Today we discussed a case where the treating physician ordered a procalcitonin assay to decide whether or not the patient had a bacterial respiratory infection. The result was (very) negative. Nonetheless they continued antibiotics. Was that the right decision?
This Lancet ID meta-analysis looks at the operating characteristics of the test. There is a lot of heterogeneity of the pooled studies which is a caveat. But to me, I'm not sure that a pooled sensitivity of 77% and specificity of 79% is all that impressive.
This would yield a positive likelihood ratio of 3.6 and a negative likelihood ratio of 0.27
If the patient has a 20% pre-test probability of bacterial sepsis the test would perform as follows:
Positive predictive value = 47%
Negative predictive value = 6%
(FYI the numbers for 10% and 30% are 28%/3% and 60%/12%)
Does that help you in the care of that patient? Maybe if it is negative; however, it depends on the context and how ill the patient is and the consequences of being among the 6%.
FYI as of 2012 an estimate of the per unit cost was $10-15 for the test... Given the volume of tests which would be (maybe unnecessarily) ordered in the emergency department each day it is no wonder that not all hospitals cover the test (ours does not at time of posting). See technology assessment 2012 available online here.
Wednesday, September 3, 2014
Tuesday, August 26, 2014
Weekly blog -- "Ebola"
We discussed Ebola today. Rather than blog I will shamelessly plug local work... See "Five things to know about Ebola"
Tuesday, August 12, 2014
Weekly blog -- "Aggressive lymphoma in an elderly patient"
Some take home reading:
This lancet oncology article discusses the challenges in treating elderly patients with hematological malignancies (link)
It also addresses "pre-chemo" treatment for DLBCL including corticosteroids for 7 days to be helpful in patients with poorer ECOG status to see if there is an improvement (but likely not helpful in ECOG 0-1)
For DLBCL reduced dose CHOP with full dose rituximab seems (on the basis of 2012 article) to be the best therapy for suitable patients. Overall survival quoted in the article ranged from 35-56% at three years.
Standardized geriatric assessment may be helpful in deciding on a treatment strategy (link)
Burkitt's lymphoma may be another animal compared to other DLBCL -- with median survivals measured in months for patients over age 70 (link) ... And with CHOP-R 2 year progression free survival is less than 30%
HyperCVAD isn't tolerated by the majority of elderly patients.
EPOCH has not been tested in the elderly, but has been investigated with some success in the younger populations (link)
Really, a clinical trial is needed.
*****
On to rasburicase -- a pricy little addition to TLS management --
One way to reduce cost is to use less drug -- this meta-analysis suggests one dose may be as good as a full course (link) as does this smaller study (link) and this one where they saved 2 million dollars over 48 patients... (link) There are more articles on this showing the same thing... (here too)
One could consider adding allopurinol after rasburicase (link) -- though it may not differ to single shot rasburicase
What was interesting is that in 2010 a Cochrane review in CHILDREN could not find an effect for the drug on renal failure or mortality (link)
A meta-analysis in ADULTS was performed (but not meta-analyzed due to heterogeneity) in 2013 which showed that uric acid goes down, but couldn't confirm hard outcomes either (link)
For a drug which costs up to $3600 per 7.5-mg vial (and you get 0.2mg/kg x 5 days if you follow the manufacturer's instructions) that is more than $30,000 per person treated (we pay much less if local data is believable)... Amazing there is no better RCT data on this drug which is recommended for anyone with "high TLS risk, being >5%" or intermediate TLS risk (1-5%) with comorbidities.
For those interested in cost-benefit articles -- here is one on rasburicase (link) which makes a number of assumptions and states the drug is cost-effective... I couldn't find the conflict of interest statements from the authors. Also the cost of the drug modelled was only $2200 for adults (total course).
Assuming the drug is only 3 times that price. I'm pretty sure this would yield significantly different conclusions about its cost-effectiveness. The CER for PREVENTION in ADULTS would be $120,000.
For treatment, that would depend on whether or not it works to prevent the downstream costs... and as I eluded to above, that is unclear.
This lancet oncology article discusses the challenges in treating elderly patients with hematological malignancies (link)
It also addresses "pre-chemo" treatment for DLBCL including corticosteroids for 7 days to be helpful in patients with poorer ECOG status to see if there is an improvement (but likely not helpful in ECOG 0-1)
For DLBCL reduced dose CHOP with full dose rituximab seems (on the basis of 2012 article) to be the best therapy for suitable patients. Overall survival quoted in the article ranged from 35-56% at three years.
