The HSV Meningitis Question

This is one of those questions that always crops up when evaluating an infant for sepsis and meningitis – should we test and/or empirically cover for herpes simplex virus infection? Just how frequently is this diagnosis made?

The answers, as described in this retrospective, multi-center study, are complex. First, the basics: 26,533 total encounters analyzed, with 112 children ultimately diagnosed with HSV meningitis. Then, it’s basically chaos. The percent of patients whose CSF was tested for HSV ranged from 12.5% to 70.9% across hospitals included, along with empiric coverage with acyclovir ranging from 4.2% to 53.0%. Rates of positive HSV results were unrelated to overall institutional testing or empiric acyclovir coverage rates, excepting in the sense that HSV infection was more frequent in younger infants – and younger infants were more likely to be tested and empirically treated, in general.  A handful of patients with ultimate diagnoses of HSV meningitis were not treated or tested initially, and were found on a subsequent visit.

The authors go into some detail regarding the questionable value of empiric treatment, citing a number needed to treat of 152 for infants 0-28 days and an NNT of 583 for infants from 29-60 days. Generally speaking, these authors agree with a prior cost-effectiveness analysis recommending waiting for the initial CSF cell count, and empirically treating those with a CSF pleocytosis. Consequently, these authors would therefore recommend testing only those ultimately treated empirically – but this is naturally a pragmatic consideration, rather than a statistically modeled balance between sensitivity and specificity.

There are a few more nuances within the paper with regard to their gold standard for diagnosis of HSV meningitis, limitations with regard to selection of patients undergoing testing, and generalizability from these tertiary referral settings, but it is still generally an interesting snapshot of data. Unfortunately, their ultimate conclusion is still back at square one – reiterating a call for specific clinical and laboratory data to help guide clinicians in selecting patients for HSV testing and empiric treatment. In the meantime, we’ll just keep doing our best to differentiate the ill child at the bedside based on gestalt and the culture of our practice setting.

“Herpes Simplex Virus Infection in Infants Undergoing Meningitis Evaluation”
http://pediatrics.aappublications.org/content/early/2017/12/29/peds.2017-1688

Influenza, Sideways

Hello, everyone! Influenza, influenza, influenza. Influenza? Influenza. Influenza influenza, influenza – influenza – influenza, influenza!

It’s that time of year in the Northern Hemisphere, following up last year’s busy season, and a terrible one in the Southern Hemisphere in the interim. At this point, for your general ambulatory patient, I hope you’ve stopped sending swabs. If you think they have it, they probably do – although, there is some respiratory syncytial virus out there, too.

But, I’ve also been surprised by a couple of people who didn’t look like typical influenza, and this little expert commentary is a nice reminder of the less-common manifestations of influenza infection. The respiratory compromise is well-documented, but patients can not uncommonly become seriously ill with myocarditis, myositis, and viral encephalitis, as well as causing less serious serious hepatic injury and acute tubular necrosis. There have also been case reports implicating influenza less frequently in a scattershot of clinically interesting entities.

Just in case you weren’t getting enough influenza in your life.

“The hidden burden of influenza: A review of the extra- pulmonary complications of influenza infection”
http://onlinelibrary.wiley.com/doi/10.1111/irv.12470/abstract [open access]

Treatment Failure, or is Treatment the Failure?

Acute respiratory tract infections – otitis media, streptococcal pharyngitis, and sinusitis – comprise virtually a laundry list for antibiotic overuse in self-limited conditions. Certainly, a subset of each of these conditions are true bacterial infections and, again, a subset of these have their resolution hastened by antibiotics – and, finally, a subset of those would have clinically important worsening if antibiotics were not used. Conversely, the harms of antibiotics are generally well-recognized,though not necessarily routinely appreciated in clinical practice.

This patient-centered outcomes study, with both retrospective and prospective portions, enrolled children diagnosed with the aforementioned “acute respiratory tract infections” and evaluated outcomes differences between those receiving “narrow-spectrum” antibiotics and those receiving “broad-spectrum antibiotics”. Before even delving into their results, let’s go straight to this quote from the limitations:

Because children were identified based on clinician diagnosis plus an antibiotic prescription to identify bacterial acute respiratory tract infections, some children likely had viral infections.

“Some children likely had viral infections” is a strong contender for understatement of the year.

