inflammatory bowel disease
Posted: Fri May 27, 2011 2:22 pm
Dear colleagues
I thought the following description may be of use to some of you.
Best Regards
Soroush
http://www.pulsetoday.co.uk/story.asp?s ... zMyMTU1MgS
2&sp_mid=36658533
Key questions on inflammatory bowel disease
25 May 11
Hospital practitioner in gastroenterology Dr John O'Malley answers GP Dr Julian Spinks's questions
on distinguishing IBD from IBS, drug therapy for Crohn's disease and the risk of cancer with
ulcerative colitis
1. We see a large number of patients with bowel problems, particularly irritable bowel syndrome
(IBS). What would alert you to the possibility of inflammatory bowel disease (IBD)?
The diagnostic journey in IBD starts with a good history in primary care. The problem with IBS and
IBD is that they share common age groups and often coexist, or to be more correct, there are often
IBS-like symptoms seen in patients with IBD. Blood is never a symptom of IBS, whereas blood in
stools (with or without diarrhoea) is the presenting feature in ulcerative colitis in over 90% of
patients. There may also be tenesmus, urgency and a colicky type of abdominal pain. As for Crohn's
disease, the features can be more diverse and many present with a mixture of abdominal pain - often
in the right iliac fossa - with diarrhoea and weight loss. Nocturnal defaecation can also be a good
sign of IBD and it is also important not to just ask how often patients pass a stool, but also how
often they get the urge to. There may also be a history of extra-intestinal manifestations of IBD,
such as joint pains and rashes.
You may get a history of relapses and remissions, but GPs should also ask about foreign travel,
exacerbating factors (especially use of NSAIDs) and smoking .
Smoking increases the risk of Crohn's disease, but decreases the risk of ulcerative colitis. It is
also worthwhile asking about previous surgery, especially appendicectomy. The risk of ulcerative
colitis is lower if a patient had an appendicectomy under the age of 20.
Examination tends to be less helpful, but may show signs of weight loss, anaemia, abdominal
tenderness or masses, and a perianal exam may also be useful. The GP should also perform a rectal
examination.
2. Are there any investigations you would recommend for a patient suspected of having IBD before
referral for sigmoidoscopy or colonoscopy, and could a CT scan be sufficient for diagnosis?
It is always useful to have a set of baseline investigations accompanying a referral, and these are
detailed in the box at the bottom of the page.1
I feel the ordering of radiology before referral can be counterproductive as it can create delays or
may well be scheduled to take place after the initial outpatient appointment. Many patients often
end up with repeated radiological investigations, and CT scanning does impart a high dose of
radiation. MRI can be very useful in diagnosing and assessing Crohn's - but again, this is a
decision best made in secondary care.
3. My local hospital has started measuring faecal calprotectin in IBD patients. What is the value of
this and is it something I should be doing?
Faecal calprotectin is a potentially interesting test. This calcium-binding protein which is
secreted by neutrophils is raised in IBD, and could possibly be an important way of differentiating
IBS from IBD. That said, it is yet to show any clear evidence of its usefulness in primary care.2
There have been concerns that the sensitivity and specificity is not yet high enough for primary
care use.3
4. When faced with a patient suffering a flare-up of IBD, what would be your first-line treatment?
Before treatment, it may well be worthwhile finding out why this relapse occurred. Although in most
cases relapse occurs sporadically, many begin after starting an NSAID or following a period of poor
compliance with treatment. Before treatment, I would also recommend contacting the designated IBD
nurse so possible follow-up can be arranged. It is also worthwhile arranging some simple blood tests
and stool cultures.
If the patient has ulcerative colitis, the treatment depends on the extent of disease and the
severity of the flare-up. Severity can be assessed using the Truelove and Witts criteria (see table,
below) but this does rely on knowing the results of blood tests.
I would recommend classing a flare-up by the number of stools per day - with mild as being less than
four stools, moderate being four to six and anything over six being severe - but overall patient
assessment also has to be mixed into the equation.
In cases of proctitis, the best approach is a topical one. Suppositories are far more useful than
enemas and are often preferred by patients. They also target the site of inflammation better and
stay there. The best drug to use is mesalazine, and normally one or two 1g doses a day will be
effective.
It is important that patients with ulcerative colitis maintain and even raise their oral dose, which
can be helpful if the topical mesalazine is not as effective as expected.
