COVID-19 RISK FACTORS: Who gets them and why. You are going to ACE this one…

Now usually I don’t go and make wild conjectures and hypotheses. But Im going to discuss a pretty interesting (wild conjecture?) one that on paper seems to make sense to me. Let’s look at the COVID-19 risk factors for who gets severe disease and put them in a molecular and biological framework. If you want you can also skip down and just look at the tables because they sum everything up and then correlates risk factor to molecular basis…The rest is me just talking’. …We will start with the risk factors

Risk Factors of COVID

As with all disease there is usually a group that is particularly susceptible to a particular disease. As information becomes more available we are better able to describe this susceptible population.  In the Severe Acute Respiratory Syndrome (SARS) epidemic in 2003 that occurred in Beijing it was noted that those with chronic medical conditions and the elderly had a significantly higher risk of developing SARS1. That outbreak was caused by the SARS-associated coronavirus (SARS-CoV).

         Coronavirus disease (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing the current pandemic. As more time and data accrue it is becoming more clear who may be at risk in this current outbreak of COVID-19. The data thus far is reported from China, Italy and the US, with the majority coming from the devastating effects of the pandemic in Italy. It would appear from the data thus far that once again age and comorbidities play a role in the risk factors of COVID (see Table 1). Those with hypertension (7.3%) and cardiac disease (7.2%) seem to have the highest associations and thus risk. These 2 groups are followed by Diabetes Mellitus (3.3%) (No data specifically distinguishing the two have been reported thus far). Men appear to be more affected by COVID-19 as well. Roughly a 60-40 mix in the confirmed but a 70-30 mix in the cohort from Italy that died (see Table 2 & 3). The age group (see Figure 2) most affected by COVID-19 appears to over-represented by the 70-79, and 80-89-year-old’s. As seen from the Italian data 112 of the 10,026 patients reported to have died were under the age of 50. Twenty-three of that group was less than 40 and of that group 6 were reported to have no co-morbidities.

TABLE 1. Comorbidities of reported COVID patients

Comorbidity# CasesN= 10473a%TotalCasesNumber DiedN= 10336b%Total of Deaths
Rheumatologic disease10.0NRNR
Immune Suppression/Cancer/ Organ transplant2352.22222.1
CNS disease70.1NRNR
>1 comorbidity1035c10.1890d0.8

# of Cases from references: 2–5, Italy contributed 10,026 cases of patients who died

b # Died from references: 2, 5

c of 10,272 cases reported

d of only 10,135 cases reported

NR=Not reported

Table 2. Number and Percent of Men and Women having Confirmed COVID-19 infection

confirmed ChinaConfirmed UKChina meta-analysisSum

Table 3. Number and Percent of Men and Women Died in Italian cohort

Died Italy

Figure 1. Number of patients who died by age group. This data is based solely on the Italian2 reported cohort of 10,026 patients who died. 

Now for the molecular basis!

Lets go back in time, long before anyone ever associated a corona virus with an incredibly severe pandemic. Before this, we in the medical field new it as “The common cold”. So how did something go from being a common cold to the second worst pandemic the world has ever seen? (1918-1919 Flu killed an estimated 50 million people*- as of today 4/3 COVID-19 has been confirmed in >1 Million people and has taken just over 53 thousand lives)? 

The “common cold” coronaviruses that we used to be able to test for came in such flavors HCoV-229E, HCoV-NL63, HCoV-OC43 (HCoV = Human Corona virus). They caused only self-limiting upper respiratory tract infections (about 30% of the common colds) 1. We never, really, bothered to make any treatments for the diseases they caused because as a 1994 study said “the presence of side-effects in treating such a mild illness is…unacceptable” 1.

Something has definitely changed. You might be surprised to know that we actually do understand what has changed since these OG corona viruses and the 2003 SARS (we now call SARS-CoV-1).

The “corona” of corona virus gets its name from spikes on the outer edge of the virus that give it a crown-like appearance (SEE THE FEATURED IMAGE ON THIS PAGE). Those spikes are how it gets into the cell. Now, in this rendition of SARS-CoV-2, those spikes sting…

In a paper so important it made it into NATURE, Li in 2003 found that SARS (CoV-1)  used the ACE2 receptor to facilitate viral entry into humans2. Sound familiar? ACE inhibitors have been used to control hypertension for years and ACE inhibition is key in the treatment of cardiovascular disorders.

Interestingly, although we have known about ACE for a long time, ACE2 was only discovered in 20003 and its discovery has been “noteworthy and might be categorized as a Classic”4. The reason for this is it has “changed our simplistic vertical concept about the renin-angiotensin-system (RAS) by pointing out the presence of dual functions of the RAS with opposing effects in cardiovascular biology”4. We now know A LOT about ACE2 (SEE FIGURE BELOW FOR BIOCHEMICAL PATHWAY). ACE2 prevents the formation of the vasopressor angiotensin II. Interestingly, the gene for this enzyme, ACE2, maps to the X chromosome in humans. Thus the male species have less ACE2 than women do. Also interesting to note is that we start out life with a high amount of ACE2 and then ACE2 becomes down regulated and decreases with age. Thus older males have the least amount of  ACE2 5! (Really starting to sound like a correlation here with risk factors!). We know that ACE2 is an essential regulator of heart function6. We also know that ACE2 is abundantly present in humans in the epithelia of the lung, small intestine, and vascular endothelium which may provide routes of entry for the SARS-CoV 7. With the SARS epidemic in 2003 we also learned a lot about SARS-CoV. We found that the CoV-1 bound tightly to ACE2 much more tightly than the corona viruses of old did. In fact now we know that SARS-CoV-2 even more efficiently recognizes and binds to ACE2 which may explain it enhanced ability to be transmitted from person to 8

So how does that translate into such severe disease? Well for that we dive deeper into ACE2. Crackower in his article in Nature created knock-out mice that could not express ACE2. The loss of ACE2 did not alter blood-pressure but did impair cardiac function causing:

Mild thinning of the left ventricle and severe reduction in contractility but without fibrosis or hypertrophy of the heart.  The damage was more similar to that seen with  myocardial stunning, which is reversible and also suggested a role for ACE2 in mediating a response to cardiac ischemia. 

