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Roseola Infantum: An Updated Review
Abstract
Background
Roseola infantum is a common viral disease that occurs during childhood worldwide.
Objective
The purpose of this article is to familiarize pediatricians with the clinical manifestations, evaluation, diagnosis, and management of roseola infantum.
Methods
A search was conducted in April, 2022, in PubMed Clinical Queries using the key terms "roseola infantum" OR “exanthem subitum” OR “sixth disease”. The search strategy included all clinical trials, observational studies, and reviews published within the past 10 years. Only papers published in the English literature were included in this review. The information retrieved from the above search was used in the compilation of the present article.
Results
Roseola infantum is a viral illness characterized by high fever that lasts 3 to 4 days, followed by the sudden appearance of rash at defervescence. The disease occurs most frequently in children between 6 months and 2 years of age. Human herpesvirus-6 (HHV-6) is the major cause of roseola infantum, followed by HHV-7. Transmission of the infection most likely results from the asymptomatic shedding of the virus in the saliva of the caregivers or other close contacts. Characteristically, the rash is discrete, rose-pink in color, circular or elliptical, macular or maculopapular, measuring 2 to 3 mm in diameter. The eruption is first seen on the trunk. It then spreads to the neck and proximal extremities. Typically, the rash blanches on pressure and subsides in 2 to 4 days without sequelae. Most children look well otherwise and appear to be happy, active, alert, and playful. The diagnosis is mainly clinical. Febrile seizures occur in 10 to 15 % of children with roseola infantum during the febrile period. In general, serious complications are rare and occur more often in individuals who are immunocompromised. There is no specific treatment. An antipyretic may be used to reduce fever and discomfort.
Conclusion
Roseola infantum is generally a benign and self-limited disease. Failure to recognize this condition may result in undue parental fear, unnecessary investigations, delay in treatment for conditions that mimic roseola infantum and complications from roseola infantum, unnecessary treatment of roseola infantum per se, and misuse of healthcare expenditure.
... Symptoms were present in most of instances (77%), with a prevalence of pruritus and pain/burning of 61 and 16%, respectively [7 && ]. The most frequently involved areas included the trunk (around two-thirds of cases) followed by lower and upper arms (around half of cases), whereas neck, face, hands and foot were reported to be affected in 18 ]. Of note, data on eruption spreading pattern are limited, yet available information tends to support a centrifugal dissemination (onset on the trunk with subsequent spreading to the extremities) ...
... The most typical feature of the skin rash associated with sixth disease is the timing of onset, as it suddenly appears in coincidence with defervescence [17]. The fever may be very high (also beyond 408C) and last 3-5 days; its occurrence and fading is usually abrupt [17][18][19]. The rash is usually typified by discrete, faint, pink-coloured, circular or elliptical macules or maculopapules, with lesions often measuring 2-3 mm in diameter [17][18][19]. ...
... The fever may be very high (also beyond 408C) and last 3-5 days; its occurrence and fading is usually abrupt [17][18][19]. The rash is usually typified by discrete, faint, pink-coloured, circular or elliptical macules or maculopapules, with lesions often measuring 2-3 mm in diameter [17][18][19]. A pale halo may sometimes be appreciated [17][18][19]. ...
Purpose of review:
Skin rashes seen during COVID-19 usually feature maculopapular or vesicular morphology, thus mimicking cutaneous eruptions occurring in other common infectious dermatoses, such as mononucleosis, chickenpox, sixth disease and measles, with possible diagnostic mistakes. In this review article, we sought to provide a practical overview about clinical appearance of skin rashes related to SARS-CoV-2 infection.
Recent findings:
The study summarizes literature evidence on clinical patterns of COVID-19-associated maculopapular or vesicular rash, with a particular emphasis on the principal points of differentiation with possible mimickers.
Summary:
Several differences do exist between rashes due to SARS-CoV-2 infection and other viral eruptions, mainly including lesions morphology, spreading pattern, symptoms and mucosal involvement. The increase of awareness of such features among clinicians may help promptly recognize COVID-19-related exanthemas in order to take proper action to manage the infection.
Human herpesvirus 6A (HHV-6A) and 6B (HHV-6B) are two closely related viruses that can infect cells of the central nervous system (CNS). The similarities between these viruses have made it difficult to separate them on serological level. The broad term HHV-6 remains when referring to studies where the two species were not distinguished, and as such, the seroprevalence is over 90% in the adult population. HHV-6B has been detected in up to 100% of infants with the primary infection roseola infantum, but less is known about the primary infection of HHV-6A. Both viruses are neurotropic and have capacity to establish lifelong latency in cells of the central nervous system, with potential to reactivate and cause complications later in life. HHV-6A infection has been associated with an increased risk of multiple sclerosis (MS), whereas HHV-6B is indicated to be involved in pathogenesis of epilepsy. These two associations show how neurological diseases might be caused by viral infections, but as suggested here, through completely different molecular mechanisms, in an autoimmune disease, such as MS, by triggering an overreaction of the immune system and in epilepsy by hampering internal cellular functions when the immune system fails to eliminate the virus. Understanding the viral mechanisms of primary infection and reactivation and their spectrum of associated symptoms will aid our ability to diagnose, treat and prevent these severe and chronic diseases. This review explores the role of HHV-6A and HHV-6B specifically in MS and epilepsy, the evidence to date and the future directions of this field.
