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A Rare and Fatal Case of Viral Encephalitis in an Immunocompetent Host
Author’s Accepted Manuscript A Rare and Fatal Case of Viral Encephalitis in an Immunocompetent Host Prathik Krishnan, Poornima Ramadas, Rumon Chakravarty, Birendra Sah www.elsevier.com
PII: DOI: Reference:
S0002-9629(16)30379-2 http://dx.doi.org/10.1016/j.amjms.2016.07.006 AMJMS244
To appear in: The American Journal of the Medical Sciences Received date: 1 May 2016 Revised date: 27 June 2016 Accepted date: 11 July 2016 Cite this article as: Prathik Krishnan, Poornima Ramadas, Rumon Chakravarty and Birendra Sah, A Rare and Fatal Case of Viral Encephalitis in an Immunocompetent Host, The American Journal of the Medical Sciences, http://dx.doi.org/10.1016/j.amjms.2016.07.006 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
A RARE AND FATAL CASE OF VIRAL ENCEPHALITIS IN AN IMMUNOCOMPETENT HOST
Krishnan, Prathik MBBS Dept of Internal Medicine, SUNY Upstate Medical University, 750 E Adams Street, Syracuse NY 13210, USA [email protected]
Ramadas, Poornima MBBS Dept of Internal Medicine, SUNY Upstate Medical University, 750 E Adams Street, Syracuse NY 13210, USA [email protected]
Chakravarty, Rumon MD Dept of Pulmonary/Critical Care, SUNY Upstate Medical University, 750 E Adams Street, Syracuse NY 13210, USA [email protected]
Sah, Birendra MD Dept of Pulmonary/Critical Care, SUNY Upstate Medical University, 750 E Adams Street, Syracuse NY 13210, USA [email protected]
Corresponding Author Krishnan, Prathik MBBS Dept of Internal Medicine, SUNY Upstate Medical University, 750 E Adams Street, Syracuse NY 13210, USA [email protected] Ph: 408-520-8886 1
Short title: HHV-6 ENCEPHALITIS IN AN IMMUNOCOMPETENT HOST
All authors declare no conflict of interest
All authors declare no Source of Funding.
Keywords: HHV6, Encephalitis, Foscarnet
A 55-year-old female with past medical history of hypertension, hyperlipidemia, depression, hypothyroidism and type 2 diabetes mellitus presented to an outside hospital with complaints of fatigue and lethargy for a few days. She also complained of low-grade fever, abdominal pain and diarrhea. As per family, a day prior to admission the patient had become very agitated and hence was taken to the emergency room. In the emergency room she was found to be extremely agitated and febrile. She was sedated and intubated for airway protection. A spinal tap was done which revealed protein of 60, glucose of 108, 0 white blood cells (WBC) and 11 red blood cells (RBC). The patient was started on acyclovir, vancomycin, ceftriaxone, ampicillin for broad coverage of infectious meningoencephalitis. A urine toxicology screen was also done which was negative. Since there was minimal improvement after five days of antibiotics, she was transferred to our facility for higher level of care. Spinal tap cultures were pending at the time of transfer. 2
The patient underwent MRI brain which did not show any acute findings. Thyroid stimulating hormone, pCO2, lactate and anion gap were all normal. EEG was done which showed no epileptiform activity but generalized slowing and semi-periodic triphasic waves. A repeat lumbar puncture was done which showed glucose 82, protein 25, RBC 11, WBC 3. Auto-immune work up significant for elevated ESR, CRP, and speckled pattern ANA. RF and dsDNA were negative. Rheumatology was consulted who recommended starting patient on 1 g solumedrol daily for possible lupus cerebritis until serological work up was complete. Further history from the family revealed patient had photosensitivity, malar rash, mouth ulcers, history of depression, and joint swelling which satisfied criteria for Systemic lupus erythematosus (SLE) and the patient had a positive family history of SLE in her sister. She was started on Plasmapheresis and received six sessions. Solumedrol was eventually decreased to 40 mg daily after five days of 1 g daily. N-methyl-D-aspartate receptor (NMDA) antibodies, Voltage-gated potassium channel (VGKC) antibodies, prion panel, cytomegalovirus IgM, Epstein-barr IgM, tau protein, Toxoplasma IgM and IgG and paraneoplastic panel were all negative. New York State encephalitis panel revealed positive Human Herpes Virus-6 (HHV-6) antigen by real time Polymerase Chain Reaction (PCR) in the CSF but did not quantify the viral load. but did not quantify the Viral Load. The patient was started on foscarnet and infectious disease were consulted. The patient completed 22 days of foscarnet but didn't have any improvement in her mental status. MR Spect completed with fairly heterogeneous activity throughout the brain, with a specific area of focally decreased uptake in the left frontal lobe. A repeat lumbar puncture was again done with fluid analysis revealing HHV-6 DNA PCR at 6200copies/ml. Due to 3
the prolonged hospital stay and in light of minimal improvement of mental status after antiviral therapy comfort care measures were instituted as per family request and patient passed away.
