Article, Rheumatology

Lactic acidemia due to an infliximab infusion reaction

a b s t r a c t

We present the case of a patient who presented to the emergency department complaining of diffuse myalgias, severe Jaw pain and chills. She met criteria for severe sepsis and received treatment including analgesia, antibi- otics, intravenous fluids, and antipyretics. Workup revealed an elevated lactate and leukocytosis however, did not reveal any infectious source. The patient had a history of Crohn’s disease and had received an infusion of infliximab ten days prior to the onset of her symptoms. After ruling out other Potential causes of lactic acidemia, her final diagnosis was determined to be the rare presentation of an infliximab infusion reaction. On reviewing the literature, we could not find another documented case of a lactic acidemia caused by an infliximab infusion reaction. The key to the treatment of this patient was steroids, antihistamines, and supportive treatment. Emer- gency physicians do not often encounter infliximab infusion reactions because they occur so infrequently. Along with more common diagnoses such as sepsis, emergency physicians should include infliximab infusion reactions on the differential diagnosis in patients receiving this medication.

(C) 2019

Introduction

We present the case of a patient who presented to the emergency department (ED) meeting criteria for severe sepsis. Her workup did not reveal any identifiable infectious source. She had a history of Crohn’s disease and had received an infusion of infliximab prior to onset of her symptoms.

case presentation“>Case presentation

A 43-year-old female presented to the ED complaining of diffuse ar- thralgias and Lip swelling that began 1 day prior. The arthralgias began insidiously and involved her hands, hips, proximal femurs, knees, lower back, and jaw. She was experiencing trismus and was unable to fully open her mouth due to the severity of the pain. The pain was self-described as severe and worse with palpation or any movement of the affected areas. There was no history of trauma or radicular com- ponent to her symptoms.

She had never had pain like this before, and had not taken any med- ications for the discomfort. The night before presenting to the ED, she had chills, complained that her mouth felt dry, and noted pain with swallowing. There were no known sick contacts, insect bites or travel

Abbreviations: ED, Emergency department; SIRS, Systemic Inflammatory Response Syndrome; CMP, Complete metabolic panel; EKG, Electrocardiogram; CRP, C-reactive pro- tein; WBC, White blood cells; CT, Computed tomography; ANA, Antinuclear antibody; IR, Infusion reaction; ARDS, Acute respiratory distress syndrome.

* Corresponding author.

E-mail address: [email protected] (N. Vigh).

outside the country. She received an infliximab infusion for treatment of Crohn’s disease about 1 week prior to symptom onset. She had previ- ously received infliximab infusions several years prior and did not have any problems with the medication. Several years ago she discontinued the use of infliximab and had been receiving vedolizumab (Entyvio(R)) infusions uneventfully with the last dose 2 months prior to this ED visit. Vital signs on presentation were: blood pressure 97/70 mm/Hg, pulse 120 bpm, respiratory rate 26, temperature 101.3?F (rectal), and oxygen saturation 97% on room air. The physical exam revealed a middle-aged Caucasian female who was tearful, restless, and obviously uncomfortable. There was pain with motion and palpation of the jaw. She was tachycardic, otherwise had a normal cardiac, respiratory, and abdominal exam. Musculoskeletal exam revealed exquisite pain with mild palpation of the knees, hips, and pelvis without evidence of edema or erythema. range of motion was full, but painful. There was no cervical, thoracic, lumbar or sacral midline tenderness. Exam of the skin revealed a non-tender cystic lesion on the left anterior tibia, no other rashes or lesions. She was Neurologically intact without any evi-

dence of acute focal deficits.

