Thedi Ziegler

Burden of Influenza in Children in the Community

BACKGROUND Influenza vaccination of healthy children is encouraged because children are frequently hospitalized for influenza-attributable illnesses. However, most children with influenza are treated as outpatients, and scarce data are available on the burden of influenza in these children. METHODS We performed a prospective study of respiratory infections in preenrolled cohorts of children < or = 13 years old during 2 consecutive respiratory seasons (2231 child-seasons of follow-up). At any sign of respiratory infection, we examined the children and obtained a nasal swab for the detection of influenza. The parents filled out daily symptom diaries. Of all the enrollees, 94% remained active participants in the study. RESULTS The average annual rate of influenza was highest (179 cases/1000 children) among children < 3 years old. Acute otitis media developed as a complication of influenza in 39.7% of children < 3 years old. For every 100 influenza-infected children < 3 years old, there were 195 days of parental work loss (mean duration, 3.2 days). CONCLUSIONS Influenza causes a substantial burden of illness on outpatient children and their families. Vaccination of children < 3 years old might be beneficial for reducing the direct and indirect costs of influenza in children.

Influenza A and B Virus Infections in Children

To obtain data on the clinical manifestations of infection, the age distribution, and the underlying conditions of children with influenza severe enough to lead to hospital referral, we performed a retrospective study of children treated at Turku University Hospital (Turku, Finland) in 1980-1999. Influenza A or B antigen was detected in the nasopharyngeal aspirates of 683 of the 15,420 children studied. The median age of children with influenza A was 2.0 years (n=544), and that of children with influenza B was 4.2 years (n=139) (P<.001). One-fourth of the children had an underlying medical condition. High fever, cough, and rhinorrhea were the most frequently recorded symptoms. Acute otitis media developed in 24% of the children, and pneumonia developed in 9% of the children. The study shows that the majority of patient hospitalizations for pediatric influenza involve previously healthy infants and young children. Laboratory confirmation of influenza is particularly important for children because the clinical presentation of the infection is less characteristic than that seen in adults.

Pandemic H1N1 2009 Influenza A Virus Induces Weak Cytokine Responses in Human Macrophages and Dendritic Cells and Is Highly Sensitive to the Antiviral Actions of Interferons

ABSTRACT In less than 3 months after the first cases of swine origin 2009 influenza A (H1N1) virus infections were reported from Mexico, WHO declared a pandemic. The pandemic virus is antigenically distinct from seasonal influenza viruses, and the majority of human population lacks immunity against this virus. We have studied the activation of innate immune responses in pandemic virus-infected human monocyte-derived dendritic cells (DC) and macrophages. Pandemic A/Finland/553/2009 virus, representing a typical North American/European lineage virus, replicated very well in these cells. The pandemic virus, as well as the seasonal A/Brisbane/59/07 (H1N1) and A/New Caledonia/20/99 (H1N1) viruses, induced type I (alpha/beta interferon [IFN-α/β]) and type III (IFN-λ1 to -λ3) IFN, CXCL10, and tumor necrosis factor alpha (TNF-α) gene expression weakly in DCs. Mouse-adapted A/WSN/33 (H1N1) and human A/Udorn/72 (H3N2) viruses, instead, induced efficiently the expression of antiviral and proinflammatory genes. Both IFN-α and IFN-β inhibited the replication of the pandemic (H1N1) virus. The potential of IFN-λ3 to inhibit viral replication was lower than that of type I IFNs. However, the pandemic virus was more sensitive to the antiviral IFN-λ3 than the seasonal A/Brisbane/59/07 (H1N1) virus. The present study demonstrates that the novel pandemic (H1N1) influenza A virus can readily replicate in human primary DCs and macrophages and efficiently avoid the activation of innate antiviral responses. It is, however, highly sensitive to the antiviral actions of IFNs, which may provide us an additional means to treat severe cases of infection especially if significant drug resistance emerges.

