An Unusual Presentation of Murine Typhus and Mononucleosis

An Unusual Presentation of Murine Typhus and Mononucleosis Abstract A 20-year-old female presented to the emergency department complaining of fever, cough, and dyspnea after a recent camping trip. The patient remained ill appearing, persistently tachycardic and dyspneic despite nebulizer treatments, and fluids in the emergency department. She was admitted for observation and gradually improved over the next 4 d. Inpatient laboratory studies indicated acute Epstein–Barr virus infection and she was discharged with a presumptive diagnosis of infectious mononucleosis. However, further testing showed a simultaneous rickettsial infection producing murine typhus. The patient ultimately recovered uneventfully once proper treatment was initiated. This patient’s presentation represents a unique description of simultaneous infectious mononucleosis and murine typhus which underscores the importance of maintaining a broad differential diagnosis in the approach to febrile illnesses. INTRODUCTION Rickettia typhi is an obligate intracellular, gram negative bacterium that causes the zoonotic infection murine typhus.1,2,5 It is most commonly transmitted by the bite of a rat flea but can also infect humans through contamination of the respiratory tract or the skin through infected rat feces.1,2,5 Human endothelial cells are targeted thus leading to vascular permeability and coagulation states.2–4 The most common seasons of transmission are summer and fall due to increased human contact with the vectors and the infection is most commonly acquired in port cities and beach resorts.1,3 However, contact with rats and their feces or flea bites are rarely reported by those affected, thus making the diagnosis difficult.1,3 Another issue in diagnosis is that the disease present similarly to a multitude of other febrile illnesses.3–6 CASE REPORT A 20-year-old female with no significant medical history presented to the emergency department (ED) in July for nonproductive cough, dyspnea, chest pain, and fever. Symptoms began 7 d after she returned from a tent camping trip to the “Four Corners” area of New Mexico. The patient reportedly cooked with filtered water and drank only bottled water. She denied any tick bites, consuming game meat, or exposure to wild animals. The patient’s vital signs were significant for heart rate of 121 beats per minute and temperature of 101.4°F. The patient appeared ill but nontoxic, and physical exam was remarkable for left anterior cervical adenopathy and diminished lung sounds to the left lower lobe. Initial complete blood count demonstrated both bandemia and atypical lymphocytosis- white blood cells 4370 cells/mm3 (21% bands, 44% lymphocytes, 13% atypical lymphocytes). Hepatic function tests showed moderate elevation of aspartate aminotransferase 295 U/L, alanine aminotransferase 234 U/L, and alkaline phosphatase 199 U/L. The serum lactate was minimally elevated at 2.3 mmol/L. An initial Epstein–Barr virus (EBV) heterophile antibody (monospot) test was negative. The patient remained dyspneic and tachycardic and was admitted for further evaluation. During the admission, EBV serologies suggested acute infection with elevated viral capsid antigen IgM, negative viral capsid antigen IgG, and negative Epstein–Barr nuclear antigen IgG. This diagnosis was confirmed by polymerase chain reaction which isolated EBV viral DNA. A CT scan of the chest/abdomen/pelvis showed mild hepatosplenomegaly but no evidence of splenic rupture. After 4 d of hospitalization, the patient was discharged home in stable condition despite a persistent bandemia of 21%. Discharge diagnosis was infectious mononucleosis with elevated transaminases secondary to viral infection. Multiple serological studies were pending at the time of discharge. Seven days after hospital discharge, a rickettsia serology panel resulted positive (IgM titer 1:64) for Rickettsia typhi, the etiologic agent of murine typhus. At that time, the patient was started on doxycycline 100 mg twice daily for 10 d. In follow-up office visits, she continued to improve. Outpatient laboratory studies showed resolution of her bandemia within 72 h of starting doxycycline although atypical lymphocytosis persisted at 12%. Liver enzymes returned to normal and the patient developed no discernable sequelae related to either infection. DISCUSSION Nonspecific febrile illness is a frequent presenting complaint in the ED. In patients with recent travel or outdoor activities murine typhus, other rickettsial diseases,1 coxiella, plague, hantavirus may need to be in the early differential diagnoses. Because of its nonspecific symptoms, longer incubation period, the abrupt onset of symptoms and the variable patient presentations it can be easily misdiagnosed.1,6 Clinical presentation varies from mild to life threatening illness.6 The incubation period may be anywhere from 6 to 20 d.4,6 Therefore, a clinician can eliminate rickettsial diseases if symptoms start later than 20 d after travel.4 The presenting symptoms are usually fever, headache, and rash,2,3,6 but patients may also present with myalgias, nausea and vomiting.4,5 Patients with IM may present with similar symptoms. Rash