Now it gets more interesting, because ACE2 also protects us from lung injury!9 In 2011 it was found that the development of ARDS is determined by the balance between ACE and ACE2 activity within the lung10. This study found that treating ACE2 knockout mice with either the by product of ACE2 (Ang1-7) or losartan (which in animal models has been shown to be lung protective but also causes sever drops in blood pressure in those with bp dysregulation such as the kind that occurs in sepsis), resulted in higher values of PaO2 in models of ARDS. They also found that in models of ARDS ACE activity was enhanced, whereas ACE2 activity was reduced in bronchoalveolar lavage fluid. Yang et al. found that an abundance of ACE2 enhanced disease severity in a mouse model of SARS-CoV-1 infection.  They introduced the human gene for angiotensin-converting enzyme 2 (hACE2) into these mice. The mice had more severe pulmonary lesions, interstitial hemorrhage, and replicated more efficiently in these mice. CoV-1 had more openings in these mice to enter into. They also found other changes such as desquamation, and vasculitis in these mice. 11

Thus, ACE2 is not only the entry receptor of the virus but also protects from lung injury. Because CoV-2 binds to it, it essentially becomes nonfunctional and can’t participate in lung repair. So SARS-CoV-2 may have become more infectious because the virus inhibits a lung protective pathway! SARS-CoV likely results in ACE2 downregulation through binding of SARS-CoV Spike protein to ACE2. It has been shown in many animal models that ACE2 is an inhibitor of lung injury. This scenario would explain how this family member of the common cold coronaviruses has turned into a worldwide pandemic.  Indeed, this information is all being used in looking for treatments (drugs and vaccines) to subdue this emergency12

We can even hypothesize further because all this becomes very interesting in the setting of ACEI’s and ARB in the treatment of hypertension. In a study by Burchill, the effect of Ramipril in combination with losartan was investigated. They found that despite ACE inhibition there was no down regulation of ACE2. Thus while it is still to early to tell one could hypothesize that the hypertension medications we take really shouldn’t affect CoV-2—but only time will tell. It is also interesting to consider the issue of ibuprofen. In a study by Qiao, the effects of ibuprofen on ACE2 were investigated in diabetic rats. It was found that Ibuprofen could blunt the cardiac fibrosis in diabetic rats by enhancement of the ACE2! Now obviously there have been “reports” of people saying not to take ibuprofen in CoV-2. In no way does this say one way or the other.  What this should do is remind us that CORRELATION IS NOT CAUSATION. We have animal data that suggests ibuprofen is protective by increasing ACE2 and we have small observational data that suggests ibuprofen may be associated with worse disease. This is not the first time ibuprofen has been associated with worse respiratory disease. In 2016 a study reported an ASSOCIATION between NSAIDs and empyema with an adjusted odds ratio of 2.79 (CI 1.4-5.58, P = .004) 13. Again this is an ASSOCIATION and should make us skeptical UNTIL WE SEE A RANDOMIZED CONTROLLED TRIAL to adjust for confounders. However, certainly titles like “Is It Time to Dump the Ibuprofen From Your Medicine Cabinet?” should be met with extreme skepticism. 

So to sum up here are the key points and their associated molecular mechanisms


1.COVID-19 (CoV-2) has higher transmission and higher virulenceSpike protein of CoV-2 binds ACE2 more tightly than CoV-1 and infinitely tighter than “the common cold”
2.COVID-19 occurs in men more than womenACE2 is carried on the X chromosome
3.COVID-19 occurs in older adults than younger adultsACE2 is down regulated with age
4.COVID-19 causes acute lung injury and ARDSACE2 is protective of lung injury and is unavailable because of binding to viral spike particles
5.COVID-19 causes myocardial injuryLack of ACE2 causes myocardial dysfunction without fibrosis or hypertrophy


1.      Wu J, Xu F, Zhou W et al. Risk factors for SARS among persons without known contact with SARS patients, Beijing, China. Emerg Infect Dis. 2004; 10: 210-216.

2.      Sanità ISD. Characteristics of COVID-19 patients dying in Italy Report based on available data on March 30th, 2020. 2020;

3.      Arentz M, Yim E, Klaff L et al. Characteristics and Outcomes of 21 Critically Ill Patients With COVID-19 in Washington State. JAMA. 2020;

4.      Deng Y, Liu W, Liu K et al. Clinical characteristics of fatal and recovered cases of coronavirus disease 2019 (COVID-19) in Wuhan, China: a retrospective study. Chin Med J (Engl). 2020;      Rodriguez-Morales AJ, Cardona-Ospina JA, Gutiérrez-Ocampo E et al. Clinical, laboratory and imaging features of COVID-19: A systematic review and meta-analysis. Travel Med Infect Dis. 2020; 101623.


1. Myint SH. Human coronaviruses: A brief review. Reviews in Medical Virology. 1994; 4: 35-46.

2. Li W, Moore MJ, Vasilieva N et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003; 426: 450-454.

3. Donoghue M, Hsieh F, Baronas E et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res. 2000; 87: E1-9.

4. Marian AJ. The discovery of the ACE2 gene. Circ Res. 2013; 112: 1307-1309.

5. Fernández-Atucha A, Izagirre A, Fraile-Bermúdez AB et al. Sex differences in the aging pattern of renin-angiotensin system serum peptidases. Biol Sex Differ. 2017; 8: 5.

6. Crackower MA, Sarao R, Oudit GY et al. Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature. 2002; 417: 822-828.

7. Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004; 203: 631-637.

8. Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus. J Virol. 2020; 94:

9. Imai Y, Kuba K, Rao S et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. 2005; 436: 112-116.

10. Wösten-van Asperen RM, Lutter R, Specht PA et al. Acute respiratory distress syndrome leads to reduced ratio of ACE/ACE2 activities and is prevented by angiotensin-(1-7) or an angiotensin II receptor antagonist. J Pathol. 2011; 225: 618-627.

11. Yang XH, Deng W, Tong Z et al. Mice transgenic for human angiotensin-converting enzyme 2 provide a model for SARS coronavirus infection. Comp Med. 2007; 57: 450-459.

12. Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Medicine. 2020; 46: 586-590.

13. Le Bourgeois M, Ferroni A, Leruez-Ville M et al. Nonsteroidal Anti-Inflammatory Drug without Antibiotics for Acute Viral Infection Increases the Empyema Risk in Children: A Matched Case-Control Study. J Pediatr. 2016; 175: 47-53.e3.

