Infections of the Respiratory Tract

I. The respiratory system is responsible for allowing gas exchange between the blood and the atmosphere. The system is arbitrarily divided into an upper tract and a lower tract. The upper tract includes the nasal sinuses, pharynx, larynx, trachea and bronchi. The lower tract consists of the bronchioles and alveoli. The highly elastic connective tissue that surrounds the alveoli is referred to as the stroma. The lungs are covered with a connective tissue membrane known as the visceral pleura (covering the lung) and parietal pleura (covering the inside of the thorax). Between these two membranes a thin layer of lubricating pleural fluid is found. The ears are considered part of this system due to the eustachian tube which connects the middle ear with the pharynx.

A. The upper respiratory system is protected by infection by mucus and the presence of normal flora on most surfaces (the trachea should not be colonized). Most of the mucous membranes are ciliated. Cilia move mucus and the pathogens trapped in the mucus to site where the mucus can be expelled from the body or swallowed and thus destroyed by the digestive system. This system is referred to as the mucociliary escalator or simply the ciliary escalator. The tonsils and adenoids form a ring of immune tissue that allow the immune system to participate in the protection of this tract.

B. The lower respiratory tract is not colonized by normal flora. Roving macrophages play an important role in destroying any microorganisms that have made it into the lower respiratory tract.

C. The ear is protected by invasion from via the external auditory canal by the presence of cerumen (ear wax) that is produced by the ceruminous glands and the barrier presented by the tympanic membrane (ear drum). Cerumen acts to trap bacteria and contains substances that inhibit the growth of many bacteria. Most infections are acquired by the movement of bacteria from the pharynx to the ear via the eustachian tube.

II. Infections of the upper respiratory tract are very common. Many epidemiological studies have shown that most of these infections are due to viruses or are an overgrowth of normal flora secondary to a viral infection. In either case little or no benefit is gained by intervention with antimicrobial drugs. Inflammation of a site is indicated by the addition of "-ititis" to the end of the name of that site. All parts of the respiratory tract are susceptible to infection and subsequent inflammation.

A. Pharyngitis (inflammation of the pharynx) is usually viral and not bacterial. One bacteria that will cause a severe pharyngitis is Streptococcus pyogenes. This organism is often referred to as being a group A b -hemolytic streptococcus. This organism will cause lesions that are pus filled. The underlying tissues will be reddened and swollen. The cervical lymph nodes will often be enlarged and painful. Fever can be extremely high.

1. Rapid identification and therapy with penicillin or similar antibiotic (most strains of S. pyogenes remain sensitive to penicillin) can avert any long-term complications. Lack of proper attention can result in the infection of the middle ear (otitis media) or spread into the lower respiratory tract resulting in pneumonia.

2. Because of the many variations in the surface proteins of this organism, which are the targets that the immune system primarily develops immunity against, different subtypes of S. pyogenes can sequentially infect the same person. Thus the immunity developed against one strain is of little benefit in fighting other strains.

4. Many persons are carriers of S. pyogenes. They harbor the organism as part of their oral normal flora or in the nasal passages. They shed the organism and can infect those with whom they come in contact with. Furthermore, dogs have been shown to be able to harbor the agent in their nasal passages.

5. Certain strains of S. pyogenes will readily invade the underlying tissues, gain access to the blood stream and spread systematically. For this reason, treatment of strep throat is essential.

6. Production of erythrogenic toxin by subtypes of S. pyogenes can lead to scarlet fever. The toxin causes a rash that results in a reddening of Caucasian skin. This reddening is not as apparent in persons of color. If the toxin is produced at high enough levels and certain as yet undetermined host factors exist, the upper layers of the skin may be sloughed off.

7. Sequela to S. pyogenes infection takes two forms. Both are believed to be due to the production of antibodies against certain proteins. Beyond knowing that S. pyogenes must cause an immune response, the role played by the bacteria in these disorders is still a matter of great debate.

a. Rheumatic fever can effect the joints, can cause generalized malaise and fever and, in its most destructive manifestation, result in damage to the endocardium especially the heart valves. Usually rheumatic fever is preceded by an untreated or undertreated case of S. pyogenes infection. After the infection has been brought under control signs of rheumatic fever will become evident.

b. Glomerulonephritis is an inflammation localized within the kidney. It involves antibody’s specific for S. pyogenes. Deposition of these antibodies on the filtration membrane of the glomerulus results in an inappropriate activation of the complement cascade. This directly or indirectly leads to the destruction of the glomerulus. Obviously this results in loss of blood cells and inappropriate levels of protein spilled into the urine.

c. In either sequela, repeated infection with another strain of S. pyogenes may exacerbate the condition. Limiting exposure to and prophylaxis against further S. pyogenes infections are often courses of action recommend.