is one of the most common early symptoms2,3 and it may lead the ED provider to an accurate diagnosis. However, it may be absent in up to 50% of patients, as it was in this case.1,5 In some cases, murine typhus may affect internal organs such as liver, kidney, brain or lung.2,4,5 Hepatomegaly and splenomegaly are uncommon and may occur in 3% of patients.7 In more severe cases, patients can develop multiorgan failure or shock2,4 with a 1–4% mortality range most likely associated with delayed or lack of antibiotics.4 Common laboratory findings include elevated transaminases, leukopenia, thrombocytopenia, and anemia.1,4 Diagnostic testing for murine typhus has evolved over the years. The Weil–Felix test was initially used, then enzyme immunoassay was introduced and today immunofluorescence assay is the gold standard for diagnosis.2 The today immunofluorescence assay is reported as antibody titer concentration that is the highest serum dilution shown as positive.4 The test is most sensitive and specific once the patient is in the convalescent state of the illness, thus making the definitive diagnosis even more difficult in the acute stages of illness.3 The serologic methods of diagnosis usually demonstrate a four-fold increase in the IgG levels specific for typhus.3 The patient in this case report appeared to have had murine typhus concomitantly with EBV infectious mononucleosis which further complicated the initial diagnosis. The presence of atypical lymphocytes suggested EBV initially but infectious mononucleosis did not adequately explain the significant bandemia. Additionally, the patient’s relative leukopenia is uncharacteristic of infectious mononucleosis which typically presents with significant elevation in the leukocyte count. These complete blood count findings are best explained by the patient’s murine typhus infection, which frequently produces leukopenia and often bandemia. This is further supported by the persistence of bandemia that rapidly resolved after treatment for murine typhus. The treatment of choice for murine typhus is doxycycline, 100 mg twice a day for a minimum of 5 d for general population and in children that weigh more than 45 kg. Chloramphenicol 250–500 mg every 6 h may be used in pregnant women4,5 or in patients allergic to doxycycline. Prompt empiric treatment is recommended when murine typhus is in the differential diagnosis.3,4 This is even more important when the patient is to be discharged home while the diagnostic test results are still pending. Decrease in fever in 48–72 h after starting doxycycline is a marker of rickettsial infections.4 CONCLUSION Murine typhus is frequently a mild disease. However, the disease can be fatal if untreated, especially in the elderly or chronically ill. The ED physician should be suspicious of a rickettsial disease with any presentation of fever with significant time spent outdoors. While the principle of Occam’s razor teaches that a single unifying diagnosis is most likely to be correct, our case demonstrates that any disease can be superimposed by a common illness such as infectious mononucleosis which may further confound the diagnosis and result in treatment delays. Had this patient been discharged from the ED or had the rickettsia panel not have been performed during her hospitalization, the diagnosis could have been missed and the case could have had a detrimental outcome. REFERENCES 1 Walter G, Botelho-Nevers E, Socolovschi C, et al.  : Murine typhus in returned travelers: a report of thirty-two cases. Am J Trop Med Hyg  2012; 86( 6): 1049– 53. Google Scholar CrossRef Search ADS PubMed  2 Peniche Lara G, Dzul-Rosado KR, Zavala Velazquez JE, et al.  : Murine typhus: clinical and epidemiological tests. Colomb Med  2012; 43( 2): 175– 80. Google Scholar PubMed  3 Basra G, Berman MA, Blanton LS.: Murine typhus: an important consideration for the nonspecific febrile illness. Case Reports in Medicine  2012 10.1155/2012/134601. 4 Aung AK, Spelman DW, Murray RJ, et al.  : Review article: rickettsial infections in southeast Asia; implications for locals and febrile returned travelers. Am J Trop Med Hyg  2014; 91( 3): 451– 60. Google Scholar CrossRef Search ADS PubMed  5 Blanton LS, Walker DH.: Flea borne rickettsioses and rickettsiae. Am J Trop Med Hyg  2017; 96( 1): 53– 6. Google Scholar CrossRef Search ADS PubMed  6 Moy WL, Ooi ST.: Case report: abducens nerve palsy and meningitis by. Rickettsia Typhi Am J Trop Med Hyg  2015; 92( 3): 620– 4. Google Scholar CrossRef Search ADS PubMed  7 Afzal Z, Kallumadanda S, Wang F, et al.  : Acute febrile illness and complications due to murine typhus, Texas, USA. Emerg Infect Dis  2017; 23: 1268– 73. Google Scholar CrossRef Search ADS PubMed  Author notes The views expressed are solely those of the authors and do not reflect the official policy or position of the U.S. Army, U.S. Air Force, the Department of Defense, or the U.S. Government. © Association of Military Surgeons of the United States 2018. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Military Medicine Oxford University Press

An Unusual Presentation of Murine Typhus and Mononucleosis

