An increasing proportion of patients with inflammatory bowel disease (IBD) are treated with biological medications. The risk of infectious complications remains a significant concern in patients treated with biologics. Treatment with biological agents in IBD is generally safe, but there may be an increased risk of certain opportunistic infections. Some of the infectious risks are class specific, whereas others are a common concern for all biologics. A careful screening, surveillance, and immunization program, in accordance with available guidelines, is important to minimize any risk of infectious complications.
Key points
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Biological medications are generally safe in patients with inflammatory bowel disease.
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Biological medications may increase the risk of certain opportunistic infections.
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The increased risk of opportunistic infections can be minimized with screening, close surveillance, and adherence to immunization guidelines.
Introduction
The treatment of inflammatory bowel disease (IBD) has rapidly evolved over the last 15 years since the introduction of the first biological medication, a monoclonal anti–tumor necrosis factor α (anti-TNF-α) agent. Since then, several other anti-TNF-α agents and other monoclonal antibodies targeting interleukin 12 (IL-12), IL-23, and cellular adhesion molecule ligands α 4 integrin and α 4 β 7 integrin have been approved, or are near approval, for the treatment of IBD. Biological medications have shown improved clinical efficacy over older therapies and are being used earlier in the disease course, in an attempt to alter the natural history of IBD. Given the increasing use of these biological medications, it is important to review the safety profile of these agents. One of the main safety issues with biological agents is the risk of infectious complications, particularly the risk of opportunistic infections.
This article contains an overview of the infectious complications of biological medications in the treatment of IBD. The first section of this article assesses the risk of serious infections with individual biological agents, and the second section focuses on specific infectious diseases. The final section deals with screening and immunization for vaccine-preventable diseases. Throughout this article, serious infections are defined as those that lead to prolonged hospitalizations, result in significant disability, are opportunistic in nature, or are life threatening or fatal. Opportunistic infections include viral infections (eg, cytomegalovirus [CMV], Epstein-Barr virus, herpes simplex virus, and varicella zoster); bacterial infections (tuberculosis [TB] and streptococcal); and fungal infections (histoplasmosis, aspergillosis, candidiasis, and blastomycosis).
Introduction
The treatment of inflammatory bowel disease (IBD) has rapidly evolved over the last 15 years since the introduction of the first biological medication, a monoclonal anti–tumor necrosis factor α (anti-TNF-α) agent. Since then, several other anti-TNF-α agents and other monoclonal antibodies targeting interleukin 12 (IL-12), IL-23, and cellular adhesion molecule ligands α 4 integrin and α 4 β 7 integrin have been approved, or are near approval, for the treatment of IBD. Biological medications have shown improved clinical efficacy over older therapies and are being used earlier in the disease course, in an attempt to alter the natural history of IBD. Given the increasing use of these biological medications, it is important to review the safety profile of these agents. One of the main safety issues with biological agents is the risk of infectious complications, particularly the risk of opportunistic infections.
This article contains an overview of the infectious complications of biological medications in the treatment of IBD. The first section of this article assesses the risk of serious infections with individual biological agents, and the second section focuses on specific infectious diseases. The final section deals with screening and immunization for vaccine-preventable diseases. Throughout this article, serious infections are defined as those that lead to prolonged hospitalizations, result in significant disability, are opportunistic in nature, or are life threatening or fatal. Opportunistic infections include viral infections (eg, cytomegalovirus [CMV], Epstein-Barr virus, herpes simplex virus, and varicella zoster); bacterial infections (tuberculosis [TB] and streptococcal); and fungal infections (histoplasmosis, aspergillosis, candidiasis, and blastomycosis).
Risk of infections in patients with IBD
Several factors may predispose patients with IBD to infections. Although the most important predisposing factor is immunosuppressive therapy, additional factors include ongoing inflammatory disease, increasing age, malnutrition, increased exposure to nosocomial pathogens, and abdominal surgery.
