doi:10.1136/gut.2006.114660
2008;57;549-558; originally published online 4 Jan 2008; Gut

Colombel
N Viget, G Vernier-Massouille, D Salmon-Ceron, Y Yazdanpanah and J-F


diagnosis
inflammatory bowel disease: prevention and
Opportunistic infections in patients with
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Opportunistic infections in patients
with inflammatory bowel disease:
prevention and diagnosis
N Viget,
1

G Vernier-Massouille,
2
D Salmon-Ceron,
3
Y Yazdanpanah,
1,4,5
J-F Colombel
2
1
Service des Maladies
Infectieuses et du Voyageur,
Centre Hospitalier de Tourcoing,
France;
2
Service d’He´pato-
gastroente´rologie, Hoˆpital
Claude Huriez, Centre Hospitalier
Universitaire de Lille, Lille
France;
3
Service des Maladies
Infectieuses, Universite´ Paris V,
Faculte´ Cochin, Paris, France;
4
EA 2694, Faculte´deMe´decine
de Lille, France;
5
Laboratoire de
Recherches E
´

conomiques et
Sociales, CNRS URA 362, Lille,
France
Correspondence to:
Professor J-F Colombel, Service
d’He´pato-gastroente´rologie,
Hoˆpital Claude Huriez, CHRU de
Lille, 59037 Lille Cedex, France;

Revised 13 November 2007
Accepted 21 November 2007
Published Online First
4 January 2008
ABSTRACT
Because of the increasing use of immunosuppressive and
biological drugs, the occurrence of opportunistic infections
has become a key safety issue for patients with
inflammatory bowel disease (IBD). Consequently,
improvement of healthcare workers’ knowledge of this
domain is urgent. In this review, the preventive measures
that would help to reduce the rate of opportunistic
infections in patients with IBD are listed, and the
management of situations frequently confronting doctors
is considered. In the absence of national and international
recommendations, the information given here should help
doctors to optimise patient outcomes.
Over the past 10 years, the treatment of inflam-
matory bowel disease (IBD) has been marked by
the increasing use of immunosuppressors, mainly
azathioprine (AZA)/6-mercaptopurine (6-MP) and

methotrexate (MTX), and by the advent of
biological therapies. The increasing evidence in
favour of immunosuppressors means that they are
being used more often and earlier in the course of
the disease. Recent data have shown that once
initiated, maintenance therapy with AZA should
be continued.
1
The introduction of biological
agents, especially inhibitors of the key proinflam-
matory cytokine tumour necrosis factor a (TNFa)
ushered in a new therapeutic era, and the use of
these agents has become increasingly widespread
since their introduction in 1998.
2
Any treatment or medication can cause unto-
ward events, and its benefit has to be weighed
against the risk of side effects. As regards immu-
nosuppressors and TNF antagonists, key safety
considerations for patients with IBD certainly
include the prevention of opportunistic infections.
These infections may either be due to an organism
which does not usually cause disease but which
may, under certain conditions, become pathogenic,
or they may constitute an unusually severe
infection by an organism which normally causes
mild disease only. Because, in different ways,
immunosuppressors and TNF antagonists inhibit
immune system activity, their association with
opportunistic infections can be viewed as an

extension of their normal, intended therapeutic
activity.
Opportunistic infections pose a difficult problem
for doctors because they are often hard to recognise
and are associated with significant morbidity and
mortality, as they are frequently serious and hard
to treat effectively. It is important to improve
gastroenterologists’ knowledge of opportunistic
infections, because this might provide a new
approach to optimising patient outcomes by
introducing new strategies for prevention or early
diagnosis.
EPIDEMIOLOGICAL ASPECTS
IBD is associated with conditions that may
predispose to opportunistic infections, such as the
lack of an appropriate innate immune response to
infectious agents (a response that may be inherent
in the disease), malnutrition, surgery and immu-
nosuppressive medication. The prevalence of
opportunistic infections in patients with IBD is
not known, but they have been regularly stated to
be a cause of death in this population in various
reports, including case reports, open series, pla-
cebo-controlled randomised clinical trials, post-
approval databases and registries.
3–13
A large num-
ber of opportunistic infections have been attrib-
uted to IBD therapies (see list in Table 1). Their
description is outside the scope of this article, but