Measuring Disease activity in ulcerative colitis
Mild
Moderate
Severe
Bloody stools/day
<4
4 or more if:
≥6 and at least one of the following:
Pulse (bpm)
<90
≤90
Temperature (Celsius)
<37.5
≤37.8
≥37.8
Haemoglobin (g/dl)
≥10.5
<10.5
ESR (mm/h)
<20
20-30
CRP
Normal
≤30
With Crohn's disease, it is important to assess what form of Crohn's the flare-up is taking. You
need to consider the site, the pattern and how severe it is.
The complexity of assessing the severity of a relapse is further complicated by the fact many
patients do not show laboratory signs of disease activity such as raised ESR/CRP. Again, a valuable
source of advice is the local IBD nursing team.
Moderately active disease is best treated with steroids at 20-40mg per day depending on severity, or
budesonide at 9mg/day. Again, this dose does need to be slowly reduced - however, even with the
slowest weaning off, patients can flare up again and this should be considered as a treatment
failure.
5. What would you do if the patient fails to improve?
If patients are unresponsive to topical mesalazine then, although not as effective, topical steroids
may be used. If no response is seen after all of this, then oral steroids will be required.
It is quite common to see patients given three-, five- or seven-day steroid courses for flare-ups.
But the best treatment for a relapse is high dose steroid therapy at 40mg/day that, after
satisfactory results, can be reduced slowly by 5mg every week to zero. I would recommend close
liaison with the hospital IBD nurse if steroid treatment is needed as the nurse can facilitate early
outpatient assessment if this does not work. Again, raising the dose of the mesalazine preparation
can be helpful.
Acute severe ulcerative colitis should be treated as a medical emergency and the patient should be
admitted. Those patients with severe active Crohn's should be admitted, especially when abdominal
pain is a major issue as there could be an obstruction requiring surgical assessment.
6. I have received conflicting advice as to whether patients with IBD should be on maintenance
therapy to prevent relapses. What are your thoughts on this?
The most common cause of relapse is non adherence to therapy, and the risk of relapse in ulcerative
colitis is five-fold in those patients who use fewer than 80% of their prescriptions for mesalazine.
Not only does long-term therapy keep the number of flare-ups to a minimum, it also reduces the risk
of colon cancer .
A flare-up of IBD can have marked effects on the physical health of the patients as well as on their
work and personal life. Many patients who are flare-up free
for many years are tempted to stop treatment, but I find adapting the medication to their lives
rather than the other way round helps.
So, for example, the use of once-daily preparations and sympathetic repeat prescribing (as in
three-monthly rather than monthly scripts) can make drug adherence easier. The role of primary care
in this is being highlighted more and more - see the UK service standard.4
7. In which circumstances would patients be put on drugs such as azothioprine, methotrexate or
infliximab?
These drugs are mainly second- and third-line treatments. Azothioprine is especially useful as an
additional treatment and can reduce the need for steroids. It is helpful in both Crohn's and
ulcerative colitis and can be effective in a maintenance role.
Another alternative for patients resistant to or dependent on steroids is methotrexate, which is
useful in inducing and maintaining remission in chronically active Crohn's, but its effect on
ulcerative colitis has been disappointing.
The monoclonal antibody infliximab has increased in both use and importance. At present, it is only
licensed for use in Crohn's that has not responded to standard immunosuppression therapy. It is
especially useful in fistulating Crohn's.
8. IBD often affects younger patients. What advice would you give to a woman with IBD who wishes to
become pregnant?
Because of the age groups affected, it is common to see pregnancy in IBD patients. Inactive IBD
makes no difference to fertility, but active disease does.
Poorly controlled IBD can lead to a higher risk of preterm labour and low-birth-weight babies. Good
preconceptual advice is essential for these patients - accentuating the need for full compliance
with therapy, review of nutritional status, treatment of anaemia and, in those taking
sulphasalazine, high-dose folate. Because of the possible adverse outcomes, it is important that
flare-ups are treated aggressively.
Medication, in the vast majority, does not need to be changed in pregnancy, but those on maintenance
doses of methotrexate should be changed to other medications before conception.
9. What complications of IBD should we be alert to in primary care, and in what circumstances should
we consider urgent referral or even admission?