Several classes of medications have been associated with systemic immunosuppression and possible increased infectious risk ( Table 1 ). A large case-control study showed that treatment with corticosteroids, azathioprine, or infliximab was associated with an odds ratio (OR) for infectious complications of 3.4, 3.1, and 4.4, respectively, and the combination of 2 or more of these agents increased the risk up to 14.5-fold. However, the increased risk of infectious complications with the combination of agents was driven mainly by the use of corticosteroids. A recent Cochrane review, with a meta-analysis of randomized controlled trials, controlled clinical trials, and open-label extension studies of biologics for several indications, reported an OR of 1.28 (95% confidence interval [CI], 1.09–1.50) for serious infections for patients on any biologic. However, a subgroup analysis of IBD trials only did not show a significantly increased risk of infection (OR, 1.28; 95% CI, 0.67–2.44). Biological medications are a heterogeneous group of agents, targeting different areas of the inflammatory cascade; the risk of opportunistic infections may be increased and seems to be biologic-class specific.
| Corticosteroids | ≥20 mg of prednisone for ≥2 wk |
| Immunomodulators | Thiopurines (azathioprine, 6-mercaptopurine) |
| Methotrexate | |
| Biologics | Anti-TNF-α (infliximab, adalimumab, certolizumab pegol, golimumab) |
| Leukocyte adhesion inhibitors (natalizumab, vedolizumab) | |
| IL-12/23 receptor antagonist (ustekinumab) |
Biological medications
Anti-TNF-α Monoclonal Antibodies
Several anti-TNF-α agents have been approved by the US Food and Drug Administration (FDA) for treatment of IBD. Infliximab (Janssen Biotech, Malvern, PA) and adalimumab (Humira, Abbvie, North Chicago, IL) have been approved for both Crohn disease (CD) and ulcerative colitis (UC). Certolizumab pegol (Cimzia, UCB, Smyrna, GA) is approved for use in only CD, and golimumab (Simponi, Janssen Biotech, Malvern, PA) was recently approved for patients with UC.
In addition to IBD, anti-TNF-α medications are approved for use in other inflammatory conditions, including rheumatoid arthritis (RA), psoriatic arthritis, ankylosing spondylitis, and psoriasis, and, therefore, abundant safety data are available. In RA, the association of anti-TNF-α medications with increased risk of infections has been clearly shown. A meta-analysis of 9 placebo-controlled trials of infliximab and adalimumab in RA yielded a pooled OR for serious infection of 2.01 (95% CI, 1.31–3.09). In a Cochrane review, a subgroup analysis stratified by type of medication reported an increased risk of serious infections with certolizumab (OR, 2.82; 95% CI, 1.27–6.29) and infliximab (OR, 1.97; 95% CI, 1.41–2.75), but not with other biologics. No increased risk was identified in patients with IBD, indicating that the risk may be specifically related to patients with RA, who are usually older and have more comorbid disease. Older patients with IBD (>65 years of age) on anti-TNF-α medications may have an increased risk of serious infections, compared with younger patients (11% vs 2.6%), further supporting the implication that increasing age is an independent risk factor. In a US-based large cohort study, initiation of an anti-TNF-α treatment was not associated with an increased risk of serious infection hospitalization rates in the first year for any indication, including in IBD (2323 patients, adjusted hazard ratio [HR], 1.10; 95% CI, 0.83–1.46). Highlighting the importance of glucocorticoid use, baseline use was associated with a dose-dependent increase in infection rate, and there was a trend toward an increased risk of infections in those patients who received concomitant anti-TNF-α with greater than 10 mg/d of glucocorticoids (adjusted HR, 1.38; 95% CI, 0.98–1.95).
More specific to IBD, a recent update to the Crohn’s TREAT (Therapy, Resource, Evaluation, and Assessment Tool) registry assessed 6723 patients with CD (3420 treated with infliximab) treated for a mean duration of 5.2 years. An increased risk of serious infections with corticosteroid therapy was again reported (HR, 1.57; 95% CI, 1.17–2.10). Infliximab was associated with an increased risk of serious infection (HR, 1.43; 95%, CI, 1.11–1.84), but the study did not evaluate whether this risk was modified by other risk factors, including disease severity and concomitant immunomodulator or corticosteroid therapy. Without this assessment, it is difficult to attribute the increased risk to anti-TNF-α therapy alone. In this cohort of patients, 4 cases of mycobacteria and 5 cases of systemic fungal infections were reported in patients treated with anti-TNF. No cases of mycobacteria and only 1 single fungal infection were reported in the patients not treated with anti-TNF-α medications.
