Investigating Infection in the Patient With RA

In 2009, a question of proper practices was brought before the Arizona Regulatory Board of Physician Assistants. The patient in question was seen in an emergency department by a PA/physician health care team for complaints of cough and fever at home. In question was the team’s decision to discharge the patient, who had a history of immunosuppression with an anti–tumor necrosis factor (anti-TNF) medication for a chronic joint disorder, without ordering laboratory tests or blood cultures. Although there is textbook instruction for evaluation of patients with infection who use agents in this drug class,¹ many clinicians may be unaware that blood cultures should be drawn as part of a proper workup.

In the United States, medications that have anti-TNF-alpha ­(anti-TNF-a) properties, including adalimumab, etanercept, and infliximab, are approved by the FDA to treat rheumatoid arthritis (RA).² Many patients take a second medication; others, a combination of medications. Options ­include methotrexate, cyclo­sporine, prednisone, and hydroxychloroquine. Typically, anti-TNF medications represent second- or third-line therapy after unsatisfactory response to disease-modifying antirheumatic drugs (DMARDs).

Although anti-TNF medications are effective for treatment of autoimmune diseases like RA, it should be noted that TNF-a is an important component in the proper functioning of the immune system. Accordingly, it is recognized that patients who use anti-TNF medications are at increased risk for infection.³ Indeed, patients with RA are already at greater risk for contracting infectious illnesses, even before immunosuppressive medications are administered.⁴

TNF is one cytokine that is responsible for humoral activation and subsequent inflammation.⁵ In RA and certain other diseases (eg, Crohn’s disease, lupus), TNF-a’s interaction with other cytokines is at least partially responsible for the inflammation that leads to RA-associated joint damage.⁵ In­fliximab and adalimumab are monoclonal antibodies developed specifically to bind with TNF-a, thereby neutralizing a pathway for further release of inflammatory cytokines. 

In contrast to recombinant soluble receptors, such as etanercept, the site-specific monoclonal antibodies for TNF-a (ie, infliximab, adalimumab) may play a greater role in suppressing macrophages, which contribute significantly to cellular immunity. Macrophage inhibition may further increase the body’s vulnerability to opportunistic infection.⁶

Anti-TNF Agents: Clinical Trials

The relationship between treatment with immunosuppressive agents (including infliximab and other anti-TNF medications) and serious infection is evident in the literature. In a 2005 study, Listing et al⁴ followed patients for 12 months after they were started on etanercept, infliximab, anakinra (another cytokine inhibitor), or DMARDs (controls). Ninety-two (26.5%) of the 346 patients who were given infliximab, compared with 6% of 601 controls, developed infection; of these, 20 patients (21.7%) had a determinable serious infection (ie, that was considered life-threatening or resulted in inpatient treatment, significant disability, or death). Thus, serious infection affected 5.8% of the patient population studied who had received infliximab.

Five of the 512 patients who used etanercept were diagnosed with sepsis, but no episodes of bacteremia were recorded among the infliximab patients. The most prevalent serious infections observed were pneumonia, infective arthritis, and various skin and subcutaneous infections (see table⁴). Less prevalent respiratory tract ailments included bronchitis, lung abscess, and pleural infection. Overall, small numbers of cases of sepsis were reported, making it difficult for the study authors to comment on the disparity of sepsis rates among treatment groups.⁴

Another prospective study followed 28 patients (median age, 53) who were treated with infliximab between 1999 and 2002.⁷ Dosages administered ranged from the standard 3 mg/kg every 8 weeks to 10 mg/kg every 4 weeks, with variation in duration of treatment. A 13% higher rate of infection was ­reported among these patients, compared with patients who received conventional therapy (DMARDs) over a two-year ­period.

Six patients were determined to have serious, life-threatening infections (ie, requiring hospitalization or IV antibiotic therapy). Of these, two were given a diagnosis of bacteremia via blood cultures. The cultures grew Streptococcus pneumoniae in one patient, who was also diagnosed incidentally with Pneumocystis carinii through bronchial washings, and the other patient had blood cultures positive for Staphylococcus aureus and bilateral necrotizing pulmonary abscesses.

Case Studies

Individual case studies of infection in patients taking infliximab or other anti-TNF agents for RA reveal specific illnesses, their time lines, and relevant patient management. Crum et al2 reported an example of the common pathogen S pneumoniae in a 47-year-old patient who developed a left lower lobe pneumonia. Three of four blood cultures were positive, CBC with differential showed abnormal results, and the patient’s temperature on presentation was 39.5°C.