Apart from flare-ups and the fistula/obstruction problems of Crohn's discussed above, the main
complications are extra-intestinal - musculoskeletal/eye problems and skin manifestations. Most need
referral to the appropriate specialist.
It must be remembered that care should be taken with using NSAIDs in arthritis. Pyoderma gangrenosum
is difficult to treat in primary care and needs referral to a dermatologist.
Anaemia is common, and is usually a combination of iron deficiency and anaemia of chronic disease,
but can also be due to vitamin B12 and folate deficiency.
Due to steroid treatment, disease and age, osteoporosis is also common and certainly calcium and
vitamin D supplementation should be given where steroid treatment is needed.
You should also be aware of the increased risk of DVT in patients with IBD.
Finally, in the course of investigation for other problems, GPs may come across patients with
abnormal LFTs. The vast majority of these will not be easily defined, but about 6% may have primary
sclerosing cholangitis.
Although rare, it has important complications of cirrhosis requiring liver transplantation. There is
also a 10-15% risk of cholangiocarcinoma and also a higher than normal risk of colon cancer.
Abnormal liver function tests seen in IBD patients, especially raised alkaline phosphatase, should
be brought to the attention of the IBD team for further investigation.
10. Ulcerative colitis is associated with increased risk of carcinoma of the bowel. What is the
actual risk and, other than screening colonoscopies, is there anything that can be done to reduce
risk?
Colon cancer risk in ulcerative colitis rises with extent of disease and length of illness. The
actual risk is debatable with papers in the early 2000s showing a cumulative risk of 2% at 10 years
to almost 20% at 30 years. Recent studies have shown lower risks of 7.6% at 30 years.5
This apparent discrepancy may be due to many factors such as better control of inflammation,
surveillance programmes and better use of colectomy.
One other positive factor which primary care can help promote is adherence to mesalazine treatment.
We have good evidence that mesalazine at optimal dosage helps prevent colon cancer either from its
action on decreasing activity or by some chemoprotective effect.
GPs can help by checking on adherence, not reducing doses when 'in remission', and by giving repeat
prescriptions which reflect the long term treatment needed.
The latter is important as it allows patients to quickly increase the dose in a flare up. I would
also urge against drug switches in patients where the symptoms are under good control.
Many gastroenterologists have noted flare ups in many patients who have been the subject of drug
switches based on cost saving and this is being researched further.
11. I have a family where two brothers both have ulcerative colitis. They are concerned about the
possibility of their children having the same problem. What advice should I give them?
About 5-20% of patients will report a family history of IBD. The link is much stronger in Crohn's
than ulcerative colitis with first degree relatives having a risk 15 times that of matched controls,
rising to 30 times with siblings of patient with Crohn's.
However, there is not 100% concordance in monozygotic twins, which suggests an environmental trigger
for the disease.
So my advice to your patients would be not to get overly concerned about their children getting IBD
but have an awareness of the symptoms and make sure the family history is mentioned to a GP when
they have any gastrointestinal symptoms. I certainly would have a lower threshold for investigation
in such patients.
12. Some patients continue to deteriorate despite attempts to manage their IBD using drugs. In
ulcerative colitis, colectomy is potentially a cure - albeit at a significant cost. But is surgery
still a good option for Crohn's?
The need for surgery in Crohn's has changed little despite the great advances in medical therapy,
such as infliximab. Put together, almost 75% of patients with CD will need surgery at some point in
the space of 10 disease years. Surgery can revolutionise the quality of life for some patients and
it is especially of use in fibrostenotic intestinal disease, but the complication and recurrence
rates can be relatively high. Laparoscopic surgery may be an option for cosmetic reasons and because
of lower wound complication rates. It is vital that surgery is undertaken by colorectal surgeons
experienced in treating IBD patients, who perform such surgery on a routine basis.
Dr John O'Malley is medical director of Mastercall, an NHS Social Enterprise based in Stockport. He
is a former GP principal and has been a hospital practitioner in gastroenterology at Wirral
University Hospital Trust for the past 18 years. He is acting secretary of the Primary Care Society
for Gastroenterology and a member of the UK IBD Audit Committee
Dr Julian Spinks is a GP in Strood, Kent
Investigations before referral
-
* FBC
* Urea and electrolytes
* Liver function tests
* ESR/CRP
* Ferritin
* Vitamin B12/folate
* Stool specimens (microscopy, culture and testing for C. difficile)
I thought the following description may be of use to some of you.
