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Viruses frequently cause lower respiratory tract infections (LRTI) in adults. Physicians often treat those infections with antibiotics because there is not enough immediately-available information to gauge whether a patient may have a viral or a bacterial infection. Unnecessary exposure to antibiotics can be harmful to patients, and it also contributes to the development of antimicrobial resistance. Because of that, it is important to find ways to help differentiate between patients who will require antibiotic treatment and those who won’t.

This is the question that the TRAP trial wanted to answer. Published in The Lancet, the results of this study, jointly funded by the National Institute of Allergy and Infectious Diseases (NIAID) and bioMérieux, demonstrate that low procalcitonin levels can be used to safely identify adults with non-pneumonia LRTI who are unlikely to benefit from antibiotic therapy.

We spoke with Sean-Xavier Neath, MD, PhD, to get his perspective on the challenges of managing patients with LRTI. Dr. Neath is an Associate Physician in Emergency Medical Services at the University of California, San Diego. 

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Challenges with LRTI Patient Management

Lower respiratory tract infections include conditions such as pneumonia, exacerbation of chronic obstructive pulmonary disease and acute bronchitis. However, infection symptoms—primarily cough and fever—are usually present regardless of disease state and underlying cause of the infection. The tools that physicians have historically had access to, such as chest x-ray and complete blood count, indicate the presence of infection, but they don’t provide information on the nature of the pathogen or the need for antibiotic treatment.

Dr. Neath notes that “in my emergency clinical practice, a majority of the patients with LRTI have viral infections, rather than bacterial infections. At the same time, the pressure to prescribe antibiotics for low-risk LRTI patients can be very strong”. Because the costs of unnecessary antibiotic use are high—both in lives and monetary expense—physicians need ways to help determine which patients truly need to be treated with antibiotics.

Sepsis Risk Assessment and Antimicrobial Stewardship with Procalcitonin

PCT aids in the risk assessment for progression to severe sepsis and septic shock.  It also aids in decision making on antibiotic therapy for patients with suspected or confirmed LRTI.  Testing PCT levels at regular intervals may help physicians decide when they can safely taper and discontinue antibiotic therapy.

Historically, we’ve always prescribed antibiotics for 7 to 10 days, which has been based on consensus guidelines” says Dr. Neath. “What we’ve realized is that’s highly variable. Procalcitonin gives us the ability to personalize the course of antibiotic therapy.

A growing body of evidence-based literature supports the use of PCT to improve the clinical management of patients with suspicion of sepsis or LRTI and to contribute to antibiotic stewardship initiatives. 

Significance of the TRAP-LRTI Trial

The results of the TRAP-LRTI trial suggest that low procalcitonin levels (defined as a PCT concentration 0.25 ng/mL or less) can be used to safely identify adults with non-pneumonia LRTI who are unlikely to benefit from antibiotic therapy, in particular, azithromycin.

The study design—a randomized, double-blind, placebo-controlled trial—relieved pressure on physicians to deviate from the study protocol because the trial had no algorithm or treatment recommendation. Instead, subjects with low PCT levels were randomized to azithromycin or placebo.  It focused on a selection of a very low-risk patient group, specifically, outpatients enrolled in clinics or EDs who had non-pneumonia LRTI.

The researchers analyzed data using a long list of outcome endpoints that went beyond clinical improvement and which have an important role in studies involving antibiotics.

[W]hat this study does,” Dr. Neath says, “is elevate this perspective about the whole patient, the whole picture, not just whether the cough went away, but whether they had diarrhea two weeks later that resulted in C. difficile or whether they had some other side effect that wouldn't have normally been noted in most trial designs.

The range and composition of the study’s outcome endpoints provide a unique depth of analysis with findings that are applicable to LRTI patient care and to antimicrobial stewardship.

Getting to the “Sweet Spot” with Procalcitonin

While Dr. Neath believes that, “PCT is an amazing tool,” he notes that, “[O]ne of the important things with any new tool is the clinician education that goes into its benefits and limitations.” Understanding how to interpret PCT results means that Dr. Neath and his colleagues are better able to navigate times of year when there are multiple viruses circulating, and they are simultaneously seeing patients with secondary bacterial infections.

Positive PCT almost always points towards a severe bacterial infection,” says Dr. Neath. “A positive viral nucleic acid test indicates that at some point the patient recently had a virus. But when a patient comes in, for instance, on day two or three with a positive viral test or positive RSV test, and a negative procalcitonin, we are right in a situation we've been talking about—this is somebody who does not need antibiotics.” By contrast, an elderly woman who had a positive viral test a week prior, but now has elevated PCT, may be at risk for a bacterial infection. “I have to pay closer attention to how I treat her,” Dr. Neath says, “And I will most likely use antimicrobials.

This study highlights the ability of procalcitonin to safely identify a patient population for whom antibacterial therapy offers no advantage when considering outcomes beyond five days and after accounting for the inherent harms of unnecessary antibacterial use.