Professor Michael Mansour is a physician-scientist with a research concentration in immune responses against invading pathogens. He attends on
the Clinical Transplant Infectious Diseases and Immunocompromised
Host Service at the Massachusetts General Hospital - Division of Infectious
Diseases, where he cares for solid and stem cell transplant recipients and
individuals with weakened immunity. He also directs several COVID-19 clinical
trials and sits on committees for the development of treatment guidelines for
COVID-19 patients. ICU Management & Practice spoke to Prof. Mansour about
the role of procalcitonin in guiding antibiotic use in COVID-19 patients.
Can you please discuss the incidence and role of secondary bacterial infections in terms of risk and mortality?
In the COVID-19 patient population, the incidence of secondary infections appears to be significant. We are beginning to appreciate a few key points: • One, bacterial respiratory infections appear to be the dominant drivers of secondary infection, although there are a significant number of bloodstream infections as well. • Two, of the bacteria, there is a mix of gram-positive and negative pathogens. We are looking at this more closely, but gram-positive bacteria such as Staphylococcus species are likely to be highly represented. • Three, despite our improved ICU care, many COVID-19 patients still experience protracted recovery periods, often leaving these patients at risk for secondary infections and prolonged empiric courses of antimicrobials.
Do you think there is an association between PCT values and severe COVID19 disease?
Yes, I do. PCT does appear to rise in the setting of COVID-19 infection. More precisely, PCT seems to rise as a patient is moving from the viremic phase to a more inflammatory one in the setting of SARS-CoV-2 infection. This rise may reflect the mounting host immune response, although further investigations are required to understand the association. The Surviving Sepsis Guidelines and the NIH treatment guidelines both recommend empiric antibacterial therapy in the management of COVID-19 critically ill adults. What is the frequency of usage of antibiotics in COVID-19 patients? Let’s consider this carefully. Initially, in the pandemic, there was a large gap in our experience and management of COVID-19 patients. Many hospitals, including where I practice, witnessed a large spike in antimicrobial usage. In fact, in my experience, the majority of patients being admitted were placed on empiric antimicrobials. What we have realised is that this practice habit is really unnecessary. While there are a significant number of secondary infections, almost half of COVID-19 patients can be treated without antibiotics. It is this portion of patients that we should focus our efforts and safely de-escalate antimicrobial therapy. Moreover, for those patients with bacterial superinfection, we need to parse out COVID-related inflammatory pathology from bacterial infection.
Research suggests that only about 10%
of COVID-19 patients have bacterial co-infection but many receive antibiotics.
What is your opinion about this?
I think 10% is probably a slight underestimate. A major difficulty in the accurate
assessment of secondary bacterial infection stems from clinical judgement of a
confusing inflammatory process in CoV-2
pathology. We have significant experience
with influenza, for example, where we
are more comfortable in judging bacterial
superinfection. In the setting of COVID19, we are still learning and defining the
difference in viral versus bacteria pathophysiology. What is progressive COVID-19
versus host response versus bacterial superinfection? These are the clinical struggles
that we, as healthcare providers, are faced
with daily when managing SARS-CoV-2
What the true superinfection rates are
will require careful examination in prospective clinical projects and trials. The careful
design of clinical trials must include not
only clinical parameters but also the use of
additional biomarker tools that will help
identify bacterial superinfection and provide
insight for the ideal and appropriate usage
What could be the consequences of unnecessary antibiotic use use?
This question is incredibly critical and really the one most central to our discussion. Over the years, we have collected a
significant amount of data and experience
related to the consequences of antimicrobial overuse. The two most immediate
concerns include antibiotic pressure to
select resistant pathogens, including MRSA,
VRE, multidrug-resistant gram-negative
bacteria, and the other is the acquisition of
nosocomial infections such as Clostridioides
(formerly Clostridium) difficile.
There are larger, theoretical level impacts
that remain under careful research scrutiny,
but more and more becoming a reality. A
good example of such an impact includes
the antibiotic influence on microbiome
dysfunction, which is gaining significant
evidence in the long-lasting impact on
overall health. We need to do our utmost
best to avoid the net negative effect of
What role can PCT play in guiding antibiotic use in COVID-19 patients?
In my opinion, there are two large roles for PCT:
- One, procalcitonin serves as a prognostic indicator of COVID-19 pathogenesis; as patients enter the inflammatory phase, there is a rise in PCT, which can potentially identify patients earlier who may require more intensive care or additional hospital resource allocation.
- Two, PCT can play a role in safely de-escalating antimicrobial usage in COVID patients. I believe the majority of these patients in the milder group can avoid antimicrobial use altogether. Our study, as well as other centres, have demonstrated that most patients with a low PCT safely discharge from the hospital.
While there has been significant data
to suggest safe de-escalation, further
research studies are required for validation.
Randomised controlled trials to confirm
the safe stewardship in COVID infection are
needed, and in fact, for these reasons, we
are currently conducting an RCT, ProSAVE
(NCT04158804), to investigate the role of
PCT-guided antimicrobial stewardship in
US-based hospitals that will include COVID19 infected patients. We look forward to
sharing our results in the near future.
Are there any studies that show the benefit of PCT-guided antibiotic stewardship in COVID-19?
Many studies suggest that PCT can be
used for de-escalation, including a recent
retrospective analysis performed here at the
Massachusetts General Hospital, which we
hope to share soon with the community.
In our data, there is good evidence that a
low PCT correlates with patients who show
no evidence of any concerning microbiology
results. I think the most important will be
to examine this hypothesis in a prospective clinical trial and define the safety and
outcome metrics of a PCT-guided strategy.
As mentioned, we have launched such an
RCT and hope to answer these important
questions in the next year.
The recommended PCT threshold is
0.25. Do you think this is a conservative
estimate, and a higher threshold could
be adopted safely?
In COVID-19, this question has become
interesting because of the nature of COVID-related inflammation that may not typically
be seen with other respiratory viral infections. In our data, the majority of patients who are eventually discharged safely fall
below the 0.25 ng/mL cut-off. In addition, those patients with a milder oxygen
requirement on the clinical ordinal scale
who do not have evidence of concerning
microbiology results (blood or sputum
cultures) are also successfully identified
using a PCT cut-off of 0.25 ng/mL.
On the other hand, when a COVIDinfected patient now requires more invasive ventilation and has a higher oxygen
requirement based on the ordinal scale,
it appears that the 0.25 ng/mL may not
provide the discriminatory performance
to separate those individuals without
significant secondary superinfection. In
this sicker cohort, a higher cut-off, such as
0.5 ng/mL may be more appropriate. This
analysis is the subject of ongoing research,
and we hope to share these results soon.
Overall, what is your opinion about the use of PCT as an antibiotic stewardship tool?
Procalcitonin has a long track record of
safety and good performance in lower
respiratory tract infections, especially in
the area of antimicrobial de-escalation.
We are now faced with rising global antimicrobial resistance. It is imperative that
we use all available tools, both biomarker
and clinical assessment, to appropriately
The COVID-19 pandemic is teaching
us that SARS-CoV-2 appears to be settling
in as a long-term member of the respiratory viral microbial ecosystem, making it
critical that we develop better approaches
to identify and treat superinfections, and,
importantly, how to then de-escalate antimicrobial use promptly.
I believe PCT can have a significant
role to play in the management of these