A case of Rickettsia felis infection-induced encephalitis in a pregnant woman

Rickettsia felis is an exclusively cytozoic Gram-negative prokaryote with cat fleas as the major vectors.[1] As early as 1918, Rickettsia felis was detected in cat fleas in Europe and named Rickettsia ctenocephali.[2] Symptoms of fever, malaise, headache, maculopapular rash and eschar are observed in patients with Rickettsia felis infection.[3] There have been gradually increasing reports on Rickettsia felis infection in recent years since molecular biology techniques are widely applied. Moreover, Rickettsia felis has been confirmed to spreads across more than 20 countries worldwide. To treat Rickettsia felis infection in the special population of pregnant women, anti-infective therapy should often be used with caution. At present, severe Rickettsia felis infection-induced complications or deaths in pregnant women have rarely been reported.

CASE

A 36-year-old female from a coastal area in China visited the emergency department of our hospital at 28 weeks and 4 days of gestation. The chief complaint was that she was found unconscious for 1 day. The patient was found lying in bed by her family at 4 p.m. on the day before the visit, with no response to calling out, white vomitus around her mouth, no eyelid ectropion or tics, stiffness or rigidity of her limbs or trunk. She was taken to a local hospital. The results of obstetric ultrasound showed that there was a single live fetus in a transverse position, with the head on the right, and hydramnios was detected. Considering the complexity of her condition, she was transferred to our center at night and subjected to physical examination. Her glasgow coma score (GCS) was 8 (E2V1M3). Then, she underwent auxiliary examinations. The results of blood routine tests were as follows: white blood cell count 19.3×10⁹/L (reference value: [3.5–9.5]×10⁹/L), neutrophil count 18.1×10⁹/L (reference value: [1.8–6.3]×10⁹/L), rapid C-reactive protein 11.2 mg/L (reference value: 0–10 mg/L), and myoglobin 1,593 ng/mL (reference value: 25–58 ng/mL). Moreover, sudden disturbance of consciousness should first rule out cerebrovascular accidents, particularly intracranial hemorrhage. As there was no magnetic resonance imaging (MRI) available in the emergency department at night, a head computed tomography (CT) scan was performed after the family gave their consent. Special precautions, including effective cervicothoracic and abdominal shielding, were taken to minimize the radiation exposure to the fetus, and no cerebral hemorrhage or other space-occupying lesions were observed. The next day, cranial MRI was performed, and the results also indicated no ischemic stroke. She was admitted to the intensive care unit (ICU) for coma for unknown reasons and pregnancy. She had a history of “depression” for several years. She had undergone fallopian tube recanalization and a surgery for head injury due to a fall in 2022. She had no scars or bony prominences on the surface of her head and denied a history of chronic diseases. There were “stray dogs and cats” around the place of residence, but she said she did not directly contact them recently. She had a history of long-term employment in a garment factory and long-term exposure to duck-down feathers. The results of physical examination at admission were as follows: bladder temperature 38.1°C, pulse 125 times/min, respiration 23 times/min, blood pressure 95/59 mmHg (1 mmHg=0.133 kPa), lethargy, bilateral pupil diameter 2.0 mm, soft neck without stiffness, dark red circular skin abrasions on the anterior neck and jaw, sensitivity to light reflex, clear breath sounds in both lungs, no obvious rhonchi or moist crackles, and pregnancy of the belly. Lumbar puncture was conducted immediately on the day of admission, and the cerebrospinal fluid was found to be clear and limpid, with a pressure of 17 cmH₂O (1 cmH₂O=0.098 kPa). No significant abnormalities were found in the combined examination of cerebrospinal fluid routine or biochemical and neurological functions. At the same time, we sent blood and cerebrospinal fluid sample for the next-generation sequencing (NGS). Ultrasonography was conducted again, and the results revealed a single live fetus in the uterine cavity at breech presentation. Continuous fetal heart monitoring was carried out. Moreover, empirical anti-infective therapy with piperacillin sodium and tazobactam sodium (4.5 g, ivgtt, q8 h) was also administered. On the second day after admission to the ICU, NGS suggested the presence of Rickettsia felis infection (blood reads 3, cerebrospinal fluid reads 377). The results of 18 tests for autoimmune encephalitis were negative. The final diagnosis was feline Rickettsia encephalitis. A hospital-wide multidisciplinary diagnosis and treatment (MDT) was organized, and the consultation suggested that doxycycline, which has a greater impact on the fetus, be avoided and replaced with the less toxic but potentially effective azithromycin for anti-infective treatment. The NGS of cerebrospinal fluid and blood was conducted again on day 9 of admission to the ICU, and negative results were obtained. The patient was fully conscious on day 3 after treatment with azithromycin (0.5 g/d, ivgtt) and transferred to the obstetrics and gynaecology ward on day 11 for further treatment. Azithromycin was used for a total of 17 d. No significant discomfort or residual neurological deficits was observed in the patient during the follow-up visit. In addition, no significant abnormalities were detected in the pregnancy tests. The patient returned to the hospital 10 weeks after discharge and delivered a healthy baby.