B. Infection of the larynx and epiglottis by bacteria and/or viruses leads to laryngitis and epiglottis. One of the most frequent causes of this condition is the bacteria Haemophilus influenzae type b. It is capable of causing a primary and severe epiglottis. Swelling of the epiglottis can lead to the obstruction of the airway especially in young children. Failure to intervene can lead to suffocation. This organism is capable of spreading systemically and infecting the meninges resulting in a rapidly progressing meningitis. Meningitis can be prevented by vaccination with the Hib vaccine (Haemophilus influenzae type b).

C. The gram-negative coccus Neisseria meningitidis is capable of causing a rapidly progressing illness that can lead to death days or even hours after the first symptoms are reported.   Several strains (or serogroups) of Neisseria meningitidis are known to exist around the world.  These serogroups are based on the polysaccharides found in the capsule. Antibodies generated against and effective in limiting the spread of one strain often have little or no effect on members of other strains.  Consequently, close contact with individuals from different geographic areas will often result in the “swapping” of Neisseria meningitidis strains.  This may be the reason for small outbreaks of the disease among new recruits in the military or on college campuses.

1.  In this country serogroups B and C have long been the predominant strains.  In the last several years serogroup Y and W-135 have emerged and are responsible for many outbreaks.  Group A, though prevalent throughout the rest of the world, is not commonly found in the USA.

a.   Many strains of Neisseria meningitidis shed their capsules as they grow.  Detection of the level of these substances in their blood is useful in determination of the severity of disease. 

b. All these strains can be found as part of the normal flora of the nasopharynx of many healthy persons.

 2. Infectious bacteria are acquired through inhalation of aerosolized respiratory secretions from carriers of Neisseria meningitidis.  They will colonize the pharynx and elicit an immune response in the newly infected individual.  This immune response does not seem to destroy the bacteria on the mucus membrane as an asymptomatic carry state may be established in persons with high antibody titers.  

a.  In susceptible individuals a pharyngitis may develop.  Invasion into the underlying tissues results in bacteria entering the lymphatics and eventually the blood stream.  This can lead to several outcomes including colonization of the meninges and/or disseminated cutaneous lesions.  The ability to spread in the blood stream usually is due to an ineffective antibody response.  Antibodies are present but they do not seem to trigger the complement cascade or act to opsinize the bacteria for further phagocytosis. 

1. Often the septicemia that results from invasion by Neisseria meningitidis (meningococcemia) results in small sites of hemorrhage (hemorrhagic lesions).  These lesions may affect any tissue.

2. When the hemorrhagic lesions occur in the dermis the resulting area of discoloration is referred to as petechia.  Larger areas are referred to as ecchymoses.  These conditions in and of themselves can lead to mortality.

b. It is believed that most of the pathology which results from infection of the meninges by Neisseria meningitidis is the result of edema and presence of toxic byproducts from the inflammatory response.  Because they have a gram-negative cell wall, destruction of the bacteria results in the liberation of endotoxins which further exacerbate the inflammatory response.   In the meninges this can result in fatal inflammation of the underlying brain tissues. 

3.Diagnosis of meningitis caused by Neisseria meningitidis usually involves recognition of symptoms.  These include stiff neck, headache and nausea.  Often the petechia are confused with other infectious diseases which cause similar pathology.  Misdiagnosis and thus mistreatment can be fatal.  Collection of CSF (by way of a spinal tap) and simple gram staining of the specimen will often demonstrate the presence of the gram-negative cocci (usually in pairs).  Serological tests to demonstrate the presence of antibodies are of little use due to the high rate of asymptomatic infection.  Serological status is only useful if rising antibody titers are observed over several days.  With meningitis though this amount of time is not available.  Laboratory tests designed to detect the presence of capsular antigens in the CSF or blood can be done.  The results of such tests are useful in confirming a diagnosis. 

4.  Even though Neisseria meningitidis has a gram-negative cell wall it is sensitive to penicillin.  I.V. administration of antibiotics is often accompanied by steroids to lessen the inflammatory response to endotoxin.  The level of endotoxin will peak several hours after therapy with antibiotics begins.  At this point patients often succumb to the effects of the inflammatory response.

