Treatment of pediatric inflammatory bowel disease (IBD) has evolved considerably and increasingly includes the use of biologic therapies such as tumor necrosis factor α inhibitors (anti-TNFα). In patients with IBD, anti-TNFα therapies such as infliximab and adalimumab are effective in inducing and maintaining remission in patients with moderate to severe Crohn disease (CD) including fistulizing, perianal, and steroid-unresponsive disease and in patients with steroid-dependent, severe, or refractory ulcerative colitis (UC). The goals of therapy with anti-TNFα are mucosal healing and prevention of long-term end-organ damage and delay in growth and development.
The benefits of immunosuppressive treatment should be weighed against potential risks, including infectious complications, and adverse outcomes resulting from withholding biologic therapy for IBD treatment and progression of underlying disease. Factors predisposing patients with IBD to potential infectious complications include severity of underlying IBD, medical comorbidities, malnutrition, leukopenia, surgery, and immunosuppressive medications. Infections complicate any immunosuppressive therapy for IBD, most frequently with glucocorticoids but also other anti-inflammatory medications, anti-metabolites, alkylating agents, and anti-TNFα (1). This risk/benefit analysis should be assessed in each individual patient before starting anti-TNFα therapy; this is particularly important in patients with a history of chronic, recurrent, or opportunistic infections, known exposure to tuberculosis, identifiable risk factors, or with underlying comorbid conditions that may further predispose them to infections.
This clinical report will focus on available infection data associated with the use of infliximab and adalimumab in pediatric patients with IBD. The appraisal of the published literature was divided by infection type among the infectious disease (ID) group members who performed independent systematic reviews of both the adult and pediatric literature using the appropriate keywords in the PubMed database. A Delphi technique was then applied, resulting in an iterative process until full consensus was achieved among the ID physicians who wrote and reviewed each section. The draft report was then reviewed by the pediatric gastroenterology group members, and overall consensus was obtained. There was insufficient pediatric specific data to provide a grading of recommendations assessment, development, and evaluation (GRADE) system regarding the quality of the evidence and strength of recommendation.
Tumor necrosis factor-α (TNF-α) is central to macrophage and phagosome activation, recruitment of neutrophils and macrophages, differentiation of monocytes, formation and maintenance of granulomas, and modulation of the inflammatory process. It is proposed that anti-TNFα agents block both soluble and cell-associated TNF-α forward signaling and induce reverse signaling leading to cell activation, apoptosis, or cytokine suppression (2). The use of anti-TNFα can reduce IBD inflammation, while at the same time inhibiting the normal inflammatory responses against infectious agents, thus rendering the IBD patient immunosuppressed. Data from adults have linked targeted blockade of TNF-α to infections caused by bacteria, mycobacteria, fungi, viruses, and parasites. In particular, infections caused by pathogens that are intracellular or dependent on macrophages and granuloma formation for killing occur at higher rates in adults treated with anti-TNFα agents compared with adults treated with other immunosuppressive medications. A comprehensive review of infections described with anti-TNFα use across distinct populations is beyond the scope of this clinical report and has been published elsewhere (3–5). In a systematic review and meta-analysis of randomized controlled clinical trials in adults receiving infliximab or adalimumab therapy for rheumatoid arthritis, the pooled odds ratio for serious infection was 2.0 (95% CI 1.3–3.1), with a number needed to harm of 59 (95% CI 39–125); infections most commonly occurred within 3 to 6 months of starting anti-TNFα therapy (6). Similarly, a recent meta-analysis of randomized controlled trials performed in adults with IBD, who received any anti-TNFα compared with placebo, found the relative risk (RR) of developing an opportunistic infection to be significantly higher with anti-TNFα use (RR 2.05, 95% CI 1.1–3.85) (7). In summary, these studies indicate that therapy with anti-TNFα therapy independently increases the risk of infection.
The comparison of serious infections in patients receiving adalimumab for both rheumatologic and gastrointestinal (GI) indications noted infection rates of 1.4 to 6.6 events/100 person-years in adults versus 2 events/100 person-years in children (8). It is important to highlight some differences between pediatric and adult patients with IBD that could theoretically predispose the pediatric patient to infections when receiving anti-TNFα therapy. Compared with their adult counterparts, children with IBD have more extensive GI disease, are more likely to require systemic steroids, and may have a more severe disease course that leads to earlier development of complications (9). Robust pediatric specific data, however, are lacking.
Whether there is an absolute increased risk of infection, in particular of serious infections in children and adolescents with IBD, receiving anti-TNFα therapies is unknown. Lack of uniformity in case definitions and severity of infections, differences in study design, concomitant use of immunosuppressive therapy, and other comorbidities limit comparisons across studies. A serious (or severe) infection has been defined in most studies as an infection that requires hospitalization or parenteral antimicrobial therapy. Given the lack of large population-based cohort studies, reports of infections in children receiving anti-TNFα therapies have been derived mainly from pharmacoepidemiological and registry studies evaluating the safety and efficacy of infliximab (REACH, DEVELOP) and adalimumab (IMAgINE, RESEAT) and are summarized in Table 1(10–13). Case reports provide additional sources of pediatric data suggesting an association of anti-TNFα therapy and infection. A recent meta-analysis of 65 pediatric studies reported that the rate of serious infections among pediatric patients with IBD treated with anti-TNFα was significantly lower than adult rates (14). Of the 5528 children included, the rate of serious infections in pediatric patients with IBD receiving anti-TNFα therapy (352/10,000 patient-years of follow-up [PYF]) was similar to the expected rates in pediatric patients receiving immunomodulator monotherapy, but rates were significantly lower than the expected rate for children receiving corticosteroids (730/10,000 PYF). A systematic literature review of infections in children with IBD receiving anti-TNFα therapies reported serious infections occurring infrequently (incidence of 0%–10%) but were quite varied, including reports of disseminated varicella, Listeria meningitis, histoplasmosis, invasive pulmonary aspergillosis, systemic nontuberculous mycobacterial (NTM) infection, disseminated cytomegalovirus (CMV), bacterial sepsis, and Pneumocystis jirovecii pneumonia (15). Most frequently, children receiving anti-TNFα therapies most frequently had mild, viral upper respiratory infections (incidences ranging from 3%–77%).
Prevention is the foundation of pediatric medical practice. The National European and Canadian pediatric (16,17) and adult position statements (18,19) provide some ID screening guidance, summarized in supplementary Table 1 (http://links.lww.com/MPG/A637). In general, the adult literature, both in rheumatology and gastroenterology patients, recommends testing for Mycobacterium tuberculosis, hepatitis B, hepatitis C, and human immunodeficiency virus (HIV) before initiating anti-TNFα (19–21). There are, however, no US consensus statements to guide practices for the screening, monitoring, or prevention of infections before initiating anti-TNFα therapies in pediatric patients with IBD. This clinical report is a consensus document that resulted from reviews performed by pediatric ID and gastroenterology physicians of the relevant published literature regarding infections in adult and pediatric patients with IBD, receiving anti-TNFα therapies. Until additional pediatric data are available to inform evidence-based recommendations for children with IBD, this consensus document provides health care professionals with information regarding the risk of serious infections and guidance for prevention, surveillance, and diagnosis of infections in pediatric patients with IBD who are or will be receiving anti-TNFα therapies.
In general, any pediatric patient with a new IBD diagnosis is a potential candidate for anti-TNFα therapy. Therefore, we recommend that screening evaluations with risk factor assessment be performed at the initial IBD diagnosis visit and before any immunosuppressive therapies are initiated. Heightened awareness, vigilant surveillance, routine and systematic preventive screening and counseling, and a high index of suspicion for infection leading to prompt diagnosis and institution of effective therapy are imperative for optimal outcomes in pediatric patients with IBD.
Summary of Findings Regarding Infection and anti-TNFα Therapy in Adult and Pediatric Patients With IBD
- Underlying IBD activity and severity are independently associated with the risk of a serious infection in adults (22).
- Patients receiving corticosteroid doses of ≥2 mg · kg−1 · day−1 or ≥20 mg/day of prednisone or equivalent for ≥2 weeks, and higher doses of methotrexate (>0.4 mg/kg/week), azathioprine (>3 mg/kg/day), 6-mercaptopurine (>1.5 mg/kg/day), or anti-TNFα therapy are considered to have a high level of immunosuppression (23). There is a trend to increased numbers of infections in infliximab-treated patients and in patients who received anti-TNFα therapy concomitantly with other immunosuppressive agents (most commonly methotrexate or corticosteroids) (12,24,25). For patients receiving ≥2 immunomodulatory medications, the risk of infection is almost 15-fold higher (OR 14.5, 95% CI 4.9–43) (24). The risk of infection may also vary with the type and duration of exposure to anti-TNFα therapy, with higher risk occurring shortly after starting anti-TNFα therapy (within 3–6 months).
- Granulomatous infections caused by bacteria, mycobacteria, and fungi are the most frequently described infections in patients receiving anti-TNFα therapies. A total of 556 granulomatous infections were reported to the Food and Drug Administration (FDA) among 346,000 patients with distinct underlying conditions (eg, rheumatologic, IBD) treated with anti-TNFα therapy from June 1998 to September 2002, totaling rates of 239/100,000 patients treated with infliximab (26).More than 70% of these granulomatous infections occurred within 3 to 6 months of starting infliximab therapy, suggesting the possibility of reactivation of latent infection.M tuberculosis was the most frequent granulomatous infection reported in 54/100,000 infliximab-treated patients. Infections caused by NTM were reported with 10-fold lower frequency than M tuberculosis infections.Fungal infections were frequent, reported in 10 to 37/100,000 infliximab-treated patients and included histoplasmosis, candidiasis, aspergillosis, and coccidioidomycosis (26). Infections with dimorphic fungi should be considered in the differential diagnosis of pneumonia in patients receiving anti-TNFα therapies.Other granulomatous infections reported included those due to Salmonella, Listeria, Brucella, and Bartonella spp.
- In general, anti-TNFα therapy should be discontinued during any severe infection. Uniform recommendations regarding resumption of anti-TNFα therapy after infections cannot be made. If and when anti-TNFα therapy can be restarted following the resolution of an infection depends on multiple factors (eg, host factors, pathogen characteristics, and severity of infection and underlying disease); each situation should be evaluated case by case. When available, data from published reports are included in each section.
- Updates regarding postmarket drug safety communications from the United States (US) FDA for providers can be found at: http://http://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm109340.htm.
Invasive and Unusual Infections in Patients With IBD Receiving TNF-α Inhibitors
In the following sections, relevant information regarding infections occurring in patients with IBD who are receiving anti-TNFα inhibitors is presented and summarized in Table 2.
IBD independently predisposes patients to bacterial infections. It is important to obtain a detailed history from the patient regarding previous bacterial infections. Perianal abscesses are a known complication of ongoing GI inflammation in patients with IBD. Data concerning an increased risk of postoperative bacterial infections after elective IBD surgery in patients receiving anti-TNFα therapies are inconclusive (27,28). Corticosteroid therapy carries a greater risk of bacterial infections in patients with IBD compared with anti-TNFα therapies. Sporadic cases of bacteremia and sepsis with Staphylococcus aureus, coagulase-negative staphylococci, and Escherichia coli, at times associated with the use of central venous catheters, however, have been described in pediatric patients with IBD receiving anti-TNFα therapy (15). Severe neutropenia associated with anti-TNFα therapy has been reported and is an additional risk factor for invasive bacterial and fungal infections. Data regarding overall increased risk of bacterial infections among patients with IBD who receive anti-TNFα therapies are conflicting, though there is an increased incidence of infections with intracellular bacteria in other groups of patients receiving anti-TNFα (6,29,30). It is recommended that the anti-TNFα therapy not be administered during severe bacterial infections requiring antibiotic therapy. TNF-α is integral in the T-cell–mediated immune destruction of intracellular pathogens; thus infections with specific intracellular bacteria are reviewed herein.
Bartonella spp. and Brucella spp.
Infections with Bartonella and Brucella spp. are potential zoonotic granulomatous infections that have been reported in adult patients receiving anti-TNFα therapies. Bartonella spp. and Brucella spp. infection rates of <1/100,000 patients have been associated with infliximab use (26). There have been no published cases of bartonellosis or brucellosis in children with IBD receiving anti-TNFα therapies.
Cats are a natural reservoir for Bartonella henselae; contact with kittens (that are asymptomatic but more likely to have bacteremia) is associated with human infection resulting from inoculation of the bacteria through a scratch or bite, or via hands contaminated by flea feces touching an open wound or mucosal surface (eg, conjunctiva). Brucellosis is a zoonotic disease of wild and domestic animals transmissible to humans via exposure to animal tissues and infected fluids. Transmission can occur through inoculation of mucous membranes, cuts in the skin, inhalation of contaminated aerosols, or ingestion of infected foods (most commonly unpasteurized dairy products).
Bartonella infections, or cat-scratch disease, may present with fever and regional lymphadenopathy and up to 25% may spread hematogenously to cause disseminated disease including granulomatous lesions in the liver, spleen, and bones, meningoencephalitis, neuroretinitis, and endocarditis.
Clinical manifestations of Brucella spp. infections are nonspecific including fever, malaise, night sweats, and headache. In children, abdominal pain and arthralgia are common and may relate to physical examination findings of hepatosplenomegaly and arthritis. Brucellosis may also present with fever and pancytopenia. In immunocompromised patients, prolonged fevers without a source and complications such as osteomyelitis, endocarditis, and meningitis may occur.
B henselae is fastidious and thus recovery in routine bacterial cultures is difficult. Serologic testing and direct testing of tissue (lymph node) or body fluids (cerebrospinal fluid [CSF], pleural) by staining and Bartonella polymerase chain reaction (PCR) are useful for diagnosis. Brucella spp. can be isolated in culture of blood, bone marrow, or sterile tissue; however, the microbiology laboratory should be contacted and made aware of the clinical suspicion for optimal processing. Serologic testing (serum agglutination test) is also used with a 4-fold rise in antibody titers obtained 2 to 4 weeks apart confirming the diagnosis. Caution when interpreting serologic results in immunocompromised hosts is warranted because the ability to mount an antibody response may be attenuated.
Screening Before Anti-TNFα
No data to support routine laboratory screening. Consider screening for risk factors (eg, exposure to animals or consumption of unpasteurized dairy products).
Prevention/Isolation/Control Measures: Standard Precautions
Screening for a history of animal exposure before initiating immunosuppressive therapy is encouraged, with appropriate safe living guidance provided. Immunocompromised people should avoid contact with cats that scratch or bite, young cats (<12 months), and all strays. In addition, all of the household pets should receive appropriate veterinary care, be up-to-date with vaccinations, and receive appropriate flea control measures. Proper hand hygiene after exposure to animals and thoroughly washing any scratches or bites promptly with soap and water is imperative. Pasteurization of dairy products for consumption is recommended.
In September 2011, the US FDA added a boxed warning based on 80 adult cases of Legionella infection in patients receiving anti-TNFα therapies reported to the FDA's Adverse Events Reporting System from 1999 to 2010, including 14 deaths (31). Most patients presented with pneumonia and had been receiving anti-TNFα therapies for a median of 10.4 months (range 1–73). Most important, the majority of patients were also receiving concomitant methotrexate, corticosteroids, or both. A second episode of confirmed legionellosis has been reported following reintroduction of anti-TNFα therapy; thus, caution is warranted if immunosuppressive therapies are resumed (32). Pediatric legionellosis has been reported in immunocompromised patients, those with underlying pulmonary disease, neonates, and children receiving systemic corticosteroids. No cases of legionellosis in children with IBD receiving anti-TNFα therapies were found in the literature.
Infection is acquired through the inhalation of aerosolized water (shower, aerosol producing devices, and humidifiers) contaminated most commonly with L pneumophila in hospital, home, and public settings. Methods of treatment of municipal water supplies affect the risk of disease within a geographic area. In the US, proven cases are reportable to local and state health departments.
Legionellosis can manifest as Legionnaires disease or Pontiac fever. Legionnaires disease is characterized by high fever, GI symptoms, and mild-to-severe pneumonia. Hyponatremia and failure to respond to β-lactam antibiotics in a patient with pneumonia and diarrhea should increase the suspicion for Legionella infection. Complications include hepatic and renal dysfunction, and hematologic derangements (thrombocytopenia, DIC). Extrapulmonary disease with Legionella spp. is rare but occurs in immunocompromised patients and most commonly in a health care environment. Suppurative arthritis, sinusitis, and endocarditis have been reported and have higher mortality rates. Pontiac fever is a milder, self-limited influenza-like illness without lower respiratory disease.
A combination of bacterial culture and Legionella antigen detection is optimal for diagnosis. Isolation of L pneumophila from respiratory tract specimens, lung tissue or fluid, or from a normally sterile site confirms Legionella infection. Detection of urinary Legionella antigen is sensitive and highly specific for L pneumophila serotype 1 but will not detect other species and serotypes that can account for up to 10% of infections. Serology is available but may not be useful in immunocompromised patients. Chest X-ray findings are nonspecific, including unilobar airspace disease, interstitial infiltrates, and pleural effusions. In immunocompromised patients, nodular infiltrates may be seen and may cavitate.
