Category: Infectious Disease

Does My Patient Have Prion Disease?

No, they don’t.

But, they might.

Between the years of 2003 and 2015, the National Prion Disease Pathology Surveillance Center captured 5,212 deaths due to prion disease in the United States. This number is clearly greater than zero, but the average annual incidence is around 1.2 cases per million population.

Not the most profound impact on your practice in the Emergency Department, but just one more element of curiosity to file away as trivia.

“Prion disease incidence in the United States, 2003-2015.”
https://www.ncbi.nlm.nih.gov/pubmed/31757870

Steroids for Severe Influenza?

There’s a little bit of evidence supporting the use of corticosteroids in both severe sepsis and in severe pneumonia. Severe influenza is both of these things, yet neither. Should we try corticosteroids?

Many have – but, unfortunately, few have rigorously evaluated it. This systematic review found 30 eligible studies, all of which were observational excepting one randomized trial. From this poor-quality data, associations between steroid use and increased mortality and increased hospital-acquired infection were observed. While this hardly excludes a potential benefit to steroids in selected cases of severe influenza, it certainly ought to encourage you to defer use of steroids until high-quality data supports the practice, if ever.

“Corticosteroids as Adjunctive Therapy in the Treatment of Influenza: An Updated Cochrane Systematic Review and Meta-analysis.”
https://www.ncbi.nlm.nih.gov/pubmed/31743228

The Vitamins in Sepsis Parade Begins

A couple years back, we saw one of the first reports describing the potential efficacy of treating sepsis with a cocktail of vitamin C, thiamine, and steroids. These observational findings have been viewed with a healthy dose of skepticism while awaiting prospective, randomized evidence with regard to their validity.

Well, here’s one of the first: a short communication from CITRIS-ALI, a randomized clinical trial that almost, sort of, not quite, addresses the question of interest. This study was designed and initiated well before the aforementioned observational report, and it examines vitamin C monotherapy in patients with sepsis and acute respiratory distress syndrome. Their primary outcome and goal was to see if vitamin C could reduce sequential organ failure assessment scores, along with biological markers of inflammation and vascular injury.

With 1,262 patients screened leading to 167 patients receiving their randomized interventions, the answer is: no. Neither modified SOFA scores, c-reactive protein, nor thrombomodulin were different between groups.

But, wait! There’s more! In fact, 46 additional pre-specified secondary outcomes – 43 of which showed no difference. These included both the esoteric – angiopoietin-2 levels, tissue factor pathway inhibitor – and patient-oriented. It is these patient-oriented outcomes that pique the most interest: at 28 days, mortality in the vitamin C group was 29.8%, as compared with 46.3% with placebo. Ventilator-free days and ICU-free days similarly favored the vitamin C cohort.

So, interesting data incapable of informing practice. Another small sample, designed (appropriately) around a different target and primary outcome, with a secondary outcome still falling into the realm of hypothesis-generating. This will likely influence no one. Anyone already giving vitamins in sepsis – cheap, likely harmless – will continue to do so, and those awaiting a more informative trial will, also, continue to do so.

“Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure”

https://jamanetwork.com/journals/jama/fullarticle/2752063

ATS + IDSA CAP 2019

As the authors of this document lead off, it has been more than 10 years since the last American Thoracic Society/Infectious Diseases Society of America community-acquired pneumonia guideline – and much has changed. And, reflecting this, Much Has Changed.

A few interesting tidbits:

  • Do not obtain blood cultures in the outpatient setting, and blood cultures are recommended as inpatients only for severe CAP and when MRSA and P. aeruginosa are being covered. This, of course, is likely moot given our current triage of potential sepsis.
  • Basic outpatient CAP should be amoxicillin, doxycycline, or macrolide (based on local resistance) monotherapy. Add in comorbidities, and combination therapy or monotherapy with a respiratory fluoroquinolone is indicated.
  • Procalcitonin is not reliable to augment clinical judgment when CAP is suspected.
  • The Pneumonia Severity Index is the preferred decision instrument to augment clinical judgement regarding hospitalization.
  • Inpatient antibiotics are universally ß-lactam plus macrolide, or monotherapy with a respiratory fluoroquinolone. Empiric MRSA and P. aeruginosa coverage is suggested only if prior infection, not in those with risk factors alone.
  • No routine empiric anerobic coverage for suspected aspiration pneumonia.
  • No routine steroids for CAP, even severe.
  • Various recommendations regarding nfluenza and suspicion of CAP – treat with both antiviral and antibiotic therapy.
  • No follow-up chest x-ray documenting resolution of infiltrates is necessary in the outpatient setting if the patient is clinically improved.

Details, doses, and rationale within – many caveats, conditional recommendations, and need for additional research.