So, with untold numbers of viral infections included, it should be no surprise these authors found no difference in “treatment failure” between narrow-spectrum and broad-spectrum antibiotics. Nor, in their prospective portion, did they identify any statistically difference in surrogates for wellness, such as missed school, symptom resolution, or pediatric quality of life. However, adverse events were higher (35.6% vs. 25.1%, p < 0.001) in the broad-spectrum antibiotic cohort, and this accompanied smaller, but consistent, differences favoring narrow-spectrum antibiotics on those wellness measures.

So, the takeaway: broad-spectrum antibiotics conferred no advantage, only harms. If you’re using antibiotics (unnecessarily), use the cheapest, most benign ones possible.

“Association of Broad- vs Narrow-Spectrum Antibiotics With Treatment Failure, Adverse Events, and Quality of Life in Children With Acute Respiratory Tract Infections”

https://jamanetwork.com/journals/jama/article-abstract/2666503

The Best Antibiotic Stewardship Money Can Buy

Believe it, or not:

Use of procalcitonin to guide antibiotic treatment in patients with acute respiratory infections reduces antibiotic exposure and side-effects, and improves survival. Widespread implementation of procalcitonin protocols in patients with acute respiratory infections thus has the potential to improve antibiotic management with positive effects on clinical outcomes and on the current threat of increasing antibiotic multiresistance.

So, should we all be jumping on the procalcitonin bandwagon? Chances are, you probably already have – check with your critical care team, and I expect you’ll find some implementation of a procalcitonin-based protocol supporting antibiotic stewardship. The underlying concept is hardly unreasonable – when sensitive markers of bacterial infection are low, antibiotics can be discontinued.

However, the evidence base – as helpfully pooled in this individual-patient meta-analysis – is nothing more than a carefully orchestrated disinformation campaign by the manufacturers of these assays. Roche, Thermo-Fisher and bioMérieux have an obvious vested business interest in publishing favorable research findings in support of procalcitonin-based treatment algorithms, and it should come as no surprise the authors have a couple items to declare:

PS, MC-C, and BM have received support from Thermo-Fisher and bioMérieux to attend meetings and fulfilled speaking engagements. BM has served as a consultant for and received research support from Thermo-Fisher. HCB and MB have received research support from Thermo-Fisher for a previous meta-analysis regarding procalcitonin. DWdL’s hospital received financial support for the randomisation tool by ThermoFisher. DS, OB, and MT have received research support from Thermo-Fisher. TW and SS have received lecture fees and research support from Thermo-Fisher. CEL has received lecture fees from Brahms and Merck Sharp & Dohme-Chibret. JC has received consulting and lecture fees from P zer, Brahms, Wyeth, Johnson & Johnson, Nektar-Bayer, and Arpida. MW has received consulting and lectures fees from Merck Sharp & Dohme-Chibret, Janssen Cilag, Gilead, Astellas, Sano , and Thermo-Fisher. FT’s institution received funds from Brahms. CC has received an unrestricted grant of €2000 from Thermo-Fisher Scientific, and non-fiancial support from bioMérieux for the ProToCOLD study. YS has received unrestricted research grants from Thermo-Fisher, bioMérieux, Orion Pharma, and Pfizer. ARF has served on advisory boards for Novavax, Hologic, Gilead, and MedImmune; and has received research funding from AstraZeneca, Sanofi Pasteur, GlaxoSmithKline, and ADMA Biologics. J-USJ declares that he was invited to the European Respiratory Society meeting 2016 by Roche Pharmaceuticals.

And, it’s clearly no coincidence most of the 26 trials included in this systematic review are authored by those same financially-supported authors above – so, it’s turtles all the way down for this meta-analysis.

The results, then, for what they’re worth, despite all the concerted effort to spin them, are rather bland. The mortality differences are zero in the outpatient settings, and small enough in the intensive care unit side to potentially be skewed by design. The only signal I might ascribe reliable in these data is: procalcitonin does reduce antibiotic exposures. This manifests in practice in two different fashions, depending on the setting. In the outpatient setting, where virtually all the antibiotics are unnecessary (one of these trials enrolled patients with “bronchitis”!), it gives the clinicians a crutch to fall back upon to prevent them from practicing bad medicine.  In the intensive care unit, it helps titrate the use of broad-spectrum intravenous antibiotics, which is likely to reduce a number of important downstream effects.  I don’t object to the latter application, but my recommendation for the former: just don’t practice bad medicine in the first place (easier said than done, sadly).

So, the takeaway I’d like to promote in the context of this article – and its simultaneously published Cochrane Review by the same, COI-infested authors – is skepticism regarding the effect sizes for procalcitonin-guided therapy. These data do not exclude its clinical utility for the stated purposes, but its use ought be considered in the narrowest of clinical situations, and probably in those at the highest-risk for harms from otherwise clinically confounded antibiotic exposures.

