on 09-Jun-2025 (Mon)

Incubation period − The typical incubation period is one to four days (average two days) [3,4]. The time between onset of illness among household contacts (known as the serial interval) is three to four days [5]

Typical signs and symptoms − Influenza characteristically begins with the abrupt onset of fever, nonproductive cough, and myalgia. Other common symptoms include including malaise, sore throat, nausea, nasal congestion, and headache [6-9].

In some cases, the onset of illness is so abrupt that patients can recall the precise time at which symptoms began. Fever usually ranges from 37.8 to 40.0°C (100 to 104°F) but can be as high as 41.1°C (106°F) [10,11].

Gastrointestinal symptoms such as vomiting and diarrhea are usually not part of influenza in adults but can occur in 10 to 20 percent of children.

Subtle findings in adults >65 years and immunosuppressed patients – Patients in these groups may present without fever and with fewer typical symptoms (eg, absence of fever or myalgias) than other patients; however, older adults are more likely to have altered mental status [2,11,12].

Typical findings such as sore throat, myalgias, and fever may be absent, and generalized symptoms such as anorexia, malaise, weakness, and dizziness may predominate.

Other less common presentations of influenza include afebrile respiratory illness (similar to the common cold) or illness with systemic signs and symptoms in the absence of respiratory tract involvement.

Variability with influenza strain – The spectrum of clinical manifestations and the severity of infection can vary with different influenza strains. As an example, vomiting and diarrhea were common among adults during the H1N1 influenza pandemic (2009 to 2010) [13]. In addition, an unusually high number of cases of parotitis was reported during the 2014 to 2015 influenza season; more than half of patients had positive tests for influenza A H3N2 [14-19].

Among vaccinated individuals, clinical manifestations may be similar but less severe.

Physical findings − Physical findings generally are few. The patient may appear hot and flushed; oropharyngeal abnormalities other than hyperemia are uncommon, even with complaints of severe sore throat. Mild cervical lymphadenopathy may be present and is more common in younger patients. Physical examination of the lungs is generally unremarkable.

Laboratory findings − Laboratory findings are generally not helpful in making the diagnosis of influenza. Leukocyte counts are normal or low early in the illness but may become elevated later [11]. White blood cell counts >15,000 cells/microL suggest bacterial superinfection.

Radiographic findings – Chest radiography is normal in patients with uncomplicated influenza.

Clinical course − Adults with uncomplicated influenza typically have fever and respiratory symptoms for about three days, after which time most show signs of improvement; complete recovery may take 10 to 14 days (longer in adults ≥65 years); however, some patients have persistent symptoms of weakness or fatigue for several weeks [1].

Groups at higher risk for influenza complications

Children <5 years, but especially <2 years*

Adults ≥65 years of age

People who are pregnant or up to 2 weeks postpartum

Residents of nursing homes and long-term care facilities

Non-Hispanic Black persons, Hispanic or Latino persons, and American Indian or Alaska Native persons¶

People with medical conditions including: Asthma Neurologic and neurodevelopmental conditions (including disorders of the brain, spinal cord, and peripheral nerve and muscle such as cerebral palsy, epilepsy, stroke, intellectual disability, moderate-to-severe developmental delay, muscular dystrophy, and spinal cord injury) Chronic lung disease (eg, chronic obstructive pulmonary disease, cystic fibrosis) Heart disease (eg, congenital heart disease, congestive heart failure, coronary artery disease) Blood disorders (eg, sickle cell disease) Endocrine disorders (eg, diabetes mellitus) Kidney diseases Liver disorders Metabolic disorders (eg, inherited metabolic disorders and mitochondrial disorders) Weakened immune system due to disease (eg, HIV, AIDS, cancer) or medication (eg, chemotherapy or radiation therapy, chronic glucocorticoids) Children <19 years of age who are receiving long-term aspirin therapy People with Class III obesity (body mass index [BMI] ≥40 or ≥140% of the 95th percentile value)

* In young children, rates of hospitalization and mortality are greatest among those <6 months of age.

¶ Possibly related to economic and social conditions (eg, poverty, multigenerational households, limited access or barriers to influenza vaccination).

Pneumonia — Pneumonia is the most common complication of influenza [20]. Forms include secondary bacterial pneumonia, mixed bacterial and viral pneumonia, or primary influenza pneumonia.

Influenza can be associated with exacerbation of underlying conditions, including chronic obstructive pulmonary disease, asthma, coronary artery disease, or heart failure.

