Comparison of initial and final diagnoses in children with acute febrile illness: A retrospective, descriptive study: Initial and final diagnoses in children with acute fever.

BACKGROUND: This study aimed to elucidate the etiologies and diagnostic errors of early-phase pediatric fever without an obvious cause. METHODS: This single-center, retrospective, descriptive study included 1334 febrile children hospitalized at Beppu Medical Center in Japan between 2014 and 2018. Eligibility criteria were age ≤12 years, axillary temperature ≥38.0°C, and fever duration ≤7 days at admission. Initial diagnoses on the day of admission and final diagnoses at defervescence were divided into initial fever with identified source (FIS) and initial fever without source (FWS) and final FIS and final FWS, respectively. The etiology of initial FWS and diagnostic discordance between initial FIS and final FIS were investigated. RESULTS: Of the 1334 participants, 94 (7.0%) were diagnosed with initial FWS. Among patients with initial FWS, final diagnoses were confirmed in 40 (43%), including Kawasaki disease in 17, urinary tract infection in 5, bacteremia in 4, exanthem subitum in 3, and the others in 11. Among the 1275 patients diagnosed with final FIS, diagnostic discordances between initial and final diagnoses were observed in 131 patients (10%). The multiple logistic regression analysis identified increased serum C-reactive protein value at admission (odds ratio [OR]: 1.09; 95% confidence interval [CI]: 1.06-1.13), exanthem subitum (OR: 409; 95% CI: 119-1399), and Kawasaki disease (OR: 14.3; 95% CI: 8.7-23.3) as independent risk factors for diagnostic discordance. CONCLUSION: Exanthem subitum and Kawasaki disease may be undiagnosed or misdiagnosed in febrile children with fever duration ≤7 days.

Did a then unknown virus, HHV-6/7, give rise to the whooping cough vaccine controversy of the 1970s?

During the 1970s there was a gross loss of public confidence in infant diphtheria-tetanus-pertussis (DTP) vaccination in the UK. As well as febrile reactions and convulsions, permanent neurological damage was ascribed to the pertussis component of the vaccine, and those concerns resonated worldwide. The subsequent recognition of human herpes virus 6 (HHV-6) and 7 (HHV-7) as common sources of fever in infancy suggests that they were the main underlying cause of what was reported as DTP constitutional side-effects. With more precise data on the incidence of HHV-6/7 and other virus infections in early life it would be possible to model the concurrence of viral illnesses with routine immunizations. Adventitious viral infections may be the cause of side-effects ascribed to the numerous childhood immunizations now being given.

Predicting the characteristics of the aetiological agent for Kawasaki disease from other paediatric infectious diseases in Japan.

Although Kawasaki disease (KD), which was first reported in the 1960s, is assumed to be infectious, its aetiological agent(s) remains unknown. We compared the geographical distribution of the force of infection and the super-annual periodicity of KD and seven other paediatric infectious diseases in Japan. The geographical distribution of the force of infection, which was estimated as the inverse of the mean patient age, was similar in KD and other paediatric viral infections. This similarity was due to the fact that the force of infection was determined largely by the total fertility rate. This finding suggests that KD shares a transmission route, i.e. sibling-to-sibling infection, with other paediatric infections. The super-annual periodicity, which is positively associated with the sum of an infectious disease's incubation period and infectious period, was much longer for KD and exanthema subitum than other paediatric infectious diseases. The virus for exanthema subitum is known to persist across the host's lifespan, which suggests that the aetiological agent for KD may also be capable of persistent infection. Taken together, these findings suggest that the aetiological agent for KD is transmitted through close contact and persists asymptomatically in most hosts.

Long-term epidemiologic longitudinal study on the effect of vaccines on public inoculation.

Public vaccination policies in Japan for several viruses have achieved favorable results. To accurately evaluate their overall effectiveness, we conducted a 45- year epidemiological survey of measles, varicella and mumps cases at our clinic. The number of patients with measles was found to be significantly decreased with the single-dose vaccination provided at public expense. However, we also witnessed an increasing trend of infection at a later age. The vaccination rates for varicella and mumps were relatively low because of their optional availability in Japan, and thus they cannot be considered to confer public protection. Although localized to a particular region, our results show that it is important to increase the immunization rate of vaccines for large-scale protection against viral infections through public programs.

Changes in Exanthema Subitum Incidence and Patient Age Distribution During the COVID-19 Pandemic in Japan.

Incidences of community-acquired infectious diseases other than COVID-19 decreased during the coronavirus disease 2019 pandemic; however, exanthema subitum incidence before (2016-2019) and during the pandemic (2020) in Niigata, Japan, did not substantially differ, although the proportion of age less than 1-year-old was lower in 2020. These findings suggest that exanthema subitum is transmitted mainly among family members, not in the community.

