Introduction

Definition of atypical pneumonia

Broadly speaking, pneumonia (inflammation and infection of the lungs) can be divided into pneumonia acquired outside of hospital settings (Community Acquired Pneumonia - CAP) and those acquired in hospital (Hospital Acquired Pneumonia or nosocomial infection). Pneumonia can be caused by a wide variety of organisms, viral, bacterial, or fungal in nature. Typical CAP is primarily an infection of the tissue of the lungs (lung parenchyma) and is most commonly caused by the bacteria Streptococcus pneumoniae, haemophilus influenzae, and Moraxella catarrhalis.¹ In atypical pneumonias, there is generalised infection of the whole body, with a component that affects the lungs rather than the focus of infection being primarily in the lung. Atypical pneumonia constitutes around 7–20% of all community-acquired pneumonia.² Atypical pneumonias are important to identify as they respond to different treatments compared with typical pneumonia and may have specific complications.

Overview of key causative agents

The causes of atypical pneumonia can be divided into those transmitted from animal species (zoonotic atypical pneumonia) and those transmitted by human-to-human contact (non-zoonotic atypical pneumonia). The main bacteria causing zoonotic atypical pneumonia are: chlamydia psittaci (psittacosis), coxiella burnetii (Q-fever), and francisella tularensis (tularemia).¹ A history of exposure or a high-risk profession (livestock workers, vets, slaughterhouse workers) may suggest a zoonotic cause. Chlamydia pneumoniae, Mycoplasma pneumoniae, and legionella species (of which there are various subtypes) are the main bacteria causing non-zoonotic atypical pneumonia.¹ 

Chlamydia pneumoniae

Characteristics

Chlamydia bacteria rely on substances found inside the body’s own cells to function and therefore live and reproduce within the cells lining the lungs and immune cells in the lungs. The term obligate intracellular pathogen is used for bacteria that have to live within the body’s own cells to survive. The bacteria exists in two forms: the elementary body, which can exist outside of the body’s cells and transmit infection to other cells, and the active form of the bacteria, or reticulate body, which exists within the host cell and can reproduce. Once the reticulate bodies have reproduced, they break down the host cell, releasing more elementary bodies. In this way, chlamydia damages lung tissue.³ There are three forms of chlamydia that can cause atypical pneumonia: chlamydia pneumoniae, the most common; chlamydia psittaci, which is spread through the feces of birds (typically parrots); and chlamydia trachomatis, which is acquired from the mother’s genital tract during childbirth and therefore generally only causes pneumonia in infants. Chlamydia is endemic (always found within the population) but may also occur in isolated epidemics (outbreaks with a geographical center).⁴ 

Clinical presentation

In most patients, chlamydia pneumoniae infections are mild; in fact, many cases will have no symptoms. Occasionally, however, there can be a severe infection leading to respiratory failure. The onset of infection is usually with non-specific flu-like symptoms, proceeding to a mild pneumonia with dry cough and shortness of breath for between one to four weeks. General aches and pains are common (myalgia), as are upper respiratory symptoms such as sore throat and earache. On examination raised temperature, signs of upper respiratory infection such as redness of the pharynx (throat) are common. Wheezing may be heard on auscultation of the lungs with a stethoscope. Enlargement of the liver and spleen may be a feature of chlamydia psittaci.¹  

Diagnostic approaches

General laboratory investigations such as full blood count and liver function tests are often unremarkable in chlamydia infections. Although the erythrocyte sedimentation rate may be raised, this is a nonspecific finding. The culture of chlamydia requires a special growth medium, which may not be available at many centers. Serology is the investigation of choice for diagnosing chlamydia pneumoniae infection. Serology involves measuring the levels of antibodies found in the bloodstream; elevated levels of chlamydia pneumoniae IgM antibodies suggest an acute infection.⁵ 

Treatment options

The treatment setting will depend on the severity of the pneumonia. In community-acquired pneumonia, the CURB 65 score, a scoring system based on physical findings (respiratory rate, blood pressure), confusion, blood urea level, and the person’s age, can be used to determine which patients require treatment in hospital. Because it takes time to obtain serology results and because in patients requiring treatment in hospitals the causative organisms may be mixed, it is usual to give both treatment for typical pneumonia and an atypical one, so treatment with a penicillin and macrolide antibiotic is usually given. Because chlamydia is an intracellular pathogen, it does not respond to beta-lactam antibiotics such as penicillin, which disrupt the cell wall, responding better to antibiotics that interfere with protein synthesis such as macrolides, eg azithromycin, clarithromycin or fluoroquinolone antibiotics such as levofloxacin or moxifloxacin.⁶ 

Implication of chlamydia pneumoniae in other disease processes

There is evidence that Chlamydia pneumoniae may be implicated in atherosclerosis, asthma, arthritis, cancers, and neurological disorders, including multiple sclerosis.⁷

Mycoplasma pneumoniae

Characteristics

Mycoplasma are the smallest and structurally simple bacteria. Unlike most bacteria, they do not have a cell wall, which means they are also not susceptible to beta-lactam antibiotics like penicillin, which disrupt the cell wall. Mycoplasma produces proteins, which allow them to stick to the cells lining the lung (respiratory epithelium), where they produce toxins such as hydrogen peroxide that damage the lung cells and result in cough. They are extracellular pathogens, which means that they do not need to enter the host's cells to divide and reproduce; instead, they divide by splitting in two and making copies of themselves (binary fission). Like chlamydia, mycoplasma infections are also endemic (always present), although outbreaks may occur in late summer months. Transmission is from person to person via aerosol (droplets from coughing) but requires close contact. For this reason, there are often outbreaks of mycoplasma in institutions such as schools, prisons, and military barracks. Only about 5-10% of people infected with mycoplasma go on to develop pneumonia. Nevertheless, mycoplasma is still the most common cause of atypical pneumonia.⁸

