Lower respiratory tract infections are considered a common cause responsible for morbidity and mortality among children [1].The clinical entity of “atypical” pneumonia” was identified well prior to the establishment of Mycoplasma pneumoniae (M. pneumoniae) as its etiology agent. In 1937, Dienes and Edstall [2] isolated the first human “mycoplasma” from an abscess in a Bartholin’s gland [3,4]. In 1944, Eaton et al. first isolated M. pneumoniae in tissue culture from a sputum sample from a patient with primary “atypical pneumonia”; was named Eaton agent [5]. At that time, it was thought to be a virus because it was resistant to penicillin and sulfonamides and passed through filters that retained bacteria. Chanok et al.[6], proposed the taxonomic name M. pneumoniae for Eaton agent in 1962 [3].

Mycoplasmas are the smallest known free-living prokaryotes, with an extremely small genome size of 580to 2200 kilobase pair [1] lacking a cell wall. The absence of a cell wall and the specialized attachment organelle facilitates close contact with the host’s respiratory epithelium, supplying the bacterium with nutrients necessary for its growth and proliferation.

M. pneumoniae is capable of infecting both the upper respiratory tract and lower respiratory tract. Clinical manifestations of M. pneumoniae can occur as mild cases of tracheobronchitis to severe atypical pneumonia that can lead to various extrapulmonary complications [8]. M. pneumoniae has been identified as the cause of up to 40% of community-acquired pneumonia (CAP) cases in children over 5 years old [1].

The correct identification of M. pneumoniae infections is critical for prescription of the appropriate therapy since since it is not possible to diagnose M. pneumoniae infection merely based on clinical signs and symptoms. In only a minority of cases, specific aetiologic diagnosis of M. pneumoniae infection is established [9]. Mycoplasmas do not have cell wall so are not susceptible to β-lactam antimicrobial drugs, macrolides are generally accepted as first choice agent for treatment, especially in children. A worldwide increase in the prevalence of macrolide resistant Mycoplasma pneumoniae (MRMP) strains has been witnessed since 2000 .In some regions of Asia, the resistance rates have been reported to be over 90% [10]. Since molecular-based assays can detect M. pnueumoniae in clinical specimens, there is a need for real point of care testing for fast detection of M. pneumoniae or its DNA and mutations in macrolide resistance gene. It is necessary to develop safe vaccines that provide protective immunity against M. pneumoniae infection. M. pneumoniae should be considered in differential diagnosis of CAP and additionally it should also be considered in co-infections which are unresponsive to commonly administered beta-lactams [11,12].

This review focuses on the many new developments that enhance our understanding of M. pneumoniae causing community-acquired lower respiratory tract infections in children.

Epidemiology of Mycoplasma pneumoniae infections

M. pneumoniae can cause both upper and lower respiratory tract infections and is endemic and epidemic worldwide in children and adults. It is primarily a disease of childhood and adolescence, with the peak incidence of infection between 5 and 15 years of age. It may be responsible for approximately about 4 to 8% of community-acquired bacterial pneumonia (CABP) cases during endemic periods, up to 20 to 40% of CABP in the general population during epidemics, increasing up to 70% in closed populations [7].

M. pneumoniae infection spreads through droplets released from the upper and lower respiratory tract and can survive in the respiratory tract for several weeks or several months with an incubation period 1to 3 weeks. Infections tend to be more common in the summer or early fall, but can occur at any time of the year. Epidemics occur primarily during M. pneumoniae epidemic cycles, in addition to endemic background patterns [13]. The cyclical epidemics (every few years) of M. pneumoniae are associated with a shift from one P1subtype to another [14,15]. Outbreaks have been reported in the closed populations (e.g. summer camps, schools, military bases, college dormitories).M. pneumoniae can also cause nosocomial infections in long- term care (LTC) facilities. Natural immunity to M. pneumoniae infections is usually short-lived and a failure of natural immunity to eliminate the organisms, leads to prolonged carriage in some instances.

Clinical Manifestations Respiratory Disease

Most M. pneumoniae infections are symptomatic, and most of these occur in children and adolescents. M. pneumoniae often causes tracheobronchitis, which manifests as a dry cough or a cough that produces mucoid or mucopurulent sputum. Many individuals may develop nonspecific symptoms that resemble an upper respiratory tract infections, such as coryza, sore throat, headache, and otitis media. In more serious cases, dyspnoea may occur, and the cough may have pertussis-like characteristics [1].

Coryza and wheezing are most likely to occur in children under five years of age, while the development of pneumonia is relatively rare. Bronchopneumonia (with one or more lobes) occurs in children aged 5 to 15 years and may require hospitalization [16]. The term “walking pneumonia” or “primary atypical pneumonia” is used to characterize the mycoplasmal respiratory disease that is characteristic of M. pneumoniae because the disease is mild, non-debilitating, and presents with the onset of pneumonic symptoms, and patient still continues to function mostly normal [1].