Congenital infections refer to a group of perinatal infections that are caused by pathogens transmitted from mother to child during pregnancy (transplacentally) or delivery (peripartum) which may have similar clinical presentations, including rash and ocular findings. TORCH is the acronym that covers these infections (toxoplasmosis, other [syphilis], rubella, cytomegalovirus, herpes simplex virus). Other important causes of intrauterine/perinatal infection include human immunodeficiency virus, varicella-zoster virus, Treponema pallidum, Zika virus, and parvovirus B19. This overview aims to describe various congenital infections beyond TORCH with a Hong Kong perspective. Intrauterine and perinatal infections are a major cause of in utero death and neonatal mortality, and an important contributor to childhood morbidity. A high index of suspicion for congenital infections and awareness of the prominent features of the most common congenital infections can help to facilitate early diagnosis, tailor appropriate diagnostic evaluation, and initiate appropriate early treatment. Intrauterine infections should be suspected in newborns with clinical features including microcephaly, seizures, cataract, hearing loss, congenital heart disease, hepatosplenomegaly, small for gestational age, and/or rash. Primary prevention of maternal infections during pregnancy is key to the prevention of congenital infection, and resources (if available) should focus on public health promotion and pre-marital counselling.
We have managed two anonymized siblings with Kawasaki disease (KD). The occurrence of KD in the elder brother alerted us to the occurrence of incomplete KD in the younger brother. Both siblings were treated with intravenous immunoglobulin and a high dose of dipyridamole with resolution of the coronary artery aneurysm. Dipyridamole was used instead of aspirin because both siblings were glucose-6-phosphate dehydrogenase deficient for which aspirin was contraindicated. To prevent damage to the coronary arteries, treatment should be started as soon as the diagnosis is made. There have been a lot of advances in medical therapy in recent years, which are reviewed together with conventional proven therapy for KD. Early diagnosis and prompt treatment are important to achieve optimal treatment outcome in KD. Family history of KD among siblings enables clinicians for an earlier diagnosis so as to prevent the disease complications particularly in patients with incomplete features.
Human herpesvirus 6 (HHV-6) is a double-stranded DNA virus part of the Herpesviridae family that colonizes nearly 100% of the human population. The virus is known to be the etiologic agent of roseola infantum, a self-limited disease in childhood and reactivation of the virus later in life is linked to potentially severe manifestations, including encephalitis, in immunosuppressed patients. It is rare in immunocompetent patients, but there have been several reports of encephalitis due to HHV-6 reactivation. We describe here a case of altered mental status and multi-organ failure in an immunocompetent woman, whose cerebrospinal fluid (CSF) was positive for HHV-6 DNA by polymerase chain reaction (PCR).
Background
Febrile seizures are the most common neurologic disorder in childhood. Physicians should be familiar with the proper evaluation and management of this common condition.
Objective
To provide an update on the current understanding, evaluation, and management of febrile seizures.
Methods
A PubMed search was completed in Clinical Queries using the key terms ‘febrile convulsions’ and ‘febrile seizures’. The search strategy included meta-analyses, randomized controlled trials, clinical trials, observational studies, and reviews.
Results
Febrile seizures, with a peak incidence between 12 and 18 months of age, likely result from a vulnerability of the developing central nervous system to the effects of fever, in combination with an underlying genetic predisposition and environmental factors. The majority of febrile seizures occur within 24 hours of the onset of the fever. Febrile seizures can be simple or complex. Clinical judgment based on variable presentations must direct the diagnostic studies which are usually not necessary in the majority of cases. A lumbar puncture should be considered in children younger than 12 months of age or with suspected meningitis. Children with complex febrile seizures are at risk of subsequent epilepsy. Approximately 30–40% of children with a febrile seizure will have a recurrence during early childhood. The prognosis is favorable as the condition is usually benign and self-limiting. Intervention to stop the seizure often is unnecessary.
Conclusion
Continuous preventative antiepileptic therapy for the prevention of recurrent febrile seizures is not recommended. The use of intermittent anticonvulsant therapy is not routinely indicated. Antipyretics have no role in the prevention of febrile seizures.
For a long time, hand, foot and mouth disease (HFMD) was seen as a mild viral infection characterized by typical clinical manifestations that spontaneously resolved in a few days without complications. In the past two decades, HFMD has received new attention because of evidence that this disease could have clinical, epidemiological and aetiological characteristics quite different from those initially thought. In contrast to previous beliefs, it has been clarified that HFMD can be associated with complications, leading to severe neurological sequelae and, rarely, to death. This finding has led to an enormous number of studies that have indicated that several viruses in addition to those known to be causes of HFMD could be associated with the development of disease. Moreover, it was found that if some viruses were more common in some geographic areas, frequent modification of the molecular epidemiology of the infecting strains could lead to outbreaks caused by infectious agents significantly different from those previously circulating. Vaccines able to confer protection against the most common aetiologic agents in a given country have been developed. However, simultaneous circulation of more than one causative virus and modification of the molecular epidemiology of infectious agents make preparations based on a single agent relatively inadequate. Vaccines with multiple components are a possible solution. However, several problems concerning their development must be solved before adequate prevention of severe cases of HFMD can be achieved.
Background
Primary Human herpesvirus-7 (HHV-7) infection usually occurs during childhood and causes several clinical manifestations: mainly exanthem subitum (roseola infantum), followed by a lifelong latent state with possible reactivation in case of immunodeficiency. Nevertheless, some considerably different approaches exist regarding the natural history of HHV-7 and the possible consequences of HHV-7 infection in immunocompetent adults. In particular, little is known about its pathogenic role in central nervous system (CNS) disease in nonimmunosuppressed adults. Specifically, in case of encephalitis, it is important to distinguish between infectious encephalitis and postinfectious encephalomyelitis for the management of patients
Case presentation
We describe here a case of encephalitis associated to human herpesvirus-7 with associated polymyeloradiculopathy in an immunocompetent patient which may contribute to the delineation of the approach to a patient profile with a similar clinical presentation and evolution to those presented in the literature.