“Diagnosis and Treatment of Adults with Community-acquired Pneumonia: An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America”
https://www.atsjournals.org/doi/10.1164/rccm.201908-1581ST

The Antibiotic Penalty on Blood Cultures

As the administrative team likes to remind us: blood cultures before antibiotics.

Blood cultures before antibiotics.

Blood cultures? Before antibiotics.

What’s the point, we say – aren’t the antibiotics the actual life-saving intervention? And the answer, when relevant, ties into identifying the specific susceptibility of the infective agent, such that antibiotics may ultimately be narrowed to the minimum necessary for cure. It’s a noble premise, at least.

But, so, what does happen when you give antibiotics first?

At least one recent retrospective study has pulled data from their health system showing a clear decrease in blood culture positivity following administration of antibiotics, but these results may be limited by potential differences between groups. In contrast, this clever little study looks at it prospectively: the same 325 Emergency Department patients with “severe manifestation of” sepsis – hypotensive or lactate >4 mmol/L – received blood culture draws both prior to, and just following, antibiotic administration.

Before antibiotics: 31.4% positive blood cultures.

After antibiotics: 19.4% positive blood cultures.

It is not a perfect study by any means, but a long story short: if you’re going to go to the trouble of drawing and processing blood cultures, draw them before you start antimicrobial treatment. But, clearly, the antimicrobials are doing their job – do it expeditiously such that your patient does not suffer from unwanted delay.

“Blood Culture Results Before and After Antimicrobial Administration in
Patients With Severe Manifestations of Sepsis”
https://annals.org/aim/fullarticle/2751453/blood-culture-results-before-after-antimicrobial-administration-patients-severe-manifestations

CRP for COPD

If you follow this blog, you’ve probably read various critiques of the use of procalcitonin to guide antibiotic prescribing. Procalcitonin, a non-specific inflammatory marker, provides a small amount of informational value regarding the underlying etiology of infection, but my underlying criticism of its envisioned use is:

  • The baseline rate of antibiotic prescribing is so poor, and the likelihood of poor outcomes so low, a safe reduction in prescribing is guaranteed.
  • It provides about the same area-under-the-curve for predicting bacterial etiologies as C-reactive protein.
  • The pro-procalcitonin studies and contributions are effectively covered in the fingerprints of the manufacturers of the assay.

So, then, replace the above complaints with – well, mostly just the top one, because here we are with CRP doing the same things for which procalcitonin is advertised, and the apparent conflict-of-interest is turned down a few notches.

In this study, 86 primary care clinics in England and Wales randomized patients with a diagnosis of COPD and a clinical diagnosis of an acute exacerbation to use of point-of-care CRP testing versus usual care. Similar to those studies seen with procalcitonin, prescribers were provided guidance with respect to various CRP levels and recommendations for either prescribing, possible prescribing, or do not prescribe. The primary outcome and secondary outcomes were associated with receipt of any antibiotics, quality of life, and adverse health outcomes.

Over the course of two years, 649 patients were randomized to the two arms, with a handful of each failing to properly undergo initial study procedures. The prescribing rate at the index visit in the “usual care” group: 69.7%. The prescribing rate with CRP: 47.7%. A winner is CRP!

Except that 76% of patients had CRP less than the threshold at which antibiotics were recommended. Another 12% were in the “antibiotics maybe” group. Thus, nearly 90% of the entire cohort were suspected of having no or limited benefit to antibiotics – so, of course any safety margin to deprescribing would be satisfied. And, considering the baseline rate of prescribing was 70%, again, there is basically no possible way a stewardship intervention could fail.

The editorial accompanying this article is darkly amusing, stating “the findings from this study are compelling enough to support CRP testing as an adjunctive measure to guide antibiotic use in patients with acute exacerbations of COPD”. However, it also goes on to note these data hardly identify “which patients (if any) truly benefit from antibiotic therapy”(emphasis mine). Some trials testing 100% antibiotic prescribing vs. zero prescribing (e.g., placebo) have found minimal, or no, benefit. As with procalcitonin, our problem is a pervasive culture of over-prescribing, and ultimate answer is the same for CRP: we don’t need to introduce a marginally informative test into this low-stakes patient population, we simply need to snap out of our collective insanity.

“C-Reactive Protein Testing to Guide Antibiotic Prescribing for COPD Exacerbations”
https://www.nejm.org/doi/10.1056/NEJMoa1803185

Yet Another Febrile Infant Rule

The Holy Grail in the evaluation of infants of less than 60 days remains safe discharge without a lumbar puncture. Boston, Philadelphia, Rochester, Step-by-Step and others have tried to achieve this noble goal over the years. And now, the Febrile Young Infant Research Collaborative has tossed their hat into the ring.