5.  Vaccines exist for certain strains though most people have been exposed to the agent and have protective immunity.   The vaccine consists of components of the bacterial capsule.   The B strain’s capsule is a very weak immunogen.   Consequently it makes a very poor vaccine. 

D. Diphtheria is caused by Corynebacterium diphtheriae a gram positive, non-spore forming rod. Highly pathogenic strains of the bacteria contain the genes for diphtherotoxin. This gene is carried by a bacteriophage and introduced into the bacteria by transduction. The bacterium is introduced by inhalation of aerosolized respiratory secretions from an infected person. Initial infection by C. diphtheriae is of the pharynx or nasal mucosal and causes inflammation. Subsequent production of the diphtherotoxin results in the inhibition of protein synthesis within the cells of the mucosa and subsequent death of these cells. Accumulation of the dead cells results in the formation of a leathery pseudomembrane which can occlude the airway. Though the pseudomembrane can be problematic for small children, it is the production of the diphtherotoxin by C. diphtheria and the resulting toxemia which is most problematic. Because the toxin in extremely low concentrations can shut down protein synthesis, systemic organ failure can occur. Most obvious is the impairment of the CNS and the heart. A toxoid vaccine exists which will allow for the generation of antibodies which can render diptheriotoxin nonpathogenic. This toxoid is given in the DPT vaccine. Persons presenting with diphtheria are treated with large doses of antisera against the toxin (diphtheria antitoxin).

E. Bordetella pertussis is a gram negative, coccobacillus. Its only known host is the human. The organism causes an infection of the lower respiratory tract the leads to whooping cough.

1. Whooping cough is characterized by violent paroxysmal coughing. Five to 20 coughs are followed by forced inhalation. The air being drawn through the glottis results in the whooping sound. Coughing can be so severe as to lead to the fracture of ribs.

a. The initial stages of the disease (catarrhal stage) last 1-2 weeks. The patient may run a fever, complain of malaise, have a runny nose and sneeze. They will have a steadily worsening cough.
b. The paroxysmal stage is marked by the violent coughing fits. This may last for 2-6 weeks. During the coughing fits respiratory function is so impeded as to lead to anoxia.
c. The convalescent stage is marked by less severe coughing. It may last up to 6 weeks.

2. Bordetella pertussis is transmitted primarily via droplets. Infection results in colonization and rapid multiplication of the bacteria on the mucous membranes of the respiratory tract. Patients are most infectious during the early, catarrhal phase of the disease and remain infectious for about 5 weeks.

3.  Pathogenesis is related to a series of events. All pathogenic strains appear to be encapsulated. Specific fimbriae proteins allow the organism to attach to the cilia of the trachea. Without this attachment, no further pathology results. The organism releases a range of toxins. The significance of most in these toxins in the pathogenic process is still not fully understood.

a. Pertussis toxin is an exotoxin that affects the cells of the ciliary escalator and other cells in the surrounding area. This toxin decouples regulatory mechanisms within the cytoplasm that modulate the cAMP second messenger system. This results in decreased activity by the phagocytic cells in the area of infection. It also increases histamine reaction.
b. Bordetella pertussis produces a substance called the tracheal cytotoxin that is toxic for ciliated respiratory epithelium. Initially it stops the ciliated cells from beating then toxin kills ciliated cells and causes their extrusion from the mucosa thus destroying the ciliary escalator. This leads to the accumulation of mucus within the lower respiratory tract and thus the coughing. Tracheal cytotoxin is not a classic bacterial exotoxin since it is not composed of protein. It is a peptidoglycan fragment released from the bacteria while the cells are growing. This toxin also leads to the release of cytokine IL-1 that leads to the fever associated with this infection.
c. As a gram-negative organism, Bordetella pertussis has a lipopolysaccharide component (endotoxin) in the outer membrane of the cell wall. This lipopolysaccharide is slightly different than those found in other gram negative organisms but elicits the same response (increased IL-1 production from phagocytic cells and consequent increased inflammation).
d. A cytoplasmic toxin released only after the death of the cell is not fully understood, but may play a role in seizures seen late in the paroxysmal stage.

