Diagnostic Considerations

In infants with signs and symptoms of classic roseola infantum, human herpesvirus 6 (HHV-6) can be the causative agent. However, since this diagnosis has various differential diagnoses, other causes for fever and rash should be excluded. In immunocompetent adults with symptomatic HHV-6 disease, the illness closely resembles mononucleosis. Infection with Epstein-Barr virus (EBV) or cytomegalovirus (CMV) should be excluded.

Because 30%-70% of HSCT recipients experience HHV-6 reactivation 2-4 weeks after transplantation, with viremia lasting an average of 1-2 weeks, routine screening is not recommended, but practice can vary by center.^[27]Risk factors for HHV-6 reactivation in this population include steroid treatment, transplantation from unrelated mismatched donors, and umbilical cord blood transplantation. This places the burden on the clinician to assess all the relevant clues for diagnosis.

For HHV-6 encephalitis in HSCT recipients, targeted diagnostics (PCR of either serum or CSF) can usually be performed by most clinical laboratories or reference centers. This should be performed in patients in whom the diagnosis of HHV-6 encephalitis is being considered.^[27]

HHV-6 encephalitis has the following features:^{[4, 5, 20]}

Neurologic symptoms consistent with encephalitis
CSF abnormalities consistent with a viral etiology of infection (elevated CSF protein, normal CSF glucose, and pleocytosis)
Positive PCR of CSF for HHV-6 (excluding ciHHV-6)
An absence of other causes of CNS dysfunction

Some studies have suggested that patients with HHV-6 encephalitis may have normal CSF cell counts and the absence of PCR positivity in the CSF, complicating diagnosis.

Confirming the diagnosis of HHV-6 disease in patients with chromosomally integrated HHV-6 can be particularly difficult owing to persistent detection of HHV-6 via PCR in the absence of active disease.^[6]Clues may include persistently high viral loads in the setting of appropriate antiviral therapy (10⁶-10⁷ copies per mL in whole blood), as well as detection of HHV-6 DNA in hair follicles and nail samples.

In addition to the conditions in the differential diagnoses, other problems to be considered include the following:

Drug eruptions ^[31]
Parvovirus (B-19)
Meningitis
Encephalitis

Differential Diagnoses

Bone Marrow Failure
Cytomegalovirus (CMV)
Early Symptomatic HIV Infection
Febrile Seizures
Fever in the Infant and Toddler
Fever of Unknown Origin (FUO)
Fifth Disease or Erythema Infectiosum
Hepatitis A
Herpes Simplex
Human Herpesvirus-7
Human Herpesvirus-8
Epstein-Barr Virus (EBV) Infectious Mononucleosis (Mono)
Meningitis
Otitis Media
Pediatric Enteroviral Infections
Rubella
Sepsis
Viral Pneumonia

Workup

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Media Gallery

Nine-month-old infant boy presented with one-day history of high-grade fever and irritability. In the emergency department, the patient underwent septic workup, including lumbar puncture (adhesive bandage), with normal cerebrospinal fluid analysis results. He was admitted to the hospital.
Nine-month-old infant boy presented with one-day history of high-grade fever and irritability. In the emergency department, the patient underwent septic workup, including lumbar puncture, with normal cerebrospinal fluid analysis results. He was admitted to the hospital. High-grade fever abruptly resolved on day 3 of hospitalization. Within a few hours, erythematous, pink papular (roseola) nonpruritic rash appeared, mainly on trunk.
N-month-old infant boy presented with one-day history of high-grade fever and irritability. In the emergency department, the patient underwent septic workup, including lumbar puncture, with normal cerebrospinal fluid analysis results. He was admitted to the hospital. High-grade fever abruptly resolved on day 3 of hospitalization. Within a few hours, erythematous, pink papular (roseola) nonpruritic rash appeared, mainly on trunk. Patient was playful after supportive therapy. Antibiotics were discontinued after 2 days of negative cultures.

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Author

John L Kiley, MD Associate Program Director, SAUSHEC Infectious Disease Fellowship Program, Department of Medicine, Infectious Disease Service, Brooke Army Medical Center/San Antonio Military Medical Center, San Antonio Uniformed Services Health Education Consortium; Assistant Professor, Department of Medicine, Uniformed Services University of the Health Sciences; Adjoint Assistant Professor of Medicine, University of Texas Health Science Center at San Antonio, Long School of Medicine

John L Kiley, MD is a member of the following medical societies: American College of Physicians, Armed Forces Infectious Diseases Society, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Coauthor(s)

Dana M Blyth, MD Associate Professor, Department of Medicine, Uniformed Services University of the Health Sciences; Adjunct Assistant Professor, Department of Medicine, University of Texas Health Science Center at San Antonio School of Medicine; Staff Physician, Department of Medicine, Infectious Disease Service, Brooke Army Medical Center, San Antonio Military Medical Center, San Antonio Uniformed Services Health Education Consortium (SAUSHEC)

Dana M Blyth, MD is a member of the following medical societies: American College of Physicians, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Chief Editor

Pranatharthi Haran Chandrasekar, MBBS, MD Professor, Chief of Infectious Disease, Department of Internal Medicine, Wayne State University School of Medicine

Pranatharthi Haran Chandrasekar, MBBS, MD is a member of the following medical societies: American College of Physicians, American Society for Microbiology, International Immunocompromised Host Society, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Additional Contributors

Michelle R Salvaggio, MD, FACP Assistant Professor, Department of Internal Medicine, Section of Infectious Diseases, University of Oklahoma College of Medicine; Medical Director of Infectious Diseases Institute, Director, Clinical Trials Unit, Director, Ryan White Programs, Department of Medicine, University of Oklahoma Health Sciences Center; Attending Physician, Infectious Diseases Consultation Service, Infectious Diseases Institute, OU Medical Center

Michelle R Salvaggio, MD, FACP is a member of the following medical societies: American College of Physicians, Infectious Diseases Society of America

Disclosure: Received honoraria from Merck for speaking and teaching.

Acknowledgements

Ruchir Agrawal, MD Chief, Allergy and Immunology, Aurora Sheboygan Clinic

Ruchir Agrawal, MD, is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American College of Allergy, Asthma and Immunology, and American Medical Association