Screening Before Anti-TNFα
No data to support routine laboratory screening.
Prevention/Isolation/Control Measures: Standard Precautions
Avoidance of known exposures to water sources that may not be completely treated according to recommended standards (eg, monochloramine treatment of municipal water supplies), especially in pediatric patients with IBD receiving anti-TNFα therapy and corticosteroids or with underlying lung disease, is prudent. Use of sterile water is recommended for the filling and terminal rinsing of nebulization devices used by immunocompromised individuals (33).
L monocytogenes is an intracellular bacterium for which TNF-α has a crucial role in host defense. In September 2011, the FDA released a drug safety communication updating the boxed warnings for the anti-TNFα class of biologics to include the risk of infections with Listeria species (spp.) (31). The report summarized the cases of serious infections due to L monocytogenes, including 7 deaths. Notably, the majority of patients were receiving combination therapy with anti-TNFα and another immunosuppressive drug (corticosteroids or methotrexate, most frequently). Cases of Listeria bacteremia and meningitis have been reported in pediatric patients with IBD (34–36). More important and similar to their adult counterparts, listeriosis occurred while receiving corticosteroid therapy and in 2 children, soon (3–7 days) after the addition of infliximab.
Listeriosis is a relatively uncommon infection that can cause severe disease in immunocompromised hosts. Infection is caused by the intracellular Gram-positive diphtheroid L monocytogenes and is most commonly transmitted via ingestion of contaminated food products by immunocompetent and immunocompromised hosts (37). Foods implicated in transmission include soft cheeses, unpasteurized milk and milk products, raw produce, and ready-to-eat delicatessen products. Infection with Listeria carries a case fatality rate of 21%, among the highest of all food-borne pathogens per the Centers for Disease Control and Prevention (CDC) surveillance systems (38).
The most common clinical syndromes of invasive listeriosis in immunocompromised patients are septicemia and central nervous system (CNS) infections including meningitis, encephalitis (rhombencephalitis), and parenchymal brain abscesses (37). Enteroinvasive GI disease, hepatic dysfunction, endophthalmitis, and endocarditis have also been described.
Identification of the organism by culture of the blood or other sterile sites, especially CSF confirms disease. Listeriosis is a notifiable disease to local and state public health departments in the US.
Screening Before Anti-TNFα
No data to support routine laboratory screening. Dietary history may be helpful in identifying patients at risk, especially during known outbreaks.
Prevention/Isolation/Control Measures: Standard Precautions
Food counseling advice was effective in decreasing the number of food-borne infections in a national cohort of patients receiving anti-TNFα therapies (39). Patients should be advised to avoid raw or unpasteurized milk and milk products (including soft cheeses), hot dogs, fermented and dry sausage, delicatessen meats, refrigerated smoked seafood, and other high-risk foods. Observe safe food preparation, consumption, and storage. Encourage appropriate washing and handling of foods and thoroughly cooking meats. Wash hands before and after handling any raw produce and promptly refrigerate and consume cut fruits and vegetables. Avoid prolonged storage of prepared ready-to-eat delicatessen foods such as meats and other prepackaged cold foods.
Ten cases of infection with Nocardia spp. were reported to the FDA among 233,000 adults with IBD receiving infliximab therapy, for a rate ratio of 4.85/100,000 treated patients (26). Most case reports in adults with IBD have occurred while receiving anti-TNFα therapy and corticosteroids or cyclosporine. One case of disseminated nocardiosis in an adolescent with CD receiving 6MP and corticosteroids was found in the literature, but there are no reported cases in pediatric patients with IBD receiving anti-TNFα (40).
Nocardiosis is caused by multiple Nocardia spp., which are ubiquitous in soil, organic matter, and water. Invasive disease occurs in immunocompromised patients, most commonly via inhalation or via direct inoculation of traumatized skin with contaminated soil.
Manifestations of nocardiosis include primary cutaneous, pulmonary, CNS, and disseminated disease. Pulmonary disease is the most common manifestation and may be acute, subacute, or chronic. Hematogenous dissemination from the lung to other organs may occur, including the liver, spleen, and skin, but with particular proclivity for the brain, leading to abscess formation.
Nocardia spp. are slow growing organisms; their isolation from bacterial cultures of blood, body fluids, or tissue specimens is diagnostic. The presence of beaded, branching Gram-positive rods that may be acid-fast in a relevant specimen, is suggestive of nocardial infection. The lab should be notified if Nocardia spp. are suspected. In immunocompromised patients with proven Nocardia pneumonia, neuroimaging is warranted to evaluate for CNS abscess formation, which may be asymptomatic.
Screening Before Anti-TNFα
No data to support routine laboratory screening.
Prevention/Isolation/Control Measures: Standard Precautions
Nocardia spp. are ubiquitous in the environment. Prompt and thorough cleaning of open wounds after contact with contaminated soil and avoiding inhalation of soil-contaminated dust are recommended.
Salmonella spp. are the most frequently reported cause of foodborne infection, with US rates of 15.9 cases/100,000 population in 2013 (41). There are sporadic reports of infections with Salmonella spp. in adults receiving anti-TNFα therapy; no cases were found in pediatric patients with IBD receiving anti-TNFα therapy (26,42).
Principal reservoirs for Salmonella spp. include birds, mammals, reptiles, and amphibians. Contact with infected reptiles, amphibians, and rodents can result in transmission of Salmonella spp. and the development of the disease. Pet turtles and iguanas are notorious as the source of Salmonella infections in young children. Transmission to humans is primarily via foods, including poultry, eggs, beef, and dairy products or via fecal oral contamination of food products or water.
Infection usually starts within the GI tract, primarily the distal small intestine and colon, but may disseminate hematogenously, causing osteomyelitis or meningitis as the most serious manifestations of infection. Clinical manifestations in adults receiving anti-TNFα therapies for both rheumatologic diseases and IBD clinical manifestations have included gastroenteritis, urinary tract infections, bacteremia, sepsis, acute cholecystitis, suppurative arthritis, and pyomyositis. Invasive infection is more likely in younger children and those who are immunocompromised.
Isolation of Salmonella spp. from cultures of stool, blood, biliary fluid, CSF, or other usually sterile body fluids confirms the diagnosis. Children, who present with severe colitis, should have stool specimens submitted for culture (43). Salmonella is a notifiable disease to local and state public health departments in the US.
Screening Before Anti-TNFα
No data to support routine laboratory screening. Assess risk by asking patients about contact with pets or other animals or consumption of foods involved in outbreaks.
Standard plus Contact Precautions for the duration of the GI illness. Prevention measures are similar to those provided for Listeria and Nocardia (above) and include good hand hygiene, proper food handling and preparation (avoidance of ingestion of raw eggs, undercooked meats, and unpasteurized dairy products), and avoiding exposure to reptiles, rodents, and animals at petting zoos or farms. Patients should be advised against having pet turtles, iguanas, or other reptiles (44).
TNF-α is important in ensuring a robust cell-mediated immune response, including granuloma formation, in response to a fungal infection. Receipt of anti-TNFα therapies increases the risk of fungal infections regardless of underlying medical conditions or other concomitant immunosuppressive medication in adults. TNF-α inhibition leads to both a blunted immune response to new exposure and allows for reactivation of fungal infections that had been previously controlled (45). It is important to obtain a detailed history from the patient regarding previous fungal infections, past and current exposures, and potential high-risk activities. Patients with a history of previous mold infection or colonization with pathogenic fungi, who perform high-risk outdoor activities or travel to endemic areas, may be at increased risk of invasive fungal infections after anti-TNFα therapy (46).
Practitioners caring for patients with IBD receiving anti-TNFα therapies should have a high index of suspicion because many signs and symptoms of possible systemic fungal infection including fever, malaise, weight loss, sweats, and abdominal pain may overlap with IBD symptoms. Patients who live in or travel to endemic areas should be monitored closely for the development of signs and symptoms of histoplasmosis, coccidioidomycosis, and blastomycosis during and after anti-TNFα treatment (47). A timely and complete diagnostic evaluation and targeted antifungal therapy are needed in these patients for optimal outcomes. In general, anti-TNFα therapy should not be administered in the setting of an invasive fungal infection, and consultation with an ID specialist is recommended.
The first case report of Aspergillus fumigatus pneumonia following anti-TNFα therapy occurred in a 25-year-old man with CD who received the first dose of infliximab 5 days before the onset of infection (48). Delayed recognition of this mold as a potential pathogen in a patient with no other risk factors for invasive fungal disease and rapid disease progression likely contributed to his death. Since then, an additional 39 cases of invasive infections with Aspergillus spp. have been reported to the FDA, resulting in rates of 7 to 12.4 cases/100,000 patients receiving infliximab and resulting in a poor prognosis (26,49). A pediatric case of invasive pulmonary aspergillosis has been reported in a 15-year-old boy with panenteric CD, after receiving 20 doses of adalimumab and methotrexate, who died from sepsis and multiorgan failure (50).
Aspergillus spp. are ubiquitous environmental fungi, found in soil and rotting vegetation. The most common route of transmission is via inhalation from environmental sources. Less commonly, direct inoculation of skin may cause disease in high-risk patients. Typical risk factors for invasive disease include prolonged and severe neutropenia and receipt of systemic corticosteroids. Aspergillus contamination of marijuana has also been implicated in pulmonary aspergillosis in immunocompromised hosts.
Infection most commonly leads to pulmonary disease, though invasive sinusitis, rhinoorbital, and CNS disease, osteomyelitis, endocarditis, endophthalmitis, GI, and cutaneous manifestations may also occur. Aspergillus spp. have a proclivity for angioinvasion; thus, immunocompromised hosts should be evaluated for disseminated infection.
Proven disease is defined by isolation of the mold in culture or identification of septate, branching fungal hyphae consistent with Aspergillus spp. invading diseased tissue on histopathology from a sterile site specimen.
Screening Before Anti-TNFα
No data to support routine laboratory screening. Assessing for construction or remodeling in the home and high-risk behaviors is prudent.
Standard precautions in health care settings. Avoidance of possible environmental exposures.
TNF-α enhances polymorphonucelar leukocyte recruitment, phagocytosis, and killing in response to systemic candidal infections. There have been reports of invasive candidal infections in patients with IBD receiving anti-TNFα therapy, most frequently associated with infliximab. Estimated rates of 5 to 20 cases/100,000 treated patients have been reported (26,46,49). Candidemia associated with central venous catheters and invasive systemic diseases, including osteomyelitis have been described in children receiving anti-TNFα therapies (15,50,51).
Candida spp. can be present on mucosal surfaces, including mouth, and GI and genitourinary tracts, without causing disease. Most infections caused by Candida spp. result from endogenous invasion. Neutropenia, disruption of mucosal barriers, and receipt of systemic corticosteroids and other immunosuppressive agents increase the risk of invasive infection. Patients requiring long-term central venous catheters, abdominal surgeries, receipt of intravenous alimentation, or broad-spectrum antibiotics are at risk for Candida infections.
Clinical manifestations vary from localized oropharyngeal and esophageal candidiasis to more invasive diseases including bloodstream infections (candidemia), osteomyelitis, endocarditis, and endophthalmitis. In patients with persistent candidemia, additional diagnostic evaluation for a deeper focus of infection is warranted, including a dilated ophthalmological examination to evaluate for endophthalmitis and a cardiac echocardiogram when candidemia is associated with a central venous catheter (52).
Proven disease requires isolation of Candida spp. from sterile body sites or demonstration of yeast-like organisms in tissue biopsies from sterile sites.
Screening Before Anti-TNFα
No data to support routine laboratory screening. In patients with known history of Candida colonization or infection, information regarding the Candida spp. and antifungal susceptibilities may guide empiric antifungal therapy, when clinically indicated.
Prevention/Isolation/Control Measures: Standard Precautions
Judicious antimicrobial usage, meticulous care of central venous catheters and other medical devices, and reduction of immunosuppression as soon as clinically feasible reduce the risk of candidemia. Prophylactic antifungal agents for the prevention of Candida infections are not recommended routinely.
Most cases associated with anti-TNFα therapies in the literature occurred in patients from endemic areas or after intense exposure (53,54). The risk of coccidioidomycosis in these patients with inflammatory arthritis was higher when compared with patients not receiving anti-TNFα therapies. Most patients were receiving concomitant immunomodulatory therapies and presented with pneumonia or disseminated disease. No cases in pediatric patients with IBD receiving anti-TNFα therapies were found in the literature.
Coccidioides immitis and Coccidioides posadasii are dimorphic fungi endemic to the soil of the southwestern United States, Mexico, and Central and South America. Inhalation of Coccidioides spores results in acute, primary infection. Coccidioidomycosis may also result from the reactivation of previous infection.
Initial inhalational exposure can result in asymptomatic, subclinical, or symptomatic infection. One half to two thirds of infections in immunocompetent hosts are subclinical; however, infections in immunocompromised hosts are more likely to progress to symptomatic disease, are frequently more severe, and carry a higher mortality rate. Pneumonia is the most common clinical presentation and is associated with dyspnea, pleurisy, or musculoskeletal pain. Constitutional symptoms including fever, fatigue, myalgia, arthralgia, and weight loss are frequent. The pneumonia is indistinguishable from other community-acquired bacterial, viral, or fungal infections, and, thus, specific diagnostic testing is required. In <10% of cases, residual pulmonary sequelae develop. Dermatologic manifestations (eg, erythema nodosum or multiforme) occur more commonly in children and may be associated with pulmonary infection or may be the sole manifestation of disease. Extrapulmonary disease may be more common in patients receiving anti-TNFα medications and other immunosuppressants (eg, high-dose corticosteroids). Disseminated disease involving bones and joints, CNS, and skin occurs more frequently in adults than in children.
Diagnostic yield is improved by using multiple testing methods, and the microbiology laboratory should be informed if there is clinical suspicion of coccidioidomycosis. Culture of infected tissue (sputum, bronchoalveolar lavage [BAL] fluid, or other tissue) using fungal media is the criterion standard for diagnosis. Blood, CSF, pleural, and peritoneal fluids, however, are less likely to have a positive culture result. Histopathology is less sensitive than culture, but direct visualization of the characteristic spherule containing endospores in infected fluid or tissue confirms infection with Coccidioides spp. Serologic testing may be helpful for diagnosis and monitoring of therapy but should be interpreted with caution in immunocompromised hosts with low or negative titers, as false-negative serologic testing has been described in immunocompromised patients with proven coccidioidomycosis (55). Enzyme-linked immunoassays for IgM and IgG antibodies are more sensitive, whereas detection by immunodiffusion or complement fixation is more specific for coccidioidomycosis. Serology can be detected as early as 1 to 2 weeks after primary infection but may lag weeks behind illness onset, especially in immunocompromised hosts; thus, repeat testing may be warranted. Persistent, high titers (≥1:16) are associated with severe and disseminated disease. As only 15% of CSF cultures are positive, CNS coccidioidomycosis is generally diagnosed by detecting complement fixing IgG antibody in CSF.
Screening Before Anti-TNFα
Not recommended routinely. Limited data regarding screening exist in solid organ transplant recipients living in endemic areas. In these transplant centers, C immitis serologies (IgM and IgG) and chest radiographs were obtained before the institution of immunosuppressive therapies, and azole prophylaxis was offered to transplant patients at higher risk for reactivation of coccidioidomycosis (56,57). It should be recognized, however, that the intensity of immunosuppression is different when comparing transplant recipients to patients receiving monotherapy with anti-TNFα agents. Furthermore, many cases of coccidioidomycosis after anti-TNFα therapy represent an acute infection and would not be detected with prescreening serology. Prophylaxis may be a consideration for certain patients receiving anti-TNFα therapy and higher doses of systemic corticosteroids, who live in endemic areas or have a history of a previous episode of coccidioidomycosis, but given the paucity of data, no firm recommendations can be provided (58). Although antifungal prophylaxis reduces the risk of infection, it does not eliminate it.
Prevention/Isolation/Control Measures: Standard Precautions
Patients should be advised to avoid endemic areas. For patients who live in endemic areas, avoidance of exposure to dust storms, construction, or other soil disrupting activities that aerosolize spores is prudent. It is unclear whether patients who are diagnosed with coccidioidomycosis can resume anti-TNFα therapy. Up to 89% of patients with a history of CNS coccidioidomycosis had relapse years after stopping antifungal therapy (56). Consultation with an ID expert is recommended.
Immune responses to Cryptococcus spp. rely on effective T-cell host responses. Cryptococcosis has been reported most commonly in patients with rheumatologic conditions receiving anti-TNFα, with estimated rates of 4.7 to 7 cases/100,000 patients receiving anti-TNFα therapy (46,49). Most patients were also receiving additional immunosuppressive agents. No cases in children with IBD receiving anti-TNFα therapies have been reported.
