HUMAN HERPESVIRUS-6 MENINGOENCEPHALITIS AND PULMONARY TUBERCULOSIS IN HIV PATIENT: A CASE REPORT

Human herpesvirus 6 (HHV-6), the causative agent of exanthema subitum in childhood, could also induce meningoencephalitis in immunocompromised individuals. We reported a case of 32-years-old woman with complaints of worsen headache, one week before admission. She also had intermittent fever and weakness in her left limb. She was admitted to a local hospital, suspected with tuberculous meningitis and pulmonary tuberculosis, and treated with anti-tuberculosis drugs, antibiotics for bacterial meningitis and steroids. She did not show any improvement, and then referred to X Surakarta General Hospital. On physical examination, we found GCS of E3V3M5, crackles and wheezing throughout the lung, neck stiffness, left hemiparesis, and clonus of the left lower leg. Laboratory results showed increasing leukocytes, reactive anti-HIV, and positive PCR for HHV-6 in the cerebrospinal fluid. On the CT scan, there were multiple hypodense lesions in the pons and right internal capsule, and communicant hydrocephalus. She was treated with highly active anti-retroviral therapy (HAART), Valganciclovir 900 mg b.i.d., steroid, anti-tuberculosis drugs and symptomatic treatment. After three weeks of admission, she began to show improvement, level of consciousness increased, and allowed went home.


INTRODUCTION
Human herpesvirus type 6 (HHV-6) is a member of the Herpesviridae family that is commonly recognized as the cause of roseola infantum -a mild and self-limiting viral syndrome that occurs during childhood (Clark, 2016).The lymphotropic HHV-6 was first isolated in 1986 in patients with lymphoproliferative disorders or human immunodeficiency virus (HIV) infection, and was further classified into two subtypes (variants A and B) in 1993, when key epidemiological and molecular differences were identified (Clark, 2016;Balakrishna et al., 2018).In some cases, primary infection leads to exanthema subitum, which is rarely complicated by meningoencephalitis.After primary infection, HHV-6 is characterized by lifelong latency in peripheral blood mononuclear cells (PBMCs), salivary glands, and brain tissue (Bozzola et al., 2012).Reactivation of infection occurs occasionally, causing fever, rash, pneumonitis, hepatitis, and, in some cases, encephalitis, during pharmacological immunosuppression or acquired immunodeficiency (Reynaud and Horvat, 2013).In immunocompetent adults, this herpesvirus is related to a mononucleosis-like syndrome, Sjogren syndrome, Hodgkin and non-Hodgkin lymphomas and meningoencephalitis (Munawwar and Singh, 2016).Recently, HHV-6 has been associated as an emerging pathogen in patients with acquired immune deficiency syndrome (AIDS) and recipients of bone marrow and solid organ transplants.
Meningoencephalitis that occurs in patient with immunosuppression is the most serious clinical manifestation associated with HHV-6 infection or reactivation (Munawwar and Singh, 2016).
Here, we describe 32-years-old woman with encephalitis related to reactivation of HHV-6.
In contrast to patients described elsewhere, our patient was confirmed with pulmonary tuberculosis, and HIV.The general strategy of antiviral therapy for HHV-6 infection may be based upon the current treatment of anti-human cytomegalovirus (anti-HCMV).The essential target is active infection.But, available drugs on the market are not efficient against active infection, thus treatments are limited to prophylactic and pre-emptive approaches (Shahani, 2014).
However, one must keep in mind that many active HHV-6 infections are asymptomatic, even in individual with immune deficiency, and can revert to latency without any therapy.Moreover, if an active HHV-6 infection is suspected, it is essential to rule out the possibility of HHV-6 reactivation (Shahani, 2014).If the latter is true, then virus reactivation may still have occurred and may be a potential source of disease.However, the patterns of transcription, indicating active virus replication are not completely known, and the quantification of transcripts is not yet standardized, which makes the interpretation of virologic findings ambiguous in many cases (Shahani, 2014).
Clinical presentation of HHV-6 encephalitis includes headache, memory impairment, confusion, seizures, altered mental status and focal neurological deficits (Bozzola et al., 2012).Our patient presented with headache, decreased level of consciousness, left extremity weakness and diplopia.
Opportunistic infections can cause a variety of ocular disorders in patient with HIV.Retrobulbar optic neuritis is rare and may be caused by herpesviruses such as Epstein-Barr virus (EBV), cytomegalovirus (CMV), varicella-zoster virus (VZV) (Jabs, 1995) and HHV-7 (Yoshikawa et al., 2003), rate of 52 times/min and a respiratory rate of 18 times/min.She was disoriented to person, place, and time, her pupils were round, regular, isochoric, and reactive to light.We also found neck stiffness, positive Brudzinski I sign, bilateral papilledema, paresis of right Oculomotor nerve, and left hemiparesis.Diagnostic lumbar puncture (LP) revealed colorless, clear, cerebrospinal fluid (CSF) with no clot.We also discovered positive Nonne-Pandy's test, total protein of 70 mg/dl, glucose level of 45 mg/dL, total cell 45 cells/µL, with 0% polymorphonuclear (PMN), and 100% mononuclear (MN) cell.We also found random blood sugar (RBS) level of 92 mg/dL.Her chest X-ray showed that active, broad lesion of pulmonary tuberculosis (TB) with mixed pneumonia, multiple bullae in the left supra hiller, and left pleural effusion.CT-scan showed multiple hypodense lesions in the pons and right internal capsule constituting an inflammation process, communicant hydrocephalus, and cerebral edema.