4. Vaccination with a suspension of killed bacterial cells began in the late 1950's. This led to striking reductions in the morbidity and mortality. Currently this vaccination for whooping cough is part of the DPT vaccine given in early childhood (The P in DPT stands for Pertussis cells). In countries where the vaccine is not used whooping cough is an important cause of mortality in children, with an estimated 51,000,000 cases and 600,000 deaths annually.

a. Unfortunately, about 20% of the children that receive the whole cell vaccine experience mild side effects particularly local erythema, swelling and tenderness, fever, and other mild systemic events such as drowsiness, fretfulness, and anorexia. About 0.1% of infants experience febrile convulsions soon after receiving the vaccine and in a very small number of cases severe or irreversible brain damage may occur. In the absence of the disease in an immune population, parents have begun to wonder if the risk of vaccinating children outweighs the risk of the disease, and the value of the whole cell vaccine has been questioned.

b.  New vaccines have been and continue to be developed in which only certain components of the bacteria are included in the vaccine and not the whole cell. These types of vaccine are referred to as acellular vaccines. Side effects are nearly eliminated with these acellular vaccines. 

c.  Currently the FDA has licensed three acellular vaccines, Infanrix, Tripedia and ACEL-IMUNE, for use.  Until recently acellular vaccines were to be used only as the 4^th and 5^th booster in the childhood vaccination schedule.  But these safer vaccines have been demonstrated to generate protective immunity when used in the initial vaccinations and have been licensed for this purpose.  

5.  Pertussis infection in the adult is fairly common and seldom diagnosed. As mentioned earlier vaccination of infants and children has nearly eliminated the incidence of pertussis in that population. But the immunity gained from childhood vaccination is short-lived. Thus adults and even adolescents are susceptible to infection by this pathogen.  Furthermore, infected adults serve as a reservoir for this pathogen.  The actual incidence of illness in the adult population is unknown but studies from a variety of clinical settings have shown that infection is surprisingly common in patients with a prolonged cough (2 weeks or longer). In these studies patients with persistent coughs were examined for the presence of B. pertussis in the respiratory tract.  The prevalence of pertussis ranged from 12% -26%!

a. Adults with pertussis generally have mild illness and few typical pertussis symptoms; however, adults often have the three classic stages noted in infants. The first stage of the illness, the catarrhal phase, lasts for 1 to 2 weeks. This stage, which is clinically indistinguishable from a viral upper respiratory infection, is characterized by the presence of runny nose, congestion, low-grade fever, and a mild cough. The paroxysmal stage of the illness, lasting 2 to 4 weeks, follows the nonspecific catarrhal stage. Patients have a distressing cough, commonly described as paroxysmal.

b. Many authorities believe that routine vaccination of adolescents and adults should be considered to decrease their burden of disease and control transmission to susceptible infants. Further study is needed in this area to determine the safest procedures and schedules for adult vaccination.

F. Sinusitis can be the result of viral or bacterial infections. Many cases of sinusitis result from an initial viral infection that inflames the sinuses. This impedes movement of mucus out of the sinus. Normal flora overgrow and further exacerbate the inflammation. When this scenario occurs the initial discharge from the nostrils will be clear and there will be little or no fever. Several days later the discharge becomes thick and green or yellow. Often a fever will occur at this point. The most common bacteria pathogens causing sinusitis are Streptococcus pneumoniae, S. pyogenes, Haemophilus influenzae or Staphylococcus aureus.

G. Bronchitis is often due to non-infectious causes such as cigarette smoke, pollution, allergies, etc. Streptococcus pneumoniae, Mycoplasma pneumoniae and several other bacterial pathogens are capable of causing infection of the bronchi. Inflammation caused by such infection can lead to difficulty breathing and a stimulation of increased mucus production. Damage can be done to the ciliary escalator resulting in difficulty moving mucus out of the lungs. Such damage is not quickly repaired and thus may have a long-term impact on the patient’s health.

H. One of the most common problems in children in the infection of the middle ear (otitis media). Movement of bacteria up the eustachian tube results an infection of this chamber of the ear. This condition is often preceded or coincident with bacterial pharyngitis. Those organism that are capable of causing pharyngitis are thus the most common bacterial pathogens responsible for otitis media. Chronic otitis media often involves infection with gram negative organisms such as members of the genera Klebsiella, Proteus or Pseudomonas. It should be stated that most ear infections are viral or will resolve with no intervention.

