Human herpesvirus 7 encephalitis in an immunocompetent adult and a literature review

HHV-7 is a widespread double-strand DNA virus in the human population that belongs to the β-herpesvirinae subfamily and replicates in CD4⁺ T lymphocytes. The virus has the ability of lifelong latency and is easy to reactivate in immunocompromised patients [1, 2]. Primary HHV-7 infection regularly occurs during childhood and may manifest several clinical symptoms, mainly fever and exanthem subitum. As for reactivation of HHV-7, HHV-7 encephalitis is a severe type of infection with epileptic seizures as its clinical manifestation. However, there are uncertain aspects about the infection route, except for the history of the infectious agent in patients. Furthermore, on the one hand, as a lymphotropic virus, it has an obvious tropism for the central nervous system(CNS), but its neuropathogenesis is underestimated [3].On the other hand, the case of encephalitis associated with HHV-7 infection in an immunocompetent patient has been rarely reported.

Thus, we manifest an immunocompetent 26-year-old woman with encephalitis with HHV-7 infection and review current literature. With the treatment of acyclovir and ganciclovir, the patient recovered to normal.

A 26-year-old female undergraduate presented to critical care medicine with a 29-day history of fever accompanied by mental and behavioral disorders. The body temperature rose, thus leading to a coma and intermittent convulsions during the last 28 days. Also, there was no significant personal history.

Before admission, she had received treatment in two hospitals. Her CSF sample was colorless, and routine analysis indicated total cells are 2/mm³, with 50% leukocytes, total protein and glucose levels were 0.341 g/L and 2.8 mmol/L, and CSF cultures were negative for bacterial and fungal organisms. Normal findings were obtained from the autoimmune encephalitis examination and cranial CT. EEG expressed irregular activity with epileptiform discharge in the anterior temporal and bilateral frontal areas. HHV-7 DNA was detected in the mNGS of CSF, she was diagnosed with meningitis and/or encephalitis in other hospitals, and then acyclovir was added. Sputum cultures were Acinetobacter baumannii and Burkholderia cepacia. After an active medical intervention, the body temperature was lower than the initial state, but progressive deterioration of the level of consciousness was uncontrolled and then led to a requirement for mechanical ventilation.

On admission, a physical examination revealed that she was unconscious and underwent mechanical ventilation via tracheostomy. Also, she had a fever, lung crackles, neck stiffness, and unconscious limb convulsions. A lumbar puncture was performed, and CSF pressure was 252 mm H₂O. The patient was empirically treated with ganciclovir, meropenem, tigecycline, micafungin, corticoids, glycerol fructose, midazolam, levetiracetam, topiramate, perampanel, clonazepam, phenobarbital. On the third evolution day, mechanical ventilation mode was converted to oxygen inhalation mode, and her condition improved.

Furthermore, anti-ANA-IgG in serum was mildly positive, but a wide spectrum of antibodies (anti-nRNP, anti-Sm, anti-SS-A, anti-Ro-52, anti-SS-B, anti-Scl-70, anti-Jo-1, anti-ACA, anti-AnuA, anti-AHA, anti-ARPA, anti-AMA-M2, anti-PCNA, anti-PM-Scl100, anti-HHV-1-IgG, anti-HHV-2-IgG, anti-Toxo-IgM, anti-CMV-IgM, anti-Rubella-IgM) in serum were normal. To check the brain function, unfortunately, her cranial CT was negative, MRI was not performed because she had been wearing a dental appliance. The second mNGS of CSF indicated Enterococcus faecium and anti-Aspergillus-IgG in the blood were positive. Thus, we added contezolid and voriconazole to alleviate the previous treatment. On the 18th day of admission, her body temperature was up again, combined with primary epilepsy, lumbar puncture was performed, and CSF pressure was 210 mmH₂O, but the CSF cultures and CSF mNGS were negative, then the blood antibodies (anti-HHV-1-IgG, anti-HHV-2-IgG, anti-Toxo-IgG, anti-CMV-IgG, anti-Rubella-IgG) was normal. With the treatment adjustment, the body temperature returned to normal, and the Glasgow Coma Score (GCS) was 15 points (E4, V5, M6). However, her memory ability was damaged, and she was transferred to a rehabilitation hospital for better treatment. Suddenly her body temperature rose again, accompanied by generalized epilepsy, then returned to our hospital the following day. The 4th CSF mNGS indicated HHV-1, EEG expressed irregular activity with a slow wave in the temporal and bilateral frontal areas, urine culture was Klebsiella pneumoniae, the patient was treated with contezolid, corticoids, levetiracetam, topiramate, Perampanel, Clonazepam, amika, ganciclovir. As time passed, her memory ability improved quickly, and she could eat by herself. Whereas she often felt choking when she ate chewy food, but the result of the gastroscopy indicated normal, to some extent implying she had a psychological disorder. Finally, with the help of humanistic concern and antiepileptic drugs, the patient recovered completely after two months.

