Category: Infectious Disease

Tying Procalcitonin to Critical Care

It has been hard, over the years, to truly identify a role for procalcitonin.  Generally speaking, its best niche seems to be as a sort of C-reactive protein on steroids – a non-specific infectious or inflammatory marker with better sensitivity than WBC.  This has led to some usage in zero-miss contexts such as neonatal sepsis, as well as a potential role in antibiotic stewardship.

These authors, many of which are supported by the manufacturers of the procalcitonin assay, evaluate its predictive power in the setting of pneumonia hospitalization, attempting to risk-stratify patients for the combined endpoint of vasopressor support or invasive ventilation.  Their goal, they say, is to use procalcitonin levels to better inform level-of-care decisions – both escalated and de-escalated – at the time of hospital admission.

They analyzed 1,770 patients from a prior pneumonia study for whom banked serum samples were adequate for procalcitonin measurement, 115 of whom met their combined critical illness endpoint.  They report risk of critical illness increased approximately linearly with procalcitonin from 4% when procalcitonin was undetectable, to 22.4% when procalcitonin was 10ng/mL or above.  The AUC for procalcitonin alone was 0.69, as compared to WBC at 0.54.  Then, they further go on to add usage of procalcitonin in conjunction with other risk-stratification scores – ATS minor criteria, PSI, and SMART-COP – provided additional discriminatory information.

This could be a potentially useful and interesting application of procalcitonin – except they don’t really make any comparisons to other available tools, other than a straw man comparison with WBC.  Would the venerable CRP have a similar AUC?  Or, better yet, a lab we already use nearly ubiquitously to detect occult severe sepsis – a lactic acid level?  The authors do not present any specific discussion of alternative approaches – of which their friends at BioMerieux probably appreciate.

“Procalcitonin as an Early Marker of the Need for Invasive Respiratory or Vasopressor Support in Adults with Community-Acquired Pneumonia”
https://www.ncbi.nlm.nih.gov/pubmed/27107491

Where Acute Otitis Media is Born

Is it 3 AM in your Emergency Department?  Is there a febrile infant with their still-awake parents straggling in the door?  Do you hear the first few bars of the “it’s just a virus” song start playing over Spotify?

This little study prospectively enrolled healthy infants at birth and followed them to their first episode of acute otitis media or 12 months of age.  They were followed specifically to determine predictive clinical and epidemiological factors influencing the first diagnosis of AOM.  Additionally, as they aged and during illness, nasopharyngeal swabs were taken to evaluate viral and bacterial flora.

Based on a sample of 367 infants followed for a total of 286 child-years, there were 887 presentations for viral URIs and 180 presentations for AOM –and all but two of AOMs were preceded by a URI.  The median time from URI presentation to AOM diagnosis was 3 days.  These authors also present a fair bit of microbiologic data regarding specific risks for URI and AOM, although these are not specifically modifiable and of lesser clinical relevance.  From a modifiable environmental outlook, however, there are a few interesting tidbits tying into what we already suspected to be true:  breastfeeding is good, the new PC13 vaccine is good, and daycare is a cesspool.

Overall, this would tend to support our typical advice to parents to have their children present for a recheck 48-72 hours following Emergency Department visit, particularly if there has not been clinical improvement or in the context of apparent clinical re-worsening.

“Acute Otitis Media and Other Complications of Viral Respiratory Infection”
https://www.ncbi.nlm.nih.gov/pubmed/27020793

Are Antibiotics Back in Favor for Abscesses?

A couple years ago, the IDSA came out with antibiotic treatment guidelines covering uncomplicated cutaneous abscesses.  The simple, straightforward treatment many of us have been advocating: incision and drainage without antibiotics.

Sadly, such days may be finished.

A few years back, a small trial found no statistically difference in clinical cure for patients randomized to trimethoprim-sulfamethoxazole or placebo – but there were concerns regarding whether the study was appropriately powered.  This, larger, multi-center, double-blind, randomized, placebo-controlled trial aims to rectify that flaw.