We’re Back Baby!! The Quick hit article: For ESBL, Just Say NO to PIP/TAZO

Effect of Piperacillin-Tazobactam vs Meropenem on 30-Day Mortality for Patients With E coli or Klebsiella pneumoniae Bloodstream Infection and Ceftriaxone Resistance
A Randomized Clinical Trial

This was a randomized, double-blinded, international multicenter pragmatic (phew! That’s a mouthful!) study to determine if piperacillin/tazobactam (pip-taz) is non-inferior to meropenem. The reason for this study is to see if there is a way to reduce carbapenems use and prevent further Carbapenem resistance acinetobacter (CRAB, not the Maryland kind). ESBL drugs are those that are by definition resistant to ceftriaxone or ceftazidime. This is a really well done trial with the trial being registered at and meeting all the important qualities of an RCT. The only missing item (which is probably a small one given how rigorous this trial was) is the fact that of all the 9 countries the US wasn’t one of them (Isn’t Canada close enough? Probably, still too close if you aren’t a fan of Trump). The study used a non-inferiority protocol with 30 day all cause mortality as the end point. Also a home run here with a very good patient oriented outcome. They randomized 378 patients and found an impressive 12.3% vs 3.7% mortality rate for pip-taz vs meropenem. Yikes! That is an 8.6% absolute risk reduction!!! In classic statistical phrasing using double negative: This trial found pip-tazo not non-inferior. They powered the study to find 454 patients but stopped at a predefined interim-analysis of 340 patients. Its bad form to stop a trial for “benefit” when you are looking for non-inferiority but not for harm. As such the trial enrolled 391 pts. In this cohort the patients had about 86% E. Coli and 14% Klebsiella. Most of the patients came from Singapore and Australia with only 1 patient coming from Canada (C’mon Canada!). Most of the infections were either urinary (~60%) or intra-abdominal infections (~15%). Interestingly, 60% of patients were deemed to have been treated with “appropriate” empiric therapy and EVEN MORE INTERESTING is the fact that almost 45% of patients had community associated acquisition. This is probably true world wide but maybe less so in the US? But we are likely heading that way. So to sum up in patients that have ESBL need meropenem not pip-tazo! For a number needed to treat version: If you will have one death for every 12 patients you treat if you use pip-tazo and not meropenem!!

The JC learning point
This trial was performed as a “non-inferiority” trial. These trials should be looked at with a scrutinizing eye! Drug companies love to use this because they don’t have to prove the drug is better, they just have to prove its not worse. The critical point here is to make sure that the correct significance (α level) is set. Non-inferiority is established at the α significance level if a confidence interval for the difference in efficacies (new – current) is contained within a safety margin interval. In this study they used a margin of +5%; so if the studies showed a mortality within 5% of each other then we would have said that pip-tazo is non-inferior to meropenem (but it didn’t). Normally when we compare to things we can use a α of 0.05. However, in non-inferiority testing we have to use an α of 0.025 because we are really performing TWO ONE-sided tests (think of it as needing a p-value for the +margin and the -margin so you cut the p-value in half ). Lastly, interpreting a non-inferiority trial as a superiority trial is OK and doesn’t require a multiple testing correction IF the 95% confidence interval for the treatment benefit excludes the non-inferiority margin AND zero is not in the confidence interval. However, the opposite approach is not true. If a superiority trial fails to reject the null hypothesis but the trial data appear to suggest treatment non-inferiority, you cannot default to non-inferiority


  1. Effect of Piperacillin-Tazobactam vs Meropenem on 30-Day Mortality for Patients With E coli or Klebsiella pneumoniae Bloodstream Infection and Ceftriaxone Resistance A Randomized Clinical Trial. JAMA. 2018;320(10):984-994. doi:10.1001/jama.2018.12163
  2. Understanding noninferiority trials. Korean J Pediatr 2012;55(11):403-407.

Fill the Tank or Rev’ the Engine… WHOA, PUMP the BRAKES: Early fixed dose norepi for septic shock?

We all know hypotension is bad. But should we fill with fluids or rev up the heart with pressors. This begs the question does early norepi help prevent hypotension and mortality? Today’s quick hit article:

Permpikul C, et al. Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER) : A Randomized Trial. Am J Respir Crit Care Med. 2019 Feb 1. doi: 10.1164/rccm.201806-1034OC. PMID 30704260.


In this prospective double blinded intention to treat analysis RCT conducted in Thailand the authors found that early fixed dose norepinephrine (0.05 mcg/kg/min) allowed for faster time to the primary outcome of “shock control” by 6 hours after diagnosis of septic shock. Shock control was defined as achievement of a MAP >65 plus urine output (>0.5 ml/kg/hr) and a lactate that cleared by 10%. They found no clinical or statistical increase in limb or organ ischemia even when norepinephrine was administered by peripheral access during the patient’s entire hospitalization. Lastly, a secondary (hypothesis generating) outcome of 28 day mortality showed a difference of 5% in favor of the fixed dose norepinephrine group which would be nice if that were real and reproducible.  


Syncope Admissions


This was a very interesting phase II, double-blind, placebo RCT with intention to treat analysis. That looked to answer the question of “shock control” in septic shock. Shock control (A COMPOSITE OUTCOME) was defined as achievement of a MAP >65 mmHg plus urine output (>0.5 ml/kg/hr) and a lactate that cleared by 10%. The interesting part comes in from their inclusion/exclusion criteria. Keep in mind that the population studied is one of the biggest predictors of generalizability in a trial. They excluded patient if they met the criteria of septic shock for MORE THAN 1 hour before randomization! I’m not really sure why they would do that. They screened 456 patients and excluded 136, 31 of which were because of shock for >1 hour.  Another weakness I found was that they did not report how they calculated the MAP and what percent had a-lines and what percent was calculated by non-invasively. This can be VERY important (See my post on MAP later). The final study randomized 155 patients to each group. The two groups looked otherwise pretty similar in their baseline characteristics. The intervention group was started on 0.5 mcg/kg/min fixed dose of epi and everyone was blinded to this intervention with a placebo in the control group. Time to getting norepi was pretty quick 93 minutes. Theoretically, you could say the norepi group could be differentiated by providers if they saw the BP go up. However, 20% of the normal saline placebo had an increase in the blood pressure.  Both groups were allowed to have open label norepi The primary outcome here was time to shock control by measured MAP, urine output, and lactate. So, that is not the most fair primary outcome since obviously time to shock control will be faster in the norepi group. 76% of the norepi group vs 48% of the placebo group met the primary outcome. An interesting feature of the study was in the COMPOSITE primary outcome less than 10% of both groups reached the lactate clearance group whereas much more of the groups (35 vs 24) reached the urine output goal. This is more reason to make me wonder how useful lactate clearance is. A secondary outcome of mortality at 28 days, although NOT statistically significant was interestingly was a 6% difference (15.5 vs 21.9) in favor of the early norepi group. THIS METRIC IS DEFINITELY SOMETHING I’D LIKE TO SEE REPEATED IN A US STUDY AS THE PRIMARY OUTCOME. Another 5% mortality is impressive. 20% is what is typical of all the other sepsis trials (ARISE, PROMISE, etc.) with sick patients showed, so that would be impressive if early norepi could decrease this subsets mortality. The last interesting point is that there was no statistical difference in limb or organ ischemia between the two groups and half of the patients had only peripheral lines. These patients were in the hospital for a median of 10 days. It would be nice to know how long the patients had the norepi running. Also, many of these patients were admitted to the wards and NOT the ICU (about 50% of both groups). These two facts in addition to all the other literature on peripheral pressor’s really makes me feel better about running norepi peripherally. However that fact that this was based in a lower resource country with admissions criteria that are different also make it not as generalizable.  So does this change practice? That waits to be seen, however, I have always felt that dumping in the magical 30ml/kg into a patient who is not hemorrhaging to be missing the point. I am biased toward giving early pressors…