Conclusions
This case may alert clinicians to consider this specific etiology in the differential diagnosis of encephalopathy in patients with suspected infectious encephalitis who do not respond to acyclovir or in patients who develop acute polymyeloradiculopathy, considering that HHV-7 may be a pathological factor and that a timely diagnosis is crucial for the early administration of specific treatment.
Electronic supplementary material
The online version of this article (doi:10.1186/s12985-017-0764-y) contains supplementary material, which is available to authorized users.
Urinary Tract Infections in Infants and Children, Page 1 of 2
Abstract
Urinary tract infections (UTI) are one of the most common infections in children and symptoms may be nonspecific. The risk of renal scarring is highest in children under 1 year of age with febrile UTI and high-grade vesicoureteral reflux (VUR). Although treatment of UTI is usually straightforward, given increased rates of antimicrobial resistance worldwide, the choice of treatment for pediatric UTI should be guided by community resistance patterns whenever feasible. The benefit of antimicrobial prophylaxis after first UTI and/or in the presence of VUR remains controversial, but a recent meta-analysis supports continuous antimicrobial prophylaxis in children with VUR, indicating a need for more research in this area.
Human herpesvirus 6B (HHV-6B) causes exanthema subitum in infants and is known to be mildly pathogenic. However, HHV-6B infection can induce febrile seizures in a high percentage of patients, and in rare cases, result in encephalitis. We detected higher levels of interleukin (IL)-1β and basic fibroblast growth factor (bFGF) in the cerebrospinal fluid (CFS) of patients with HHV-6B encephalitis when compared to those in patients with non-HHV-6B-induced febrile seizures. In vitro, IL-1β and bFGF enhanced HHV-6B gene expression in infected U373 astrocytes during the initial and maintenance phases of infection, respectively. These findings indicated that IL-1β and bFGF contribute to HHV-6B growth and the onset of encephalitis.
Human Herpesviruses 6A, 6B, and 7, Page 1 of 2
Abstract
Human herpesviruses 6A, 6B, and 7 (HHV-6A, HHV-6B, HHV-7), are members of the family Herpesviridae, subfamily Betaherpesvirinae, and genus Roseolovirus. The three viruses are genetically close to each other and to cytomegalovirus (CMV), the type-species of human betaherpesviruses. Like other human herpesviruses, they are ubiquitous and establish a lifelong latent infection which originates further reactivations and reinfections. Early after the recent discovery of the three viruses, these properties, as well as the genetic relationship with CMV, have been a potent rationale for speculating on their potential pathogenicity in the immunocompromised population. The pathogenic role of HHV-6, this term collectively referring to HHV-6A and HHV-6B, is now ascertained in immunocompromised subjects whereas the clinical impact of HHV-7 infection appears less important in this domain. However, numerous questions are still pending, regarding diagnostic as well as therapeutic approaches targeted to these three viruses. Due to their strong similarities, the three viruses will be presented together throughout the chapter and specific details will be given for each of them within the different sections when needed. Diagnostic Microbiology of the Immunocompromised Host, Second Edition
Objectives:
Infants and children with upper respiratory tract infection (URI) often have concurrent acute otitis media (AOM). Young infants have fewer specific symptoms than older children. The purpose of this study was to evaluate the usefulness of symptoms and other risk factors in predicting the presence of AOM in infants.
Methods:
Healthy infants, age less than four weeks, were enrolled and followed prospectively for up to age one year. Infants were scheduled for a research visit when their parents noted the onset of symptoms. At each URI visit, parents first reported the severity of symptoms. An investigator then diagnosed the presence or absence of concurrent AOM. Risk factors and symptom scores for infants with and without AOM were studied.
Results:
Infants (N=193, mean age at first URI 3.9±2.5 months) experienced 360 URI episodes and 63 AOM events. Symptoms consisting of fever, earache, poor feeding, restless sleep, and irritability together (ETG-5) were statistically associated with the prediction of AOM (P=0.006). A multiple variable statistical model (J-Score) that included day care attendance, age, severity of cough and earache best predicted AOM (P<0.001), with 95% specificity. Both ETG-5 and J-score yielded relatively low sensitivity for AOM prediction.
Conclusions:
In infants with URI in the first year of life, severity of symptoms was significantly associated with concurrent AOM. Daycare attendance, presence and severity of earache and cough added to better correlation. These observations may have clinical application in identification of infants at risk for AOM.
Measles (Rubeola), although considered eradicated in the United States, still causes periodic outbreaks. Vaccine refusal leads to vulnerable pockets of individuals who may become infected once the virus is imported from countries where it is endemic. In turn, these individuals may spread the virus to young infants and to other vulnerable individuals. Many healthcare providers are not familiar with this disease or with the factors that contribute to the risk of spread. Measles causes a serious febrile illness that may lead to pneumonia, blindness, deafness, neurological disorders, and even death. Patients with measles need supportive care and administration of oral vitamin A. The measles vaccine is highly effective and considered extremely safe, but misinformation about the safety of this and other vaccines has decreased immunization coverage in some areas of the country. Mandatory immunization laws exist in every state and have been upheld by courts including the United States Supreme Court, but laws and exemptions vary among states. Nurses can play a strong role in care of patients with measles, case identification, and prevention of transmission. Most importantly, because nurses hold positions of trust in their communities, they should be tireless frontline advocates for immunization. The purpose of this article is to provide information on measles, its transmission, signs and symptoms, treatment, prevention, and relevant laws and regulations.
