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Medical Microbiology Respiratory System - Pneumonia Streptococcus Pneumoniae, Chlamydia and Legionella Dr. Sameer Naji, MB, BCh, PhD (UK) Dean Assistant Head of Basic Medical Sciences Dept. Faculty of Medicine The Hashemite University Life History Streptococcus pneumoniae is found worldwide. It resides asymptomatically in the nasopharynx of healthy carriers. The respiratory tract, sinuses, and nasal cavity are the parts of host body that are usually infected. However, in susceptible individuals, such as elderly and immuno-compromised people and children, the bacterium may become pathogenic, spread to other locations and cause disease. The route by which this organism is spread is from human to human in the form of aerosol droplets When inside the host the organism’s primary site of pneumococcal colonization is the nasopharynx. From this site it can aspire to the lungs, eventually spread to the blood and traverse the blood-brain barrier to the meninges, once inside the blood it can cause infections throughout the body Microbiological characteristics Streptococcus pneumoniae is a gram-positive coccus. Usually they are found in pairs of cocci, or diplococci, but they may also occur in short chains or singly. When cultured on blood agar they demonstrate alpha hemolysis. They are non motile organisms Virulence is caused by the chemical composition of the capsule. There are over 90 serotypes of S. pneumoniae which causes great difficulty when trying to develop a vaccine for this bacterium. The capsule interferes with phagocytosis by preventing C3b opsonization of the bacterial cells Diseases S. pneumoniae is the leading cause of pneumonia in all ages. It is characterized by four stages. 1. In the first stage the lung alveoli fill up with a serous fluid which is thought to be stimulated by the cell wall of the organism. This fluid contains a lot of organisms but little inflammatory cells. The spread of the organism throughout the lungs is mediated by this fluid. 2. In the second stage, neutrophils, which are attracted by the S. pneumoniae and there chemotactic signals and the host cell’s alternate pathway, invade the alveoli. Also red blood cells are recruited to this site. 3.In the third stage, mostly neutrophils are packed into the alveoli and very few bacteria remain. 4.In the final stage, macrophages eliminate the remaining residue from the inflammatory response As one can see, the damage which is done to the lung is largely a result of the host’s inflammatory response, which causes the buildup of fluids in the lungs. If S. pneumoniae is allowed to persist in the lungs it can then invade the blood, which causes bacteremia. When in the blood it can traverse the blood-brain barrier and infect the meninges, which results in meningitis. S. pneumoniae is also associated with diseases in other parts of the respiratory tract including the paranasal sinuses, which is better known as sinusitis, and the middle ear can become infected, which is known as otitis media. It has also been known to cause peritonitis, an inflammation of the peritoneum, the membrane that lines the abdominal wall, and it is also implicated in causing arthritis Diagnosis A gram stain is performed from the sputum of the infected patient. The presence of neutrophils (>25 neutrophils and <10 epithelial cells per high power field) and greater than ten gram-positive diplococci usually results in the diagnosis of Streptococcus pneumoniae. For further conformation of this organism, it is streaked on blood agar. When on blood agar the organism should exhibit alpha-hemolysis, which is characterized as a zone of green coloring around the colonies of bacteria on the agar, the streaked organisms must also exhibit bile solubility and optochin sensitivity as well as fermentation of inulin to have greater assurance that this organism is in fact S. pneumoniae Epidemiology S. pneumoniae most commonly inflicts children, the elderly, and other people with weakened immune systems. The incidence among adults exhibits a midwinter peak and a striking dip in the summer, due to closer living conditions during the winter. Up until 2000, S. pneumoniae infections caused 100,000-135,000 hospitalizations for pneumonia, 6 million cases of otitis media, and 60,000 cases of invasive disease, which included 3300 cases of meningitis. Incidence in the U.S. showed geographic variation from 21 to 33 cases per 100,000 people. Interestingly enough, Alaska native adults have an 8 times higher disease rate and Alaskan infants a 4 times higher rate than the benchmark U.S. community as they remain indoors and live in crowded conditions and poor ventilated homes, this increases the transmission and therefore the incidence of S. pneumoniae in this area Treatment There are several different treatment options for S. pneumoniae infections. For mild and severe pneumococcal infections penicillin G is used. Due to a growing