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© Association of Military Surgeons of the United States 2018. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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Abstract

Abstract A 20-year-old female presented to the emergency department complaining of fever, cough, and dyspnea after a recent camping trip. The patient remained ill appearing, persistently tachycardic and dyspneic despite nebulizer treatments, and fluids in the emergency department. She was admitted for observation and gradually improved over the next 4 d. Inpatient laboratory studies indicated acute Epstein–Barr virus infection and she was discharged with a presumptive diagnosis of infectious mononucleosis. However, further testing showed a simultaneous rickettsial infection producing murine typhus. The patient ultimately recovered uneventfully once proper treatment was initiated. This patient’s presentation represents a unique description of simultaneous infectious mononucleosis and murine typhus which underscores the importance of maintaining a broad differential diagnosis in the approach to febrile illnesses. INTRODUCTION Rickettia typhi is an obligate intracellular, gram negative bacterium that causes the zoonotic infection murine typhus.1,2,5 It is most commonly transmitted by the bite of a rat flea but can also infect humans through contamination of the respiratory tract or the skin through infected rat feces.1,2,5 Human endothelial cells are targeted thus leading to vascular permeability and coagulation states.2–4 The most common seasons of transmission are summer and fall due to increased human contact with the vectors and the infection is most commonly acquired in port cities and beach resorts.1,3 However, contact with rats and their feces or flea bites are rarely reported by those affected, thus making the diagnosis difficult.1,3 Another issue in diagnosis is that the disease present similarly to a multitude of other febrile illnesses.3–6 CASE REPORT A 20-year-old female with no significant medical history presented to the emergency department (ED) in July for nonproductive cough, dyspnea, chest pain, and fever. Symptoms began 7 d after she returned from a tent camping trip to the “Four Corners” area of New Mexico. The patient reportedly cooked with filtered water and drank only bottled water. She denied any tick bites, consuming game meat, or exposure to wild animals. The patient’s vital signs were significant for heart rate of 121 beats per minute and temperature of 101.4°F. The patient appeared ill but nontoxic, and physical exam was remarkable for left anterior cervical adenopathy and diminished lung sounds to the left lower lobe. Initial complete blood count demonstrated both bandemia and atypical lymphocytosis- white blood cells 4370 cells/mm3 (21% bands, 44% lymphocytes, 13% atypical lymphocytes). Hepatic function tests showed moderate elevation of aspartate aminotransferase 295 U/L, alanine aminotransferase 234 U/L, and alkaline phosphatase 199 U/L. The serum lactate was minimally elevated at 2.3 mmol/L. An initial Epstein–Barr virus (EBV) heterophile antibody (monospot) test was negative. The patient remained dyspneic and tachycardic and was admitted for further evaluation. During the admission, EBV serologies suggested acute infection with elevated viral capsid antigen IgM, negative viral capsid antigen IgG, and negative Epstein–Barr nuclear antigen IgG. This diagnosis was confirmed by polymerase chain reaction which isolated EBV viral DNA. A CT scan of the chest/abdomen/pelvis showed mild hepatosplenomegaly but no evidence of splenic rupture. After 4 d of hospitalization, the patient was discharged home in stable condition despite a persistent bandemia of 21%. Discharge diagnosis was infectious mononucleosis with elevated transaminases secondary to viral infection. Multiple serological studies were pending at the time of discharge. Seven days after hospital discharge, a rickettsia serology panel resulted positive (IgM titer 1:64) for Rickettsia typhi, the etiologic agent of murine typhus. At that time, the patient was started on doxycycline 100 mg twice daily for 10 d. In follow-up office visits, she continued to improve. Outpatient laboratory studies showed resolution of her bandemia within 72 h of starting doxycycline although atypical lymphocytosis persisted at 12%. Liver enzymes returned to normal and the patient developed no discernable sequelae related to either infection. DISCUSSION Nonspecific febrile illness is a frequent presenting complaint in the ED. In patients with recent travel or outdoor activities murine typhus, other rickettsial diseases,1 coxiella, plague, hantavirus may need to be in the early differential diagnoses. Because of its nonspecific symptoms, longer incubation period, the abrupt onset of symptoms and the variable patient presentations it can be easily misdiagnosed.1,6 Clinical presentation varies from mild to life threatening illness.6 The incubation period may be anywhere from 6 to 20 d.4,6 Therefore, a clinician can eliminate rickettsial diseases if symptoms start later than 20 d after travel.4 The presenting symptoms are usually fever, headache, and rash,2,3,6 but patients may also present with myalgias, nausea and vomiting.4,5 Patients with IM may present