HHV-6 is a double standard envelope DNA virus discovered in 1986. It was demonstrated later to be the causative agent of exanthem subitum in infants. The virus has two variants, A and B. Similar to other herpes viruses; HHV6 remains latent in lymphocytes, salivary glands and brain. If the host becomes immunocompromised, reactivation can occur. HHV-6 Variant B has been reported to occur in 40 to 60% of BMT and solid organ transplant. HHV-6 can also cause encephalitis of variable severity in immunocompetent hosts but less than 30 cases has been reported1,2.
Although there are multitude of tests to diagnose HHV6 including PCR, Enzyme-Linked Immunosorbent Assay (ELISA) and Indirect fluorescent antibody (IFA). Detection of nucleic acid by PCR may indicate an active or latent infection. Quantitative PCR is deemed the most appropriate as it can detect viral loads and can be followed over time. HHV-6 viral loads in CSF varies widely in patients with HHV-6 encephalitis, with median values of approximately 15,000 to 30,000 copies/mL (range 600 to 1,000,000 copies/mL)3. Real-time PCR is a method that was initially used in our patient, which distinguishes between HHV-6 subtypes although it doesn’t give a viral load. Reverse transcription PCR detects messenger RNA and, thus, indicates actively replicating virus. This can be helpful, especially when dealing with cellular specimens (eg, whole blood or peripheral blood mononuclear cells). Reverse transcription PCR is not widely available. 4
A variety of tests are available for the detection of HHV-6 antibody responses. These include indirect immunofluorescence assays, anti-complement immunofluorescence, competitive radioimmunoassay, and neutralization and enzyme immunoassays. The sensitivity of these assays varies. They do not distinguish between the HHV-6A and -B variants, and there is crossreactivity with HHV-7. Because most people over two years of age are seropositive for HHV-6, a single positive result cannot be interpreted. Seroconversion from negative to positive is good evidence of primary infection. HHV-6 IgM develops within four to seven days of infection. However, approximately 5 percent of healthy adults are IgM positive at any given time, making this test unreliable for a definitive diagnosis4.
There is continued debate of the clinical relevance of HHV-6 in the CSF of immunocompetent adults even in the presence of encephalomyelitis1. The virus has a tropism for glial cells and PBMCs and remains latent in all infected individuals. Therefore, the presence of HHV-6 does not necessarily establish a pathogenic role5. However, in several autopsy specimens from immunocompetent patients with encephalitis, either HHV-6 early protein was localized by immunohistochemistry or HHV-6 nucleic acid was localized by in situ hybridization, specifically in involved portions of the brain. This suggests HHV-6 as the etiology in these cases6.
In reported cases of HHV-6 encephalitis patchy abnormal MRI signal in the cerebral cortex and white matter has been described. Hypoglycorrhachia in CSF has also been described 7. Although our patient showed patchy frontal lobe lesion, no hypoglycorrachia was noted on CSF. It is likely 5
that the patient did not have low levels of glucose in her CSF as she was being given high dose steroids at that time and her blood glucose levels were high.
