A Case Report of Salmonella muenchen Enteritis Causing Rhabdomyolysis and Myocarditis in a Previously Healthy 26-Year-Old Man Will Chapple MD, MPH; Jon Martell MD; Joy S. Wilson MD; and Don T. Matsuura MD Abstract

This case report examines an unusual presentation of a non-typhoidal Salmonella serovar with limited prevalence in the literature. This is the first case report to associate specifically the Salmonella muenchen serovar with rhabdomyolysis and myocarditis. This case report reviews the diagnostic criteria for myocarditis and explores the diagnostic dilemma of troponin elevation in the setting of rhabdomyolysis. It demonstrates that Salmonella muenchen has the ability to present in a broad range of individuals with complications extending beyond classical gastrointestinal symptoms. This report also concludes that diagnosis of the many possible complications from non-typhoidal Salmonella infections can be difficult due to patient comorbidities, variability in the severity of the illnesses, laboratory test limitations, and imaging limitations. When a patient presents with elevated troponins in the setting of rhabdomyolysis a careful workup should be done to evaluate for ischemic causes, myocarditis, or false elevation secondary to rhabdomyolysis.

Keywords

Salmonella muenchen, Non-typhoidal salmonella, rhabdomyolysis, myocarditis, troponin

Introduction Salmonella is a genus of gram negative bacteria with 2,449 known serotypes.1 It is an important cause of diarrheal illness in humans and its presenting symptoms and potential complications are noted below. Infections are caused by ingestion of contaminated food products including both animal and plant based foods. Contact with reptiles and persons infected with Salmonella can also spread disease.1 Thus, safe practices in food production and handling have been instrumental in combating these types of infection. Salmonella muenchen accounted for 6,055 of 441,863 (1.3%) cases of documented Salmonella infection in the United States between 1987-1997.1 Human cases of this Salmonella serotype in Hawai‘i County in 2011 was 0.64 cases per 100,000 population.2 A 1999 outbreak of Salmonella muenchen affecting 157 people in seven states was related to contaminated alfalfa sprouts from Wisconsin.3 In the Wisconsin outbreak the prevalence of symptoms were as follows: diarrhea (97%), abdominal cramps (84%), fatigue (81%), chills (68%), headache (68%), fever (66%), nausea (65%), body aches (61%), and vomiting (37%).3 There was a 10% hospitalization rate but no report of complication rates. No deaths were reported. Two recent outbreaks of Salmonella muenchen occurred in June 2015 and November of 2015. The first outbreak tracked 22 cases over 17 states. This outbreak was due to contact with crested geckos kept as pets.4 The second outbreak infected 26 individuals in 12 states and was presumptively traced to contaminated alfalfa sprouts.5 The symptoms, physical exams, and biochemical findings in

victims of these recent outbreaks are not specifically described. Salmonella muenchen infections usually present with fever, diarrhea and abdominal cramping. Victims are usually young children, the elderly, or the immunocompromised. We report a case of Salmonella muenchen in an immunocompetent adult with myocarditis and rhabdomyolysis. This case demonstrates that Salmonella muenchen has the ability to present in a broad range of individuals with complications extending beyond classical gastrointestinal symptoms. Case Description A 26-year-old man with a history of migraine headaches presented to the emergency department in Hilo, Hawai‘i with a four day history of progressive symptoms including fever, chills, total body myalgia with chest pain, one episode of un-witnessed hemoptysis (pink frothy sputum), non-bloody emesis, abdominal pain, and non-bloody diarrhea. His maximum temperature on the first day of admission was 101.7 F without other vital sign abnormalities. The white blood cell count was elevated to 18.4 x 103μL (normal range 3.8-11.2) with 15% bands. The patient met Systemic Inflammatory Response Syndrome (SIRS) criteria with fever and leukocytosis. He was admitted to the hospital with the diagnosis of probable sepsis. He was given intravenous (IV) fluids and treated empirically for sepsis with IV ceftriaxone and IV metronidazole. Chest X-ray, complete abdominal ultrasound, and initial electrocardiograms (ECG’s) were unremarkable. Computerized tomography (CT) scan of the abdomen and pelvis showed mild colitis. Stool cultures were eventually positive for Salmonella muenchen.

