tamiflu?

Those who are paid to love it, by a wide margin.

This brief evaluation, published in Annals of Internal Medicine, asks the question: is there a relationship between financial conflicts-of-interest, and the outcomes of systematic reviews regarding the use of neuraminidase inhibitors for influenza?  To answer such a question, these authors reviewed 37 assessments in 26 systematic reviews, published between 2005 and 2014, and evaluated the concluding language of each as “favorable” or “unfavorable”.  They then checked each author of each systematic review for relevant conflicts of interest with GlaxoSmithKline and Roche Pharmaceuticals.

Among those systematic reviews associated with author COI, 7 of 8 assessments were rated as “favorable”.  Among the remaining 29 assessments made without author COI, only 5 were favorable.  Of the reviews published with COI, only 1 made mention of limitations due to publication bias or incomplete outcomes reporting, versus most of those published without COI.

Shocking findings to all frequent readers, I’m sure.

“Financial Conflicts of Interest and Conclusions About Neuraminidase Inhibitors for Influenza”
http://www.ncbi.nlm.nih.gov/pubmed/25285542

Original link in error … although, it’s a good article, too!
http://www.ncbi.nlm.nih.gov/pubmed/24218071

Still Adrift in Ignorance Over Blood Cultures

While supervising residents, one of the frequent diagnostic suggestions in undifferentiated febrile patients is: blood cultures.  As an Emergency Physician, the utility of blood cultures – short of diagnosing endocarditis or another primary hematogenous source – is vanishingly small.  After all, the source of infection is nearly universally somewhere else – lung, urine, CSF, skin & soft tissue – and relying on the blood to give you the answer two days later is an unreliable and impractical proposition.

This study is yet another attempt at identifying patients with high likelihood of bacteremia, retrospectively analyzing 5,499 patients at Odense University Hospital for whom blood cultures were drawn.  This cohort, representing roughly half of all patients presenting to the Emergency Department, had positive blood culture results 7.6% of the time.  CRP, temperature, and SIRS criteria were evaluated as potential predictive variables – and, unfortunately, the positive likelihood ratios of each were only between 2 and 3, and the negative likelihood ratios associated with each were all 0.4.  The authors combine these criteria and promote their absence as a rule-out, with a negative predictive value of 99.5% – but, common sense ought obviate trying to diagnose bacteremia in an afebrile patient with no SIRS criteria, and the NPV performance is more related to the low prevalence of disease than the utility of their criteria.

Really, the most interesting element of this study: the massive volume of blood cultures performed, with 92% of them true negative or false positive.  Costs for blood cultures vary by facility, and range from $15-$50, with patient charges typically a significant multiplier beyond.  A low yield might be important if the diagnoses were changing management and improving outcomes, but the vast majority of culture results are clinically unimportant.  These authors have not described particularly strong positive predictors – but they’ve illustrated the massive scope of the problem.

“How do bacteraemic patients present to the emergency department and what is the diagnostic validity of the clinical parameters; temperature, C-reactive protein and systemic inflammatory response syndrome?”

Bizarrely Alarmist Pediatric URI Study

In our new Gawker and Buzzfeed-fueled, short-attention span reality, attention-grabbing headlines are essential.  So, let me come up with the modern headline for news coverage of this latest article, published in Pediatrics:  “Is your child’s next cold a killer?”

Seriously, as covered by Medscape (subscription required):

“As many as 1 in 3 children seeking treatment in the emergency department for influenza-like illnesses (ILI) at the peak of influenza season are at high risk of suffering severe complications, such as pneumonia.”

But, that’s hardly the case.  The study upon which they report is an observational cohort of ILI presenting to a tertiary children’s hospital.  To be eligible for inclusion, children needed to have ILI, defined as fever + cough/sore throat, and have “moderate to severe” symptoms.  However, their definition of “moderate to severe” is not based on any specific clinical criteria – it’s based off the surrogate of whether a clinician judged venipuncture and viral testing necessary.