C neoformans and C gattii are encapsulated fungi that cause human disease. Cryptococcus spores are found in soil that is contaminated with bird guano. Although this fungus may be found worldwide, it is endemic in California, southwestern and pacific northwestern United States, and in British Columbia in Canada, Mexico, and Central and South America. Inhalation of the fungal spores occurs with activities causing soil disruption.
Pulmonary cryptococcosis is the most common clinical manifestation of infection, presenting as fever, cough, and chest pain. Extrapulmonary disease may occur more commonly in immunocompromised hosts and includes disseminated disease, arthritis, cutaneous lesions (pyoderma gangrenosum), and meningitis. Manifestations of CNS disease include severe headache, enlarged ventricles or space-occupying lesions, and symptoms of elevated intracranial pressure. Meningitis, however, may also follow an indolent course. Disease results from a new acute infection or from reactivation of a previous exposure in an endemic region.
Isolation of the fungus from body fluids or tissue specimens using fungal media is diagnostic. Immunocompromised patients with cryptococcal pneumonia should be evaluated for disseminated disease, including performing blood and CSF cultures and cryptococcal antigen testing. A fundoscopic examination, neuroimaging, and measurement of CSF opening pressure are strongly recommended. Cryptococcal antigen detection in CSF has a diagnostic sensitivity of 94% for meningitis and if detected in serum, 90% for lung disease. Antigen detection is available in most clinical microbiology laboratories. False-negative results are uncommon but may be caused by a prozone effect or by a nonencapsulated strain. CSF cell count, protein, and glucose may be normal, despite a large organism load on CSF stains and isolation in culture. Anti-TNFα therapy should be withheld during invasive infection; however, it is important not to completely withdraw all immunosuppressive therapies at once to minimize the risk of developing an immune reconstitution inflammatory syndrome (IRIS) (59). If and when anti-TNFα therapy can be resumed after cryptococcal infection is unclear. Consultation with an ID expert is recommended.
Screening Before anti-TNFα
No data to support routine laboratory screening. A history of past cryptococcal infection may be helpful in choosing empiric therapy for acute infection episodes after anti-TNFα therapy is begun and in certain patients, in considering secondary prophylaxis until immune reconstitution is achieved (60).
Prevention/Isolation/Control Measures: Standard Precautions
Avoidance of high-risk activities associated with aerosolization of soil is prudent. Routine antifungal prophylaxis is not generally recommended.
Histoplasmosis is the most common endemic mycosis in the US, prevalent in the Ohio and Mississippi River valleys, and in parts of Mexico and Central and South America. Rates of histoplasmosis in adult patients receiving anti-TNFα exceed the overall national rates of infection (26). Anti-TNFα agents blunt the host's TH1 response resulting in impaired macrophage activation, lymphocyte proliferation, and inhibition of granuloma formation (61). Infection occurs either by reactivation, reexposure and reinfection, or as newly acquired infection (49). In 2008, the FDA issued a warning about the risk for pulmonary and disseminated histoplasmosis in patients receiving infliximab or other anti-TNFα based on 240 reports of histoplasmosis cases, with 12 fatal outcomes (FDA alert, September 4, 2008, http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124185.htm).
The largest case series describing histoplasmosis in pediatric patients with IBD receiving anti-TNFα therapies included 5 patients with a median age of 14 years (range 13–21) with CD (range of duration of disease 10 months to 10 years) who had received 2 to 13 doses of infliximab (n = 4) or adalimumab (n = 1) and a concomitant immunomodulator (6-MP or methotrexate) but had not been receiving systemic corticosteroids for ≥2 months (62). All of them presented with nonspecific complaints including intermittent fevers, malaise, decreased appetite, and abdominal pain, and 4 had mild respiratory symptoms. All of them received antifungal therapy and survived; anti-TNFα therapy was successfully reinstituted in 2 patients a median of 2 years after the Histoplasma diagnosis.
Histoplasmosis is the most common cause of invasive fungal infection in patients receiving anti-TNFα therapies, with a mortality rate of ∼20% in adults (46,49). Infection is acquired primarily through inhalation; soil disruption especially of soil rich with bat or bird guano that results in aerosolization of microconidia is considered an important risk factor.
Most cases of histoplasmosis are subclinical in immunocompetent hosts. When symptomatic, the most common clinical manifestation is acute pneumonia, indistinguishable from a community-acquired pneumonia. Larger inocula cause more severe disease leading to reticulonodular infiltrates and hypoxemia. Most important, symptoms of histoplasmosis may be indistinguishable from manifestations of IBD, including extraintestinal manifestations. Patients may present with unexplained or prolonged fevers and nonspecific symptoms such as fatigue, weight loss, or night sweats, and some may develop skin or mouth lesions. Patients receiving anti-TNFα therapies are at higher risk of disseminated histoplasmosis, including hepatosplenomegaly, adenopathy, and bone marrow suppression reflected as pancytopenia. Dissemination may occur early in the illness and after instituting anti-TNFα therapy.
Anti-TNFα therapy should not be administered in the setting of proven or probable histoplasmosis. Clinicians, however, should also be aware of the possibility of paradoxical clinical worsening despite documented improvement in the fungal infection that may follow discontinuation of anti-TNFα therapy and is consistent with an IRIS (63). The optimal time to restart anti-TNFα therapy after the diagnosis of acute histoplasmosis is unknown; some experts recommend that anti-TNFα therapy not be resumed. In a small subset of 7 adult patients with histoplasmosis, anti-TNFα therapy was restarted after a mean of 10 months of antifungal therapy (range 6–12 months) with no relapse noted during ≥1 year of follow-up (63). In a larger retrospective review of 98 patients receiving anti-TNFα and diagnosed with histoplasmosis, 97% had anti-TNFα therapy initially discontinued, and 34% resumed anti-TNFα therapy after a median of 12 months (range 1–69 months) (64). There was recurrence in 3 patients, 2 of whom had restarted anti-TNFα therapy; mortality rate was 3.2%. Consultation with an ID specialist is recommended.
If histoplasmosis is suspected, diagnostic testing should include evaluation of histopathology, fungal blood and tissue cultures, antigen detection in both urine and blood, and serologic testing. The performance characteristics of each diagnostic test will depend on the clinical histoplasmosis syndrome, and the extent and timing of histoplasmosis infection. In general, multimodal testing will optimize diagnostic sensitivity. For example, the sensitivity of antigen detection varies by clinical manifestation (higher in disseminated vs local pulmonary disease), underlying immunosuppression, and disease severity (65). The highest diagnostic sensitivity is achieved when both urine and serum antigen testing are performed concomitantly. Antigen testing can also be performed on BAL fluid. Serologic testing should include antibody testing by both complement fixation (higher sensitivity) and immunodiffusion (higher specificity) methods. Of note, negative results do not eliminate histoplasmosis as a possible etiology, and both antigen and antibody testing may be negative in the setting of active infection.
Screening Before Anti-TNFα
At this time, there are no data to support routine screening with serologic testing or antigen detection, even in endemic areas given the low sensitivity when used in this scenario. Risk factor assessment, however, is encouraged before starting anti-TNFα therapy in all patients (Table 3). In particular, if significant recent exposure or symptoms of active or recent (in the previous 2 years) histoplasmosis are elicited, additional testing may be recommended, including a chest radiograph (63). Patients with history, clinical, or laboratory findings suggestive of active histoplasmosis should receive antifungal therapy with itraconazole for ≥3 months before starting anti-TNFα therapy, and antifungal therapy should be continued for ≥1 year if anti-TNFα therapy must be used (66). Continued surveillance of symptoms and urinary antigen level monitoring (every 3 months and as clinically indicated) should be performed.
Prevention/Isolation/Control Measures: Standard Precautions
As per the FDA, for patients who have resided or reside in regions where histoplasmosis is endemic, the benefits and risks of anti-TNFα treatment should be carefully considered before initiation of therapy. Universal antifungal prophylaxis for patients living in endemic areas who are receiving anti-TNFα therapy is not routinely recommended. In outbreak situations and in patients who have recovered from active histoplasmosis in the 2 years before anti-TNFα therapy, itraconazole prophylaxis may be considered (66). The efficacy and optimal duration of antifungal prophylaxis are unknown. Providing advice to patients about avoiding exposure to Histoplasma is encouraged.
Pneumocystis jirovecii (Formerly Pneumocystis carinii)
Pneumocystis jirovecii (formerly Pneumocystis carinii) is the species that infects humans. Because both cellular and humoral immune dysfunction are risk factors for Pneumocystis pneumonia (PCP), CD4+ lymphocyte counts alone are not reliable for PCP risk assessment in HIV-negative immunocompromised patients (67). Immunosuppressive therapies that increase the risk for PCP include high-dose steroids (even during the tapering phase), calcineurin inhibitors, and receipt of anti-TNFα.
Review of the FDA adverse event reporting system identified 84 cases of PCP in adults during infliximab therapy, of which 16 patients had IBD, most commonly CD (n = 14) (68). Concomitant immunosuppressive medications included methotrexate, prednisone, azathioprine, leflunomide, 6-mercaptopurine, and cyclosporine. The risk of PCP was highest early (≤6 months) in treatment; the mean time to PCP infection was 21 days (±18 days) from infliximab infusion (mean of 2.1 infusions ± 1.3), and 23 (27%) patients died. PCP mortality rate is greater in the non-HIV population and may be owing to a more intense inflammatory response. The exact incidence of PCP in patients with IBD receiving immunomodulatory therapy is not known but is likely less than that observed in solid organ transplant recipients (5%–15%) and may be less than in patients with rheumatologic conditions who do not receive PCP prophylaxis (1%–6%) (69). The first pediatric case of PCP was described in an 8-year-old child with CD who had been receiving infliximab for 15 months (70). This case occurred together with disseminated histoplasmosis. An adolescent girl with CD developed PCP while receiving infliximab for 2 months and concomitant prednisone, methotrexate, and mycophenolate mofetil (25).
No environmental reservoir outside of human colonization has been identified for Pneumocystis species. High rates of detection have been demonstrated in healthy adults, and patients at risk for PCP may be asymptomatically colonized before developing disease. Rare instances of patient-to-patient transmission have been reported; it is likely that the load of Pneumocystis organisms is so low in most non-HIV immunocompromised patients that patient-to-patient transmission would occur only under very unusual circumstances of a combination of host, strain, and environmental factors.
HIV-negative immunocompromised patients present most often with an acute onset of respiratory symptoms including dry cough and fever that may progress to respiratory failure. Associated mortality is increased compared with HIV-infected patients who have a more insidious onset; mortality may be as high as 30% to 60%. The more abrupt clinical presentation in patients with IBD may be a reflection of a more exuberant inflammatory response to relatively few organisms. If steroids are used to treat IBD, they may mask the signs and symptoms of PCP. Despite respiratory distress and hypoxemia, auscultation of lung fields may be normal. Radiographic features seen most commonly are bilateral interstitial and/or alveolar infiltrates that involve the lower lobes more than the upper lobes. A diffuse reticulonodular pattern, however, may also develop.
Demonstration of the fungi in lung tissue with methenamine silver stain has been the criterion standard for diagnosis. Commercially available fluorescein-conjugated monoclonal antibody and PCR tests for detection of P jirovecii DNA in expectorated or induced sputum, BAL fluid, or deep tracheal aspirate has decreased the need for lung biopsy.
Screening Before Anti-TNFα
No data to support routine laboratory screening. Assessment of degree of immunosuppression recommended.
Prevention/Isolation/Control Measures: Standard Precautions
Chemoprophylaxis using trimethoprim-sulfamethoxazole, aerosolized or intravenous pentamidine, dapsone, or atovaquone has been associated with a 91% reduction in occurrence of PCP in a meta-analysis of the experience in immunocompromised patients with hematologic cancers or solid organ transplants (71). Although the indication for chemoprophylaxis in HIV-infected patients can be determined by the CD4+ lymphocyte count, such data do not exist for patients with IBD who are receiving immunosuppressive therapies. There are no published, evidence-based guidelines for PCP prophylaxis in the IBD literature, and the recommendation at present is to consider on a case-by-case decision (19,72).
In an analysis of the LifeLink Health Plan Claims Database 1997–2009, the crude incidence of PCP in patients with IBD was 10.6/100,000 (73). Patients with CD and those who were receiving steroids (with or without other immunosuppressive therapies) were at the greatest risk for PCP. In a meta-analysis of randomized trials of PCP prophylaxis in non-HIV immunocompromised patients, prophylaxis was warranted when the risk of PCP is ≥3.5% in adults, with a number needed to treat 19 patients (95% CI 17–42) to prevent 1 case of PCP (71). In a review of the literature, Okafor and colleagues (74) identified the following risk factors for PCP:
- Patients on high-dose corticosteroids (risk factor: daily dose of ≥6 mg).
- Patients receiving multiple immunosuppressive agents, including corticosteroids plus anti-metabolites, a biologic agent, or a calcineurin inhibitor.
- Lymphopenia (absolute lymphocyte count <600 cells/mm3, CD4+ count <300 cells/mm3, or leukopenia).
- Patients with multiple comorbidities (especially adults with chronic obstructive pulmonary disease).
- Patients >55 years.
European consensus guidelines recommend PCP prophylaxis for adult patients with IBD who are receiving an anti-TNFα agent as part of either a triple immunomodulation regimen or if anti-TNFα is given in conjunction with a calcineurin inhibitor (19,75). Similar recommendations for PCP prophylaxis in children are advised. Severity of disease and specific comorbidities may be an additional consideration in pediatric patients with IBD receiving combination immunosuppression. For example, PCP prophylaxis is advised for malnourished children receiving dual immunosuppression (that includes a combination of anti-TNFα and either a calcineurin inhibitor or high-dose corticosteroids) and in children <6 years of age with severe IBD manifestations in whom a primary immunodeficiency disorder is likely (17). Current consensus guidelines for the management of pediatric patients with severe, corticosteroid-refractory UC recommend that children receiving combination immunosuppressive regimens (anti-TNFα with calcineurin inhibitors or cyclosporine) also be considered for PCP prophylaxis (43).
Soon after the FDA approval of infliximab in 1998, the role of TNF-α in preventing mycobacterial disease was further characterized and screening recommendations emerged (supplementary Table 1, http://links.lww.com/MPG/A637). It became evident that TNF-α plays a critical role in the host immune response against intracellular microorganisms. Murine and human studies have shown that TNF-α deficiency impairs granuloma organization leading to increased organism burden and premature death (76). We describe the presentation, epidemiology, diagnostics, and suggested screening for both M. tuberculosis and NTM infections in pediatric patients with IBD.
Herein, “disease” refers to illness with M. tuberculosis, whereas “infection” refers to patients with latent tuberculosis infection (LTBI) who are asymptomatic.
Adults with IBD are at increased risk for serious mycobacterial infections because of the severity and duration of underlying IBD disease, advanced age, and use of corticosteroid therapy (24,77,78). In addition, adult data demonstrate increased rates of M. tuberculosis disease in patients with IBD treated with anti-TNFα agents (26,77,79–82). Treatment with anti-TNFα increases the risk of M. tuberculosis infections 4- to 5-fold higher in adult patients with IBD compared with an anti-TNFα unexposed cohort (77,78,83). The risk of developing M. tuberculosis disease is greatest in the initial 3 months after anti-TNFα exposure, most likely representing reactivation of LTBI and inability to maintain granulomas, with progression to disease; this appears to be greater with the use of infliximab compared with adalimumab (84). A recent systematic review evaluating the risk of M. tuberculosis reactivation in adult IBD and rheumatology patients found that whereas anti-TNFα use independently increased the risk of M. tuberculosis disease, the risk was further increased when an anti-TNFα was combined with either methotrexate or azathioprine (83). Less frequently, anti-TNFα therapy can also predispose to new TB infections that progress rapidly to active disease (26,79).
It is unknown to what extent anti-TNFα therapy increases the risk of mycobacterial infections in children and adolescents with IBD or whether they are predisposed to these infections because of the underlying IBD. Two cases of M. tuberculosis disease have been reported in pediatric patients with IBD during anti-TNFα therapy, and both presented with disseminated disease (85). The low incidence of TB disease in pediatric patients with IBD treated with anti-TNFα may be due in part to overall lower incidence of M. tuberculosis infection in children and to evolving screening recommendations before starting immunosuppressive therapies.
In the US, foreign-born individuals have a higher rate of M. tuberculosis infection. Three-quarters of pediatric patients with tuberculosis in the US in 2008–2010 had potential TB exposures through foreign-born parents or residence outside of the US (86). Additional risk factors include exposure to a person with active pulmonary tuberculosis that has not been treated, travel to endemic regions, or medical conditions that increase the risk of progression to disease, such as immunosuppressive therapy (87). A review of tuberculosis in children with comorbidities demonstrates the importance of screening and the increased mortality associated with tuberculosis in this high-risk population (88).