Febrile convulsion is a common disorder in children. Viral infections such as human herpes virus 6 (HHV-6) which results in roseola infantum may contribute to developing seizure. The objective of this study was to determine the prevalence of HHV-6 by detecting DNA in cerebrospinal fluid (CSF) of children with febrile convulsion and without any rash of roseola infantum.
In this descriptive cross-sectional study, CSF of 100 children younger than 2 years of age with febrile convulsion was evaluated for detecting HHV-6 DNA by PCR. All of them were referred to emergency ward in Pediatric Medical Center from March 2010 to March 2011. General information, clinical manifestations, laboratory tests and outcomes were collected in the questionnaires.
One hundred children including 59 males and 41 females were evaluated. HHV-6 was detected from CSF in six patients (6%) by PCR. Mean age was 8 months old. All children were younger than 12 months old. The most common primary manifestation was fever alone. None of them had rash. Majority of cases occurred in winter. All patients recovered without any encephalitis.
These findings showed that primary infection with HHV-6 is frequently associated with febrile convulsion in infants which may be at risk for subsequent development of epilepsy.
Shortly after the discovery of human herpesvirus 6 (HHV-6), two distinct variants, HHV-6A and HHV-6B, were identified. In 2012, the International Committee on Taxonomy of Viruses (ICTV) classified HHV-6A and HHV-6B as separate viruses. This review outlines several of the documented epidemiological, biological, and immunological distinctions between HHV-6A and HHV-6B, which support the ICTV classification. The utilization of virus-specific clinical and laboratory assays for distinguishing HHV-6A and HHV-6B is now required for further classification. For clarity in biological and clinical distinctions between HHV-6A and HHV-6B, scientists and physicians are herein urged, where possible, to differentiate carefully between HHV-6A and HHV-6B in all future publications.
CASE PRESENTATION
An 11-month-old boy presented to our hospital with a 3-day history of fever and irritability. Physical examination revealed redness and swelling at the base of the palatine tonsils (Figure 1, arrows) and mild cervical lymphadenopathy. A single round papule with intense erythema was appreciated at the right base of the palatine tonsil. Additionally, multiple small whitish lesions surrounded by erythema were observed on the left uvulo-palatoglossal junction. These whitish lesions were suspected to represent the formation of ulcers. There was no white moss in the pharynx. There was no skin rash, mucosal hyperemia, or Koplik’s spots; this suggested that a diagnosis of measles or rubella was less likely. Rapid antigen tests for group A beta streptococci (Quick Navi Strep A2; Denka Corporation, Niigata, Japan) and adenoviruses (Rapid Tester RSV-Adeno; Sekisui Medical Corporation, Tokyo, Japan) were negative. His fever subsided the following day without medication, and a faint pink, nonpruritic, maculopapular, and scattered skin rash appeared on the trunk (Figure 2). The skin rash disappeared spontaneously within a week.
Introduction:
Roseola infantum is always considered to be among the differential diagnosis of young patients with fever and leukopenia whom to be strictly isolated with the preliminary diagnosis of COVID-19 until otherwise proven during the pandemic.
Results:
Human herpes virus-6 (HHV-6) polymerase chain reaction (PCR) blood test was performed in 4 of 7 patients with a clinical diagnosis of roseola infantum and all found to be HHV-6 PCR positive. The most striking laboratory finding in all patients was leukopenia. HHV-6 PCR tests were found to be positive. Severe acute respiratory syndrome coronavirus-2 testing were found to be negative in all patients.
Conclusion:
During the peak of the pandemic, children continued to present with fever because of viral infections other than COVID-19.
During local small measles outbreak in Japan, 3 adolescents with febrile skin rash suspected as having measles were diagnosed with primary human herpesvirus (HHV)-7 infection. Primary HHV-7 infection can cause exanthem subitum in not only young children but also adolescents. HHV-7 should be considered as a possible causative agent for adolescent febrile skin rash during the measles outbreak.
Human herpesvirus‐6 (HHV‐6) is a common pathogen affecting the human population. Primary HHV‐6 infection generally occurs during infancy and causes exanthema subitum. Moreover, HHV‐6 may exhibit inherited chromosomally integrated HHV‐6 (iciHHV‐6) in certain individuals. Although iciHHV‐6 is generally known to be nonpathogenic, it may cause reactivation in patients with primary immunodeficiency disease (PID). XIAP deficiency is a rare PID characterized by recurrent hemophagocytic lymphohistiocytosis (HLH). It has been reported that the Epstein‐Barr virus primarily cause HLH; however, the other pathogens, including HHV‐6, can also cause this complication. We encountered a case of XIAP deficiency accompanied by iciHHV‐6. He suffered from recurrent HLH, for which allogeneic bone marrow transplantation (BMT) was performed as a curative therapy. During the course of BMT, the patient experienced HLH three times, but there was no reactivation of endogenous HHV‐6 from iciHHV‐6. Finally, the patient achieved complete donor chimerism and a decline in HHV‐6 DNA copy number in whole blood. This case report demonstrates no evidence of reactivation of iciHHV‐6 during BMT in a patient with XIAP deficiency.
Background
It is well known that febrile seizure is common complication of exanthem subitum. In this study, we compared the clinical features and backgrounds of complex febrile seizure patients with and without primary HHV-6B infection.
Methods
Sixty-two patients were enrolled after experiencing their first febrile seizure. Primary HHV-6B infection was confirmed when HHV-6B DNA was detected and HHV-6B antibody was negative in serum obtained during the acute phase of infection. Patient backgrounds such as age, gender and features of seizures were evaluated between patients with and without HHV-6B infection.