I. The "common cold" is a viral infection of the upper respiratory tract. Clinical the common cold is typified by a runny nose, sneezing, low grade fever and headache. In some cases nausea may also accompany this condition. Several types of virus are responsible for causing colds. Most of these viruses infect only the epithelia cells of the mucosa and do not cause disseminated infection. These viruses are easily transmitted by aerosol transmission but are more effectively transmitted by fomites (such as doorknobs, children’s toys, etc.)

1. If no nausea is present it is more than likely a virus known as a Rhinovirus. This virus will not replicate in tissues that are warmer than 35° C. The lining of the nasal epithelium is often below this temperature and thus will support the growth of the cells. The virus has trouble infecting cells lining the trachea, bronchi or alveoli because they are usually at normal body temperature (37° C). This virus is capable of causing a sinusitis. The inflammation of the sinus can then lead to accumulation of mucus and a secondary bacterial infection. There are over 100 antigentically distinct rhinoviruses. The immunity generated against one strain has little or no effect on any other strain. This antigentic diversity has thwarted efforts to develop an effective vaccine against this pathogen.

2. Coronaviruses are another cause of the common cold. These viruses are not limited to the nasal mucosa by temperature and can spread into the gastrointestinal tract. Such spread leads to nausea and vomiting.

III. Historically infections of the lower respiratory tract have caused staggering mortality. Bacterial pathogens have in large part been controlled by antimicrobial drugs and vaccines. Viral infections of the lower respiratory tract continue to have the potential to causes high levels of mortality. In the elderly and debilitated patient this type of infection still causes significant mortality.

A. One of the most significant bacterial diseases is that which is caused by Streptococcus pneumoniae. Once referred to as Diplococcus pneumoniae, this organism is routinely found as part of the normal throat flora of healthy persons. It is responsible for most cases of community acquired pneumonia. The pneumonia that results from successful colonization of the lung by this organism is often referred to as strep pneumonia or pneumococcal pneumonia. Depending on the strain of S. pneumoniae, the condition of the patient and the stage of infection at which the patient seeks medical attention, mortality can exceed 30% of those who are hospitalized.

1. S. pneumoniae is not a particularly resourceful bug, it is not known to produce exoenzymes or exotoxins that increase its virulence. Consequently it usually only infects patients that are moderately to severely compromised or are very young or very old. Even during the acute phase of an infection most of the damage caused is due to the body’s reaction to the invasion by S. pneumoniae, not the organism itself

a. Patients that have a compromised mucociliary escalator are particularly prone to invasion by S. pneumoniae. Viral infection of the trachea, exposure to toxic chemicals (including those found in cigarette smoke) and damage done during invasive procedures can result in reduced ciliary activity.

b. Patients that have been confined to bed are prone to infection with this organism. Often the horizontal position allows for some pooling of fluids in the lungs. This increased fluid interferes with normal function of phagocytic cells.

2. Once established in the lung macrophages and neutrophils (PMN’s) have a trouble engulfing S. pneumoniae due to the makeup of its capsule. Early researchers recognized that certain strains of S. pneumoniae were much more pathogenic than other strains. The difference was shown to be related to the polysaccharides and glycoproteins that make up the capsule. It appears that the capsule of certain strains interfere with the attachment of phagocytes to the bacteria. Obviously this keeps the bacteria from being ingested.

a. The presence of bacteria and their metabolic byproducts results in a rather pronounced but ineffective inflammatory response. This response results in the influx of fluids into the alveolar spaces within the lung. Areas that fill with fluid are referred to as consolidations and appear as bright areas on an X-ray. Often blood is released into the exudate as the inflammatory response intensifies. This gives the sputum a reddish (rust) color.

b. The increased permeability induced by the various chemicals released during the inflammatory response increase the ability of S. pneumoniae to gain entry into the blood stream and thus spread to other sites within the body. Most commonly this involves spread to the serous membranes that line the thoracic cavity (pleura) resulting in inflammation of these membranes (pleuritis) Though rare, spread of S. pneumoniae to the lining of the brain and spinal cord (meninges) can occur. This results in inflammation of these lining (meningitis). Due to the difficulty in getting antibiotics across the blood-brain barrier and the edema which results from bacterial growth at any site, bacterial meningitis is often fatal.

c. S. pneumoniae can also spread from the throat into the eustachian tubes and eventually into the middle ear resulting in otitis media.

