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Atypical Bacterial Pneumonia
Introduction
Pneumonia is a lower respiratory tract infection that primarily affects the pulmonary parenchyma. Viruses, fungi, and bacteria can all cause pneumonia. Atypical bacterial pneumonia is caused by bacterial species less frequently associated with pneumonia compared to typical bacterial species, such as Gram-positive Streptococcus pneumoniae or Staphylococcus aureus. These atypical bacteria are also more difficult to detect using traditional Gram stain and standard culture methods.[1] Examples of atypical bacteria include Mycoplasma pneumoniae, Chlamydia (formerly Chlamydophila) pneumoniae, and Legionella species. Similar to typical bacterial pneumonia, the severity of pneumonia can range from mild to life-threatening, with uncomplicated disease resolving with outpatient antibiotics and complicated cases progressing to septic shock, acute respiratory distress syndrome, and death.[2] Atypical bacterial pneumonia affects all age groups and can account for up to 40% of community-acquired pneumonia cases.[3] M. pneumoniae alone is estimated to account for over 2 million cases and 100,000 hospitalizations in the United States.[4][5] Atypical bacterial pneumonia can cause mortality in both adults and children, and epidemics may occur every few years.[6] Atypical bacteria are known to cause a disproportionate disease burden in children older than 5 and adolescents.[7][8] These bacteria can initially present subacutely and progress to constitutional symptoms.[9] Proper evaluation of suspected atypical bacterial pneumonia, including a detailed history, physical examination, and targeted investigations, is crucial for the interdisciplinary management of this condition.
Please see StatPearls' companion resource, "Bacterial Pneumonia," for further information.
Etiology
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Etiology
Pneumonia is acquired when a sufficient volume of pathogenic organisms bypasses the body's cough and laryngeal reflexes to reach the parenchyma. This process can result from exposure to large volumes of pathogens in inspired air, increasingly virulent pathogen exposure, aspiration, or impaired host defenses. Given the various environments in which pneumonia can be acquired, the diagnosis is often broadly classified into community-acquired or hospital-acquired.[1] Pneumonia may also be further classified as viral, bacterial, or atypical bacterial based on the pathogen identified for treatment. Atypical bacterial pneumonia can arise from various sources. The most commonly identified pathogens include:
- M. pneumoniae, often associated with close living conditions such as schools and military barracks
- Legionella pneumophila from stagnant water sources
- L. longbeachae from potting mixes
- C. pneumoniae [1][10][11]
Other atypical bacterial species may be associated with pneumonia depending on the geographical risk region. These species include:
Epidemiology
An estimated 7% to 20% of community-acquired pneumonia cases are caused by atypical bacterial microorganisms.[5] Due to their intracellular nature, these pathogens are not visible on Gram stain and are difficult to culture; therefore, the actual number of bacterial pneumonia cases attributable to atypical microorganisms is unknown, but given similar treatments, specific etiology is often unnecessary.[15] Age is often the only reliable predictor in adults, though particular risk factors may exist for atypical bacterial pneumonia organisms, as listed below.