In the largest single-center experience (Leuven, Belgium) to date, the long-term safety of anti-TNF-α agents was assessed in 1400 patients with CD. Half of the patients received infliximab, and they were followed for a median of approximately 5 years. The incidence rate of serious infections in the 2 groups was not significantly different (1.6 per 100 patient-years in the infliximab group versus 1.1 per 100 patient-years in the control group). In the largest population-based cohort study (British Columbia, Canada), the association between serious bacterial infections and infliximab and other immunosuppressive agents was assessed in 10,662 patients with IBD. The event rate of serious bacterial infection was 4.28 per 1000 patient-years (95% CI, 0.11–23.8), but this was not significantly increased compared with patients receiving corticosteroids or immunomodulators.
The risk of infectious complications with anti-TNF-α monotherapy in patients with IBD does not seem to be increased in terms of overall infections. However, these studies may not be large enough to detect rare opportunistic infections (see specific infection section).
IL-12/23 Monoclonal Antibody (Ustekinumab)
Ustekinumab (Stelara, Janssen Biotech, Malvern, PA) is a fully human IgG1κ monoclonal antibody that blocks the biological activity of IL-12 and IL-23 through their common p40 subunit. Ustekinumab is approved for the treatment of plaque psoriasis and has been extensively evaluated for this indication, with long-term (≤5 years) follow-up safety data available. The most common infectious complications reported include respiratory tract infections, mainly nasopharyngitis, but the rate was not different from the placebo group. There has been no reported increased risk of serious infections, including TB, compared with placebo.
Ustekinumab is being studied for the treatment of CD and is not yet approved, but it has been used off-label in patients in anti-TNF-refractory patients. In a randomized controlled trial of ustekinumab, in patients with anti-TNF-resistant CD, serious infections were reported in 5 patients receiving 6 mg of ustekinumab per kg body weight ( Clostridium difficile infection, viral gastroenteritis, urinary tract infection, anal abscess, and vaginal abscess), in 1 patient receiving 1 mg/kg (staphylococcal infection in a central catheter), and in 1 patient receiving placebo (anal abscess) during the induction phase. During the maintenance phase, there were no major adverse infectious events, including TB or other serious opportunistic infections.
Overall, there does not seem to be an increased risk of serious infections or TB reactivation with ustekinumab. However, the IL-12/23 pathways are important for host protection against mycobacterial infection and reactivation. Therefore, the decreased risk of TB reactivation with ustekinumab may be secondary to better screening for latent TB.
Cellular Adhesion Molecule α 4 Integrin Monoclonal Antibody (Natalizumab)
Natalizumab (Tysabri, Biogen Idec, Cambridge, MA and Elan Pharmaceuticals, South San Francisco, CA) is a humanized IgG4 monoclonal antibody against α 4 -integrin–mediated leukocyte migration. It was first approved by the FDA for use in multiple sclerosis (MS) but was withdrawn from the market in 2005 because of several reports of progressive multifocal leukoencephalopathy (PML) caused by John Cunningham (JC) virus reactivation. It was reapproved in 2008 under a specialized surveillance program (TOUCH [Tysabri Outreach: Unified Commitment to Health]). In 2008, natalizumab was also approved for CD, in patients with evidence of active inflammation who did not respond or could not tolerate anti-TNF-α therapy.
The largest available data on the risk of PML, in patients on natalizumab, comes from studies in MS. Among 99,571 patients with MS treated with natalizumab, 212 cases of PML were recorded (2.1 cases per 1000 patients). Patients who were positive for anti-JC virus antibodies, had taken immunosuppressive medications before the initiation of natalizumab therapy, and had received 25 to 48 months of natalizumab treatment had the highest estimated risk (incidence, 11.1 cases per 1000 patients; 95% CI, 8.3–14.5), whereas patients lacking antibodies to JC virus had a significantly lower risk of PML (0.09 cases or less per 1000 patients; 95% CI, 0–0.48).
