A Case of Trimethoprim-Sulfamethoxazole-Induced Aseptic Meningitis Masquerading as Septic Shock Free

ABSTRACT

Trimethoprim-sulfamethoxazole-induced aseptic meningitis (TSIAM) is a rare adverse reaction to a commonly prescribed antibiotic. We describe a case of severe TSIAM which resembled septic shock. A 30-year-old male with relapsed Hodgkin’s lymphoma 25 days status post autologous stem cell transplant presented to our clinic for evaluation of trimethoprim-sulfamethoxazole (TMP-SMX) hypersensitivity. After review of patient’s history and records, we had a low suspicion for a TMP-SMX adverse reaction and conducted an oral challenge to one 160 mg/800 mg tab of TMP-SMX. Four hours later, the patient developed vomiting, lightheadedness, and disorientation with progression to rigors, fever, tachycardia, and hypotension. He was admitted for fluid resuscitation and broad-spectrum antibiotic coverage for neutropenic fever and possible septic shock. A lumbar puncture performed due to complaints of headache, photophobia, and neck pain showed 375 white blood cells/µL with 73% neutrophil predominance, normal glucose (75 mg/dL), and elevated protein (101 mg/dL); additional cerebrospinal fluid (CSF) studies were negative for infectious etiologies. Fever and headache resolved by hospital day 4, at which time patient was discharged home. We believe this case represents TSIAM given the characteristic timing of symptom onset, CSF findings, and timing of symptom resolution without other clear etiology found on extensive infectious evaluation. It is important for allergists to recognize TSIAM, including its potential presentation as shock, in order to appropriately diagnose and counsel patients who seek evaluation for TMP-SMX adverse reactions.

INTRODUCTION

Drug-induced aseptic meningitis is a rare adverse reaction to trimethoprim-sulfamethoxazole (TMP-SMX). It is the most common antibiotic to be implicated in this syndrome.^1,2 We describe a dramatic case of TMP-SMX-induced aseptic meningitis (TSIAM) that resembled septic shock.

CASE REPORT

A 30-year-old male with relapsed Hodgkin’s lymphoma 25 days status post (s/p) autologous stem cell transplant was referred to our clinic for evaluation of possible TMP-SMX hypersensitivity. The patient was placed on dapsone following his stem cell transplant for Pneumocystis carinii (jiroveci) pneumonia (PCP) prophylaxis but was experiencing myelosuppression on that agent. He was therefore started on TMP-SMX. The patient did not recall having a reaction to any sulfa drug in the past and he did not recall ever taking an oral medication that made him sick.

Review of his electronic medical record revealed he had taken TMP-SMX 7 years prior for dysuria. He remembered this episode and relayed that he was quite ill when he started the medication and that his illness progressively worsened despite taking the medication. The records indicate that when he presented to his primary care manager the day after TMP-SMX was prescribed, he was “slightly disoriented,” had vomiting/diarrhea, body aches, and fever to 104.2°F. He had a rash described as “not raised” and denied itching. He was admitted to the intensive care unit for presumed urosepsis with hypotension. Urine and blood cultures revealed no bacterial growth. At discharge, a statement was written in his medical record that his illness could be related to an allergic reaction to TMP-SMX; however the patient did not recall this information. He remembers being told it was due to infection.

In review of the patient’s history and available records, we had a low suspicion for an adverse reaction to TMP-SMX. After obtaining informed consent, the patient underwent an oral challenge with a TMP-SMX double strength tablet (160 mg/800 mg) in our clinic. The patient was monitored for 2 hours without side effect and was released home at his baseline health. Four hours after the medication challenge, the patient developed vomiting, lightheadedness, and disorientation. His vitals were initially stable with a normal exam and no rash. He was given 1 L normal saline and promethazine for continued vomiting. Two hours later, the patient developed rigors and fever to 103°F with systolic blood pressure in the 90s and heart rate in 140s.

The patient was admitted to the ICU and started on broad-spectrum antibiotic coverage with vancomycin, piperacillin-tazobactam, and levofloxacin for possible septic shock in the setting of neutropenia (absolute neutrophil count 573/µL). He was also given methylprednisolone, diphenhydramine, and ranitidine to treat an adverse drug reaction to TMP-SMX, although of note he had no urticaria, angioedema, pruritus, or bronchospasm to indicate an anaphylactic reaction. He complained of a bilateral temporal headache associated with photophobia and pain with extension of the neck, for which a lumbar puncture was performed.

