Article Text
Abstract
Ehrlichiosis is a tickborne illness that can lead to an increased risk of death without appropriate treatment. According to Centers for Disease Control and Prevention, there has been a rise in incidence. We present a case of an immunocompetent patient who reported tick removal after hiking. Chest imaging showed pulmonary vascular congestion, extensive bilateral airspace and bibasilar moderate-dependent pleural effusions. Transthoracic echocardiography showed moderate pulmonary hypertension with right ventricular systolic pressure of 56.3 mm Hg. Ehrlichia chaffeensis PCR testing came back positive. Doxycycline was started in the emergency department and continued for 14 days. The patient had a resolution of the pulmonary hypertension and decrease in tricuspid regurgitation. However, mild mitral regurgitation was persistent. The pulmonary hypertension may be caused by the patient’s response to ehrlichiosis infection, but it may also be explained by the development of acute respiratory distress syndrome, which has been documented in multiple studies.
- Infections
- Cardiovascular medicine
- Pulmonary hypertension
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Background
Ehrlichiosis is a tickborne illness caused by an obligate intracellular gram-negative bacterium of the ehrlichia genus. The genus includes Ehrlichia chaffeensis and Ehrlichia ewingii which are spread by the lone star tick (Amblyomma americanum). It also includes Ehrlichia muris eauclairensis which is spread by the blacklegged tick (Ixodes scapularis).1 In the USA, 30% of reported cases of Ehrlichiosis is due to E. chaffeensis.2 In a study by Heitman et al (2016), cases of E. chaffeensis are highest in the states of Oklahoma, Missouri, Delaware, Arkansas, Virginia and Tennessee.3 However, Centers for Disease Control and Prevention (CDC) reports that in 2019 nearly half of all reported cases occurred in New York, North Carolina, Arkansas and Missouri.2 The transmission occurs in the summer months, peaking in the months of May–4 July, which coincides with the feeding cycle of the lone star tick.4 5
Infection with Ehrlichia species is due to the endocytosis of the organism by the mononuclear phagocytic system of the body.5 It uses immune evasion mechanism and can infiltrate multiple organs such as brain meninges, lungs, kidneys, gastrointestinal tract and heart.6 The initial illness is due to the host’s inflammatory response after tick exposure. Patients can present with influenza-like symptoms such as fever, chills, headache, malaise, myalgia and nausea.7 After 7–14 days of exposure, a rash may appear on the trunk with sparing of the hands and feet but it is only seen in less than 30% of adult patients.7
Treatment is with doxycycline, a bacteriostatic antibiotic that binds to 30S prokaryotic ribosomal unit during protein synthesis.7 Severe cases of ehrlichiosis can lead to an increased risk of death without appropriate treatment.8
Case presentation
A woman in her 60s went hiking and reported a tick exposure. She presented 12 days after the bite at the emergency department (ED) with body pain, generalised headache and fatigue. On physical examination, she was afebrile at 36.9°C, low blood pressure of 96/57, with clear and equal lung sounds, and without rashes. There was no jugular venous distension. S1 and S2 were normal and heart examination was negative for murmurs or extra heart sounds. Laboratory studies revealed low leucocyte count of 2.50×109/L (normal: 4.5–11.0×103/µL) with a differential count of 0.51 (51%) band and low platelet count of 42×109/L (normal: 140–450×103/µL). Liver enzymes were elevated—alanine aminotransferase of 150 U/L and aspartate aminotransferase of 161 U/L. C reactive protein was also elevated at 90.610 mg/L while lactic acid was normal at 1.1 mmol/L (normal: 0.5–2.0 mmol/L). A CT head without intravenous contrast was normal. Blood culture, urine culture, tick panel (serum anaplasma antibodies, Rocky Mountain spotted fever antibodies, ehrlichia antibodies and DNA) were ordered. A peripheral blood smear was reviewed, and no parasites and organisms were noted.
Investigations
She was subsequently admitted to the inpatient floor unit where repeat laboratories still revealed leucopenia, thrombocytopenia and elevated liver enzymes. A chest X-ray (figure 1) the following day showed pulmonary vascular congestion and interstitial oedema pattern, but the patient had persistently low BP (mean arterial pressure <65 mm Hg) so intravenous fluid was increased to 125 mL/hour with a total of 5.5 L bolus. Repeat lactic acid was still normal at 0.8 mmol/L. Empiric antibiotics with vancomycin 1 g for one dose and piperacillin-tazobactam 4.5 g every 4 hours were started in the ED and were continued on the floors. Doxycycline 100 mg every 12 hours was also started due to a history of tick exposure. She was initially diagnosed as viral syndrome. Overnight for persistent hypotension, additional 1 L of normal saline was given. Subsequently, a decision to start norepinephrine intravenously was made and she was transferred to the intensive care unit (ICU) for severe sepsis.