number of penicillin resistant S. pneumoniae this organism has become a greater concern. It has a natural transformation system in which genetic material is exchanged between two organisms. Therefore, bacteria that have developed antibiotic resistance, whether due to mutation or natural selection, can often pass these traits to other bacteria. This natural transformation is accelerated by the fact that these bacteria have a relatively fast growth rate and achieve large cell densities in an infectious setting Because of these natural attributes the spread of the antibiotic resistant genes is cause for great concern. Fortunately, Erythromycin has been shown to work well on these penicillin resistant bacteria Prevention For the prevention of this disease, a vaccine is currently offered which has a 23-valent capsular polysaccharide which protects against the most common strains But due to the great antigenic variety of the S. pneumoniae, which has at least 90 different strains, a universal vaccine cannot be developed Chlamydial Pneumonias Overview Three chlamydial organisms are pathogenic to humans: Chlamydophila pneumoniae, Chlamydophila psittaci, and Chlamydia trachomatis. These are small, gram-negative, obligate intracellular organisms. All three species can cause pneumonia in humans. C pneumoniae causes mild pneumonia or bronchitis in adolescents and young adults. Older adults may experience more severe disease and repeated infections. C psittaci causes psittacosis or ornithosis after exposure to an infected bird. Ornithosis is the preferred term, because almost any bird can transmit the organism. The clinical spectrum of C psittaci infection ranges from an asymptomatic infection to a fulminant toxic syndrome. Patients with ornithosis most commonly present with pneumonia or fever of unknown origin. C trachomatis is an important cause of sexually transmitted diseases, including trachoma, pelvic inflammatory disease, and cervicitis. C trachomatis can also cause pneumonia, primarily in infants and young children. Document cases of pneumonia due to C trachomatis have been reported in immunocompromised adults and laboratory workers. Mode of transmission The mode of transmission is different among the three species (C pneumoniae, C psittaci, and C trachomatis), but all can cause systemic disease by hematogenous spread. Respiratory secretions transmit C pneumoniae from human to human, whereas infected birds transmit C psittaci to humans via a respiratory route through direct contact or aerosolization. [2] Birds known to cause ornithosis include cockatiels, parrots, parakeets, macaws, chickens, ducks, turkeys, pigeons, and sparrows, among others. When a pregnant woman have a C trachomatis infection of the cervix, the organism is transmitted when the infant passes through the infected birth canal. C trachomatis infection may cause neonatal conjunctivitis, nasopharyngitis, otitis media, and pneumonitis. The tendency to chronic inflammation is typical, and chronic persistent infection may occur if a neonatal infection remains untreated. Immunity to chlamydial organisms is usually not persistent, leading to repeated and chronic infections, particularly in the ocular and urogenital systems. Epidemiology C. pneumoniae pneumonia The estimated number of cases of C. pneumoniae pneumonia per year in the United States is 300,000, and the pathogen is estimated to cause 1-20% of communityacquired pneumonia (CAP) cases among adults. In contrast, the incidence may be as high as 50% in children with CAP Although C pneumoniae pneumonias occur every year, epidemiologic studies suggest a 4-year cycle. This disease is more common in males (60-90%) than in females, a difference possibly due to cigarette smoking. The incidence of C pneumoniae pneumonia is highest among the elderly C. psittaci pneumonia Psittacosis was first reported in Europe in 1879. Anyone exposed to an infected bird is at risk for infection with C psittaci. This disease is found worldwide and year-round, with most cases being sporadic. Cases of ornithosis in the United States declined after the introduction of antibiotic-laced bird feed and a quarantine period of 30 days for imported birds. From 1988-1998, 813 cases of psittacosis in humans were reported to the US Centers for Disease Control and Prevention (CDC). [11] The Council of State and Territorial Epidemiologists revised the case definition for psittacosis in June 2009 to include more stringent laboratory criteria for confirmed and probable cases. As a result, only 4 cases of psittacosis were reported in 2010, as compared with an average of 16 (range: 9–25) cases reported from 2000-2009. [12] Additional information about case reporting of psittacosis can be found through the National Association of State Public Health Veterinarians. Approximately 70% of the psittacosis cases with a known source of infection result from exposure to a pet bird. The diagnosis of psittacosis can be difficult, and