Best Regards
Soroush
http://www.pulsetoday.co.uk/story.asp?s ... zMyMTU1MgS
2&sp_mid=36658533
Key questions on inflammatory bowel disease
25 May 11
Hospital practitioner in gastroenterology Dr John O'Malley answers GP Dr Julian Spinks's questions
on distinguishing IBD from IBS, drug therapy for Crohn's disease and the risk of cancer with
ulcerative colitis
1. We see a large number of patients with bowel problems, particularly irritable bowel syndrome
(IBS). What would alert you to the possibility of inflammatory bowel disease (IBD)?
The diagnostic journey in IBD starts with a good history in primary care. The problem with IBS and
IBD is that they share common age groups and often coexist, or to be more correct, there are often
IBS-like symptoms seen in patients with IBD. Blood is never a symptom of IBS, whereas blood in
stools (with or without diarrhoea) is the presenting feature in ulcerative colitis in over 90% of
patients. There may also be tenesmus, urgency and a colicky type of abdominal pain. As for Crohn's
disease, the features can be more diverse and many present with a mixture of abdominal pain - often
in the right iliac fossa - with diarrhoea and weight loss. Nocturnal defaecation can also be a good
sign of IBD and it is also important not to just ask how often patients pass a stool, but also how
often they get the urge to. There may also be a history of extra-intestinal manifestations of IBD,
such as joint pains and rashes.
You may get a history of relapses and remissions, but GPs should also ask about foreign travel,
exacerbating factors (especially use of NSAIDs) and smoking .
Smoking increases the risk of Crohn's disease, but decreases the risk of ulcerative colitis. It is
also worthwhile asking about previous surgery, especially appendicectomy. The risk of ulcerative
colitis is lower if a patient had an appendicectomy under the age of 20.
Examination tends to be less helpful, but may show signs of weight loss, anaemia, abdominal
tenderness or masses, and a perianal exam may also be useful. The GP should also perform a rectal
examination.
2. Are there any investigations you would recommend for a patient suspected of having IBD before
referral for sigmoidoscopy or colonoscopy, and could a CT scan be sufficient for diagnosis?
It is always useful to have a set of baseline investigations accompanying a referral, and these are
detailed in the box at the bottom of the page.1
I feel the ordering of radiology before referral can be counterproductive as it can create delays or
may well be scheduled to take place after the initial outpatient appointment. Many patients often
end up with repeated radiological investigations, and CT scanning does impart a high dose of
radiation. MRI can be very useful in diagnosing and assessing Crohn's - but again, this is a
decision best made in secondary care.
3. My local hospital has started measuring faecal calprotectin in IBD patients. What is the value of
this and is it something I should be doing?
Faecal calprotectin is a potentially interesting test. This calcium-binding protein which is
secreted by neutrophils is raised in IBD, and could possibly be an important way of differentiating
IBS from IBD. That said, it is yet to show any clear evidence of its usefulness in primary care.2
There have been concerns that the sensitivity and specificity is not yet high enough for primary
care use.3
4. When faced with a patient suffering a flare-up of IBD, what would be your first-line treatment?
Before treatment, it may well be worthwhile finding out why this relapse occurred. Although in most
cases relapse occurs sporadically, many begin after starting an NSAID or following a period of poor
compliance with treatment. Before treatment, I would also recommend contacting the designated IBD
nurse so possible follow-up can be arranged. It is also worthwhile arranging some simple blood tests
and stool cultures.
If the patient has ulcerative colitis, the treatment depends on the extent of disease and the
severity of the flare-up. Severity can be assessed using the Truelove and Witts criteria (see table,
below) but this does rely on knowing the results of blood tests.
I would recommend classing a flare-up by the number of stools per day - with mild as being less than
four stools, moderate being four to six and anything over six being severe - but overall patient
assessment also has to be mixed into the equation.
In cases of proctitis, the best approach is a topical one. Suppositories are far more useful than
enemas and are often preferred by patients. They also target the site of inflammation better and
stay there. The best drug to use is mesalazine, and normally one or two 1g doses a day will be
effective.
It is important that patients with ulcerative colitis maintain and even raise their oral dose, which
can be helpful if the topical mesalazine is not as effective as expected.