In the ICU, she had generalised headache which was treated with acetaminophen and oxycodone. She also had shortness of breath for which she was given furosemide 20 mg intravenously and was placed on 4 L per minute of oxygen via nasal cannula. Transthoracic echocardiogram (TTE) was ordered which showed ejection fraction (EF) of 60%–65%, mild mitral regurgitation, mildly dilated left atrium, moderate tricuspid regurgitation and moderate pulmonary hypertension. Right ventricular systolic pressure (RVSP) was 56.3 mm Hg with normal right atrium (figure 2). A TTE was available a year prior to admission which showed mild tricuspid regurgitation, mild mitral regurgitation, normal left atrium, EF of 60%–65% with RVSP measuring 26.4 mm Hg (figure 3). In both echocardiography results, the right ventricular cavity was normal in size and function. A 12-lead ECG was ordered which showed normal sinus rhythm, low voltage QRS, and nonspecific T wave abnormalities. ECG did not show ST depression, inversions in V1–V3, QTC or QRS prolongation, right ventricular hypertrophy and axis deviation seen in some cases of pulmonary hypertension. Cardiology was consulted and they recommended to repeat echocardiogram after the diuresis. A ventilation and perfusion scan was done which was indeterminate so the decision was to do a CT angiography of the chest which showed no pulmonary embolism but with moderate effusions bilaterally. Bilateral leg ultrasound was performed which was negative for thrombosis. Chest CT scan (figure 4) with contrast was done which showed extensive bilateral airspace and bibasilar moderate-dependent pleural effusions. A chest X-ray the following day showed progression of left pleural effusion.
The patient had persistent shortness of breath despite adequate oxygen saturation. Eventually, the patient tested positive for E. chaffeensis via Real-time PCR testing of DNA. The analytical performance was done by a commercial laboratory which collects 0.7 mL whole blood in EDTA tube. Antibodies against E. chaffeensis were also done which showed false negative results. E. chaffeensis antibody IgG was <1:64 and IgM was <1:20.
Treatment
Doxycycline 100 mg every 12 hours was empirically started at the ED due to the history of tick exposure. The patient’s symptoms resolved after 5 days of doxycycline, and she passed 6 min walk test and was subsequently discharged. Repeat chest X-ray (figure 5) showed resolution of pulmonary vascular congestion. Doxycycline was continued on discharge to complete 14 days.
Outcome and follow-up
The patient has returned to her usual activities without any shortness of breath. Three months postdischarge, a repeat chest CT (figure 6) showed resolution of the bilateral pleural effusions and the extensive bilateral pulmonary opacities seen previously. However, a few linear opacities remained at the bilateral lung bases, which may represent areas of atelectasis or residual scarring. A repeat echocardiogram was done which showed resolution of pulmonary hypertension with RVSP decreasing to 19.2 mm Hg (figure 7), a decrease in the tricuspid regurgitation from moderate to mild and increased EF of 65%–70%. Mild mitral regurgitation was persistent. The leucopenia, thrombocytopaenia and liver enzymes went back to normal.