Early Oseltamivir Treatment of Influenza in Children 1–3 Years of Age: A Randomized Controlled Trial

BACKGROUND Oseltamivir provides modest clinical benefits to children with influenza when started within 48 hours of symptom onset. The effectiveness of oseltamivir could be substantially greater if the treatment were started earlier during the course of the illness. METHODS We carried out a randomized, double-blind, placebo-controlled trial of the efficacy of oseltamivir started within 24 hours of symptom onset in children 1-3 years of age with laboratory-confirmed influenza during the seasons of 2007-2008 and 2008-2009. Eligible children received either orally administered oseltamivir suspension or a matching placebo twice daily for 5 days. The children received clinical examinations, and the parents filled out detailed symptom diaries for 21 days. RESULTS Of 408 randomized children who received the study drug (oseltamivir, 203, and placebo, 205), 98 had laboratory-confirmed influenza (influenza A, 79, and influenza B, 19). When started within 12 hours of the onset of symptoms, oseltamivir decreased the incidence of acute otitis media by 85% (95% confidence interval, 25%-97%), but no significant reduction was observed with treatment started within 24 hours. Among children with influenza A, oseltamivir treatment started within 24 hours shortened the median time to resolution of illness by 3.5 days (3.0 vs 6.5 days; P = .006) in all children and by 4.0 days (3.4 vs 7.3; P = .006) in unvaccinated children and reduced parental work absenteeism by 3.0 days. No efficacy was demonstrated against influenza B infections. CONCLUSIONS Oseltamivir treatment started within 24 hours of symptom onset provides substantial benefits to children with influenza A infection. Clinical trials registration. ClinicalTrials.gov identifier: NCT00593502.

Respiratory virus infection as a cause of prolonged symptoms in acute otitis media

We studied respiratory viruses in 22 children with acute otitis media who had failed to improve after at least 48 hours of antimicrobial therapy. The mean duration of preenrollment antimicrobial therapy was 4.8 days. For comparison we studied 66 children with newly diagnosed acute otitis media. Respiratory viruses were isolated from middle ear fluid or from the nasopharynx, or both, significantly more often in the patients unresponsive to initial antimicrobial therapy than in the comparison patients (68% vs 41%, p less than 0.05). Viruses were recovered from the middle ear fluid in 32% of the study patients and from 15% of the comparison group. Bacteria were isolated from the middle ear fluid of four (18%) children in the study group; one child had an isolate resistant to initial antimicrobial therapy. All four children with bacteria in the middle ear fluid had evidence of concomitant respiratory virus infection. Our results indicate that respiratory virus infection is often present in patients with acute otitis media unresponsive to initial antimicrobial therapy, and may explain the prolongation of symptoms of infection. Resistant bacteria seem to be a less common cause of failure of the initial treatment.

Accuracy of Clinical Diagnosis of Influenza in Outpatient Children

In a prospective study, children < or =13 years of age with respiratory infections were examined. At each visit, a nasal swab specimen was obtained for the detection of influenza, and the physician recorded his or her opinion on whether the child had influenza. Among 2288 infections, the overall sensitivity of the clinical diagnosis of influenza was 38% and the positive predictive value was 32%.

Impact of Influenza B Lineage-level Mismatch between Trivalent Seasonal Influenza Vaccines and Circulating Viruses, 1999-2012