Standardized geriatric assessment may be helpful in deciding on a treatment strategy (link)
Burkitt's lymphoma may be another animal compared to other DLBCL -- with median survivals measured in months for patients over age 70 (link) ... And with CHOP-R 2 year progression free survival is less than 30%
HyperCVAD isn't tolerated by the majority of elderly patients.
EPOCH has not been tested in the elderly, but has been investigated with some success in the younger populations (link)
Really, a clinical trial is needed.
*****
On to rasburicase -- a pricy little addition to TLS management --
One way to reduce cost is to use less drug -- this meta-analysis suggests one dose may be as good as a full course (link) as does this smaller study (link) and this one where they saved 2 million dollars over 48 patients... (link) There are more articles on this showing the same thing... (here too)
One could consider adding allopurinol after rasburicase (link) -- though it may not differ to single shot rasburicase
What was interesting is that in 2010 a Cochrane review in CHILDREN could not find an effect for the drug on renal failure or mortality (link)
A meta-analysis in ADULTS was performed (but not meta-analyzed due to heterogeneity) in 2013 which showed that uric acid goes down, but couldn't confirm hard outcomes either (link)
For a drug which costs up to $3600 per 7.5-mg vial (and you get 0.2mg/kg x 5 days if you follow the manufacturer's instructions) that is more than $30,000 per person treated (we pay much less if local data is believable)... Amazing there is no better RCT data on this drug which is recommended for anyone with "high TLS risk, being >5%" or intermediate TLS risk (1-5%) with comorbidities.
For those interested in cost-benefit articles -- here is one on rasburicase (link) which makes a number of assumptions and states the drug is cost-effective... I couldn't find the conflict of interest statements from the authors. Also the cost of the drug modelled was only $2200 for adults (total course).
Assuming the drug is only 3 times that price. I'm pretty sure this would yield significantly different conclusions about its cost-effectiveness. The CER for PREVENTION in ADULTS would be $120,000.
For treatment, that would depend on whether or not it works to prevent the downstream costs... and as I eluded to above, that is unclear.
Tuesday, July 29, 2014
Weekly blog - Overwhelming Post Splenectomy Infection (OPSI)
I couldn't do better than to refer you to the great "Care of the Asplenic Patient" NEJM article from July 24... Get that here.
What was discussed was this (?false!) belief that ceftriaxone ought not be used in patients with sickle cell anemia due to a fear of antibiotic associated hemolysis. I do believe that rare drug adverse events do exist -- but I'm uncertain we should en masse change our practices over the fear of rare events.
There certainly is a literature on ceftriaxone induced hemolytic anemia (drug induced hemolytic anemia, DIHA), occuring in sickle cell anemia patients as well as other patients (see here). In this reference lab, of 169 cases of drug induced hemolysis reported there were 15% of them due to CTX -- the proportion due to CTX increasing as the rates of CEFOTETAN use went down. In fact, CTX was the number two reported agent for DIHA!
PIP-TAZO has also been linked to drug induced severe and acute hemolysis... (see here) ... oh, and in the report of ceftriaxone I referenced above -- Guess who was number one cause? PIPERACILLIN.
... also there are case reports for the FLUOROQUINOLONES as well... (see here)
The key is that these are RARE events given the frequency in which these agents are used. The keen clinician is mindful that they exist but does not knee-jerk avoid very useful agents for potential fatal infections out of a fear of rare events.
People can die from adverse reactions to CT contrast (example). This doesn't mean that we shouldn't use CT contrast. Rather it means that CT contrast should be used when the expected benefit of contrast exceeds the risks.
***
As discussed, fluoroquinolones carry they own risks -- particularly in sickle patients who may be receiving QTc prolonging medications (think torsades) like methadone or other narcotics. They may also (in our setting) be associated with an increased risk of C. difficile.
Piperacillin-Tazobactam seemingly would cover most S. pneumoniae but I really cannot say how effective it would be against AMPICILLIN resistant Neiserria species or beta-lactamase negative ampilillin resistant (BLNAR) H. infuenzae, which would likely be resistant. Ceftriaxone has been used in Neiserrial and BLNAR infections.
What was discussed was this (?false!) belief that ceftriaxone ought not be used in patients with sickle cell anemia due to a fear of antibiotic associated hemolysis. I do believe that rare drug adverse events do exist -- but I'm uncertain we should en masse change our practices over the fear of rare events.
There certainly is a literature on ceftriaxone induced hemolytic anemia (drug induced hemolytic anemia, DIHA), occuring in sickle cell anemia patients as well as other patients (see here). In this reference lab, of 169 cases of drug induced hemolysis reported there were 15% of them due to CTX -- the proportion due to CTX increasing as the rates of CEFOTETAN use went down. In fact, CTX was the number two reported agent for DIHA!