Bacterial pneumonia complicates approximately 0.5 percent of influenza cases in healthy young individuals and at least 2.5 percent of cases in older individuals and those with predisposing conditions [ 21].

Bacterial pneumonia typically occurs within a few days of influenza onset [ 22].

Primary influenza pneumonia should be suspected in patients with persistent symptoms and signs (including high fever and dyspnea) after three to five days of acute influenza.

Patients with secondary bacterial pneumonia often demonstrate initial improvement in influenza symptoms and signs (including abatement of fever), followed by relapse of fever as well as cough productive of purulent sputum.

Patients with mixed viral and bacterial pneumonia may have either a gradual progression of symptoms or a transient improvement followed by worsening.

Radiographic manifestations of primary influenza pneumonia include bilateral reticular or reticulonodular opacities, with or without superimposed consolidation (image 1) [23]. Less common manifestations include focal areas of consolidation, particularly in the lower lobes, without reticular or reticulonodular opacities. High-resolution computed tomography may demonstrate multifocal peribronchovascular or subpleural consolidation and/or ground glass opacities (image 2 and image 3) [23,24].

The organisms most commonly implicated in secondary bacterial pneumonia among patients with influenza are Streptococcus pneumoniae, Staphylococcus aureus (both methicillin sensitive and methicillin resistant), and group A Streptococcus [25]. Less common coinfecting bacteria include Pseudomonas aeruginosa, Haemophilus influenzae, Klebsiella pneumoniae, Moraxella catarrhalis, and Escherichia coli.

Influenza infection has been associated with cardiac complications including myocardial infarction (MI), heart failure, myositis, myocarditis, and pericarditis

ECG changes are frequently observed in patients with influenza; such findings are usually attributable to underlying cardiac disease rather than viral infection. However, transient ECG changes have also been observed in patients with acute influenza in the absence of pre-existing cardiovascular disease [26]

In a cross-sectional study including more than 80,000 adults with influenza, nearly 12 percent had an acute cardiovascular event; the most common events were acute heart failure (aHF) and acute ischemic heart disease (aIHD) [27]. Factors associated with increased risk for these events included older age, tobacco use, underlying cardiovascular disease, diabetes, and renal disease.

Acute myocardial infarction (MI) – Several studies have shown an association between influenza and acute MI [27-30]:

Among study patients hospitalized with influenza, those who were vaccinated were significantly less likely to develop aHF (risk ratio 0.86, 95% CI 0.80-0.92) and aIHD (risk ratio 0.80, 95% CI 0.74-0.87) than those who were unvaccinated

In another study including 364 hospitalizations for acute MI within one year before and one year after a positive test result for influenza, 20 occurred during the ‘risk interval’ (first seven days after respiratory specimen collection) and 344 occurred during the "control interval" (one year before and one year after the risk interval) [28]. The incidence ratio of an admission for acute MI during the risk interval (compared with the control interval) was 6.05 (95% CI 3.86-9.50). No increased incidence was observed after day 7. Incidence ratios for acute MI within seven days after detection of influenza B, influenza A, respiratory syncytial virus, and other viruses were 10.11, 5.17, 3.51, and 2.77, respectively.

Myocarditis and pericarditis are rare complications of influenza [29,30]. In one study of fatal cases of influenza B infection, myocardial injury was observed in 20 of 29 patients (69 percent) with cardiac specimens available for histology; 10 of these had unequivocal myocarditis [31]. No viral antigens were detected immunohistochemistry, suggesting that myocardial injury is not a direct effect of the virus

Influenza has been associated with a broad range of neurologic complications; these include seizures, encephalopathy, encephalitis, cerebrovascular accident, acute disseminated encephalomyelitis, and Guillain-Barré syndrome (GBS) [32-36].

In a case-control study including of GBS cases recorded in the United Kingdom General Practice Research Database between 1990 and 2005, the relative incidence of GBS within 90 days of an influenza-like illness was 7.35 (95% CI 4.36-12.38); the greatest relative incidence was within 30 days (16.64, 95% CI 9.37-29.54) [37]. In contrast, no evidence of an increased risk for GBS within 90 days after seasonal influenza vaccine was observed (relative incidence 0.76, 95% CI 0.41-1.40).

Musculoskeletal complications of influenza include severe myositis and rhabdomyolysis; these occur more frequently in children than adults [38]. While myalgias are a prominent feature of influenza, true myositis is less common.