Lactate for Safely Screening Sepsis?



A lactate >4 in this prospective observational cohort study of almost 1000 patients with the “CMS” definition of sepsis was helpful in predicting “clinical deterioration” with an positive likelihood ratio (+LR) of 10.7 but only a negative likelihood ratio (-LR) of 0.8. Approximately 9% of patients with lactate >4 where sent home. However, a lactate of >2 only had a positive likelihood ratio (+LR) of 2 and a negative likelihood ratio(-LR) of 0.8. Lactate alone of >2 and less than 4 was not useful in predicting who had clinical deterioration or who didn’t. CMS uses a cutoff of 2 mmol/L

Ever since “sepsis” has become the only reason for a fever, the screening for mortality predictors has been the holy grail. Lactate has been promulgated as the “Lost Ark” of these biomarkers. However, just as with any single biomarker that has since been used it lacks the sensitivity and specificity we need and has rarely been tested agains physician gestalt. Remember that the THREE BIGGEST Sepsis trials all used a cutoff of lactate >4 after “fluid resuscitation”. Remember that CMS uses a lactate of >2…

Here, another article to remind us of the test characteristics of lactate arrives. In this very good prospective observational cohort study of adult ED patients satisfying the original sepsis definition the authors seek to find how good is lactate.  The authors looked at cutoff of both 2 and 4 mmol/L as the “discriminatory” zone of mortality. They do use a composite outcome of “clinical deterioration” which they define as: death, endotracheal intubation, vasoactive medication administration for a minimum of 1 h, noninvasive positive pressure ventilation (NIPPV) for a minimum of 1 h, or ICU admission for a minimum of 24 h. 985 patients met the original sepsis definition. Of these 84 patients (8.5% – shows you how good our sepsis definition is….) met the primary outcome of clinical deterioration and half of that 4% met the primary outcome while still in the ED. 

A lactate > 4.0 mmol/L  had a +LR of 10.7 (95% CI 6.3–18.3)and -LR 0.8 (95% CI, 0.7–0.9) for for predicting deterioration ( Sp 97.4% (95% CI 94.1–100%); Sn 27.4% (95% CI 17.8–36.9%). Of those patients with a lactate of 4 8.7% were discharged home and did not meet the primary outcome. 

A lacate of >2.0 mmol/L  had a +LR of 2.0 (95% CI 1.7–2.3) and -LR 0.5 (95% CI 0.4–0.7) for predicting deterioration, (Sn 67% (95% CI 55–76%); Sp of 66% (95% CI 63–69%). Of patients with a lactate < 2.0 mmol/L, 224 (56.1%) were discharged home and did not meet the primary outcome (which means half DID meet the primary outcome)

Of note those with a lactate 2.0-3.9 mmol/L 90% did NOT meet “clinical deterioration” and 10% did meet clinical deterioration 

Thus a lactate >4 was useful in predicting poor outcome but anything less was not useful either way (in reassuring no detioration or not).

This literature isn’t new but it is recent and should remind us that a normal lactate doesn’t help, nor does a lactate less than 4. Thanks CMS for more useless “meaningful use”…

Antibiotic StewardSHIP…Moveover Titanic…there’s a new failure in town.

Tamma, et al. Rethinking How Antibiotics Are Prescribed: Incorporating the 4 Moments of Antibiotic Decision Making Into Clinical Practice. 2018 Dec 27. doi: 10.1001/jama.2018.19509. [Epub ahead of print]


BOTTOM LINE: Providers should be asking themselves: “What is the likelihood my patient has an infection and that it requires antibiotic therapy?”

Those who know me, know my passion for medicine can occasionally turn into a status rant-icus type soliloquy on the failures of modern medicine (I feel one of those coming on me like a seizure…). One of these high horses I like to ride is on a term that has come to have as much meaning and futility as “military intelligence” or “President Trump”…that term is antibiotic stewardship.

I think its easy to know to whom I am referring. For instance, if you have ever in one breath prescribed “a zpack, prednisone, and albuterol” then I am referring to you; if you reflexively say flouroquinolone when you hear words that start with Sinu-, bronch-, or cyst- and end in -itis, then I’m referrering to you; if you have ever used the words “just to be safe” as your clinical decision aid to give antibiotics, then I’m referring to you; if you use the terms “strong” and “weak” to describe antibiotics, then I am referring to you; and lastly if anyone has ever asked you “so what infection are you actually treating?!” Then I am definitely referring to you. (By the way I think a great use of machine learning would be to develop a wristband that shocks providers who type keystrokes recognized as -itis and then Rx an antibiotic.)

Thus much like music to my ears or more appropriately propofol to my seizure I came upon the opinion paper in JAMA entitled “Rethinking How Antibiotics Are Prescribed: Incorporating the 4 Moments of Antibiotic Decision Making Into Clinical Practice”….Ahh had they only incorporated the word zen into the title then I might have been able to sleep more between these night shifts. I think this is a must read!

The article delineates a 4 step process (much shorter than 12) to thoughtfully redirect the thinking of antibiotic prescriptions. 

(Zen) Moment #1: (an antibiotic “TIMEOUT”)

This is the most important step! “Does this patient have an infection that requires antibiotics?