some important points are worth mentioning. All
kinds of infection have been associated with the
use of corticosteroids, AZA/6-MP, MTX, cyclos-
porin and TNF antagonists, even though some
specific effects may be due to their mechanism of
action.
14
For instance, by leading to T lymphocyte
apoptosis, AZA/6-MP metabolites may, in parti-
cular, predispose to infection by viruses such as
cytomegalovirus (CMV), varicella zoster virus
(VZV) or Epstein–Barr virus (EBV).
14 15
In the case
of TNF antagonists, the risk of reactivating
granulomatous diseases and infections, in which
host defences are particularly macrophage depen-
dent, is of particular concern. The prevalence and
awareness of specific infections may vary from
country to country, as it does, for instance, for
Histoplasmosis in endemic or non-endemic
regions.
3 16–18
Recent safety concerns have focused
on biological drugs, but it should be remembered
that older traditional therapies have been less well
scrutinised and that they all carry risks. It is
difficult to attribute the causes of adverse effects
such as opportunistic infections to a specific drug.
Because these infections are rare, large cohorts are

needed to determine their precise incidence in IBD
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patients, and also to establish the excess risk
associated with the use of a specific medication.
Other sources of bias in assessing the actual risk
include the ‘‘learning curve’’ inherent in new drug
use, and exposure to multiple agents. Doctors
should be aware that the combination of immu-
nosuppressors, including steroids, and TNF antago-
nists may substantially increase the risk of
opportunistic infections. In a recent case–control
study from the Mayo Clinic, the odds ratio for
opportunistic infections associated with the use of
corticosteroids, AZA/6-MP or infliximab was 2.6
(95% CI 1.4 to 4.7), and increased to 12.9 (95% CI
4.5 to 37.0) when two or more drugs were used.
17
PREVENTION
Admittedly, there are no universal recommenda-
tions for the management of opportunistic infec-
tions, and the following statements merely reflect
either guidelines from national scientific societies
or authors’ opinions. The present method for
prevention of opportunistic infections rests on a
thorough clinical and laboratory work-up before
starting the administration of immunosuppressors
and/or TNF antagonists, and on vaccinations,
chemoprophylaxis and, when indicated, appropri-

ate control of underlying chronic viral infections.
Clinical and laboratory work-up (Box)
Patients should be questioned about their history
of bacterial infections, especially frequent infec-
tions such as those involving the urinary tract.
19 20
The risk of latent or active tuberculosis is evaluated
from the following information: date of the last
BCG vaccination, previous contacts with infected
patients, country of origin, prolonged stays in
countries where tuberculosis is endemic, and any
history of latent or active tuberculosis and the
treatment received. In addition, patients must
report any history of infection by VZV and herpes
simplex virus (HSV), especially primary varicella in
childhood and HSV recurrences in recent years.
Lastly, immunisation status against tetanus,
diphtheria, poliomyelitis, rubella, measles, mumps
and hepatitis B should be determined.
The possible presence should be actively
explored of various systemic and/or local symp-
toms of infection such as fever, sweating, chills,
weight loss, cough, dyspnoea, haemoptysis, chest
pain, cardiac murmur, dysuria and increased
frequency or urgency of urination. Dental status
needs to be evaluated and appropriate dental care
performed.
21
To reduce the risk of Candida
septicaemia, fungal infections such as oral and

vaginal candidosis or intertrigo should be identified
and appropriately treated. In connection with this,
an increased incidence of abnormal Papanicolaou
(Pap) smears and cervical dysplasia, probably due
to the enhancement of chronic cervical infection by
human papillomavirus (HPV), was recently
reported in women with IBD treated with immu-
nosuppressors.
22 23
Gynaecological examination and
cervical cancer screening should therefore be
systematically planned for women with IBD before
and during treatment with immunosuppressors
and TNF antagonists.
21–23
Patients with a history of
urinary tract infection or urinary symptoms should
have a urine test.
According to present recommendations, neutro-
phil and lymphocyte cell counts should be
performed before starting IBD treatment, and
regularly monitored thereafter. Immuno-suppres-
sive therapy may lower the neutrophil count,
14
possibly causing neutropenia, which is associated
with rapidly progressing life-threatening infec-
tions.
14
In neutropenic patients, any infections
must be urgently evaluated, and prompt empirical

antimicrobial therapy administered. A heightened
index of suspected infection is essential, because
symptoms of infection may be minimal in this
population, due to a blunted inflammatory
response. Long-term systemic corticosteroid ther-
apy (.1 month) induces dose-dependent lympho-
cyte depletion and, when combined with other
immunosuppressive agents, has a cumulative
adverse effect on lymphocytopenia. A lymphocyte
count ,600/mm
3
and, more specifically, a CD4 cell
count ,300/mm
3
are predictive of infection.
24 25
Monitoring CD4 cell counts in patients with a
total lymphocyte count (600/mm
3
may help to
identify those at high risk of certain infections such
Table 1 Opportunistic infections reported with immunosuppressant therapy in
inflammatory bowel disease
Factors that may predispose to
infectious complications in IBD
IBD (disease type and extension, disease duration)
Malnutrition
Immunosuppressive medications
Leucopenia from immunosuppressive medications
Surgery