Abbreviations ANA: Antinuclear antibodies AST: Aspartate aminotransferase BUN: Blood urea nitrogen CCP: Cyclic citrullinated peptide antibody CHF: Congestive heart failure CK: Creatine kinase CT: Computed tomography cTnI: Cardiac troponin-I CMV: Cytomegalovirus EBV: Epstein-Barr virus ECG: Electrocardiogram IV: Intravenous HIV: Human immunodeficiency virus MRI: Magnetic resonance imaging SIRS: Systemic inflammatory response syndrome

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The remainder of the infectious workup was negative including evaluation for stool ova and parasites, C. difficile toxin, two consecutive days of blood cultures, group A streptococcus cultures, and serological testing for the following: leptospirosis, influenza, parvovirus B19, human immunodeficiency virus (HIV), epstein-barr virus (EBV), hepatitis A, B, and C, and cytomegalovirus (CMV). Rheumatological workup was negative including rheumatoid factor, antinuclear antibodies (ANA), cyclic citrullinated peptide antibody (CCP) and double stranded DNA antibodies. Urinalysis and urine toxicology was non-contributory. The patient denied tobacco, alcohol, and drug use. He states that one of his children had a flu-like illness for 2 weeks prior to hospital admission. He is a welder by trade. He has chickens in his yard which he feeds but states he does not have frequent close contact with the chickens. On day six from the reported onset of symptoms the creatine kinase (CK) peaked at 9,836 U/L (normal range 58-220). Aspartate aminotransferase (AST) peaked at 207 U/L (normal range less than 31) on day seven of illness. Renal function [blood urea nitrogen (BUN) and creatinine] remained normal throughout the hospitalization. On day seven of illness, cardiac troponin-I (cTnI) levels were found to be elevated and peaked eight hours later at 13.12 ng/mL (normal range < 0.04). At this point a cardiology consultation was obtained. No ECG abnormalities were noted at the time but the patient still complained of intermittent “chest tightness.” Transthoracic echocardiography on that day was negative for systolic or diastolic heart failure, hypokinesis or wall motion abnormalities. Serial ECG’s showed the development of asymptomatic inferolateral T-wave inversion on day eight and nine with resolution on day ten of illness. CT cardiac angiography showed no abnormalities. Cardiac magnetic resonance imaging (MRI) was not available on island. The patient was discharged on day 8 of hospitalization after resolution of his presenting symptoms. He was given a 14-day course of ciprofloxacin for the Salmonella infection. He was given aspirin and metoprolol due to the complication of myocarditis. At a five-month cardiology follow-up visit the patient had made a full recovery and was without residual symptoms. His ECG on follow up was normal. His treadmill stress test on that date was also normal. Discussion The purpose of this case report is to discuss the potential complications of Salmonella diarrheal infections and to examine the diagnostic difficulty of troponin elevation in the setting of rhabdomyolysis. There have been case reports of other nontyphoidal Salmonella infections causing rhabdomyolysis6-8 but no reports associated specifically with Salmonella muenchen. This is likely because of the low incidence of human infections related to this specific serotype. One study noted the non-typhoidal Salmonella serotype prevalence in a case series ending in 1984. Salmonella muenchen was found to be the causative organism for 2 of 137 cases of Salmonella associated meningitis and 2 of 150 cases of Salmonella associated osteomyelitis. Neither rhabdomyolysis nor myocarditis were included as a complica-