“Effect of procalcitonin-guided antibiotic treatment on mortality in acute respiratory infections: a patient level meta-analysis”
https://www.ncbi.nlm.nih.gov/pubmed/29037960

Also, if you’re persistent enough to scroll to page 126 in the Cochrane Review full text, you glean this lovely pearl:
Philipp Schuetz received support (paid to his employer) from Thermo Fisher, Roche Diagnostics, Abbott and bioMerieux to attend meetings and fulfil speaking engagements. These conflicts breach Cochrane’s Commercial Sponsorship Policy (Clause 3), therefore Philipp Schuetz will step down as lead author at the next update of the review. Dr Schuetz’s declared conflicts were referred to the Funding Arbiter Panel and Cochrane’s Deputy Editor-in-Chief who have agreed this course of action but as an exception which does not set a precedent for similar situations in the future.

Alas, Abscesses [heart] Antibiotics

“Fake news!” All you need for effective treatment for abscesses is an incision and drainage procedure – adjunctive antibiotics are just unnecessary exposures with only marginal benefit, at best.

Then, unfortunately, two trials have been published in the New England Journal of Medicine showing benefit for antibiotics – either trimethoprim-sulfamethoxazole or clindamycin – improve the rate of clinical cure. The magnitude of benefit was somewhere in the range of a number needed to treat between 7 and 14, with infrequent harms, suggesting the balance of benefit may favor antibiotics. However, the abscesses included in these study tended to be large, suggesting perhaps these results weren’t easily generalizable.

This is a subgroup analysis of one of these two studies, trying to dredge out a specific population for whom antibiotics weren’t actually of value. And, unfortunately, for the purists among us, the results are bleak. Accounting for the diminishing statistical power and reliability of such an analysis, there are few useful signals within these data. Neither the size of the abscess nor the area of surrounding erythema reliably predicted diminishing returns from adjunctive antibiotics, nor did presence of fever or comorbid illness. The only probably reliable signal in these data, consistent with results in the era prior to MRSA, shows antibiotics are probably unnecessary for those who are not infected with staphylococci. Unfortunately, until that point where the causative agent can be easily ascertained at the time of I&D procedure, these data aren’t terribly useful in a practical sense.

So, the benefit is not universal, but it’s nothing at which to scoff. Perhaps a delayed antibiotic strategy could be considered, but, it seems most patients ought be offered antibiotics following drainage of a clinically significant abscess.

“Subgroup Analysis of Antibiotic Treatment for Skin Abscesses”
http://www.annemergmed.com/article/S0196-0644(17)31383-5/abstract

CT (Almost) Never Before LP

The guidelines describing the patients with suspected bacterial meningitis for whom neuroimaging is indicated prior to lumbar puncture are quite broad. The Infectious Disease Society of America includes virtually every imaginable mental status or immune system impairment, and guidelines in Europe are similar. The anachronistic concern: cerebral herniation in the setting of increased intracranial pressure leading to an otherwise potentially avoidable death. But, guidelines in Sweden are different. In Sweden, their neuroimaging guidelines suggest only those virtually comatose or with focal neurologic signs should undergo CT prior to LP.

In this review of patients with acute bacterial meningitis from a Swedish registry, the authors attempt to parse out whether a decision to perform CT is not only unnecessary – but also potentially harmful. They analyze 815 patients ultimately diagnosed with bacterial meningitis and stratify them by those who received LP without CT, LP before CT, and CT before LP. Presenting features and comorbid medical conditions were abstracted retrospectively, and the results were analyzed with respect to the varying guideline recommendations, mortality, and functional outcomes.

The clear winner: CT rarely before LP, as in Sweden. By their guidelines, only ~7% of those ultimately diagnosed with bacterial meningitis had indication for CT prior to LP – but, unfortunately, 52% of patients underwent imaging anyway. The reason for “winning” if adherent to the Swedish strategy, however, was not just reduced resource utilization – it was mortality and functional outcomes. Mortality was almost halved in those for whom Swedish guidelines were followed, only rarely CT prior to LP. The authors attribute the signals for the underlying mortality difference to a greater percentage of patients receiving antibiotics within 1 hour or 2 hours when no CT was performed.