Concomitant disease
Viral infections Virus Varicella zoster
Virus Herpes simplex
Cytomegalovirus
Epstein–Barr virus
Human papilloma virus
Bacterial infections Escherichia coli
Salmonella spp.
Streptococcus pneumoniae
Clostridium difficile
Staphylococcus spp.
Mycobacterium tuberculosis
Legionella pneumophila
Listeria monocytogenes
Mycobacterium avium spp. or xenopi
Nocardia
Parasite and fungal infections Candida spp.
Pneumocystis jiroveci (carinii)
Aspergillus spp.
Histoplasmosis
Cryptococcus spp.
Toxoplasma gondii*
Coccidioides immitis
Leishmania donovani
Blastomycoses
*Toxoplasma gondii has not been reported with immunosuppressant therapy in patients with IBD in the past, but
may potentially occur.
IBD, inflammatory bowel disease.
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as Pneumocystis jiroveci, and to guide chemoprophy-
laxis.
Hepatitis C virus (HCV), hepatitis B virus (HBV)
and HIV serologies are required before starting
immunosuppressive therapy. Fatal cases of infec-
tious mononucleosis and EBV-associated lym-
phoma have been reported in patients on AZA, 6-
MP and cyclosporin.
26–31
However, no reactivation
of latent EBV infection was detected in patients
with rheumatoid arthritis treated by infliximab.
32
Moreover, similar EBV viral loads have been found
in patients with Crohn’s disease, with or without
immunosuppressors, and in EBV-seropositive con-
trols.
33
Consequently, serological tests for EBV
should not be performed before starting immuno-
suppression. In patients without a clear history of
varicella immunisation, VZV titres should be
tested. Those with negative titres are at risk of
varicella and may require vaccination. Malignant
varicella infections have indeed been reported in
IBD patients on immunosuppressive therapy,
especially anti-TNF blockers.
34 35
CMV reactivation

has been described during MTX, AZA/6-MP and
infliximab therapy.
36 37
CMV serology is useful to
identify patients who have already been in contact
with the virus (ie, who have positive IgG CMV
titres), and are therefore at risk of CMV reactiva-
tion. However, subsequent CMV serology in such
cases is useless. In contrast, patients with negative
IgG CMV titres will be at risk of primary CMV
infection, and in that case serology may be useful
for diagnosis.
Every country has provided specific guidelines
for managing the risk of tuberculosis in patients
due to start treatment with a TNF antagonist.
38–44
Establishing a diagnosis of latent tuberculosis can
Systematic work-up to consider before immunomodulatory agents and/or tumour necrosis factor antagonist initiation
Detailed interview
c History of travel and/or living in tropical areas or countries with endemic infections
c History of bacterial infections,
c History of fungal infections: oral and vaginal candidosis, intertrigo
c Risk of latent or active tuberculosis:
– date of the last BCG vaccination
– history of contact with tuberculosis patients
– country of origin, prolonged stay in countries where tuberculosis is endemic
– history of latent or active tuberculosis and treatment given
c History of VZV infection
c History of herpes simplex virus infection: frequency and severity of recurrences
c Immunisation status for tetanus, diphtheria and poliomyelitis, and date of vaccination (was the patient vaccinated against these diseases

within the past 10 years?)
c Immunisation status for rubella, measles and mumps, and date of vaccination
c Immunisation status for hepatitis B and, in vaccinated patients, testing for the presence of hepatitis B antibodies
c Future plans to travel abroad to endemic areas (to consider whether the patient may need live virus vaccines such as the one for yellow
fever)
Clinical examination
c Identification of systemic and/or local possibly active infections
c Evaluation of dental status
c Gynaecological visit and pap smear
Laboratory tests
c Neutrophil count
c Lymphocyte count and, in the case of lymphopenia, CD4 lymphocyte count
c C-reactive protein
c Urine analysis in patients with a history of urinary tract infection, and urinary symptoms
c VZV serology in patients without a clear history of varicella immunisation
c CMV serology
c HCV, HBV and HIV serology*
– In patients with HCV or HBV chronic viral infection, alanine aminotransferase (ALT) assay, and determination of the stage of liver
fibrosis and of necroinflammatory activity
– In patients with HIV, CD4 cell count and viral load
c Eosinophil count, stool examination and strongyloidiasis serology for patients having lived in a tropical area
Other procedures
c Tuberculin skin test (according to each country’s specific guidelines)
c Pulmonary chest x ray
*Patients with a history of hepatitis B vaccination should be tested for the presence of hepatitis B antibodies.
CMV, cytomegalovirus; HBV, hepatitis B virus; HCV, hepatitis C virus; VZV varicella zoster virus.
Recent advances in clinical practice
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be a problem because purified protein derivative