There have been no in vivo studies—except for case reports—that have addressed treatment of HHV-6 infection8. Ganciclovir resistant HHV-6 has also been reported. In our case patient completed three weeks of foscarnet but no response was seen.
In conclusion we present a rare case of HHV-6 encephalitis in an immunocompetent adult who failed to show significant clinical improvement despite three weeks of foscarnet therapy.
References
1. Caserta, Mary T. "Human herpesvirus 6 infection of the central nervous system." Current infectious disease reports 6.4 (2004): 316-321. 2. Birnbaum, T., Padovan, C. S., Sporer, B. et al (2005). Severe meningoencephalitis caused by human herpesvirus 6 type B in an immunocompetent woman treated with ganciclovir. Clinical infectious diseases, 40(6), 887-889. 3. Reddy, Sushruth, and Pradip Manna. "Quantitative detection and differentiation of human herpesvirus 6 subtypes in bone marrow transplant patients by using a single real-time polymerase chain reaction assay."Biology of Blood and Marrow Transplantation 11.7 (2005): 530-541. 6
4. Suga, S., Yoshikawa, T., Asano, Y. et al (1992). IgM Neutralizing Antibody Responses to Human Herpesvirus‐6 in Patients with Exanthem Subitum or Organ Transplantation. Microbiology and immunology, 36(5), 495-506. 5. Whitley, Richard J., and Fred D. Lakeman. "Human herpesvirus 6 infection of the central nervous system: is it just a case of mistaken association?."Clinical Infectious Diseases 40.6 (2005): 894-895. 6. Novoa, L. J., Nagra, R. M., Nakawatase, T. et al (1997). Fulminant demyelinating encephalomyelitis associated with productive HHV‐6 infection in an immunocompetent adult.Journal of medical virology, 52(3), 301-308. 7. Denes, E., Magy, L., Pradeau, K., Alain, S. et al (2004). Successful treatment of human herpesvirus 6 encephalomyelitis in immunocompetent patient. Emerg Infect Dis, 10(4), 729-731. 8. Dewhurst, Stephen. "Human herpesvirus type 6 and human herpesvirus type 7 infections of the central nervous system." Herpes: the journal of the IHMF11 (2004): 105A-111.
7
PII: DOI: Reference:
S0002-9629(16)30379-2 http://dx.doi.org/10.1016/j.amjms.2016.07.006 AMJMS244
To appear in: The American Journal of the Medical Sciences Received date: 1 May 2016 Revised date: 27 June 2016 Accepted date: 11 July 2016 Cite this article as: Prathik Krishnan, Poornima Ramadas, Rumon Chakravarty and Birendra Sah, A Rare and Fatal Case of Viral Encephalitis in an Immunocompetent Host, The American Journal of the Medical Sciences, http://dx.doi.org/10.1016/j.amjms.2016.07.006 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
A RARE AND FATAL CASE OF VIRAL ENCEPHALITIS IN AN IMMUNOCOMPETENT HOST
Krishnan, Prathik MBBS Dept of Internal Medicine, SUNY Upstate Medical University, 750 E Adams Street, Syracuse NY 13210, USA [email protected]
Ramadas, Poornima MBBS Dept of Internal Medicine, SUNY Upstate Medical University, 750 E Adams Street, Syracuse NY 13210, USA [email protected]
Chakravarty, Rumon MD Dept of Pulmonary/Critical Care, SUNY Upstate Medical University, 750 E Adams Street, Syracuse NY 13210, USA [email protected]
Sah, Birendra MD Dept of Pulmonary/Critical Care, SUNY Upstate Medical University, 750 E Adams Street, Syracuse NY 13210, USA [email protected]
Corresponding Author Krishnan, Prathik MBBS Dept of Internal Medicine, SUNY Upstate Medical University, 750 E Adams Street, Syracuse NY 13210, USA [email protected] Ph: 408-520-8886 1
Short title: HHV-6 ENCEPHALITIS IN AN IMMUNOCOMPETENT HOST
All authors declare no conflict of interest
All authors declare no Source of Funding.