BACKGROUND Influenza B virus strains in trivalent influenza vaccines are frequently mismatched to the circulating B strains, but the population-level impact of such mismatches is unknown. We assessed the impact of vaccine mismatch on the epidemiology of influenza B during 12 recent seasonal outbreaks of influenza in Finland. METHODS We analyzed all available nationwide data on virologically confirmed influenza infections in all age groups in Finland between 1 July 1999 and 30 June 2012, with the exclusion of the pandemic season of 2009-2010. We derived data on influenza infections and the circulation of different lineages of B viruses during each season from the Infectious Diseases Register and the National Influenza Center, National Institute for Health and Welfare, Finland. RESULTS A total of 34 788 cases of influenza were recorded. Influenza A accounted for 74.0% and influenza B for 26.0% of all typed viruses. Throughout the 12 seasons, we estimated that 41.7% (3750 of 8993) of all influenza B infections were caused by viruses representing the other genetic lineage than the one in the vaccine. Altogether, opposite-lineage influenza B viruses accounted for 10.8% of all influenza infections in the population, the proportion being highest (16.8%) in children aged 10-14 years and lowest (2.6%) in persons aged ≥70 years. CONCLUSIONS The population-level impact of lineage-level mismatch between the vaccine and circulating strains of influenza B viruses is substantial, especially among children and adolescents. The results provide strong support for the inclusion of both influenza B lineages in seasonal influenza vaccines.

Viral Etiology of Common Cold in Children, Finland

To the Editor: The common cold is regarded as a viral disease. In the first years of the 21st century, several new respiratory viruses have been identified, such as human metapneumovirus (hMPV), coronaviruses NL63 and HKU1, and human bocavirus (HBoV). Many studies have addressed the role of these viruses in hospital settings, but few studies have been conducted among outpatients. We examined the etiology of the common cold in young children who were newly symptomatic but had no need of hospital care. We hypothesized that the etiology could be detected in all cases by using modern diagnostics that test for 16 viruses in outpatients. Between February 1996 and April 1998, we collected nasopharyngeal aspirate samples in an outpatient setting from 194 Finnish children having newly onset (<48 h) symptoms of common cold but no acute otitis media (AOM) or other symptoms demanding antimicrobial therapy (1). The mean age of the study population was 2.1 years (range 0.7–3.9 years), and 81% attended day care. The parents of all participants gave written informed consent, and the study protocol was approved by the Ethics Committee of Turku University Hospital in Turku, Finland. The nasopharyngeal aspirate samples were processed freshly for antigen detection (respiratory syncytial virus [RSV]; parainfluenza viruses 1, 2, and 3; influenza A and B viruses; and adenovirus) by time-resolved fluoroimmunoassay (2). Stored samples were subjected to nucleic acid testing (NAT) for picornaviruses; RSV; coronaviruses 229E, OC43, NL63, and HKU1; influenza C virus; HBoV; hMPV; and adenovirus. Recently, these samples were reanalyzed for rhinovirus and enterovirus using real-time PCR for the amplification step (1,3–6). At least 1 respiratory virus was detected in 179 (92%) of 194 children. Rhinovirus was the most common respiratory virus, found in 138 (71%) children (Table). Other viruses were found in varying proportions: HBoV was present in 27 (14%) children; adenovirus was found in 23 (12%) (3 were positive by antigen detection, and 23 by NAT); enterovirus was present in 20 (10%); coronaviruses were found in 11 (6%) (NL63:7; HKU1:2; 229E/OC43:2); influenza viruses were present in 11 (6%) (A:4; B:1; C:6); RSV was shown in 8 (4%) (all were positive by antigen detection and NAT); parainfluenza viruses were present in 7 (4%) (1:1; 3:6); and hMPV was found in 3 (2%). The Table shows the concomitant occurrence of all viruses. Among children with a positive viral finding, 46 (26%) had 2 viruses, and 10 (6%) had 3 or 4 viruses concomitantly. The viruses occurring most frequently with other viruses were adenovirus (100%), HBoV (81%), and enterovirus (75%). Table Positive viral findings in 194 children with newly onset uncomplicated common cold, Finland, 1996–1998 Although our diagnostic panel was incomplete, lacking parechoviruses and parainfluenza type 4 virus, we detected >1 respiratory viruses in 92% of the children who had a common cold. As expected, rhinovirus was the leading cause of the common cold in these children. The role of picornaviruses was also emphasized by the abundance of enteroviruses. Enterovirus has gained attention mainly in severe infections, e.g., meningoencephalitis, and is rarely included in diagnostics for respiratory infections. However, PCR has shown that enterovirus commonly causes upper and lower respiratory infections that may be complicated by AOM or expiratory wheezing (4,7). Thus, enterovirus should be included in the diagnostic panels of respiratory infections. HBoV was the second most prevalent virus in our study population. Since its discovery in 2005, HBoV positivity has been reported in 3%–19% of different study populations (8). Its pathogenic role has been questioned because most HBoV cases are co-infections with other viruses (8), and 81% of those testing positive for HBoV in our study had co-infections. However, adenovirus and enterovirus reached similar co-infection frequencies, likely because of prolonged postinfection viral shedding of these agents. HBoV–specific immunoglobulin (Ig) M and IgG antibody responses were recently reported in children with wheezing, suggesting that HBoV induces a systemic infection and is probably a true causative agent of lower respiratory tract disease (9). Our study indicates that HBoV may also be a common cause of common cold in young children. However, we found hMPV, coronaviruses NL63 and HKU1, and influenza C virus in 1%–4% of the children, suggesting that these viruses play a minor role in childhood common cold. Our study may underestimate the role of RSV and hMPV because we excluded children with AOM, which is frequently related to these viruses. Multiple viral findings were common in our study, and 3 children had 4 viruses concomitantly, a logical finding because young children are constantly exposed to respiratory viruses, especially if they attend day care. A recent follow-up study showed that almost all viral findings were related to symptoms, thus supporting the argument that most, if not all, viruses are causative agents (10). A possible causative agent of the common cold can be found in nearly all children who have a cold, and rhinovirus is the leading causative agent. In our study, HBoV was also found frequently, but the recently discovered viruses hMPV and coronaviruses NL63 and HKU1 played a minor role in the common cold of young children.