with similar symptoms. Rash is one of the most common early symptoms2,3 and it may lead the ED provider to an accurate diagnosis. However, it may be absent in up to 50% of patients, as it was in this case.1,5 In some cases, murine typhus may affect internal organs such as liver, kidney, brain or lung.2,4,5 Hepatomegaly and splenomegaly are uncommon and may occur in 3% of patients.7 In more severe cases, patients can develop multiorgan failure or shock2,4 with a 1–4% mortality range most likely associated with delayed or lack of antibiotics.4 Common laboratory findings include elevated transaminases, leukopenia, thrombocytopenia, and anemia.1,4 Diagnostic testing for murine typhus has evolved over the years. The Weil–Felix test was initially used, then enzyme immunoassay was introduced and today immunofluorescence assay is the gold standard for diagnosis.2 The today immunofluorescence assay is reported as antibody titer concentration that is the highest serum dilution shown as positive.4 The test is most sensitive and specific once the patient is in the convalescent state of the illness, thus making the definitive diagnosis even more difficult in the acute stages of illness.3 The serologic methods of diagnosis usually demonstrate a four-fold increase in the IgG levels specific for typhus.3 The patient in this case report appeared to have had murine typhus concomitantly with EBV infectious mononucleosis which further complicated the initial diagnosis. The presence of atypical lymphocytes suggested EBV initially but infectious mononucleosis did not adequately explain the significant bandemia. Additionally, the patient’s relative leukopenia is uncharacteristic of infectious mononucleosis which typically presents with significant elevation in the leukocyte count. These complete blood count findings are best explained by the patient’s murine typhus infection, which frequently produces leukopenia and often bandemia. This is further supported by the persistence of bandemia that rapidly resolved after treatment for murine typhus. The treatment of choice for murine typhus is doxycycline, 100 mg twice a day for a minimum of 5 d for general population and in children that weigh more than 45 kg. Chloramphenicol 250–500 mg every 6 h may be used in pregnant women4,5 or in patients allergic to doxycycline. Prompt empiric treatment is recommended when murine typhus is in the differential diagnosis.3,4 This is even more important when the patient is to be discharged home while the diagnostic test results are still pending. Decrease in fever in 48–72 h after starting doxycycline is a marker of rickettsial infections.4 CONCLUSION Murine typhus is frequently a mild disease. However, the disease can be fatal if untreated, especially in the elderly or chronically ill. The ED physician should be suspicious of a rickettsial disease with any presentation of fever with significant time spent outdoors. While the principle of Occam’s razor teaches that a single unifying diagnosis is most likely to be correct, our case demonstrates that any disease can be superimposed by a common illness such as infectious mononucleosis which may further confound the diagnosis and result in treatment delays. Had this patient been discharged from the ED or had the rickettsia panel not have been performed during her hospitalization, the diagnosis could have been missed and the case could have had a detrimental outcome. REFERENCES 1 Walter G, Botelho-Nevers E, Socolovschi C, et al.  : Murine typhus in returned travelers: a report of thirty-two cases. Am J Trop Med Hyg  2012; 86( 6): 1049– 53. Google Scholar CrossRef Search ADS PubMed  2 Peniche Lara G, Dzul-Rosado KR, Zavala Velazquez JE, et al.  : Murine typhus: clinical and epidemiological tests. Colomb Med  2012; 43( 2): 175– 80. Google Scholar PubMed  3 Basra G, Berman MA, Blanton LS.: Murine typhus: an important consideration for the nonspecific febrile illness. Case Reports in Medicine  2012 10.1155/2012/134601. 4 Aung AK, Spelman DW, Murray RJ, et al.  : Review article: rickettsial infections in southeast Asia; implications for locals and febrile returned travelers. Am J Trop Med Hyg  2014; 91( 3): 451– 60. Google Scholar CrossRef Search ADS PubMed  5 Blanton LS, Walker DH.: Flea borne rickettsioses and rickettsiae. Am J Trop Med Hyg  2017; 96( 1): 53– 6. Google Scholar CrossRef Search ADS PubMed  6 Moy WL, Ooi ST.: Case report: abducens nerve palsy and meningitis by. Rickettsia Typhi Am J Trop Med Hyg  2015; 92( 3): 620– 4. Google Scholar CrossRef Search ADS PubMed  7 Afzal Z, Kallumadanda S, Wang F, et al.  : Acute febrile illness and complications due to murine typhus, Texas, USA. Emerg Infect Dis  2017; 23: 1268– 73. Google Scholar CrossRef Search ADS PubMed  Author notes The views expressed are solely those of the authors and do not reflect the official policy or position of the U.S. Army, U.S. Air Force, the Department of Defense, or the U.S. Government. © Association of Military Surgeons of the United States 2018. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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Military MedicineOxford University Press

Published: May 18, 2018

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