So, 125,940 children were screened during the study period, and this cohort comprises the, presumably, sickest 241 of those.  Of those 241, over half had one of a predefined list of high-risk conditions: asthma, neurologic/neuromuscular disease, respiratory disease, heart disease, or immunosuppression.  And, yes, about 40% of each cohort developed a complication – most frequently pneumonia.  But, it should not be concluded there are killer viruses everywhere – rather, the sickest ILI, particularly those children who presumably appeared ill despite lacking underlying chronic illness, are the tiny cohort at higher risk of subsequent complication.

The authors also try to single out H1N1 influenza as an independent risk factor for subsequent complications.  11/29 patients with H1N1 influenza developed pneumonia, compared with 1/20 patients without, leading to their conclusion H1N1 confers particular risk.  However, 22/29 of patients diagnosed with H1N1 carried high-risk comorbidities, compared with only 10/20 in the non-H1N1 influenza cohort.  Yes, H1N1 probably increases risk of respiratory complications, but these data may not reliably support their conclusion.

“Severe Complications in Influenza-like Illnesses”
http://pediatrics.aappublications.org/content/early/2014/07/29/peds.2014-0505.abstract

Updated IDSA Soft Tissue Infection Guidelines

Our infectious disease experts have bestowed upon us an update in the management of skin and soft tissue infection.  This is particularly relevant in our new Age of MRSA, where over-reaction and antibiotic overuse has become the norm – and almost certain to usher in a new, more dire, era of resistant pathogens.

But, this update provides a lovely pathway describing the treatment options for SSTIs that, happily, includes many narrow spectrum antibiotics.  Non-abscess SSTIs may be managed with simple penicillins or first-generation beta-lactams.  Purulent pathology is managed simply by incision and drainage – and antibiotics added only in the setting of moderate or severe disease.  They also, importantly, note most impetigo should be treated solely with topical antibiotic ointment.

There are a handful of odd statements, however.  Cultures are still recommended, but the authors acknowledge treatment is reasonable without.  Considering avoidance of cultures in uncomplicated SSTI is part of ACEP’s Choosing Wisely Recommendations, I’d prefer to see revised phrasing from the authors in the associated passages.  Recommendations for antibiotic prophylaxis after dog and cat bites appropriately require specific risk-factors for superinfection, but may yet still be overly broad.  At least, however, the level of evidence supporting their recommendation is appropriately cited as “low”.

And, of course, it’s always nice to be reminded of the appropriate treatment of glanders.

Finally, the recommendations do not overtly appear to reflect the influence of financial conflicts, despite many authors declaring substantial COI.

“Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections: 2014 Update by the Infectious Diseases Society of America”

The Broken ED Sepsis Quality Measure

Are there yet sufficient mandates in the Emergency Department?  Door-to-physician times, door-to-CT time in acute ischemic stroke, door-to-analgesia for long bone fractures – and, on the horizon, National Quality Forum proposed measures for delivery of sepsis bundle components within 3 and 6 hours.

The problem? As these authors discover, even for patients ultimately receiving a diagnosis of severe sepsis and septic shock, many do not meet those criteria within 3 hours, or in the Emergency Department.  These authors perform a retrospective review of 113 patients from a public Level 1 trauma center and 372 from a university teaching hospital who received who received at least a provisional diagnosis of severe sepsis or septic shock.  According to their review, 9.8% of patients at the trauma center and 15.3% of patients did not meet criteria for severe sepsis or septic shock within 3 hours of arrival.

No one disputes early recognition and treatment of sepsis is a cornerstone of quality Emergency Department care.  However, retrospective application of sepsis definitions to the initial time period of presentation is clearly a Quixotic quest.  Chasing every last potential severe sepsis patient will only lead to further unintended consequences, inappropriate care, and resource over-utilization – particularly because most patients with SIRS in the Emergency Department are never diagnosed with an infection.

Just as with OP-15, we should continue to work against implementation of this measure.

“Many Emergency Department Patients With Severe Sepsis and Septic Shock Do Not Meet Diagnostic Criteria Within 3 Hours of Arrival”
http://www.ncbi.nlm.nih.gov/pubmed/24680548