(PPD) screening is difficult to interpret in patients
with previous BCG vaccination, and because of
frequent anergy in patients on concomitant
immunosuppressive therapy.
45
Two new immuno-
logical methods T-SPOT TB (Oxford Immunotec,
Abingdon, UK) and QuantiFERON TB Gold (QFT-
G; Cellestis, Carnegie, Australia) have become
available for the diagnosis of active and latent
tuberculosis.
45 46
Both are based on interferon c ex
vivo assays involving gene products in the
Mycobacterium tuberculosis genome that are absent
in BCG and most environmental mycobacteria. In
particular, these tests seem to be more specific than
the PPD test for the diagnosis of latent tuberculosis
in immunocompetent patients.
47
Nevertheless,
there are only limited data concerning their
sensitivity in immunocompromised patients and,
moreover, recent publications have pointed out a
higher frequency of indeterminate results with
these tests in immunocompromised patients.
48–50
Consequently, further clinical studies are needed to
establish the performance of these tests in IBD
patients.

Preventive strategies
Education
The education of patients is essential for the
prevention and treatment of opportunistic infec-
tions. Patients need to be taught about them, and
how to recognise early symptoms. Rapid 24 h
access to a clinical team is mandatory. Because
cases of listeriosis have been described during
treatment with TNF antagonists, recommenda-
tions have been made to avoid certain foods
implicated in listerosis transmission, such as those
made from unpasteurised milk, as well as processed
foods such as soft cheese, cold cuts of meat—that
is, delicatessen processed meats, hot dogs and
refrigerated paˆte´s.
51 52
Salmonella infections have
also been reported in patients taking TNF blockers.
Salmonella is harboured by raw or undercooked
eggs, poultry and meats. Advising patients to avoid
eating high-risk foods when they start treatment
with TNF antagonists may reduce the incidence of
emerging opportunistic infections.
51 52
Vaccinations (Table 2)
Vaccines are certainly underutilised in patients
with IBD. In the USA, in 2005, only 76 out of 169
patients with IBD (45%) remembered that they
had been immunised against tetanus within the
past 10 years, 47 (28%) reported regularly receiving

flu shots and 15 (9%) said they had had a
pneumococcal vaccine injection.
56
Adult patients
with IBD should undergo combined vaccination
against tetanus, diphtheria and inactivated polio-
myelitis every 10 years. There are no recommenda-
tions regarding vaccination against pertussis.
However, given the current resurgence of this
disease,
57
vaccination is now recommended in some
countries such as the USA in combination with
vaccination against tetanus, poliomyelitis and
diphtheria.
54
Patients with IBD should be vaccinated
against influenza annually. Vaccine for pneumococ-
cal disease with the 23-valent strain should be
administered every 5 years. IBD patients with no
detectable hepatitis B surface (HBs) antibodies
should be vaccinated against hepatitis B, using a
three-dose immunisation schedule. For patients with
no clear history of varicella, immunisation should be
tested and varicella vaccine considered for those who
are immunologically naı¨v e .
56
Nevertheless, doctors
should keep in mind that this vaccine is a live
attenuated virus vaccine and cannot be admini-

strated if the patient is on immunosuppressive
therapy, or if immunosuppressors should be
urgently initiated. When varicella vaccine is con-
sidered, a two-dose vaccination schedule (with at
least 4 weeks between doses) is recommended for
adults, because their seroconversion rates are lower
than those of children.
58
On account of the growing
concern regarding HPV infections in young women
with IBD,
22 23
a place may be accorded in the future
to the new recombinant HPV vaccine in this
population. However, no data are currently available
for immune response to such vaccination or for its
duration in immune-compromised patients in gen-
eral and in patients with IBD in particular.
55
Lastly,
one should check that all IBD patients were
immunised in childhood against rubella, measles
and mumps. When this is not the case, it is not yet
clear whether the combined vaccine against these
diseases needs to be administered to adults, given the
low risk of acquiring them in industrialised coun-
tries.
In addition to safety issues, the use of immuno-
suppressive agents, alone or in combination, may
affect the natural immune response to vaccine