Yes, there are cases in severe infections where early antibiotics makes sense, but that does not translate down to an otitis media, or worse a fever! Just as all the glitters isn’t gold…all that has a temp is not an infection. Let’s go back to considering a differential (inflammation, medication, etc) and seeing if there is an alternate reason for the fever. Conversely, some causes of fever are viral and don’t need antibiotics. In fact, there is much literature currently on asymptomatic bacturia and I question giving antibiotics to all urinalyses… So ask yourself “what is the likelihood of an infection that requires antibiotic therapy.

(Zen) Moment #2:

Have I ordered appropriate cultures before starting antibiotics? What empiric antibioitcs should be started? Although not all patients need cultures we should culture appropriately. The authors state that most patients with community acquired pneumonia, abdominal, and no purple tissue cellulitis are NOT high risk for MRSA and may not need vancomycin (I am definitely guilty of not using enough empiric nafcillin/ancef)

(Zen) Moment #3:

A day or more has passed, can I stop antibiotics or narrow the therapy? Can I change from IV to oral therapy? There is much literature on physicians continuing therapy despite culture data to the opposite. 

(Zen) Moment #4:

What duration of antibiotic therapy for this patients diagnosis is needed? Remember the timelines we use are have minimal evidence behind them. Some will say that most bacterimia is cleared after 2-3 doses of IV abx. We should be using patient response to therapy rather than opinion based guidelines.

I love this article and think everyone should read it as a reminder. The more we remind ourselves of the literature the better we will do with decreasing unnecessary antibiotic use. 

Maybe the authors should have changed the name of the article to “An Antibiotic Timeout”. There more I think about this concept the more I like it. 

I better go check my EEG…

Macrolide Resistance: Is Resistance Futile?

There hasn’t been an update to the IDSA/ATS guidelines for CAP (community acquired pneumonia) since 2007 (I keep hearing they will be out soon). These guidelines recommend
 a macrolide antibiotic as first-line therapy for previously healthy patients who have no risk factors for drug-resistant S. pneumonia (SPN) infection (strong recommendation) and a combination of a macrolide and a beta-lactam for patients who require hospitalization but not in the ICU 1.  In the last few years, concerns for macrolide resistance have been discussed (I’m looking at you EM-RAP). Paradoxically no real affects on clinical outcomes have been shown. Referred to as the aptly named in vivo-in vitro paradoxthere are divergent findings of macrolide resistance and clinical outcome. Lets talk amongst ourselves, shall we?


Macrolide resistance is a thing! But the clinical studies don’t yet support the concerns of the in vitro findings of resistance.  The IDSA/ATS guidelines have not been updated since 2009 and its still OK to use macrolide monotherapy when high levels of strep pneumo resistance are unlikely. So what to do? If I’m worried about compliance I’ll still prescribe OUTPATIENT azithromycin alone (especially if I feel atypicals are the cause and at least until new IDSA guidelines come out). If I am at all “worried” I will add in a beta-lactam. For HOSPITALIZED PATIENTS OR SEVERE DISEASE NEVER USE AZITHROMYCIN ALONE.  RESISTANCE MAY BE ANNOYING BUT ITS NOT YET FUTILE


     I’m not disagreeing with macrolide resistance in general, I just don’t think it’s futile to use these even as monotherapy in CAP. Typically Azithromycin resistance is defined as an MIC >2 μg/mL) and sometimes very high resistance levels are seen. However there seems to be disparate results between MIC’s and clinical cure rates.   I think the misperception is best seen in Zhanel’s article 3on clinical cure rates. This study looked at community acquired respiratory infections (CARTI) and azithromycin resistance in streptococcus pneumoniae. Overall if you look at the study there was about a 10% difference in clinical cure rate in those treated with azithromycin for ALL respiratory tract infections. HOWEVER, in this group they included the following as CARTI: acute otitis media (sometimes air comes out of my ear when I sneeze but I don’t think its part of the respiratory tract!), CAP, acute bacterial exacerbations of chronic bronchitis and acute bacterial sinusitis. They found 1127 patients with CARTI of which they found 29% (112/388) of subjects with SPN had AZ-R. Overall, clinical cure rates in CARTI subjects treated with azithromycin were higher for in AZ-S (89.4%) versus AZ-R (78.6%; P=0.003). BUT if you look at CAP alone for AZ-S vs AZ-R the failure rates were 3/52 vs 2/27 (p=0.986) and the cure rates were 49/52 (94%) vs 25/27 (93%), respectively. These are small numbers true so lets look at some more studies.

      In this study by Yanagiharathey looked at a 3 (Three??? Yes three) day course of azithromycin in adults with mild to moderately severe CAP, and to determine whether in vitro macrolide resistance in of SPNis related to clinical failure. A good clinical response was defined as improvement of 3 of the 4 following outcomes: 1) resolution of fever 2) resolution of wbc’s, 3) improvement of CRP and 4) improvement of CXR findings. They found a good response in 13/17 (76%) and an ineffective response in 4/17 (23%). Strangely, 6 of 7 patients in whom high-level resistance was documented (MICs >256 μg/mL) showed good clinical responses. If you look at CAP alone for AZ-S vs. AZ-R the failure rates were 0/2 vs. 4/12 and the cure rates were 2/2 vs. 8/12, respectively.

     In this study, Kohno5 looked at moderate-to-severe community-acquired pneumonia.  They found that despite mostly having AZ-R strains in Japan, clinical efficacy and bacterial eradication were achieved in 10 of 11 patients. If we combine these 3 studies (not a great meta-analysis I know…) for AZ-R then you would have 43/50 (86%) good responses and 7/50 (14%) poor responses and this is in places with the highest rates of resistance… 6

     Lastly, in this study by Cillonizlooked at outcomes in AZ-S vs. AZ-R.  They found 30-day mortality in AZ-S to be 32/493 (6%) vs. AZ-R 9/133 (7%, p=0.93) and ICU admission to be 140/493 (28%) vs. 32/133 (24%, p=0.29). 

Indeed there is some thought that macrolide antibiotics have additional properties than just their bacteriostatic/bacteriocidal properties. Some studiessuggest that macrolides have anti-inflammatory properties and prevent the production of pro-inflammatory mediators and cytokines. This recent study of lowered mortality in CAP would agree with a reduction of all cause in hospital mortality and a 10% difference (not statistically significant) in 30-day mortality.  Here, Arnold et al.looked at 549 patients with CAP and bacteremia where 247 (45%) were treated with a macrolide and 302 (55%) were not.  The unadjusted 30-day mortality was 18.4% in the macrolide group, and 29.6% in the non-macrolide group (RR=0.81, CI 0.50–1.33; P = 0.41). Unadjusted in-hospital all-cause mortality was 7.3% in the macrolide group, and 18.9% in the non-macrolide group (RR= 0.54, CI 0.30–0.98; P = 0.043).