M. pneumoniae is the most frequently identified microorganism associated with atypical bacterial respiratory infections.[7] This microorganism can affect up to 50% of adolescents and is also prevalent among children older than 5 in crowded areas.[16] A large multicenter study found M. pneumoniae as a causative organism in up to 19% of community-acquired pneumonia cases in individuals aged 5 or older.[8] In the United States, it has been reported as an attributable cause of community-acquired pneumonia in up to 32.5% of cases.[5] Despite its prevalence, isolation of M. pneumoniae may represent colonization rather than infection, especially in those with mild disease or asymptomatic carriage.[17] An observational study conducted in the Netherlands involving 202 children found that isolated M. pneumoniae was detected in 16.2% of children with suspected pneumonia. However, it was also found in 21% of asymptomatic children, suggesting a high seroprevalence in the population, consistent with other studies.[16][17] M. pneumoniae infections tend to be more common with advancing age, especially among older individuals, where it ranks second only to S. pneumoniae in hospitalized community-acquired pneumonia cases.[5] Symptoms may take 4 to 20 days to appear following exposure, which is spread via aerosols from human-to-human transmission. The infection can occur year-round but is most frequently observed in the summer and fall in the United States and Asia.[18][19][20] Outbreaks are common in small communities and enclosed spaces, such as schools and military barracks.[21] The organism is transmitted from person to person, and the infection typically spreads slowly. Epidemics may occur every few years, lasting for prolonged periods. This pattern may be related to its longer incubation period and its ability to remain in the respiratory tract of infected hosts for long periods.[20][22]
C. pneumoniae is also a common cause of atypical bacterial pneumonia, contributing to 6% to 20% of cases.[23][24] Infections tend to occur in the summer and fall in the Northern Hemisphere, whereas in Australia, they are most frequently observed in the fall.[25][26] Transmission occurs through human-to-human contact but is inefficient, leading to most outbreaks being contained at the household level.[27] Immunocompromised hosts are more at risk of infection and severe disease. However, the incubation period is long (approximately 3-4 weeks), symptoms are typically mild, and some patients may experience asymptomatic infection.[28] Despite individuals aged 5 to 15 having a high rate of infection, C. pneumoniae infection is common in older individuals and can result in higher mortality rates compared to younger populations.[27][29] The prevalence of C. pneumoniae infection increases with age, and seroprevalence indicating exposure is found in 50% of adults by 20 years of age, and >95% by 50 years of age.[30]
L. pneumophila, unlike Mycoplasma and Chlamydia, is not transmitted person-to-person, and infection typically occurs through host-environmental interactions, particularly with stagnant freshwater and artificial water systems.[31] Contaminated drinking water, humidifiers, nebulizers, ventilation, and cooling systems have all been linked with cases of legionellosis.[32][33][34] The incubation period can range anywhere from 2 to 10 days.[35] Males are more affected than females, and older age groups, immunosuppression, and cigarette smoking all appear to be independently associated with legionellosis. L. pneumophila has been recorded in 1% to 3% of all community-acquired pneumonia cases and contributes up to 26% of all atypical pneumonia, but it may also be asymptomatic in some cases.[36] In a larger population survey, L. longbeachae was found in only 5% of 556 community-acquired pneumonia cases in Thailand.[37] Prevalence tends to be higher in younger age groups, and mortality is lower than for L. pneumophila cases.[38] L. longbeachae is typically associated with natural soil mixtures within hot and humid potting environments. Inoculation is thought to occur through inhaled exposure to contaminated potting mix and poor hygiene while gardening or landscaping.[39]
Please see StatPearls' companion resources, "Mycoplasma Pneumonia", "Chlamydia Pneumonia," and "Legionnaires Disease" for further information.
Pathophysiology
Atypical bacteria that cause pneumonia are often obligate intracellular organisms, making them difficult to culture and identify on Gram stain.[1] M. pneumoniae, C. pneumoniae, and Legionella species are typically gram-negative bacteria, but each has unique virulence factors and characteristics that allow them to survive in hostile environments, including against host defenses. These bacteria are acquired after inhalation of contaminated aerosolized droplets, and, except Legionella species, are transmitted from human to human.[34][33][34] When the inoculating bacteria overwhelm the host defenses, it causes a proliferation of the infectious agent. The pathogen replication triggers the host immune response, leading to inflammation, alveolar irritation, and impairment.[40] These immune responses result in the following signs and symptoms—cough, sputum production, dyspnea, tachypnea, and hypoxia.[41] Atypical bacterial pneumonia infections result in less lobar consolidation and are more likely to be associated with interstitial and bronchopneumonia radiological changes on imaging.[42] Therefore, many patients have subacute presentations and do not appear toxic in these cases; hence, the common term walking pneumonia is typically associated with M. pneumoniae. However, this can be a misnomer, as M. pneumoniae can still progress to shock and mechanical ventilation.[43] Due to their intracellular nature, these infections are often challenging to treat because antibiotics must be able to penetrate intracellularly to reach their intended target.
