Clinical and Etiological Study of Influenza Like Illness Outbreak in Children: An Office-Based Study

Introduction

Manifestations of Influenza viral infections in children are similar to many other respiratory viruses such as parainfluenza, Respiratory syncitial virus (RSV), rhinovirus and adenovirus.¹ A broadly encompassing term, Influenza like illness (ILI) is used to describe them for clinical and epidemiological purposes.² It is important to distinguish between influenza and other viral etiologies as only the former has specific antiviral therapy.

After waning of second COVID wave and emergence of influenza season, we saw an outbreak of ILI in outpatient and indoor.

The study aimed to ascertain proportions of influenza and non-influenza viruses in severe ILI. We also attempted to study clinical or epidemiological patterns differentiating between influenza and non-influenza etiologies of ILI.

Resurgence of RSV infections was predicted in the literature after waning of COVID-19 wave.³ Expecting dominant RSV circulation this year, we decided to test the children presenting with ILI with viral panel which included only influenza A, B and RSV, thereby reducing the cost and turnaround time.

Study question

What is the relative contribution of influenza A, B and RSV in children presenting with severe ILI?

Type of study

Case control study.

Material and Methods

The study was conducted among patients recruited from a single pediatric practice. All patients presenting with ILI with persistent and increasing severity of illness with at least three days of initial symptoms were included; ILI-category C4 were offered testing for influenza viral panel. The patients who underwent polymerase chain reaction (PCR) test were enrolled for the study. Their clinico-epidemiological features were entered in a proforma. The study was continued till no severe ILI cases and positive PCR results were observed for at least two consecutive weeks. This was assumed to be the endpoint of the outbreak. Some of these patients were also tested for COVID-19 RT-PCR (Reverse transcriptase polymerase chain reaction) as per administration policy or clinical suspicion.

Microbiological methods

Nasopharyngeal swabs were collected in 3 mL Viral Transport medium (VTM) and transported to molecular laboratory following standard biosafety measures. All samples were processed using Cepheid Xpert Xpress Flu/RSV Assay on the GeneXpert Instrument Systems. This is an automated multiplex real-time, reverse transcriptase polymerase chain reaction (RT-PCR) assay for qualitative detection and differentiation of Influenza A, Influenza B and Respiratory Syncytial virus (RSV) viral RNA. The assay detects unique sequences in the genes that encode influenza A matrix (M), influenza A basic polymerase (PB2), influenza A acidic protein (PA), influenza B matrix (M), influenza B non-structural protein (NS), and the RSV A and RSV B nucleocapsid. Each test was performed using a single use disposable cartridge that contains target- specific reagents and in built controls.

Informed consent and institutional ethical committee approvals were obtained.

Proportion of ILI due to influenza A and B, RSV were determined from this cohort.

Clinical data of children who tested positive for RSV was compared with children who were positive with influenza.

Sample size calculation

Assuming a null hypothesis that there is no difference in the proportion of influenza and RSV in patients presenting with severe ILI, with confidence level of 95% and power to detect 0.90, the total sample size calculated was 96.

Definitions for the study

ILI: Fever with cough in preceding 10 days (WHO)¹

Severe ILI: Patients with severe symptoms or with worsening clinical course after 72 hours of illness.⁵

Upper respiratory tract infection (URTI): Clinical syndrome with fever and rhinitis or pharyngeal congestion with or without cough.

Lower respiratory tract infection (LRTI): Clinical syndrome with fever with cough and increased respiratory rate or wheezing.

Family history: Presence of febrile or non-febrile respiratory illness in immediate contact of the patients in the past 15 days.

Results

This year we saw an outbreak of ILI in the third week of June. We started enrolling patients for the study from 27^th of June. The study lasted till 21st of October.

Clinico-epidemiological data

A total 112 cases with severe ILI were seen, which included 41 girls and 71 boys. Average age in completed months was 51 months with a range of 0-187 months (Median - 38 months).

Average duration of fever when the tests were advised was 4.056 days.

Around 51 patients had only URTI while 48 patients had LRTI. Wheeze was documented in 21 patients at the time of presentation. Around 18 patients presented with associated gastrointestinal symptoms, while 10 patients showed associated neurological symptoms (convulsions 2, giddiness 2, delirium1, drowsiness 3, myositis 2).

