Managing community-acquired pneumonia during flu season

HOW BACTERIA INVADE THE LUNGS

The pathophysiology of CABP involves both host defense and microbial virulence factors.

The airways are most commonly exposed to microbes by microaspiration of upper airway flora, although hematogenous seeding of the lungs in a bacteremic patient or contiguous spread of infection from an adjacent site can also occur.

Mucociliary clearance and the cough reflex are important initial defenses against infection and can be inhibited by neurologic diseases and conditions that impair the mucociliary mechanism. Mucosal immune cells, including macrophages and neutrophils, recognize invading pathogens and generate an antibody response.

Regulation of the host inflammatory response to infection depends on a complex interaction between immune cells, inflammatory cytokines (eg, tumor necrosis factor alpha, interleukin 1-beta, and interleukin 6), and anti-inflammatory cytokines such as interleukin 1 receptor antagonist and soluble tumor necrosis factor receptor type I.²²

The interaction and timing of the inflammatory and anti-inflammatory response are essential in manifesting an appropriate host response to infection. An inadequate inflammatory response can lead to sepsis and death, but an excessive, late anti-inflammatory response can lead to a systemic inflammatory response such as ARDS. Polymorphisms within the genes coding for these factors may explain the variation in severity of illness among patients with CABP.²³

HOW INFLUENZA DOES ITS DAMAGE

There are three types of influenza virus: A, B, and C. Type A causes most human infections. The influenza A virus envelope comprises a lipid bilayer that contains the projecting glycoproteins hemagglutinin and neuraminidase. Influenza viruses are named on the basis of these proteins and are designated with an H and an N, respectively, each followed by a number referring to the subtype.

Influenza infection begins when the virus makes contact with the epithelium. Hemagglutinin binds to the host cell and allows viral entry, where it begins replication. Neuraminidase prevents viral aggregation and facilitates the release of virus from infected cells.²⁴

Mature virions are released and spread to neighboring host cells; this process is associated with desquamation and inflammation of the airways, causing cough, rhinorrhea, and sore throat. Systemic symptoms are associated with the induction of interferon, which causes fever and myalgia.²⁵

Recovery and immunity to influenza infection occurs through both humoral and cell-mediated immunity, with antibodies directed against the specific hemagglutinin and neuraminidase antigens of the infecting virus. Immunity wanes over time and with antigenic drift of circulating viruses, making the host susceptible to recurrent influenza infection.²⁴

Influenza is often complicated by bacterial superinfection

The influenza virus acts synergistically with certain bacteria to increase infectivity, and this may explain why influenza is often complicated by bacterial superinfection.

Mechanisms leading to bacterial superinfection include increased binding and invasion of bacteria, increased viral replication, and modification of the host inflammatory response. Some S aureus strains produce a protease that directly activates influenza virus hemagglutinin; other bacteria can activate plasminogen to promote influenza replication. The resulting increase in proteases in host tissues promotes activation of influenza through cleavage of hemagglutinin.²⁶

The influenza virus also causes damage to the airway epithelial layer, leading to increased exposure of the binding sites necessary for adherence of S pneumoniae.²⁷

CLINICAL PRESENTATION OF COMMUNITY-ACQUIRED PNEUMONIA

Although CAP is common, agreement on its essential clinical signs and symptoms is surprisingly limited, due in part to heterogeneous patient presentations and in part to interobserver variability. The reader is referred to two excellent reviews on this topic.^28,29

The diagnosis of CAP is made on clinical grounds, based on a combination of signs and symptoms. Symptoms of pneumonia can include cough, fever, chills, sputum production, dyspnea, and pleuritic pain. Physical findings can include tachypnea, tachycardia, hypoxemia, and consolidation or rales on auscultation. Laboratory data may show leukocytosis or elevated C-reactive protein, and radiographic studies may show evidence of a new infiltrate.^21,30,31

Clinical presentation of influenza

Seasonal influenza as a cause of CAP is difficult to distinguish from bacterial causes. The clinical presentation of seasonal influenza most commonly includes fever or subjective feverishness, cough, myalgia, and weakness.³² In a recent multivariate analysis, five clinical features were shown to be predictive of pandemic H1N1 influenza pneumonia rather than CABP: age younger than 65 years, absence of confusion, white blood cell count less than 12 × 10⁹/L, temperature higher than 38°C (100.4°F), and bilateral opacities on radiography.^32,33

Complicated influenza infection can be either primary viral pneumonia or bacterial superinfection.

During the 1918 influenza pandemic, which predated the ability to isolate viruses, two clinical syndromes emerged: an ARDS associated with the rapid onset of cyanosis, delirium, and frothy blood-tinged sputum; and an acute bronchopneumonia characterized by necrosis, hemorrhage, edema, and vasculitis.^34,35 The first syndrome has subsequently been shown to be associated with primary viral pneumonia, while the second is caused by bacterial superinfection. Modern reexamination of 1918 data has shown that bacterial superinfection was likely the reason for the distinctly fulminant presentation of that pandemic.^36,37

The 2009 H1N1 influenza pandemic caused relatively mild disease in most patients. However, those with severe pneumonia more commonly developed ARDS from primary influenza pneumonia than from bacterial superinfection.¹⁷

A third influenza-associated infection is secondary bacterial pneumonia, which follows influenza infection and mimics the presentation of CABP. A typical patient presents with a recent history of influenza-like illness, followed 4 to 14 days later by a recurrence of fever, dyspnea, productive cough, and consolidation on chest radiographs.³⁸ Leukocytosis with an increased number of immature neutrophil forms, prolonged duration of fever, and elevated erythrocyte sedimentation rate are more likely in patients with secondary bacterial pneumonia.³⁹ Isolates from sputum samples commonly include S pneumoniae, S aureus, H influenzae, and other gram-negative rods.⁴⁰

In recent flu seasons, methicillin-resistant S aureus (MRSA) has emerged as a cause of severe secondary pneumonia. Most of these isolates carry genes for the toxin Panton-Valentine leukocidin; the associated mortality rate is as high as 33%.^41,42 Although community-acquired MRSA pneumonia has only been reported in case series, distinct clinical features that have been described include severe pneumonia with high fever, hypotension, shock, respiratory failure, leukopenia, and multilobar and cavitary infiltrates.⁴³

WHEN TO SUSPECT INFLUENZA

The triad of fever, cough, and abrupt onset are the best predictors of influenza, but no single combination of signs and symptoms predict influenza infection with 100% certainty. Therefore, an understanding of local epidemiologic data regarding circulating influenza is essential to maintain a high index of suspicion.⁴⁴

It is appropriate to suspect influenza in:

• Anyone who is epidemiologically linked to a known outbreak of influenza
• Children, adults, and health care workers who have fever and abrupt onset of respiratory symptoms
• Patients with fever plus exacerbation of underlying pulmonary disease
• Severely ill patients with fever or hypothermia, especially during influenza season.⁴⁵