This probably overstates the magnitude of harm relating to CT use, as delays in antibiotics are probably more accurately delays in diagnosis, rather than logistics impacting timely delivery of antibiotics. After all, even in those with LP prior to CT, only 41% received steroids plus adequate antibiotics, so I expect the magnitude of effect seen here likely ties more reliably to confounding individual patient factors not easily adjusted for in a retrospective analysis.

That said, I do think the Swedes are doing the right thing – the vast majority of CTs were unhelpful. Their guidelines for neuroimaging – deep coma and/or lateralizing neurologic signs – will probably pick up any relevant findings (like the subdural empyema in this series), and reduce waste while obviating any possible delays in care.

“Lumbar puncture performed promptly or after neuroimaging in adult bacterial meningitis: A prospective national cohort study evaluating different guidelines”
https://academic.oup.com/cid/article-abstract/doi/10.1093/cid/cix806/4110207/Lumbar-puncture-performed-promptly-or-after

Enough with the Coughing!

Every Emergency Physician who has worked a night shift knows this all too well – the child brought to the ED in the middle of the night for a cough, keeping the entire family up, and the cough has been going on for weeks.

And, the not-at-all-satisfying answer: “This is pretty normal.”

This is yet another publication describing the natural history of symptoms following an upper respiratory illness. These authors in Australia enrolled children evaluated in the Emergency Department for an upper respiratory infection featuring cough. They enrolled 839 children and attempted to follow them for four weeks after the index visit, as well as through follow-up with a pulmonology specialist if seen for persistent, unresolving cough. Nearly 300 of the initially enrolled cohort was lost to follow-up over the course of the month, but of those who were contacted, two-thirds still had cough at 7 days, and a quarter were still coughing at day 21. Ultimately 171 – or 20.4% – were still coughing at day 28 and eligible for pulmonologist evaluation. Of these, about a third were identified to have a previously undiagnosed underlying chronic respiratory disorder (asthma, bronchiectasis, etc.) and about half were given the diagnosis of persistent bacterial bronchitis.

The general takeaway here is that coughs generally linger – but once a cough has persisted beyond 2-3 weeks, it is reasonable to consider alternative precipitating diagnoses other than the initial URI.

“Chronic cough postacute respiratory illness in children: a cohort study”
https://www.ncbi.nlm.nih.gov/pubmed/28814419

Steroids, Not Universally Useful For Wheezing

In asthma, steroids are fantastic. The earlier, the better. In bronchiolitis, another wheezing-spectrum illness, mostly probably not. How about the general, ambulatory, viral lower respiratory tract infections with wheezing?

This randomized, controlled trial enrolled patients at family practice clinics in Britain with non-asthmatic wheezing relating to a suspected “chest infection”. Patients received either 40mg of oral prednisolone for five days or matching placebo. The primary outcome was duration of moderately bad or worse cough, as recorded by a patient-reported symptom diary, with secondary outcomes of subsequent antibiotic use, cumulative symptom scores, and quality of life scores, and other resource utilization measures.

These authors enrolled 401 patients, 398 of whom received the study intervention. There were no important differences between enrolled groups at baseline – and, there were no reliable, important differences in measured outcomes, either the primary symptom-related outcome, or any of the secondary outcomes.

The strength of this evidence is not such that it eliminates the possibility of a clinically important benefit for a subgroup of patients, but I consider it practice-changing because there was such little reliable evidence at baseline. I have certainly felt it was reasonable to discharge patients with suspected viral LRTI, wheezing, and bronchospasm on an oral steroid based on a low risk profile and at least a hoped-for, physiologically-justified, benefit. Now, the onus is on a subsequent trial to demonstrate said benefit before resuming such practice.

“Effect of Oral Prednisolone on Symptom Duration and Severity in Nonasthmatic Adults With Acute Lower Respiratory Tract Infection”
http://jamanetwork.com/journals/jama/article-abstract/2649201

Predicting Treatment Failure in AOM

Like most infectious diseases, acute otitis media generally breaks down into three cohorts. There are viral infections, for which early antimicrobial therapy is virtually, by definition, unhelpful. Then, there are true bacterial infections – many of which resolve without substantial morbidity regardless of antimicrobial treatment, and those which require antimicrobial therapy to prevent such. The trick, and where modern medicine typically fails miserably, is rapidly predicting into which of these cohorts a patient may fall – a conundrum leading to the epidemic of antibiotic overuse.