The hallmark of acute myositis is extreme muscle tenderness, most commonly involving the lower extremities. In severe cases, muscle swelling and bogginess may be observed.

Laboratory findings may include elevated serum creatine phosphokinase; myoglobinuria with associated renal failure has also been described [39,40]. (See "Rhabdomyolysis: Clinical manifestations and diagnosis".)

The pathogenesis of the myositis is not well understood; isolation of influenza virus from muscle has been described [41]. (See "Overview of viral myositis".)

Critically ill patients may present with multiorgan failure, shock, and sepsis. Respiratory failure, acute respiratory distress syndrome, and refractory hypoxemia may occur, as well as acute kidney injury and renal failure [1]. Levels of hepatic aminotransferases may be elevated but liver failure is rare.

Forms of concomitant infection among patients with influenza include pneumonia, bacteremia, meningitis, and aspergillosis. Evaluation for concomitant infection is warranted for patients with influenza who remain febrile for more than three to five days, develop fever after defervescence, or demonstrate worsening symptoms

Bacteremia and toxic shock syndrome associated with S. aureus or S. pyogenes infection in the setting of influenza has been described [42].

An association between meningococcal meningitis and influenza has been described [43].

Invasive pulmonary aspergillosis among patients with influenza admitted to the intensive care unit has been reported [44,45]

The Infectious Diseases Society of America (IDSA) published updated guidelines on the diagnosis and management of influenza in 2018 [2].

Our recommendations are generally in keeping with those of the IDSA and CDC.

The diagnosis of influenza should be suspected in patients with abrupt onset of fever, cough, and myalgia when influenza virus is circulating. Other symptoms, such as malaise, sore throat, nausea, nasal congestion, and headache, are common in the setting of influenza as well as some other viral illnesses.

Among adults ≥65 years and immunocompromised patients, influenza should also be suspected during an influenza outbreak in the setting of atypical systemic symptoms, with or without fever.

Among adults <65 years with acute febrile respiratory illness who are not at high risk for influenza complications (table 1), do not require hospital admission, and have undergone diagnostic evaluation for coronavirus disease 2019 (COVID-19), a clinical diagnosis of influenza may be made during influenza season based on clinical manifestations; in such cases, influenza testing is not required to confirm a clinical diagnosis [49,50].

Detection of influenza virus can reduce unnecessary testing for other etiologies, reduce inappropriate antibiotic use, improve the effectiveness of infection prevention and control measures, and increase the appropriate use of antiviral medications [2].

When influenza virus is circulating – During influenza season, individuals who warrant testing include [2]:

• Patients who are immunocompromised or at high risk for complications (table 1) presenting with influenza-like illness, pneumonia, or nonspecific respiratory illness (eg, cough without fever)

• Patients with acute respiratory symptoms (with or without fever), and either exacerbation of a chronic medical condition (such as asthma, chronic obstructive pulmonary disease, or heart failure) or an influenza complication (such as pneumonia)

• Hospitalized patients with either acute respiratory symptoms (with or without fever) or exacerbation of a chronic medical condition (such as asthma, chronic obstructive pulmonary disease, or heart failure)

When influenza virus is not circulating − When influenza virus is not circulating, testing for the groups outlined above warrants consideration in the setting of relevant epidemiologic exposure (eg, exposure to a person diagnosed with influenza, an influenza outbreak, an outbreak of respiratory illness of uncertain cause, or recent travel in an area with known influenza activity).

Negative antigen test results should be interpreted with caution; false-negative results are common [47]. For this reason, antigen detection assays should not be used in hospitalized patients unless molecular assays are unavailable [2]. In addition, antiviral therapy should not be discontinued based on negative antigen test results.

Follow-up testing with a molecular assay is warranted in the following circumstances [2,47,48]:

• Patients with a negative antigen test in the setting of high community influenza activity and clinical indication for laboratory confirmation of infection. (See 'Whom to test' above.)

• Patients with a positive antigen test in the setting of low community influenza activity, given the possibility of a false-positive result.

• Patients with recent exposure to pigs or poultry, in the setting of concern for infection with a novel influenza A virus.

Molecular assays − The preferred tool for diagnosis of influenza is a molecular assay (nucleic acid amplification test), given its high sensitivity and specificity.

Specimen collection — Specimens should be obtained as soon after illness onset as possible, preferably within four days of symptom onset [2].

Nasopharyngeal specimens are preferred over other specimens to optimize virus detection. A video demonstrating the proper technique for nasopharyngeal specimen collection can be found at the New England Journal of Medicine website.