History and Physical
Patients often present with prolonged constitutional symptoms. Although not found to be predictive, it is traditionally taught that patients with atypical bacterial pneumonia infections present gradually, often accompanied by a viral prodrome that includes a sore throat, headache, nonproductive cough, and low-grade fevers.[9] Atypical infections rarely have an obvious consolidation area on auscultation/imaging compared to pneumococcal pneumonia. In addition, extra-cardiopulmonary symptoms are often observed; for example, Mycoplasma infections have been associated with vasculitis and thrombosis, and L. pneumophila is classically associated with gastrointestinal ailments and electrolyte abnormalities.[21][44][45] Despite the classical thought that bullous myringitis is associated with M. pneumoniae, it has been rarely documented in the literature compared to typical bacteria such as S. pneumoniae and Haemophilus influenzae.
M. pneumoniae is a significant cause of atypical bacterial pneumonia. Symptoms may include malaise, cough, myalgia, and sore throat. The cough is often dry and worsens at night, often appearing as intractable. Most cases of M. pneumoniae infection are mild and resolve on their own. M. pneumoniae can also cause a variety of extrapulmonary symptoms such as glomerulonephritis, erythema nodosum, urticaria, erythema multiforme, aseptic meningitis, Guillain–Barré syndrome, and cerebral ataxia.[21] Individuals with preexisting lung disease may develop empyema, pneumothorax, or even respiratory distress syndrome. A parapneumonic effusion can be associated with restricted chest expansion on the affected side.
C. pneumoniae infection commonly presents with a sore throat, cough, and headache, persisting for several weeks or even months. In some individuals, it can lead to pneumonia, otitis media, and bronchitis.[24] Besides acute infection, C. pneumoniae can also cause chronic infection in individuals with preexisting respiratory conditions, such as asthma and chronic obstructive pulmonary disease.[46] Asymptomatic infection may also occur and may only be evidenced by serosurveys.
L. pneumophila can be associated with severe lower respiratory tract infections. Several serotypes exist, and infection tends to occur in close quarters.[36] Human-to-human transmission is rare; most cases are due to inhalation of the pathogen from contaminated water sources such as humidifiers, whirlpools, respiratory therapy equipment, water faucets, and air conditioners.[32][33] Stagnant water provides an environment for organisms to proliferate. Individuals at risk for Legionella may have diabetes mellitus, malignancy, renal or liver failure, and those who have recently undergone plumbing work at home.[38] Once acquired, patients may present with altered mental status, cough, fever, and respiratory distress. Of the atypical bacterial pneumonia organisms, Legionella species are more likely to have a severe course, and the illness can quickly become severe if not treated promptly. Although extrapulmonary symptoms are rare, many patients develop severe respiratory distress, often requiring mechanical ventilation.[47]
Evaluation
In a nontoxic-appearing patient, particularly in the outpatient setting, a high clinical suspicion is sufficient to pursue empiric treatment. Blood work may reveal leukocytosis, and sputum Gram stain may show an accumulation of inflammatory cells without any identifiable organisms.[48] Urea levels may be elevated, and although leukocytosis may not always be present in most individuals, it is more likely to be elevated in older age groups. Other laboratory investigations, including serology and molecular testing, often complement and further help risk-stratify individuals and direct treatment.[1] In addition to assessing leukocytosis, some providers may evaluate a left-shift typical of legionellosis or perform a procalcitonin test to help differentiate between viral and bacterial etiologies. However, the yield of pro-calcitonin in the clinical setting is often mixed.[49][50][51][52] Legionella species infection may be associated with hyponatremia on electrolyte testing.[53] Patients admitted to the hospital with suspected atypical bacterial pneumonia should undergo urinary antigen testing for L. pneumophila species, as L. longbeachae may not be detected by this test. Swabs should also be taken to exclude viral causes using multiplex polymerase chain reaction testing (PCR). Depending on the setting and resources of the healthcare institution, PCR testing can also be run on multiplex panels that include atypical bacterial organisms, including Legionella, Chlamydia, and Mycoplasma, that appear equivalent to standard single-organism PCR and sequencing.[54][55] Serology testing can be used to confirm cases, but given the time taken to obtain paired samples to analyze for immunoglobulin titer rise or seroconversion, these tests may not assist in the acute clinical setting.[56][57] In addition, it is important to obtain blood cultures to exclude associated bacteremia and, if necessary, collect deep sputum cultures or bronchoalveolar lavage specimens to exclude typical bacterial infections and other infectious causes, such as viruses and fungi, particularly in immunosuppressed patients. These tests can also help identify the growth of atypical bacteria despite the lower yield compared to molecular testing.[1][54] These efforts may ultimately assist with later antimicrobial rationalization and de-escalation of antibiotics once the patient has improved.