Detection of human herpesvirus 7 infection in young children presenting with exanthema subitum.

In this study, we assessed the prevalence of human herpesvirus-7 (HHV-7) in 141 serum samples from children less than four years of age with exanthematic disease. All samples were negative for measles, rubella, dengue fever and parvovirus B19 infection. Testing for the presence of human herpesvirus-6 (HHV-6)-specific high avidity IgG antibodies by indirect immunofluorescence assay (IFA) revealed two main groups: one composed of 57 patients with recent primary HHV-6 infection and another group of 68 patients showing signs of past HHV-6 infection. Another 16 samples had indeterminate primary HHV-6 infection, by both IgG IFA and IgM IFA. Serum samples were subjected to a nested polymerase chain reaction to detect the presence of HHV-7 DNA. Among patients with a recent primary HHV-6 infection, HHV-7 DNA was present in 1.7% of individuals; however, 5.8% of individuals tested positive for HHV-7 DNA in the group with past primary HHV-6 infection. Among the 16 samples with indeterminate diagnosis, 25% (4/16) had HHV-7 DNA (p < 0.002). We hypothesise that HHV-7 might be the agent that causes exanthema. However, a relationship between clinical manifestations and the detection of virus DNA does not always exist. Therefore, a careful interpretation is necessary to diagnose a primary infection or a virus-associated disease. In conclusion, we detected HHV-7 DNA in young children from the state of Rio de Janeiro, Brazil.

Predominant human herpesvirus 6 variant A infant infections in an HIV-1 endemic region of Sub-Saharan Africa.

Human herpesvirus 6, HHV-6, commonly infects children, causing febrile illness and can cause more severe pathology, especially in an immune compromised setting. There are virulence distinctions between variants HHV-6A and B, with evidence for increased severity and neurotropism for HHV-6A. While HHV-6B is the predominant infant infection in USA, Europe and Japan, HHV-6A appears rare. Here HHV-6 prevalence, loads and variant genotypes, in asymptomatic compared to symptomatic infants were investigated from an African region with endemic HIV-1/AIDS. DNA was extracted from blood or sera from asymptomatic infants at 6 and 18 months age in a population-based micronutrient study, and from symptomatic infants hospitalised for febrile disease. DNA was screened by qualitative and quantitative real-time PCR, then genotyped by sequencing at variable loci, U46 (gN) and U47 (gO). HIV-1 serostatus of infants and mothers were also determined. HHV-6 DNA prevalence rose from 15% to 22% (80/371) by 18 months. At 6 months, infants born to HIV-1 positive mothers had lower HHV-6 prevalence (11%, 6/53), but higher HCMV prevalence (25%, 17/67). HHV-6 positive febrile hospitalized infants had higher HIV-1, 57% (4/7), compared to asymptomatic infants, 3% (2/74). HHV-6A was detected exclusively in 86% (48/56) of asymptomatic HHV-6 positive samples genotyped. Co-infections with both strain variants were linked with higher viral loads and found in 13% (7/56) asymptomatic infants and 43% (3/7) HIV-1 positive febrile infants. Overall, the results show HHV-6A as the predominant variant significantly associated with viremic infant-infections in this African population, distinct from other global cohorts, suggesting emergent infections elsewhere.

A population-based study of primary human herpesvirus 6 infection.

BACKGROUND: Serologic studies indicate that human herpesvirus 6 (HHV-6) infects 90 percent of children by two years of age. Little is known about the acquisition, virologic course, and clinical manifestations of HHV-6 infection. METHODS: We prospectively studied a cohort of 277 children from birth through the first two years of life to define the pattern of acquisition of HHV-6. The children's saliva was tested weekly for HHV-6 DNA with the use of the polymerase chain reaction. Parents maintained a daily log of signs and symptoms of illness in their children. RESULTS: Primary HHV-6 infection occurred in 130 children, with cumulative percentages of 40 percent by the age of 12 months and 77 percent by the age of 24 months. The peak age of acquisition was between 9 and 21 months. The acquisition of HHV-6 was associated with female sex (adjusted hazard ratio, 1.7; 95 percent confidence interval, 1.2 to 2.4) and having older siblings (adjusted hazard ratio, 2.1; 95 percent confidence interval, 1.4 to 2.9). Among 81 children with a well-defined time of acquisition of HHV-6, 93 percent had symptoms, and 38 percent were seen by a physician. None had seizures. As compared with children who had other illnesses, those with primary HHV-6 infection were more likely to have fever (P=0.003), fussiness (P=0.02), diarrhea (P=0.03), rash (P=0.003), and roseola (P=0.002) and were more likely to visit a physician (P=0.003). CONCLUSIONS: The acquisition of HHV-6 in infancy is usually symptomatic and often results in medical evaluation. Roseola occurs in a minority of patients, and febrile seizures are infrequently associated with primary HHV-6 infection. Older siblings appear to serve as a source of HHV-6 transmission.