Natalizumab is less frequently used in CD compared with MS. Reports of PML in patients with CD treated with natalizumab have been rare since its reintroduction in 2008. As of October 2011, 1 case had been reported in CD. In 2 recently published series, including a total of 113 patients with CD treated with natalizumab, no cases of PML occurred. The results of JC serology were not reported in these series. It is unclear whether the risk factors for PML reported for MS can be extrapolated to CD, but JC serology should be completed, and treatment should be reserved for seronegative patients. In addition, immunosuppressive medications should be discontinued, and the treatment duration should be limited, because almost all the cases of PML have occurred after longer durations of treatment. The value of monitoring anti-JC virus antibody titers in patients already on the treatment is unclear.
Natalizumab is not associated with a significant risk of other serious infections (excluding JC virus reactivation). In the induction and maintenance trial of natalizumab for CD, which included 905 patients in the induction phase and 339 in a 1-year maintenance phase, serious infections were rare. Influenza and influenzalike illness were significantly more frequent in the actively treated patients (12% vs 5%, P <.05). In addition, 1 case each of varicella pneumonia and CMV hepatitis were reported in the natalizumab group. In a recently published case series, 24% (13/54) to 37% (13/30) had experienced at least 1 serious infectious adverse event, including bacteremia, catheter-related infections, pneumonia, Clostridium difficile infection, fungal infection, or herpes zoster. It seems unlikely that natalizumab poses a specific risk of reactivation of latent TB; however, at least 2 cases of TB in patients with MS treated with natalizumab have been published.
Overall, the use of natalizumab in CD is limited by the risk of PML, and newer agents that are gut specific are likely favored (see later discussion).
Cellular Adhesion Molecule α 4 β 7 Integrin Monoclonal Antibody (Vedolizumab)
Vedolizumab (Entyvio, Takeda Pharmaceuticals, Cambridge, MA) is a humanized monoclonal antibody that exclusively targets the α 4 β 7 integrin, blocking the migration of the lymphocytes to the bowel. The mode of action of this agent is similar to that of natalizumab, but the lymphocyte trafficking inhibition of vedolizumab is gut specific. Vedolizumab has proved to be effective for induction and maintenance of remission in UC and, to a lesser extent, in CD. In the CD trial, the prevalence of serious infectious adverse effects between the treatment and placebo arms was not significantly different (5.5% and 3%, respectively). The most commonly reported infectious adverse effect was nasopharyngitis in both the treatment and placebo groups (12.3% and 8%). Single cases of sepsis, septic shock, and latent TB were reported among the 814 patients who received at least 1 dose of vedolizumab. In the UC trial, the incidence of serious infections in the active treatment arm and the placebo arm was similar (1.9% and 2.9%, respectively), and the most commonly reported adverse effect was again nasopharyngitis (12.9% vs 9.5%). In these trials, with 1186 patients exposed to vedolizumab, no cases of PML were reported. Given the gut-specific mechanism of action of vedolizumab, it is important to note that an increased risk of enteric infections was not reported. In an open-label extension study including 72 patients with CD and UC treated for 549 (± 191) days, serious infections were rare, with the most serious being 1 case of Salmonella enterica sepsis. The risk of serious infections does not seem to be increased with vedolizumab, and, given its gut selectivity, the risk of PML seems negligible.