tion in this case series9 and the exact risk of these complications remains unknown with Salmonella enteritis. Etiology and Diagnosis of Myocarditis Myocarditis was suspected in this patient based on symptoms, laboratory studies and ECG findings. The etiology of myocarditis can be divided into infectious, immune-mediated, and toxic myocarditis. Some bacterial infectious causes include Staphylococcus, Streptococcus, Pneumococcus, Meningococcus, Lyme disease, Rickettsial diseases, and Leptospirosis. Fungal causes can include Aspergillus, Actinomyces, Blastomyces, and Histoplasma. Parasitic infectious causes include Toxoplasma, Leishmania, Trichinella spiralis, and Echinococcus granulosus.10 Viral infections have also been implicated and include coxsackie viruses, polio viruses, influenza, dengue virus, cytomegalovirus (CMV), epstein-barr virus (EBV), and parvovirus. Immune mediated causes include infection-negative lymphocytosis, systemic lupus erythematosus, rheumatoid arthritis, Kawasaki’s disease, inflammatory bowel disease, thyrotoxicosis, sarcoidosis, and allergic drug reactions. Toxic myocarditis can be caused by amphetamine or cocaine abuse, lithium, clozapine, heavy metal poisoning, envenomation, radiation, beri-beri, or pheochromocytoma.10 Endomyocardial biopsy is the gold-standard for diagnosis of myocarditis regardless of etiology. However, most patients are not candidates for this procedure because of its high risks. ECG changes can also occur during the initial weeks of illness. Less than 50% of patients with myocarditis present with ST segment elevation or T-wave inversion (the most sensitive ECG criteria for myocarditis). Echocardiograms are used in suspected cases of myocarditis but miss many mild cases.11 Certain nuclear medicine tracers can also be used for a non-specific diagnosis of myocarditis but are rarely used in clinical practice due to tracer availability. Due to its safety profile and consistent accuracy in diagnosis, the cardiac MRI has become the standard tool to confirm the diagnosis of myocarditis.11 However, cardiac MRI is not always available in rural settings and clinical diagnostic criteria for myocarditis includes multiple factors which are discussed below. Differential Diagnosis of Cardiac Troponin Elevation Cardiac troponin-I (cTnI) is a very common and useful laboratory indicator of cardiac myocyte injury. Caution must be used in interpreting this test in situations of concurrent rhabdomyolysis. cTnI can be falsely elevated in cases of rhabdomyolysis and it is very difficult to determine if there is both cardiac injury and rhabdomyolysis. A study including 109 emergency room patients with rhabdomyolysis and elevated cTnI determined the presence of true cardiac injury by having either ECG or echocardiographic evidence of myocyte injury regardless of chronicity in the hospitalization.12 This study found a 55% prevalence of elevated cTnI and a 17% false positive elevation of cTnI in patients with rhabdomyolysis. There was poor correlation between peak cTnI and total creatine kinase (CK) and no correlation between magnitude of peak cTnI between true

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and false positive cases. Of note, the mean for peak cTnI was 2.2±4.2 ng/mL vs 1.9±3.4 ng/mL for true positive and false positive cases respectively; meaning this test is not helpful to differentiate true from false cTnI elevation. Another study examining the cause of elevated cTnI in rhabdomyolysis patients concluded that the cTnI elevation is not related to the degree of muscle injury but rather to the cause of rhabdomyolysis. The authors noted illicit substance use, hypotension, and sepsis to be the leading causes of cTnI elevation.13 In this case the diagnosis of myocarditis is based on the presence of chest pain, the asynchronous rise in cTnI after the peak of the CK levels and the presence of ECG changes during the peak of symptoms which subsequently resolved. Source of Infection It is unclear how this patient contracted this enteric infection. Chickens and turkeys account for the highest isolates of Salmonella muenchen in animals2 and this patient did keep chickens at home. It is possible, therefore, that this case could be due to food contamination, contact with a previously infected family member, or other unknown causes. It is interesting that pet geckos have been implicated in recent outbreaks of Salmonella muenchen, as the prevalence of wild geckos in Hawaiian households is very high. In Hawai‘i, the prevalence of Salmonella in the wild gecko populations can vary. In 1982, researchers found 10 of 13 sites on the island of Hawai‘i with geckos positive for Salmonella. The highest incidence of Salmonella-infected geckos was 22.2% with the overall average being 11.9%. The authors postulate that one likely mode of transmission to humans could be through gecko feces. The prevalence of shedding in feces varies as well. Their study found 1.8% of gecko feces positive for Salmonella 14 and another study on the island of Oahu showed 30.4% of gecko feces testing positive.15 The incidence of gecko to human transmission of non-typhoidal Salmonella infections remains unknown and could be a subject of future research. Diagnosis In a healthy young man in excellent physical condition the presence of cardiac complications went unrecognized. The patient was in the hospital for two days before a troponin level was obtained. His chest pain was masked by full body aches and normal initial ECG’s. When a troponin was obtained, the presence and magnitude of the findings were completely unexpected. A more careful history was negative for other risk factors such as drug abuse, family history of early cardiac disease or congenital metabolic disease. Although his stool culture was positive for Salmonella muenchen, blood cultures obtained on the fourth and fifth days of illness remained negative. His clinical picture, vital signs and laboratory data did not offer other reasons for rhabdomyolysis such as hypotension, dehydration, or marked electrolyte abnormalities. It is possible that the complications are from bacteremia that had cleared by the time the patient presented to a health care setting or secondary to systemic release of bacterial toxin.16