In this retrospective query of their Pediatric Health Information System and other electronic medical records, these authors identified 181 non-ill appearing patients across 11 Emergency Departments with invasive bacterial infection, defined as bacteremia in either blood or cerebrospinal fluid. Using 362 matched controls as a comparison cohort, these authors used the typical logistic regression route to tease out the strongest predictors of IBI – age in days, observed temperature, absolute neutrophil count, and urinalysis result. Subsequently, they condensed the continuous variables into cut-offs maximizing area under the curve. These cut-offs were then incorporated into a scoring system based on the strength of their adjusted odds ratio, and then the final output was validated on the derivation set using k-fold cross-validation with 10 sets.

The final result using their best cumulative score cut-off: sensitivity of 98.8% (95% CI 95.7-99.9) with 31.3% specificity. The two cases missed were that of a 3-day old and a 40-day old otherwise afebrile in the ED with normal UA and an ANC <5185. The authors ultimately conclude their score, if validated, may have best value as a one-way prediction tool primarily to reduce current routine invasive testing, owing to its poor specificity. Certainly, I agree it does not have much value in those who might otherwise not undergo testing; a more specific risk score may be better, if not clinician gestalt.

The other tidbit I might mention is whether there could be value in incorporating time-of-onset of fever into their evaluation. We’ve seen in other studies a few of the fallouts with regard to sensitivity of IBI stem from recency of illness onset, and it may be falsely reassuring to find a normal ANC early in an illness course. Furthermore, these authors do not specifically mention whether the lack of fever in the ED could have been associated with prehospital antipyretic use. Finally, their data collection does not appear to incorporate respiratory swab results; readily available respiratory viral panel results may also prove useful in ruling out IBI.

While these data are certainly alluring, considering the desire to avoid invasive procedures in young infants, substantial prospective work is still likely required.

As a sad aside, the authors state:

However, these criteria were developed >25 years ago, and the epidemiology of serious bacterial infections has changed considerably since that time.

Unfortunately, as vaccination frequency continues to decline, even since patients were enrolled for this study, our “modern” cohort may better begin to resemble that of 25 years ago.

“A Prediction Model to Identify Febrile Infants ≤60 Days at Low Risk of
Invasive Bacterial Infection”

https://www.ncbi.nlm.nih.gov/pubmed/31167938

Upping Your CSF Game

WBCs? Glucose? Gram stain? Next-generation genetic sequencing?

It’s the NEJM again, so you know the fingerprints of financial and professional conflict of interest pervade, but this study is still fairly typical of the types of infectious disease diagnostics on the horizon. Why wait for any specific organism to grow – over the course of days – when you can simply try and match DNA fragments floating around to those of various viral and bacterial pathogens?

The promise probably doesn’t quite meet the hype in this study, based out of UCSF, where many of those working on the project hold shares of the patent on the technology. In this prospective multicenter study, these authors recruited patients, ostensibly, who were diagnostic challenges – “idiopathic meningitis, encephalitis, or myelitis in patients who had not received a diagnosis at the time of enrollment”. The vast majority of those enrolled were ultimately encephalitis and meningitis. Then, this wasn’t specifically a formal trial as much as it was a collected case series with a 1-year convenience time frame, constrained by funding and testing capacity.

The authors screened 482 patients for a final study population of 204. Of these 204, their next-generation sequencing methods made a diagnosis in 32. Of these 32, 19 had already been made by further directed clinical evaluation. Of those final 13, then, in which the NGS assay was the only method of diagnosis, this information augmented clinical management in 7. The supplementary appendix details these specific impacts on management – although, in reality, few of the vignettes are terribly compelling. A handful of cases confirmed a suspected diagnosis, leading to clinicians to narrow antibiotic or antifungal therapy, while others “reassured” clinicians they were on the right course. The NGS assay did, however, occasionally detect clinically important pathogens and guide directed treatment, including Nocardia and S. mitis meningitis whose conventional testing was otherwise negative. Unfortunately, despite the addition of this testing, no conclusive final diagnosis was ever made in half their cohort.

At present, this sort of testing is not likely to be within the scope of the Emergency Department – these represent complex cases with low diagnostic yield, and even while this method picks up some new diagnoses, it also misses others established by conventional means. That said, this sort of technology will likely yet only improve, decrease in cost, and additional applications will edge closer to mainstream care.

“Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis”

https://www.nejm.org/doi/full/10.1056/NEJMoa1803396

The United Colors of Sepsis

Here it is: sepsis writ Big Data.

And, considering it’s Big Data, it’s also a big publication: a 15 page primary publication, plus 90+ pages of online supplement – dense with figures, raw data, and methods both routine and novel for the evaluation of large data sets.