Keywords: HHV6, Encephalitis, Foscarnet
A 55-year-old female with past medical history of hypertension, hyperlipidemia, depression, hypothyroidism and type 2 diabetes mellitus presented to an outside hospital with complaints of fatigue and lethargy for a few days. She also complained of low-grade fever, abdominal pain and diarrhea. As per family, a day prior to admission the patient had become very agitated and hence was taken to the emergency room. In the emergency room she was found to be extremely agitated and febrile. She was sedated and intubated for airway protection. A spinal tap was done which revealed protein of 60, glucose of 108, 0 white blood cells (WBC) and 11 red blood cells (RBC). The patient was started on acyclovir, vancomycin, ceftriaxone, ampicillin for broad coverage of infectious meningoencephalitis. A urine toxicology screen was also done which was negative. Since there was minimal improvement after five days of antibiotics, she was transferred to our facility for higher level of care. Spinal tap cultures were pending at the time of transfer. 2
The patient underwent MRI brain which did not show any acute findings. Thyroid stimulating hormone, pCO2, lactate and anion gap were all normal. EEG was done which showed no epileptiform activity but generalized slowing and semi-periodic triphasic waves. A repeat lumbar puncture was done which showed glucose 82, protein 25, RBC 11, WBC 3. Auto-immune work up significant for elevated ESR, CRP, and speckled pattern ANA. RF and dsDNA were negative. Rheumatology was consulted who recommended starting patient on 1 g solumedrol daily for possible lupus cerebritis until serological work up was complete. Further history from the family revealed patient had photosensitivity, malar rash, mouth ulcers, history of depression, and joint swelling which satisfied criteria for Systemic lupus erythematosus (SLE) and the patient had a positive family history of SLE in her sister. She was started on Plasmapheresis and received six sessions. Solumedrol was eventually decreased to 40 mg daily after five days of 1 g daily. N-methyl-D-aspartate receptor (NMDA) antibodies, Voltage-gated potassium channel (VGKC) antibodies, prion panel, cytomegalovirus IgM, Epstein-barr IgM, tau protein, Toxoplasma IgM and IgG and paraneoplastic panel were all negative. New York State encephalitis panel revealed positive Human Herpes Virus-6 (HHV-6) antigen by real time Polymerase Chain Reaction (PCR) in the CSF but did not quantify the viral load. but did not quantify the Viral Load. The patient was started on foscarnet and infectious disease were consulted. The patient completed 22 days of foscarnet but didn't have any improvement in her mental status. MR Spect completed with fairly heterogeneous activity throughout the brain, with a specific area of focally decreased uptake in the left frontal lobe. A repeat lumbar puncture was again done with fluid analysis revealing HHV-6 DNA PCR at 6200copies/ml. Due to 3
the prolonged hospital stay and in light of minimal improvement of mental status after antiviral therapy comfort care measures were instituted as per family request and patient passed away.
HHV-6 is a double standard envelope DNA virus discovered in 1986. It was demonstrated later to be the causative agent of exanthem subitum in infants. The virus has two variants, A and B. Similar to other herpes viruses; HHV6 remains latent in lymphocytes, salivary glands and brain. If the host becomes immunocompromised, reactivation can occur. HHV-6 Variant B has been reported to occur in 40 to 60% of BMT and solid organ transplant. HHV-6 can also cause encephalitis of variable severity in immunocompetent hosts but less than 30 cases has been reported1,2.
