Mycoplasma pneumoniae Pneumonia
PKGhatak, MD
The bacterial Mycoplasma pneumoniae is more intriguing than the pulmonary diseases it produces in humans. Mycoplasma is the smallest self replicating organism that has the smallest genomes. It is a small bacterium without a cell wall. Phylogenetically Mycoplasma pneumoniae (M. pneumoniae) belongs to Clostridia. The bacterial body is covered by a single layer membrane (bacterial body has double layered membrane). The cytoplasm has very few organelles and no limiting membrane. The nucleus is a circular double helix without a nuclear membrane. The nucleus contains only 500 to 1,000 base pairs. M. pneumoniae is dependent on the host for nutrients because of having only a limited number of enzymes and protein manufacturing capacity, The bacteria are pleomorphic mostly short filaments measuring 100 nm (nanometer) X 1000nm exists as a parasite in living organisms, and round or oval forms measuring 300 nm are detected in laboratory grown culture medium. It can change shape because of an absence of a cell wall, and it passes through bacterial filters. It is poorly stained, and requires a special DNA stain, Hoechst stain. It is difficult to observe under an ordinary microscope because of its small size.
In nature, M. pneumonia lives as a saprophyte and parasite. The infective filamentous form has a harpoon like terminal organelle and is used to attach to the respiratory epithelium and is able to resist removal by mucociliary escalator. A protein, P 1, is present on the surface membrane, it performs multiple important functions – it is an adhesion protein to respiratory epithelial cells, P 1 gives the bacteria its virulence, P 1 is antigenic and antibodies are produced against it. Human RBC contains P I/i protein. M. pneumoniae antibodies react with this RBC antigen and produce hemagglutination. Mycoplasma uses the terminal filament for gliding motion in a liquid medium. The bacteria are difficult to grow in the laboratories, require cholesterol and other nutrients including the newborn calf's serum to grow. Laboratories nicknamed Mycoplasma “crabgrass” because the bacteria are difficult to detect, easily contaminate lab equipment and especially cell cultures lines, and are difficult to get rid of. It can be successfully cultured on a special agar plate and takes about 3 weeks to grow. The colony looks like fried eggs with the sunny side up.
The bacteria multiply by binary fission, and subsequently, the filaments break into coccus forms. The growing bacterial bodies often do not separate completely and appear as branches fungus like and so named as Mycoplasma ( mykes = fungus, plasma = formed). Also has a tender nickname Mollicute. (molli = soft, cute = skin). The nuclear material is passed to the dividing bacteria by a terminal disc like organelle. At times the nuclear separation is incomplete and appears as a multinucleated form. In infection, the bacteria produce H2O2, superoxide radicals and malondialdehyde at the infection site and they are toxic to tissues and result in the desquamation of respiratory epithelium. Denuded respiratory epithelium triggers the cough reflex. The cough continues, even if the infection is controlled because the regrowth of surface epithelium takes time to cover the denuded area.
The biochemical peculiarities of Mycoplasma are also colorful, but not entered into because this will be an unnecessary diversion.
The infection is due to person to person transmission via large sized droplets, and the bacteria remain attached to a respiratory epithelium and thus remain infective. The incubation period is 3 weeks. Children under 6 months of age are protected due to maternal antibodies. Children of kindergarten age show significant infection in the winter months. Older children in high school age and junior college age students have the highest infection rate. Repeated infections are natural order, adults are much less susceptible. Many studies show high antibodies in the adult population confirming the notion that infection is much more common than recognized.
Signs and symptoms of upper respiratory infection due to M. pneumoniae are not anything as spectacular as the colorful bacterial features. However, M. pneumoniae pneumonia has some interesting aspects. M. pneumoniae pneumonia was one of the many causes of Atypical Pneumonia and Community Acquired pneumonia. Beginning in 1930 the atypical pneumonia was called Walking Pneumonia. In 1944 M. pneumoniae pneumonia was named after Dr. Monroe Eaton as Eaton Agent pneumonia. He demonstrated bacterial filter filtrate of infected secretion from animals produces the same disease in susceptible animals (Koch's postulate), later Dr. Eaton successfully grew M. pneumoniae in eggs. Between 1945 and 1955 M. pneumoniae infections were also called Pleurodynia like organism pneumonia. Finally in 1955 M. pneumoniae was named M. pneumoniae pneumonia. In 1889 Albert Bernhard Frank coined the name Mycoplasma after detecting fungus like organisms in the plant cell cytoplasm. Endemic M. pneumoniae pneumonia appears in cycles of 3 to 7 years. Many students in summer camps, military recruits, adults and children are especially hit hard during endemics.