Role of human herpesvirus 6 infection in young Brazilian children with rash illnesses.

BACKGROUND: Human herpesvirus type 6 (HHV-6) has been shown to infect almost all children by 4 years of age. Primary infection causes an undifferentiated febrile illness, with approximately 30% of children exhibiting the classic clinical manifestations of exanthem subitum. Even with typical clinical presentation, exanthem subitum is frequently misdiagnosed as measles or rubella. Our aim was to describe the frequency and clinical manifestations of HHV-6 infection in children less than 4 years of age enrolled in a study designed to define the etiology of rash diseases. PATIENTS AND METHODS: The study was conducted between January 1998 and December 2006 at a general hospital and a large primary health care unit from Niterói, Rio de Janeiro, Brazil. Sera from 223 children, in whom measles, rubella, dengue fever, and parvovirus B19 infections were excluded, were studied for anti-HHV-6 antibodies using an indirect immunofluorescence test. Demographic and clinical data of those patients were described. RESULTS: Ninety-seven (43.5%) of the children had evidence of primary HHV-6 infection. The age of onset peaked at 6-11 months and 75% of the HHV-6 infection occurred in children between 6 and 17 months. Only 21% of the HHV-6 cases had a typical roseola-like illness and 73% and 46%, respectively, fulfilled the clinical criteria of measles and rubella suspected case. CONCLUSIONS: Our study confirms the importance of HHV-6 infection in young children and highlights the difficulties of diagnosing a rash illness on clinical grounds alone.

Risk factors for the early acquisition of human herpesvirus 6 and human herpesvirus 7 infections in children.

OBJECTIVE: Human herpesviruses 6 and 7 (HHV-6 and HHV-7) are common infections in children, but risk factors for their early acquisition have not been described. METHODS: Excess sera from children 12 to 31 months of age enrolled in a cross-sectional, random survey were tested for human herpesviruses 6 and 7 infection, as measured by using immuno-blot and immunofluorescence assays. RESULTS: Of 164 children 131 (80%) had antibody to HHV-6, and 79 (47%) of 167 had antibody to HHV-7. In logistic regression analysis low income [odds ratio (OR), 2.9; 95% confidence intervals (CI), 1.02 to 8.7] and having more than 1 sibling (OR=2.1, 95% CI=0.9 to 5.1) were risk factors for HHV-6 infection after adjusting for age, whereas month of test (OR=2.7, 95% CI=1.3 to 5.9) and Black race (OR=2.0, 95% CI=0.9, 4.6) were associated with a higher prevalence of HHV-7 infection. In contrast having ever been breast-fed appeared to protect against HHV-7 infection (OR=0.5, 95% CI=0.3 to 1.1). CONCLUSIONS: Despite studies linking both HHV-6 and HHV-7 with exanthem subitum, risk factors for the early acquisition of HHV-6 and HHV-7 are distinct. Subsequent studies investigating the transmission of HHV-6 should explore family size and other factors associated with poverty, whereas breast-feeding should be examined as a protective factor for HHV-7 infection.

A practitioner's guide to human herpesvirus-6 (HHV-6) and human herpesvirus-7 (HHV-7).

Human herpesvirus-6 (HHV-6) and HHV-7 are newly recognized ubiquitous human viruses first discovered in patients with AIDS or lymphoproliferative disorders. Much more information is available about the clinical characteristics of infection with HHV-6 than HHV-7. Primary infection with HHV-6 occurs in early childhood and is most commonly manifested as an undifferentiated highly febrile illness, with seizures noted to be the most common complication. A subset of children develop the classic manifestations of roseola infantum or exanthem subitum. Other neurologic diseases in adults such as encephalitis and multiple sclerosis also have been linked to HHV-6; however, the role of HHV-6 in these clinical entities has not been fully elucidated. Although HHV-6 and HIV are both tropic for CD4+ lymphocytes and interact in vitro, there is no evidence at present that HHV-6 plays a role in HIV disease. HHV-7 is similar to HHV-6 in genetic organization and structure. Little is known of the clinical characteristics of infection with HHV-7 or its ability to cause disease in children or reactivation in adults.

Outbreaks of human-herpes virus 6 (HHV-6) infection in day-care centers in Belém, Pará, Brazil.

