Viral Infections of Toronto Children During 1965: II. Measles Encephalitis and Other Complications

Among 16 cases of measles encephalitis observed in Toronto during 1964 and 1965, including six who were stuporous or comatose on admission and five who presented with convulsions, measles virus was isolated from CSF of one patient, rising titres of measles antihemagglutinin were detected in another patient, and 14 showed high antibody titres in sera collected as early as two to five days after onset of the measles rash. Increasing levels of measles antibody were detected in paired sera from three of seven patients with uncomplicated measles, and elevated antihemagglutinin titres were found in 16 cases of measles without neural involvement. Measles virus was isolated from lung tissue of a fatal case of giant cell pneumonia. Administration of pooled human gamma globulin to one leukemic patient, and of leukocytes from a convalescent donor to another leukemic child, may have assisted their recovery from measles.     

Salivary diagnosis of measles: a study of notified cases in the United Kingdom, 1991-3.

OBJECTIVES--To validate a method for salivary diagnosis of measles and to assess the diagnostic accuracy of notified cases of measles. DESIGN--Blood and saliva samples were collected within 90 days of onset of symptoms from patients clinically diagnosed as having measles and tested for specific IgM by antibody capture radioimmunoassay. SETTING--17 districts in England and one in southern Ireland during August 1991 to February 1993. SUBJECTS--236 children and adults with measles notified by a general practitioner. RESULTS--Specific IgM was detected in serum in only 85 (36%) of the 236 cases. In cases associated with outbreaks and tested within six weeks of onset, 53/57 (93%) of samples were IgM positive, thereby confirming the sensitivity of serum IgM detection as a marker of recent infection. The serological confirmation rate was lower in cases with a documented history of vaccination (13/87; 15%) than in those without (70/149; 47%) and varied with age, being lowest in patients under a year, of whom only 4/36 (11%) were confirmed. Measles specific IgM was detected in 71/77 (92%) of adequate saliva samples collected from patients with serum positive for IgM. In cases where measles was not confirmed, 6/101 had rubella specific IgM and 5/132 had human parvovirus B19 specific IgM detected in serum. CONCLUSIONS--The existing national surveillance system for measles, which relies on clinically diagnosed cases, lacks the precision required for effective disease control. Saliva is a valid alternative to serum for IgM detection, and salivary diagnosis could play a major role in achieving measles elimination. Rubella and parvovirus B19 seem to be responsible for a minority of incorrectly diagnosed cases of measles in the United Kingdom and other infectious causes of measles-like illness need to be sought.     

Epidemiology of Subacute Sclerosing Panencephalitis (SSPE) in Germany from 2003 to 2009: A Risk Estimation

Subacute sclerosing panencephalitis (SSPE) is a fatal long-term complication of measles infection. We performed an estimation of the total number of SSPE cases in Germany for the period 2003 to 2009 and calculated the risk of SSPE after an acute measles infection. SSPE cases were collected from the Surveillance Unit for Rare Paediatric Diseases in Germany and the Institute of Virology and Immunobiology at the University of Würzburg. The total number of SSPE cases was estimated by capture-recapture analysis. For the period 2003 to 2009, 31 children with SSPE who were treated at German hospitals were identified. The capture-recapture estimate was 39 cases (95% confidence interval: 29.2–48.0). The risk of developing SSPE for children contracting measles infection below 5 years of age was calculated as 1∶1700 to 1∶3300. This risk is in the same order of magnitude as the risk of a fatal acute measles infection.     

Protective role of human antibody to the fusion protein of measles virus

Absorption of a pooled human gamma globulin preparation with acetone-treated measles virus-infected cells removed all antibodies to measles virus antigens except a portion of the antibody to the fusion (F) protein. The residual anti-F antibody had hemolysis-inhibiting and virus-neutralizing activities, inhibited spread of infection through cell fusion, and was effective in protection of passively immunized mice from fatal measles encephalitis, providing evidence for the protective role of human antibody to the F protein of measles virus.     

Mortality and morbidity caused by measles in children with malignant disease attending four major treatment centres: a retrospective review.