immunisation, and therefore its efficacy. For
example, after vaccination against hepatitis B,
IBD patients treated with long-term immunosup-
pressive agents may exhibit a suboptimal serologi-
cal response.
62 63
Testing for serological immunity
should therefore be performed after hepatitis B
vaccination. In individuals with a poor response to
the usual vaccine doses (ie, 10–100 IU/ml HBs
antibodies) an additional booster dose can be
proposed.
64
Note, however, that this does not
necessarily apply to all vaccines. For example, in
patients on TNF blockers, low rates of seroconver-
sion after pneumococcal vaccination were not
confirmed in recent studies.
65
A satisfactory
response to influenza vaccine has been reported
in rheumatoid arthritis patients receiving immu-
nosuppressive agents.
66
Patients with IBD are very likely to need
immunosuppressive therapy in the course of their
disease. Given the advisability of performing
immunisation before starting treatment with
immunosuppressive agents, we believe that the
best time for immunisation is at diagnosis, unless

significant protein-caloric malnutrition is observed.
Chemoprophylaxis
In patients with suspected latent or active tuber-
culosis, anti-TNFa therapy should be postponed
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and antituberculosis treatment given, according to
local guidelines.
38–44
Data on P jiroveci prophylaxis
are scarce. In our opinion, based on data from other
diseases, it should be considered for two categories
of patients: (1) those on chronic treatment with
multiple immunosuppressants (at least two agents,
including steroids)
14 67
and (2) those with lympho-
penia (lymphocyte count of ,600/ml), and low
CD4+ T lymphocyte counts (,300/ml).
25 68
However, further studies are needed to identify
precisely those patients at risk for P jiroveci in
whom prophylaxis should be considered. When
prophylaxis is considered, trimethoprim-sulpha-
methoxazole (TMP-SMZ) is the prophylactic agent
of choice, with a single one-strength tablet daily
(80–400 mg), half a double-strength tablet daily
(160–800 mg) or a double-strength tablet three
times a week.

14
If TMP-SMZ is not tolerated,
alternative prophylactic regimens include dapsone,
aerosolised pentamidine, and atovaquone.
69 70
Patients who have frequent and/or severe
recurrences (.4) of HSV disease can be given daily
suppressive therapy with oral acyclovir or valaci-
clovir. Severe strongyloidiasis is a preventable life-
threatening disease (59% mortality has been
reported in case series) which may occur in
patients who have lived or travelled in endemic
countries during the 30 years before onset.
71
These
patients should be screened for hypereosinophilia
(which may be absent or minimal in 50% of cases),
and serological testing for Strongyloides species and
stool examination should be prescribed. Patients
with positive screening tests and/or unexplained
hypereosinophilia, as well as a history of travel or
residence indicative of exposure to Strongyloides
stercoralis, should be empirically treated, preferably
with ivermectin
72 73
before starting immunosup-
pressive therapy.
Treatment of underlying chronic viral infections
Although cases of fulminant hepatitis and hepatitis
B reactivation are rare, they have been reported in

patients with chronic hepatitis B infection (ie, the
presence of HBs antigens (HBsAgs), with or with-
out detectable viraemia) after starting treatment
with anti-TNF drugs,
74 75
corticosteroids, AZA,
MTX or cyclophosphamide.
76 77
In untreated
HBsAg-positive patients, several authors have
recommended starting lamivudine at least 3 weeks
before immunosuppressive therapy.
75 78
Other anti-
HBV nucleosides (ie, entecavir) or nucleotides (ie,
adefovir), alone or combined with lamivudine,
should in future be considered, because today
lamivudine monotherapy is no longer standard
care for chronic hepatitis B patients.
Immunosuppressive agents, especially TNF
antagonists, have traditionally been contraindicated
for HIV-infected patients. Thanks to the use of
highly active antiretroviral therapy (HAART), viral
replication can now be controlled, and immune
reconstitution induced. Immuno-suppressive agents
and TNF antagonists in particular could be used for
treated HIV-infected patients with high CD4+ T
lymphocyte cell counts (.500/ml) who have been
stabilised by antiretroviral therapy (ART).
79–81