Although there are multitude of tests to diagnose HHV6 including PCR, Enzyme-Linked Immunosorbent Assay (ELISA) and Indirect fluorescent antibody (IFA). Detection of nucleic acid by PCR may indicate an active or latent infection. Quantitative PCR is deemed the most appropriate as it can detect viral loads and can be followed over time. HHV-6 viral loads in CSF varies widely in patients with HHV-6 encephalitis, with median values of approximately 15,000 to 30,000 copies/mL (range 600 to 1,000,000 copies/mL)3. Real-time PCR is a method that was initially used in our patient, which distinguishes between HHV-6 subtypes although it doesn’t give a viral load. Reverse transcription PCR detects messenger RNA and, thus, indicates actively replicating virus. This can be helpful, especially when dealing with cellular specimens (eg, whole blood or peripheral blood mononuclear cells). Reverse transcription PCR is not widely available. 4
A variety of tests are available for the detection of HHV-6 antibody responses. These include indirect immunofluorescence assays, anti-complement immunofluorescence, competitive radioimmunoassay, and neutralization and enzyme immunoassays. The sensitivity of these assays varies. They do not distinguish between the HHV-6A and -B variants, and there is crossreactivity with HHV-7. Because most people over two years of age are seropositive for HHV-6, a single positive result cannot be interpreted. Seroconversion from negative to positive is good evidence of primary infection. HHV-6 IgM develops within four to seven days of infection. However, approximately 5 percent of healthy adults are IgM positive at any given time, making this test unreliable for a definitive diagnosis4.
There is continued debate of the clinical relevance of HHV-6 in the CSF of immunocompetent adults even in the presence of encephalomyelitis1. The virus has a tropism for glial cells and PBMCs and remains latent in all infected individuals. Therefore, the presence of HHV-6 does not necessarily establish a pathogenic role5. However, in several autopsy specimens from immunocompetent patients with encephalitis, either HHV-6 early protein was localized by immunohistochemistry or HHV-6 nucleic acid was localized by in situ hybridization, specifically in involved portions of the brain. This suggests HHV-6 as the etiology in these cases6.
In reported cases of HHV-6 encephalitis patchy abnormal MRI signal in the cerebral cortex and white matter has been described. Hypoglycorrhachia in CSF has also been described 7. Although our patient showed patchy frontal lobe lesion, no hypoglycorrachia was noted on CSF. It is likely 5
that the patient did not have low levels of glucose in her CSF as she was being given high dose steroids at that time and her blood glucose levels were high.
There have been no in vivo studies—except for case reports—that have addressed treatment of HHV-6 infection8. Ganciclovir resistant HHV-6 has also been reported. In our case patient completed three weeks of foscarnet but no response was seen.
In conclusion we present a rare case of HHV-6 encephalitis in an immunocompetent adult who failed to show significant clinical improvement despite three weeks of foscarnet therapy.
References
1. Caserta, Mary T. "Human herpesvirus 6 infection of the central nervous system." Current infectious disease reports 6.4 (2004): 316-321. 2. Birnbaum, T., Padovan, C. S., Sporer, B. et al (2005). Severe meningoencephalitis caused by human herpesvirus 6 type B in an immunocompetent woman treated with ganciclovir. Clinical infectious diseases, 40(6), 887-889. 3. Reddy, Sushruth, and Pradip Manna. "Quantitative detection and differentiation of human herpesvirus 6 subtypes in bone marrow transplant patients by using a single real-time polymerase chain reaction assay."Biology of Blood and Marrow Transplantation 11.7 (2005): 530-541. 6
4. Suga, S., Yoshikawa, T., Asano, Y. et al (1992). IgM Neutralizing Antibody Responses to Human Herpesvirus‐6 in Patients with Exanthem Subitum or Organ Transplantation. Microbiology and immunology, 36(5), 495-506. 5. Whitley, Richard J., and Fred D. Lakeman. "Human herpesvirus 6 infection of the central nervous system: is it just a case of mistaken association?."Clinical Infectious Diseases 40.6 (2005): 894-895. 6. Novoa, L. J., Nagra, R. M., Nakawatase, T. et al (1997). Fulminant demyelinating encephalomyelitis associated with productive HHV‐6 infection in an immunocompetent adult.Journal of medical virology, 52(3), 301-308. 7. Denes, E., Magy, L., Pradeau, K., Alain, S. et al (2004). Successful treatment of human herpesvirus 6 encephalomyelitis in immunocompetent patient. Emerg Infect Dis, 10(4), 729-731. 8. Dewhurst, Stephen. "Human herpesvirus type 6 and human herpesvirus type 7 infections of the central nervous system." Herpes: the journal of the IHMF11 (2004): 105A-111.
7