The clinical presentation of respiratory disease caused by M. pneumoniae is indistinguishable from other atypical pathogens, notably many respiratory viruses, Chlamydophila pneumoniae and Streptococcus pneumoniae. M. pneumoniae causes cough, fever and unilateral crackles. Chest auscultation may reveal coarse rales and rhonchi if the disease is limited to tracheobronchitis and fine inspiratory rales and dullness at the base of the lungs if pneumonia has developed. It is often difficult to distinguish M. pneumoniae pneumonia from viral pneumonia clinically, so this has influenced the recommendations for the use of antibiotics in the treatment of pneumonia in children [17].

Radiographically, M. pneumoniae infections may be indistinguishable from a viral lower respiratory tract infections, with patchy airspace consolidation and ground-glass opacities. The more obvious radiographic abnormalities are often in the lower lobes. Unilateral pleural effusions are especially common in children.

Asthma

M. pneumoniae infection is associated with asthma. The infection may precede asthma onset, exacerbate the asthma [18], or play a role in chronic asthma in some children and adults. Extrapulmonary manifestations, M. pneumoniae can cause extrapulmonary manifestations in almost every organ, including the skin, hematologic, cardiovascular, musculoskeletal, and nervous   systems.   The   most   common   manifestations are dermatological and neurological system illnesses. These extrapulmonary manifestations may be caused by three different mechanisms such as direct local effects of bacteria, by indirect effects or after bacterial dissemination [19].

The most common manifestations are dermatological and neurological system illnesses. Skin complications may occur in up to 25% of patients such as erythema multiforme, anaphylactoid purpura Stevens–Johnson syndrome and urticaria. M. pneumoniae is the most common cause of encephalitis in children, accounting for up to 13% of cases [20]. There are also other neurological complications such as Guillain-Barre Syndrome (ascending paralysis) and acute demyelinating encephalopathy [8].

It can also cause autoimmune hemolytic anemia, septic arthritis, rhabdomyolysis and rarely plays a role in cardiac manifestations. Other nonspecific symptoms, such as conjunctivitis, iritis, and uveitis, may have an immunological basis, as no pathogens were detected in ocular tissue [21].

Carriage

Like many other respiratory pathogens, M. pneumoniae can be carried asymptomatically in the respiratory tract. The detection rate of M. pneumoniae DNA in the respiratory tract of healthy children without respiratory symptoms was 21% in a Dutch study [22], and 56% in an American study [23]. In children with M. pneumoniae CAP, co-existence of M. pneumoniae with other pathogens has also been described, and was recently reported in 28% of the patients [24].

Laboratory Diagnosis

The current methods for diagnosing M. pneumoniae infection can be achieved using culture, serology, or molecular-based methods.

A. Culture

Culture methods have been the gold standard for diagnosis but is time-consuming, laborious and expensive and colonies become visible in 2-5 weeks, therefore, for routine diagnosis is not recommended.

B. Serology

Serum testing is more sensitive than culture for detecting M. pneumoniae infection.

Cold Agglutinins

Cold agglutinin testing was once considered a valuable tool, but it is not a highly specific indicator of M. pneumoniae. Cross- reacting cold agglutinins are produced in about 50% of M. pneumoniae infections and disappears within 6 to 8 weeks.

Complement fixation test (CFT)

The complement fixation test (CFT) to detect antibodies against M. pneumoniae lacks sensitivity and specificity and has been replaced by alternative methods.

Detection of  Mycoplasma pneumoniae-Specific Antibodies

The most reliable serological diagnosis of M. pneumoniae is when antibody titers of 4-fold or greater are detected in paired serum samples obtained 2 to 3 weeks apart and tested concurrently for IgM and IgG antibodies [3]. The most widely used serological methods are enzyme-linked immunosorbent assays (ELISA) to detect immunoglobulin M (IgM), IgG, and IgA antibodies to M. pneumoniae, although other methods e.g. particle agglutination (PA) assays and immunofluorescence methods were also used.

C. Detection of Mycoplasma pneumoniae-Specific Nucleic Acids

Nucleic acid amplification techniques (NAATs) have the potential to provide rapid, sensitive and specific results and can support appropriate early antibiotic treatment. With higher analytical sensitivity and shorter turnaround times, NAAT is increasingly considered the “new gold standard”. They are available with a great variation of methods used, including variability of target, NAAT (conventional, nested, real-time; monoplex vs. multiplex; polymerase chain reaction (PCR) vs. isothermal amplification technologies), detection formats, and different platforms. The main gene targets used in PCR assays to detect M. pneumoniae are the P1adhesin gene, ATPase operon, CARDS toxin gene,16S-23rRNA spacer,16S rRNA, dnaK, pdhA, tuf, parE, ptsL, and the noncoding repetitive element in repMp1 [25,26]. Conventional PCR for M. pneumoniae has mostly been replaced by real-time PCR. NAAT is not recommended in children not suspected of having typical manifestations of mycoplasmal infection [24]. Besides PCR, other NAAT formats include loop-mediated isothermal amplification (LAMP), nucleic acid sequence-based amplification (NASBA), and strand displacement assay (SDA).