Measles is a major cause of mortality and morbidity in children receiving treatment for leukaemia. A review was made of all the documented cases of measles in children in first remission from acute lymphoblastic leukaemia at four major treatment centres in 1974-84. Over the 11 years reviewed 1043 children with acute lymphoblastic leukaemia were referred to these centres. Fifty one (4.9%) died while in first remission and 15 (29.4%) of these deaths were due to measles or its complications: 12 cases of pneumonia, 10 of them fatal; and six cases of encephalitis, five of them fatal and the sixth child left severely handicapped. These children would have had at least a 50% chance of long term survival. The severity of measles in the immunocompromised patient reinforces the need to improve the poor uptake of measles immunisation in Britain.     

Epstein-Barr virus but not cytomegalovirus is associated with reduced vaccine antibody responses in Gambian infants

Background

Epstein-Barr virus (EBV) and cytomegalovirus (CMV) are persistent herpesviruses that have various immunomodulatory effects on their hosts. Both viruses are usually acquired in infancy in Sub-Saharan Africa, a region where childhood vaccines are less effective than in high income settings. To establish whether there is an association between these two observations, we tested the hypothesis that infection with one or both viruses modulate antibody responses to the T-cell independent meningococcal polysaccharide vaccine and the T-cell dependent measles vaccines.

Methodology/Principal Findings

Infection with EBV and CMV was diagnosed by the presence of virus-specific IgM in the peripheral blood or by the presence of IgG at higher levels than that found in umbilical cord blood. Anti-meningococcus IgG and IgM were quantified by ELISA. Anti-measles antibody responses were quantified by haemagglutinin antibody inhibition assay. Infants infected with EBV had reduced IgG and IgM antibody responses to meningococcal polysaccharides and to measles vaccine. Infection with CMV alone predicted no changes in the response to meningococcal polysaccharide. While CMV alone had no discernable effect on the antibody response to measles, the response of infants infected with both CMV and EBV was similar to that of infants infected with neither, suggesting that the effects of CMV infection countered the effects of EBV on measles antibody responses.

Conclusions

The results of this exploratory study indicate that infection with EBV is associated with reduced antibody responses to polysaccharides and to measles vaccine, but suggest that the response to T-cell dependent antigens such as measles haemagglutinin may be restored by infection with CMV.     

Protective effect of measles virus inoculation on subacute sclerosing panencephalitis virus-infected mice

The Biken strain of subacute sclerosing panencephalitis (SSPE) virus caused a fatal neurologic disease in adult mice after intracerebral inoculation. However, the mice were completely protected from the disease when a high dose of measles virus was given intracerebrally after the SSPE virus infection. The measles virus inoculation induced interferon production and immune responses. An experiment with athymic nude mice showed that interferon and anti-measles antibody were able to prolong the incubation period of the disease but not to protect the SSPE virus-infected nude mice from death. For complete protection, T lymphocytes appeared to be essential. The present study suggested that the protective effect of measles virus inoculation is basically due to the induction of immune responses and that SSPE virus infection in mice is susceptible to immune reactions.     

Measles outbreak in 31 schools: risk factors for vaccine failure and evaluation of a selective revaccination strategy.

OBJECTIVE: To examine the risk factors for measles vaccine failure and to evaluate the effectiveness of a selective revaccination strategy during a measles outbreak. DESIGN: Matched case-control study. SETTING: Thirty-one schools in Mississauga, Ont. SUBJECTS: Eighty-seven previously vaccinated school-aged children with measles that met the Advisory Committee on Epidemiology''s clinical case definition for measles. Two previously vaccinated control subjects were randomly selected for each case subject from the same homeroom class. INTERVENTIONS: All susceptible contacts were vaccinated, and contacts who had been vaccinated before Jan. 1, 1980, were revaccinated. When two or more cases occurred in a school all children vaccinated before 1980 were revaccinated. MAIN OUTCOME MEASURES: Risk of measles associated with age at vaccination, time since vaccination, vaccination before 1980 and revaccination. RESULTS: Subjects vaccinated before 12 months of age were at greater risk of measles than those vaccinated later (adjusted odds ratio [OR] 7.7, 95% confidence interval [CI] 1.6 to 38.3; p = 0.01). Those vaccinated between 12 and 14 months of age were at no greater risk than those vaccinated at 15 months or over. Subjects vaccinated before 1980 were at greater risk than those vaccinated after 1980 (adjusted OR 14.5, 95% CI 1.5 to 135.6). Time since vaccination was not a risk factor. Revaccination was effective in reducing the risk of measles in both subjects vaccinated before 1980 and those vaccinated after 1980 (adjusted OR reduced to 0.6 [95% CI 0.1 to 5.3] and 0.3 [95% CI 0.13 to 2.6] respectively). However, only 18 cases were estimated to have been prevented by this strategy. CONCLUSIONS: Adherence to routine measles vaccination for all eligible children is important in ensuring appropriate coverage with a single dose. The selective revaccination strategy''s high labour intensiveness and low measles prevention rate during the outbreak bring into question the effectiveness of such a strategy.     