In a report of two cases of severe abdominal infection during administration of anti-TNF medication, one 40-year-old woman using infliximab for severe RA presented with a temperature of 39.2°C and a three-day history of abdominal pain. Escherichia coli was identified from blood cultures, although urine cultures were negative. CT led to a diagnosis of pyelonephritis. The patient had become septic but improved after 48 hours’ therapy with IV cefuroxime and gentamicin.⁸

The second patient was a man, age 60, with a two-week history of abdominal pain and a six-month history of effective etanercept use for persistent psoriatic arthritis. Contrast-­enhanced CT revealed a large splenic abscess, and blood cultures identified infection with S aureus. Management began with unsuccessful high-dose IV antibiotics, followed by laparotomy and splenectomy, postsurgical sepsis, and finally, high-dose inotropic therapy that proved effective.⁸

Infection With Listeria monocytogenes

Listeria monocytogenes, a pathogen sometimes identified in patients who receive anti-TNF-a therapy, has been the focus of several case reports. For example, Gluck et al⁹ describe a 60-year-old woman with a history of RA and previous treatment with multiple therapies who had recently completed a five-month regimen with infliximab (10 mg/kg every 4 weeks). Fourteen days after receiving her last dose, she presented to a hospital with anemia, fever (measurement undisclosed), and abdominal pain. She was given multiple diagnoses, including a gastric ulcer without hemorrhage, a pulmonary infiltrate, and acute cholecystitis. After she underwent cholecystectomy, her condition deteriorated, and head CT revealed several small subarachnoid hemorrhages and severe brain edema.

The patient experienced multi–organ system failure and died after a brain-stem herniation. What should be noted is that a blood culture taken one day after her surgery was positive for L monocytogenes, as was an intraoperative gallbladder swab-culture for the same organism—this, despite presumed antibiotic therapy.

A second patient described by Gluck et al⁹ was a 62-year-old woman with RA who developed cholecystitis after her second dose of infliximab, administered over a two-week period (200 mg IV/dose). As in the previous case, the patient manifested cerebral edema and had a fever after undergoing cholecystectomy. Blood cultures performed after the surgery were positive for L monocytogenes. The patient recovered slowly with proper antibiotic therapy, including ampicillin and gentamicin.

A third example of listeriosis involved a 52-year-old patient with RA who presented with symptoms including fever and abdominal pain. CT led to a diagnosis of terminal ileitis. One of two blood cultures taken was positive for L monocytogenes.⁶

Finally, a 79-year-old patient with a long-standing diagnosis of RA and prosthetic hips reported a fever of three weeks’ duration and left leg pain. As the patient had no fever on initial presentation, blood cultures were not drawn until five days after he was admitted. Three of four blood cultures were positive for L monocytogenes.⁶

Less Common Infections

Other less common bacterial etiologies have also been reported in the literature, including a fatal case of Salmonella enteritidis septicemia with a pleural empyema after treatment with infliximab.¹⁰ Another fatality was reported in a 54-year-old man who had necrotizing fasciitis, with a group A hemolytic streptococcus that grew in blood cultures. The patient, who had been taking in­fliximab, had no report of fever before or during his hospitalization.¹¹

Discussion

Although infliximab is effective for controlling the symptoms of RA, clinicians must be attentive to fever in patients who use it—even a patient-­reported fever that may not be present on physical exam. Due to the potential blunting of the immune response associated with infliximab use, a serious underlying infection can occur without fever. General malaise may be the only symptom a patient reports.

Infliximab and other anti-TNF medications are included in a textbook list of immunosuppressive medications whose use warrants special attention for patients who are evaluated for infection in an emergency setting. According to Burns,¹ “Rapid diagnosis and early initiation of therapy are essential in preventing serious morbidity and mortality in immunocompromised patients who often have subtle or unusual presentations and are difficult to ­diagnose.”¹

Active tuberculosis (ATB) is another serious illness that has been reported with infliximab use.^12,13 Patients should be screened for TB before taking infliximab, but clinicians must also be aware that ATB can develop as an unwanted result of infliximab therapy. Standard blood cultures may not be an effective means of identifying ATB.