In
untreated patients who need immunosuppressive
agents, earlier initiation of ART may be considered if
the CD4 cell count is lower than 500/ml.
DIAGNOSIS
Listing the specific symptoms of each opportunis-
tic infection is outside the scope of this article. The
purpose of this section is to help doctors to manage
specific clinical situations frequently encountered
in IBD patients on immunomodulatory agents
and/or TNF antagonists.
In immunocompromised patients, fever is the
principal and sometimes the only manifestation of
serious infection,
82
and has long been recognised to
constitute an urgent clinical problem, especially in
patients with severe neutropenia (ie, an absolute
neutrophil count ,500/mm
3
) and/or lymphocyto-
penia and low CD4 cell counts. The management
Table 2 Vaccines and recommendations for their use in immune compromised
inflammatory bowel disease patients*
53
Illness Type of vaccine
Recommendation in immune-
compromised patients
Diphteria{ Purified anatoxin Recommended
Tetanus{ Purified anatoxin Recommended

Poliomyelitis{ Oral route: live attenuated Contraindicated
Injectable: inactivated Recommended
Pertussis{ Acellular antigen Authorised
Hepatitis B Recombinant peptide Recommended
Pneumococcal disease 23-valent purified capsular
antigen
Recommended
7-valent conjugated capsular
antigen
Authorised (indicated for children only)
Influenza Inactivated virus Recommended
Human papillomavirus
infection1
Recombinant L1 protein Authorised
Measles, mumps and rubella Live attenuated Contraindicated
Chickenpox" Live attenuated Contraindicated
Hepatitis A** Inactivated virus Authorised
Yellow fever** Live attenuated Contraindicated
Cholera** Oral killed Use with caution
Oral live Contraindicated
Meningococcal disease** Conjugate polysaccharide C Authorised
Polysaccharide combined A+C Authorised
Polysaccharide combined
A+C+W+Y
Authorised
Typhoid** Vi capsular polysaccharide Authorised
Rabies** Cell culture-derived vaccine Authorised
Japanese encephalitis** Inactivated virus Authorised
Tick-borne encephalitis** Inactivated virus Use with caution
Haemophilus influenzae B

disease
Conjugated capsular
polyosidique antigen
Authorised
*Immune-compromised patients are defined as: (1) treatment with glucocorticoids: prednisone >20 mg/day
equivalent for 2 weeks or more, and within 3 months of stopping; (2) treatment with methotrexate; (3) treatment
with 6-mercaptopurine/azathioprine; treatment with infliximab or other tumour necrosis factor-blocking agent; (4)
significant protein-caloric malnutrition.
{Adult patients with inflammatory bowel diseaseshould undergo combined vaccination against tetanus, diphtheria
and poliomyelitis every 10 years.
{A booster dose could be administered at least once in adults, following each country’s recommendation on
pertussis vaccination, in combination with vaccination against tetanus, poliomyelitis and diphtheria.
54
1In young women with inflammatory bowel disease, human papilloma virus vaccination could be proposed; the
same schedule as that recommended for the general population should be used.
55
"Should be performed before starting treatment with immunosuppressive agents, the best time for immunisation
being at diagnosis.
**To prevent travel-related illnesses.
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of febrile patients must include a thorough
exploration of their history, and physical examina-
tion of the oral cavity, lungs, gastrointestinal tract,
nervous system, skin, soft tissues and indwelling
catheter sites. It is important to ascertain whether
there are any symptoms or signs that can help to
pinpoint the site of infection, although this may
often not be found. Repeated blood cultures should

be performed before starting empirical antibiother-
apy. In patients with a central venous catheter,
blood cultures, together with a quantitative assay,
may be performed on samples from this catheter.
83
Chest radiography and urine tests should also be
systematically performed. Measurement of C-
reactive protein (CRP) can be useful for differentia-
tion between infection and inflammatory symp-
toms due to IBD. Although CRP increases during
IBD flares,
84 85
it is usually higher in cases of
infection, especially bacterial infections.
86
In stu-
dies conducted in patients with connective tissue
diseases and rheumatic or autoimmune disorders,
serum procalcitonin (PCT) has exhibited good
sensitivity and specificity for early diagnosis of
systemic bacterial infections.
87–91
PCT has not been
formally tested in IBD patients with suspected
infections, and cannot be recommended in routine
practice. Nevertheless, given the promising interest
in this marker in other inflammatory diseases, its
use should be also explored in IBD patients.
Fever with mild respiratory tract symptoms
In febrile patients with shortness of breath, cough,

