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With Acute HHV6 Infection Archives ofDisease in Childhood 1990; 6s: 1297-1300 1297 ORIGINAL ARTICLES Arch Dis Child: first published as 10.1136/adc.65.12.1297 on 1 December 1990. Downloaded from Roseola infantum and other syndromes associated with acute HHV6 infection W L Irving, J Chang, D R Raymond, R Dunstan, P Grattan-Smith, A L Cunningham Abstract mother is pregnant, and to exclude either the Eight cases of acute human herpesvirus type need to prescribe antibiotics in a febrile child, 6 (HHV6) infection in infants were diagnosed or the diagnosis of antibiotic allergy. serologically by the demonstration of IgM anti-HHV6 (8/8) and a significant change in Methods total anti-HHV6 antibody titre (6/8). Four SELECTION OF SERA infants were sufficientlyill to require admission During the course of this study (December 1988 to hospital and further investigations: one to February 1990) all sera sent to the virology with encephalitis and three with gross hepato- laboratory, Westmead Hospital, from infants splenomegaly, two of whom had evidence of up to the age of 3 years were tested for evidence simultaneous infection with another herpes- of recent HHV6 infection. In addition, sera virus. The remaining four infants had an from infants presenting with hepatospleno- illness compatible with roseola infantum, megaly were kindly referred to us from the although this diagnosis had not been made Royal Alexandra Hospital for Children, Sydney, clinically. Sera from two of those infants with the Royal Children's Hospital, Melbourne, and rash had been sent for analysis to exclude the Royal Brisbane Hospital, Brisbane. The rubella because the infants' mothers were infants fell into the following diagnostic cate- pregnant. The other two had received anti- gories (number of sera): neonates with jaundice, biotics when febrile, and the subsequent congenital abnormalities, or those labelled for appearance of the roseola rash had raised the screening for toxoplasma, other viruses, possibility of antibiotic allergy. rubella, cytomegalovirus, and herpes virus The data suggest that there are clinical (n=3 1); children with fever (n=6); rash syndromes in addition to roseola infantum (n=2 1); encephalitis (n=6); hepatomegaly associated with the presence of IgM anti- and/or splenomegaly (n=10); glandular fever HHV6, in which serological screening for like illness (including tonsillitis, lymph- evidence of acute HHV6 infection may be adenopathy (n= 17); clinical details not given useful. (n=7); and miscellaneous (father carrier of hepatitis B virus, nephrotic syndrome, ?idio- http://adc.bmj.com/ pathic thrombocytopenia, ?mumps, ?dengue Human herpesvirus type 6 (HHV6) is a recently identified human lymphotropic virus of diverse (n=5). cell tropism in vitro. 1-3 Serological surveys have shown a high prevalence of antibodies to SEROLOGY HHV6, and have suggested that the majority of Sera were screened by indirect immunofluor- occur year HHV6 infections in the first of escence for the presence of IgM and IgG anti- on October 1, 2021 by guest. Protected copyright. life.' Descriptions of clinical illness in infants HHV6 antibodies as previously described, associated with seroconversion to HHV6 are using acetone fixed HHV6 infected J Jhan cells Westmead Hospital, limited to the syndrome of roseola infantum (a T cell line) as substrate. 10 Briefly, sera were Sydney, Australia, Virology Unit, (also known as exanthem subitum), two infants screened at dilutions of 1/100 for IgG and 1/20 Department of with a rash and lymphadenopathy and two for IgM in phosphate buffered saline containing Infectious Diseases infants with a hepatitic illness, one fatal.'9 1% casein. Screen positive sera were retested for and Microbiology There are additional reports of acute W L Irving HHV6 IgM after a 1/10 dilution in an anti-IgG reagent J Chang infection in older children and adults associated (Gullsorb, Gull Laboratories) for absorption of A L Cunningham with hepatitic and infectious mononucleosis like IgG and removal of rheumatoid factor. Fluor- Department of illnesses. 10 11 escein conjugated second antibodies used were Paediatrics In order to identify possible clinical con- sheep antihuman immunoglobulin (Wellcome), P Grattan-Smith sequences of acute HHV6 infections we have and F(ab')2 fragment goat antihuman IgM Mount Druitt D R Raymond devised a strategy for screening sera for the (Kallestad). No non-specific fluorescence was presence of IgM anti-HHV6.10 This has been seen when sera were tested acetone fixed Prince of Wales using Children's Hospital, applied to sera from infants presenting with a uninfected J Jhan cells as a negative control. Sydney variety ofillnesses, resulting in the identification Commercially available enzyme immunoassay R Dunstan of eight acute HHV6 infections, none of which kits were used for the detection of IgG and IgM Correspondence to: had been diagnosed clinically as roseola in- anticytomegalovirus (Pharmacia), and IgG and Dr W L Irving, Department of fantum. The clinical features of those eight IgM antirubella