Discussion
Ehrlichiosis has been increasing in frequency due to advancements in the recognition of the disease and the spread of the Lone Star tick due to climate change. This case happened during the peak months of ehrlichiosis congruent to the report by Biggs et al. Data on ehrlichiosis causing pulmonary manifestations in humans, let alone pulmonary hypertension, are scarce.9 At the same time, severe forms of ehrlichiosis are commonly seen in immunocompromised adults including one report of meningoencephalitis.10
This report shows a case of an immunocompetent patient who developed severe sepsis and pulmonary hypertension after ehrlichiosis infection. The patient tested positive in E. chaffeensis PCR but was false negative in E. chaffeensis antibody IgG and IgM testing. It is important to note that antibody testing was only taken during admission and was not repeated after 2–4 weeks so there was no seroconversion status reported nor a 4-fold rise in the titres that is usually expected and considered the most sensitive.11 Since the sample was collected during the acute phase of the disease, a negative IgG and IgM test does not exclude the diagnosis.12 The diagnosis was made through PCR testing which has relatively high (60%–85%) sensitivity especially if antibiotics have not been administered yet.12
The patient was generally healthy and did not have any significant cardiac pathologies prior to admission. Pulmonary hypertension was seen in the 50% increase in the RVSP during the admission. This case is noteworthy because pulmonary hypertension in ehrlichiosis is not commonly reported in human infection. To date, no literature has reported this incidence. However, the pathophysiology of this pulmonary manifestation is not well defined. Various published studies including the CDC had reported incidence of acute respiratory distress syndrome (ARDS) in ehrlichiosis.13 The CT scan and chest X-ray of the patient showed airspace fluid accumulation consistent with ARDS. In a study by Fishbein et al, they reported that 7 out of 237 cases of human ehrlichiosis had pulmonary infiltrates.13 In an study by Bakken et al, they found 14 out of 32 patients who were positive for E. chaffeensis had evidence of pulmonary infiltrates with 7 of them requiring intubation and mechanical ventilatory support.14 It is possible that the pulmonary hypertension was due to the ARDS which eventually led to the worsening tricuspid regurgitation.
Although less likely, it may be related to patient’s response to infection. Ehrlichiosis target leucocytes including monocytes, macrophages and neutrophils through the secretion of proteins and alteration of host defence proteins (IL-5, IL-18, chemokine receptors 2, 3 and 4 and Major Histocompatibility Class II). Ehrlichiosis also causes increased TNF-alpha which is associated with severe sepsis causing a fatal disease.15 The pulmonary hypertension in ehrlichiosis infection has only been documented in published studies related to dogs.16 Pulmonary hypertension in dogs is due to direct damage to the alveolar septa and lung endothelium by cellular infiltration and inflammation.17 The ehrlichiosis may explain the pulmonary hypertension seen in this case, but it still needs further investigation.
This case report highlights the need to consider ehrlichiosis as one of differential diagnosis in a patient manifesting with new-onset pulmonary hypertension, especially in patients in at-risk locations and during peak months.
According to Hamburg et al, delay in treatment increases the risk for ICU admission and the need for mechanical ventilation. It also causes longer hospital stays and illness duration.18 Although this patient was immediately started on the appropriate therapy in the ED. She did not present herself for treatment until 12 days after exposure. This delay may have led to the worsening course of her disease. It is recommended to have a lower threshold for treatment of doxycycline given patient did not present with typical rash and symptoms. However, this highlights the need for an increased awareness of the general population about tick bites and early symptom recognition, especially in areas where this infection is endemic. In addition, increased awareness on the use of 0.5% permethrin on clothes, the use of insect repellents (DEET, picaridin) before hiking, protective clothing and removal of ticks are also beneficial to prevent such occurrences.
Patient’s perspective
Being an active and healthy woman in my 60s, it was difficult to accept that I had to go through this ordeal. I exercise on a regular basis, and I try to eat healthy as much as I can being a member of the medical field myself. The reversal of role, my experiences as a patient, was eye-opening. My headaches that were so severe, and my shortness of breath that felt like I had to gasp for air even with minimal activity made me feel weak and helpless. It surprised me how a simple tick bite which I had admittedly thought was non-life threatening to a person as active and as healthy as me can lead to such damaging effects on my lungs and heart.
Learning points
Ehrlichiosis should be considered as one of the differential diagnoses in a patient manifesting with new-onset pulmonary hypertension at high-risk locations and during peak months of ehrlichiosis infection.
Further research is needed to explain the pulmonary hypertension in patients with ehrlichiosis but may be related to the development of ARDS in ehrlichiosis or patient’s immune response to the infection.
There is a need for increased awareness of ehrlichiosis symptom recognition and preventive treatment especially in endemic areas.
Ethics statements
Patient consent for publication
References
Footnotes
X @raymartmacasaet, @poorvabhide
Contributors The following authors were responsible for drafting the text, sourcing and editing clinical images, investigation results, drawing original diagrams and algorithms, and critical revision for important intellectual content: All the authors cited in the manuscript had substantial contributions to the concept and design, the execution of the work or the analysis and interpretation of the case; drafting or revising the manuscript and have read and approved the final version of the paper. RM: conceptualisation, visualisation, writing-original draft, writing-review and editing. FK, PB: case management, writing-original draft, writing-review and editing. PF: conceptualisation, writing-review and editing. The following authors gave final approval of the manuscript: RM, FK, PB, PF.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.