Children and adolescents with TB disease can present with fever, fatigue, weight loss, poor weight gain, night sweats, and persistent, unremitting cough (>2 weeks). Chest radiographs can demonstrate extensive involvement, sometimes with evidence of miliary disease. Cavitary lesions and pleural effusions are more likely to occur in teenagers. Receipt of anti-TNFα may also lead to atypical disease manifestations with mycobacterial infections. Pediatric and adult patients with IBD may be more likely to present with disseminated or extrapulmonary tuberculosis (15,79,85). Extrapulmonary disease may present with lymph node, spleen, CNS, or skeletal involvement. Improved awareness of the clinical presentation of M. tuberculosis disease will allow for optimal management.
Definitive diagnosis of TB disease relies on microbiological confirmation with a clinical scenario suggestive of tuberculosis as proposed by an expert panel (89). For M. tuberculosis disease, this includes isolating the organism by acid fast bacilli (AFB) culture of gastric aspirates, sputum, pleural fluid, BAL, bone marrow, lymph node, or CSF. In younger children, this requires 3 gastric aspirates collected in the early morning on separate days. Histologic evaluation for AFB or granulomas from tissue biopsy can be helpful in establishing the diagnosis. Isolates from cultures usually are identified within 6 to 8 weeks for M. tuberculosis. Overall yield, however, can be as low as 30% to 50% in pediatric patients because of paucibacillary disease. Nucleic acid amplification tests (NAATs) performed on sputum and extrapulmonary specimens are more sensitive and rapid than culture techniques. Some pediatric patients may need to be treated for TB disease based on clinical scenario, radiographic imaging, immunodiagnostic test results, and risk factors, without definitive culture results, but every effort should be made to identify an isolate for resistance testing. The management of suspected or proven TB disease may benefit from input from a pediatric ID specialist.
Immunodiagnostics are adjuncts to diagnosis and include a tuberculin skin test (TST) or interferon-γ release assays (IGRAs) such as quantiferon-TB or T-SPOT.TB. A positive reaction of either immunodiagnostic helps establish a diagnosis of LTBI or M. tuberculosis disease; however, none can differentiate between active TB disease and LTBI. In addition, a negative test does not reliably exclude the possibility of TB disease.
Both TST and IGRAs have limitations in diagnosing TB disease and LTBI in children. TST reading can be compromised if not performed and read by experienced personnel within 48 to 72 hours after placement. Positive results can occur in a person with NTM infection or in persons who received the bacille Calmette-Guerin (BCG) vaccine; false-negative results may occur in immunocompromised hosts, patients receiving systemic corticosteroids, and in patients with severe TB disease. Administration of live virus vaccines can affect TST results. For example, measles vaccine can temporarily suppress tuberculin reactivity for 4 to 6 weeks; the effect of live-attenuated influenza, varicella, and yellow fever vaccines on TST reactivity is unknown. It is recommended that TST testing be performed on the same day as live virus immunization. If it cannot, then TST testing should be postponed for ≥4 to 6 weeks. Similarly, IGRAs are also susceptible to variable results if improperly collected or not promptly processed, when performed in immunocompromised hosts or in patients with leukopenia, and results may not always be reproducible (90). The effect of live virus vaccination on IGRA results is also not known. There have been conflicting results as to whether the TST or IGRA is more reliable in patients with IBD; each method can be negatively impacted by age, immune status, immunosuppressive therapy, and underlying IBD disease activity (87,91,92).
The diagnosis of LTBI requires a positive immunodiagnostic test in a patient who is asymptomatic and has a negative chest X-ray. The experience with IGRAs in children was recently reviewed and a strategy for testing recommended in a technical report from the American Academy of Pediatrics (AAP) (90). The choice of immunodiagnostic test used (TST or IGRA) depends on the presence of risk factors, age, and receipt of the BCG vaccine. Adult guidelines (from the US and Europe) reviewed in a consensus statement had varying recommendations using 1 or both modalities and different cutoffs for TST positivity (93). In children, TST and IGRAs have similar sensitivity rates; IGRAs are more specific in areas of low M. tuberculosis disease burden and in BCG-vaccinated persons at 90% to 100%, compared with 56% for the TST when evaluating for LTBI (90).
Screening Before and During Anti-TNFα
We recommend that all patients with IBD be routinely screened for TB risk factors before administering anti-TNFα agents, ideally at the time of initial IBD diagnosis before any immunosuppressive therapy is started, and annually during anti-TNFα therapy. Screening includes a thorough evaluation of TB risk factors such as birth place, travel to endemic regions, disease exposure, possible concerning symptoms (eg, >2 weeks of cough), and whether the person previously received BCG vaccine. Any symptomatic patient requires further diagnostics.
In addition, we also recommend immunodiagnostic screening of all pediatric patients with IBD with both a TST and an IGRA at the time of IBD diagnosis and before initiation of anti-TNFα therapy, to increase diagnostic sensitivity (87,90). A TST cutoff value of 5 mm of induration should be considered positive in all pediatric and adolescent patients with IBD. Patients with an indeterminate IGRA result should have the IGRA repeated, ensuring the specimens are processed correctly according to the manufacturer's directions. It is not uncommon for immunocompromised children to have discordant results of TST and IGRA testing; however, if either test is positive, further diagnostic evaluation is recommended. If either the TST or the IGRA is positive or the second IGRA remains indeterminate, we recommend that a chest radiograph be performed to assess for M. tuberculosis disease. If imaging is negative in an asymptomatic patient with a positive immunodiagnostic result, the patient should be treated for LTBI for ≥2 months before starting anti-TNFα therapy, with a total duration of 9 months of mycobacterial therapy (19,94). Adherence to anti-mycobacterial agent(s) should be ascertained before initiating anti-TNFα therapy.
Any symptomatic person requires additional diagnostic evaluation for possible M. tuberculosis disease, even if TST and IGRA results are both negative. In general, anti-TNFα therapy should not be administered in the setting of active M. tuberculosis infection. If there is concern for pulmonary or extrapulmonary TB disease, consultation with an ID expert is advised.
For patients diagnosed with TB disease, when to resume anti-TNFα therapy safely depends on the extent of TB disease, clinical response to TB therapy, and severity of underlying IBD. In a study of adults with rheumatologic conditions, 6 of the 13 patients who developed TB disease while receiving anti-TNFα therapy were able to restart biologic therapy: 4 within 2 months of starting TB therapy, and 2 after completion of TB therapy (95). None developed recurrence of M. tuberculosis disease after resuming anti-TNFα therapy, at a mean of 30.6 months of follow-up.
Annual screening of patients who continue anti-TNFα therapy should be performed by risk factor assessment as previously described. This includes reevaluation of travel and possible TB exposures in the past year. Repeat immunodiagnostics should also be considered; however, the optimal testing strategy (which test(s) and how often) for evaluation is not known. In patients receiving anti-TNFα with identification of new risk factors (especially known exposure to a case of pulmonary TB or travel to an TB endemic region) or in those receiving corticosteroids and negative prior immunodiagnostics, consideration should be given to performing both TST (if prior TST negative) and IGRA to increase sensitivity, with consideration of performing a chest X-ray. Screening pediatric patients with IBD who have no new concerning risk factors and are not receiving triple immunosuppression or corticosteroids, with a single immunodiagnostic assay may be sufficient, but data are lacking to guide further recommendations. If LTBI is diagnosed in an asymptomatic patient, anti-TNFα therapy should be withheld, and antimicrobial therapy for LTBI provided for ≥2 months before restarting anti-TNFα therapy. If a patient has already been diagnosed and treated for LTBI, then annual screening should include careful assessment of possible exposures, symptoms, and a chest X-ray, as clinically indicated.
Airborne isolation plus standard precautions are recommended for active M. tuberculosis disease, including those with cavitary pulmonary tuberculosis or extensive pulmonary disease, positive sputum AFB smears, and children undergoing procedures that cause aerosolization of respiratory secretions including intubation, bronchoscopy, or administration of nebulized therapies. In addition, all household contacts should be evaluated for TB disease. Visitors of hospitalized patients with newly diagnosed TB disease should be screened before they are allowed to visit.
Adult patients with IBD treated with anti-TNFα agents are at increased risk of developing NTM infections (77). It is unknown if pediatric patients with IBD receiving anti-TNFα therapy are similarly at increased risk of NTM infections and whether risk is impacted by anti-TNFα therapy. One case of systemic Mycobacterium avium complex (MAC) infection was reported in an 11-year-old girl with CD who presented with generalized lymphadenopathy after receipt of infliximab followed by adalimumab (96).
NTM are ubiquitous organisms in nature, found in soil, food, water, and animals. MAC, M haemophilum, M fortuitum, M abscessus, and M marinum are the most common species that cause disease in children. The portal of entry for NTM infection is varied and can occur if there is disruption of the skin barrier (skin abrasions, penetrating trauma, and the presence of central venous catheters), or through the oropharyngeal mucosa and the GI and respiratory tracts.
Manifestations of NTM infection in children can include fever, rash, cough, generalized lymphadenopathy, anorexia, and weight loss. NTM infections in children are often localized and most commonly cause cervical lymphadenitis (especially in children <5 years of age), followed by soft tissue and pulmonary infections, and rarely skeletal infections (97). In immunocompromised pediatric patients, NTM infections can cause disseminated disease and catheter-associated bloodstream infections.
Definitive diagnosis of NTM infection requires isolation of the pathogen by culture or detection in tissue or body fluids by molecular methods. NTM isolates that grow rapidly on special culture media may be identified as early as 2 to 3 weeks. Sites of NTM culture depend on clinical presentation but may include BAL, sputum, wounds, peritoneal fluid, CSF, bone marrow, blood, or lymph node tissue. Multiple blood cultures may need to be obtained to isolate the pathogen in the setting of disseminated NTM disease because of intermittent bacteremia. If unable to isolate the pathogen in culture, a probable diagnosis relies on clinical presentation. Use of immunodiagnostic tests for the diagnosis of NTM infection have not been well studied and, when performed, are often inconclusive, and therefore not helpful in establishing the diagnosis.
Screening Before Anti-TNFα
There are no data to support routine laboratory testing, but screening for high-risk activities may be prudent.
Standard precautions are recommended for children who are hospitalized with NTM infections. Patients should be advised to avoid cleaning and changing water in aquariums and to avoid exposure to soil that may be aerosolized, including potting soil (98).
Data derived primarily from the rheumatology literature indicate that ∼30% of all infections and 11% of serious infections related to anti-TNFα therapy are caused by viruses (99,100). In general, anti-TNFα therapy should not be administered in the setting of severe, active viral infections.
Upon initial exposure to CMV, latent infection is established in hematopoietic cells, mainly lymphocytes. TNF-α is required for regulation of CMV replication and dissemination; therefore, recipients of anti-TNFα agents could have an increased risk of reactivation of CMV infection. The true incidence and burden of CMV disease in patients with IBD and those receiving anti-TNFα therapy is unknown. When CMV reactivation occurs in patients with IBD treated with immunomodulators, clinical manifestations can vary from asymptomatic or minimally symptomatic to severe disease. Prospective studies in patients with CD or rheumatoid arthritis have shown no evidence of significant CMV reactivation (measured by CMV PCR in plasma) following infliximab infusion. Similarly, infliximab treatment does not appear to affect colonic tissue CMV viral load (101). CMV reactivation has been detected most commonly in the GI tract of patients with steroid refractory UC, with a prevalence of 32% (102). It remains unclear, however, to what extent CMV detection contributes to IBD disease, posing a challenge for diagnosis and management (103–106). Proven cases of CMV disease, including enteritis, pneumonia, secondary hemophagocytic lymphohistiocytosis, and disseminated disease have been reported in patients with IBD receiving immunosuppressive therapies, including anti-TNFα agents (107–111). In children, primary CMV infection is more likely than in adults. Few pediatric cases have been reported, including a fatal case of disseminated CMV in a child with CD receiving infliximab and 6-mercaptopurine (112–114).
CMV is common in all the socioeconomic groups from developed and developing countries. CMV may be transmitted from person to person through infected body fluids. Patients with compromised immune systems are the most likely to develop symptomatic disease upon exposure, especially if they are seronegative. Health care personnel working in children's hospitals do not have an increased rate of CMV seroconversion compared with the general population (115).
CMV may cause infection (detection of CMV) or disease (evidence of end organ involvement). It is also important to note that CMV infection may represent a primary, symptomatic infection in children, as opposed to reactivation with asymptomatic or mild, self-limited symptoms in adults. Active CMV disease manifestations include retinitis, pneumonitis, hepatitis, colitis, and encephalitis. In patients with IBD who develop a severe colitis flare, it is recommended that biopsies be performed to evaluate for CMV disease, particularly in children with steroid-resistant UC (19,43,75). Discontinuation of anti-TNFα and other immunosuppressive therapies is recommended for proven CMV disease (19).
Tests to detect CMV that were formerly used (eg, tissue culture, shell vial centrifugation culture assay, and the detection of pp65 antigen) have been replaced by quantitative nucleic acid tests, usually PCR, to detect and quantify CMV DNA or RNA in blood or other body fluids (116). The detection of CMV in urine or the presence of CMV IgM antibodies is nonspecific and not helpful for diagnosing disease associated with an acute infection. Detection of CMV RNA in plasma is indicative of active replication, whereas detection of CMV DNA may indicate latent viral infection or, if rising, active replication. Although high CMV copy numbers in blood by PCR may increase the index of suspicion for CMV and has high sensitivity for systemic infection, it is not definitive and may be falsely negative in patients with CMV colitis. It is important to note that given the high sensitivity of the PCR assays, CMV detection in tissue by PCR methods alone does not have sufficient specificity to confirm disease (117). When tissue biopsies are obtained, histologic examination may reveal characteristic cell types, and in situ hybridization can be used to confirm and quantify the amount of CMV in tissue. Mucosal viral loads of CMV have been reported to be useful for identifying viral colitis that responds to anti-CMV antivirals in refractory IBD in adults but are not standardized. In patients with evidence of CMV end organ disease, an ophthalmological examination to exclude the presence of CMV retinitis is also prudent (19,101,102). Discontinuation of immunosuppressive agents is recommended when systemic CMV disease (eg, colitis, hepatitis, and meningoencephalitis) is diagnosed.
Screening Before Anti-TNFα Therapy
Screening for CMV infection before beginning therapy with anti-TNFα agents is not recommended routinely; detection of CMV IgG is indicative of latent infection and does not reliably predict conditions that would require prophylaxis or therapy in this population. For those individuals with severe UC who are failing steroid therapy, transitioning to second line or augmented immunosuppressive therapies including anti-TNFα, and in whom there is a suspicion for CMV colitis, biopsies of colonic tissue should be examined by histopathology and immunohistochemistry to confirm the presence of CMV end organ disease that would warrant antiviral treatment (19,112).
No additional isolation measures beyond standard precautions are recommended in health care facilities for patients who have CMV infection with or without disease (118). The highest concentrations of CMV are found in urine, saliva, and blood; therefore, use of hand hygiene and gloves according to standard precautions when in contact with blood or body fluids will protect health care personnel and pregnant women from acquiring CMV. Following standard precautions with all patients is especially important because most patients who are shedding CMV are not identified. Outside of the health care environment, special care should be taken by immunocompromised and pregnant individuals when changing diapers, feeding a young child, wiping a young child's nose or saliva, and handling children's toys.
Hepatitis B Virus
Hepatitis B virus (HBV) persists after infection and can be reactivated when patients receive immunosuppressive therapies. TNF-α is critically involved in the control of HBV replication and in stimulation of anti-HBV T-cell responses. Reactivation of hepatitis B infection in unimmunized adults with IBD receiving anti-TNFα has been reported since 2003 (101,119,120). No cases in children with IBD have been reported. Risk of reactivation was higher in patients who received infliximab concomitantly with other immunosuppressive therapies or had detection of HBV DNA but was lower in patients who received antiviral prophylaxis (120). In the absence of anti-viral therapy, patients with chronic HBV infection treated with anti-TNFα agents have experienced elevations in viral loads and serum transaminases with clinically apparent disease and even death. The time after receiving anti-TNFα agents and before reactivation is highly variable. Additionally, some children may not have received the complete HBV vaccine series before their IBD diagnosis or initiation of immunosuppressive therapy. In 1 published series, 75 of the 87 (86%) previously immunized children with IBD treated with anti-TNFα agents were considered immune against HBV infection based on hepatitis B surface antibodies (anti-HBs) levels ≥10 μIU/mL or an anamnestic response to a single HBV booster dose (121). Of note, the nonresponders received infliximab at an increased frequency than the responders.
HBV is blood-borne and may be transmitted during the perinatal period, household contacts of an actively infected individual, exposure to blood, or during sexual contact with an individual who is a carrier or is actively infected. Patients may be at risk of HBV from being born in a country with high (>8%) HBV prevalence, local incidence rates, current or previous lifestyle practices, hemodialysis, or those with a history of hepatitis C infection, jaundice, or liver disease of uncertain etiology. Nonhospital health care–associated outbreaks of HBV infection associated with failure to use safe injection practices have occurred in long-term care facilities, assisted living facilities, and outpatient endoscopy centers (122). The overall prevalence of chronic HBV infection in children is much lower than in adults, likely owing to the introduction of universal administration of HBV vaccine to infants in 1990 in the US (refer to safe living section and Tables 4 and 5 for more information on hepatitis B vaccination).