In ill-appearing individuals or those in whom the diagnosis is uncertain, a chest x-ray is the diagnostic gold standard. Classic imaging findings in atypical pneumonia include patchy infiltrates, sometimes bilateral in distribution, and interstitial patterns, but these may reflect worse changes than what the patient presents with.[58] The chest x-ray may show a mild infiltrative process with hilar adenopathy.[29] On computed tomography (CT) imaging, bronchial wall thickening, centrilobular nodule formation, ground glass attenuation, and consolidation may be more evident in atypical bacterial pneumonia compared to typical bacterial pneumonia.[59] Atypical bacterial pneumonia is less commonly associated with lobar consolidations and complicated parenchymal findings such as empyema. Severe manifestations may still occur with the atypical bacterial pneumonia organisms, and acute respiratory distress syndrome and alveolar hemorrhage should still be considered in the critically unwell patient.[60][61] Bedside ultrasonography can potentially differentiate between atypical bacterial pneumonia and viral causes through the higher detection of dynamic air bronchograms in up to 71.4% of cases.
Treatment / Management
Atypical organisms such as M. pneumoniae, C. pneumoniae, and Legionella species lack cell walls; therefore, beta-lactam antibiotic monotherapy is not recommended.[1] If the treating clinician suspects atypical bacterial pneumonia, empirical treatment may be warranted before further investigations, depending on the severity of illness in the patient. In more severe cases, investigations outlined in evaluating atypical bacterial pneumonia patients should be conducted to exclude other infectious causes, assess severity and microbiological burden, and guide antibiotic rationalization and stewardship practices. In moderate-to-severe cases, empirical antibiotics should be started within 4 hours and ideally as soon as possible in the setting of sepsis to reduce the risk of deterioration.[62](A1)
First-line treatment for atypical bacterial pneumonia typically involves the macrolide family of antibiotics, although resistance is emerging.[63][64] Azithromycin is the most common and is available in intravenous and oral formulations with similar bioavailability; the short treatment course of 3 to 5 days (500 mg on the first day, 250 mg subsequently) is tolerable in many patients and efficacious for mild-to-moderate disease.[9] Clarithromycin 500 mg twice daily is an alternative to azithromycin. Other outpatient antibiotics include fluoroquinolone (such as levofloxacin 750 mg daily or gemifloxacin 320 mg daily in the United States) and tetracycline (doxycycline 100mg twice daily for 5-7 days). However, guidelines often differ in their use based on local dispositions.[65] For hospitalized patients with more severe cases, macrolides are often combined with broad-spectrum antimicrobials, including ceftriaxone, cefotaxime, and piperacillin-tazobactam or ampicillin-sulbactam, depending on the severity of illness, to cover a broad spectrum of pathogens. However, intravenous fluoroquinolone monotherapy has been considered in some jurisdictions.[3][64] In these instances, close cardiac monitoring is required due to the risk of tachyarrhythmias, such as torsades de pointes.[66] Despite these recommendations, clinicians often have challenges in understanding when to use combination therapy without guidelines.[67](A1)
Clinician tools such as the CURB-65 or SMART-COP scores and the pneumonia severity index are frequently used to stratify management into outpatient management, admission, or intensive care admission. However, these tools are yet to supplant clinical judgment regarding the appropriate management of patients with pneumonia, including atypical bacterial pneumonia.[49][62][68][69] Well-appearing individuals in whom an atypical organism is suspected can likely be managed with outpatient antibiotics and symptomatic care, while monitoring for potential complications.(A1)