Several types of infection may occur, with or without confirmation by positive blood cultures, including viral and fungal infections. Even bacterial infections, such as a urinary tract infection or bacterial pneumonia, may not yield positive blood cultures immediately, if ever. Each of these has been included among serious illnesses associated with use of anti-TNF medications.⁴ Nevertheless, blood cultures—Gram-stain, anaerobic, and aerobic blood cultures with sensitivities—should be considered an important component of any comprehensive infectious disease evaluation.

Although the purpose of this article has been to emphasize the importance of blood cultures in the timely diagnosis and treatment of patients taking ­anti-TNF medications who present with symptoms of infectious disease, it is important to remember that blood cultures are only part of a full infectious disease workup.

Conclusion

The clinical studies and case presentations discussed here serve to remind clinicians that timely acquisition and evaluation of blood cultures are essential to the identification of serious bacteriologic pathogens, and to the chances of recovery in the RA patient with a systemic infection who is immunosuppressed as a result of treatment with infliximab or other anti-TNF agent. Rapid identification of pathogenic organisms will facilitate the implementation of appropriate therapy, thus avoiding the often-deadly outcomes of severe infection and sepsis. Gram-stain, anaerobic, and aerobic blood cultures with sensitivities should be considered the standard of care in any infliximab-treated patient who presents with fever, a patient report of a fever, or any other signs, symptoms, or patient history that could suggest infection.

While this article focuses for the most part on infections associated with infliximab use, the same strategy in standard of practice should apply to all patients who use anti-TNF therapy for treatment of RA.

In 2009, a question of proper practices was brought before the Arizona Regulatory Board of Physician Assistants. The patient in question was seen in an emergency department by a PA/physician health care team for complaints of cough and fever at home. In question was the team’s decision to discharge the patient, who had a history of immunosuppression with an anti–tumor necrosis factor (anti-TNF) medication for a chronic joint disorder, without ordering laboratory tests or blood cultures. Although there is textbook instruction for evaluation of patients with infection who use agents in this drug class,¹ many clinicians may be unaware that blood cultures should be drawn as part of a proper workup.

In the United States, medications that have anti-TNF-alpha ­(anti-TNF-a) properties, including adalimumab, etanercept, and infliximab, are approved by the FDA to treat rheumatoid arthritis (RA).² Many patients take a second medication; others, a combination of medications. Options ­include methotrexate, cyclo­sporine, prednisone, and hydroxychloroquine. Typically, anti-TNF medications represent second- or third-line therapy after unsatisfactory response to disease-modifying antirheumatic drugs (DMARDs).

Although anti-TNF medications are effective for treatment of autoimmune diseases like RA, it should be noted that TNF-a is an important component in the proper functioning of the immune system. Accordingly, it is recognized that patients who use anti-TNF medications are at increased risk for infection.³ Indeed, patients with RA are already at greater risk for contracting infectious illnesses, even before immunosuppressive medications are administered.⁴

TNF is one cytokine that is responsible for humoral activation and subsequent inflammation.⁵ In RA and certain other diseases (eg, Crohn’s disease, lupus), TNF-a’s interaction with other cytokines is at least partially responsible for the inflammation that leads to RA-associated joint damage.⁵ In­fliximab and adalimumab are monoclonal antibodies developed specifically to bind with TNF-a, thereby neutralizing a pathway for further release of inflammatory cytokines. 

In contrast to recombinant soluble receptors, such as etanercept, the site-specific monoclonal antibodies for TNF-a (ie, infliximab, adalimumab) may play a greater role in suppressing macrophages, which contribute significantly to cellular immunity. Macrophage inhibition may further increase the body’s vulnerability to opportunistic infection.⁶

Anti-TNF Agents: Clinical Trials

The relationship between treatment with immunosuppressive agents (including infliximab and other anti-TNF medications) and serious infection is evident in the literature. In a 2005 study, Listing et al⁴ followed patients for 12 months after they were started on etanercept, infliximab, anakinra (another cytokine inhibitor), or DMARDs (controls). Ninety-two (26.5%) of the 346 patients who were given infliximab, compared with 6% of 601 controls, developed infection; of these, 20 patients (21.7%) had a determinable serious infection (ie, that was considered life-threatening or resulted in inpatient treatment, significant disability, or death). Thus, serious infection affected 5.8% of the patient population studied who had received infliximab.

