Introduction

Pneumonia

Pneumonia may be defined as an infection of the lung characteristically involving the alveolar space. It is a severe infection, in which the air sacs fill with pus and other liquid.¹

Typical and atypical pneumonia

Typical pneumonia generally begins with a sudden, high fever and chills, followed by coughing with phlegm ².The term atypical pneumonia was originally used with viral community-acquired pneumonias (CAPs), which presented clinically and radiologically different from bacterial CAPs. If elderly people have atypical pneumonia, they particularly have fewer or slightly different symptoms, insteadstarting off slowly with a mild fever, headache, and joint pain. Instead of coughing up phlegm, they often have a dry cough.³

Overview

Influenza virus infection is one of the most contagious airway infectious diseases, and can cause acute febrile respiratory illness. This results in varying degrees of systemic symptoms, ranging from mild fatigue to respiratory failure and even death. 

It generally occurs during the winter season of both northern and southern hemispheres. It results in high morbidity rates in people of all ages and a high mortality rate, particularly for children and adults over 60 years old, patients with chronic illnesses, and pregnant women.⁴

Influenza virus belongs to the family Orthomyxoviridae and comes in three subtypes: A, B and C. All three subtypes of influenza virus are similar in structure, however differ with the type of immune response produced.

Influenza viruses are approximately 80-120 nm in size and are roughly spherical or ovoid in shape. All contain single-stranded, negative-sense, segmented RNA genomes ⁵. Influenza can seriously affect people in any age group, while implications appear to be highest among children younger than age two, adults aged 65 or older, and people of any age with certain medical conditions, such as chronic heart, lung, kidney, liver, blood or metabolic diseases (like diabetes), or weakened immune systems. 

Generally, seasonal influenza shows mild to moderate respiratory infection with a high attack rate but low mortality, while a pandemic has high mortality due to highly virulent strains. Severe influenza in adults is characterised by severe muscle aches and a dry cough,  which may cause patients to cough up blood. Children below the age of 5 year present with a cough, or difficult or fast breathing⁶

Connection between influenza and pneumonia

Seasonal influenza has a significant effect on public health. The attack rates of influenza in unvaccinated populations were estimated to be 10%-20% globally during the epidemics. One of the most important epidemics, the 2009 influenza A (H1N1) pandemic, was estimated to cause between 150,000 and 575,000 excess deaths, boosting the concern about the possible adverse outcomes of influenza and the interest in the underlying risk factors.⁷

Pneumonia is one of the most common complications associated with influenza. It can be caused by primary virus infection, or secondary bacterial infection that occurs during or following initial infection with the influenza virus. Secondary bacterial infection increases the risk of death in patients with viral respiratory infectious disease, including influenza; however, it is an underestimated problem.⁸

While clinically similar in pathogen, the timing of onset, and risk factors, secondary bacterial pneumonia differs from primary viral pneumonia caused by influenza. This includes outcomes and thus possibly requires different preventive and control measures. However, most investigations into influenza patients have concentrated on the risk factors for viral pneumonia and its impact on death, rather than those for secondary bacterial pneumonia. Generally, the effect of secondary bacterial pneumonia on mortality is often ignored, and its risk factors are not well known. Thus, assuming that secondary bacterial pneumonia is a major risk factor for death among patients with influenza.⁹

Pneumonia

Pneumonia is broadly classified into three subtypes according to the clinical setting in which the patient develops symptoms of infection.

• Community-acquired pneumonia (CAP) or atypical pneumonia
• Hospital-acquired pneumonia
• Ventilator-associated pneumonia

Atypical pneumonia

CAP or Atypical pneumonia is defined as an infection of the lower respiratory tract, acquired in a non-hospitalised setting, with clinical symptoms of acute infection and new obstruction developed on a chest radiograph, if one is obtained.

The common causative microorganisms for CAP are Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus. While an evidence-based approach to the epidemiology of pneumonia is complex, the exact etiologic microorganisms remain unknown in almost 60% of cases.

Currently, Moraxella catarrhalis, Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella species are considered common causes of CAP. The enhanced ability to identify other microorganisms, such as viruses, which frequently co-infect patients with bacterial respiratory infections, also adds variability and complications to current pneumonia management.¹⁰

Atypical pneumonia generally is characterized by a symptom complex that includes headache, low-grade fever, cough, sore throat, fatigue, mild chills, chest pain and malaise.