production of sputum, pleuritic chest pain and/or
focal chest signs, chest x ray should be performed
immediately and oxygen saturation determined.
For patients with normal chest x ray but abnormal
oxygen saturation rates, CT is needed. If the chest
x ray and/or CT indicate a diagnosis of pneumonia,
sputum and blood cultures should be performed, as
well as tests for atypical pathogens, including
Mycoplasma pneumoniae, Chlamydia sp., Coxiella
burnetii and Legionella sp., and more especially for
the Legionella urinary antigen. The possible pre-
sence of Tubercle bacillus should be explored in
gastric aspirates collected on three consecutive
days. Pneumococcal urinary antigen may be pre-
sent in patients with severe pneumonia. In severely
immunosuppressed patients, or after failure of a
first-line empirical antibiotic therapy, fibreoptic
bronchoscopia with bronchoalveolar lavage must
be envisaged, together with a search for specific
uncommon bacterial agents (i.e. mycobacteria and
nocardia), fungal agents (i.e. histoplasmosis, cryp-
tocococcosis and aspergillosis), and parasitic agents
(i.e. P jiroveci) (figs 1 and 2).
Fever with digestive symptoms
In IBD patients on immunosuppressive therapy,
the persistence or relapses of gastrointestinal tract
symptoms, especially diarrhoea, may be due to
exacerbation of the underlying IBD or enteric
infections.
92 93

In general, doctors should first
exclude a potential enteric infection before con-
sidering an exacerbation of the underlying IBD. In
this regard, stool cultures with examination for
parasites, and testing for Clostridium difficile toxin
92–
94
are necessary. Urgent colonoscopy with biopsies
may be considered, especially when stool micro-
biological analyses are negative. Herpesviridae
infections, HSV and more especially CMV
95
(fig 3), may be responsible for acute IBD attacks.
HSV can be diagnosed, either by isolating the virus
in a culture of the affected tissue, or by histo-
pathological examination of the affected tissue
showing nucleated ground-glass herpes inclusions
in the cells. For CMV, the best diagnostic method
is to confirm its presence by histological analy-
sis.
96 97
Biopsies should be performed on the ulcer
interface with the intact mucosa.
Histopathological examination based on standard
Figure 1 Chest x ray. Pneumocystis jiroveci pneumonia
following initiation of infliximab and azathioprine therapy
in a patient with Crohn’s disease. Note the opacity of the
lower right lobe. (From Seddik et al
67
with permission.)

Figure 2 Thoracic CT. Pneumocystis jiroveci pneumonia
following initiation of infliximab and azathioprine therapy
in a patient with Crohn’s disease. Note the bilateral
alveolar opacities in the two inferior and the middle lobes.
(From Seddik et al
67
with permission.)
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554 Gut 2008;57:549–558. doi:10.1136/gut.2006.114660
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staining reveals cytomegalic cells that often con-
tain an intranuclear inclusion, usually eccentrically
placed, surrounded by a clear halo. This, however,
represents late-stage infected cells.
Histopathological examination based on immu-
nostaining using monoclonal antibodies has been
shown to be more sensitive,
95 98 99
but may lead to
overestimation of the prevalence of CMV colitis.
96
The PCR for the detection of CMV in tissues is also
a highly sensitive technique, but it is not specific
for active CMV diagnosis. Serum CMV PCR and
PP65 antigenaemia, which quantifies the number
of blood leucocytes infected with CMV, are good
indicators of CMV dissemination. In particular,
they may be useful for monitoring the response to
antiviral therapy.
100

Serological tests are not usually
of much interest for the diagnosis of HSV or CMV,
because most adults are seropositive for IgG
antibodies.
101
Fever with nervous system symptoms
In patients on immunosuppressive agents, the
diagnosis of central nervous system (CNS) infec-
tions depends on clinical manifestations, the
acuteness or subacuteness of the clinical presenta-
tion, and an analysis of the type of immune defect
undermining the patient’s host defences. Patients
may be classified according to the following
manifestations: meningeal signs, mass lesions,
encephalopathy, seizures or a stroke-like presenta-
tion.
102
CNS infections by Aspergillus are charac-
terised either by mass lesions (eg, brain abscess) or
by cerebral infarcts, but rarely by meningitis. In
contrast, Cryptococcus neoformans usually presents
as subacute meningitis with fever and headache,
but not neck stiffness. Mass lesions tend to have a
subacute or chronic presentation, and meningitis
and encephalitis a more acute presentation. In
immunocompromised patients, agents that
weaken B lymphocyte function are liable to cause
meningitis with encapsulated bacterial pathogens.
In contrast, when T lymphocyte or macrophage
function is impaired, patients are liable to develop