PIP-TAZO has also been linked to drug induced severe and acute hemolysis... (see here) ... oh, and in the report of ceftriaxone I referenced above -- Guess who was number one cause? PIPERACILLIN.
... also there are case reports for the FLUOROQUINOLONES as well... (see here)
The key is that these are RARE events given the frequency in which these agents are used. The keen clinician is mindful that they exist but does not knee-jerk avoid very useful agents for potential fatal infections out of a fear of rare events.
People can die from adverse reactions to CT contrast (example). This doesn't mean that we shouldn't use CT contrast. Rather it means that CT contrast should be used when the expected benefit of contrast exceeds the risks.
***
As discussed, fluoroquinolones carry they own risks -- particularly in sickle patients who may be receiving QTc prolonging medications (think torsades) like methadone or other narcotics. They may also (in our setting) be associated with an increased risk of C. difficile.
Piperacillin-Tazobactam seemingly would cover most S. pneumoniae but I really cannot say how effective it would be against AMPICILLIN resistant Neiserria species or beta-lactamase negative ampilillin resistant (BLNAR) H. infuenzae, which would likely be resistant. Ceftriaxone has been used in Neiserrial and BLNAR infections.
So, I would agree with the uptodate article on the issue (link) -- ceftriaxone should proabably be the "go to drug" in asplenic patients with sickle-cell anemia and probable infection in the asplenic host.
With a careful observation for worsening hemolysis and consideration of an early change in the face of the rare, but severe, side effect of intravascular hemolysis. And an attention to proper dosing in the very young or very underweight individuals.
Tuesday, July 22, 2014
Weekly blog -- Harms of benzodiazepines in the elderly...
In Choosing Wisely, The Canadian Geriatrics Society advised physicians and patients to refrain from using benzodiazepines as first-line treatment for insomnia in older adults (link).
To quote them:
"The number needed to treat with a sedative-hypnotic for improved sleep is 13, whereas the number needed to harm is only 6"
Adverse events include:
To quote them:
"The number needed to treat with a sedative-hypnotic for improved sleep is 13, whereas the number needed to harm is only 6"
Adverse events include:
- Cognitive impairment (link)
- Hip Fracture
- In this cohort study there was a 10-40% increased rate of hip fracture in users of sedative-hypnotics including benzodiazepines and non-benzo sedative hypnotics (link).
- Shockingly the population attributable risk may be as high as 8.2%! (link)
- Respiratory events in patients with chronic lung illnesses
- In this cohort (Ontario) patients with COPD who received benzos had an increased rate of adverse respiratory events (link)
- Increased risk of death in this population (link)
- All cause mortality:
- In this cohort, sleeping pills were associated with a 3 fold increase of death (link).
- Similar effect size in this cohort (link)... 4 deaths per 100 people over 7.6 years.
- Pneumonia and death in age <60 (link)
- Car accidents
- FDA advisory of sedative/hypnotics and car accident risk (and need to reduce dose) (link)
Below is a must read for those who are interested in reducing benzodiazepine use in the frail elderly...I think it is a real example of success in intervening against potentially (probably) inappropriate prescription drug use.
(And yes, before anyone sends me angry emails, I know that maybe INSOMNIA is associated with all of these adverse events and that the sedatives may be the "innocent bystander"... To you, I can only say, "primun non nocere"... Show me the randomized controlled trial...)
Tuesday, July 15, 2014
Weekly blog - Liver lesions (to aspirate or not to aspirate)
Aspirations
of liver lesions... it’s not just about their hopes and dreams.
Today in
rounds we discussed a case of liver lesion and debated as to whether or not it should
have been drained. In the case of a
cystadenocarcinoma you may want to avoid drainage to prevent disease
dissemination; in contrast, drainage of a pyogenic liver abscess is a common
therapeutic and diagnostic procedure.
Here’s a
review on how to differentiate cystadenocarcinoma from liver abscess: https://webvpn.mcgill.ca/http/www.sciencedirect.com/science/article/pii/S0039610910000393
The
bottom line is that a cystadenocarcinoma that secretes mucin can be difficult
to distinguish from a pyogenic abscess based on imaging.
It can be helpful to identify patient risk factors for
pyogenic abscess. In a susceptible
patient presenting with infectious symptoms, you will likely aspirate the lesion to avoid unnecessary surgical
intervention and the associated morbidity and mortality.