Clinical Presentation

Mycoplasma infection may affect both the upper and lower airways. Upper respiratory symptoms include sore throat and earache, which develop quickly into an intractable dry cough. Many patients may be asymptomatic. The clinical presentation is difficult to distinguish from chlamydia pneumoniae. Rarely can there be a generalized skin rash called erythema multiforme and, in a handful of cases, irritation of the brain and meninges: mycoplasma meningoencephalitis. About 25% of cases will have some gastrointestinal disturbance such as nausea, vomiting, or loss of appetite. Non-specific muscle inflammation and transient inflammation of the joints occur in around 15% of patients. Haemolysis (breakdown of the body’s red blood cells) and cardiac involvement is seen in some patients. Examination findings aside from fever and signs of pharyngeal inflammation and wheeze on auscultation of the chest may be unremarkable.¹

Diagnostic approaches

Because most patients with mycoplasma are encountered in an outpatient setting and empirical treatment is usually successful, specific testing is not usually performed. However, in patients with indications for hospital admission, blood tests and x-rays may be normal or show raised white cell count and, in some cases, patchy areas of shadowing (consolidation) on chest x-rays. Whilst not available at all centers, PCR (polymerase chain reaction), which tests for mycoplasma genetic material, is both rapid and accurate. Serology tests, including complement fixation and enzyme immunoassay provide suitable alternatives, although for optimum diagnosis both an acute and a convalescent sample are required. Attempting to grow cultures of mycoplasma in the laboratory from respiratory secretions is not routinely attempted as mycoplasma requires a special medium to culture and even then is difficult to grow, thus this test is not particularly sensitive.⁹

Treatment strategies

Macrolide antibiotics (e.g., azithromycin, clarithromycin), doxycycline (7-14 days), or fluoroquinolone antibiotics (e.g., levofloxacin, moxifloxacin (7-14 days) are effective against Mycoplasma pneumoniae. In most cases, treatment is empirical and given in the community. Resistance to macrolide antibiotics is reported, so an alternative antibiotic should be considered if there is a lack of clinical response.⁹

Legionella pneumophila

Characteristics

Legionella is a gram-negative bacterium responsible for the most serious of the atypical community-acquired pneumonias. It is termed a facultatively intracellular pathogen, which means it can live and reproduce either inside or outside the body’s cells. Legionella causes Legionaire’s disease. This disease was named after an outbreak of the disease in a hotel hosting the annual convention of the American Legion in 1976. Legionella was isolated from water in the air-conditioning system.¹⁰ There are many different species of legionella; however, 80% of cases of Legionaire’s disease are caused by serotype 1. Legionella breeds in stagnant water sources, preferring warm water, so is often found in air conditioning systems in large buildings or other sources like hot tubs. In air conditioning systems, the water is aerosolized, which spreads the bacteria. The incidence in Europe is 1.2-1.4 cases per 100,000. Legionaire’s disease has a particularly high mortality rate for community-acquired pneumonia, with a mortality rate of 10%.¹¹

Clinical manifestations

The clinical symptoms of Legionare’s disease are headache, confusion, fever, cough, shortness of breath and fatigue, nausea, and vomiting occurring 2-10 days following exposure to a contaminated water source. Abdominal pain and diarrhea are frequent, as is pleuritic chest pain. Frequently, Legionnaire’s disease occurs in a pattern of outbreaks located around the source, e.g., a particular hotel. On examination, fever, chest signs, including signs of consolidation, relative bradycardia, and microscopic haematuria (small amounts of blood in the urine) may be detected.¹

Diagnostic methods

Routine blood tests may show a raised white cell count and elevation of inflammatory markers (ESR and CRP). Specific abnormalities found in Legionaire’s disease are low sodium and phosphate levels and the presence of microscopic blood on dip testing. Urinary antigen testing for Legionella yields a rapidly available result; however, this is only available for serotype 1.¹² Culture of Legionella in the laboratory is from sputum and requires a special growth medium; however, it is considered 100% specific. It has the disadvantage of taking time to perform, by which time patients will have already been commenced on antibiotics, which affect the ability to culture Legionella bacteria.¹³ PCR (Polymerase Chain Reaction), which detects genetic material from the Legionella bacteria, can be performed; however, this will only be available at certain centers. ³ Chest X-rays may show lobar consolidation (shadowing of the lung encompassing most or all of one of the lobes of the lung). Serology tests are useful for retrospective diagnosis.

Treatment

Patients suspected of having Legionnaire’s disease usually require treatment in hospitals. Around 50% of patients may need treatment in the intensive care unit. Treatment is both supportive—oxygen, intravenous fluid replacement, and sometimes corticosteroids and antimicrobial. Because Legionella is an intracellular bacteria, antibiotics that disrupt protein formation are required. Treatment is with macrolide antibiotics, eg clarithromycin or fluoroquinolones, eg. levofloxacin or moxifloxacin.¹⁴ Despite this, mortality remains high, rising to 10-50% in the elderly or immunosuppressed.¹⁵ Public health specialists should be involved in order to help isolate and contain the source of outbreaks.

Summary

Pneumonia due to atypical bacterial organisms represents between 7 and 20% of all pneumonia acquired in the community. Mycoplasma pneumoniae and chlamydia pneumoniae are the most common organisms causing atypical bacterial pneumonia. Legionella pneumophila is a rare but important cause of atypical pneumonia as it causes Legionnaires disease, which has a high mortality rate. Atypical pneumonia does not respond to the same antibiotic regimens as typical pneumonia, and specific antibiotic treatment is indicated. Zoonoses (diseases transmitted from animals to humans) make up a small number of cases of atypical pneumonia but are nevertheless important in people in high-risk professions.