Children are more likely than other age groups to become infected with influenza A and B at times when these viruses are circulating,1 with one-third of infants typically becoming infected in their first year of life.2 This translates into a substantial demand for healthcare resources; in the United States, for example, infants 6 to 23 months account for considerably more influenza-related outpatient clinics and emergency department visits than older children.3,4 Influenza also causes many young children to be hospitalized, and infants in their first year of life are more likely to need hospital treatment than older children.5–7 Mortality rates in infants 0 to 6 months are more than 4 times higher than those in older children and adolescents.8 Vaccination affords substantial protection against influenza in young children, but is not recommended for infants <6 months.9 Uptake of influenza vaccination in the very young is low–only 21% of children 6 to 23 months across 8 US sites were fully vaccinated in a recent survey10 and only 7% of all children in Spain.11
The antiviral agent oseltamivir (Tamiflu, F. Hoffmann-La Roche Ltd, Switzerland) is widely approved for use in children 1 to 12 years, and is an effective intervention for the treatment and prophylaxis of influenza in this group.12,13 The emergence of pandemic (H1N1) 2009 has also led to approval in Europe and Emergency Use Authorization in the United States of oseltamivir for treatment of infants <1 year with pandemic influenza.14–18 Two Japanese groups have published brief retrospective reports of their experience of treating influenza with oseltamivir in infants in the first year of life. The larger of the 2 case series, in which oseltamivir was given to 103 infants, found no evidence of encephalopathy but did not report any other outcomes.19 In the smaller series (47 infants), adverse events were rare and serious complications absent, and fever duration was significantly shorter than in untreated controls 1 to 15 years old.20
This article reports a retrospective analysis of oseltamivir in infants <1 year with influenza in a European teaching hospital during a 5-year period.
MATERIALS AND METHODS
The current study is a retrospective analysis of the medical records of infants <1 year at diagnosis who were admitted to a major German teaching hospital (Klinikum Worms, Worms) during 5 consecutive influenza seasons (2003–2007). The aim of the study was to evaluate clinical presentation as well as the clinical outcome and safety of oseltamivir therapy. Infants were included if they presented with influenza-like symptoms of sudden onset, either with fever (body temperature [measured rectally] >38°C; with or without focus) or without fever but contact with influenza cases in the family. Influenza was confirmed by rapid influenza test (Influenza A/B Rapid Test, Roche Diagnostics, Mannheim, Germany) of throat swab samples. If the test result was positive for influenza and the severity of illness warranted hospitalization, parents were offered the option of off-label treatment with oseltamivir for their child, commencing within 48 hours of symptom onset. In line with hospital policy, no child started treatment later than 48 hours after symptom onset. In subjects for whom parental consent was given, the dosage of oseltamivir was 2 mg/kg of body weight twice daily for 5 days. Infants who were vaccinated against influenza or receiving immunosuppressants were excluded.
For each infant included in the study, data were collected on demographics, clinical history, symptoms and findings from physical examination, results of laboratory tests (at admission and afterward), other therapeutic interventions, and the clinical course during the hospital stay. Tolerability of oseltamivir was evaluated from the frequency of side-effects emerging after oseltamivir had started and treatment efficacy assessed by the duration of fever from the time that treatment started.
Patient Characteristics on Admission
In total, 157 eligible infants were included in the analysis (Table, Supplemental Digital Content 1, http://links.lww.com/INF/A349). The mean age of the patient group was 6.3 months and slightly more boys than girls were included. Comorbidities were uncommon (<10%). Most (75%) infants were admitted from the emergency outpatient department. No infants had received influenza vaccination, but 72% of infants had received at least one routine childhood vaccination. Most infants had been ill with fever at admission for less than 24 hours (Fig. 1).