Measuring Disease activity in ulcerative colitis
Mild
Moderate
Severe
Bloody stools/day
<4
4 or more if:
≥6 and at least one of the following:
Pulse (bpm)
<90
≤90
Temperature (Celsius)
<37.5
≤37.8
≥37.8
Haemoglobin (g/dl)
≥10.5
<10.5
ESR (mm/h)
<20
20-30
CRP
Normal
≤30
With Crohn's disease, it is important to assess what form of Crohn's the flare-up is taking. You
need to consider the site, the pattern and how severe it is.
The complexity of assessing the severity of a relapse is further complicated by the fact many
patients do not show laboratory signs of disease activity such as raised ESR/CRP. Again, a valuable
source of advice is the local IBD nursing team.
Moderately active disease is best treated with steroids at 20-40mg per day depending on severity, or
budesonide at 9mg/day. Again, this dose does need to be slowly reduced - however, even with the
slowest weaning off, patients can flare up again and this should be considered as a treatment
failure.
5. What would you do if the patient fails to improve?
If patients are unresponsive to topical mesalazine then, although not as effective, topical steroids
may be used. If no response is seen after all of this, then oral steroids will be required.
It is quite common to see patients given three-, five- or seven-day steroid courses for flare-ups.
But the best treatment for a relapse is high dose steroid therapy at 40mg/day that, after
satisfactory results, can be reduced slowly by 5mg every week to zero. I would recommend close
liaison with the hospital IBD nurse if steroid treatment is needed as the nurse can facilitate early
outpatient assessment if this does not work. Again, raising the dose of the mesalazine preparation
can be helpful.
Acute severe ulcerative colitis should be treated as a medical emergency and the patient should be
admitted. Those patients with severe active Crohn's should be admitted, especially when abdominal
pain is a major issue as there could be an obstruction requiring surgical assessment.
6. I have received conflicting advice as to whether patients with IBD should be on maintenance
therapy to prevent relapses. What are your thoughts on this?
The most common cause of relapse is non adherence to therapy, and the risk of relapse in ulcerative
colitis is five-fold in those patients who use fewer than 80% of their prescriptions for mesalazine.
Not only does long-term therapy keep the number of flare-ups to a minimum, it also reduces the risk
of colon cancer .
A flare-up of IBD can have marked effects on the physical health of the patients as well as on their
work and personal life. Many patients who are flare-up free
for many years are tempted to stop treatment, but I find adapting the medication to their lives
rather than the other way round helps.
So, for example, the use of once-daily preparations and sympathetic repeat prescribing (as in
three-monthly rather than monthly scripts) can make drug adherence easier. The role of primary care
in this is being highlighted more and more - see the UK service standard.4
7. In which circumstances would patients be put on drugs such as azothioprine, methotrexate or
infliximab?
These drugs are mainly second- and third-line treatments. Azothioprine is especially useful as an
additional treatment and can reduce the need for steroids. It is helpful in both Crohn's and
ulcerative colitis and can be effective in a maintenance role.
Another alternative for patients resistant to or dependent on steroids is methotrexate, which is
useful in inducing and maintaining remission in chronically active Crohn's, but its effect on
ulcerative colitis has been disappointing.
The monoclonal antibody infliximab has increased in both use and importance. At present, it is only
licensed for use in Crohn's that has not responded to standard immunosuppression therapy. It is
especially useful in fistulating Crohn's.
8. IBD often affects younger patients. What advice would you give to a woman with IBD who wishes to
become pregnant?
Because of the age groups affected, it is common to see pregnancy in IBD patients. Inactive IBD
makes no difference to fertility, but active disease does.
Poorly controlled IBD can lead to a higher risk of preterm labour and low-birth-weight babies. Good
preconceptual advice is essential for these patients - accentuating the need for full compliance
with therapy, review of nutritional status, treatment of anaemia and, in those taking
sulphasalazine, high-dose folate. Because of the possible adverse outcomes, it is important that
flare-ups are treated aggressively.
Medication, in the vast majority, does not need to be changed in pregnancy, but those on maintenance
doses of methotrexate should be changed to other medications before conception.
9. What complications of IBD should we be alert to in primary care, and in what circumstances should
we consider urgent referral or even admission?