Cerebrospinal fluid (CSF) examination revealed 375 white blood cells (WBCs)/µL with 73% neutrophil predominance and normal glucose (75 mg/dL) with elevated protein (101 mg/dL). CSF cytology showed no organisms on gram stain and no malignant epithelial cells or Reed–Sternberg cells. Blood, urine, and CSF cultures remained without any bacterial growth. Respiratory viral panel polymerase chain reaction (PCR) tests and cultures were all negative, including influenza A/B, respiratory syncytial virus, parainfluenza virus 1-4, human metapneumovirus, rhinovirus, enterovirus, adenovirus, human coronavirus, Chlamydophila pneumoniae, Mycoplasma pneumoniae, and Bordetella pertussis.

Extensive CSF studies including acid fast staining, fungal culture, viral culture, herpes simplex virus 1/2 PCR, arbovirus antibody (Ab) panel, Cryptococcus Ab and antigen, and adenosine deaminase were all negative. He had normal hepatic and renal panels. Tryptase and histamine levels ordered on admission came back normal at 8 and <1.5 ng/mL, respectively. Aseptic meningitis was suspected, although antibiotics were continued, given partially treated bacterial meningitis could not be ruled out. His headache and fever resolved by hospital day 4. He was released the following day with close outpatient follow-up after being afebrile for 24 hours. He was discharged home to complete a 5-day course of levofloxacin.

DISCUSSION

Although this patient’s clinical course has multiple complicating factors, we believe it represents a case of TSIAM given the onset of symptoms within hours of taking the drug, characteristic CSF findings, quick resolution of symptoms after TMP-SMX was discontinued, and no other cause found despite extensive work-up of infectious etiologies. We believe this was a repeat reaction, with the patient’s prior hospitalization for “urosepsis” being his initial episode. Repeat episodes of culture-negative urosepsis have been reported in other cases before the final diagnosis of TSIAM was made.^3,4 Although other drugs to which our patient was exposed, such as ranitidine and methylprednisolone, can also cause aseptic meningitis, we feel TMP-SMX to be the most likely cause given his symptoms of concern began after exposure to TMP-SMX but before exposure to other possible culprit medications. TMP-SMX therefore remains as the main suspect source despite the lack of definitive testing to rule out other medications as possible contributors.

CSF findings typical for TSIAM include increased WBC count with neutrophil predominance and elevated protein. Given that these findings do not exclude incompletely treated bacterial meningitis in a patient on antibiotics, it takes an astute clinician to consider this diagnosis. The occurrence of meningitis-like syndromes with clinical features of sepsis on multiple occasions has been reported in the past, emphasizing the importance of recognizing TMP-SMX as a source of aseptic meningitis especially when an extensive battery of infectious testing has been obtained without identifying a source.^5–13

The pathophysiology of TSIAM is not fully understood but has been hypothesized by prior studies to include type III (immune complex-mediated) or type IV (delayed type) hypersensitivity reactions to the meninges, rather than type I (IgE-mediated) reactions.^2,13 Due to its ability to cross the blood–brain barrier, TMP-SMX may also cause direct chemical irritation to the meninges.¹³ Although localized meningeal signs with otherwise limited symptoms can be more readily indicative of TSAIM rather than truly toxic bacterial meningitis, our patient’s immunocompromised status could have contributed to the presentation more strongly resembling septic shock.

Some studies indicate that hypersensitivity to the sulfonamide component of TMP-SMX is the primary source of adverse drug reactions.¹⁴ This data should not extrapolated to TSIAM given its undefined, but unlikely IgE-mediated, mechanism of pathology. Of note, literature review has demonstrated that it is possible for either component of TMP-SMX to trigger aseptic meningitis.^2,14 In general, the appropriate counseling for a patient with a history of TSIAM would be to avoid both TMP-SMX as well as its component medications in isolation.

For patients whose history is concerning for TSIAM, available diagnostics are limited. Skin-prick testing (SPT) is not of clinical utility in the evaluation of suspected TSIAM, as SPT in general has not been validated for TMP-SMX hypersensitivity and furthermore assesses only IgE-mediated pathology, which based on symptomatology is unlikely to be the driver of TSIAM.^2,13,14 In a patient whose history of adverse drug reaction to TMP-SMX is unclear, oral challenge could be considered as it is the gold standard for determining the presence or absence of a TMP-SMX adverse drug reaction. In this context, it is necessary that the challenge be to a clinically relevant dose, such as the dose prescribed for PCP prophylaxis in our case, in order to extrapolate that the patient will tolerate the medication at the prescribed dosage.

CONCLUSION

We present this case to help clinicians better understand the spectrum of severity with which TSAIM can present, with the goal of early recognition and reduced morbidity by timely cessation of the causative medication. While it is a lesser known complication of TMP-SMX among clinicians, it is important for the allergist to recognize this syndrome for the appropriate diagnosis and counseling of the patient.

ACKNOWLEDGMENTS

None declared.

FUNDING

None declared.

CONFLICT OF INTEREST STATEMENT

None declared.

REFERENCES

Author notes