The covid-19 pandemic has educated the general public that the virus can produce deadly diseases from its effects on cytokines, chemokines and immune cells. Mycoplasma pneumoniae can cause complications by all these mechanisms. Mycoplasma pneumoniae prefers to be a parasite and produces locally tissue damage from toxins. Symptoms are persistent cough, increased respiratory discharge, low grade fever and headaches. Pneumonia when it develops is patchy, interstitial, sub-segmental and usually peribranchial. A small amount of pleural effusion may also occur. In x-rays, pneumonia appears more extensive than clinically suspected.
At about 7 days after infection, the body begins generating IgM antibodies. Both IgG and IgM antibodies are produced. IgM antibodies are short lived and their presence indicates a recent infection. IgG-complement-fixing antibodies used to be the main laboratory test for the detection of a recent M. pneumoniae infection. The IgG antibodies can persist for up to 4 years. A rising titer of 4 times to 64 times is used as the diagnostic criteria by some labs.
In the first few days of respiratory infection antibodies produced are cold sensitive, and cause hemagglutination at a low temperature (0 degree C), but appear only in about 50% of cases and last only a week. Moreover, other infections/ diseases can produce cold agglutinins also. Fortunately, all these tests are abandoned or in the process to being abundant and should be considered as relics of the past. The direct detection of Mycoplasma antigen by DNA probe, bacterial DNA detection by nuclear amplification, PCR and various other modified PCR test technologies have replaced serological tests for the diagnosis of acute M. pneumoniae pneumonia. But serology tests have their place in research.
Complications.
The incidence of extrapulmonary complications is about 25 %. Most commonly seen in skin, manifested as erythema multiforme. Steven Johnson syndrome rarely happens. Complications involving the GI tract, musculoskeletal and other systems are seen but are minor and self-limiting. More serious complications are Hematological and neurological.
Hemolytic anemia.
Hemolytic anemia is a serious complication of Mycoplasma infection. Antibodies produced against the P1 surface antigen of Mycoplasma pneumoniae cross react with RBC I antigen and produce hemolysis in cold temperatures. This is called cold hemagglutination. This is not however unique to Mycoplasma. This is also seen in Infectious mononucleosis, Cytomegalovirus infection, SARS-CoV2 viral infection, and Aggressive B-cell lymphoma.
Hemophagocytic lymphohistiocytosis (HLH) syndrome.
It is rare but important because this is a potentially fatal disease. Macrophages become cannibalistic and start to devour RBC, Platelets, WBC and the precursor cells in the bone marrow. This transformation of macrophages is brought about by cytokines. Enlarged spleen, jaundice and pancytopenia are distinctive features. An increase in acute phase reactants in serum and in the peripheral smears erythrophagocytosis in macrophages are seen. In delayed diagnosis the outcome is bad.
Neurological complication.
The neurological complications are many. But fortunately, only about 1 to 7 % of cases develop neurological complications. The neurological complications are of two categories- early and late.
Early. Aseptic meningitis is due to M. pneumoniae invasion of the CNS (central nervous system). But controversies of the pathogenesis of neurological diseases continue. Those who support direct invasion mention that the blood vessels develop endothelial cellular gaps making entry of bacteria to the meninges possible. The DNA of M. pneumoniae is detected in the cerebrospinal fluid in 10 out of 17 cases in one series, but only in 1 to 10 % of cases of other CNS complications.
Late. Transverse myelitis and thrombotic lesions of CNS are due to microvascular platelet thrombi. Gillian-Barrie syndrome, Polyradiculitis are considered autoimmune manifestations. It is known that M. pneumoniae surface glycolipid is antigenic and antibodies cross-react with the myelin of the nerve sheath or to the neurons. Other CNS diseases are encephalitis and meningoencephalitis. All these late neurological complications are due to Cytokines induced or autoimmune diseases.
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