Is childhood asthma being underdiagnosed and undertreated?

Thirty-four cases of asthma in children referred to outpatient clinics in Newcastle upon Tyne (16 cases) and London (18 cases) were reviewed. In both cities there was evidence of inappropriate diagnosis and treatment by general practitioners. One of the main factors seemed to be doctors'' reluctance to use the word "asthma," even when a history of episodic wheezing strongly suggested the diagnosis. Freer use of the word "asthma" might help parents to co-operate in managing asthmatic children and allow them to be better prepared to cope with severe asthmatic attacks if they occur.     

Subacute sclerosing panencephalitis in papua new guinean children: the cost of continuing inadequate measles vaccine coverage

Introduction

Subacute sclerosing panencephalitis (SSPE) is a late, rare and usually fatal complication of measles infection. Although a very high incidence of SSPE in Papua New Guinea (PNG) was first recognized 20 years ago, estimated measles vaccine coverage has remained at ≤70% since and a large measles epidemic occurred in 2002. We report a series of 22 SSPE cases presenting between November 2007 and July 2009 in Madang Province, PNG, including localized clusters with the highest ever reported annual incidence.

Methodology/Principal Findings

As part of a prospective observational study of severe childhood illness at Modilon Hospital, the provincial referral center, children presenting with evidence of meningo-encephalitis were assessed in detail including lumbar puncture in most cases. A diagnosis of SSPE was based on clinical features and presence of measles-specific IgG in cerebrospinal fluid and/or plasma. The estimated annual SSPE incidence in Madang province was 54/million population aged <20 years, but four sub-districts had an incidence >100/million/year. The distribution of year of birth of the 22 children with SSPE closely matched the reported annual measles incidence in PNG, including a peak in 2002.

Conclusions/Significance

SSPE follows measles infections in very young PNG children. Because PNG children have known low seroconversion rates to the first measles vaccine given at 6 months of age, efforts such as supplementary measles immunisation programs should continue in order to reduce the pool of non-immune people surrounding the youngest and most vulnerable members of PNG communities.     

Cyclin E expression and early cervical neoplasia in ThinPrep specimens. A feasibility study

OBJECTIVE: To investigate cyclin E expression as a possible marker for early cervical neoplasia using ThinPrep gynecologic specimens from premenopausal women. STUDY DESIGN: Archived ThinPrep liquid-based cervical/endocervical specimens (Cytyc Corporation, Boxborough, Massachusetts, U.S.A.) diagnosed as human papillomavirus infection (HPV) (20), atypical squamous cells of undetermined significance (ASCUS) (48) and within normal limits (WNL)/benign cellular changes (BCC) (21) were resampled in duplicate, fixed in 95% ethanol, subjected to immunocytochemical staining with the cyclin E antibody (clone 13A3, Novocastra Laboratories Ltd., Newcastle upon Tyne, U.K.) and HPV antibody (clone K1H8, Dako Corporation, Carpinteria, California, U.S.A.) and the expression scored by two pathologists and correlated with the cytologic diagnosis. A case was scored as positive if it contained > 10 abnormal squamous cells with nuclear immunocytochemical staining. RESULTS: The cylin E antibody assay was positive in 20 (100%) cases cytologically diagnosed as HPV. These cases were also anti-HPV antibody positive. Four cases (19%) cytologically diagnosed as WNL/BCC were cyclin E positive. Of these, two were anti-HPV antibody positive. Thirty-four (73%) cases cytologically diagnosed as ASCUS were positive for the cyclin E assay and for anti-HPV antibody staining. CONCLUSION: Cyclin E expression correlates strongly with morphologic features of HPV in ThinPrep specimens and may serve as a surrogate marker for HPV infection and early cervical preneoplastic lesions.     