Results
Thirty complex febrile seizure patients were diagnosed with primary HHV-6B infection. Those with primary HHV-6B infection (median, 13 months; range, 7–39 months) were significantly younger than those without primary HHV-6B infection (median, 19 months; range, 10–59 months) (P=0.001), and the proportion of males was significantly higher in patients without primary HHV-6B infection (male/female, 25/7) than in those with the infection (male/female, 14/16) (P=0.017). An interval between fever onset and seizures more than 24 hours after fever onset were significantly more common in the patients with primary HHV-6B infection (15 of the 30 patients) than in those without primary HHV-6B infection (2 of the 32 patients) (P <0.001).
Conclusions
The younger age at onset, the different gender ratio with febrile seizure due to other causes, and the length of interval between fever and seizures were features of complex febrile seizure associated HHV-6B infection. These findings may suggest a different mechanism of complex febrile seizure onset with due to other causes.
Human herpesvirus 6 (HHV-6) infection is the cause of roseola infantum in children. The reactivation of HHV-6 is associated with multiple clinical syndromes including encephalitis and myelitis, especially in haematopoietic stem cell transplant recipients. However, the virus can cause encephalitis in other immunosuppressed as well as immunocompetent individuals. We report a case of a 70-year-old woman who was immunocompromised secondary to treatment of rheumatoid arthritis with leflunomide and methotrexate. The patient presented with acute ataxia, diplopia and dysarthria. MRI brain showed an enhancing lesion in the midbrain. The diagnosis of HHV-6 encephalitis was made after HHV-6 A DNA was detected in both serum and cerebrospinal fluid. Treatment consisted of a 3-week course of intravenous ganciclovir along with physiotherapy. At a 3-month follow-up, repeat MRI brain showed a decrease in size and oedema of the lesion and the patient’s neurological function was improved.
Human herpesvirus 6A (HHV-6A) and 6B (HHV-6B) are members of the genus Roseolovirus in the Betaherpesvirinae subfamily. HHV-6B infects humans in the first years of life, has a seroprevalence of more than 90% and causes Roseola Infantum, but less is known about HHV-6A. While most other herpesviruses maintain their latent genome as a circular episome, HHV-6A and HHV-6B (HHV-6A/B) have been shown to integrate their genome into the telomeres of infected cells. HHV-6A/B can also integrate into the chromosomes of germ cells, resulting in individuals carrying a copy of the virus genome in every nucleated cell of their bodies. This review highlights our current understanding of HHV-6A/B integration and reactivation as well as aspects that should be addressed in the future of this relatively young research area. It forms part of an online symposium on the prevention and therapy of DNA virus infections, dedicated to the memory of Mark Prichard.
A rash is a disseminated eruption of cutaneous lesions with great variation in appearance, cause, and severity. When the physician is facing a rash, the history and physical examination of the patient are extremely important for the identification of the disease and its causal agent.
There are various causes for a rash, which may be infectious, allergic, or rheumatologic, besides many others. Rashes associated with mucosal ulcers may have causes related to viral and bacterial infections or drug reactions. They may be associated with measles; erythema infectiosum; roseola infantum; rubella; hand, foot, and mouth disease; pityriasis rosea; dengue fever; chikungunya; zika; scarlet fever; meningococcal diseases; syphilis; and exanthematous drug eruptions.
A 10-year-old Malay boy living in Malaysia presented with fever, rhinorrhea, cough, and red and watery eyes for 3 days. The child also had malaise, anorexia, headache, and photophobia. His parents could not recall whether he had been in contact with anyone unwell. There was no history of recent travel or drug taking. His parents did not know his immunization history well.
On examination, the child’s temperature was 39.5°C, heart rate 93 beats per minute, respiratory rate 24 breaths per minute, and blood pressure 100/60 mm Hg. Diffuse bilateral conjunctival injection was noted (Figure 1). Examination of the oral cavity showed multiple small white papules on an erythematous background on the posterior buccal mucosa bilaterally (Figure 2). The pharynx was erythematous. Shotty lymph nodes were noted in the cervical areas bilaterally.
The patient developed an erythematous morbilliform rash on the face the following day (Figure 1). The rash became confluent as it spread to the neck, trunk, and extremities over the next 2 days. The rash lasted for 7 days and faded in the same directional pattern as it appeared. Fever subsided and fine desquamation was noted as the rash faded.
HHV-6A and HHV-6B are ubiquitous human betaherpesviruses sharing more than 80% homology. HHV-6B is the most common cause of encephalitis in transplant patients and its primary infection may cause the exanthema subitum and febrile seizures in infants. HHV-6A and HHV-6B are able to infect several immune cell types such as T cells, monocytes and dendritic cells (DCs). In this study we found that HHV-6 B derived from patients affected by exanthema subitum impaired monocyte differentiation into DCs, as the infected cells acquired less CD1a DC marker and retained more CD14 monocyte marker. In agreement with the previous finding that HHV-6B dysregulated autophagy and induced endoplasmic reticulum (ER) stress in cells in which it replicated, here we found that these effects occurred also in differentiating monocytes and that ER stress relief, by using the chemical chaperone sodium 4-phenylbutirate (PBA), partially restored DC formation. This suggests that the induction of ER stress, likely exacerbated by autophagy inhibition, could contribute to the immune suppression induced by HHV-6B derived from exanthema subitem patients.
Objective:
This cohort study, based on the design of a prior study in the United States, was conducted to elucidate the clinical features of primary human herpesvirus-6B (HHV-6B) infection.
Methods:
Between June 2014 and May 2016, febrile children younger than 5 years who visited the emergency room (ER) and underwent blood examination were enrolled in this study.