many more cases may be undiagnosed or unreported C. trachomatis pneumonia In infants, an estimated 12,000 cases of pneumonia due to C trachomatisoccur each year, and approximately 522% of pregnant women are thought to have C trachomatis infection of the cervix; 30-50% of neonates born to infected mothers show culture evidence of infection. Of infected neonates, 15-25% present with clinical conjunctivitis and/or nasopharyngitis which can develop into neonatal pneumonitis in some cases, and approximately 11-20% of infants born to infected mothers develop symptomatic pneumonia before 8 weeks of age. [13] Adult cases have been reported in immunocompromised hosts Clinical Presentation C. pneumoniae pneumonia Most patients infected with C. pneumoniae remain asymptomatic. The incubation period is approximately 34 weeks. Symptoms develop in a biphasic pattern characterized by an initial period of upper respiratory tract symptoms (eg, rhinitis, laryngitis, pharyngitis, sinusitis), followed by symptoms of pneumonia after 1-4 weeks. Fever is present in the first several days, less often after 1 week. Cough is prominent, with scant sputum production and may persist for weeks to months despite therapy, along with malaise. Hoarseness is more common than in mycoplasma or other pneumonias. Headache occurs in as many as 60% of cases C. psittaci pneumonia Exposure to birds, especially sick ones, is a clue to the diagnosis of C. psittaci pneumonia Pet shop employees and poultry industry workers are also at risk The incubation period is 5-14 days or longer. Disease severity ranges from mild to severe with associated systemic illness. Mortality occurs in less than 5% Fever is the most common symptom and may reach 39.440.5°C Nonproductive cough has been observed in 50-80% of cases. Chest pain is common, but pleuritic pain is rare C. trachomatis pneumonia Nasal obstruction/discharge, cough, and tachypnea are common symptoms in C. trachomatis infection. Infants are usually symptomatic for 3 weeks or longer before presentation. Most patients are afebrile and only moderately ill. Scattered crackles with good breath sounds are characteristic. Wheezing is usually absent. Conjunctivitis and middle ear abnormality are present in half of C. trachomatis pneumonia cases Laboratory Tests in Chlamydial Pneumonias Serological testing or polymerase chain reaction (PCR) for the diagnosis of C. pneumoniae. Despite evident drawbacks, serology is still considered the gold standard, but this is likely to change. The preferred serologic test is microimmunofluorescence (MIF) with an IgM titer ≥1:16 or a 4fold increase in IgG titer. Culture for C. pneumoniae is technically complex and time consuming. Isolation of the organism by culture For C. psittaci compatible clinical illness with a 4-fold rise (to a reciprocal titer of 32 or greater by paired sera collected at least 2 weeks apart) in CF or MIF. Detection of an IgM titer of 16 or greater against C psittaci by MIF Clinical findings suggest the diagnosis of C. trachomatis pneumonia. chlamydial inclusions or elementary bodies on Giemsa-stained smears of the conjunctivae or nasopharynx confirms the diagnosis. Antichlamydial IgM titer may be elevated in infected infants • Treatment of Chlamydial Pneumonias The goals of pharmacotherapy are to eradicate infection, reduce morbidity, and prevent complications. Tetracyclines and macrolides are the drugs of choice for chlamydial pneumonias. Tetracyclines are bacteriostatic in nature; they work by inhibiting protein synthesis. Macrolides inhibit bacterial growth, possibly by blocking dissociation of peptidyl t-RNA from ribosomes, thus causing cessation of RNA-dependent protein synthesis. AZD0914 (AstraZeneca) is a novel DNA-gyrase inhibitor, which has in-vitro activity against C. trachomatis and C. pneumoniae comparable to commonly used antimicrobials such as levofloxacin, azithromycin, and doxycycline. Legionellosis (Legionnaires’ Disease) Legionella is a genus of Gram-negative bacilli that take their name from the American Legion convention where they were first discovered. The species designation of the prime human pathogen, Legionella pneumophila, reflects its propensity to cause pneumonia. Legionella species are widespread in the environment. Transmitted through aerosolization or aspiration of Legionella-contaminated water, but it is NOT spread by human-human interaction Immunocompromised individuals are most susceptible LEGIONELLOSIS Legionellae are inhaled into the lung from an aquatic source in the environment. Once there, they produce a destructive pneumonia marked by headache, fever, chills, dry cough, and chest pain. Although there may be multiple foci in both lungs and extension to the pleura, spread outside the respiratory tree is very rare. EPIDEMIOLOGY The widely publicized outbreak of pneumonia among attendees of the July 21st, 1976 American Legion convention in Philadelphia led to the isolation of a previously unrecognized