Viral shedding and clinical illness in naturally acquired influenza virus infections

Abstract

Background: Volunteer challenge studies have provided detailed data on viral shedding from the respiratory tract before and through the course of experimental influenza virus infection. There are no comparable quantitative data to our knowledge on naturally acquired infections.

Methods: In a community-based study in Hong Kong in 2008, we followed up initially healthy individuals to quantify trends in viral shedding on the basis of cultures and reverse-transcription polymerase chain reaction (RT-PCR) through the course of illness associated with seasonal influenza A and B virus infection.

Results: Trends in symptom scores more closely matched changes in molecular viral loads measured with RT-PCR for influenza A than for influenza B. For influenza A virus infections, the replicating viral loads determined with cultures decreased to undetectable levels earlier after illness onset than did molecular viral loads. Most viral shedding occurred during the first 2-3 days after illness onset, and we estimated that 1%-8% of infectiousness occurs prior to illness onset. Only 14% of infections with detectable shedding at RT-PCR were asymptomatic, and viral shedding was low in these cases.

Conclusions: Our results suggest that "silent spreaders" (ie, individuals who are infectious while asymptomatic or presymptomatic) may be less important in the spread of influenza epidemics than previously thought.

Table 1

Comparison of Characteristics of 59 Secondary Influenza Virus Infections with 76 Excluded Infections

Table 2

Initial Symptoms and Signs of Naturally Acquired Influenza A and B Virus Infections Reported at Acute Respiratory Illness (ARI) Onset

Figure 1

Patterns of viral shedding and symptoms and signs in naturally acquired influenza A and B virus infections by day relative to acute respiratory illness (ARI) onset (day 0). Top row: Viral shedding for children (plus signs) and adults (circles), and the geometric mean viral shedding (solid lines) of (A) 26 individuals with influenza A and (B) 18 individuals with influenza B virus infections. The lower limit of detection of the reversetranscription polymerase chain reaction assay was ∼900 copies/mL (gray line). Second row: Median tissue culture infectious dose (TCID₅₀) of specimens collected from children (plus signs) and adults (circles), and the geometric mean TCID₅₀ of (C) influenza A and (D) influenza B. Third row: Symptoms and signs for subjects with (E) influenza A and (F) influenza B virus infection are split into lower respiratory (dotted line), upper respiratory (dashed line), and systemic (solid line). Bottom row: Mean tympanic temperature associated with (G) influenza A and (H) influenza B virus infections. ARI onset is defined as at the first day with ⩾2 of the 7 signs or symptoms listed in Table 2. Individuals with asymptomatic or subclinical infections were excluded. NTS, nose and throat swab specimen.

Figure 2

Association between replicating (by median tissue culture infectious dose [TCID₅₀]) and molecular (by reverse-transcription polymerase chain reaction) influenza A viral shedding by day since acute respiratory illness (ARI) onset for children (plus signs) and adults (circles). Linear regression lines are plotted where there are ⩾3 points. ARI onset is defined as at the first day with ⩾2 of the 7 symptoms or signs listed in Table 2. NTS, nose and throat swab specimen.

Figure 3

Association between replicating (by median tissue culture infective dose [TCID₅₀]) and molecular (by reverse-transcription polymerase chain reaction) influenza B viral shedding by day since acute respiratory illness (ARI) onset for children (plus signs) and adults (circles). Linear regression lines are plotted where there are ⩾3 points. ARI onset is defined as at the first day with ⩾2 of the 7 symptoms or signs listed in Table 1. NTS, nose and throat swab specimen.

Figure 4

Proportion of infectiousness remaining by time since acute respiratory illness (ARI) onset in the course of naturally acquired influenza A virus infection. Infectiousness assumed proportional to (A) molecular viral shedding, (B) log₁₀ molecular viral shedding, and (C) presence of molecular viral shedding in excess of 900 copies/mL under the fitted curve.

Figure 5

Association between tympanic temperature and molecular influenza A viral shedding by reverse-transcription polymerase chain reaction by day since acute respiratory illness (ARI) onset for children (plus signs) and adults (circles). Linear regression lines are plotted where there are ⩾3 points. ARI onset is defined as at the first day with ⩾2 of the 7 signs or symptoms listed in Table 1. NTS, nose and throat swab specimen.