Infection with HBV may be asymptomatic, associated with acute or chronic hepatitis, liver failure resulting in liver transplantation or death, and in rare instances, may be associated with the development of hepatocellular carcinoma.
Diagnostic Testing and Screening Before Anti-TNFα
In general, anti-TNFα therapy is not recommended to be started in patients with active HBV infection, and caution is advised for patients with a known history of chronic or recurrent HBV infection with liver injury (defined as Child-Pugh classes B or C). Thus, medical and immunological status assessment before starting anti-TNFα therapy is recommended. Identification of patients at high risk for HBV reactivation by screening is important; however, the optimal screening, monitoring, and anti-viral strategies have not been established (19,123–125). Immunization records should be reviewed to determine whether a patient has received a 3-dose series of HBV vaccine, and seroresponse should be confirmed. The following tests should be performed to document immunity and to determine whether the patient is infected with HBV: hepatitis B surface antigen (HBsAg), anti-HBs, and hepatitis B core antibody (anti-HBc). If anti-HBc is the only antibody that is positive, a HBV DNA load should be measured. Patients may be found to have only anti-HBc for the following reasons:
- False-positive reactivity attributed to nonspecific reactions with competitive anti-HBc enzyme immunoassays (EIAs) and cross-reactivity with interfering serum substances or with IgA- or IgM-related molecules produced from nonspecific HBV-activated B-lymphocytes;
- Passive transfer of antibody from recently received immunoglobulin products; or
- Low level of chronic carriage with loss of other markers of HBV infection.
In such patients, HBV DNA in the blood should be determined; if HBV DNA load is negative, a true infection with HBV is unlikely. Patients with chronic HBV infection should be screened by laboratory testing (eg, liver enzymes and HBV DNA) every 2 to 3 months during and after cessation of immunomodulator therapy (19,125). Antiviral prophylaxis or therapy may be required in some patients with chronic HBV infection or if there is viral reactivation (125). Patients who test positive for HBV should also be tested for HIV and hepatitis A and C viruses.
Because HBV is transmitted via blood and body fluids in health care settings, infected patients should be managed using standard precautions with special attention to safe injection procedures (118,126). The equipment used for invasive procedures (eg, endoscopes) must be processed according to the most recent multisociety guideline on reprocessing flexible GI endoscopes (127). Patients should be counseled to avoid high-risk behaviors.
Recently, the American Gastroenterological Association has drafted guidelines regarding the prevention and treatment of hepatitis B reactivation during immunosuppressive therapy (125). High- and moderate-risk patients who are HBsAg positive (or HBsAg negative, but anti-HBc positive), who do not have liver injury, and require anti-TNFα therapy may be candidates for antiviral prophylaxis and viral monitoring during anti-TNFα therapy; it is recommended that antiviral prophylaxis be continued for ≥6 months after immunosuppressive therapy is discontinued. Pooled effect estimates demonstrated that antiviral prophylaxis was associated with an 87% RR reduction of HBV reactivation (95% CI 70–94) and RR reduction of 84% (95% CI 58–94) of HBV-associated hepatitis flares (125). Antiviral therapy does not eliminate the risk of hepatocellular carcinoma, as such surveillance should continue to be performed in at-risk individuals. An expert in the treatment of pediatric HBV infection should be consulted for the most up-to-date prevention and treatment strategies.
Hepatitis C Virus
Routes of transmission and clinical manifestations of hepatitis C virus (HCV) infection are similar to those of HBV, but HCV may be associated with a more prolonged period of silent infection. Although effective chemotherapeutic regimens for HCV infections exist, no intervention has proved to prevent transmission either preexposure or postexposure. Acute HCV during anti-TNFα therapy has not been reported. HCV infection has been rarely reported in patients receiving anti-TNFα therapy but long-term data are lacking (101,128,129). Progression of liver disease in patients with chronic HCV and liver injury receiving anti-TNFα has been reported. HCV infection in children with IBD during treatment with anti-TNFα therapies has not been reported.
Similar to HBV, HCV is a blood-borne pathogen that is acquired via blood or mucous membrane exposure to infected blood or body fluids. The most common route of HCV infection in young children is maternal-fetal transmission; the perinatal transmission rate is ∼5%. Specific behavioral risk factors for HCV include the use of injectable illicit drugs and tattooing, HIV infection, and sexual activity. Increased use of nonhospital health care facilities, exposure to hemodialysis centers, endoscopy, and drug diversion by HCV-infected individuals also contribute to the risk of acquisition of HCV infection (122). Outbreaks in nonhospital settings have highlighted the importance of observing safe injection practices (130).
In contrast to HBV, TNF-α appears to contribute to the pathogenicity of HCV infection, triggering hepatocyte apoptosis and perpetuating liver inflammation (101). It is generally recommended to avoid anti-TNFα agents in patients with acute HCV infection or chronic HCV with significant liver injury (Child-Pugh classes B or C). To date, however, the use of anti-TNFα in patients with chronic HCV infection without liver disease appears to be safe; concomitant anti-HCV treatment is not recommended in this group during anti-TNFα treatment (131). It is worth noting that the majority of these data are derived from adult patients with rheumatoid arthritis and chronic HCV, receiving etanercept. Adult patients with IBD, particularly with CD, treated with interferon therapy for HCV may be at risk for exacerbation of intestinal inflammation and the development of mixed cryoglobulinemia (101). An expert in the treatment of pediatric HCV infection should be consulted for the most up-to-date treatment strategies.
Updated guidance for diagnostic HCV testing is available (132,133). There are 2 groups of tests: IgG antibody EIAs for HCV and NAATs to detect HCV RNA. A rapid blood test has been approved for use in patients ≥15 years of age for the detection of antibody. Third generation EIAs are 97% sensitive and >99% specific. A reactive antibody test should be followed by NAAT testing. In immunocompromised patients in whom antibody testing may be falsely negative, both antibody and NAAT testing should be sent concomitantly. The detection of HCV RNA confirms infection. Consultation with an expert in pediatric HCV is recommended. New short-term therapeutic agents have been identified for the treatment of HCV infections, but there is no experience in children. Patients who test positive for HCV should also be tested for HIV, HBV, and hepatitis A.
Screening Before Anti-TNFα
In the presence of risk factors or elevated liver enzymes, screening for HCV antibody is recommended. If positive, HCV RNA testing should be performed. In patients already receiving immunosuppressive therapy, concomitant screening with HCV antibody and NAAT testing is recommended.
Because HCV is transmitted via blood in health care settings, infected patients should be managed using standard precautions with special attention to safe injection procedures (118,126). Equipment used for invasive procedures (eg, endoscopes) must be processed according to the most recent multisociety guideline on reprocessing flexible GI endoscopes (127). Patients should be counseled to avoid high-risk behaviors.
Following either immunization or natural primary infection, varicella-zoster virus (VZV) persists lifelong in dorsal root ganglia with the potential for clinical reactivation manifesting as shingles (zoster). The risk of zoster is lower in those who have received the vaccine than in those who have had natural primary infection. Overall, the incidence of primary varicella infection and associated morbidity and mortality in children has decreased since the licensure of the varicella-zoster vaccine in 1995 (134). Two doses of VZV vaccine are recommended.
Reviews of VZV infections in patients with IBD have reported both clinical primary varicella and zoster infections (15,99). Rates of 11.3/1000 patient-years have been reported for patients with IBD receiving anti-TNFα therapies (135). Anti-TNFα therapy may be a particular risk factor for severe primary infection, as TNF-α blockade allows for viral replication and dissemination of the virus in the early stages of infection. Corticosteroids (mean daily dose ≥10 mg), thiopurines, and anti-TNFα agents have been associated with an increased risk of VZV primary infection and reactivation; the risk is higher in those receiving combination immunosuppressive therapies.
Primary varicella infection occurs more frequently in patients with CD than in those with UC, likely in part because of the increased immunosuppression in CD (99). The duration of time between starting immunosuppression and the development of either primary or reactivated VZV infection varies from a few days to years.
Primary VZV infection may be more severe and may increase the risk of disseminated disease in patients receiving immunosuppressive therapy. Patients with IBD treated with various immunosuppressive regimens who develop primary varicella have a case fatality rate of up to 25% (99). Disseminated VZV infection includes visceral involvement and may present with pneumonia, hepatitis, encephalitis, and disseminated intravascular coagulation (99). Reactivation of herpes zoster may have a prodrome of pain and tingling in a dermatomal distribution before the appearance of the vesicular rash. Depending on the location, a variety of neurologic syndromes have been described. Early diagnosis and initiation of antiviral therapy will decrease morbidity and mortality. In general, it is recommended that anti-TNFα therapy not be administered during an active herpes zoster infection. The decision to withhold immunosuppressive therapy during the VZV infection or to completely discontinue anti-TNFα agents, however, must be made individually based on the need for the immunosuppressive agents, severity of viral and underlying disease, and response to antiviral therapy, as data are lacking to make a single recommendation.
The appearance of VZV infections may be atypical in immunocompromised patients; therefore, diagnostic testing of skin lesions should always be performed. A scraping of the base of the vesicular lesion is the preferred specimen and should be sent for VZV PCR testing before initiating antiviral therapy. VZV PCR testing has improved diagnostic sensitivity compared with viral culture and Tzanck smear (136). VZV can be detected by PCR in whole blood during acute episodes of both primary varicella and herpes zoster but is less sensitive than testing of scrapings of skin lesions. VZV PCR may also be performed on CSF in the presence of encephalitis but is infrequently positive. Serology is not reliable in immunocompromised hosts to confirm acute infection but should be used for initial screening before immunosuppressive therapy is initiated (see below).
Screening Before Anti-TNFα therapy
The history of receipt of 2 doses of varicella vaccine should be obtained, and if the patient has not received 2 doses of varicella vaccine, immunity must be documented by measuring VZV IgG antibody in the blood before initiation of anti-TNFα therapy. A history of disease is not reliable unless confirmatory diagnostic testing was performed and results can be obtained. If the patient has protective antibody or confirmed prior history of VZV infection, primary varicella is unlikely to occur. In adults with IBD, the positive and negative predictive values for a reported history of VZV exposure were 93% and 0%, respectively (137).
Any patient with suspected VZV infection who is hospitalized should be placed in an airborne infection isolation room. Contact precautions are added until all skin lesions are dried and scabbed over and no new lesions are appearing. In ambulatory settings, the patient should be placed promptly in a negative pressure examination room or if such is not available, a mask is placed on the patient who is then escorted promptly into an examination room. Once it is clear that the lesions of herpes zoster are localized to a single dermatome, airborne precautions are no longer needed, but contact precautions are continued as described above.
Ideally, those who have not received the vaccine or are seronegative should receive 2 doses of vaccine (separated by >4 weeks for patients ≥13 years of age or ≥3 months if 1–12 years of age) ≥4 weeks before anti-TNFα blockers or any immunosuppressive regimen is initiated (23). With the prolonged interval recommended between the first and second doses and the frequent use of steroids or other immunosuppressive therapy in patients with IBD, this may, however, not be possible. Patients with IBD who are already receiving immunosuppression with high-dose corticosteroids or anti-TNFα therapies should not receive VZV vaccine (23). Guidelines differ regarding the recommendation for administration of varicella vaccine in nonvaricella immune patients with chronic inflammatory diseases who are receiving long-term but low-dose immunosuppression; the strength of the recommendation and quality of the data to support this practice is weak and low, respectively. Receipt of varicella vaccine is not contraindicated in household or close contacts of immunocompromised patients. Refer to Table 3 for more information regarding immunizations in immunocompromised individuals and their close contacts.
Immunosuppressed individuals who are not immune to VZV should avoid exposure to people known to have primary varicella or reactivated herpes zoster that is not localized or cannot be covered completely. If a seronegative, immunosuppressed patient has been exposed to an individual with medically diagnosed chickenpox, VariZIG (Cangene Corporation, Winnipeg, Canada) should be administered according to the CDC recommendations (138). Antiviral prophylaxis should be considered if there has been a previous episode of shingles in patients at high risk for reactivation, including those requiring augmented immunosuppression (99).
Selected Infections Occurring in Pediatric Patients With IBD, No Confirmed Association With Anti-TNFα Use
Patients with IBD have a 3-fold increased susceptibility to C difficile infection compared with the general population and may be higher in patient with UC compared with patients with CD (139). A disproportionate increase in C difficile–associated hospitalizations is reported among pediatric patients with IBD in the US from 1997 to 2011 (140). Enteric infections may contribute to symptomatic relapses in patients with IBD, with C difficile being detected most frequently (141). Underlying disease activity was significantly greater in pediatric patients with IBD with C difficile infection than in uninfected patients (142).
C difficile is acquired from the environment or via the fecal–oral route from direct contact with another colonized or infected patient or by indirect contact via carriage on the hands of health care personnel. Preceding antibiotic use, hospitalization, use of gastrostomy and jejunostomy tubes, and gastric acid suppression are established risk factors for C difficile infection. Data regarding the contribution of immunomodulatory therapies to increasing infection rates are scant. Corticosteroid therapy increases the risk for C difficile infections in patients with IBD; however, this association was not found with anti-TNFα therapies (143,144).
C difficile asymptomatic colonization of the GI tract occurs soon after the neonatal period, in children <5 years of age, and is most frequent in infants <1 year of age. Asymptomatic C difficile colonization has also been described in patients with IBD without other identifiable risk factors (145). The spectrum of disease caused by C difficile varies from mild or moderate GI illness characterized by watery diarrhea and mild abdominal pain to severe colitis and toxic megacolon. Patients with IBD may not develop pseudomembranes but have a higher frequency of severe disease requiring colectomy (146).
Testing for C difficile toxin is prudent in patients with IBD > 2 years of age with risk factors, who present with worsening GI tract symptoms in an attempt to ascertain whether exacerbation is because of infection or underlying IBD (43). If NAAT is used, 1 diarrheal stool specimen with a negative PCR result excludes C difficile–associated diarrheal infection with a sensitivity of 93% to 100% and a specificity of 100% (147). Optimally, a combination of a sensitive test (NAAT) with a specific test (cell cytotoxin immunoassay) may provide more accurate information to guide treatment decisions (148). A NAAT should not be performed for the test of cure given the persistence of positivity for weeks or months following the resolution of disease (149).
Screening Before Anti-TNFα
No data to support routine laboratory screening.
Standard plus contact precautions with bleach cleaning of surfaces must be followed. Practicing antimicrobial stewardship and proper isolation precautions, including meticulous hand washing are the most effective prevention methods. Because alcohol-based hand hygiene products do not inactivate C difficile spores, the use of soap and water for hand hygiene is recommended by most experts; however, there are no data that demonstrate a reduction in transmission associated with hand washing with soap and water versus waterless alcohol-based products.
Primary infection with or reactivation of Epstein–Barr virus (EBV) is an important risk factor for the development of lymphoproliferative disease including lymphoma in transplant recipients. Increased risk of lymphoma has been reported in patients with IBD treated with thiopurines (19,150–152). Cases of EBV-associated lymphoma following primary disease have also been described with other immunosuppressive therapies, generally in combination (153–155). The data with anti-TNFα monotherapy are less clear, though no obvious signal for increased infection rates has been identified. Several studies of patients with IBD or rheumatoid arthritis treated with infliximab have not demonstrated EBV reactivation by infliximab therapy (156,157). There was no increased risk of development of EBV-associated lymphoma in patients with IBD treated with anti-TNFα agents who had high EBV viral loads; however, long-term clinical outcomes were not documented (158,159). In a recent systematic review, the risk of lymphoma was no greater among children with IBD who received anti-TNFα agents compared with those treated with other immunomodulator therapies (14). Primary EBV infection leading to lymphoproliferative disease in a teenager with CD has been reported (160).
EBV is a ubiquitous virus. Primary infection in healthy individuals is asymptomatic or may be associated with an infectious mononucleosis syndrome that is most often mild. After primary infection, the virus remains latent in B lymphocytes in individuals with intact immune systems. EBV may be shed in saliva and only those with very close contact are at risk of acquiring infection.
Data are lacking concerning the clinical presentation of EBV-associated lymphoma associated with anti-TNFα inhibitor therapy. Patients who have been treated with thiopurines may present with hemophagocyctic lymphohistiocytosis (HLH) caused by primary EBV infection, lymphoproliferative syndromes, or lymphoma (161,162). Of note, 5 pediatric patients with IBD treated with systemic steroids, but not with anti-TNFα, developed HLH associated with primary EBV infection (163).