Apart from flare-ups and the fistula/obstruction problems of Crohn's discussed above, the main
complications are extra-intestinal - musculoskeletal/eye problems and skin manifestations. Most need
referral to the appropriate specialist.
It must be remembered that care should be taken with using NSAIDs in arthritis. Pyoderma gangrenosum
is difficult to treat in primary care and needs referral to a dermatologist.
Anaemia is common, and is usually a combination of iron deficiency and anaemia of chronic disease,
but can also be due to vitamin B12 and folate deficiency.
Due to steroid treatment, disease and age, osteoporosis is also common and certainly calcium and
vitamin D supplementation should be given where steroid treatment is needed.
You should also be aware of the increased risk of DVT in patients with IBD.
Finally, in the course of investigation for other problems, GPs may come across patients with
abnormal LFTs. The vast majority of these will not be easily defined, but about 6% may have primary
sclerosing cholangitis.
Although rare, it has important complications of cirrhosis requiring liver transplantation. There is
also a 10-15% risk of cholangiocarcinoma and also a higher than normal risk of colon cancer.
Abnormal liver function tests seen in IBD patients, especially raised alkaline phosphatase, should
be brought to the attention of the IBD team for further investigation.
10. Ulcerative colitis is associated with increased risk of carcinoma of the bowel. What is the
actual risk and, other than screening colonoscopies, is there anything that can be done to reduce
risk?
Colon cancer risk in ulcerative colitis rises with extent of disease and length of illness. The
actual risk is debatable with papers in the early 2000s showing a cumulative risk of 2% at 10 years
to almost 20% at 30 years. Recent studies have shown lower risks of 7.6% at 30 years.5
This apparent discrepancy may be due to many factors such as better control of inflammation,
surveillance programmes and better use of colectomy.
One other positive factor which primary care can help promote is adherence to mesalazine treatment.
We have good evidence that mesalazine at optimal dosage helps prevent colon cancer either from its
action on decreasing activity or by some chemoprotective effect.
GPs can help by checking on adherence, not reducing doses when 'in remission', and by giving repeat
prescriptions which reflect the long term treatment needed.
The latter is important as it allows patients to quickly increase the dose in a flare up. I would
also urge against drug switches in patients where the symptoms are under good control.
Many gastroenterologists have noted flare ups in many patients who have been the subject of drug
switches based on cost saving and this is being researched further.
11. I have a family where two brothers both have ulcerative colitis. They are concerned about the
possibility of their children having the same problem. What advice should I give them?
About 5-20% of patients will report a family history of IBD. The link is much stronger in Crohn's
than ulcerative colitis with first degree relatives having a risk 15 times that of matched controls,
rising to 30 times with siblings of patient with Crohn's.
However, there is not 100% concordance in monozygotic twins, which suggests an environmental trigger
for the disease.
So my advice to your patients would be not to get overly concerned about their children getting IBD
but have an awareness of the symptoms and make sure the family history is mentioned to a GP when
they have any gastrointestinal symptoms. I certainly would have a lower threshold for investigation
in such patients.
12. Some patients continue to deteriorate despite attempts to manage their IBD using drugs. In
ulcerative colitis, colectomy is potentially a cure - albeit at a significant cost. But is surgery
still a good option for Crohn's?
The need for surgery in Crohn's has changed little despite the great advances in medical therapy,
such as infliximab. Put together, almost 75% of patients with CD will need surgery at some point in
the space of 10 disease years. Surgery can revolutionise the quality of life for some patients and
it is especially of use in fibrostenotic intestinal disease, but the complication and recurrence
rates can be relatively high. Laparoscopic surgery may be an option for cosmetic reasons and because
of lower wound complication rates. It is vital that surgery is undertaken by colorectal surgeons
experienced in treating IBD patients, who perform such surgery on a routine basis.
Dr John O'Malley is medical director of Mastercall, an NHS Social Enterprise based in Stockport. He
is a former GP principal and has been a hospital practitioner in gastroenterology at Wirral
University Hospital Trust for the past 18 years. He is acting secretary of the Primary Care Society
for Gastroenterology and a member of the UK IBD Audit Committee
Dr Julian Spinks is a GP in Strood, Kent
Investigations before referral
-
* FBC
* Urea and electrolytes
* Liver function tests
* ESR/CRP
* Ferritin
* Vitamin B12/folate
* Stool specimens (microscopy, culture and testing for C. difficile)