Five of the 512 patients who used etanercept were diagnosed with sepsis, but no episodes of bacteremia were recorded among the infliximab patients. The most prevalent serious infections observed were pneumonia, infective arthritis, and various skin and subcutaneous infections (see table⁴). Less prevalent respiratory tract ailments included bronchitis, lung abscess, and pleural infection. Overall, small numbers of cases of sepsis were reported, making it difficult for the study authors to comment on the disparity of sepsis rates among treatment groups.⁴

Another prospective study followed 28 patients (median age, 53) who were treated with infliximab between 1999 and 2002.⁷ Dosages administered ranged from the standard 3 mg/kg every 8 weeks to 10 mg/kg every 4 weeks, with variation in duration of treatment. A 13% higher rate of infection was ­reported among these patients, compared with patients who received conventional therapy (DMARDs) over a two-year ­period.

Six patients were determined to have serious, life-threatening infections (ie, requiring hospitalization or IV antibiotic therapy). Of these, two were given a diagnosis of bacteremia via blood cultures. The cultures grew Streptococcus pneumoniae in one patient, who was also diagnosed incidentally with Pneumocystis carinii through bronchial washings, and the other patient had blood cultures positive for Staphylococcus aureus and bilateral necrotizing pulmonary abscesses.

Case Studies

Individual case studies of infection in patients taking infliximab or other anti-TNF agents for RA reveal specific illnesses, their time lines, and relevant patient management. Crum et al2 reported an example of the common pathogen S pneumoniae in a 47-year-old patient who developed a left lower lobe pneumonia. Three of four blood cultures were positive, CBC with differential showed abnormal results, and the patient’s temperature on presentation was 39.5°C.

In a report of two cases of severe abdominal infection during administration of anti-TNF medication, one 40-year-old woman using infliximab for severe RA presented with a temperature of 39.2°C and a three-day history of abdominal pain. Escherichia coli was identified from blood cultures, although urine cultures were negative. CT led to a diagnosis of pyelonephritis. The patient had become septic but improved after 48 hours’ therapy with IV cefuroxime and gentamicin.⁸

The second patient was a man, age 60, with a two-week history of abdominal pain and a six-month history of effective etanercept use for persistent psoriatic arthritis. Contrast-­enhanced CT revealed a large splenic abscess, and blood cultures identified infection with S aureus. Management began with unsuccessful high-dose IV antibiotics, followed by laparotomy and splenectomy, postsurgical sepsis, and finally, high-dose inotropic therapy that proved effective.⁸

Infection With Listeria monocytogenes

Listeria monocytogenes, a pathogen sometimes identified in patients who receive anti-TNF-a therapy, has been the focus of several case reports. For example, Gluck et al⁹ describe a 60-year-old woman with a history of RA and previous treatment with multiple therapies who had recently completed a five-month regimen with infliximab (10 mg/kg every 4 weeks). Fourteen days after receiving her last dose, she presented to a hospital with anemia, fever (measurement undisclosed), and abdominal pain. She was given multiple diagnoses, including a gastric ulcer without hemorrhage, a pulmonary infiltrate, and acute cholecystitis. After she underwent cholecystectomy, her condition deteriorated, and head CT revealed several small subarachnoid hemorrhages and severe brain edema.

The patient experienced multi–organ system failure and died after a brain-stem herniation. What should be noted is that a blood culture taken one day after her surgery was positive for L monocytogenes, as was an intraoperative gallbladder swab-culture for the same organism—this, despite presumed antibiotic therapy.

A second patient described by Gluck et al⁹ was a 62-year-old woman with RA who developed cholecystitis after her second dose of infliximab, administered over a two-week period (200 mg IV/dose). As in the previous case, the patient manifested cerebral edema and had a fever after undergoing cholecystectomy. Blood cultures performed after the surgery were positive for L monocytogenes. The patient recovered slowly with proper antibiotic therapy, including ampicillin and gentamicin.