With the usual exclusions for patients with serious comorbid disease, these authors enrolled 1,265 to ultimately analyze 1,247.  Acute abscesses of greater than 2.0cm, but still appropriate for outpatient management, were randomized either to 7 days of TMP-SMX or identical-appearing placebo.  There were several different follow-up time frames: for initial clinical improvement, “test of cure”, and for secondary outcomes of abscess recurrence.

There’s not much debate on the outcome – with the TMP-SMX arm generating a fairly consistent ~7% absolute cure rate improvement over placebo.  In the per-protocol population, which excluded patients lost to follow-up, cure rate was 92.9% in the TMP-SMX group versus 85.7% in the placebo cohort.  Furthermore, throughout every meaningful secondary outcome – particularly new skin infection at another site or an infection occurring in a household member – TMP-SMX was favored in proportions of similar absolute magnitude.  Adverse events were similar between each group, without a preponderance of apparent harms from TMP-SMX.

An NNT of ~14 is nothing at which to scoff.  The costs of the intervention are fairly low.  We are definitely missing some of the granular detail in this first publication, and it is difficult to say whether it’s generalizable to smaller abscess or how to manage abscesses with minimal surrounding cellulitis.  I look forward to these follow-up analyses to potentially improve the precision of treatment – but, in the meantime, it may be time to roll back some of our antibiotic stewardship movements in MRSA-endemic regions.

“Trimethoprim–Sulfamethoxazole versus Placebo for Uncomplicated Skin Abscess”
http://www.nejm.org/doi/full/10.1056/NEJMoa1507476

Changing Clinician Behavior For Low-Value Care

I’ve reported in general terms several times regarding, essentially, the shameful rate of inappropriate antibiotic prescribing for upper respiratory infections.  Choosing Wisely says: stop!  However, aggregated data seems to indicate the effect of Choosing Wisely has been minimal.

This study, from JAMA, is a prospective, cluster-randomized trial of multiple interventions in primary care practices aimed at decreasing inappropriate antibiotic use.  All clinicians received education on inappropriate antibiotic prescribing.  Then, practices and participating clinicians were randomized either to electronic health record interventions of “alternative suggestion” or “accountable justification”, to peer comparisons, or combinations of all three.

The short answer: it all works.  The complicated answer: so did the control intervention.  The baseline rate of inappropriate antibiotic prescribing in the control practices was estimated at 37.1%.  This dropped to 24.0% in the post-intervention period, and reflected a roughly linear constant downward trend throughout the study period.  However, each different intervention, singly and in combination, resulted in a much more pronounced drop in inappropriate prescribing.  While inappropriate prescribing in the control practices had reached mid-teens by the end of the study period, each intervention group was approaching a floor-level in the single digits.  Regarding safety interventions, only one of the seven intervention practice clusters had a significantly higher 30-day revisit rate than control.

While this study describes an intervention for antibiotic prescribing, the basic principles are sound regarding all manner of change management.  Education, as a foundation, paired with decision-support and performance feedback, as shown here, is an effective strategy to influence behavioral change.  These findings are of critical importance as our new healthcare economy continues to mature from a fee-for-service free-for-all to a value-based care collaboration.

“Effect of Behavioral Interventions on Inappropriate Antibiotic Prescribing Among Primary Care Practices”
http://www.ncbi.nlm.nih.gov/pubmed/26864410

Radiation Therapy for the Common Cold

We overuse computed tomography for many things – popular topics in the literature (and on this blog) are mostly minor head injury, renal colic, and CT pulmonary angiograms.  But, it is not simply these modalities that have increased in the preceding decades, as this research letter shows.  CT use has also increased for such apparently benign conditions as non-acute upper respiratory symptoms.