If nasopharyngeal specimens are not available, nasal and throat swab specimens should be collected and combined for testing. If it is possible to obtain only one specimen, nasal swab is preferred.

Flocked swabs (with fibers projecting outward) should be used rather than nonflocked swabs, to increase diagnostic yield [51]. Swabs should be immersed in antibiotic-containing transport fluid immediately after collection.

For ventilated patients with negative test results from upper respiratory tract specimens, endotracheal aspirate or bronchoalveolar lavage fluid specimens should be obtained for testing. Influenza virus replication in the lower respiratory tract may be greater and more prolonged than in the upper respiratory tract.

Respiratory specimens for influenza virus testing should be transported on ice and then refrigerated.

There is no role for testing from nonrespiratory sites such as serum, urine, stool, or cerebrospinal fluid.

Hospitalized patients with suspected seasonal influenza or novel influenza A virus infection should be tested using whatever diagnostic test is most readily available for initial diagnosis. If the initial diagnostic test does not identify A(H1) or A(H3), an influenza A subtyping diagnostic test should be ordered promptly.

Antiviral resistance — Evaluation for antiviral resistance should be pursued for patients in the following circumstances [2]:

● Patients who develop influenza infection while receiving or immediately following receipt of postexposure prophylaxis with a neuraminidase inhibitor or baloxavir.

● Immunocompromised patients and patients with severe influenza who remain ill despite treatment with a neuraminidase inhibitor or baloxavir, with evidence of persistent influenza virus replication (demonstrated by persistently positive RT-PCR or viral culture results after 7 to 10 days of antiviral therapy).

● Patients with persistent symptoms of influenza who were treated with subtherapeutic dosing of a neuraminidase inhibitor or baloxavir.

In such cases, a respiratory sample should be sent to the state or regional laboratory for resistance testing, where phenotypic and/or genotypic assays are performed.

Additional diagnostic evaluation — Further diagnostic evaluation is warranted in patients with influenza and:

● Signs and symptoms suggestive of pneumonia (cough with dyspnea, tachypnea, hypoxia, and fever)

● Abnormalities on lung auscultation

● Persistent fever for >3 to 5 days

● Development of fever after initial defervescence

● Worsening symptoms

Novel influenza A viruses warrant consideration in the setting of exposure to infected birds, animals, or animal material, or to an ill person with novel influenza A virus infection.

Novel influenza A virus infection cannot be distinguished from seasonal influenza A virus infection by clinical findings or commercially available tests; it must be diagnosed by specific influenza A molecular assays at public health laboratories.

Fatigue, headache, diarrhea, olfactory disorders (such as anosmia or hyposmia), and taste disorders (such as ageusia or hypogeusia) are more common with COVID-19 than with influenza [55]

A positive test result for either influenza or COVID-19 does not rule out coinfection when both viruses are circulating.

The common cold can be caused by several different viruses, including rhinoviruses, parainfluenza, and common cold coronaviruses. In general, compared with influenza, cold symptoms are usually milder, nasal congestion is more common, and colds rarely result in serious health problems or complications.

In studies limited to patients aged 60 years or older, the combination of fever, cough, and acute onset (LR, 5.4; 95% CI, 3.8- 7.7), fever and cough (LR, 5.0; 95% CI, 3.5-6.9), fever alone (LR, 3.8; 95% CI, 2.8- 5.0), malaise (LR, 2.6; 95% CI, 2.2-3.1), and chills (LR, 2.6; 95% CI, 2.0-3.2) increased the likelihood of influenza to the greatest degree. The presence of sneezing among older patients made influenza less likely (LR, 0.47; 95% CI, 0.24-0.92).

For decreasing the likelihood of influenza, the absence of fever (LR, 0.40; 95% confidence interval [CI], 0.25-0.66), cough (LR, 0.42; 95% CI, 0.31-0.57), or nasal congestion (LR, 0.49; 95% CI, 0.42-0.59) were the only findings that had summary LRs less than 0.5.

Influenza-like illness, defined by the Centers for Disease Control and Preven- tion (CDC) US Influenza Sentinel Pro- viders Surveillance Network as tempera- ture higher than 37.8°C (100°F) plus either cough or sore throat (www.cdc .gov/flu/weekly/fluactivity.htm) but sometimes defined differently by oth- ers, is a syndrome characterized by other nonspecific symptoms that may be seen with a variety of upper respiratory tract infections.