A third example of listeriosis involved a 52-year-old patient with RA who presented with symptoms including fever and abdominal pain. CT led to a diagnosis of terminal ileitis. One of two blood cultures taken was positive for L monocytogenes.⁶

Finally, a 79-year-old patient with a long-standing diagnosis of RA and prosthetic hips reported a fever of three weeks’ duration and left leg pain. As the patient had no fever on initial presentation, blood cultures were not drawn until five days after he was admitted. Three of four blood cultures were positive for L monocytogenes.⁶

Less Common Infections

Other less common bacterial etiologies have also been reported in the literature, including a fatal case of Salmonella enteritidis septicemia with a pleural empyema after treatment with infliximab.¹⁰ Another fatality was reported in a 54-year-old man who had necrotizing fasciitis, with a group A hemolytic streptococcus that grew in blood cultures. The patient, who had been taking in­fliximab, had no report of fever before or during his hospitalization.¹¹

Discussion

Although infliximab is effective for controlling the symptoms of RA, clinicians must be attentive to fever in patients who use it—even a patient-­reported fever that may not be present on physical exam. Due to the potential blunting of the immune response associated with infliximab use, a serious underlying infection can occur without fever. General malaise may be the only symptom a patient reports.

Infliximab and other anti-TNF medications are included in a textbook list of immunosuppressive medications whose use warrants special attention for patients who are evaluated for infection in an emergency setting. According to Burns,¹ “Rapid diagnosis and early initiation of therapy are essential in preventing serious morbidity and mortality in immunocompromised patients who often have subtle or unusual presentations and are difficult to ­diagnose.”¹

Active tuberculosis (ATB) is another serious illness that has been reported with infliximab use.^12,13 Patients should be screened for TB before taking infliximab, but clinicians must also be aware that ATB can develop as an unwanted result of infliximab therapy. Standard blood cultures may not be an effective means of identifying ATB.

Several types of infection may occur, with or without confirmation by positive blood cultures, including viral and fungal infections. Even bacterial infections, such as a urinary tract infection or bacterial pneumonia, may not yield positive blood cultures immediately, if ever. Each of these has been included among serious illnesses associated with use of anti-TNF medications.⁴ Nevertheless, blood cultures—Gram-stain, anaerobic, and aerobic blood cultures with sensitivities—should be considered an important component of any comprehensive infectious disease evaluation.

Although the purpose of this article has been to emphasize the importance of blood cultures in the timely diagnosis and treatment of patients taking ­anti-TNF medications who present with symptoms of infectious disease, it is important to remember that blood cultures are only part of a full infectious disease workup.

Conclusion

The clinical studies and case presentations discussed here serve to remind clinicians that timely acquisition and evaluation of blood cultures are essential to the identification of serious bacteriologic pathogens, and to the chances of recovery in the RA patient with a systemic infection who is immunosuppressed as a result of treatment with infliximab or other anti-TNF agent. Rapid identification of pathogenic organisms will facilitate the implementation of appropriate therapy, thus avoiding the often-deadly outcomes of severe infection and sepsis. Gram-stain, anaerobic, and aerobic blood cultures with sensitivities should be considered the standard of care in any infliximab-treated patient who presents with fever, a patient report of a fever, or any other signs, symptoms, or patient history that could suggest infection.

While this article focuses for the most part on infections associated with infliximab use, the same strategy in standard of practice should apply to all patients who use anti-TNF therapy for treatment of RA.

In 2009, a question of proper practices was brought before the Arizona Regulatory Board of Physician Assistants. The patient in question was seen in an emergency department by a PA/physician health care team for complaints of cough and fever at home. In question was the team’s decision to discharge the patient, who had a history of immunosuppression with an anti–tumor necrosis factor (anti-TNF) medication for a chronic joint disorder, without ordering laboratory tests or blood cultures. Although there is textbook instruction for evaluation of patients with infection who use agents in this drug class,¹ many clinicians may be unaware that blood cultures should be drawn as part of a proper workup.

In the United States, medications that have anti-TNF-alpha ­(anti-TNF-a) properties, including adalimumab, etanercept, and infliximab, are approved by the FDA to treat rheumatoid arthritis (RA).² Many patients take a second medication; others, a combination of medications. Options ­include methotrexate, cyclo­sporine, prednisone, and hydroxychloroquine. Typically, anti-TNF medications represent second- or third-line therapy after unsatisfactory response to disease-modifying antirheumatic drugs (DMARDs).

Although anti-TNF medications are effective for treatment of autoimmune diseases like RA, it should be noted that TNF-a is an important component in the proper functioning of the immune system. Accordingly, it is recognized that patients who use anti-TNF medications are at increased risk for infection.³ Indeed, patients with RA are already at greater risk for contracting infectious illnesses, even before immunosuppressive medications are administered.⁴

TNF is one cytokine that is responsible for humoral activation and subsequent inflammation.⁵ In RA and certain other diseases (eg, Crohn’s disease, lupus), TNF-a’s interaction with other cytokines is at least partially responsible for the inflammation that leads to RA-associated joint damage.⁵ In­fliximab and adalimumab are monoclonal antibodies developed specifically to bind with TNF-a, thereby neutralizing a pathway for further release of inflammatory cytokines. 