Signs and Symptoms on Admission
The mean temperature on admission for all infants was 38.8°C (range: 36.4°–40.5°C), and 140 infants (90%) had a temperature of ≥38°C (Fig., Supplemental Digital Content 2, http://links.lww.com/INF/A350). Of the remaining 17 patients, fever had abated in 15 infants whose parents had administered antipyretics, and body temperature was not documented in 2 other infants. A range of signs and symptoms other than fever were also recorded at admission, most commonly (in >10% of infants): rhinitis (85%), pharyngitis (84%), cough (66%), feeding difficulties (40%), otitis media (25%), rattling sounds (rales) (20%), conjunctivitis (18%), and vomiting (16%) (Table, Supplemental Digital Content 3, http://links.lww.com/INF/A351). In 7 of 10 infants who were receiving antibiotics at admission for infections such as pneumonia or otitis media, these drugs were discontinued after influenza had been confirmed.
Laboratory Findings at Admission
Selected blood chemistry and hematology results are shown in Table 1. Five infants had C-reactive protein concentrations of >50 mg/L on admission, associated with coexisting infections such as pneumonia and meningitis. Leukocyte count was 5000/μL or less in 25 infants (16%) and more than 15,000/μL in 19 infants (12%), with leukocytosis being evident in 1 infant (a count of 52,000/μL). Abnormal results on urinalysis were recorded in 25 infants (16%), for example proteinuria, acetonuria, or leukocyturia.
In 19 infants whose condition deteriorated during treatment, C-reactive protein was retested: it was raised in 4 infants (to >50 mg/L in 3), lower in 5, and unchanged in 10. Follow-up urinalysis tests were normal in all except one infant with confirmed urinary Escherichia coli infection.
All infants completed the 5-day course of treatment except one in whom therapy was stopped following repeated vomiting after dosing. During oseltamivir therapy, additional symptoms (not seen at initial presentation) were observed in 78 infants (50%). Most of these were gastrointestinal, namely vomiting (62 infants; 39%), which was more common after the first oseltamivir dose, and diarrhea (34; 22%)–these 2 events were mild in intensity and no medical intervention was needed. In 11 (7%) infants, infectious gastroenteritis was proven: rotavirus was found in the stool samples of 10 infants and Salmonella in one other. Other adverse behaviors and symptoms were refusal to feed (6 cases), restlessness (6), exanthema (4), and sensitivity to touch (2).
During the course of hospitalization, one or more complications were diagnosed in 84 (54%) infants. The most common of these was nutritional difficulties, diagnosed in 41 infants of whom 24 required intravenous fluids. Other diagnosed complications seen in more than 2% of infants were conjunctivitis (13; 8%), pneumonia and bronchitis (each in 9 [6%] infants), and febrile convulsions (7 [4%] cases on admission and before the initiation of oseltamivir therapy). After admission, an additional 10 infants (6%) started treatment with antibiotics for secondary infections (pneumonia, 4; otitis media, 2; meningitis, sepsis, streptococcal angina and paronychia, 1 each).
Because most infants presented at the hospital quickly after onset of influenza-like symptoms, 141 (90%) infants started oseltamivir treatment within 24 hours of symptom onset. The remaining infants started oseltamivir within 48 hours of symptom onset. Body temperature fell to ≤38°C in 128 (82%) infants within 36 hours of the start of treatment and in a further 8 (5%) within 48 hours (Fig. 1). As measured from the start of fever symptoms, the duration of fever (the time taken for body temperature to fall to ≤38°C) was 48 hours or less in 102 (65%) infants.
Oseltamivir is an effective and well-tolerated antiviral that is widely approved for the treatment and prophylaxis of influenza in children 1 to 12 years. Experience in infants <1 year is more limited, but health authorities in Europe and the United States have recently authorized the use of oseltamivir for the treatment of pandemic (H1N1) 2009 influenza in this patient group.14–18 Our analysis of clinical characteristics and response to treatment in a series of infants <1 year who received a 5-day course of oseltamivir according to our center's treatment protocol and with the informed consent of parents provides useful indicators of the utility of this antiviral agent in this vulnerable age group.