An emerging recombinant human enterovirus 71 responsible for the 2008 outbreak of Hand Foot and Mouth Disease in Fuyang city of China

Molecular characterization of wild-type measles viruses in China during 1995-2004 demonstrated that genotype H1 was endemic and widely distributed throughout the country. H1-associated cases and outbreaks caused a resurgence of measles beginning in 2005. A total of 210,094 measles cases and 101 deaths were reported by National Notifiable Diseases Reporting System (NNDRS) and Chinese Measles Laboratory Network (LabNet) from 2006 to 2007, and the incidences of measles were 6.8/100,000 population and 7.2/100,000 population in 2006 and 2007, respectively. Five hundred and sixty-five wild-type measles viruses were isolated from 24 of 31 provinces in mainland China during 2006 and 2007, and all of the wild type virus isolates belonged to cluster 1 of genotype H1. These results indicated that H1-cluster 1 viruses were the predominant viruses circulating in China from 2006 to 2007. This study contributes to previous efforts to generate critical baseline data about circulating wild-type measles viruses in China that will allow molecular epidemiologic studies to help measure the progress made toward China's goal of measles elimination by 2012.     

Recurring measles epidemic in Vietnam 2005-2009: implication for strengthened control strategies

Background: Measles remains a serious vaccine preventable cause of mortality in developing nations. Vietnam is aiming to achieve the level of immunity required to eliminate measles by maintaining a high coverage of routine first vaccinations in infants, routine second vaccinations at school entry and supplementary local campaigns in high-risk areas. Regular outbreaks of measles are reported, during 2005-2009.Methods: National measles case-based surveillance data collected during 2005-June 2009 was analyzed to assess the epidemiological trend and risk factors associated with measles outbreak in Vietnam.Results: Of the 36,282 measles suspected cases reported nationwide, only 7,086 cases were confirmed through laboratory examination. Although cyclical outbreaks occurred between 2005 and 2009, there was no definite trend in measles outbreaks during these periods. Overall, 2438 of measles confirmed cases were among children ≤5 years and 3068 cases were among people ≥16 years. The distribution with respect to gender skewed towards male (3667 cases) significant difference was not observed (P= 0.1693). Unsurprisingly, 4493 of the confirmed cases had no history of vaccination (X² <0.01). The northern and highland regions were identified as the main endemic foci and the spatial distribution changed with time. The occurrence of cases, in a considerable proportion of vaccinated population, is not only a reflection of the high vaccination coverage in Vietnam but also portrays a possibility of less than 100% vaccine efficacy. More so, in order to prevent measles in adults, high-risk groups must be identified and catch-up for selected groups selected.Conclusions: This study therefore reinforces the need for continued improvement of surveillance system and to probe into the possible role of changes in age-distribution of cases if the effective control of measles is to be achieved.     

Increased risk of death from measles in children with a sibling of opposite sex in Senegal.

OBJECTIVE--To examine whether contracting measles from a sibling of the opposite sex affects mortality. DESIGN--Prospective registration during 15-20 years of all births and deaths, including 243 measles related deaths. Measles infection was not registered; however, as in fatal cases measles was probably contracted from a maternal sibling the risk of dying during measles outbreaks was examined in families with two boys, two girls, or a boy and a girl. SETTING--31 small villages in two rural areas of eastern Senegal. SUBJECTS--766 children living in families with two children aged under 10 years during outbreaks of measles, 107 (14%) of whom died of measles. MAIN OUTCOME MEASURE--Deaths from measles, size of village, age and sex of maternal siblings. RESULTS--The interval between outbreaks in the same village was greater than 10 years. The risk of dying of measles was significantly related to age, increasing with the age difference between siblings and decreasing with the size of village. In a multiple logistic regression analysis adjusting for these background factors, children in families with a boy and a girl had a significantly higher mortality than children in families with two boys or two girls (odds ratio = 1.81, 95% confidence interval 1.17 to 2.82). The increase in risk was the same for boys and girls in families with two children one of whom was a boy and one a girl. CONCLUSION--Cross sexual transmission may be an important determinant of severity of measles infection.     