There are two major mechanisms mediating resistance to macrolides. The ermB gene encodes a methyltransferase that causes ribosomal methylation resulting in a phenotype that reduces susceptibility to macrolides (and lincosamide FYI). This mechanism results in the highest macrolide resistance. The second mechanisms is the mefA gene which codes for an antibiotic efflux pump removing the drug from the SPN. Macrolides are concentrated intra-cellularly, and this is thought to result in increased drug delivery to the site of infection, and exposure to high concentrations of drug following phagocytosis, which may overcome low level resistance. Possibly high-level resistance may be clinically relevant , however that was not exactly the case in the above Yanagihara study.

So in summary, macrolide resistance is definitely real. However, there really does not seem to be a huge affect clinically when azithromycin resistance is encountered. Furthermore, Azithromycin resistance is probably more likely in its uses other than CAP, like otitis media and sinusitis (and other infections I don’t treat with antibiotics). So how do we use this information? Well I would NEVER use macrolides alone for hospitalized patients. I still believe that for hospitalized patients macrolides and beta-lactams are the way to go. In fact, I like to add azithromycin to even my ICU patients just in case there is something magical about the macrolides. For outpatient management of mild CAP I think there is still a role for macrolide monotherapy. We all know that compliance is not great with patients and I feel in mild disease I’d rather they take 1 once a day antibiotic rather than have to add in a beta-lactam and have them not take it.


  1. Mandell LA, Wunderink RG, Anzueto A et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007; 44 Suppl 2, S27-72.
  2. Bishai W. The in vivo-in vitro paradox in pneumococcal respiratory tract infections. J Antimicrob Chemother 2002; 49, 433-436.
  3. Zhanel GG, Wolter KD, Calciu C et al. Clinical cure rates in subjects treated with azithromycin for community-acquired respiratory tract infections caused by azithromycin-susceptible or azithromycin-resistant Streptococcus pneumoniae: analysis of Phase 3 clinical trial data. J Antimicrob Chemother 2014; 69, 2835-2840.
  4. Yanagihara K, Izumikawa K, Higa F et al. Efficacy of Azithromycin in the Treatment of Community-acquired Pneumonia, Including Patients with Macrolide-Resistant Streptococcus pneumoniae Infection. Internal Medicine 2009; 48, 527-535.
  5. Kohno S, Tateda K, Kadota J et al. Contradiction between in vitro and clinical outcome: intravenous followed by oral azithromycin therapy demonstrated clinical efficacy in macrolide-resistant pneumococcal pneumonia. J Infect Chemother 2014; 20, 199-207.
  6. Cheng AC, Jenney AWJ. Macrolide resistance in pneumococci-is it relevant. Pneumonia (Nathan) 2016; 8, 10.
  7. Cilloniz C, Albert RK, Liapikou A et al. The Effect of Macrolide Resistance on the Presentation and Outcome of Patients Hospitalized for Streptococcus pneumoniae Pneumonia. Am J Respir Crit Care Med 2015; 191, 1265-1272.
  8. Ianaro A, Ialenti A, Maffia P et al. Anti-inflammatory activity of macrolide antibiotics. J Pharmacol Exp Ther 2000; 292, 156-163.
  9. Arnold FW, Lopardo G, Wiemken TL et al. Macrolide therapy is associated with lower mortality in community-acquired bacteraemic pneumonia. Respir Med 2018; 140, 115-121.





Sometimes things aren’t as they seem.  As an attending I often hear from a resident “Hey got an easy one for ya, 50 y/o diabetic with bilateral cellulitis vanc given, I’ll get some admit labs” followed by a precipitous mic drop.

I was told once that a good attending “makes a difficult case simple and a simple case difficult” I believe that more and more these days. So is a simple case of cellulitis really that simple? Well in a study by Weng in 2016, 30% of 259 pts were misdiagnosed with cellulitis. A similar study by Li also 30 percent of 116 patients were incorrectly diagnosed as cellulitis” in a study by Li in 116 patients. Thirty percent is a large number, but does it surprise me? Not really.  I have heard so many times a patient is getting admitted for “bilateral cellulitis”.  So you are telling me there are two skin infections starting at the feet and racing to the groin like two trains approaching each other??? If you think about it kind of doesn’t make sense that this would exist much. Maybe in a very immune-compromised patient it can occur but otherwise the patient should be really sick. If I really think about it in IVDU patients with skin abscess all over even they don’t have bilateral cellulitis! In fact every case report of bilateral cellulitis I found was actually on how “bilateral cellulitis” was the WRONG diagnosis.

So if its not cellulitis then what is it (we will get back to the bilateral part in a bit)?


I asked an intern what is his approach to a patient differential diagnosis. “Worst first” he said. I chuckled a bit since I appreciate alliteration. But in an overall way he is on the right track so on that note lets start off with the worst: Necrotizing fasciitis (NF). However, this will not be a lengthy discussion because there are so many good resources on NF. Instead I want to focus on some pearls for this diagnosis. To start one thing that makes me feel better is this quote in Clinical infections disease by Anaya “Establishing the diagnosis of necrotizing soft tissue infections is not easy”. Thanks for that, what no clinical correlation recommended? The typical findings of blisters/bullae, crepitus, gas, fever, tachycardia, hypotension, and shock have a low sensitivity of only 10-40%.  Well is there anything that can help us? When all else fails examine the patient. We need to see if the area is necrotic. So, one helpful trick is the “finger test”in the almost brilliantly named BMJ article “Necrotizing Fasciitis: Always used the finger” (which I would have said give them the finger but the Brits always have to be proper). Here a test incision is made in the suspected area of approximately 2 cm. A positive test would be characterized by the absence of normal blood flow, dirty’ dishwater’ colored fluid and discoloration of the fat. Then a rapid finger sweep at the level of the fascia can be carried out. If the tissues dissect with minimal resistance this again favors the diagnosis.



The simplest way to think about this would be to say there is cellulitis and then there is everything else. So what are some pearls for the diagnosis of these tricksters?