Thus, during the peak week of the 2003- 2004 outbreak, about 1 of every 13 pri- mary care visits in the United States was for an influenza-like illness

Based on CDC sentinel data, patient visits to a primary care practitioner’s of- fice for influenza-like illnesses peak at 3.3% to 7.1% during influenza season.4

Laboratory surveillance monitoring in the United States showed that the ma- jority of samples in the 2003-2004 in- fluenza season tested negative for influ- enza. Although not specifically reported, the implication is that these patients of- ten had other viruses such as rhinovi- ruses, adenoviruses, and parainflu- enza. While many of these are relatively benign and self-limited, others may be quite serious; for example, early infec- tion during an epidemic of the corona- virus causing severe acute respiratory syndrome (SARS) produced influenza- like illness.7Bacterial agents, including Legionella species, Chlamydia pneumo- niae, Mycoplasma pneumoniae, and Strep- tococcus pneumoniae, may also be re- sponsible for influenza-like illnesses

thus, the final data (TABLE 1) are based on 6 studies and included 7105 pa- tients.12,14,20,23,25,26

None of the studies assessed the pre- cision of signs or symptoms of influ- enza. Measurements of objective clini- cal signs such as temperature are assumed to have high precision

“Fever- ishness” was reported by the patient and could have been based on either a tem- perature taken at home or a subjective sense of having an elevated tempera- ture.

The studies presented used varying defi- nitions for fever, ranging from 37.8°C to 38.5°C (Table 1). We defined fever as “present” or “absent” based on the individual article definitions

The patient’s sense of fever- ishness and vaccination history pro- vided homogeneous results across stud- ies.

The heteroge- neity, expressed in the confidence in- tervals (CIs), never moved a finding from useless (LR approaching 1) to ob- viously useful (LR so different from 1 that it would make influenza ex- tremely likely or extremely unlikely)

No single clinical finding consis- tently had a positive LR high enough to clinically “rule in” influenza, nor did any single finding have a negative LR low enough to clinically “rule out” in- fluenza (Tables 2 and 3).

For decreasing the likelihood of influ- enza, the absence of fever (LR, 0.40; 95% CI, 0.25-0.66), cough (LR, 0.42; 95% CI, 0.31-0.57), or nasal conges- tion (LR, 0.49; 95% CI, 0.42-0.59) were the only findings with an LR less than 0.5.

Feverishness, myalgia, malaise, sore throat, and sneezing each had a posi- tive and negative LR that were indis- tinguishable from 1.0 and therefore of no diagnostic value for the patients in studies that evaluated the entire age spectrum.

limited to those aged 60 years or older, the strongest univariate indica- tors of influenza were fever (LR, 3.8; 95% CI, 2.8-5.0), malaise (LR, 2.6; 95% CI, 2.2-3.1), and chills (LR, 2.6; 95% CI, 2.0-3.2)

Among older patients ex- clusively, the presence of sneezing re- duced the likelihood of influenza (LR, 0.47; 95% CI, 0.24-0.92).

Two studies, by Govaert et al14 and Monto et al,20 assessed the diagnostic usefulness of the symptom combina- tion of fever and cough in persons aged 60 years or older and in the unre- stricted age group (Table 3). The LRs when both fever and cough were pres- ent were 5.0 and 1.9, respectively.

The data presented indi- cate that the strongest predictor of in- fluenza was the acute onset of both fe- ver and cough in patients aged 60 years or older

One study found that different clinical pre- sentations were associated with the in- fluenza type,12 but another study showed no difference.20

The dif- ferent study populations may also have had very different clinical characteris- tics due to the pool from which they were drawn. The studies from Europe were more likely to include patients from home. It is conceivable that these patients may have been more or less ill, have had more or fewer symptoms, and have had a different prevalence of in- fluenza when compared with the popu- lations from the United States or other countries

While all of the studies recruited pa- tients only during influenza season, some were specifically undertaken dur- ing epidemics. Thus, the prevalence of disease varies considerably in the pub- lished reports of the clinical findings. It is possible that clinical characteris- tics of the disease change between sea- sons based on the strain of influenza. All of the studies were performed be- fore the recent epidemic of SARS

Monto et al20 suggest that the posi- tive predictive value of clinical signs and symptoms increased with increasing duration from illness onset. The 6 stud- ies presented in this article had vari- able durations of symptoms.

Once the clinical criteria are used to establish the presence of an influenza- like illness, there is little information other than epidemiologic data that is useful for guiding diagnostic and thera- peutic decision making.