In this case the question eventually emerged as to whether the patient’s troponins were elevated due to rhabdomyolysis or to true myocarditis. The magnitude of troponin elevation was itself very impressive. This patient’s troponin peak was greater than 6 times higher than the average false-positive and true-positive troponin peak in patients with rhabdomyolysis in the study mentioned above.12 A normal CT cardiac angiography ruled out ischemic cause for the troponin elevation. In regards to diagnosis of the myocarditis, there are criteria proposed by the European Society of Cardiology Working Group on Myocardial and Pericardial disease from 2013.10 These criteria proposed clinical diagnosis of myocarditis with acute (less than three months) or subacute (three months or greater) cardiac symptoms and at least one positive study on ECG, holter monitor, stress test, cardiac markers, cardiac imaging, or tissue characterization by cardiac MRI. Asymptomatic patients must meet two of the above criteria. Echocardiography had been normal but this does not rule out milder cases of myocarditis.11 The diagnosis of myocarditis was confirmed by the patient’s symptoms, inferolateral T-wave inversion on ECG, and elevated troponins. Treatment The question arises as to whether the early diagnosis of rhabdomyolysis and myocarditis would have changed management and outcomes for this patient. His rhabdomyolysis was treated with aggressive I.V. fluids as well as antibiotic therapy to treat the underlying cause. The primary reason to give IV fluids for rhabdomyolysis is to prevent kidney injury.17 The incidence of rhabdomyolysis induced acute kidney injury (AKI) was found to be 58% in patients with a CK greater than 5,000 U/L.18 Aggressive intravenous fluid administration for rhabdomyolysis in a patient with concurrent myocarditis has risks. Most concerning is flash pulmonary edema in the setting of myocarditis related acute congestive heart failure (CHF), which has been noted in a severe case of non-typhoidal Salmonella induced myocarditis.8 In a patient with multiple comorbidities and possibly poor baseline cardiac function this would have to be carefully addressed; however, in a young healthy patient as described above with no echocardiographic evidence of global myocardial hypokinesia and a preserved ejection fraction, this was not a great concern.. Conclusion This is the first case report of Salmonella muenchen serotype causing either rhabdomyolysis or myocarditis. Complications from non-typhoidal Salmonella infections are rare but can include rhabdomyolysis, myocarditis, meningitis, endocarditis, pericarditis, mycotic aneurysms, pneumonia, empyema, urinary tract infections, genital infections, both septic and reactive arthritis, osteomyelitis, and soft tissue infections.6,9 Diagnosis of complications from non-typhoidal Salmonella infections can be difficult due to patient comorbidities, variability in the severity of the illnesses, laboratory test limitations, and imaging limitations. A careful assessment and high index of suspicion can help aid diagnostic and treatment approaches. In addition, when a patient presents with elevated troponins in the setting

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of rhabdomyolysis a careful workup should be done to evaluate for ischemic causes, myocarditis, or false elevation secondary to rhabdomyolysis. Conflict of Interest None of the authors identify any conflicts of interest. Author’s Affiliation: - Hilo Medical Center, Hilo, HI (WC) Correspondence to: Will Chapple MD, MPH; Email: [email protected] References

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