Upon arrival to the ED she met criteria to initiate the sepsis protocol which included basic labs as well as blood cultures and lactic acid, chest x-ray, Urine analysis and culture, Electrocardiogram , a 30 cc/ kg bolus of intravenous fluids (IVF), and initiation of broad spectrum anti- biotics. Pertinent laboratory findings included a leukocytosis of 18 x 109/L. The complete metabolic panel demonstrated a potassium of 2.9 mmol/L, a bicarbonate of 18 mmol/L, and creatinine of 1.3 mg/ dL. Her chest x-ray was unremarkable. Her EKG showed sinus tachycar- dia. She had an elevated lactic acid of 5.4 mmol/L which increased to

5.8 mmol/L within the first two hours of presentation, despite fluid

https://doi.org/10.1016/j.ajem.2019.11.005

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850.e2 N. Vigh, D. Levy / American Journal of Emergency Medicine 38 (2020) 850.e1850.e3

resuscitation. Her troponin was negative. C-reactive protein (CRP) was elevated at 88.5 mg/L. She was negative for influenza. Her urinalysis contained 56 white blood cells and a large amount of Leukocyte esterase; however, it was not a clean catch and the culture did not show any significant bacterial growth. Computed tomography (CT) scans of the brain, chest, abdomen and pelvis without contrast were without ab- normality within the limitation of the Non-contrast studies.

The patient required opioid pain medication at regular intervals to control her pain. As per the sepsis protocol she received a 30 cc/kg fluid bolus and broad spectrum antibiotics including vancomycin (Vancocin(R)) and piperacillin- tazobactam (Zosyn(R)). Her hypotension did improve after the initial fluid bolus which was 3.2 L. Initially she be- came hypertensive to 146/96 and then normotensive at 124/79. While in the ED she became hypoxic to 89% on room air and required 2 L sup- plemental oxygen via nasal cannula. A repeat chest x-ray was not per- formed at this time, and the cause of her hypoxia was unknown. The intensivist admitted the patient to the medical intensive care unit (MICU) for Close monitoring. Consultants on the case included neurol- ogy, rheumatology and infectious disease. Additional workup included a lumbar puncture, antinuclear antibodies (ANA), Rheumatoid factor, and Lyme titers without discovery of a specific unifying diagnosis. On hospital day 2, the patient developed hives and pruritus which was tem- porarily relieved by diphenhydramine (Benadryl(R)) and famotidine (Pepcid(R)). Despite treatment, she continued to develop intermittent hives with pruritus throughout her hospital stay.

Since we were unable to find another cause of her elevated lactate, it is believed that she was experiencing a drug reaction caused by the infliximab infusion. She received steroids, methylprednisolone (Solumedrol(R)) 40 mg IV daily and continued to receive diphenhydra- mine (Benadryl(R)) and famotidine (Pepcid(R)). On hospital day 2 the pro- viders discontinued the antibiotics, and her lactic acidemia and leukocytosis improved over the course of her hospital stay. By hospital day 6, her symptoms completely resolved and her lab studies returned to normal. Upon Discharge home she was asymptomatic.

Discussion

Infliximab is a chimeric IgG1 monoclonal antibody that binds to and neutralizes the inflammatory cytokine, tumor necrosis factor-? (TNF- ?). TNF-? is involved in the pathogenesis of a number of inflammatory diseases and therefore infliximab is currently approved for the treat- ment of many inflammatory diseases including, but not limited to, Crohn’s disease and ulcerativE colitis. In inflammatory bowel diseases infliximab prevents the TNF-? mediated pro-inflammatory cascade which decreases the activation and proliferation of Intestinal mucosal T cells as well as preserves the intestinal epithelial barrier integrity by preventing enterocyte apoptosis [1,2].

Infliximab, like all medications, has the potential to cause adverse re- actions. Patients may experience an infusion reaction (IR) which may be acute, defined as symptoms occurring during the infusion or up to 24 h after the infusion, or a delayed reaction defined as symptoms occurring greater than 24 h after the infusion but within 14 days of the infusion. The most common symptoms associated with a delayed reaction in- clude headache, nausea, vomiting, urticaria/rash and myalgia [1,2]. Many studies have evaluated the overall incidence of infliximab infu- sion reactions both acute and delayed and have determined that de- layed infusion reactions in general are very rare, especially a serious delayed reaction like the reaction experienced by the patient in the pre- sented case. A reported overall incidence of both acute and delayed IRs in Crohn’s disease patients was 6.1%, with delayed infusion reactions ac- counting for only 0.6% of the total number of infusions [3]. A large retro- spective chart review of 796 patients who received a total of 5581 infliximab infusions found that only 2.0% of infusions were associated with an IR with only 0.2% of infusions being associated with a severe re- action and only 0.1% of infusions resulting in a reaction requiring an emergency department visit [1]. In the TREAT registry (Crohn’s Therapy,