infections caused by intracellular pathogens,
including fungi, particularly Aspergillus, Nocardia,
viruses such as HSV, JC virus, CMV or human
herpesvirus-6 (HHV-6), and parasites, particularly
Toxoplasma gondii. The involvement of other sites
may also be helpful for diagnosing opportunistic
infections. For example, combined lung and brain
mass involvement may be suggestive of nocardia
infection.
In patients with meningeal signs and/or ence-
phalopathy, a lumbar puncture should be per-
formed, with strain culture or serology of cerebral
spinal fluid (CSF). CSF cultures are especially
important for the detection of encapsulated
bacterial pathogens such as Streptococcus pneumo-
niae or Listeria monocytogenes, and for mycobacteria
detection. Special CSF staining for cryptococcosis
diagnosis should be performed, and PCRs of CSF
are necessary for CMV, HSV, VZV, T gondii and JC
virus detection. MRI should be performed for
patients with encephalopathy, and may be of great
value for diagnosing progressive multifocal leu-
coencephalopathy due to JC virus, as reported for
patients treated with natalizumab.
103
For patients
with mass CNS lesions, MRI should also be
performed and tissue biopsy may be considered.
In such cases the diagnosis should distinguish
between tuberculosis, lymphoma and toxoplasmo-

sis. When possible, lumbar puncture is desirable in
these patients. For example, a positive EBV-PCR in
the CSF may suggest CNS lymphoma.
104 105
However, because treatment response for toxo-
plasmosis occurs early, in patients with compatible
MRI of the brain empirical treatment against this
disease should be initiated. Early response to
treatment usually confirms toxoplasmosis diagno-
sis.
Fever with dermatological signs
In the case of febrile dermatological conditions,
bacterial infections, fungal infections, viral infec-
tions and non-infectious syndromes such as
eczemas, toxidermias and vasculitis can be sug-
gested.
106
Bacterial infections are attributable to
streptococci and staphylococci. They may be
benign, like folliculitis, or more severe, like
Figure 3 Endoscopic picture of severe colitis in the
sigmoid colon in a patient with Crohn’s disease. Biopsies
from this area revealed cytomegalovirus.
Prevention: practice points
c IBD patients have an increased risk of opportunistic infections (OIs).
c Immunosuppressors (IS) taken alone or in combination increase the risk of OI
occurrence.
c History of OIs should be reviewed before considering IS therapy.
c A thorough clinical work-up with an evaluation of dental status and
gynaecological exam are necessary before starting IS.

c A lymphocyte count ,600/mm
3
with a CD4 count ,300 mm
3
are predictive
of infection.
c Hepatitis C virus, hepatitis B virus and HIV serologies are required before
starting IS.
c In patients in whom IS and/or a TNF antagonist are planned to be started, local
guidelines for managing the risk of tuberculosis should be strictly followed.
c Education of patients is essential for the prevention of OIs.
c Vaccination status should be checked and recommended vaccines
administered before starting IS.
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erysipelas and cellulitis. Life-threatening infections
such as necrotising fasciitis have also been
described, especially in patients on TNF antago-
nists.
106–108
The diagnosis of these infections is
mainly based on clinical manifestations.
However, blood tests for local bacteria, and blood
cultures, are necessary before starting any empiri-
cal antibiotic therapy. Fungal infections are rarely
febrile, except for local cutaneous candidaemia.
Viral infections are caused by herpesviridae, espe-
cially HSV and VZV. The diagnosis of these
conditions is usually based solely on clinical

manifestations (fig 4). However, in the case of
atypical lesions, virological analysis can be per-
formed directly on a recent lesion by PCR and/or
immunofluorescence and/or viral culture.
Use of immunosuppressors and/or TNF antagonists
in patients with a history of opportunistic infection
In the absence of prospective data for patients
whose infections have been diagnosed, immuno-
suppressive therapy should be withdrawn and
steroids discontinued as quickly as possible.
When immunosuppressive therapy is considered
to have major clinical value, it should be resumed,
but exactly when is not clear. This probably
depends on the nature and severity of the infec-
tion, and in any case resumption can only be
considered once the infection is under control.
Multidisciplinary deliberations involving the gas-
troenterologist, infectious disease specialist and
specialist of the affected organ are probably
necessary to decide when to resume immunosup-
pressive therapy, on a case by case basis.
CONCLUSION
In view of the increasing use of immunosuppres-
sive agents and of more and more aggressive
therapies, patients with IBD and their doctors
should acquire far more knowledge and greater
awareness of opportunistic infections. The chal-
lenge to the medical practitioner rests not only on
the maximally efficient management of inflamma-
tory disease, but also on the ability to recognise

common and uncommon infections. The risk/
benefit profile of a particular drug or therapeutic
strategy should be considered for each category of
patients. In the absence of national and interna-
tional recommendations, we believe that the
organisation of a consensus conference on this
topic would help to standardise and optimise care.
Competing interests: None.
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