  1. Cellulitis is rarely bilateral! Fact!
    1. Corollary: Vascular dermatitis is usually bilateral
  2. Elevate the leg when you examine it! Dependent redness is often mistaken for cellulitis, but erythema promptly disappears after elevating the leg at the bedside. Dependent redness is often asymptomatic, but can be associated with rest pain from arterial insufficiency.
  3. Stasis dermatitis (AKA venous eczema) is the most common mimic of cellulitis.
  4. Superficial thrombophlebitis can appear similar to lymphangitis however DVT of the lower limb rarely causes cutaneous erythema EXCEPT in the proximal thigh, where the femoral vein lies just below the skin surface
  5. Cellulitis is not typically itchy, its painful
    1. Corollary: IF the area is insensate worry about Nec Fasc!
  6. Malignancy affecting the lymphatics of the lower extremities can closely mimic cellulitis!
  7. Failure of  antibiotics should make you think twice about the diagnosis of cellulitis
  8. Cellulitis should have inguinal lymphadenopathy
  9. Confluent Erythema Nodosum can have a similar appearance but will have a different feel since it is a panniculitis
    1. Corollary: Cellulitis should be smooth and not be made up of firm nodules!
  10. Erythema Multiform can have a similar appearance and mistaken for allergic reaction or cellulitis.


Stasis Dermatitis (aka Venous Eczema):

  • Ill-defined, bilateral, pitting edema of the lower extremities, typically with erythema, hyperpigmentation, serous drainage, and su- perficial desquamation
  • Chronic venous insufficiency causes micro- vascular changes and microthrombi leading to acute cutaneous inflammation
  • ill-defined erythematous plaque with overlying pigment changes and super- ficial desquamation, as well as nonpitting edema


  • Necrosis, and fibrosis of the subcutaneous fat, especially in women
  • It usually develops much more slowly than cellulitis—over weeks to month
  • A sclerosing panniculitis classically described as an “inverted champagne bottle” or “inverted bowling pin” appearance of the leg, ie, the diameter of the leg is sharply narrowed directly below the calf
  • There is an acute and a chronic phase. The acute phase is characterized by inflammation and erythema, and the chronic phase is characterized by fibrosis
  • The acute phase can be difficult to differentiate from cellulitis. venous insufficiency, cutaneous changes of stasis dermatitis, and the absence of systemic symptoms all point to lipodermatosclerosis.

Contact Dermatitis

  • The lesion is a painful, nonpruritic, well-demarcated, erythematous, weeping plaque with scattered vesicles at the periphery, as well as superficial desquamation and scaling.
  • Ask about recent changes in medications, soaps, and laundry detergents, new hobbies, or recent surgeries. The involved site is often confined to the area where the allergen contacted the skin


  • Localized edema of an affected extremity, with induration, erythema, and secondary cutaneous changes such as hyperkeratosis, dyspigmentation, and wart-like architecture
  • Has the patient undergone lymph node dissection? Has the patient had an injury in the affected leg? Lymphedema is overwhelmingly unilateral and nonpitting, and is often seen in overweight people

Eosinophilic cellulitis, or Wells syndrome

  • It is a recurrent hypersensitivity reaction to a drug, to a vaccine, or to an insect bite, or to a viral or fungal infection that pre- sents on the extremities as localized erythema, edema, and induration with sharp borders and a green or gray hue
  • Patients tend to report itching and burning that precedes the
  • onset of plaques the complete blood count typically shows a transient hypereosinophilia


  • is a rare disorder that causes episodes of heat, redness, and burning discomfort provoked by heat and dependency and relieved by elevation and cooling of the extremity
  • Primary occurs more common in women than men
  • Can be a marker of systemic disease associated with: myeloproliferative neoplasms of polycythemia vera, essential thrombocythemia, and chronic myelogenous leukemia.
  • Age of onset is typically in the forties and fifties.
  • The symptoms are nearly always intermittent, with episodes usually lasting from a few minutes to a few hours, but occasionally lasting for several days
  • They are typically provoked or worsened by limb dependency, exercise, and heat and alleviated by the opposite of these


  • The onset of an attack is abrupt, causing severe pain, tenderness, erythema, swelling, and warmth over the affected joint.
  • Evolves rapidly, reaching its maximal intensity within 6 to 12 hours.
  • Commonly expands a considerable distance beyond the joint itself, producing extensive cutaneous inflammation that may strongly resemble cellulitis.
  • Fever occasionally occurs,
  • Careful examination, , usually indicates that the origin of the inflammation is clearly in the synovial space, rather than the soft tissues
  • Movement of the affected joint and pressure over it produce exquisite pain that is less intense with compressing adjacent inflamed, non- articular tissue
  • Don’t order a serum uric acid! It doesn’t help!


  1. Weng QY, Raff AB, Cohen JM, Gunasekera N, et al. Costs and consequences associated with misdiagnosed lower extremity cellulitis. JAMA Dermatol.
  2. Li et al. Outcomes of Early Dermatology Consultation for Inpatients Diagnosed With Cellulitis. JAMA Dermatol. 2018 May 1;154(5):537-543.
  3. Anaya et al. Necrotizing Soft-Tissue Infection: Diagnosis and Management. Clinical Infectious Diseases, Vol. 44, No. 5 (Mar. 1, 2007), pp. 705-710
  4. Necrotizing Fasciitis: Always use the finger. BMJ 2005;330:830
  5. Lower limb cellulitis and its mimics Part II. Conditions that simulate lower limb cellulitis. J Am Acad Dermatol 2012;67:177.e1-9.
  6. Keller EC. cellulitis mimics. Cleveland Clinic Journal Of Medicine. 79: 8 2012 547- 552

Quick Hit Article #8: Say No To Flouro(Quinolone) in Pyelo

Quick Hit Article: Pyelonephritis treatment in the community emergency department: Cephalosporins vs. first-line agents.

Vogler 2018 Aug 8. pii: S0735-6757(18)30652-1

The Bottom Line: In this retropsective chart review with moderate (not optimal) methods, patients placed on cephalosporins had significantly less treatment failure (0% vs 23%, p< 0.001) than when placed on either TMP/SMX or Fluoroquinolones.


Abx in pyelonephritis-2

(Really) Quick Hit Article #7 – LR does not clinically increase serum lactate. If you believe in lactate…come along with me…

Source: J Emerg Med. 2018 Jul 20. pii: S0736-4679(18)30602-4

Today’s (really) quick hit is a neat little article trying to answer the question “Does Lactated Ringers increase your serum lactic acid.  Given that sepsis seems to be the only diagnosis of anymore, can our friend lactic acid still help us if we are giving 30 ml/kg of LR?