Production of atypical measles in rhesus macaques: evidence for disease mediated by immune complex formation and eosinophils in the presence of fusion-inhibiting antibody.

The severe disease atypical measles occurred when individuals immunized with a poorly protective inactivated vaccine contracted measles, and was postulated to be due to a lack of fusion-inhibiting antibodies. Here, rhesus macaques immunized with formalin-inactivated measles vaccine developed transient neutralizing and fusion-inhibiting antibodies, but no cytotoxic T-cell response. Subsequent infection with measles virus caused an atypical rash and pneumonitis, accompanied by immune complex deposition and an increase in eosinophils. Fusion-inhibiting antibody appeared earlier in these monkeys than in non-immunized monkeys. These data indicate that atypical measles results from previous priming for a nonprotective type 2 CD4 T-cell response rather than from lack of functional antibody against the fusion protein.     

Severe pandemic 2009 H1N1 influenza disease due to pathogenic immune complexes

Pandemic influenza viruses often cause severe disease in middle-aged adults without preexisting comorbidities. The mechanism of illness associated with severe disease in this age group is not well understood. Here we find preexisting serum antibodies that cross-react with, but do not protect against, 2009 H1N1 influenza virus in middle-aged adults. Nonprotective antibody is associated with immune complex-mediated disease after infection. We detected high titers of serum antibody of low avidity for H1-2009 antigen, and low-avidity pulmonary immune complexes against the same protein, in severely ill individuals. Moreover, C4d deposition--a marker of complement activation mediated by immune complexes--was present in lung sections of fatal cases. Archived lung sections from middle-aged adults with confirmed fatal influenza 1957 H2N2 infection revealed a similar mechanism of illness. These observations provide a previously unknown biological mechanism for the unusual age distribution of severe cases during influenza pandemics.     

Age Is a Critical Risk Factor for Severe Fever with Thrombocytopenia Syndrome

Background

Severe Fever with Thrombocytopenia Syndrome (SFTS) is an emerging infectious disease in East Asia. SFTS is a tick borne hemorrhagic fever caused by SFTSV, a new bunyavirus named after the syndrome. We investigated the epidemiology of SFTS in Laizhou County, Shandong Province, China.

Methods

We collected serum specimens of all patients who were clinically diagnosed as suspected SFTS cases in 2010 and 2011 in Laizhou County. The patients'' serum specimens were tested for SFTSV by real time fluorescence quantitative PCR (RT-qPCR). We collected 1,060 serum specimens from healthy human volunteers by random sampling in Laizhou County in 2011. Healthy persons'' serum specimens were tested for specific SFTSV IgG antibody by ELISA.

Results

71 SFTS cases were diagnosed in Laizhou County in 2010 and 2011, which resulted in the incidence rate of 4.1/100,000 annually. The patients ranged from 15 years old to 87 years old and the median age of the patients were 59 years old. The incidence rate of SFTS was significantly higher in patients over 40 years old and fatal cases only occurred in patients over 50 years old. 3.3% (35/1,060) of healthy people were positive to SFTSV IgG antibody. The SFTSV antibody positive rate was not significantly different among people at different age groups.

Conclusion

Our results revealed that seroprevalence of SFTSV in healthy people in Laizhou County was not significantly different among age groups, but SFTS patients were mainly elderly people, suggesting that age is the critical risk factor or determinant for SFTS morbidity and mortality.     