Treatment failures are common due to antibiotic resistance, poor patient compliance, and inability to tolerate oral medications, among other factors.[1][70] In addition, some patients may have autoimmune conditions, primary respiratory pathology, or obstructing lung lesions/other opacities of non-infective etiology that may obscure consolidation, leading to an incorrect diagnosis.(A1)
Up to 20% to 30% of patients may have a parapneumonic effusion on the chest x-ray or CT chest.[71][72][73][74][75] If this fluid does not resolve, empyema may develop. Aspiration and fluid drainage are highly recommended if the pH is less than 7.2.[76](A1)
In children younger than 5, atypical bacterial pathogens are less common, with the incidence and frequency of atypical pathogens increasing with age.[8] Bacterial isolates may only be cultured less than 15% of the time, and less so for atypical pathogens, given the predominance of viral pathogens in children younger than 5.[77] As such, the evidence for empirical coverage of atypical bacterial pneumonia in children remains uncertain. [70] Of the bacterial causes of pneumonia, typical bacterial pathogens predominate. Therefore, when pneumonia is suspected in children younger than 5, the empirical outpatient treatment is amoxicillin, typically administered for 3 to 10 days.[70][78] The data behind antimicrobial duration are historically arbitrary, and more recent randomized trials suggest shorter durations may be similar in efficacy to longer durations. Duration should instead be guided by clinical status and exclusion of persisting sources of infection, such as empyema or parapneumonic effusions. Amoxicillin/clavulanate and co-trimoxazole have shown efficacy comparable to amoxicillin in children and can be considered alternative antimicrobial therapies.[79] Despite the uncertainty of evidence, the addition of clarithromycin or azithromycin can be considered for atypical bacteria in children if symptoms do not improve within 48 hours.[70] Macrolides are recommended for children older than 5 for 10 days.[77] Children who develop severe disease require parenteral therapy, which may include amoxicillin/clavulanate in addition to macrolides. In certain cases, fluoroquinolones may be an alternative, along with oxygen supplementation.[78](A1)
Older patients with atypical pneumonia often have altered mental signs and underlying comorbidities, which increase their risk for aspiration. In these cases, anaerobic coverage should be considered. Broad-spectrum empirical antimicrobial options include amoxicillin/clavulanate, piperacillin/tazobactam, or meropenem. Alternatively, metronidazole (500 mg twice daily) can be added to regimens that lack anaerobic coverage.[64](A1)
Criteria for Admission
Differential Diagnosis
The differential diagnosis for atypical bacterial pneumonia is similar to that for bacterial pneumonia and typically spans the cardiac, respiratory, and musculoskeletal systems. From the cardiac system, pericarditis and myocarditis can present in the setting of viral symptoms and should be considered. Within the respiratory system, distinguishing between the upper and lower respiratory tracts is essential. The upper respiratory system includes pharyngitis, sinusitis, and more emergent conditions such as epiglottitis and retropharyngeal abscess. For the lower respiratory tract, a chest x-ray and CT differentiate bronchitis/bronchiolitis from pneumonia. The diagnosis becomes more complex when an abnormal infiltrate is detected on imaging; in such cases, it is crucial to distinguish between atypical/viral/bacterial pneumonia, polymicrobial aspiration, and sterile chemical pneumonitis. Other non-infectious respiratory mimics include asthma and chronic obstructive pulmonary disease.[9] Lastly, it is essential to consider musculoskeletal complaints such as costochondritis and rib dysfunction; however, they frequently lack constitutional symptoms.