A serologic panel that includes IgM and IgG antibodies to the viral capsid antigen (VCA), antibodies to the early antigen (EA) complex and to Epstein–Barr nucleic acid (EBNA) may be used to diagnose infection. Because EBNA antibody is not present in serum until several weeks to months after infection, its presence excludes a primary infection. EBV DNA can be detected in blood and quantitated by PCR and in situ hybridization for EBV RNA (EBER) is useful for detection of virus in tissue. Mucosal EBV viral loads were found to be useful for identifying viral colitis in adults with refractory IBD; however, there are too few data to make recommendations for diagnosis or treatment (116). EBV viral load surveillance in solid organ transplant recipients has been used to monitor for possible posttransplant lymphoproliferative disorder (PTLD) in high-risk patients; however, despite high sensitivity, it has poor specificity for PTLD (164). Furthermore, the detection and significance of a chronic, low-level EBV viral load is not completely understood in the IBD population. As such, currently there are no data to support this practice or guidelines for monitoring of EBV in patients with IBD receiving immunosuppressive therapy. Tissue histopathology in conjunction with EBER detection is the criterion standard for diagnosis of EBV-driven lymphoproliferative syndromes and lymphoma.
Screening Before Anti-TNFα Therapy
There is no definite indication to screen for EBV infection in children with IBD before the treatment with anti-TNFα agents. Performing an EBV panel that includes VCA IgM, VCA IgG, EA, and EBNA antibodies, however, may be useful to ascertain whether the patient has had a past infection, as primary EBV infection, if severe, may warrant antiviral therapy and is associated with higher risk for lymphoproliferative disease. Further research on this topic is needed in the IBD population.
Prevention/Isolation/Control Measures: Standard Precautions
The transmission of EBV is by intimate contact (eg, kissing), blood transfusion, and transplantation of stem cells, tissue, or solid organs; therefore, there are no specific isolation precautions beyond standard precautions that are recommended for health care facilities when caring for patients who have EBV infection.
Human Immunodeficiency Virus (HIV)
Infection with HIV increases the risk of opportunistic infections, particularly if CD4 T cells are <200/mm3 (or CD4 percentage <15%) in individuals ≥6 years of age or if CD4 counts are <500 cells/mm3 (or CD4 percentage <15%) in children ages 1 to <6 years, and for all HIV-infected infants ages <12 months regardless of CD4 count or percentage (165,166). The risk of opportunistic infections is directly proportional to the viral load measured in blood and inversely proportional to the absolute CD4 count. The widespread use of highly active antiretroviral therapy (HAART) and prophylaxis has reduced the transmission, morbidity, and mortality associated with pediatric HIV. There are conflicting reports of the effect of anti-TNFα agents on the progression of HIV infection; therefore, these agents should not be withheld if needed but very close HIV load monitoring is required. Case reports describe the successful use of anti-TNFα therapies to treat inflammatory conditions in the setting of well-controlled HIV infection in adults receiving HAART (167).
Modes of transmission of HIV include sexual contact, percutaneous blood exposure, mucous membrane exposure, perinatal transmission, including via breast-feeding or feeding of blood-tinged premasticated food, and transfusion of infected blood. Pediatric acquired immunodeficiency syndrome (AIDS) cases now account for <1% of all reported cases of AIDS in the US as a result of the implementation of comprehensive programs to interrupt perinatal transmission. The rate of HIV acquisition during adolescence, however, has continued to increase in association with sexual exposures and illicit drug use.
A total of 40% to 90% of newly diagnosed HIV infections may be associated with an acute retroviral syndrome (eg, fever, malaise, lethargy, myalgia, headache, adenopathy) that occurs 1 to 4 weeks following exposure and lasts <14 days. As individuals who are untreated become more immunosuppressed, they may present with general systemic deterioration, weight loss, unexplained fever, generalized lymphadenopathy, hepatosplenomegaly, pneumonia, and manifestations of the various opportunistic infections for which immunosuppressed individuals are at risk. Coinfection with HCV is present in 80% of HIV-infected patients who use intravenous illicit drugs and have hepatitis.
The diagnosis of HIV infection is confirmed by following the testing algorithm approved by the FDA in 2014 that uses a fourth generation HIV 1/2 antigen/antibody combination immunoassay that allows for the detection of infection sooner than previous immunoassays (described below in the screening section). When clinical suspicion for recent HIV infection is high, testing by immunoassay and HIV-quantitative viral load testing can be performed simultaneously.
Initial Screening Before Anti-TNFα Therapy
The CDC recommends routine HIV screening of adolescents ≥13 years of age in health care settings in the US regardless of history or underlying medical conditions, unless the documented site-specific prevalence of undiagnosed HIV infection falls below 0.1% (168). In 2013, the US Preventive Services Task Force recommended routine HIV screening of all adolescents ≥15 years of age and of younger adolescents who are at increased risk (169). Repeat annual screening is recommended in those patients who are at high risk of acquiring HIV infection. Screening for HIV infection according to the most recent testing methodology described in the CDC/PHS recommendations (http://www.cdc.gov/hiv/guidelines/testing.html) is encouraged. Screening of patients <13 years of age may be considered, depending on risk factors and the degree of anticipated immunosuppression. Testing begins with a combination immunoassay that detects HIV-1 and HIV-2 antibodies and HIV-1 p24 antigen. All specimens reactive on this initial assay undergo supplemental testing with an immunoassay that differentiates HIV-1 from HIV-2 antibodies. Specimens that are reactive on the initial immunoassay and nonreactive or indeterminate on the antibody differentiation assay proceed to HIV-1 nucleic acid testing for resolution.
Because HIV may be transmitted via blood in health care settings, infected patients should be managed using standard precautions with special attention to safe injection practices (118,126). Adolescents with IBD who are or are likely to become sexually active should be counseled on effective preventive measures, availability, and limitations of postexposure and preexposure chemoprophylaxis, and the potential impact of HIV infection on the course of their IBD. Patients should be counseled to avoid high-risk behaviors.
Respiratory viral infections in children are frequent and are more likely to occur as primary infections. Respiratory tract infections, presumably viral, were the most frequently reported type of mild and severe infections in pediatric patients with IBD receiving anti-TNFα therapies (15,170). Although viruses are known to cause pneumonitis in immunocompromised hosts, no data are reported on the degree of risk of respiratory viral infections in children with IBD who are treated with anti-TNFα agents.
Respiratory viruses generally cause seasonal community outbreaks which may vary by geographic location and year. Viral shedding may be prolonged (weeks to months) in the immunocompromised host.
Clinical disease caused by respiratory viruses in patients treated with anti-TNFα blockers does not seem to be substantially different from disease in other patients.
The most sensitive diagnostic test for respiratory virus detection is a multiplex PCR panel that detects a variety of respiratory viruses. Because not all commercially available panels detect the same virus, it is important to know which test is used at one's own institution. Rapid diagnostic tests available for RSV are reliable but less sensitive that multiplex PCR panels. Diagnostic testing for influenza virus in symptomatic individuals is encouraged during the influenza season to identify patients who may benefit from antiviral therapy and to facilitate appropriate infection control measures.
Screening Before Anti-TNFα
Routine screening for respiratory viruses in asymptomatic individuals is not recommended.
Isolation precautions recommended by the Healthcare Infection Control and Practices Advisory Committee and the Centers for Diseases Control and Prevention for viral respiratory infections should be followed in health care facilities (118). For most respiratory tract viruses, contact plus standard precautions are recommended. Droplet precautions are added for influenza, adenovirus, and rhinovirus. Consistent hand hygiene and avoidance of crowds and individuals who have respiratory tract infections are general measures that will help reduce the risk of illness. Inactivated influenza vaccine is recommended for all immunocompromised patients during the influenza season. Inactivated or live attenuated influenza vaccine is recommended for all contacts of immunocompromised patients (23).
There is no evidence that therapy with anti-TNFα agents increases the risk of parasitic infections. Parasitic infections with toxoplasmosis, strongyloides, malaria, and many cases of leishmaniasis, mostly in Europe and South America, have been reported in patients receiving anti-TNFα therapies, particularly in patients with underlying rheumatologic disease (111,171–175). No cases of parasitic infections have been published in children with IBD. These sporadic reports have epidemiological risk factors identified, highlighting the importance of a high index of suspicion and thorough history.
Pediatric and adolescent patients with IBD are at increased risk for vaccine preventable illnesses (VPIs) and more fulminant disease associated with these infections than immunocompetent individuals. This risk can be exacerbated by disease severity and immunosuppressive therapies, including immunomodulators, corticosteroids, or biologics. Attention should be paid to vaccination status and attempts made to optimize vaccination at the time of diagnosis, especially because patients with IBD are increasingly receiving immunosuppressive medications earlier in their disease course. Several gastroenterology publications highlight the need to review immunizations at the time of the first GI visit (176,177). The evaluation and vaccination strategy described in Tables 2 and 4 should be incorporated into the initial visits. These recommendations are in line with recent reviews, guidelines, and position statements in the gastroenterology and infectious disease literature but provide additional detail on other aspects important in the primary evaluation to optimize health (eg, HIV and serologies) (23,178). Parents may be reluctant to have their children receive vaccines, such as influenza vaccine, because of inadequate knowledge, concern for adverse effects, or incorrect fear of causing an IBD flare. Studies evaluating the immunogenicity and safety of vaccines in children with IBD, however, have not found an increased risk of serious adverse effects or disease flares after vaccination (179–183).
All inactivated vaccinations should be updated according to the current AAP and Advisory Committee on Immunization Practices (ACIP) vaccine schedule and as clinically indicated, using an accelerated catch-up schedule as long as the minimum window between doses has elapsed (184). Reasons to give a vaccine on an earlier schedule include the risk of more severe illness in patients with IBD who develop a VPI and impaired vaccine immunogenicity once immunosuppressive therapy is introduced. For newly diagnosed pediatric patients with IBD, inactivated vaccines should optimally be given ≥2 weeks before immunosuppressive therapy is started. Although there are no safety concerns if given later, this time interval may allow for a more robust seroresponse before immunosuppression. Patients with established IBD already receiving anti-TNFα and other immunosuppressive therapies should receive inactivated vaccines in accordance with the ACIP vaccine schedule. Diminished immune responses may occur in some patients, but inactivated vaccines can be given safely.
Studies evaluating the immunogenicity of inactivated vaccines in children with IBD are limited. Generally, most studies have shown that they respond adequately to inactivated vaccines, though response may vary by vaccine type and be impaired if administered while receiving immunosuppressive therapies. Pediatric patients with IBD have demonstrated adequate response to the 13-valent pneumococcal conjugate vaccine and hepatitis A vaccine when compared with healthy controls (182,185). Receipt of human papillomavirus vaccine was found to be safe and highly immunogenic in pediatric patients with IBD, even while immunosuppressed (181). Other studies, however, found that immune responses to influenza and the pneumococcal polysaccharide vaccine may be impaired in patients with IBD while on concurrent immunosuppressive medications (179,186). The HBV series may need to be repeated in this population because they may be at risk for higher rates of waning antibodies. One study of mostly adolescent patients with IBD found that only 56% (49/87) had protective levels against HBV infection despite completing the 3-dose vaccine series. In the group of 38 patients who were nonimmune despite receiving a full HBV series, 34 received a single booster dose; 26 of these 34 patients (76%) had an adequate response noted 4 weeks later (121). Patients receiving infliximab therapy were at increased risk for inadequate response. Pediatric patients with IBD with inadequate HBV antibody levels after the primary vaccine series should repeat the 3-dose series. The immune response should be rechecked 2 months after completion of the third dose to ensure the concentration of anti-HBs is ≥10 μIU/mL. The combined hepatitis A and hepatitis B (Twinrix, GlaxoSmithKline Biologicals, Rixensart, Belgium) vaccine may be more immunogenic than the monovalent HBV vaccine and may offer an advantage. No recommendations are available on how to proceed if a patient continues to have inadequate response after HBV revaccination. Table 4 provides a summary of vaccination strategies in pediatric patients with IBD.
We encourage completion of the live vaccine series for varicella and measles–mumps–rubella (MMR) soon after the patient is diagnosed with IBD and before any (low or high level) immunosuppressive therapy is started. Pediatric and adolescent patients with IBD should have VZV serologies obtained as defined in Table 4. A retrospective review of newly diagnosed pediatric patients with IBD found that only 77% had serologic evidence of varicella immunity, highlighting the importance of checking for both vaccine administration and serologic confirmation (187). Obtaining serologies should also be considered for patients who were only able to receive 1 dose of either VZV or MMR. Results of serologic testing can guide vaccination practices, and in nonimmune patients with IBD who have significant exposure to varicella or measles, this serologic information can help guide postexposure measures, including passive immunoprophylaxis.
We strongly encourage providing live virus vaccines at IBD diagnosis in nonimmune patients because it may take 2 to 3 weeks to establish a postvaccine immunogenic response and because live virus vaccines should ideally be administered ≥4 weeks before initiation of any immunosuppressive therapy (23,176). Initiation of immunosuppression should not be delayed to provide live vaccines if immediate treatment is needed for the underlying IBD. Thus, providing live virus vaccine at IBD diagnosis provides a window period to optimize the immune response to vaccination and safely escalate immunosuppressive therapies later in the IBD course in a timely fashion, if clinically needed.
Once immunosuppressive therapies are started, live vaccines are generally contraindicated currently. In the US, live vaccines include MMR, VZV, live attenuated influenza vaccine, oral typhoid, and yellow fever vaccines. The degree of immunosuppression that is considered high level and may hamper immune response to vaccination or compromise safety includes patients receiving any anti-TNFα agent (at any dosage) or other biologic agent (eg, rituximab), corticosteroid therapy with a daily dose of ≥20 mg (or in patients weighing <10 kg, >2 mg/kg/day), methotrexate (>0.4 mg/kg/wk), azathioprine (>3 mg/kg/day), or 6-mercaptopurine (>1.5 mg/kg/day) (23,176). For similar safety and efficacy reasons, live virus vaccines should not be given after discontinuation of high-level immunosuppression, unless 3 months have elapsed since the last dose.
The Infectious Diseases Society of America guidelines state that VZV vaccine is the only live vaccine that can be considered in patients with chronic inflammatory diseases without evidence of varicella immunity who are receiving chronic, low-level immunosuppression (strength of recommendation, weak; quality of evidence, very low) (23). This consideration, however, deviates from recommendations by the ACIP and Centers for Disease Control and Prevention. Concern for severe illness after exposure to varicella or measles and experience of safe administration of live vaccines in other significantly immunocompromised pediatric patients suggest that the benefit of vaccination may outweigh potential risks, depending on the extent of immunosuppression. Six patients (ages 6–20 years, 2 receiving anti-TNFα agents) with IBD received VZV vaccine while immunosuppressed without adverse events; 5 demonstrated seroconversion and immunogenicity (188). No prospective studies, however, have been conducted and additional data are needed to evaluate the immunogenicity and safety of MMR and VZV vaccinations in pediatric patients with IBD receiving immunosuppressive therapy.
Close household contacts of patients with IBD should be encouraged to be fully immunized according to the adult immunization schedule to minimize the risk of transmitting a VPI to a pediatric IBD patient (23,189). All of the live virus vaccines (with the exception of oral polio vaccine that is no longer used in the US) and smallpox vaccine may be given safely to household contacts of patients with IBD receiving immunosuppressive therapies.
All patients should be evaluated for history of viral, bacterial, and mycobacterial infections as detailed in Tables 2 and 4. This includes a review of vaccine records, prior illnesses, risk factors, and immunodiagnostics and serologies, if available.
Strategies for Safe Living and Infection Prevention in Patients With IBD
Since 2009, several documents have been published that provide guidance for safe living to patients with immunocompromising conditions that lead them to be vulnerable to certain types of infections (190–192). Pathogen-specific safe living recommendations are incorporated into the prevention section of the discussion for each pathogen in this document. Because every possible situation encountered cannot be anticipated, the principals of safe living for individuals with underlying medical conditions receiving immunosuppressive agents are summarized in Table 5. It is important to note that although vaccines are available for protection against some agents encountered in areas outside of the US, response to those vaccines may not be optimal, or those vaccines may be contraindicated during periods of treatment with potent immunosuppressive agents, including anti-TNFα therapy. For more details about unusual situations, ID and travel medicine experts should be consulted.
Refer to the following CDC websites for additional materials:
Opportunities for Research
Given limited pediatric data, multiinstitutional studies assessing incidence, microbiology, and severity of infections in pediatric patients with IBD receiving anti-TNFα therapies are necessary to understand the burden of disease and better assess whether laboratory screening has a role for certain infections. Additional data regarding optimal vaccination strategies are also needed. These efforts would provide data for evidence-based recommendations, optimize preventive strategies, including identification of a subset of patients who may benefit from prophylaxis, and how best to monitor for infections during anti-TNFα treatment.
When we recall Harald Hirschsprung (1830–1916), we think of primarily his eponymous hypertrophy of the colon, yet he was a extraordinarily keen observer who published 4 case histories of esophageal atresia with tracheoesophageal fistula (1861), elaborated on controlled hydrostatic reduction of ileocecal intussusception (1876) using enema therapy, and meticulously described 2 postmortem cases of pyloric stenosis in 1888. Thereafter, the treatment of pyloric stenosis was primarily via dilatation and gastroenterostomy, until Conrad Ramstedt (1867–1963) introduced his method of pylorotomy. In an address to the 5th annual meeting of the British Association of Paediatric Surgeons (1958), Selwyn Taylor quoted Ramstedt:
At the laparotomy on August 23, 1911, I was astonished at the pyloric tumour as thick as my thumb. After I had split the tumour down to the mucosa for a distance of about 2 cm. I had the impression that the stenosis had been relieved. I still tried, however, to accomplish the plastic procedure by transverse suture of the muscle edges. However, the tension on the sutures was so very strong that the first one cut through immediately. Then the thought shot through my head, “A plastic alteration of the cut edges is completely unnecessary; the stenosis seems to be already relieved by a simple splitting… .” [I] left the cut gaping, covering it with a tab of omentum for safety sake and ended the operation.