At the minimum, to put a general handle on it, this work primarily demonstrates the heterogeneity of sepsis. As any clinician knows, “sepsis” – with its ever-morphing definition – ranges widely from those generally well in the Emergency Department to those critically ill in the Intensive Care Unit. In an academic sense, this means the patients enrolled and evaluated in various trials for the treatment of sepsis may be quite different from one another, and results seen in one trial or setting may generalize poorly to another. This has obvious implications when trying to determine a general set of care guidelines from these disparate bits of data, and resulting in further issues down the road when said guidelines become enshrined in quality measures.

Overall, these authors ultimately define four phenotypes of sepsis, helpfully assigned descriptive labels using the letters of the greek alphabet. These four phenotypes of sepsis are derived from retrospective administrative data, then validated on additional retrospective administrative data, and finally the raw data from several prominent clinical trials in sepsis, including ACCESS, PROWESS, and ProCESS. The four phenotypes were derived by clustering and refinement, and are described by the authors as effectively: a mild type with low mortality; a cohort of those with chronic illness; a cohort with systemic inflammation and pulmonary disease; and a final cohort with liver dysfunction, shock, and high mortality.

We are quite far, however, from needing to apply these phenotypes in a clinical fashion. Any classification model is highly dependent upon the inputs, and in this study the inputs are the sorts of routine clinical data available from the electronic health record: vital signs, demographics, and basic labs. Missing data was common, including, for example, lactate levels, which was not obtained on 80% of patients in their model. These inputs then dictate how many different clusters you obtain, how the relative accuracy of classification diminishes with greater numbers of clusters, as well whether the model begins to overfit the derivation data set.

Then, this is a little bit of a fuzzy application in the sense these data represent as much different types of patients with sepsis, as it represents different types of sepsis. Consider the varying etiologies of sepsis, including influenza pneumonia, streptococcal toxic shock, or gram-negative bacteremia. These different etiologies would obviously result in different host responses depending on individual patient features. These phenotypes derived here effectively mash up causative agent with the underlying host, muddying clinical application.

If clinical utility is limited, then what might the best utility for this work? Well, this goes back to the idea above regarding translating work from clinical trials to different settings. A community Emergency Department might primarily see alpha-sepsis, a community ICU might see a lot of beta-sepsis, while an academic ICU might see predominantly delta-sepsis. These are important concepts to consider – and potentially subgroup-analyses to perform – when evaluating the outcomes of clinical trials. These authors do several simulations of clinical trials while varying the composition of phenotypes of sepsis, and note potentially important effects on primary outcomes. Pathways of care or resuscitation protocols could potentially be more readily compared between trial populations if these phenotypes were calculated.

This is a challenging work to process – but an important first step in better recognizing the heterogeneity in potential benefits and harms resulting from various interventions. The accompanying editorial does really a very excellent job of describing their methods, outcomes, and utility, as well.

“Derivation, Validation, and Potential Treatment Implications of Novel Clinical Phenotypes for Sepsis”
https://jamanetwork.com/journals/jama/fullarticle/2733996

“New Phenotypes for Sepsis”
https://jamanetwork.com/journals/jama/fullarticle/2733994

More Bad News for Influenza Antivirals

Deep in the throes of influenza season, I’m sure the oseltamivir is flying off the shelves around the country. In Japan, however, it’s baloxavir that’s flying off the shelves. Unfortunately, as was presaged by the data from their definitive clinical trial, resistance to baloxavir is rapidly increasing.

And, now, tucked into this retrospective look at “early” versus “late” oseltamivir treatment in the critically ill – additional data regarding its general futility. In this 1,330 patient ICU cohort of patients who received osteltamivir within 48 hours of symptom onset (“early”) or later (“late”), overall mortality was 46.8% – and no different between the two groups. There are obvious issues here with regards to confounding and baseline differences, but it should be apparent a beneficial treatment … provides some benefit.

The authors did observe an absolute 10% survival advantage associated with “early” treatment in those infected with A/H3N2 – but as this accounted for a minority of their cases, overall, the entire cohort was a wash. This is consistent with another review specific to data from the 2009A/H1N1 pandemic. Mortality in included studies was only 8%, but no survival advantage was seen in those treated with oseltamivir. While universal and indiscriminate treatment with neuraminidase inhibitors is engrained in the conflict-of-interest-infested IDSA guidelines, one can only hope these data points encourage additional prospective evaluation into the true narrow value of our tools for the treatment of influenza.

“Effect of early oseltamivir treatment on mortality in critically ill patients with different types of influenza: a multi-season cohort study”

https://www.ncbi.nlm.nih.gov/pubmed/30753349