In contrast to recombinant soluble receptors, such as etanercept, the site-specific monoclonal antibodies for TNF-a (ie, infliximab, adalimumab) may play a greater role in suppressing macrophages, which contribute significantly to cellular immunity. Macrophage inhibition may further increase the body’s vulnerability to opportunistic infection.⁶

Anti-TNF Agents: Clinical Trials

The relationship between treatment with immunosuppressive agents (including infliximab and other anti-TNF medications) and serious infection is evident in the literature. In a 2005 study, Listing et al⁴ followed patients for 12 months after they were started on etanercept, infliximab, anakinra (another cytokine inhibitor), or DMARDs (controls). Ninety-two (26.5%) of the 346 patients who were given infliximab, compared with 6% of 601 controls, developed infection; of these, 20 patients (21.7%) had a determinable serious infection (ie, that was considered life-threatening or resulted in inpatient treatment, significant disability, or death). Thus, serious infection affected 5.8% of the patient population studied who had received infliximab.

Five of the 512 patients who used etanercept were diagnosed with sepsis, but no episodes of bacteremia were recorded among the infliximab patients. The most prevalent serious infections observed were pneumonia, infective arthritis, and various skin and subcutaneous infections (see table⁴). Less prevalent respiratory tract ailments included bronchitis, lung abscess, and pleural infection. Overall, small numbers of cases of sepsis were reported, making it difficult for the study authors to comment on the disparity of sepsis rates among treatment groups.⁴

Another prospective study followed 28 patients (median age, 53) who were treated with infliximab between 1999 and 2002.⁷ Dosages administered ranged from the standard 3 mg/kg every 8 weeks to 10 mg/kg every 4 weeks, with variation in duration of treatment. A 13% higher rate of infection was ­reported among these patients, compared with patients who received conventional therapy (DMARDs) over a two-year ­period.

Six patients were determined to have serious, life-threatening infections (ie, requiring hospitalization or IV antibiotic therapy). Of these, two were given a diagnosis of bacteremia via blood cultures. The cultures grew Streptococcus pneumoniae in one patient, who was also diagnosed incidentally with Pneumocystis carinii through bronchial washings, and the other patient had blood cultures positive for Staphylococcus aureus and bilateral necrotizing pulmonary abscesses.

Case Studies

Individual case studies of infection in patients taking infliximab or other anti-TNF agents for RA reveal specific illnesses, their time lines, and relevant patient management. Crum et al2 reported an example of the common pathogen S pneumoniae in a 47-year-old patient who developed a left lower lobe pneumonia. Three of four blood cultures were positive, CBC with differential showed abnormal results, and the patient’s temperature on presentation was 39.5°C.

In a report of two cases of severe abdominal infection during administration of anti-TNF medication, one 40-year-old woman using infliximab for severe RA presented with a temperature of 39.2°C and a three-day history of abdominal pain. Escherichia coli was identified from blood cultures, although urine cultures were negative. CT led to a diagnosis of pyelonephritis. The patient had become septic but improved after 48 hours’ therapy with IV cefuroxime and gentamicin.⁸

The second patient was a man, age 60, with a two-week history of abdominal pain and a six-month history of effective etanercept use for persistent psoriatic arthritis. Contrast-­enhanced CT revealed a large splenic abscess, and blood cultures identified infection with S aureus. Management began with unsuccessful high-dose IV antibiotics, followed by laparotomy and splenectomy, postsurgical sepsis, and finally, high-dose inotropic therapy that proved effective.⁸

Infection With Listeria monocytogenes

Listeria monocytogenes, a pathogen sometimes identified in patients who receive anti-TNF-a therapy, has been the focus of several case reports. For example, Gluck et al⁹ describe a 60-year-old woman with a history of RA and previous treatment with multiple therapies who had recently completed a five-month regimen with infliximab (10 mg/kg every 4 weeks). Fourteen days after receiving her last dose, she presented to a hospital with anemia, fever (measurement undisclosed), and abdominal pain. She was given multiple diagnoses, including a gastric ulcer without hemorrhage, a pulmonary infiltrate, and acute cholecystitis. After she underwent cholecystectomy, her condition deteriorated, and head CT revealed several small subarachnoid hemorrhages and severe brain edema.