The diagnostic evaluation of HHV-7 encephalitis needs to be guided by epidemiologic laboratory tests, imaging examinations, and clinical proof. The information is as follows. For the first line of investigation, HHV-7 DNA was detected in CSF, but there was no abnormal personal history (information provided by her relatives). For the second line of investigation, on day 1, the respiratory pathogen spectrum (Legionella, Mycoplasma pneumonia, Chlamydia pneumonia, Respiratory syncytial virus, Adenovirus, Influenza virus A, Parainfluenza virus, Coronavirus) were negative. However, Influenza-virus-B-IgM in serum was positive. Hepatitis viruses (Hepatitis A, Hepatitis B, Hepatitis C, Hepatitis E), Treponema pallidum, and Human immunodeficiency virus were negative, and sputum cultures were Acinetobacter baumannii and Burkholderia cepacia, we added antibiotics. On day 3, tubercle bacillus was negative, and bacterial cultures in the blood and CSF were negative. On day 7, a wide spectrum of blood antibodies (anti-nRNP, anti-Sm, anti-SS-A, anti-Ro-52, anti-SS-B, anti-Scl-70, anti-Jo-1, anti-ACA, anti-AnuA, anti-AHA, anti-ARPA, anti-AMA-M2, anti-PCNA, anti-PM-Scl100) were negative, anti-ANA-IgG was mildly positive, its titers were more than 1:100. However, these indications had no high specificity for the diagnostic of the disease. On day 8, Neisseria meningitides and Cryptococcal neoformans(serum and CSF) were also negative, then a wide spectrum of CSF antibodies (anti-HHV-1-IgG, anti-HHV-2-IgG, anti-Toxo-IgM, anti-CMV-IgM, anti-Rubella-IgM) was negative. Third line investigation, the cranial CT was negative, but the MRI was not performed because the dental appliance affected the result. Finally, on day 8, Enterococcus faecium was detected in the mNGS CSF, and we added contezolid combined with clinical proof. Then the mNGS of CSF indicated HHV-1 on day 33. The patient was treated with ganciclovir for about 6 weeks intermittently.

Viral encephalitis is the acute inflammatory phase of brain parenchyma induced by a viral infection. The clinical symptoms of it include fever and/or seizure; some patients with viral encephalitis cannot find the pathogenic virus. So the differential diagnosis of this patient excluded bacterial and fungal meningitis, malaria, structural brain lesions, toxic and metabolic encephalopathies, and other noninfectious causes of encephalopathy. The mNGS of CSF indicated HHV-7 DNA that supported HHV-7 as the most likely cause of encephalitis. After we added ganciclovir, the HHV-7 DNA was not detected. Due to the HHV-7 infection characterizations and the lack of HHV-7 avidity testing, we cannot distinguish between the secondary and the primary infection.

Among the viral encephalitides, HHV-7 encephalitis is associated with epilepsy. The seizures have been divided into late unprovoked and acute symptomatic. The current case represents the latter and may have a better outcome than the former [3]. Besides that, as for individual treatment, there is a huge gap between the expectation of antiviral therapy and the outcome of patients.

These cases in the table elucidate the similar clinical manifestation and the evolution of the cases in the literature. Patients’ ages ranged from 26 to 52, with a median of 35 years and only one female. The mortality was 14.2%, and ganciclovir was given to 6 patients [4‐9]. Ganciclovir and foscarnet were recommended in immunocompromised patients with HHV-6 infection [10], but the treatment of encephalitis associated with the human herpesvirus-7 infection is still limited and unclear. It was common to see ganciclovir, acyclovir, foscarnet, and intravenous immunoglobulin therapy used in HHV-7 encephalitis. Also, some cases were improved without antiviral agents [11, 12]. In a retrospective analysis, we added ganciclovir empirically, but foscarnet had higher vitro activity than ganciclovir against HHV-7. The foscarnet was highly recommended in the literature [5, 9, 13]. Foscarnet would be a great choice for reducing the length of stay in the intensive care unit and the severity of HHV-7 encephalitis (Table 1).

As for unknown reasons of encephalitis cases present with seizures, the mNGS and PCR of CSF are options for identifying the potential causes, and HHV-7 infection could result in serious CNS disease that should be kept in mind. HHV-7 DNA has enough high specificity to guide the next treatment, and early clinical intervention is crucial, yet there is a great distance to search for the best treatment for HHV-7 encephalitis.