Diagnostic investigations include oxygen saturation in air, white blood cell (WBC) count, hemoglobin, liver functions tests, urinary legionella antigen, sputum culture, molecular diagnosis of Mycoplasma pneumoniae or chlamydia pneumoniae, chest X-ray and nasopharyngeal PCR.¹¹

Age plays a significant role as a risk factor, with younger adults, as well as children in close community conditions, are more susceptible to Mycoplasma pneumoniae. In comparison, people over 50 years are at higher risk for Legionella pneumophila infection. The underlying conditions that result in a raised susceptibility include chronic lung diseases, weakened immune system, diabetes and heart failure. 

Lifestyle factors, including smoking and alcoholism, and environmental exposures related to crowded conditions or during travel, can further elevate the likelihood of contracting atypical pneumonia. Other major risk factors include being of the male sex, immunomodulating drugs, and impaired T-cell immunity. However, atypical pneumonia may occur in any individual, irrespective of their risk factors.¹²

Impact of atypical pneumonia on recovery from influenza

Around 30-40% of hospitalised patients with laboratory confirmed influenza are diagnosed with acute pneumonia. Such patients with pneumonia are more likely to be young (<5 years old), old (>65 years old), caucasian, or nursing home residents, and people with chronic lung or heart disease and a history of smoking are more likely to be immunocompromised.¹³

Of the severe infections in the 1957 and 1968 influenza pandemics, approximately 50% to 70% involved secondary bacterial infection, with the decrease attributed to the advent of antibiotics. Among those infected with the 2009 H1N1 virus, coinfection was estimated to have occurred in about 30%, particularly among those who died from the disease. Despite the progress in medicine and the wide availability of powerful antibacterial and antiviral agents, influenza and pneumonia are still on the list of the most common causes of death in the United States and worldwide.

Generally, the pathogenesis of post-viral bacterial pneumonia represents a complex process involving various host and microbial mechanisms that allow secondary opportunistic bacterial infections to arise in virally infected individuals.¹⁴

The incidence of bacterial pneumonia parallels the seasonality of viral infections, peaking during peak viral seasons. Data from the 2009 H1 N1 epidemic suggest that co-infection typically occurs in the first 6 days of influenza infection, although it can arise as late as 14 days following other viral infections.

This delay likely represents the time needed for viral replication and the immunomodulatory effects of infection to occur. Patients with secondary pneumonia have a more severe, protracted course with increased mortality compared with patients without prior viral infection. Although patients with comorbid conditions or at extremes of age are at increased risk for complicated influenza infections, previously healthy patients may also develop severe respiratory failure and death from bacterial pneumonias following influenza, underscoring the clinical significance of this problem.¹⁵

Most recently, a large group from Australia and New Zealand reported that during winter 2017, the predominant strain (H3N2) virus strain was associated with an unknown high level of viral and bacterial pneumonia leading to ICU admission, even surpassing the 2009 H1N1 pandemic.¹⁶

Treatment, prevention, and management

The most common atypical organism, M. pneumoniae, has no cell walls; therefore, beta-lactam antibiotics are not recommended. There is no need to do blood cultures before starting treatment; however, sputum should be obtained for Gram stain and culture. For hospitalized patients, treatment with antibiotics should be initiated within 4 hours.

First-line treatment is the macrolide family of antibiotics, although resistance is emerging. The most common is azithromycin, which is available in both intravenous and oral forms; the short course of therapy, only 5 days, enhances patient compliance. Other outpatient antibiotics include fluoroquinolone and tetracycline. These are also often used in older or more toxic-appearing patients when other more pyogenic organisms are also suspected. For patients in whom hospital admission is required for presumed community-acquired pneumonia, a broadened approach is often used, adding a beta-lactam such as ceftriaxone to azithromycin.

Clinician tools such as the CURB 65 score and the pneumonia severity index are commonly utilized to assess whether outpatient or inpatient medical treatment is most appropriate. Well-appearing patients in whom an atypical organism is suspected can be treated with outpatient antibiotics and symptomatic care.

Treatment failures are not uncommon due to resistance to antibiotics, poor compliance, and an inability to tolerate oral medications. In addition, some patients have obstructing lung lesions or an incorrect diagnosis.