Resource, Evaluation, and Assessment Tool), a multicenter prospective observational registry of Crohn’s disease patients in the United States, the per-infusion reaction rate to infliximab was found to be only 3.0% of the 53,003 total infusions, with only 0.05% of reactions being classi- fied as serious [4]. An additional multicenter retrospective chart review of patients with Crohn’s disease found the per- infusion reaction rate to be only 3.5% with less than 0.1% of all infusions being associated with a serious reaction [5]. These studies consistently demonstrate that both acute and delayed reactions to infliximab are rare and a serious reaction requiring an emergency department visit occurs in less than 1% of infusions.

The cause of this serum-sickness like reaction to infliximab infusions is due to a reaction of the foreign antigen (infliximab) with specific IgG antibodies which induces the formation of Immune complexes. The time it takes to produce these specific IgG immune complexes explains the delay of 7-10 days in the infusion reaction. The immune complexes deposit in blood vessels, skin and joint tissue. They induce mast cell de- granulation leading to release of pro-inflammatory cytokines, and at- tract granulocytes which results in vascular and tissue damage. The resulting clinical symptoms include fever, arthralgia, myalgia, rash and dyspnea [2,6]. Another symptom of delayed reactions repeatedly men- tioned is jaw pain as seen in our case. There has been only 1 case report in which the serum sickness like reaction developed into a life threaten- ing Acute respiratory distress syndrome [2].

Due to the Rare occurrence of delayed infusion reactions, clinical tri- als are not feasible, and therefore a specific protocol of how to manage these reactions is not available. Symptomatic treatment includes anti- histamines for relief of pruritus, acetaminophen for fever, and/or ar- thralgia and myalgia, and oral or intravenous corticosteroids for high fever, severe arthralgia and/or extensive rash [2]. The severe pain expe- rienced by the patient presented in this case required narcotics for pain relief. Our patient did show improvement with the use of IV steroids, antihistamine, H2 blocker, antipyretics, and narcotics.

Studies have shown that episodic treatment with infliximab and re- sumption of infliximab infusions after a prolonged drug free interval have been found to increase the risk of IRs as compared to scheduled treatment [2,6,7]. There have been a few case reports that presented a serum-sickness like reaction after reintroducing the patient to infliximab. The patients presented similarly to our patient in this case, with fever, severe arthralgias, myalgias, rash, and elevated CRP, with all microbiologic explorations being negative [6,7]. Our patient’s presen- tation is unique in that she presented mimicking sepsis with signs of end organ damage indicated by hypotension and elevated lactate and displayed signs of hypoxia requiring monitoring in the intensive care unit.

Conclusion

This case demonstrates how important it is for emergency depart- ment physicians to be aware of serious medication reactions and keep them on the vast list of potential differential diagnoses. This case dem- onstrates the rare presentation of a serious delayed reaction which only occurs in less than 1% of infliximab infusions and thus is not com- monly encountered by emergency department physicians [1,3,4,5]. Tak- ing a Detailed history was extremely important in making the diagnosis in this patient, ruling out any infectious source as well as taking a mul- tidisciplinary approach leading to the diagnosis of a serum-sickness like reaction due to an infusion of infliximab.

Declarations

Ethics Approval and Consent to Participate: Not applicable. Consent for Publication: Not applicable.

Availability of Data and Materials: Not applicable. Funding: Not applicable.

N. Vigh, D. Levy / American Journal of Emergency Medicine 38 (2020) 850.e1850.e3 850.e3

Authors’ Contributions: NV and DL evaluated and treated the pa- tient. All authors read and approved the final manuscript.

Acknowledgments: Not applicable.

Declaration of Competing Interest

The authors declare that they have no competing interests.

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