Specific infections
Bacterial Infections
TB
There is an increased risk of reactivating TB with all currently used anti-TNF-α medications ( Table 2 ). Mycobacteria (and other granulomatous infections) are sequestered within granulomas, and because TNF-α is required for the continued maintenance of granuloma structure, there is an increased risk of reactivation with this class of medications. This risk is now incorporated as a black-box warning for all medications in this class. A Swedish study that included patients with RA reported that anti-TNF-α agents were associated with a 4-fold increase in the risk of TB, whereas in a US study including more than 10,000 patients with RA, the incidence of TB was 8-fold to 10-fold higher in patients treated with infliximab. In 70 cases of TB (patients with IBD and RA) reported under the MedWatch FDA program, TB was diagnosed shortly after the start of treatment (a median of 12 weeks or 3 infusions) and in areas of low prevalence, suggesting reactivation of a latent disease rather than a new onset. TB presented mainly as extrapulmonary disease (57%) and was reported to be associated with a mortality risk of up to 13%. For biologics other than TNF-α inhibitors, data on the risk of TB are limited.
| Bacterial | Clostridium difficile |
| Legionella pneumophila | |
| Nocardia species | |
| Salmonella species | |
| Streptococcus pneumoniae | |
| TB | |
| Viral | CMV |
| Epstein-Barr virus | |
| Hepatitis B (reactivation) | |
| Herpes simplex virus | |
| Human papillomavirus | |
| Influenza | |
| JC virus reactivation with natalizumab | |
| Fungal and parasitic infections | Aspergillosis |
| Candida species | |
| Coccidiomycosis | |
| Cryptococcosis | |
| Cryptosporidiosis | |
| Histoplasmosis |
Screening for latent TB
There is a consensus concerning the need for screening for latent TB infection (LTBI), albeit the optimal screening strategy still needs to be clarified. In all patients, the risk of LTBI should be assessed by medical history, physical examination, and tuberculin skin test (TST). A TST is considered to be positive when the induration is at least 5 mm in diameter. In addition, suspicious radiologic findings, such as calcifications, linear opacities, and pleural thickening, should also be considered suggestive of TB. In patients considered to have latent TB, chemoprophylaxis should be administered. The therapeutic guidelines may vary between geographic regions as a result of variations in drug susceptibility and prevalence of multidrug-resistant strains.
The common prophylactic regimen consists of oral isoniazid (INH) for 6 to 9 months. If there is a need for a prompt initiation of a biological treatment, INH should precede the biological treatment of at least 3 weeks, unless there is a truly urgent clinical need for biological therapy.
Even although pretreatment screening and prophylactic treatment reduce the risk of active TB significantly, patients treated with anti-TNF-α medications are still susceptible to TB. Patients with an initial negative LTBI screening may develop active TB, as well as patients who have been treated with a prophylactic treatment.
Screening for LTBI with TST has multiple limitations, such as a high rate of interobserver variability, false positivity secondary to BCG vaccination, and repeated TST testing. Moreover, the sensitivity of TST is low in immune-compromised patients or patients receiving immunosuppressive therapy, especially systemic corticosteroids.
In 2008, an additional screening modality was introduced into clinical practice. Interferon γ release assays (IGRA) (QuantiFERON Gold In-Tube, QFT-GIT, Cellestis, Carnegie, VIC, Australia and T-SPOT.TB, Oxford Immunotec, Abingdon, UK) measure interferon γ response to Mycobacterium tuberculosis proteins. This assay does not require recurrent visits and provides a quantitative readout not susceptible to operator influence. The specificity is significantly better compared with TST, and the sensitivity may be improved in immunosuppressed patients. The concordance between the TST and QFT-GIT was found to be only moderate (K = 0.4152, P = .0041) in a large American cohort with IBD. Immunomodulator or anti-TNF-α treatments do not seem to significantly interfere with the IGRA results; however, systemic corticosteroid treatment, with doses of prednisone of 10 mg/d or greater, severely depress the accuracy of both IGRA and TST. Because IGRA testing is associated with higher costs, it is unclear whether it should be routinely incorporated into the screening strategy or whether it should be offered as an alternative or a complementary test for TST. Given the increased risk of false-negative results with both tests, in the context of immunosuppression, it is recommended to test for latent TB early in the course of disease, before the need for systemic immunosuppressive therapy arises.