Rhinovirus in acute otitis media

Low positive results were somewhat easier to distinguish by EIA than LA, because the minimal color change produced in the EIA was more apparent than the few agglutinated latex particles in the LA test. However, some of the low positive Abbott Testpack Strep A and Cards Strep A plus and minus endpoints had an irregularly or partially filled vertical line that was neither clearly positive nor clearly negative, making interpretation difficult. The Icon Strep A tests resulted in the presence or absence of a clearly outlined central dot on a white background, giving unequivocal results, with only minimal experience required for interpretation.

Minor Changes in the Hemagglutinin of Influenza A(H1N1)2009 Virus Alter Its Antigenic Properties

Background The influenza A(H1N1)2009 virus has been the dominant type of influenza A virus in Finland during the 2009–2010 and 2010–2011 epidemic seasons. We analyzed the antigenic characteristics of several influenza A(H1N1)2009 viruses isolated during the two influenza seasons by analyzing the amino acid sequences of the hemagglutinin (HA), modeling the amino acid changes in the HA structure and measuring antibody responses induced by natural infection or influenza vaccination. Methods/Results Based on the HA sequences of influenza A(H1N1)2009 viruses we selected 13 different strains for antigenic characterization. The analysis included the vaccine virus, A/California/07/2009 and multiple California-like isolates from 2009–2010 and 2010–2011 epidemic seasons. These viruses had two to five amino acid changes in their HA1 molecule. The mutation(s) were located in antigenic sites Sa, Ca1, Ca2 and Cb region. Analysis of the antibody levels by hemagglutination inhibition test (HI) indicated that vaccinated individuals and people who had experienced a natural influenza A(H1N1)2009 virus infection showed good immune responses against the vaccine virus and most of the wild-type viruses. However, one to two amino acid changes in the antigenic site Sa dramatically affected the ability of antibodies to recognize these viruses. In contrast, the tested viruses were indistinguishable in regard to antibody recognition by the sera from elderly individuals who had been exposed to the Spanish influenza or its descendant viruses during the early 20th century. Conclusions According to our results, one to two amino acid changes (N125D and/or N156K) in the major antigenic sites of the hemagglutinin of influenza A(H1N1)2009 virus may lead to significant reduction in the ability of patient and vaccine sera to recognize A(H1N1)2009 viruses.