This is a secondary analysis of a pediatric AOM trial, first published in the New England Journal of Medicine, looking at which patients were more likely to potentially fail conservative treatment. The intervention arm received amoxicillin/clavulanate, and treatment failure occured in 31.7% of children – vastly favoring the antibiotic arm – 44.9% vs. 18.6%. In theory, this exaggerated treatment effect might help better illuminate any small predictors – but, unfortunately, with only 319 patients, meaningful statistical significance on this data dredge is hard to come by. Worse still, the best predictor of treatment failure (or, really, lack thereof)? A peaked tympanogram (A and C curves) – you know, because we’re all routinely measuring tympanometry. Grossly bulging tympanic membranes were predictive of treatment failure, which has some face validity, at least – but, again, this is as compared between severe, moderate, and mild, which requires pneumatic otoscopy to differentiate.

The question here primarily concerns: can you take away good conclusions from bad data? The magnitude of the treatment effect seen in this trial far exceeded the treatment effect expected from antibiotics in other trials. And, consistent with that questionable generalizability, their findings reflect the stringent criteria determining their diagnosis of AOM. Then, they are relying upon their misguided definition for treatment failure, which relies on otoscopic signs, the same ones that will be colinear with worsened disease on initial examination. Unfortunately, the net result of all of this meandering is essentially no clinically useful insight. Considering the limitations the examination of the screaming ill toddler, more pragmatic approaches are necessary.

“Prognostic Factors for Treatment Failure in Acute Otitis Media”

http://pediatrics.aappublications.org/content/early/2017/08/04/peds.2017-0072

I&D Alone or With Antibiotics for the Little Guys

Most physicians provide adjunctive antibiotic therapy for large abscesses following incision and drainage – the sorts where you need a bucket and a hose. Less clear has been the small abscess – but, in the age of MRSA, the fear factor has led many to cover these, regardless. Recent evidence suggests there is a small absolute benefit to antibiotic use and clinical cure, with an NNT around 14, along with other apparent benefits regarding re-infection and spread to household contacts. These trials, however, still enrolled patients with abscesses much larger than typically encountered in routine practice.

This trial is specifically designed to break the glass on “smaller skin abscesses” – just like in the title! What does small mean to these authors? It means a suppurative cavity of 5cm in diameter, or, up to the size of a cupcake:
abscess cakeSo, before we even start, we can see we may end up with issues regarding generalizability to many of the abscesses we encounter in the Emergency Department.

This trial is comprised of three arms – clindamycin, trimethoprim-sulfamethoxazole, and placebo – and enrolled 786 patients in an attempt to detect a 10% difference between arms while accounting for 20% attrition rate. The primary outcome was test of cure at 10 days after therapy, with a variety of secondary outcomes, including new infections at one month and treatment-related adverse events.

The winner, if one can be crowned, was not placebo. At the test of cure visit in the intention-to-treat population – and likewise, the population that could be evaluated – placebo lagged behind both clindamycin and TMP-SMX by approximately a 12% absolute magnitude of difference. Recurrent infections at the same site, or another site, were lowest in the clindamycin group at 6.8% – and similar between TMP-SMX and placebo, at 13.5% and 12.4%, respectively. However, clindamycin was implicated in the highest rate of adverse events, at 21.9%, compared with TMP-SMX and placebo, at 11.1% and 12.5%, respectively. Most of the difference in adverse events can be attributed to diarrhea illness, although clostridium difficile was not isolated in any cases. There was one case of systemic hypersensitivity reaction thought to be related to TMP-SMX.

There were two main drivers for the difference in test of cure between the placebo cohort and the two antibiotic cohorts, and these were use of rescue antibiotics during the follow-up period and new infections at another site. The use of rescue antibiotics is not necessarily a reliable measure of treatment failure, but it is still reasonable to suggest this difference would not arise by chance alone, despite the small sample. Regarding generalizability to practice, the minority of abscesses were cupcake-sized, but these were still fairly substantial infections. The median size of the abscess was about 2.2cm in diameter, with surrounding erythema of 5.9cm in greatest dimension.

The takeaway, then, hinges on the generalizability of their population to your individual patient. If these are “smaller” skin abscesses, then I wager the bulk of my abscess encounters are for “tinier” abscesses. I doubt this changes much current practice with regard to antibiotics, or antibiotic selection, for those treating abscesses in the 2+cm range, but I expect the differences in cure rates shrink for smaller lesions. It falls within the realm of acceptable practice variation to weigh the harms of antibiotic use with the chance of recurrence or new infection for those lesions.

“A Placebo-Controlled Trial of Antibiotics for Smaller Skin Abscesses”

http://www.nejm.org/doi/full/10.1056/NEJMoa1607033