Results:
Fifty-nine (12%) of the 491 patients were diagnosed with primary HHV-6B infection. The rates of both simple and complex febrile seizure were significantly higher in patients with primary HHV-6B infection than in those without (P < 0.001 and P = 0.008, respectively). The median age at primary HHV-6B infection was 15 months. Forty-seven (79.7%) of the 59 patients with primary HHV-6B infection were younger than 2-year-old. Clinical features were compared between HHV-6B-infected patients older and younger than 2 years. The frequency of apparent infection (exanthema subitum) was significantly higher in the younger patients (P = 0.01). The median leukocyte (P = 0.01) and lymphocyte (P < 0.001) counts in the patients older than 2 years were significantly lower than those in the younger patients.
Conclusions:
Primary HHV-6B infection accounted for 12% of ER visits. Secondary febrile seizures, in particular the complex type, were considered to be a major contributor to the disease burden of primary HHV-6B infection. The timing of primary HHV-6B infection occurred at older ages than in past reports, and the frequency of inapparent infection was higher in older patients.
Rubella is generally a mild and self-limited disease in children. During pregnancy, rubella can have potentially devastating effects on the developing fetus. Postnatal rubella is transmitted primarily by inhalation of virus-laden airborne droplets or direct contact with infected nasopharyngeal secretions. In susceptible pregnant women, the virus may cross the placenta and spread through the vascular system of the developing fetus. Postnatally acquired rubella typically begins with fever and lymphadenopathy, followed by an erythematous, maculopapular rash. The rash classically begins on the face, spreads cephalocaudally, becomes generalised within 24 hours, and disappears within 3 days. Maternal rubella, especially during early pregnancy, may lead to miscarriage, intrauterine fetal death, premature labour, intrauterine growth retardation, and congenital rubella syndrome. Cataracts, congenital heart defects, and sensorineural deafness are the classic triad of congenital rubella syndrome and they typically occur if the fetal infection occurs in the first 11 weeks of gestation. Laboratory confirmation of rubella virus infection can be based on a positive serological test for rubella-specific immunoglobulin M antibody; a four-fold or greater increase in rubella-specific immunoglobulin G titres between acute and convalescent sera; or detection of rubella virus RNA by reverse transcriptase-polymerase chain reaction. Treatment is mainly symptomatic. Universal childhood immunisation and vaccination of all susceptible patients with rubella vaccine to decrease circulation of the virus are cornerstones to prevention of rubella and, more importantly, congenital rubella syndrome.
Group A β-haemolytic Streptococcus or Streptococcus pyogenes is a gram-positive coccus that tends to grow in chains. Streptococcus pyogenes is the cause of many important human diseases, ranging from pharyngitis and mild superficial skin infections to life-threatening systemic diseases. Infections typically begin in the throat or skin. Mild Streptococcus pyogenes infections include pharyngitis (strep throat) and localised skin infections (impetigo). Erysipelas and cellulitis are characterised by multiplication and lateral spread of Streptococcus pyogenes in deep layers of the skin. Streptococcus pyogenes invasion and fascial involvement can lead to necrotising fasciitis, a life-threatening condition. Scarlet fever is characterised by a sandpaper-like rash in children with fever and is caused by a streptococcal toxin. Severe infections that lead to septicaemia or toxic shock syndrome are associated with high mortality. Autoimmune reactions cause characteristic syndromes such as rheumatic fever and nephritis. Epidemiology, disease presentation, diagnosis, and treatment of paediatric patients in Hong Kong with group A β-haemolytic Streptococcus are reviewed in this article. Streptococcus pyogenes disease is readily treatable, as the organism is invariably sensitive to penicillin. Delayed treatment of this common childhood pathogen is associated with significant mortality and morbidity.
Measles (rubeola) is a highly contagious vaccine-preventable disease caused by the measles virus-a virus of the Paramyxoviridae family. The illness typically begins with fever, runny nose, cough, and pathognomonic enanthem (Koplik spots) followed by a characteristic erythematous, maculopapular rash. The rash classically begins on the face and becomes more confluent as it spreads cephalocaudally. Laboratory confirmation of measles virus infection can be based on a positive serological test for measles-specific immunoglobulin M antibody, a four-fold or greater increase in measles-specific immunoglobulin G between acute and convalescent sera, isolation of measles virus in culture, or detection of measles virus ribonucleic acid by reverse transcriptase-polymerase chain reaction. Complications occur in 10% to 40% of patients, and treatment is mainly symptomatic. Bacterial superinfections, if present, should be properly treated with antibiotics. To eradicate measles, universal childhood immunisation and vaccination of all susceptible individuals with measles vaccine would be ideal. In developed countries, routine immunisation with measles-containing vaccine is recommended, with the first and second doses at ages 12 to 15 months and 4 to 6 years, respectively. The World Health Organization recommends that the first and second doses of measles-containing vaccine be given at ages 9 months and 15 to 18 months, respectively, in countries with high rates of measles transmission.
We studied the etiology of pediatric acute encephalitis/encephalopathy (pAEE) using epidemiological data obtained from a nationwide survey in Japan. Two-step questionnaires were sent to the pediatric departments of hospitals throughout the country in 2007, querying the number of the cases during 2005-2006 as the first step, and asking for the details of clinical information as the second step. In all, 636 children with pAEE (age ≤ 15 years) were enrolled. For the known etiology of pAEE (63.5% of the total cases), 26 microbes and 2 clinical entities were listed, but the etiology of 36.5% remained unknown. Influenza virus (26.7%), exanthem subitum (12.3%), and rotavirus (4.1%) were the most common, and the incidence of pAEE peaked at the age of 1 year. This trend was common among all etiologies. Among the neurological symptoms observed at the onset of pAEE, seizures were observed more often in patients aged ≤ 3 years, although abnormal speech and behavior were also common in older children. Undesirable outcomes (death and neurological sequelae) occurred at high rates in patients with any known etiology other than mycoplasma. In conclusion, these findings provide comprehensive insight into pAEE in Japan.