Prognosis
The majority of patients with suspected atypical bacterial pneumonia can be successfully treated on an outpatient basis. There is typically a complete resolution of symptoms and a low morbidity and mortality. Treatment is often uneventful in the absence of significant comorbid conditions, vital sign abnormalities, and a toxic appearance. As with all clinical diseases, not every case follows the expected course. Close follow-up and adherence with management strategies are necessary to monitor for disease progression. A smaller proportion of patients may require hospitalization due to disease progression, as indicated by the pneumonia severity index, SMART-COP, and CURB-65 scores. Several risk factors are associated with poorer outcomes, including an increased risk of early mortality.[82] These factors include increased age, hypothermia, altered mental status, multilobar pneumonia, shock at presentation, preexisting congestive cardiac failure, valvular heart disease, atrial fibrillation, diabetes mellitus, chronic renal impairment, and malnutrition.[83][84][85][86] Death from atypical bacterial pneumonia is rare but can occur in patients with comorbidities and older individuals, with mortality rates reaching up to 11% among those admitted to intensive care.[51]
Complications
Similar to typical bacterial pneumonia, the most prominent complications include respiratory failure, sepsis, multiorgan failure, coagulopathy, and exacerbation of preexisting comorbidities.[87] Other potential complications of bacterial pneumonia include:
- Lung fibrosis [88]
- Destruction of lung parenchyma
- Necrotizing pneumonia [89]
- Cavitation
- Empyema [90]
- Pulmonary abscess
- Death
Given the known extrapulmonary manifestations of atypical bacterial pneumonia, particularly for M. pneumoniae, autoimmune conditions can occur. Guillain–Barré syndrome, including its Miller Fisher syndrome variant; erythema multiforme; erythema nodosum; hemolytic anemia (cold agglutinin disease); autoimmune encephalitis; and transverse myelitis have all been noted to occur with or following M. pneumoniae infection, though they occur in only approximately 0.1% of cases.[91][92][93][94] According to case reports, L. pneumophila can rarely be associated with panniculitis, myositis, and rhabdomyolysis.[95][96] Similarly, according to the limited literature available, C. pneumoniae can rarely be associated with endocarditis and pleuro-pericarditis.[97] Epidemiological studies suggest an association between C. pneumoniae infection and an increased risk of lung cancer, warranting further investigation.[98][99]
Deterrence and Patient Education
As with the deterrence and education required for patients with bacterial pneumonia, atypical bacterial pneumonia should be similarly managed. Smoking cessation, maintenance of oral and hand hygiene, and limitation of hazardous alcohol intake should be emphasized given their associations with pneumonia.[100][101][102][103] The older individuals should be encouraged to obtain influenza and pneumococcal vaccinations to limit the risk of secondary or co-infections when unwell with atypical bacterial pneumonia.[104][105]
Pearls and Other Issues
Key considerations in the management and monitoring of atypical bacterial pneumonia include:
- Most patients respond with clinical improvement within 48 to 72 hours.
- The chest x-ray findings lag behind clinical features and may take 6 to 12 weeks to resolve.[42]
- If patients fail to improve within 72 hours, another cause should be suspected, such as antibiotic resistance or the development of complications, such as empyema.
Enhancing Healthcare Team Outcomes
The diagnosis and management of atypical bacterial pneumonia are often challenging due to the often delayed availability of laboratory results, making clinical judgment essential. An interprofessional team, including an emergency department physician, infectious disease consultant, nurse practitioner, internist, radiologist, and pharmacist, is key to effective management. Given the potential delays in diagnosis, treatment should not be postponed if atypical pneumonia is suspected and the patient is not improving.
The pharmacist should educate the patient on medication adherence and the importance of having the annual influenza vaccine among at-risk and older patients. Nurses should closely monitor patients for respiratory distress, nutrition, and mental status changes. For outpatient management, an infectious disease nurse should follow up with patients in a clinic to ensure proper recovery. If complications arise, the infectious disease physician should reassess the patient for appropriate management, with radiology involved in evaluating any related complications.[106] To minimize morbidity and mortality, it is essential to monitor patients until complete resolution of symptoms is achieved.[107] Close communication and coordination among the interprofessional team are vital for improving patient outcomes.
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