Table 9.

List of Differential Diagnoses to Consider for Patients With Influenza Who Do Not Improve or Have Clinical Deterioration With Antiviral Treatment^a

Differential Diagnoses	Supportive Tests and Clinical Clues
Inadequate NAI exposure	Inadequate antiviral dosing (oral, IV, inhaled) Inadequate bioavailability: • For oral administration (vomiting, poor compliance, esterase deficiency in converting oseltamivir phosphate to oseltamivir carboxylate) • For inhaled administration (inadequate delivery to sites of infection, poorly tolerated or poor compliance) Late initiation of NAI treatment relative to illness onset or after severe illness has occurred, with ongoing viral replication, including in the lower respiratory tract
Extrapulmonary complications of influenza virus infection of the respiratory tract: • Encephalopathy or encephalitis • Myocarditis, pericarditis • Myositis, rhabdomyolysis	No other etiology identified to explain findings associated with current influenza virus infection of the upper or lower respiratory tract
Postinfluenza immune-mediated neurologic complications • Encephalitis or ADEM • Guillain-Barré syndrome	No other etiology identified to explain neurologic findings associated with recent influenza virus infection of the upper or lower respiratory tract
Community-acquired bacterial coinfection with influenza (eg, pneumonia, otitis media, sinusitis, tracheitis, meningitis, toxic shock syndrome)	Clinical indicators, imaging studies, laboratory markers (eg, CRP procalcitionin), bacterial cultures or specific tests from sterile sites and upper/lower respiratory tract, current and prior antibiotic exposure history. Bacterial meningitis can occur during influenza virus infection or after influenza has resolved.
Community-acquired viral coinfection with influenza (eg, RSV, HMPV, adenovirus)	Multiple viruses can be detected by multiplex respiratory viral PCR testing.
Hospital-acquired infectionb (bacterial, viral, fungal), DIC, septic shock	• Ventilator-associated pneumonia • Healthcare-associated pneumonia • Catheter-related bloodstream infection • Catheter-associated UTI
NAI-resistant influenza virus infection	Persistent virus detection during or after NAI therapyc; detection of molecular marker(s) associated with NAI resistance; or notification of community circulation of NAI-resistant viruses (testing per guidance)
Respiratory failure, ARDS with influenza	Lower respiratory tract complications can occur without bacterial coinfection. Respiratory failure and ARDS can occur with or without bacterial coinfection of the lower respiratory tract
Multiorgan dysfunction or failure (respiratory failure, acute kidney injury, or renal failure), DIC, septic shock	Clinical indicators, imaging studies, laboratory markers (eg, CRP)
Cardiovascular event: MI, angina, arrhythmias	Clinical indicators, imaging studies, laboratory markers
Pulmonary event: poor control of underlying comorbid condition (eg, COPD, heart failure), pulmonary embolism	Clinical indicators, imaging studies
Cerebrovascular events: CVA	Imaging studies, neurological assessment
Immune deficiency with inadequate antiviral response (eg, chemotherapy or other immunosuppression, pregnancy)	Clinical history and appropriate laboratory tests
Reye syndrome	Hyperammonemia, hypoglycemia, fatty liver, altered mental status (especially if the patient received salicylates or was on long-term aspirin therapy)
Immunocompromised host-specific syndromes	Rejection, hemolytic uremic syndrome, sirolimus pneumonitis/serositis

Abbreviations: ADEM, acute disseminated encephalomyelitis; ARDS, acute respiratory distress syndrome; CRP C-reactive protein; COPD, chronic obstructive pulmonary disease; CVA, cerebrovascular accident; DIC, disseminated intravascular coagulation; HMPV, human metapneumovirus; IV, intravenous; MI, myocardial infarction; NAI, neuraminidase inhibitor; PCR, polymerase chain reaction; RSV, respiratory syncytial virus; UTI, urinary tract infection.

^aIf an obvious alternative source is not identified, consider other sites of infection (eg, aspiration in neurologically impaired, endocarditis, Clostridium difficile colitis)

^bNosocomial influenza virus infection can complicate other conditions requiring hospitalization.

^cPersistent detection of influenza viral RNA after antiviral treatment does not necessarily indicate that antiviral-resistant virus infection is present.