This is a National Hospital Ambulatory Medical Care Survey analysis, with all the sampling limitations inherent to such a data source, evaluating CT usage for upper and lower respiratory complaints between 2001 and 2010.  CT usage in 2001 for such complaints ranged from a 0.5% of visits for non-acute URI, to 3.1% of visits for acute LRTI symptoms.  In 2010, such usage ranged from 3.6% to 12.1%.  Despite all this added cost and extensive evaluation, management of these patients remained unchanged: both antibiotic use and admission rates were steady.

The NHAMCS is an imprecise tool to full discern the reasons for visit on a granular level, but the relative increase in advanced imaging is consistent with increases in CT usage for other indications.  Obviously, the radiation itself has no known therapeutic potential – so, therefore, the clear conclusion is simply the unfortunate presence of additional low-value care.

“Use of Computed Tomography in Emergency Departments in the United States: A Decade of Coughs and Colds”
http://www.ncbi.nlm.nih.gov/pubmed/26720289

The Antibiotic Mandatory Waiting Period?

It has become generally accepted within the medical community the vast majority of cases of pediatric otitis media will resolve without antibiotics.  However, the tradition of treating OM with antibiotics is slow to wane, fueled by momentum and parental expectations.  Some success has been achieved with delayed-prescription strategies, where parents are provided with antibiotics, but encouraged to wait a few days and observe for spontaneous improvement.

These authors applied the same school of thought to benign upper respiratory tract infections – sinusitis, pharyngitis, and bronchitis.  They randomized 398 patients with common URTI-spectrum symptoms to one of four treatment strategies:  immediate antibiotic initiation; antibiotics provided immediately, but patient encouraged to wait-and-see a few days for spontaneous improvement; antibiotics available for pick-up three days later, if desired; and no antibiotics.  The primary outcome was duration and severity of symptoms, with various secondary outcomes of absenteeism, satisfaction, and antibiotic utilization.

The results of this study are a little bit mixed.  The patients initiating antibiotics immediately had shorter symptoms duration than any other strategy.  The sample sizes are small, and the standard deviation of symptoms in each cohort is huge, but it’s probably reasonable to estimate antibiotic use truncated moderate or severe symptoms by about a day or a day and a half from a 5-6 day illness duration.  Twelve of 98 randomized to no prescription ultimately crossed over to antibiotics.

But the remainder, despite their randomization to benign neglect, improved regardless, without any detectable difference in safety outcomes.  After all, the majority of these infections are either viral, or self-limited bacterial infections handled by the body’s natural immune system without complications.

The interesting outcomes, however, were the two delayed-antibiotic strategies.  Compared to the 91% antibiotic usage rate of the immediate antibiotic group, the patient-initiated and delayed-collection strategies resulted in 33% and 23% antibiotic usage rates, respectively.  Symptom duration, as to be expected, was mildly attenuated, falling between immediate antibiotic use and no antibiotics.

Is this the happy medium strategy needed to finally divorce ourselves from our addiction to unnecessary care for URTI disease?  “Choosing Wisely” as a general philosophy doesn’t seem to have had the desired effect – how about an executive action to mandate the same waiting period for antibiotics as we have for guns?

“Prescription Strategies in Acute Uncomplicated Respiratory Infections: A Randomized Clinical Trial”
http://www.ncbi.nlm.nih.gov/pubmed/26719947

The Disutility of Acetaminophen for Influenza

Wait … what?

This headline: “Acetaminophen Appears To Be Ineffective Against Flu.”

Hopefully, when you saw that either in the ACEP member daily news e-mail, or on the Reuters distribution, you had the same befuddled reaction as me.  Even better, the coverage includes this fascinating fearmongering from one of the authors:

“What this study does is raise some very serious questions about the real evidence base for using acetaminophen routinely for anyone that has the flu.”

Actually, it doesn’t.