Invasive meningococcal disease associated with a very high case fatality rate in the North-West of Poland

The aim of the study was to investigate invasive meningococcal disease in the North-West of Poland, associated with a case fatality rate of 42.9%, where among the first 11 cases, eight had fatal outcome. All fatal cases were diagnosed as fulminant meningococcal severe sepsis with Waterhouse-Friderichsen syndrome and disseminated intravascular coagulation. Serotyping and pulsed-field gel electrophoresis analysis revealed that the high case fatality rate was not associated with the dissemination of one epidemic clone. However, six cases, all with good outcomes, were caused by C:2b:(P1.2,P1.5) isolates of the same pulsed-field gel electrophoresis type belonging to ST8 complex/Cluster A4.     

TNF-α Acts as an Immunoregulator in the Mouse Brain by Reducing the Incidence of Severe Disease Following Japanese Encephalitis Virus Infection

Japanese encephalitis virus (JEV) causes acute central nervous system (CNS) disease in humans, in whom the clinical symptoms vary from febrile illness to meningitis and encephalitis. However, the mechanism of severe encephalitis has not been fully elucidated. In this study, using a mouse model, we investigated the pathogenetic mechanisms that correlate with fatal JEV infection. Following extraneural infection with the JaOArS982 strain of JEV, infected mice exhibited clinical signs ranging from mild to fatal outcome. Comparison of the pathogenetic response between severe and mild cases of JaOArS982-infected mice revealed increased levels of TNF-α in the brains of severe cases. However, unexpectedly, the mortality rate of TNF-α KO mice was significantly increased compared with that of WT mice, indicating that TNF-α plays a protective role against fatal infection. Interestingly, there were no significant differences of viral load in the CNS between WT and TNF-α KO mice. However, exaggerated inflammatory responses were observed in the CNS of TNF-α KO mice. Although these observations were also obtained in IL-10 KO mice, the mortality and enhanced inflammatory responses were more pronounced in TNF-α KO mice. Our findings therefore provide the first evidence that TNF-α has an immunoregulatory effect on pro-inflammatory cytokines in the CNS during JEV infection and consequently protects the animals from fatal disease. Thus, we propose that the increased level of TNF-α in severe cases was the result of severe disease, and secondly that immunopathological effects contribute to severe neuronal degeneration resulting in fatal disease. In future, further elucidation of the immunoregulatory mechanism of TNF-α will be an important priority to enable the development of effective treatment strategies for Japanese encephalitis.     

Disease characteristics and serological responses in patients with differing severity of COVID-19 infection: A longitudinal cohort study in Dhaka,Bangladesh

BackgroundCOVID-19 caused by SARS-CoV-2 ranges from asymptomatic to severe disease and can cause fatal and devastating outcome in many cases. In this study, we have compared the clinical, biochemical and immunological parameters across the different disease spectrum of COVID-19 in Bangladeshi patients.Methodology/Principal findingsThis longitudinal study was conducted in two COVID-19 hospitals and also around the community in Dhaka city in Bangladesh between November 2020 to March 2021. A total of 100 patients with COVID-19 infection were enrolled and classified into asymptomatic, mild, moderate and severe cases (n = 25/group). In addition, thirty age and sex matched healthy participants were enrolled and 21 were analyzed as controls based on exclusion criteria. After enrollment (study day1), follow-up visits were conducted on day 7, 14 and 28 for the cases.Older age, male gender and co-morbid conditions were the risk factors for severe COVID-19 disease. Those with moderate and severe cases of infection had low lymphocyte counts, high neutrophil counts along with a higher neutrophil-lymphocyte ratio (NLR) at enrollment; this decreased to normal range within 42 days after the onset of symptom. At enrollment, D-dimer, CRP and ferritin levels were elevated among moderate and severe cases. The mild, moderate, and severe cases were seropositive for IgG antibody by day 14 after enrollment. Moderate and severe cases showed significantly higher IgM and IgG levels of antibodies to SARS-CoV-2 compared to mild and asymptomatic cases.Conclusion/SignificanceWe report on the clinical, biochemical, and hematological parameters associated with the different severity of COVID-19 infection. We also show different profile of antibody response against SARS-CoV-2 in relation to disease severity, especially in those with moderate and severe disease manifestations compared to the mild and asymptomatic infection.