Taylor S. Arch Dis Child 1959;34:20–23
Conrad Ramstedt (1867–1963)
—Contributed by Angel R. Colón, MD
1. Aberra FN, Lichtenstein GR. Methods to avoid infections
in patients with inflammatory bowel disease. Inflamm Bowel Dis
2. Peake ST, Bernardo D, Mann ER, et al Mechanisms of action of anti-tumor necrosis factor alpha agents in Crohn's disease. Inflamm Bowel Dis
3. Koo S, Marty FM, Baden LR. Infectious complications associated with immunomodulating biologic agents. Infect Dis Clin North Am
4. Raychaudhuri SP, Nguyen CT, Raychaudhuri SK, et al Incidence and nature of infectious disease in patients treated with anti-TNF agents. Autoimmun Rev
5. Wallis RS. Biologics and infections
: lessons from tumor necrosis factor blocking agents. Infect Dis Clin North Am
6. Bongartz T, Sutton AJ, Sweeting MJ, et al Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections
and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA
7. Ford AC, Peyrin-Biroulet L. Opportunistic infections
with anti-tumor necrosis factor-alpha therapy in inflammatory bowel disease: meta-analysis of randomized controlled trials. Am J Gastroenterol
8. Burmester GR, Panaccione R, Gordon KB, et al Adalimumab: long-term safety in 23 458 patients from global clinical trials in rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis and Crohn's disease. Ann Rheum Dis
9. Van Limbergen J, Russell RK, Drummond HE, et al Definition of phenotypic characteristics of childhood-onset inflammatory bowel disease. Gastroenterology
10. Hyams J, Crandall W, Kugathasan S, et al Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn's disease in children. Gastroenterology
11. Baldassano R, Colletti RB, Cucchiara S, et al Serious infections
and associated risk factors in patients receiving infliximab and immunotherapies for children with inflammatory bowel disease: DEVELOP Registry Data. Gastroenterology
12. Hyams JS, Griffiths A, Markowitz J, et al Safety and efficacy of adalimumab for moderate to severe Crohn's disease in children. Gastroenterology
13. Rosh JR, Lerer T, Markowitz J, et al Retrospective Evaluation of the Safety and Effect of Adalimumab Therapy (RESEAT) in pediatric Crohn's disease. Am J Gastroenterol
14. Dulai PS, Thompson KD, Blunt HB, et al Risks of serious infection or lymphoma with anti-tumor necrosis factor therapy for pediatric inflammatory bowel disease
: a systematic review. Clin Gastroenterol Hepatol
15. Toussi SS, Pan N, Walters HM, et al Infections
in children and adolescents with juvenile idiopathic arthritis and inflammatory bowel disease treated with tumor necrosis factor-alpha inhibitors: systematic review of the literature. Clin Infect Dis
16. Le Saux N. Biologic response modifiers to decrease inflammation: focus on infection risks. Paediatr Child Health
17. Veereman-Wauters G, de Ridder L, Veres G, et al Risk of infection and prevention in pediatric patients with IBD: ESPGHAN IBD Porto Group commentary. J Pediatr Gastroenterol Nutr
18. Van Assche G, Lewis JD, Lichtenstein GR, et al The London position statement of the World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn's and Colitis Organisation: safety. Am J Gastroenterol
19. Rahier JF, Magro F, Abreu C, et al Second European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections
in inflammatory bowel disease. J Crohns Colitis
20. D’Haens GR, Panaccione R, Higgins PD, et al The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn's and Colitis Organization: when to start, when to stop, which drug to choose, and how to predict response? Am J Gastroenterol
21. Furst DE, Keystone EC, Braun J, et al Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2010. Ann Rheum Dis
2011; 70 (suppl 1):i2–i36.
22. Lichtenstein GR, Feagan BG, Cohen RD, et al Serious infection and mortality in patients with Crohn's disease: more than 5 years of follow-up in the TREAT registry. Am J Gastroenterol
23. Rubin LG, Levin MJ, Ljungman P, et al 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis
24. Toruner M, Loftus EV Jr, Harmsen WS, et al Risk factors for opportunistic infections
in patients with inflammatory bowel disease. Gastroenterology
25. Lawrance IC, Radford-Smith GL, Bampton PA, et al Serious infections
in patients with inflammatory bowel disease receiving anti-tumor-necrosis-factor-alpha therapy: an Australian and New Zealand experience. J Gastroenterol Hepatol
26. Wallis RS, Broder MS, Wong JY, et al Granulomatous infectious diseases associated with tumor necrosis factor antagonists. Clin Infect Dis
27. Serradori T, Germain A, Scherrer ML, et al The effect of immune therapy on surgical site infection following Crohn's Disease resection. Br J Surg
28. Billioud V, Ford AC, Tedesco ED, et al Preoperative use of anti-TNF therapy and postoperative complications in inflammatory bowel diseases: a meta-analysis. J Crohns Colitis
29. Peyrin-Biroulet L, Deltenre P, de Suray N, et al Efficacy and safety of tumor necrosis factor antagonists in Crohn's disease: meta-analysis of placebo-controlled trials. Clin Gastroenterol Hepatol
30. Dixon WG, Watson K, Lunt M, et al Rates of serious infection, including site-specific and bacterial intracellular infection, in rheumatoid arthritis patients receiving anti-tumor necrosis factor therapy: results from the British Society for Rheumatology Biologics Register. Arthritis Rheum
31. FDA. FDA Drug Safety Communication: drug labels for the tumor necrosis factor-alpha blockers now include warnings about infection with Legionella
bacteria. In: FDAU, editor. US: Department of Health and Human Services; 2011.
32. Tubach F, Ravaud P, Salmon-Ceron D, et al Emergence of Legionella pneumophila
pneumonia in patients receiving tumor necrosis factor-alpha antagonists. Clin Infect Dis
33. Tablan OC, Anderson LJ, Besser R, et al Guidelines for preventing health-care–associated pneumonia, 2003: recommendations of CDC and the Healthcare Infection Control Practices Advisory Committee. MMWR Recomm Rep
2004; 53 (RR-3):1–36.
34. Chuang MH, Singh J, Ashouri N, et al Listeria
meningitis after infliximab treatment of ulcerative colitis. J Pediatr Gastroenterol Nutr
35. Kamath BM, Mamula P, Baldassano RN, et al Listeria
meningitis after treatment with infliximab. J Pediatr Gastroenterol Nutr
36. Miranda-Bautista J, Padilla-Suarez C, Bouza E, et al Listeria monocytogenes
infection in inflammatory bowel disease patients: case series and review of the literature. Eur J Gastroenterol Hepatol
37. Silk BJ, Date KA, Jackson KA, et al Invasive listeriosis in the Foodborne Diseases Active Surveillance Network (FoodNet), 2004-2009: further targeted prevention needed for higher-risk groups. Clin Infect Dis
2012; 54 (suppl 5):S396–S404.
38. CDC. Vital signs: Listeria
illnesses, deaths, and outbreaks—United States, 2009–2011. MMWR
39. Davies R, Dixon WG, Watson KD, et al Influence of anti-TNF patient warning regarding avoidance of high risk foods on rates of listeria
and salmonella infections
in the UK. Ann Rheum Dis
40. Abreu C, Rocha-Pereira N, Sarmento A, et al Nocardia infections
among immunomodulated inflammatory bowel disease patients: a review. World J Gastroenterol
41. Johnson NB, Hayes LD, Brown K, et al CDC National Health Report: Leading Causes of Morbidity and Mortality and Associated Behavioral Risk and Protective Factors-United States, 2005-2013. MMWR Surveill Summ
42. Rim JY, Tenorio AR. Salmonella
septic arthritis in a patient with Crohn's disease on infliximab. Inflamm Bowel Dis
43. Turner D, Travis SP, Griffiths AM, et al Consensus for managing acute severe ulcerative colitis in children: a systematic review and joint statement from ECCO, ESPGHAN, and the Porto IBD Working Group of ESPGHAN. Am J Gastroenterol
44. Pickering LK, Marano N, Bocchini JA, et al Exposure to nontraditional pets at home and to animals in public settings: risks to children. Pediatrics
45. Allendoerfer R, Deepe GS Jr. Blockade of endogenous TNF-alpha exacerbates primary and secondary pulmonary histoplasmosis by differential mechanisms. J Immunol
46. Tsiodras S, Samonis G, Boumpas DT, et al Fungal infections
complicating tumor necrosis factor alpha blockade therapy. Mayo Clin Proc
47. Ordonez ME, Farraye FA, Di Palma JA. Endemic fungal infections
in inflammatory bowel disease associated with anti-TNF antibody therapy. Inflamm Bowel Dis
48. Warris A, Bjorneklett A, Gaustad P. Invasive pulmonary aspergillosis associated with infliximab therapy. N Engl J Med
49. Wallis RS, Broder M, Wong J, et al Reactivation of latent granulomatous infections
by infliximab. Clin Infect Dis
2005; 41 (suppl 3):S194–S198.
50. Russell RK, Wilson ML, Loganathan S, et al A British Society of Paediatric Gastroenterology, Hepatology and Nutrition survey of the effectiveness and safety of adalimumab in children with inflammatory bowel disease. Aliment Pharmacol Ther
51. Huang A, Huang C, Kugathasan S. Vertebral osteomyelitis due to Candida parapsilosis
in a child with Crohn disease while receiving anti-TNF therapy. J Pediatr Gastroenterol Nutr
52. Pappas PG, Kauffman CA, Andes DR, et al Clinical practice guidelines for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis
53. Bergstrom L, Yocum DE, Ampel NM, et al Increased risk of coccidioidomycosis in patients treated with tumor necrosis factor alpha antagonists. Arthritis Rheum
54. Dweik M, Baethge BA, Duarte AG. Coccidioidomycosis pneumonia in a nonendemic area associated with infliximab. South Med J
55. Blair JE, Coakley B, Santelli AC, et al Serologic testing for symptomatic coccidioidomycosis in immunocompetent and immunosuppressed hosts. Mycopathologia
56. Galgiani JN, Ampel NM, Blair JE, et al Coccidioidomycosis. Clin Infect Dis
57. Miller R, Assi M. Endemic fungal infections
in solid organ transplantation. Am J Transplant
2013; 13 (suppl 4):250–261.
58. Winthrop KL. Risk and prevention of tuberculosis and other serious opportunistic infections
associated with the inhibition of tumor necrosis factor. Nat Clin Pract Rheumatol
59. Gupta M, Jafri K, Sharim R, et al Immune reconstitution inflammatory syndrome associated with biologic therapy. Curr Allergy Asthma Rep
60. Perfect JR, Dismukes WE, Dromer F, et al Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis
61. Wood KL, Hage CA, Knox KS, et al Histoplasmosis after treatment with anti-tumor necrosis factor-alpha therapy. Am J Respir Crit Care Med
62. Dotson JL, Crandall W, Mousa H, et al Presentation and outcome of histoplasmosis in pediatric inflammatory bowel disease
patients treated with antitumor necrosis factor alpha therapy: a case series. Inflamm Bowel Dis
63. Hage CA, Bowyer S, Tarvin SE, et al Recognition, diagnosis, and treatment of histoplasmosis complicating tumor necrosis factor blocker therapy. Clin Infect Dis
64. Vergidis P, Avery RK, Wheat LJ, et al Histoplasmosis complicating tumor necrosis factor-alpha blocker therapy: a retrospective analysis of 98 cases. Clin Infect Dis
65. Hage CA, Ribes JA, Wengenack NL, et al A multicenter evaluation of tests for diagnosis of histoplasmosis. Clin Infect Dis
66. Wheat LJ, Freifeld AG, Kleiman MB, et al Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis
67. Reid AB, Chen SC, Worth LJ. Pneumocystis jirovecii
pneumonia in non-HIV-infected patients: new risks and diagnostic tools. Curr Opin Infect Dis
68. Kaur N, Mahl TC. Pneumocystis jiroveci
) pneumonia after infliximab therapy: a review of 84 cases. Dig Dis Sci
69. Sepkowitz KA. Opportunistic infections
in patients with and patients without acquired immunodeficiency syndrome. Clin Infect Dis
70. Tschudy J, Michail S. Disseminated histoplasmosis and pneumocystis
pneumonia in a child with Crohn disease receiving infliximab. J Pediatr Gastroenterol Nutr
71. Green H, Paul M, Vidal L, et al Prophylaxis of Pneumocystis
pneumonia in immunocompromised non-HIV-infected patients: systematic review and meta-analysis of randomized controlled trials. Mayo Clin Proc
72. Poppers DM, Scherl EJ. Prophylaxis against Pneumocystis
pneumonia in patients with inflammatory bowel disease: toward a standard of care. Inflamm Bowel Dis
73. Long MD, Farraye FA, Okafor PN, et al Increased risk of pneumocystis jiroveci
pneumonia among patients with inflammatory bowel disease. Inflamm Bowel Dis
74. Okafor PN, Nunes DP, Farraye FA. Pneumocystis jiroveci
pneumonia in inflammatory bowel disease: when should prophylaxis be considered? Inflamm Bowel Dis
75. Calvet X, Panes J, Alfaro N, et al Delphi consensus statement: quality indicators for inflammatory bowel disease comprehensive care units. J Crohns Colitis
76. Roach DR, Bean AG, Demangel C, et al TNF regulates chemokine induction essential for cell recruitment, granuloma formation, and clearance of mycobacterial infection. J Immunol
77. Winthrop KL, Baxter R, Liu L, et al Mycobacterial diseases and antitumour necrosis factor therapy in USA. Ann Rheum Dis
78. Marehbian J, Arrighi HM, Hass S, et al Adverse events associated with common therapy regimens for moderate-to-severe Crohn's disease. Am J Gastroenterol
79. Keane J, Gershon S, Wise RP, et al Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med
80. Colombel JF, Sandborn WJ, Panaccione R, et al Adalimumab safety in global clinical trials of patients with Crohn's disease. Inflamm Bowel Dis
81. Debeuckelaere C, De Munter P, Van Bleyenbergh P, et al Tuberculosis infection following anti-TNF therapy in inflammatory bowel disease, despite negative screening. J Crohns Colitis
82. Hanauer SB, Feagan BG, Lichtenstein GR, et al Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet
83. Lorenzetti R, Zullo A, Ridola L, et al Higher risk of tuberculosis reactivation when anti-TNF is combined with immunosuppressive agents: a systematic review of randomized controlled trials. Ann Med
84. Wallis RS. Tumour necrosis factor antagonists: structure, function, and tuberculosis risks. Lancet Infect Dis
85. Cruz AT, Karam LB, Orth RC, et al Disseminated tuberculosis in 2 children with inflammatory bowel disease receiving infliximab. Pediatr Infect Dis J
86. Winston CA, Menzies HJ. Pediatric and adolescent tuberculosis in the United States, 2008–2010. Pediatrics
87. Pickering LKBC, Kimberlin DW, Long SS. AAP.. Tuberculosis. Red Book: 2012 Report of the Committee on Infectious Diseases. 29 ed. Elk
. Grove Village, IL: American Academy of Pediatrics; 2012. 736–759.
88. Cruz AT, Merchant O, Zafar A, et al Tuberculosis exposure, infection and disease among children with medical comorbidities. Pediatr Infect Dis J
89. Graham SM, Ahmed T, Amanullah F, et al Evaluation of tuberculosis diagnostics in children: 1. Proposed clinical case definitions for classification of intrathoracic tuberculosis disease. Consensus from an expert panel. J Infect Dis
2012; 205 (suppl 2):S199–S208.
90. Starke JR. Interferon-gamma release assays for diagnosis of tuberculosis infection and disease in children. Pediatrics
91. Papay P, Eser A, Winkler S, et al Factors impacting the results of interferon-gamma release assay and tuberculin skin test in routine screening for latent tuberculosis in patients with inflammatory bowel diseases. Inflamm Bowel Dis
92. Schoepfer AM, Flogerzi B, Fallegger S, et al Comparison of interferon-gamma release assay versus tuberculin skin test for tuberculosis screening in inflammatory bowel disease. Am J Gastroenterol
93. Solovic I, Sester M, Gomez-Reino JJ, et al The risk of tuberculosis related to tumour necrosis factor antagonist therapies: a TBNET consensus statement. Eur Respir J
94. Singh JA, Furst DE, Bharat A, et al 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken)
95. Kim YJ, Kim YG, Shim TS, et al Safety of resuming tumour necrosis factor inhibitors in patients who developed tuberculosis as a complication of previous TNF inhibitors. Rheumatology (Oxford)
96. Jordan N, Waghmare A, Abi-Ghanem AS, et al Systemic Mycobacterium avium complex
infection during antitumor necrosis factor-alpha therapy in pediatric Crohn disease. J Pediatr Gastroenterol Nutr
97. Pickering LKBC, Kimberlin DW, Long SS. AAP. Diseases caused by nontuberculous mycobacteria. Red Book: 2012 Report of the Committee on Infectious Diseases
. Elk Grove Village, IL: American Academy of Pediatrics; 2012. 759–767.