Roseola infantum is a clinical syndrome characterized by high fever followed by the emergence of a rash. Case reports have documented an association between bulging fontanelles and roseola. We propose a novel mechanism for the development of intracranial hypertension caused by human herpesvirus 6-induced cytokine elevation leading to increased cerebrospinal fluid production.
A recent outbreak in Minnesota underscores the need to maintain vigilance and adhere to best practices in immunization and containment of known cases.
Human herpesviruses 6A, 6B, and 7 (HHV-6A, HHV-6B, HHV-7) are genetically related to cytomegalovirus. They belong to the Roseolovirus genus and to the Betaherpesvirinae subfamily. They infect T cells, monocytes-macrophages, epithelial cells, and central nervous system cells. These viruses are ubiquitous and are responsible for lifelong chronic infections, most often asymptomatic, in the vast majority of the general adult population. HHV-6B is responsible for exanthema subitum, which is a benign disease of infants. HHV-6A and HHV-6B also cause opportunistic infections in immunocompromised patients: encephalitis, hepatitis, bone marrow suppression, colitis, and pneumonitis. Their etiological role in chronic diseases such as multiple sclerosis, cardiomyopathy, and thyroiditis is still controversial. The pathogenicity of HHV-7 is less clear and seems to be much more restricted. Chromosomal integration of HHV-6A and HHV-6B is transmissible from parents to offspring and observed in about 1% of the general population. This integration raises the question of potential associated diseases and can be a confounding factor for the diagnosis of active infections by both viruses. The diagnosis of HHV-6A, HHV-6B, and HHV-7 infections is rather based on gene amplification (PCR), which allows for the detection and quantification of the viral genome, than on serology, which is mainly indicated in case of primary infection. Ganciclovir, foscarnet, and cidofovir inhibit the replication of HHV-6A, HHV-6B, and HHV-7. Severe infections may thus be treated but these therapeutic indications are still poorly defined.
Objective:
Urinary tract infection (UTI) is the most common bacterial infection in childhood. UTI may be the sentinel event for underlying renal abnormality. There are still many controversies regarding proper management of UTI. In this review article, the authors discuss recent recommendations for the diagnosis, treatment, prophylaxis, and imaging of UTI in childhood based on evidence, and when this is lacking, based on expert consensus.
Source of data:
Data were obtained after a review of the literature and a search of Pubmed, Embase, Scopus, and Scielo.
Summary of data:
In the first year of life, UTIs are more common in boys (3.7%) than in girls (2%). Signs and symptoms of UTI are very nonspecific, especially in neonates and during childhood; in many cases, fever is the only symptom.
Conclusions:
Clinical history and physical examination may suggest UTI, but confirmation should be made by urine culture, which must be performed before any antimicrobial agent is given. During childhood, the proper collection of urine is essential to avoid false-positive results. Prompt diagnosis and initiation of treatment is important to prevent long-term renal scarring. Febrile infants with UTIs should undergo renal and bladder ultrasonography. Intravenous antibacterial agents are recommended for neonates and young infants. The authors also advise exclusion of obstructive uropathies as soon as possible and later vesicoureteral reflux, if indicated. Prophylaxis should be considered for cases of high susceptibility to UTI and high risk of renal damage.
A bulging fontanel in an infant is generally regarded as a sign of serious central nervous system disease. It may be caused by meningitis, hydrocephalus, cerebral hemorrhage, brain abscess, or tumor. Benign intracranial hypertension, a syndrome of increased intracranial pressure with a normal ventricular system and a cerebrospinal fluid of normal composition, also will produce a bulging fontanel. Hypoparathyroidism,1 hypovitaminosis A,2,3 hypervitaminosis A,4 hypophosphatasia,5 marked anemia,6 chlortetracycline therapy,7 Addison's disease,8 and pulmonary emphysema,9 have been reported as causes of benign intracranial hypertension. Scattered reports10,11,12 of the association of roseola infantum with a bulging fontanel have appeared in the literature. The following report of 2 cases is being presented as further illustration of this disease as a cause of benign intracranial hypertension.
Case 1.—A 5-month-old white boy was in good health until 3 days prior to admission, when the mother noted that
Introduction
Roseola infantum, first described by Zahorsky1 in 1913, is generally considered a benign disease; indeed, Kempe2 noted there are no reported fatalities. Serious sequelae are usually stated to be virtually nonexistent. However, the possibility has been suggested in a comprehensive view of the subject,3 that some of the sudden deaths in infancy may be caused by roseola. No clear instances of this have been reported, no doubt owing to the difficulties of making a positive identification of the disease in the preeruptive stage and the inability to isolate the virus in tissue culture.Roseola infantum is the commonest exanthem under the age of 2 years, and infection is perhaps almost universal before the age of 5 years.3 The disease is characterized by the relative absence of prefebrile prodromata, an abrupt onset, and a rapid temperature rise. Irritibility and listlessness are variable; the patient is usually
The roseoloviruses, human herpesvirus-6A -6B and -7 (HHV-6A, HHV-6B and HHV-7) cause acute infection, establish latency, and in the case of HHV-6A and HHV-6B, whole virus can integrate into the host chromosome. Primary infection with HHV-6B occurs in nearly all children and was first linked to the clinical syndrome roseola infantum. However, roseolovirus infection results in a spectrum of clinical disease, ranging from asymptomatic infection to acute febrile illnesses with severe neurologic complications and accounts for a significant portion of healthcare utilization by young children. Recent advances have underscored the association of HHV-6B and HHV-7 primary infection with febrile status epilepticus as well as the role of reactivation of latent infection in encephalitis following cord blood stem cell transplantation.