infectious agent, L. pneumophila. In nature, Legionella species are ubiquitous in fresh water particularly in warm weather. Transmission to humans is possible when the water supply of buildings becomes colonized and the system includes devices that create aerosols. Most outbreaks have occurred in or around large buildings such as hotels, factories, and hospitals involving cooling towers or some other part of the air-conditioning system. Some hospital outbreaks have implicated respiratory devices and potable water coming from parts of the hot water system such as hot tubs, cooling towers, hot water tanks, faucets and shower heads. PATHOGENESIS L. pneumophila attacks the lung, producing a necrotizing multifocal pneumonia. Microscopically, the process involves the alveoli and terminal bronchioles, with relative sparing of the larger bronchioles and bronchi . The inflammatory exudate contains fibrin, polymorphonuclear neutrophils (PMNs), mechanisms involving multiple molecules. One outer membrane protein (OMP) binds C3, facilitating phagocyte recognition, and induces pores in the membrane of the macrophage. Another OMP called macrophage invasion potentiator (Mip) determines cell entry. Inside the vacuole the bacteria continue to replicate by preventing phagosomelysosome fusion and instead recruiting rough endoplasmic reticulum to the phagosome. LEGIONELLOSIS: CLINICAL ASPECTS MANIFESTATIONS Legionnaires’ disease is a severe toxic pneumonia that begins with myalgia and headache, followed by a rapidly rising fever. A dry cough may develop and later become productive, but sputum production is not a prominent feature. Chills, pleuritic chest pain, vomiting, diarrhea, confusion, and delirium may all be seen. Radiologically, patchy or interstitial infiltrates with a tendency to progress toward nodular consolidation are present unilaterally or bilaterally. A less common form of disease called Pontiac fever (named for a 1968 Michigan outbreak), is a nonpneumonic illness with fever, myalgia, dry cough and a short incubation period (6 to 48 hours). Pontiac fever is a self-limiting illness and may represent a reaction to endotoxin or hypersensitivity to components of the Legionella or their protozoan hosts. Difference between Legionnaires' disease and Pontiac Fever Legionnaires' disease (LD) Clinical features Radiographic pneumonia Pneumonia, cough, fever Yes Pontiac Fever (PF) Flu-like illness (fever, chills, malaise) without pneumonia No Incubation period 2-14 days after exposure 24-72 hours after exposure Etiologic agent Legionella species Legionella species Attack rate Isolation of organism Outcome < 5% > 90% Possible Never Hospitalization common Case-fatality rate: 5-30% Hospitalization uncommon Case-fatality rate: 0% DIAGNOSIS The best means is direct fluorescent antibody (DFA) smears combined with culture of infected tissues. For this purpose, a high-quality specimen is preferred, because the organism may not be found in sputum. Typically, the Gram smear shows no bacteria, but the organisms are demonstrated by DFA using L. pneumophila-specific conjugates. It is positive in only 25 to 50% of cultureproved cases. Cultures must be made on buffered charcoal yeast extract (BCYE) agar medium that meets the growth requirements of Legionella. The diagnosis of legionellosis can also be established by polymerase chain reaction (PCR) amplification of a rRNA gene common to all Legionella species TREATMENT The best information on antimicrobial therapy is still provided by the original Philadelphia outbreak. Patients treated with erythromycin clearly did better than those given the penicillins, cephalosporins, or aminoglycosides. Subsequently, it was shown that most Legionella produce β-lactamases. In vitro susceptibility tests and animal studies have confirmed the activity of erythromycin and showed that tetracycline, rifampin, and the newer quinolones are also active. Although the other antimicrobics are sometimes used in combination, erythromycin and the newer macrolides (azithromycin, clarithromycin) remain the agents of choice. PREVENTION The prevention of legionellosis involves minimizing production of aerosols in public places from water that may be contaminated with Legionella. Although outbreaks connected with large buildings have received the most attention, cases have been traced to sources as common as the mists used in supermarkets to make the vegetables look shiny and fresh. Prevention is complicated by the fact that Legionella bacteria are relatively resistant to chlorine and heat. They have been isolated from hot water tanks held at over 50° C. Methods for decontaminating water systems are still under evaluation. Some outbreaks have been aborted by hyperchlorination, by correcting malfunctions in water systems, or by temporarily elevating the system temperature above 70° C. The installation of silver and copper ionization systems similar to those used in large swimming pools has been effective.