The Bottom Line:
In healthy (Non-ED) volunteers 30 ml/kg of LR modestly increased the serum lactate at 5 min after the infusion of fluid by about 1 mmol/L. This was statisticaly significant but probably not clinically relevant. Interestingly, the health patients baseline lactate was 1.05 in both groups. 

 The Graphic

 LR vs NS for lactate

The Details:

This is a simple but well done randomized double blinded controlled trial that was even prospectively registered at! They took healthy volunteers and gave each 30 ml/kg of NS and LR to 15 patients in each group. They measured the lactate in the contralateral arm and found the LR to increase from 1.06 to 1.99 and NS to increase the lactate form 1.05 to 1.42. The increase in lactate by LR was statistically significant compared to baseline. That being said it is still probably not a clinically significant difference but we cannot extrapolate this to septic ED patients. Besides they drew the lactate at 5 min after infusion. What happens at the 2 or 3-hour mark? Is it still increased? We will never know. Interestingly, the authors state, “…our study only had enough resources to check 1 repeat lactate and 1 repeat metabolic panel”. So in the end while this is interesting it’s probably not enough to make me worry that I have spuriously elevated my lactate by giving LR.

So keep giving LR or NS or whatever you fancy to resuscitate patients.



Yes, summer in Arizona is hot but we aren’t talking weather – hot. We are talking fever – hot, as in, is our ED temperature measurements correct? The scientist part of me wants accuracy, the caring part of me wants not to put things in peoples bum! So, is there a happy medium when it comes to detecting fever in the ED without doing a rectal on every patient? Let’s take a look at the literature.

Bottom Line:

Below I review three articles looking specifically at Temporal artery thermometers (TAT). There were some comparisons to axillary temperatures as well but this was not the focus. All the studies looked at both febrile and afebrile patients. Much of the evidence look at pediatric and geriatric patients who are unable to tell us if they feel febrile (not that most adults can tell either). I think the literature pretty conclusively shows that axillary temperatures are the pits (careful this might get worse). For Temporal Temps the findings were not much better. In summary TAT are not very accurate for representing core temps. One article summed it up best “Thus, it seems that TAT could replace tympanic thermometers with the caveat that both methods are inaccurate1. From the studies overall, you get a +LR of 12 and a -LR of 0.3. That is if a patient is febrile according to the TAT then it is probably correct. However. if a patient is not febrile by TAT then they may still have a temp. So, what can we say? TAT are not very accurate. However, I still don’t think every patient needs a rectal temp. If I think a patient is febrile then I am probably just as correct as the TAT. If I really am worried I can get a rectal temp. So here is how I do it. If I see a patient has a temp (>38C) on the vitals by TAT then I am good. If a patient has an environmental exposure or altered I will get a rectal temp. If they are afebrile by TAT but feel warm or tachycardic then I’m pretty sure they have a temp. If they have unexplained tachycardia I work that up (sometimes just shared decision making with the patient) until I am comfortable that no emergent condition exists.

The details for the three articles are below.

The first article is by Brosinksi in “Comparison Of Temporal Artery Versus Rectal Temperature In Emergency…” 2. These authors looked at a single facility on a remote island (sounds nice). The enrolled 126 pediatric patients and 125 geriatric patients They included febrile and afebrile pediatric patients 3 years old and younger and geriatric patients aged 65 and older, all whom were unable to participate in an oral temperature assessment owing to their inability to follow commands, mouth breathing, respiratory distress, or facial/ oral trauma. They excluded patients with injuries or deformities at the temporal site or those with behavorial problems who may be disturbed by temporal measurement. Each patient underwent one rectal temp (RT) and 3 temporal artery temps (TAT) measurements – Thank god it wasn’t the other way around! For the pediatric group they found the false positive rate of predicting RT fever by TAT for pediatric patients is 14.7%, and the false negative rate is 9.8%, yielding sensitivity of 90%, and specificity of 85%. The overall accuracy was 87%. The 95% confidence interval (CI) for a reading on an individual patient was ± 2.36°. For the geriatric group they found the false positive rate of predicting RT fever by TAT to be 6.0% and false negative rate 25.9%, yielding sensitivity 74.1%, and specificity 94.0%. The overall accuracy is 85%. The CI for a reading on an individual patient was ± 2.97°.

The next article is by Forrest 3 and is entitled “Temporal artery and axillary thermometry comparison with rectal thermometry in children presenting to the ED”. They studied 85 children 1 day to 36 months with and without a fever and excluded active chemo, neutropenia or a child “in distress”. Using a standard cutoff for fever of a rectal temp of > 38.0 °C, the sensitivity and specificity for detecting fever were 11.5% and 100%, respectively for axillary. For TAT, the sensitivity and specificity for detecting fever were 61.5% and 93.3%, respectively. The mean temperature difference in the febrile group was >0.5 °C for TAT and >1.0 °C in axillary measurements.

The last article is a systematic review 1 that looked at TAT and compared it to a core temp. The primary outcome was measurement accuracy of the index test compared to a reference standard, expressed as pooled estimates of mean temperature difference. They pooled 37 included articles together to get 5026 study participants of which 1301 were adults and 3725 were children. The found a difference of −0.19°C (95% CI of −1.16 to 0.77°C). There was a trend towards larger differences from the reference for febrile patients, with an underestimation of the temperature. They found an overall Sn of 72% and a Specificity of 94%. This study made the best summary I could find: Our results indicate that TAT is not sufficiently accurate to replace one of the reference methods… Although inaccurate, the results are similar to those with tympanic thermometers…Thus, it seems that TAT could replace tympanic thermometers with the caveat that both methods are inaccurate.


  1. Geijer, H., Udumyan, R., Lohse, G. & Nilsagård, Y. Temperature measurements with a temporal scanner: systematic review and meta-analysis. BMJ Open 6, e009509 (2016).
  2. Brosinski, C., Valdez, S., Riddell, A. & Riffenburgh, R. H. Comparison of Temporal Artery Versus Rectal Temperature in Emergency Department Patients Who Are Unable to Participate in Oral Temperature Assessment. J Emerg Nurs 44, 57-63 (2018).
  3. Forrest, A. J. et al. Temporal artery and axillary thermometry comparison with rectal thermometry in children presenting to the ED. Am J Emerg Med 35, 1855-1858 (2017).