Other granulomatous infections
Listeria monocytogenes
Listeria monocytogenes is a gram-positive food-borne pathogen that is resistant to most cooking techniques. In immune-competent individuals, it frequently leads to mild gastroenteritis, but in immunosuppressed individuals, the infection may result in sepsis, as well as meningoencephalitis, arthritis, and cholecystitis. L monocytogenes infection is associated with a 30% risk of spontaneous abortion in pregnant patients. More than 40 cases of listeriosis (15 with IBD) associated with anti-TNF-α therapy have been published. Most patients were older than 50 years and were treated with at least 2 immunosuppressive medications. Prevention measures include avoidance of unpasteurized milk or cheese, uncooked meat, and raw vegetables, especially during pregnancy. Anti-TNF-α treatment should be discontinued as soon as suspicion of infection arises.
Nocardiosis
Nocardia species may lead to severe systemic infection, associated with significant mortality and morbidity, usually from central nervous system involvement. At least 7 cases of nocardiosis (4 with IBD) in anti-TNF-treated patients have been described in the literature, with most receiving concomitant immunosuppressive therapy at the time of diagnosis.
Clostridium difficile
IBD is an independent risk factor for development of Clostridium difficile –associated diarrhea (CDAD), with a risk ratio of 2.9 compared with control individuals without IBD. The incidence of CDAD is steadily increasing in patients with IBD. Immunosuppressive therapy is an established risk factor for development of CDAD; however, it is not clear whether biologics pose any specific risk. In a large cohort of more than 10,000 patients with IBD, infliximab was not associated with a risk of CDAD, whereas corticosteroid-treated patients had at least a 3-fold increase in the incidence of CDAD. Continued immunosuppressive treatment in patients with IBD with CDAD seems to be associated with an increased risk of colectomy.
Additional bacterial infections
Several bacterial infections, such as Streptococcus pneumoniae , Legionella pneumophila , and Salmonella species, pose an increased risk to patients with IBD on immunosuppressive therapy, but there are no specific data in patients on biological agents.
Fungal Infections
Pneumocystis carinii
Immunosuppression is the main risk factor associated with Pneumocystis carinii pneumonia (PCP) infection. As of 2009, at least 119 cases of PCP in patients on biologics had been published. PCP prophylaxis should be considered in all patients receiving triple immunosuppression (corticosteroids, immunomodulators, and biological therapy).
Granulomatous fungal infections
Anti-TNF-α therapy is associated with an increased risk of granulomatous fungal infections, such as histoplasmosis and coccidioidomycosis. In 2008, a black-box FDA warning was issued on the TNF-α blockers regarding this risk. Up to 2008, more than 240 cases of histoplasmosis in patients on anti-TNFs were published. Most of the afflicted patients were living in the endemic areas and were receiving concomitant immunosuppression.
Other fungal infections
More than 20 cases of Cryptococcus neoformans infection in patients treated with anti-TNF-α medications for various indications have been published, mostly in patients on concomitant immunosuppression. Several cases of aspergillosis, systemic candidiasis, and cryptococcal and cryptosporidial infections have been reported in anti-TNF-treated patients as well.
Viral Infections
Hepatitis B
The prevalence of hepatitis B virus (HBV) in patients with IBD is similar to that of the general population. Chronic immunosuppressive therapy may lead to reactivation of latent hepatitis B infection, potentially resulting in fulminant hepatitis. Although more common in patients receiving systemic chemotherapy, cases of reactivation of the virus under TNF-α inhibitors have been published. Screening for HBV should be undertaken on diagnosis, preferably before the need for immunosuppressive therapy arises. Cases of reactivation have been described not only in hepatitis B surface antigen (HBsAg)-positive patients but also in HBsAg-negative/anti-HBC (hepatitis B core antigen)-positive patients. In anti-TNF-α patients, reactivation has been described as early as after the second infusion and as late as 2 years from the start of therapy. Patients receiving concomitant immunosuppressives or corticosteroids have the highest risk of reactivation. Hepatitis B reactivation is associated with significant morbidity and mortality. In the largest case series to date, two-thirds of the patients with HBV reactivation (HBsAg-positive patients) developed hepatic failure. HBV chemoprophylaxis is recommended in HBsAg-positive patients receiving immunomodulatory therapy; however, no clear recommendation exists in regards to anti-HBC-positive patients. In chronic HBsAg-positive carriers, antiviral prophylaxis with nucleotide/nucleoside analogues is recommended before administering immunosuppressive agents. Patients with high baseline HBV DNA levels (>2000 IU/mL) should continue antiviral treatment until end points applicable to nonimmunosuppressed patients are reached. If immunosuppressive therapy is expected to last more than 1 year, nucleotide/nucleoside analogues with a lower propensity than lamivudine for generating drug-resistant mutations may be preferred. Preferably, a hepatologist should be involved in the initiation and monitoring of antiviral therapy in these patients. All seronegative (negative or low-titer HBsAb) patients should be vaccinated at diagnosis; however, this occurs in less than half of the patients. It is safe to administer the standard vaccination protocol to patients with IBD on immunosuppressive medications, but the response may be significantly reduced, and an intensified vaccination protocol may be required. Postvaccination HBsAb titers should be monitored, and, if nonprotective (<10 mIU/mL), a booster dose or revaccination should be administered.