D. Non-amplified antigen detection Immunochromatographic (lateral flow) assay is used for pathogen detection at the point of care. Another immunochromatographic assay used colloidal gold to detect M. pneumoniae (P1 gene) with 100% sensitivity and 97.4% specificity compared to real-time PCR. NA-SERS-NA-SERS (Nanorod array surface-enhanced Raman spectroscopy) is a new research method for the detection of M. pneumoniae [27]. The Raman signal enhancement permits the acquisition of unique SERS spectra within seconds without the need for sample amplification by growth or PCR [28].

Matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) potentially limits its usefulness for M. pneumoniae due to the time-consuming and insensitive nature of the prerequisite culture in order to perform MALDI-TOF MS.[25].

Treatment and Macrolide-resistant

Mycoplasma pneumoniae M. pneumoniae lacks a cell wall. Hence it is insensitive to the penicillins and other β-lactam antibiotics. In children with M pneumoniae infection, macrolides are recommended as first line antibiotic treatment [3]. Quinolones are still not recommended for use in children, although ciprofloxacin has been shown to be safe in children. In the early 2000s, the emergence of Macrolide resistance Mycoplasmasa pneumoniae (MRMP) was observed in Japan due to point mutations in the peptidyl-transferase loop of the 23S rRNA, most commonly the A2063G mutation, which then spread to Asia, Europe, and North America (8). Quinolones, tetracyclines or glycylcyclines tigecyclines [29], may lead to clinical improvement after failure of macrolide therapy in children.

Vaccination

There is currently no vaccine to protect against M. pneumoniae infections. Various types of M. pneumoniae vaccines include inactivated, live-attenuated, and subunit vaccines [30]. Human vaccine has yet to develop a vaccine suitable for general use, specifically targeting the emergence of MRMP.

M. pneumoniae can cause respiratory infections in persons of all ages and can account for a significant portion of community acquired bacterial pneumonia (CABP), especially during epidemics. Extrapulmonary manifestations have been reported in almost every organ. With molecular tests capable of detecting M. pneumoniae in clinical samples with same-day turnaround, diagnostic laboratories can now provide improved microbiological diagnosis, but quick detection of M. pneumoniae or its DNA, as well as mutations in the macrolide resistance gene, requires real point-of-care testing. Antibiotics are urgently needed for the implementation of MRMP therapy that can be used safely in children. Clinicians managing patients infected with COVID?19 should be alert to M. pneumoniae coinfection, which may exacerbate clinical symptoms during this COVID?19 outbreak. Development of a safe vaccine would provide protective immunity and would be an important step in reducing the level of M. pneumoniae infection.

Contribution

Surinder Kumar: Concept and design of the study; Writing– Writing original draft, revision, and final approval of the version. Sourabh Kumar: Concept and design of the present study,Writing- Participated in original draft, revision, final approval of the version.

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Mycoplasma pneumoniae (M. pneumoniae) causes respiratory tract infections in all age groups but older children and young adults are more affected than other age groups. Atypical pneumonia was described as a distinct and mild form of community-acquired pneumonia (CAP) already before M. pneumoniae had been discovered and recognized as its cause. M. pneumoniae is estimated to be the cause of up to 40% of community acquired pneumonia in children over 5 years of age. Extrapulmonary manifestations have been reported in almost every organ. The correct diagnosis of M. pneumoniae infections is critical to initiate the appropriate therapy, since it is not possible to diagnose M. pneumoniae infection merely based on clinical signs and symptoms. Empirical therapy is, therefore, given in most cases. The current methods for diagnosing M. pneumoniae infection can be achieved using culture, serology, or molecular-based methods.Mycoplasmas do not have cell wall so are not susceptible to β-lactam antimicrobial drugs, macrolides are generally accepted as first choice agent for treatment, especially in children. Emergence of macrolide resistant M. pneumoniae is now being reported in children, in more than 95% of M. pneumoniae isolates, which may be associated with severe clinical features and more extrapulmonary complications. This review focuses on the many new developments that enhance our understanding of M. pneumoniae causing community-acquired lower respiratory tract infections in children

• Mycoplasma pneumoniae

• Children

• Polymerase chain reaction

• Serology

Kumar S, Kumar S (2023) Mycoplasma Pneumoniae as a Causative Agent of Community-Acquired Lower Respiratory Tract Infections in Children. Ann Pediatr Child Health 2023; 11(5): 1325.