98. De Groote MA, Pace NR, Fulton K 3rd, et al Relationships between Mycobacterium
isolates from patients with pulmonary mycobacterial infection and potting soils. Appl Environ Microbiol
99. Cullen G, Baden RP, Cheifetz AS. Varicella zoster virus infection in inflammatory bowel disease. Inflamm Bowel Dis
100. Kim SY, Solomon DH. Tumor necrosis factor blockade and the risk of viral infection. Nat Rev Rheumatol
101. Shale MJ, Seow CH, Coffin CS, et al Review article: chronic viral infection in the anti-tumour necrosis factor therapy era in inflammatory bowel disease. Aliment Pharmacol Ther
102. Dave M, Purohit T, Razonable R, et al Opportunistic infections
due to inflammatory bowel disease therapy. Inflamm Bowel Dis
103. Ayre K, Warren BF, Jeffery K, et al The role of CMV in steroid-resistant ulcerative colitis: a systematic review. J Crohns Colitis
104. Lawlor G, Moss AC. Cytomegalovirus in inflammatory bowel disease: pathogen or innocent bystander? Inflamm Bowel Dis
105. Kandiel A, Lashner B. Cytomegalovirus colitis complicating inflammatory bowel disease. Am J Gastroenterol
106. Hommes DW, Sterringa G, van Deventer SJ, et al The pathogenicity of cytomegalovirus in inflammatory bowel disease: a systematic review and evidence-based recommendations for future research. Inflamm Bowel Dis
107. D’Ovidio V, Vernia P, Gentile G, et al Cytomegalovirus infection in inflammatory bowel disease patients undergoing anti-TNFαlpha therapy. J Clin Virol
108. Cascio A, Iaria C, Ruggeri P, et al Cytomegalovirus pneumonia in patients with inflammatory bowel disease: a systematic review. Int J Infect Dis
109. Babu TG, Boctor D, Davey A, et al Cytomegalovirus-associated hemophagocytic syndrome in a child with Crohn disease receiving azathioprine. J Pediatr Gastroenterol Nutr
110. Helbling D, Breitbach TH, Krause M. Disseminated cytomegalovirus infection in Crohn's disease following anti-tumour necrosis factor therapy. Eur J Gastroenterol Hepatol
111. Salmon-Ceron D, Tubach F, Lortholary O, et al Drug-specific risk of non-tuberculosis opportunistic infections
in patients receiving anti-TNF therapy reported to the 3-year prospective French RATIO registry. Ann Rheum Dis
112. Pickering O, Weinstein T, Rubin LG, et al Fatal disseminated cytomegalovirus infection associated with infliximab and 6-mercaptopurine therapy in a child with Crohn disease. Pediatr Infect Dis J
113. Chirumamilla SR, He C, Racusen LC, et al Acute kidney injury in a girl with ulcerative colitis and cytomegalovirus-induced focal segmental glomerular sclerosis. World J Pediatr
114. Ghidini B, Bellaiche M, Berrebi D, et al Cytomegalovirus colitis in children with inflammatory bowel disease. Gut
115. Balcarek KB, Bagley R, Cloud GA, et al Cytomegalovirus infection among employees of a children's hospital. No evidence for increased risk associated with patient care. JAMA
116. Ciccocioppo R, Racca F, Paolucci S, et al Human cytomegalovirus and Epstein–Barr virus infection in inflammatory bowel disease: need for mucosal viral load measurement. World J Gastroenterol
117. Ljungman P, Griffiths P, Paya C. Definitions of cytomegalovirus infection and disease in transplant recipients. Clin Infect Dis
118. Siegel JD, Rhinehart E, Jackson M, et al 2007 Guideline for Isolation Precautions: preventing transmission of infectious agents in health care settings. Am J Infect Control
2007; 35 (10 suppl 2):S65–S164.
119. Esteve M, Saro C, Gonzalez-Huix F, et al Chronic hepatitis B reactivation following infliximab therapy in Crohn's disease patients: need for primary prophylaxis. Gut
120. Perez-Alvarez R, Diaz-Lagares C, Garcia-Hernandez F, et al Hepatitis B virus (HBV) reactivation in patients receiving tumor necrosis factor (TNF)-targeted therapy: analysis of 257 cases. Medicine
121. Moses J, Alkhouri N, Shannon A, et al Hepatitis B immunity and response to booster vaccination in children with inflammatory bowel disease treated with infliximab. Am J Gastroenterol
122. Thompson ND, Perz JF, Moorman AC, et al Nonhospital health care-associated hepatitis B and C virus transmission: United States, 1998–2008. Ann Intern Med
123. Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults: American College Of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol
124. Hwang JP, Lok AS. Management of patients with hepatitis B who require immunosuppressive therapy. Nat Rev Gastroenterol Hepatol
125. Reddy KR, Beavers KL, Hammond SP, et al American Gastroenterological Association Institute guideline on the prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology
126. Michelin A, Henderson DK. Infection control guidelines for prevention of health care-associated transmission of hepatitis B and C viruses. Clin Liver Dis
127. Petersen BT, Chennat J, Cohen J, et al Multisociety guideline on reprocessing flexible GI endoscopes: 2011. Infect Control Hosp Epidemiol
128. Papa A, Felice C, Marzo M, et al Prevalence and natural history of hepatitis B and C infections
in a large population of IBD patients treated with anti-tumor necrosis factor-alpha agents. J Crohns Colitis
129. Pompili M, Biolato M, Miele L, et al Tumor necrosis factor-alpha inhibitors and chronic hepatitis C: a comprehensive literature review. World J Gastroenterol
130. Perz JF, Thompson ND, Schaefer MK, et al US outbreak investigations highlight the need for safe injection practices and basic infection control. Clin Liver Dis
131. Brunasso AM, Puntoni M, Gulia A, et al Safety of anti-tumour necrosis factor agents in patients with chronic hepatitis C infection: a systematic review. Rheumatology (Oxford)
132. Mack CL, Gonzalez-Peralta RP, Gupta N, et al NASPGHAN practice guidelines: diagnosis and management of hepatitis C infection in infants, children, and adolescents. J Pediatr Gastroenterol Nutr
133. CDC. Testing for HCV infection: an update of guidance for clinicians and laboratorians. MMWR
134. Marin M, Zhang JX, Seward JF. Near elimination of varicella deaths in the US after implementation of the vaccination program. Pediatrics
135. Winthrop KL, Baddley JW, Chen L, et al Association between the initiation of anti-tumor necrosis factor therapy and the risk of herpes zoster. JAMAV 309
136. Leung J, Harpaz R, Baughman AL, et al Evaluation of laboratory methods for diagnosis of varicella. Clin Infect Dis
137. Kopylov U, Levin A, Mendelson E, et al Prior varicella zoster virus exposure in IBD patients treated by anti-TNFs and other immunomodulators: implications for serological testing and vaccination guidelines. Aliment Pharmacol Ther
138. Updated recommendations for use of VariZIG—United States, 2013. MMWR
139. Rodemann JF, Dubberke ER, Reske KA, et al Incidence of Clostridium difficile
infection in inflammatory bowel disease. Clin Gastroenterol Hepatol
140. Sandberg KC, Davis MM, Gebremariam A, et al Disproportionate Rise in Clostridium difficile
-Associated Hospitalizations Among US Youth With Inflammatory Bowel Disease, 1997–2011. J Pediatr Gastroenterol Nutr
141. Mylonaki M, Langmead L, Pantes A, et al Enteric infection in relapse of inflammatory bowel disease: importance of microbiological examination of stool. Eur J Gastroenterol Hepatol
142. Pascarella F, Martinelli M, Miele E, et al Impact of Clostridium difficile
infection on pediatric inflammatory bowel disease
. J Pediatr
143. Schneeweiss S, Korzenik J, Solomon DH, et al Infliximab and other immunomodulating drugs in patients with inflammatory bowel disease and the risk of serious bacterial infections
. Aliment Pharmacol Ther
144. Das R, Feuerstadt P, Brandt LJ. Glucocorticoids are associated with increased risk of short-term mortality in hospitalized patients with Clostridium difficile
-associated disease. Am J Gastroenterol
145. Clayton EM, Rea MC, Shanahan F, et al The vexed relationship between Clostridium difficile
and inflammatory bowel disease: an assessment of carriage in an outpatient setting among patients in remission. Am J Gastroenterol
146. Issa M, Vijayapal A, Graham MB, et al Impact of Clostridium difficile
on inflammatory bowel disease. Clin Gastroenterol Hepatol
147. Schutze GE, Willoughby RE. Clostridium difficile
infection in infants and children. Pediatrics
148. Polage CR, Gyorke CE, Kennedy MA, et al Overdiagnosis of Clostridium difficile
Infection in the Molecular Test Era. JAMA Intern Med
149. Burnham CA, Carroll KC. Diagnosis of Clostridium difficile
infection: an ongoing conundrum for clinicians and for clinical laboratories. Clin Microbiol Rev
150. Khan N, Abbas AM, Lichtenstein GR, et al Risk of lymphoma in patients with ulcerative colitis treated with thiopurines: a nationwide retrospective cohort study. Gastroenterology
151. Subramaniam K, D’Rozario J, Pavli P. Lymphoma and other lymphoproliferative disorders in inflammatory bowel disease: a review. J Gastroenterol Hepatol
152. Vos AC, Bakkal N, Minnee RC, et al Risk of malignant lymphoma in patients with inflammatory bowel diseases: a Dutch nationwide study. Inflamm Bowel Dis
153. Allen PB, Laing G, Connolly A, et al EBV-associated colonic B-cell lymphoma following treatment with infliximab for IBD: a new problem? BMJ Case Rep
154. Schwartz LK, Kim MK, Coleman M, et al Case report: lymphoma arising in an ileal pouch anal anastomosis after immunomodulatory therapy for inflammatory bowel disease. Clin Gastroenterol Hepatol
155. Van Hauwaert V, Meers S, Verhoef G, et al Rectal non-Hodgkin's lymphoma in an infliximab treated patient with ulcerative colitis and primary sclerosing cholangitis. J Crohns Colitis
156. Torre-Cisneros J, Del Castillo M, Caston JJ, et al Infliximab does not activate replication of lymphotropic herpesviruses in patients with refractory rheumatoid arthritis. Rheumatology (Oxford)
157. Lavagna A, Bergallo M, Daperno M, et al Infliximab and the risk of latent viruses reactivation in active Crohn's disease. Inflamm Bowel Dis
158. Reijasse D, Le Pendeven C, Cosnes J, et al Epstein–Barr virus viral load in Crohn's disease: effect of immunosuppressive therapy. Inflamm Bowel Dis
159. Magro F, Santos-Antunes J, Albuquerque A, et al Epstein–Barr virus in inflammatory bowel disease-correlation with different therapeutic regimens. Inflamm Bowel Dis
160. Gidrewicz D, Lehman D, Rabizadeh S, et al Primary EBV infection resulting in lymphoproliferative disease in a teenager with Crohn disease. J Pediatr Gastroenterol Nutr
161. Virdis F, Tacci S, Messina F, et al Hemophagocytic lymphohistiocytosis caused by primary Epstein–Barr virus in patient with Crohn's disease. World J Gastrointest Surg
162. Nissen LH, Nagtegaal ID, de Jong DJ, et al Epstein–Barr virus in inflammatory bowel disease: the spectrum of intestinal lymphoproliferative disorders. J Crohns Colitis
163. Biank VF, Sheth MK, Talano J, et al Association of Crohn's disease, thiopurines, and primary Epstein–Barr virus infection with hemophagocytic lymphohistiocytosis. J Pediatr
164. Allen UD, Preiksaitis JK. Epstein–Barr virus and posttransplant lymphoproliferative disorder in solid organ transplantation. Am J Transplant
2013; 13 (suppl 4):107–120.
167. Cepeda EJ, Williams FM, Ishimori ML, et al The use of anti-tumour necrosis factor therapy in HIV-positive individuals with rheumatic disease. Ann Rheum Dis
168. Branson BM, Handsfield HH, Lampe MA, et al Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health-care settings. MMWR Recomm Rep
2006; 55 (RR-14):1–17.
169. Moyer VA. Screening for HIV: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med
170. Hyams J, Walters TD, Crandall W, et al Safety and efficacy of maintenance infliximab therapy for moderate-to-severe Crohn's disease in children: REACH open-label extension. Curr Med Res Opin
171. Young JD, McGwire BS. Infliximab and reactivation of cerebral toxoplasmosis. N Engl J Med
172. Krishnamurthy R, Dincer HE, Whittemore D. Strongyloides stercoralis hyperinfection in a patient with rheumatoid arthritis after anti-TNF-alpha therapy. J Clin Rheumatol
173. Geraghty EM, Ristow B, Gordon SM, et al Overwhelming parasitemia with Plasmodium falciparum infection in a patient receiving infliximab therapy for rheumatoid arthritis. Clin Infect Dis
174. Guedes-Barbosa LS, Pereira da Costa I, Fernandes V, et al Leishmaniasis during anti-tumor necrosis factor therapy: report of 4 cases and review of the literature (additional 28 cases). Semin Arthritis Rheum
175. Zanger P, Kotter I, Kremsner PG, et al Tumor necrosis factor alpha antagonist drugs and leishmaniasis in Europe. Clin Microbiol Infect
176. Wasan SK, Baker SE, Skolnik PR, et al A practical guide to vaccinating the inflammatory bowel disease patient. Am J Gastroenterol
177. Lu Y, Bousvaros A. Immunizations in children with inflammatory bowel disease treated with immunosuppressive therapy. Gastroenterol Hepatol
178. Robinson CLACoIP. Recommended Immunization Schedules for Persons Aged 0 through 18 years—United States, 2016. MMWR
179. deBruyn JC, Hilsden R, Fonseca K, et al Immunogenicity and safety of influenza vaccination in children with inflammatory bowel disease. Inflamm Bowel Dis
180. Mamula P, Markowitz JE, Piccoli DA, et al Immune response to influenza vaccine in pediatric patients with inflammatory bowel disease. Clin Gastroenterol Hepatol
181. Jacobson DL, Bousvaros A, Ashworth L, et al Immunogenicity and tolerability to human papillomavirus-like particle vaccine in girls and young women with inflammatory bowel disease. Inflamm Bowel Dis
182. Banaszkiewicz A, Targonska B, Kowalska-Duplaga K, et al Immunogenicity of 13-valent pneumococcal conjugate vaccine in pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis
183. Benchimol EI, Hawken S, Kwong JC, et al Safety and utilization of influenza immunization in children with inflammatory bowel disease. Pediatrics
184. Robinson CL. Advisory Committee on Immunization Practices Recommended Immunization Schedules for Persons Aged 0 Through 18 Years—United States, 2016. MMWR
185. Radzikowski A, Banaszkiewicz A, Lazowska-Przeorek I, et al Immunogenecity of hepatitis A vaccine in pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis
186. Lee CK, Kim HS, Ye BD, et al Patients with Crohn's disease on anti-tumor necrosis factor therapy are at significant risk of inadequate response to the 23-valent pneumococcal polysaccharide vaccine. J Crohns Colitis
187. Ansari F, Baker RD, Patel R, et al Varicella immunity in inflammatory bowel disease. J Pediatr Gastroenterol Nutr
188. Lu Y, Bousvaros A. Varicella vaccination in children with inflammatory bowel disease receiving immunosuppressive therapy. J Pediatr Gastroenterol Nutr
189. Waszczuk K, Waszczuk E, Mulak A, et al A “cocoon immunization strategy” among patients with inflammatory bowel disease. Eur J Gastroenterol Hepatol
190. Yokoe D, Casper C, Dubberke E, et al Safe living after hematopoietic cell transplantation. Bone Marrow Transplant
191. Avery RK, Michaels MG. Strategies for safe living after solid organ transplantation. Am J Transplant
2013; 13 (suppl 4):304–310.
192. Saiman L, Siegel JD, LiPuma JJ, et al Infection prevention and control guideline for cystic fibrosis: 2013 update. Infect Control Hosp Epidemiol
2014; 35 (suppl 1):S1–S67.
193. Ruemmele FM, Veres G, Kolho KL, et al Consensus guidelines of ECCO/ESPGHAN on the medical management of pediatric Crohn's disease. J Crohns Colitis
194. Nordgaard-Lassen I, Dahlerup JF, Belard E, et al Guidelines for screening, prophylaxis and critical information prior to initiating anti-TNF-alpha treatment. Dan Med J
infections; pediatric inflammatory bowel disease; tumor necrosis factor α inhibitors
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