This is a randomized, double-blind, placebo-controlled study of patients with suspected influenza, treating with five days of either scheduled acetaminophen or placebo.  The primary outcome was the area under the cure for quantitative PCR influenza log(10) viral load from baseline to day 5.  Patients were admitted to a clinical trials unit for the first 48 hours, then followed up in clinic at day 5 and day 14.  Secondary outcomes included symptom scores for health and temperatures of each patient.  The authors based their power calculation on the standard deviation for PCR viral load, and estimated to have 80% power to detect a difference greater than that standard deviation, they would need 80 patients with influenza.

Over the course of two influenza seasons, 2011 and 2012, they were able to enroll: 46

More specifically, they enrolled 46 patients with PCR-confirmed influenza.  The other 34 patients had false-positives on the rapid assay used for enrollment, and could not be included in their primary outcome analysis.  Because of their inadequate sample size, it is therefore mostly nonsensical to comment on their failure to find statistical differences in their outcomes.  However, there do not appear to be any potentially clinically important clues hiding in plain sight.

Bafflingly, one of their discussion points notes “These findings raise questions about the anti-pyretic efficacy of paracetamol in influenza and other respiratory infections.”  The mean temperature in the 80 patients randomized to placebo never even exceeded a 38°C “fever” threshold.  Then, the mean temperature was actually normal on day 2-5.  To suggest acetaminophen fails to normalize fever in respiratory infection compared with placebo, fever ought be relatively ubiquitous in the study population.  Otherwise, there simply isn’t any clinical feasibility of detecting a difference.

Finally, what makes the questions about the use of acetaminophen most bizarre, the study was actually undertaken to confirm the safety of acetaminophen.  Their clinical trial registration states:

“Paracetamol is recommended for the routine treatment of fever and systemic symptoms in influenza. However, this recommendation is contrary to evidence which suggests that the presence of fever is protective in infections. This study aims to investigate whether the regular use of an antipyretic (paracetamol) during acute infection with influenza may prolong viral shedding and clinical symptoms.”

Setting aside the inability of their sample size to actually address their outcomes – their conclusions are based on a failure to detect a difference.  Therefore, their original concerns over potential harms from the anti-pyretic nature of acetaminophen ought to have been allayed!

Quite a long way from the headline at the top of this post.

“Randomized controlled trial of the effect of regular paracetamol on influenza infection”
http://www.ncbi.nlm.nih.gov/pubmed/26638130

You Can Make Unnecessary Care Go Away

Low-value care is such a pervasive problem, ABIM developed the Choosing Wisely initiative.  However, Choosing Wisely is, unfortunately, a disengaged and toothless activity.  And it hasn’t worked.

But, as this study shows, you can eliminate unnecessary care with a more proactive and involved approach.

This is a quality improvement collaborative across 21 hospitals aimed at reducing the use of unnecessary or ineffective care relating to bronchiolitis.  As we’ve seen time and time again, if anything works at all for bronchiolitis, the ambiguity over its effectiveness probably means the effect size is clinically meaningless.  To this end, these hospitals banded together to deploy a QI program targeting reductions in bronchodilator use, steroid use, chest radiography, and other process measures.  Across all measures, the pre- and post-intervention measures demonstrated pooled meaningful and statistically significant improvement.  Bronchodilator use dropped from 46.2% to 32.7%, steroids from 10.9% to 2.2%, and CXRs from 12% to 6.7%.  A secondary effect of these interventions was a reduction in length of stay by 5 hours, from 49.6 to 44.6.

Success!

Of course, the QI intervention did not have the same effect at all participating hospitals.  Some, clearly, were on the ball, and almost entirely eliminated some unnecessary care (steroids).  Others, however, had no change from baseline, or, even, an increase – like two hospitals demonstrating 150%+ increase in bronchodilator use, and three hospitals with 100%+ increases in CXR use.  It would be interesting to see some qualitative analysis regarding the lack of improvement at certain hospitals.