Hand, foot, and mouth disease (HFMD) is a common, typically self-limited viral syndrome in children and adults. It is marked by fever, oral ulcers, and skin manifestations affecting the palms, soles, and buttocks, with symptoms usually lasting less than 1 week. Because it has the potential to reach epidemic levels in the United States, general practitioners need to be aware of it.
Human herpesvirus-6 (HHV-6) is a cause of exanthema subitum and, sometimes, of febrile seizures. However, the pathogenesis of febrile seizures associated with HHV-6 infection remains unclear. We investigated serum matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinases-1 (TIMP-1) levels in infants with HHV-6 infection. Serum levels of both MMP-9 and TIMP-1 were significantly higher in infants with HHV-6 infection than in controls. Serum TIMP-1 levels were significantly higher in infants with febrile seizures than in infants without febrile seizures. Serum MMP-9/TIMP-1 ratios were significantly lower in infants with febrile seizures than in infants without febrile seizures. In infants with HHV-6 infection, positive correlations were found between serum MMP-9 concentrations and the white blood cells (WBC) count, and between serum TIMP-1 concentrations and the WBC count. Positive correlations were also found between the amounts of HHV-6 DNA and the ratios of MMP-9/TIMP-1 in infants with HHV-6 infection. In conclusion, we suggest that high serum levels of MMP-9 and TIMP-1 in infants with HHV-6 infection may induce dysfunction of the blood–brain barrier, eventually causing febrile seizures.
This chapter reviews the major neurologic manifestations associated with mumps and rubella infection. Both mumps and rubella demonstrate neurotropism and are associated with multiple central nervous system infectious as well as parainfectious syndromes. While infections are waning globally with the successful implementation of large-scale vaccination programs, these viruses remain important pathogens given inconsistent vaccination in some areas of the developing world, particularly so in politically unstable regions. The facility of international travel for unimmunized individuals continues to contribute to neurologic complications across the globe. Important elements of neuropathogenesis, disease epidemiology and natural history, and associated clinical syndromes of mumps and rubella infection are highlighted in this chapter.
Infectious mononucleosis is a disease primarily of adolescence and early adulthood. The risk of splenic injury and chronic fatigue make return-to-play decisions a challenge for the clinician caring for athletes with infectious mononucleosis.
Data were obtained from the PubMed and MEDLINE databases through December 2012 by searching for epidemiology, diagnosis, clinical manifestations, management, and the role of the spleen in infectious mononucleosis.
Clinical review.
Level 4.
Infectious mononucleosis is commonly encountered in young athletes. Its disease pattern is variable and can affect multiple organ systems. Supportive care is the cornerstone, with little role for medications such as corticosteroids. Physical examination is unreliable for the spleen, and ultrasound imaging has limitations in its ability to guide return-to-play decisions. Exercise does not appear to place the young athlete at risk for chronic fatigue, but determining who is at risk for persistent symptoms is a challenge.
Return-to-play decisions for the athlete with infectious mononucleosis need to be individualized because of the variable disease course and lack of evidence-based guidelines.
Roseola infantum, also known as exanthem subitum or sixth disease, is a generally benign febrile exanthem of infancy. It has a characteristic clinical course of high fever followed by the appearance of an exanthem upon defervescence. Febrile seizures are a frequent complication. Roseola is caused by infection with human herpesviruses 6 or 7 (HHV-6/7), which are acquired at a young age. Diagnosis is made by serology or by virus detection in body fluids and tissues. Treatment of roseola is supportive; recovery is usually complete with no significant sequelae. However, HHV-6/7 can reactivate in immunocompetent as well as immunocompromised individuals with severe systemic consequence.
Acute encephalopathy with biphasic seizures and late reduced diffusion has become increasingly common among various types of human herpesvirus 6B (HHV-6B) encephalitis at the time of primary viral infection. The aim of the present study is to explore the pathophysiology of HHV-6B-associated acute encephalopathy with biphasic seizures and late reduced diffusion. Five cytokines and five chemokines were measured in serum and cerebrospinal fluid (CSF) obtained from 12 HHV-6B-associated acute encephalopathy with biphasic seizures and late reduced diffusion patients and 19 control exanthem subitum (without complications) patients. Serum interleukin (IL)-10 (P = 0.007) and IL-8 (P = 0.025) were significantly higher in the patients with the disease than controls. Serum IL-1β (P = 0.034) and monocyte chemoattractant protein (MCP)-1 (P = 0.002) were significantly higher in the controls than patients with the disease. In patients with the disease, IL-10 (P = 0.012), regulated on activation normal T cell expressed and secreted (RANTES; P = 0.001), and monokine induced by interferon γ (MIG; P = 0.001) were significantly higher in serum than CSF, meanwhile IL-6 (P = 0.034), IL-8 (P = 0.034), and MCP-1 (P = 0.001) were significantly higher in CSF than serum. Additionally, serum IL-10 was significantly higher in the disease patients with sequelae than those without sequelae (P = 0.016). Several cytokines and chemokines may be associated with the pathogenesis of acute encephalopathy with biphasic seizures and late reduced diffusion. Moreover, the regulation of cytokine networks appears to be different between peripheral blood (systemic) and central nervous system. J. Med. Virol. 9999: XX-XX, 2013. © 2013 Wiley Periodicals, Inc.
. We report a 10-month-old boy with acute meningo-encephalitis associated with exanthem subitum. It has recently been reported that human herpesvirus-6 is the causative agent of exanthem subitum, and to our knowledge our case is the first report of meningo-encephalitis associated with HHV-6 infection.