antibodies (Behring). IgM anti- Microbiology, University infants described here illustrate that HHV6 Epstein-Barr virus was assayed using an in Hospital, Queen's Medical Centre, Nottingham serology may be useful in the investigation of house enzyme immunoassay,12 and IgG anti- NG7 2UH. infants with encephalitis or hepatosplenomegaly, Epstein-Barr virus by indirect immunofluor- Accepted 23 July 1990 in the investigation of a rash in an infant whose escence using Epstein-Barr virus infected 1298 Irving, Chang, Raymond, Dunstan, Grattan-Smith, Cunningham Acute HHV6 infection in infants: serological data Case No Age Illness Date of HHV6 Cytomegalovirus Epstein-Barr virus Other negative Arch Dis Child: first published as 10.1136/adc.65.12.1297 on 1 December 1990. Downloaded from (sex) (months) serum serology sample IgGt IgM IgG IgM IgG IgM Epstein- (days)* Barr nuclear antigen 1 (F) 13 Encephalitis 0 1024 Positive Negative Herpes simplex 10 1024 Positive Positive Negative Negative virus,4 mumps, 24 512 Negative mycoplasma, measles, 185 256 Negative enterovirus, varicella 2 (M) 10 Hepatosplenomegaly 0 16 Negative Negative Negative 16 128 Positive Negative Negative Negative 42 128 Negative 3 (M) 6 Hepatosplenomegaly 0 8 Positive Negative Negative 2560 NegativeS Negative 14 2048 Positive Negative Negative 2560 Positive Negative 4 (M) 16 Hepatosplenomegaly 0 512 Positive Equivocal Positive Positive Negative 13 512 Positive 5 (M) 12 Roseola infantum 0 8 Negative Measles, adenovirus, 15 256 Positive Negative Negative Negative enterovirus, rubella 6 (F) 8 Roseola infantum 0 8 Positive Positive Negative Negative Negative Measles, rubella 11 256 Positive Positive Negative Negative Negative 7 (M) 19 Roseola infantum 0 <4 Positive Negative Negative Negative Negative Measles 27 64 Negative 8 (F) 8 Roseola infantum 0 64 Positive Measles, rubella 7 128 Positive *Day 0 taken as the date of the first serum sample. tTitre as determined by immunofluorescence. *Herpes simplex virus, complement fixation titre less than 4 in all samples. SEpstein-Barr virus IgM negative by enzyme immunoassay but positive by fluorescence. marmoset lymphoblastoid cells as substrate. She was treated with phenobarbitone (loading Anti-Epstein-Barr nuclear antigen antibodies dose of 10 mg/kg followed by 5 mglkg/24 hours) (anti-EBNA) were determined by an anti- and acyclovir (10 mg/kg every eight hours for 10 complementary immunofluorescent tech- days). No further seizures occurred and by 24 nique.'3 All other antibody titres were assayed hours after admission her neurological state had by a standard complement fixation test. returned to normal. She continued to spike temperatures up to 385°C over the next few days but otherwise completed her course of Results acyclovir without further problems. When last Sera from eight patients were found to contain reviewed at age 19 months there were no IgM anti-HHV6. The serological results are defmite neurological signs. She had been walking summarised in the table. for three months and her parents stated she had a vocabulary of 50 words. Repeat computed tomography showed atrophic changes in the left CASE REPORTS frontotemporal region. Case I http://adc.bmj.com/ A 13 month old girl presented with right sided focal seizures. She had been unwell for one Case 2 week, initially with rhinorrhoea and cough, and This 10 month old boy had been admitted to in the two days before admission became hospital with a febrile fit and pneumonia, and increasingly lethargic and began vomiting. Four then discharged. One week later he presented right sided seizures with variable involvement with a history of two days of fever followed by arm, each less than 10 the appearance of a dense fine rubelliform rash of face, and leg, lasting on October 1, 2021 by guest. Protected copyright. minutes, occurred on the morning of admission. over the limbs and trunk (but not face), 7 cm Onexamination she was drowsyandmiserable, hepatomegaly and 4 cm splenomegaly, and with a temperature of 37-9°C. A blotchy shotty diffuse lymphadenopathy, none of which erythematous rash was present over her upper had been present during his hospital stay. A full trunk. Her eyes tended to deviate to the left and blood count showed a haemoglobin concentration there were signs of mild right sided weakness. of 10 9 g/l, a leucocyte count of 12 6x 109/1 with Results of investigations were haemoglobin a lymphocytosis of 55% and 26% atypical mono- concentration 13 g/l, white cell count nuclear cells. Liver function tests were normal. 15 1 x 109/1 with 75% granulocytes and platelets The rash lasted for 24 hours only. The cause of 236x 109/l. Serum electrolytes, blood glucose, his hepatosplenomegaly remained unclear. His calcium, magnesium, and phosphate concen- physical signs resolved slowly over the following trations were all normal. In the cerebrospinal three months, eventually disappearing com- fluid there was one polymorph, 14 mononuclear pletely. cells and 85 red blood cells x 109/l. Cerebro- spinal fluid protein was 160 mg/l and glucose 5-5 mmol/l.
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