But, in general, widespread improvement in unnecessary care can be realized.  In contrast to Choosing Wisely, it requires motivated agents of change and constant feedback.  The Choosing Wisely lists and their elements, unfortunately, seem adrift.

“A Multicenter Collaborative to Reduce Unnecessary Care in Inpatient Bronchiolitis”

The Slow Demise of Antibiotics for Diverticulitis

We have been prescribing antibiotics for diverticulitis for an eternity.  Some patients, after all, do quite poorly without – and progress to perforation, sepsis, and death.  Very few clamor for such an outcome.  The question with diverticulitis has never been “antibiotics?”, only “inpatient or outpatient”?

Now, this dogmatic practice seems ripe to change.

This latest bit of published literature is an observational series from Sweden.  These authors followed up their previously-published randomized trial with an initial foray into practice change, considering the consistent harms of antibiotic overuse.  They prospectively enrolled 155 patients with CT-verified, uncomplicated diverticulitis and simply followed them after discharge without antibiotics.  Management consisted solely of pain control, typically paracetamol (acetaminophen), an initial liquid diet, and then gradual progression to full diet as tolerated.  Patients were followed daily by phone, at 1 week in clinic, and at 3 months again in clinic.

Of these 155 patients, there were a mere 4 treatment failures requiring admission.  This treatment failure rate is similar to the ~2.5% rate expected with antibiotics.  Two progressed to perforation and a third developed abscess – the last of which was apparent on re-review of the initial CT.  Each patient with progression was treated with antibiotics as an inpatient and recovered.

This is, however, an observational trial, and there were another 66 patients diagnosed with uncomplicated diverticulitis in the same time period but missed for enrollment.  This leads to concerns regarding selection bias, although the few presented clinical characteristics of the missed patients were similar to those included in the trial.  Patients were also excluded on the basis of many comorbidities thought to increase the risk of treatment failure, and those treated as inpatients.

But, at the least, in this trial and those prior, there is clearly a cohort of uncomplicated diverticulitis that derives little benefit from antibiotics.  And, furthermore, these few trials have not gone unnoticed: new guidelines in several countries, including the American Gastroenterological Association, have updates reflecting the validity of selective antibiotic use.

The evidence quality to date is still cumulatively low – but this is probably a treatment change paradigm just about ready for prime-time.

“Outpatient, non-antibiotic management in acute uncomplicated diverticulitis: a prospective study”
http://www.ncbi.nlm.nih.gov/pubmed/25989930

“American Gastroenterological Association Institute Guideline on the Management of Acute Diverticulitis”
http://www.ncbi.nlm.nih.gov/pubmed/26453777

Hypertonic Saline No Help for Bronchiolitis

There’s probably no common illness with quite so much flailing about in the evidence base than bronchiolitis.  Between bronchodilators, steroids, saline, and epinephrine, they’ve thrown the kitchen sink at it.  Some show potential benefit, while others do not.

This is another study following up the suspected benefit of nebulized hypertonic (3%) saline in reducing length of stay in hospitalized patients.  In a randomized trial, these authors enrolled 227 patients to receive either nebulized 3% saline or 0.9% saline placebo.  There were no important differences between patients randomized to each arm.  By all outcome measures – intensive care unit admission, objective deterioration of respiratory status, inpatient length-of-stay, or readmission – there was no difference between therapies.

The effect seen here – with seemingly contradictory results – is probably precisely as predicted by Ioannidis’ statistical theory regarding “Why Most Published Research Findings are False”.  Simply put, the prior probability of any of these treatments being helpful is quite low – and the extent of random bias associated most of these studies high.  The net effect, then, is the posterior probability associated with any significant finding is barely changed.

Nebulized hypertonic saline is probably harmless, but if it’s not helpful, it still doesn’t have a role.

“3% Hypertonic Saline Versus Normal Saline in Inpatient Bronchiolitis: A Randomized Controlled Trial”
http://pediatrics.aappublications.org/content/early/2015/11/04/peds.2015-1037