Close to 50-60% of the patients may have a parapneumonic effusion on the chest x-ray. If this fluid does not resolve, empyema is common. If the pH is below 7.2, aspiration and drainage of the fluid are highly recommended.

In children under the age of 5 years, the atypical pathogens are uncommon; however, if suspected, amoxicillin is used for 7-14 days. For those children older than 5 years, therapy should include a macrolide. Children who develop atypical pneumonia are more likely to be hospitalised and often will require parenteral therapy in addition to oxygen therapy.

Less common presentations of atypical pneumonia in elderly patients are changes in mental status and the presence of one or more comorbid conditions that also predispose to aspiration. In these cases, coverage for anaerobes should also be provided.¹⁷

Vaccination plays a crucial role in preventing the complications of both influenza and pneumonia. Influenza and pneumococcal vaccines have proved to be highly effective in preventing serious outcomes of the disease. The influenza vaccine has been estimated to reduce flu-related hospitalisations by 40-60% in the general population. Pneumococcal vaccines are highly effective in preventing invasive pneumococcal disease, with effectiveness rates ranging from 60-80% in adults. Such vaccines stimulate the body's immune system to produce antibodies against certain pathogens, reducing the possibility of infection and other serious complications.

Prognosis

Most patients in whom an atypical infection is suspected can be successfully managed as an outpatient. There is usually a complete resolution of symptoms, with low morbidity and mortality. Treatment is usually uneventful in the absence of significant comorbid conditions, abnormalities of vital signs, and a toxic appearance. As with all clinical diseases, not every case follows its expected course. Close follow-up and compliance are necessary to monitor for disease progression.¹⁸

Future preventions

The management and diagnosis of atypical pneumonia are usually difficult because laboratory results may not be promptly available, therefore needing clinical acumen. Infection is best managed by an interprofessional team including an emergency department physician, infectious disease consultant, nurse practitioner, internist, radiologist, and a pharmacist. 

Diagnosis is usually delayed; thus, one should never delay treatment if atypical pneumonia is suspected. The patient should be counselled about medication adherence and the need for an annual flu vaccination by the pharmacist. Nurses should carefully observe for signs of respiratory distress and changes in nutritional status, as well as changes in mental status. If these patients are being treated as an outpatient, they should be followed in a clinic by an infectious disease nurse to ensure recovery is taking place ¹⁹.

The majority of patients are managed as outpatients and usually without sequelae. However, some atypical pneumonia may not take the usual course and instead culminate in severe symptoms, which require hospital admission. In order to avoid the morbidity and mortality, it is important that these patients are  followed up until full resolution of the symptoms is obtained. Close communication between the interprofessional team is vital to obtain improved outcomes.²⁰

Summary

Clinical management and Public Health for atypical pneumonia, especially together with influenza infection, is particularly challenging. This is due to complex interactions between viral and bacterial etiologic agents causing worse outcomes, especially in more susceptible populations. Early diagnosis and proper management hold the key to improvement in patient outcomes.The use of macrolide antibiotics for atypical pneumonia and the importance of vaccination against both influenza and pneumococcal disease highlight the need for a comprehensive approach to prevention and treatment. 

Furthermore, with antibiotic resistance continuing to emerge, research and development of new treatment options will go on. It is vital that health care providers areaware of the diagnosis and management with respect to these respiratory infections, especially during peak seasons, for the purpose of reducing morbidity and mortality rates from influenza and atypical pneumonia.

 Summary of key points

• Atypical pneumonia, also known as community-acquired pneumonia (CAP), is characterized by a symptom complex including headache, low-grade fever, cough, and fatigue
• Common causative agents of atypical pneumonia include Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella species
• Influenza virus infection can significantly increase the risk of developing secondary bacterial pneumonia, which can occur during or after the initial viral infection.
• About 30-40% of hospitalised patients with confirmed influenza are diagnosed with acute pneumonia
• Secondary bacterial pneumonia following influenza infection is associated with more severe outcomes and increased mortality rates
• The incidence of bacterial pneumonia parallels the seasonality of viral infections, peaking during peak viral seasons
• First-line treatment for atypical pneumonia typically involves macrolide antibiotics, with azithromycin being a common choice
• Vaccination against both influenza and pneumococcal disease plays a crucial role in preventing complications from these infections