Figure 2 .
Figure 2. Brain CT scan showed multiple hypodense lesions in pons and right internal capsule.In the emergency department, prophylactic Dexamethasone 10mg q.i.d. and Acetazolamide 500mg was given to reduce intracranial pressure.Meningitis/encephalitis nucleic acid amplification testing (NAAT) of CSF sample using nested PCR was done after performing LP in the ward.Five microliters of extracted DNA from CSF sample were amplified in a 50 µl reaction mixture syphilis and cryptococcus are the most important non-viral etiologies.In our case, microbiological examination of CSF samples only identified HHV-6.HIV could have been involved as a primary pathogen in optic neuritis or Oculomotor nerve palsy, but the moderate HIV viral load in the CSF contrasting with the high level in plasma, and the low ratio CSF/plasma, adding to the visual complaint before HAART introduction were strong arguments for the solely pathogenic role of HHV-6 infection.On the other side, retrobulbar optic neuritis and Oculomotor nerve palsy might also be worsen as an adverse effect of antiretroviral drugs, particularly Didanosine and Zidovudine(Cobo et al.,   Three drugs initially developed to target HCMV infection have been shown to be efficient against HHV-6 infection, both in vitro and in vivo: Ganciclovir, Foscarnet, and Cidofovir(Agut et al., 2015).Acyclovir, a widely available antiviral drug against HSV and VZV infections, is active against HHV-6 in vitro, but only at very high concentrations.The three efficient anti-HHV-6 compounds exhibit the same inhibition activity against both HHV-6A and HHV-6B in vitro(Bozzola et al., 2012;Agut et al. 2015).The mechanisms of this antiviral activity are similar for both HCMV and HHV-6: the viral DNA polymerase is specifically inhibited by the tri-phosphorylated form of Ganciclovir, and the di-phosphorylated form of both Cidofovir, and Foscarnet(Yamanishi et al., 2013;Agut et al., 2015).Ganciclovir and Foscarnet have been known to be effective against HHV-6 and previous reports have demonstrated good clinical outcomes with both drugs.In this case, our patient was treated with Valganciclovir for 21 days, due to unavailability of Ganciclovir, Cidofovir, and Forcarnet.CONCLUSIONCentral nervous system (CNS) involvement due to HHV-6 should be considered in meningoencephalitis case with advanced HIV/AIDS and T CD4 + cell counts less than 200 cells/µL.Abnormal CSF analysis may help to diagnose encephalitis caused by HHV-6, as it was in our case.The diagnosis is confirmed by the detection of HHV-6 genome by PCR.Early diagnosis followed by specific therapy based on Ganciclovir or Foscarnet and HAART could improve patient's condition.
The initial symptoms of this case were admission.She had no history of vaccination.There was no family history of similar symptoms.There is no history of overseas travel before admission.On physical examination, she was subfebrile, normotensive, and bradycardic, with a heart