Around 59 of these patients were treated on Outpatient basis, while 53 patients were hospitalized. Eight of the hospitalized patients needed intensive care.

PCR results

Out of the 112 children, 100 children showed positive PCR result for either influenza or RSV. 62 (55.35%) were detected RSV positive, while 40 (35.7%) were positive for influenza viruses. Out of 64 patients tested for Severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), three patients (4.68%) tested positive. Nine tested negative for all the viruses. Co-infection of RSV and influenza B was detected in two patients.

Influenza A and B was detected in 22 and 18 cases, respectively.

Month-wise distribution of ILI cases demonstrated a peak in the month of July with gradual tapering of the outbreak in subsequent three months. Both RSV and Influenza A peaked in the month of July. Influenza B activity was seen later in the outbreak (Figure 1).

Influenza was significantly more common in children above six years of age. In younger children less than 3 years of age, RSV was common (Table 1).

The risk of getting hospitalized, including the need for intensive care was not different for both etiologies (Table 2).

*In OPD, there were two co-infections. All negative one in each group. Chi square test (done for influenza and RSV etiologies) not significant X(1,102) =1.4322, p value .488542

Analysis of clinical presentation suggested that in a child presenting with only URTI, RSV infection was nearly three times less likely than Influenza (OR 0.353, p=0.0003). LRTI and wheeze were more likely in RSV (odds ratio 1.21 and 3.68 respectively, p <0.0001) (Table 3).

Family history was positive in 46.77% of RSV cases and 57.14% of influenza cases. This difference was not statistically significant (Difference in risk 0.13, p=0.1515, ns). All the three children with SARS -COV2 had positive family history.

Discussion

Influenza like illness is commonly seen during outbreaks around monsoon season. We conducted our study in ILI-category C (severely ill children) for ethical, practical and scientific reasons. Mild cases would not need such a test in clinical practice. Our viral panel showed 89.28% sensitivity in diagnosing relevant pathogen (n=100, N=112; two patients had co-infection, three were positive for SARS-Co-V2). WHO definition for ILI is often used for the diagnosis and surveillance of influenza activity in the community.6 Contribution of different viruses in causing ILI seem to differ in different studies. In our cohort, majority of the patients (58.03%, n=65) were positive for non-influenza pathogens. RSV was the predominant pathogen (55.35 %, 62 of 112 cases). Comparable to ours, other studies have reported up to 45-65% of ILI cases caused by non-influenza viruses.⁷

Contrasting with these are the results from surveillance study conducted in eastern India which reported Influenza in majority of the samples from ILI patients and only 7% were RSV.⁸ Also, a laboratory-based study during 2015 influenza outbreak in North India reported that 25.3% of the samples demonstrated influenza virus and 14% were non-influenza viruses. RSV contributed to mere 2.5% of the samples.⁹

In a study conducted in Rajasthan over a period of 13 months among hospitalized patients under five years of age with severe acute respiratory infections (SARI), the most prominent pathogen was human Metapneumovirus.¹⁰

The predominance of RSV detected in our study is in tune with the reports of increased and unseasonal RSV circulation from many countries.¹¹ This is possibly due to accumulation of susceptible population due to severe restrictions on social interaction during pandemic months.³ The dominance of RSV could be due to simultaneous seasonal circulation of influenza and RSV, as both are in circulation during monsoon in this part of the country where the study was undertaken.

The low positivity for SARS-CoV-2 (4.6%, 3 out of 64 tested) could be due to timing of the study (after waning of SAARS-CO-V 2 second wave). It also reinforces the fact that severe ILI is uncommon in children with COVID-19.

There were indicators to suggest that URTI was common in influenza. LRTI and wheeze were significantly common in RSV. However, the study was inadequately powered to detect these differences significantly.

No clinical or epidemiological feature was exclusive to any viral etiology, and hence it was not possible to arrive at a viral etiology on clinical grounds alone.

Limitations

This is not a population-based study, the data was from a single pediatric practice. The study only included patients with severe disease. The year of study may not represent a typical year due to school closure and restricted social interactions which may alter the spread of viruses.

Conclusion

Clinician should be aware of the wide range of viral etiology for the ILI and should take the assistance of viral diagnostic tests whenever possible. Judicious selection of appropriate viral panel makes the test more acceptable to clinicians and patients.

Financial assistance

Nil

Conflict of interest

Nil