DISCUSSION

Rickettsia felis is classified as a spotted fever group of rickettsiae that can infect humans and different animals. In addition to cat fleas, Rickettsia felis has also been detected in arthropods such as fleas, ticks, mites and lice.[4] In 1994, the first human case of Rickettsia felis infection was reported in the USA.[5] Rickettsia felis infection has also been reported in Mexico, Brazil, France, Germany, Spain, Sweden, Israel, South Korea, Thailand, Laos, New Zealand and other countries and regions.[6] Recently, it has been reported that Rickettsia felis infection is prevalent to some extent in China.[7]

Some patients may exhibit neurological signs.[8] Rickettsial infections can easily be neglected in patients without rash, eschar or evidence of arthropod bites, and many patients may be misdiagnosed because Rickettsia felis infection shares symptoms with other rickettsial infections and virus infections. Rickettsia felis infection-induced encephalitis has similar clinical manifestations and cerebrospinal fluid testing results to viral encephalitis and autoimmune encephalitis, so it may be misdiagnosed. Therefore, the recognition of central nervous system (CNS) rickettsial infection is crucial. In this case, the prominent clinical manifestation was disturbance of consciousness without antecedent infection or inducement, with light coma as the original symptom. After excluding cerebrovascular diseases, intracranial infection was first considered, and this disease might lead to more serious complications and even endanger the life of the pregnant woman and the fetus. Based on clinical symptoms and general laboratory tests, we may easily suspect a case of encephalitis. However, it is still difficult to determine the pathogen. For example, the symptoms of neurological infections caused by Anaplasma phagocytophilum in the spleen are also similar.[9] Even with a complete MRI, it is still difficult to distinguish. Only through further pathogenic examination can a diagnosis be made.

Currently, it is believed that tetracycline derivatives, mainly doxycycline, are the most effective antibacterial drugs for the treatment of rickettsial infections.[10] Furthermore, chloramphenicol and macrolide antibacterial agents (e.g. azithromycin, clarithromycin and locillomycin) can also be used to treat rickettsial infections.[11] For Rickettsia felis infection combined with CNS infection, doxycycline is preferred because it can penetrate the blood-brain barrier more easily.

However, it was extremely difficult to sustain the pregnancy in this case because she previously had her fallopian tube recanalized, which drastically limited the available therapeutic therapy options. The application of tetracycline antibiotics can cause permanent tooth stain on the fetus.[12,13] After multidisciplinary consultation and discussion, including the pharmacy department, azithromycin, which penetrates the blood-brain barrier but has less impact on the fetus, was chosen for treatment.[14] After treatment with azithromycin, metagenomic detection of pathogenic microorganisms in the cerebrospinal fluid was conducted again, and the cerebrospinal fluid was negative for Rickettsia felis, indicating that azithromycin can be used to treat CNS infection caused by Rickettsia.

Rickettsia felis infection can lead to CNS infection with symptoms of encephalitis. The reason why this patient had mild systemic symptoms may be as follows. 1) Rickettsia felis infecting this patient has relatively low virulence. 2) According to the mNGS results, the number of pathogens is still low. 3) The patient is a young woman whose immune system has the capacity to stop the infection from replicating.

CONCLUSION

Rickettsia felis is an emerging rickettsial pathogen that is widely distributed in mammals, humans and ectoparasites. In clinical practice, the actual incidence rate, clinical signs and severity of Rickettsia felis infection in humans should be further determined, and its effect on public health should be assessed. In particular, anti-infective treatment should be carefully considered for the specific population of pregnant women.