A total of 730 children aged less than 7 years, attending 8 day-care centers (DCCs) in Belém, Brazil were followed-up from January to December 1997 to investigate the occurrence of human-herpes virus 6 (HHV-6) infection in these institutional settings. Between October and December 1997 there have been outbreaks of a febrile- and -exanthematous disease, affecting at least 15-20% of children in each of the DCCs. Both serum- and- plasma samples were obtained from 401 (55%) of the 730 participating children for the detection of HHV-6 antibodies by enzyme-linked immunosorbent assay (ELISA), and viral DNA amplification through the nested-PCR. Recent HHV-6 infection was diagnosed in 63.8% (256/401) of them, as defined by the presence of both IgM and IgG-specific antibodies (IgM+/IgG+); of these, 114 (44.5%) were symptomatic and 142 (55.5%) had no symptoms (p = 0.03). A subgroup of 123 (30.7%) children were found to be IgM-/IgG+, whereas the remaining 22 (5.5%) children had neither IgM nor IgG HHV-6- antibodies (IgM-/IgG-). Of the 118 children reacting strongly IgM-positive (> or = 30 PANBIO units), 26 (22.0%) were found to harbour the HHV-6 DNA, as demonstrated by nested-PCR. Taken the ELISA-IgM- and- nested PCR-positive results together, HHV-6 infection was shown to have occurred in 5 of the 8 DCCs under follow-up. Serological evidence of recent infections by Epstein-Barr virus (EBV) and parvovirus B19 were identified in 2.0% (8/401) and 1. 5% (6/401) of the children, respectively. Our data provide strong evidence that HHV-6 is a common cause of outbreaks of febrile/exanthematous diseases among children attending DCCs in the Belém area.

Seroepidemiology of human herpesvirus 6 in a population seen in the University Hospital, Kuala Lumpur, Malaysia.

Sera from healthy donors and patients stored over a period of 2 years, aged 1 to 83 years, were examined for reactivity to human herpes virus 6 (HHV-6) by the standard indirect immunofluorescence assay (IFA). Of the 600 serum specimens screened, 502 showed positive reactivity to HHV-6. This gives an overall seropositive rate of 83.7%. There is no significant difference in the overall positive rate between the ethnic groups (Chinese, Malays, Indians) (chi 2 = 0.35 df = 2 p > 0.05). However, there is significant difference in the positive rates at the extreme age groups of 1 year as well as 61 years and above. From birth up to below 1 year of age, the seroprevalence rate was 82%. At one year of age the positive rate decreased to 66% before gradually rising so that the percentage seropositivity of 6 to 10 years old becomes similar to that in older children and adults (11 to 40 years). The positive rate then starts to decline after 40 years of age. Using a standardized scoring system, the corresponding antibody titer was found to be high in the very young population and starts to decline after the age of 15 years. This suggests that in our population group, primary infection occurs mainly in the pediatric age group. It also accounts for the low positive rate in the age group of 61 years and above, as by then the titer had fallen to the level below the detection limits of the assay system.

[A study of standardization of surveillance data 1). Significance of "corrected value of patients" and its application to exanthema subtium and erythema infectiosum].

It is suggested that "Corrected value of patients" is a useful method in comparing prefectural surveillance data. "Corrected value of patients" is calculated as follows: Ratio of the number of reported patients for 5 years of each prefecture of each infectious diseases to number of the national scale is called "Corrected rate". The number to be divided is called "Corrected value of patient", individually reported number of patients of the surveillance divided by "Corrected rate". Because the "Corrected value of patients" is based on the number of reported patients for 5 years, the unequality among epidemics which differ become similar. As the value of practical usage is well recognized, 3-dimensional graphs can be used for weekly reports, not only for Exanthema subitum but also for Erythem infectiosum.

The association of uvulo-palatoglossal junctional ulcers with exanthem subitum: a 10-year paediatric outpatient study.

A 10-year follow-up of children having exanthem subitum (ES) seen in an outpatient paediatric clinic, Kuala Lumpur, Malaysia shows that uvulo-palatoglossal junctional (UPJ) ulcer is a reliable early clinical sign of ES. During this period, 1,977 children (1,086 males, 891 females) had adequate follow-up from the age of 3 months to 24 months old. 897 children (478 males, 419 females) were noted to have UPJ ulcers. Of these 897 children, 855 (459 males, 396 females) presented with the classical clinical features of ES of maculopapular rash following 3 to 4 days of fever. The positive predictive value and the negative predictive value of UPJ ulcers in the clinical diagnosis of ES are 95.3% and 100% respectively. Among the 855 children with clinical features of ES, a provisional diagnosis of ES could be made in 781 children during the pre-eruptive phase by the presence of the UPJ ulcers. The other 74 children already had the rash at the time of consultation at the clinic. The peak age of occurrence of ES was 6 months old with 98.2% of the total cases of ES seen between the age of 4 and 12 months. There was no significant gender difference in the incidence of ES nor any seasonal variation. Mild to moderate diarrhoea was the other commonly associated clinical feature which usually presented from the third febrile day onwards.