The patient experienced multi–organ system failure and died after a brain-stem herniation. What should be noted is that a blood culture taken one day after her surgery was positive for L monocytogenes, as was an intraoperative gallbladder swab-culture for the same organism—this, despite presumed antibiotic therapy.

A second patient described by Gluck et al⁹ was a 62-year-old woman with RA who developed cholecystitis after her second dose of infliximab, administered over a two-week period (200 mg IV/dose). As in the previous case, the patient manifested cerebral edema and had a fever after undergoing cholecystectomy. Blood cultures performed after the surgery were positive for L monocytogenes. The patient recovered slowly with proper antibiotic therapy, including ampicillin and gentamicin.

A third example of listeriosis involved a 52-year-old patient with RA who presented with symptoms including fever and abdominal pain. CT led to a diagnosis of terminal ileitis. One of two blood cultures taken was positive for L monocytogenes.⁶

Finally, a 79-year-old patient with a long-standing diagnosis of RA and prosthetic hips reported a fever of three weeks’ duration and left leg pain. As the patient had no fever on initial presentation, blood cultures were not drawn until five days after he was admitted. Three of four blood cultures were positive for L monocytogenes.⁶

Less Common Infections

Other less common bacterial etiologies have also been reported in the literature, including a fatal case of Salmonella enteritidis septicemia with a pleural empyema after treatment with infliximab.¹⁰ Another fatality was reported in a 54-year-old man who had necrotizing fasciitis, with a group A hemolytic streptococcus that grew in blood cultures. The patient, who had been taking in­fliximab, had no report of fever before or during his hospitalization.¹¹

Discussion

Although infliximab is effective for controlling the symptoms of RA, clinicians must be attentive to fever in patients who use it—even a patient-­reported fever that may not be present on physical exam. Due to the potential blunting of the immune response associated with infliximab use, a serious underlying infection can occur without fever. General malaise may be the only symptom a patient reports.

Infliximab and other anti-TNF medications are included in a textbook list of immunosuppressive medications whose use warrants special attention for patients who are evaluated for infection in an emergency setting. According to Burns,¹ “Rapid diagnosis and early initiation of therapy are essential in preventing serious morbidity and mortality in immunocompromised patients who often have subtle or unusual presentations and are difficult to ­diagnose.”¹

Active tuberculosis (ATB) is another serious illness that has been reported with infliximab use.^12,13 Patients should be screened for TB before taking infliximab, but clinicians must also be aware that ATB can develop as an unwanted result of infliximab therapy. Standard blood cultures may not be an effective means of identifying ATB.

Several types of infection may occur, with or without confirmation by positive blood cultures, including viral and fungal infections. Even bacterial infections, such as a urinary tract infection or bacterial pneumonia, may not yield positive blood cultures immediately, if ever. Each of these has been included among serious illnesses associated with use of anti-TNF medications.⁴ Nevertheless, blood cultures—Gram-stain, anaerobic, and aerobic blood cultures with sensitivities—should be considered an important component of any comprehensive infectious disease evaluation.

Although the purpose of this article has been to emphasize the importance of blood cultures in the timely diagnosis and treatment of patients taking ­anti-TNF medications who present with symptoms of infectious disease, it is important to remember that blood cultures are only part of a full infectious disease workup.

Conclusion

The clinical studies and case presentations discussed here serve to remind clinicians that timely acquisition and evaluation of blood cultures are essential to the identification of serious bacteriologic pathogens, and to the chances of recovery in the RA patient with a systemic infection who is immunosuppressed as a result of treatment with infliximab or other anti-TNF agent. Rapid identification of pathogenic organisms will facilitate the implementation of appropriate therapy, thus avoiding the often-deadly outcomes of severe infection and sepsis. Gram-stain, anaerobic, and aerobic blood cultures with sensitivities should be considered the standard of care in any infliximab-treated patient who presents with fever, a patient report of a fever, or any other signs, symptoms, or patient history that could suggest infection.

While this article focuses for the most part on infections associated with infliximab use, the same strategy in standard of practice should apply to all patients who use anti-TNF therapy for treatment of RA.