In this large retrospective analysis, one of our main findings is the similar initial clinical presentation in infants <1 year and older children. These children commonly presented with pharyngitis, rhinitis and cough in addition to fever, but during the course of disease and oseltamivir treatment, a higher incidence of vomiting (39%) and diarrhea (22%) was observed than in a large study of 695 infants and children aged 1 to 12 years (incidences of 14.3% and 8.8%, respectively).12 In that study, vomiting was the only adverse event to be reported with a higher frequency than placebo (8.5%).12 In the current analysis, vomiting was most often seen after the first dose of drug, and subsequent doses were better tolerated. It is possible that this extent of vomiting and diarrhea is due to the influenza infection itself, but interpretation of this finding in the absence of a control group is difficult. Diarrhea was recorded in only one of a cohort of 47 Japanese children aged <1 year who received oseltamivir.15 There are several possible reasons for the higher rates of gastrointestinal events that we observed. First, the clinical presentation of influenza may differ among geographical areas according to the specific viral strains in circulation. Second, 11 children were positive for another infectious agent (rotavirus or Salmonella) that may have caused the gastrointestinal symptoms. Because we did not test for other viruses that can cause gastroenteritis, in particular norovirus (which is increasingly epidemiologically relevant) and adenovirus, we cannot exclude the possibility that vomiting and diarrhea might have been attributable to other infectious agents.
Disorders of central nervous system function have been reported in some influenza patients receiving oseltamivir, particularly in Japan.21 Such events are more prevalent in children <5 years,22 but the etiology of these events is still uncertain, given that influenza infection itself is associated with central nervous system disorders.23 In our study, convulsions that were initially noted in 7 cases at admission did not reoccur after the start of oseltamivir therapy. Reduced awareness was initially observed in 6 patients, but not seen in any patient during oseltamivir therapy. Restlessness was seen in 7 patients at admission, and noted in 6 patients after the start of therapy, one of whom had sepsis-like-illness and another had meningococcal meningitis. Consistent with our findings, retrospective analysis of a series of 103 infants aged <1 year treated with oseltamivir in Japanese hospitals did not find any signs of encephalopathy.19
Feeding difficulties were evident in 40% of the individuals in this study on admission, and these persisted during treatment in just over one-quarter of the infants. We also found some of the complications of influenza typically seen in older children, notably lower respiratory tract infections (pneumonia or bronchitis) in 11% and conjunctivitis in 8%. Although the most common infective complication in children with influenza is otitis media, which is found in approximately 20% of children <15 years,12,23,24 this was rare in the infants in our study, being recorded in only 4 (2%). Ten infants were receiving antibiotics at the time of admission to hospital; these drugs were discontinued in 7 infants who had respiratory symptoms. Subsequently, 10 additional infants received antibiotics, most commonly for pneumonia or otitis media.
Although our study was limited by the lack of a control group, the resolution of fever in these infants gave some indication of the efficacy of a 5-day course of oseltamivir. Fever resolved in less than 48 hours in 87% of the infants in our study, a result similar to that in the study by Whitley et al,12 in which median fever duration was 44 hours in infants and children 1 to 12 years treated with oseltamivir. In a retrospective analysis of Japanese children, mean fever duration in a series of 47 infants <1 year who received oseltamivir was 2.7 days, very similar to the 2.5 days in treated controls 1 to 15 years and significantly shorter than the 4.2 days in untreated controls also 1 to 15 years (P < 0.0001).20
In this study, all infants received oseltamivir twice daily for 5 days at a dose of 2 mg/kg of body weight. In Europe, this dose has recently been approved for use in infants 0- to 1-month-old, while twice-daily doses of 2.5 mg/kg are recommended for infants >1 to 3 months, and 3 mg/kg for infants >3 to 12 months.16 In the United States, approved twice-daily doses are 12 mg for infants <3 months, 20 mg for infants 3 to 5 months, and 25 mg for infants 6 to 11 months.18
This is the largest reported series of children <1-year-old treated with oseltamivir for influenza. The comparison of our findings with previously published data in older children suggests that oseltamivir has an acceptable tolerability profile and seems efficacious for the treatment of influenza in infants <1-year-old, a group who are at particularly high risk of hospitalization. This hypothesis warrants further testing in prospective, controlled studies.
The authors thank Prof. H. Schroten and Dr. T. Tenenbaum (University Children's Hospital, Mannheim, Germany) for carefully reading the manuscript and the helpful discussions. Medical writing and editorial assistance for the development of this article were provided by Roger Nutter and Scott Malkin at Gardiner-Caldwell Communications, Macclesfield, UK.
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