Host factors and susceptibilities for pyogenic liver abscess:
· * delayed treatment of intraabdominal processes (appendicitis,
diverticulitis, cholecystitis)
· * biliary obstruction, stenting, or manipulation
· * diabetes/immunosuppression/congenital immune deficiency (i.e. Chronic Granulomatous Disease)
· * endocarditis or IVDU (leading to hematogenous spread)
The original 1946 NEJM article describing the “five ways in which
pyogenic organisms invade the liver”:
See previous blog on this issue here and my color rendition of the mechanisms
Microbiology
(not an exhaustive list):
·
Polymicrobial, gram negatives and anaerobes
·
S. milleri /S.
anginosus, S. aureus, S.pyogenes (and other gram positive cocci),
·
Klebsiella pneumonia (think of this pathogen in patients with
diabetes, particularly with monomicrobial abscess with metastatic spread to other organs)
·
Other: Candida,
Tuberculous, Burkholderia. Amebiasis.
Some
diagnostic pearls pertaining to liver abscess:
·
Initially, an abscess may be hyperechoic and
indistinct; but with maturation and pus formation, it becomes hyperechoic with
a distinct margin. Thick pus or multiple small lesions might be confused with
solid lesions
·
Peripheral
enhancement on CT is VERY helpful!
·
Don’t forget
to do blood cultures (non invasive, though sensitivity only about 40%)
·
I Infectious
symptoms may only occur late. “Large infections with bacteria of modest
virulence can develop with only subtle symptoms.” To illustrate this point, here is a case of pyogenic liver abscess, caused by
strep mitis:
Any discussion of indolent abscess should also include a nod to S. milleri group organisms.
To learn
about klebsiella pneumonia liver abscess (a 2013 review of the European
literature with some illustrative case reports from the journal Infection):
See the previous blog on this particular entity here.
Finally, a “NEJM
case records of the Massachusetts General Hospital”, looks at a case of liver
abscess (read more to find out what interesting pathogen was involved in this
case!)
- egm and tcl
Tuesday, July 8, 2014
Weekly Blog - Whipple's disease with amyloidosis
Since it was mentioned I thought it would be worth a quick note on Whipple's disease:
See review NEJM here.
It is a disease mostly described in men (>85%)
The majority of patients have:
* Weight loss (>90%)
* Diarrhea (80%)
* Arthritis (70%)
Neurologic symptoms or the classic occular findings are seen in 33% and <10% respectively.
"Roughly 15% of patients with Whipple's disease do not have the classic signs and symptoms of the disease"
Diagnosis is made through:
* PAS staining of GI biopsies -- usually several are required
* PCR on tissue or blood/CSF can also be positive
* Electron microscopy can also be used
Treatment:
CEFTRIAXONE induction, TMP/SMX consolidation
Alternative: DOXYCYCLINE
Note that discussed patient also had evidence of a monoclonal light chain in the urine prompting suspicion of amyloidosis (not seen on biopsy of the gut, nor in the serum).
There are several case reports of Whipple's disease being associated with amyloidosis (particularly with renal involvement -- i.e. nephrotic syndrome; also presenting with wasting illness without diarrhea like that discussed)
This case has the full report if you are a McGillian -- here.
Also see here, here, here and here . (many not available online)
Yes, the patient may not have Whipple's disease -- but it is curable and compatible with the illness (which primary amyloidosis, the alternative, is not in the specific patient's condition).
See review NEJM here.
It is a disease mostly described in men (>85%)
The majority of patients have:
* Weight loss (>90%)
* Diarrhea (80%)
* Arthritis (70%)
Neurologic symptoms or the classic occular findings are seen in 33% and <10% respectively.
"Roughly 15% of patients with Whipple's disease do not have the classic signs and symptoms of the disease"
Diagnosis is made through:
* PAS staining of GI biopsies -- usually several are required
* PCR on tissue or blood/CSF can also be positive
* Electron microscopy can also be used
Treatment:
CEFTRIAXONE induction, TMP/SMX consolidation
Alternative: DOXYCYCLINE
Note that discussed patient also had evidence of a monoclonal light chain in the urine prompting suspicion of amyloidosis (not seen on biopsy of the gut, nor in the serum).
There are several case reports of Whipple's disease being associated with amyloidosis (particularly with renal involvement -- i.e. nephrotic syndrome; also presenting with wasting illness without diarrhea like that discussed)
This case has the full report if you are a McGillian -- here.
Also see here, here, here and here . (many not available online)
Yes, the patient may not have Whipple's disease -- but it is curable and compatible with the illness (which primary amyloidosis, the alternative, is not in the specific patient's condition).
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