Hepatitis C
The prevalence of hepatitis C virus (HCV) in patients with IBD is similar to that of the general population. There are no data to suggest that biologics are associated with reactivation or exacerbation of the course of HCV. Anti-TNF-α medications are generally considered safe in patients with HCV.
CMV
CMV infection is common in the healthy adult population. Reported seropositivity rates for CMV-IgG range within 87% to 100%, depending on the age and geographic location. In immunocompromised patients, CMV infection or reactivation may lead to a systemic disease or end-organ involvement, manifesting as severe pneumonitis, hepatitis, or colitis. In patients with acute severe UC, CMV has been reported to be present in the colonic tissue of 21% to 34% of patients, and it is present in 33% to 36% of steroid-refractory cases. The clinical significance of detecting CMV in patients with UC remains debatable. Many of these CMV biopsy-positive patients have been treated with anti-TNF-α medications without obvious complication, but it is still unclear whether these agents pose any specific risk in the context of an active CMV infection.
Varicella zoster virus
Varicella zoster virus (VZV) can be associated with a significant morbidity and mortality in immunocompromised patients. Severe multidermatomal shingles and disseminated varicella infection with end-organ involvement (meningoencephalitis, pneumonitis, hepatitis, colitis) have been reported. However, the increased risk of VZV reactivation is not specific only to biologics. In a recent large cohort study, including more than 33,000 patients treated with anti-TNF-α medications and 27,000 control individuals treated with nonbiological anti-inflammatory medications for various indications (3850 patients with IBD), the risk of herpes zoster was similar in patients with IBD treated with anti-TNF-α agents and with thiopurines. VZV-related complications can be easily prevented by vaccination. A live attenuated VZV vaccine has been associated with a 61% reduction in the burden of VZV-related illness in children, and a 51% reduction in the risk of shingles. Because this vaccine should not be administered after onset of systemic immunosuppression, VZV-IgG status should be checked as early as possible in the course of the disease, with prompt vaccination of the seronegative patients.
Human immunodeficiency virus
Several case series and case reports describing patients who are infected with human immunodeficiency virus (HIV) and were treated with anti-TNF-α medications for various indications have been published. There is no evidence of an adverse impact with these agents on the course of HIV.
Human papillomavirus
There is an increased incidence of human papillomavirus (HPV)-associated warts or condylomata in patients taking immunosuppressants; however, no data suggesting a specific association with biologics are available. Routine prophylactic immunization starting at 9 to 11 years of age is now recommended routinely. Because this is not a live vaccine, immunomodulator or anti-TNF-α therapy is not a contraindication for vaccination. Current or previous infection with HPV is not a contraindication for initiation of immunomodulator or biological therapy.
Related posts:
Anti–Tumor Necrosis Factor-α Monotherapy Versus Combination Therapy with an Immunomodulator in IBD
Update on Anti-Tumor Necrosis Factor Agents in Crohn Disease
Lymphocyte Homing Antagonists in the Treatment of Inflammatory Bowel Diseases
Biologics of IBD
The Use of Biologic Agents in Pregnancy and Breastfeeding
Update on Janus Kinase Antagonists in Inflammatory Bowel Disease
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