3. In most cases of adult pneumococcal pneumonia, the patient has a predisposing condition (immune compromised, bedridden, recent surgery, viral infection, etc.) that allow the S. pneumoniae that are part of that person’s normal flora to spread into the lungs. Infants, young children in day-care and nursing home patients often acquire the organisms exogenously. Because S. pneumoniae usually is an opportunistic infection its seasonal pattern of occurrence coincides with that of other lung infections, increasing in the winter months and decreasing in the summer months.

4. With most pneumonia patients S. pneumoniae must be suspected, especially if they have any of the predisposing factors. A chest X-ray will reveal consolidation in the lungs.

a. As mentioned earlier, S. pneumoniae produces alpha hemolysis on blood agar. If growth is inhibited by optochin (applied in a disc similar to the ones used to test antibiotic sensitivities in lab) then the organism is S. pneumoniae not Streptococcus viridans.

b. Both tests are rapidly being replaced by ELISA tests.

5. Treatment usually consists of penicillin or one of the narrow spectrum derivatives. The level of penicillin resistance was less than .02% (2 cases in 10,000) as recently as the mid-1980’s. The prevalence of drug resistant strains of S. pneumoniae (DRSP) has rapidly increased to levels of 2-5% of isolates from the general populations and much higher levels in pediatric and nursing home populations. Cephalosporins or vancomycin (in regions where cephalosporin resistant strains of S. pneumoniae have been reported) are recommended as empirical treatment regimes in the case of advanced pneumonia and pneumococcal meningitis.

a. Because of the rapid emergence of DRSP the Advisory Committee on Immunization Practices and Procedures recommends that elderly and young children (but not less than two years of age) thought to be at increased risk for pneumococcal pneumonia receive the polyvalent pneumococcal capsular polysaccharide vaccine (Pneumovax and Pnu-immune). This vaccine contains the polysaccharides found within the capsules of the 23 most common pathogenic strains of S. pneumoniae. It allows this population to develop high levels of antibodies against these strains.

b. It should be stressed that early and effective therapy of S. pneumoniae can lead to immediate improvement. If antimicrobial therapy is delayed and the infection progresses the prognosis becomes much grimmer.

 B. Mycoplasmas are group of bacteria that lack a cell wall.  They are pleomorphic, growing as both coccal and a filmentatious cells.  Mycoplasmas were once thought to be intracellular parasites.  That is now known to be false.  These bacteria establish a strong interaction with the cell membrane of epithelial cells.

1.  Mycoplasma pneumoniae is the etiologic agent for what is often referred to as atypical pneumonia or walking pneumonia.  They are often referred to as PPLOs (pleuropneumonia like organisms).  Infection leads to pneumonia that usually does not require hospitalization.  In urban populations and among school aged children 20% or more of the diagnosed pneumonia may be due to M. pneumoniae. 

a.  M. pneumoniae is spread via aerosolized respiratory droplets from an infected person.   Transmission is thought to require prolonged close contact with an infected person, thus spread within families and among students is most common.

b.  M. pneumoniae infection typically results in a cough, chest pain and fever.    Infection of the pharynx results in symptoms similar to those seen with strep throat.  A tracheobronchitis can result that can lead to bronchial spasm.  Symptoms generally begin 15-25 days after exposure. The symptoms generally develop slowly, over a period of two to four days.  The highest incidence is in children ages 5 to 20 years old, but pneumonia occurs in adults as well.

c.  In most cases, the infected person does not seek medical intervention.  Diagnosis involves growth on specifically enriched media or use of DNA probes on clinical samples (usually sputum). 

d.  Since mycoplasmas lack a cell wall, cephalosporins and beta-lactams (penicillin, etc.) have no effect on them.  Erythromycin and tetracycline (both inhibitors of protein synthesis) are effective against this organism. 

 C. Chlamydia are unique bacteria. They have an inner and outer membrane and are categorized as gram-negative organisms. Yet, they do not engage in metabolic activity or binary fission unless they have invaded a eukaryotic cell.  Thus, members of the genus Chlamydia are all considered obligate intracellular parasites.  These organisms lack the mechanisms to make ATP and thus are unable to survive without a host cell providing them with energy.   They have an unusual dimorphic life cycle and infect through a metabolically inactive spore-like form.    The life cycle of a Chlamydia includes a small, infectious spore (elementary body), which can survive outside the cell and a larger, metabolically active cell (reticulate body), which is found only within a host cell.  The infectious elementary body enters cells by way of phagocytosis.  They convert into the reticulate body within the phagocytic vacuole and begin to grow.  The action of lysosomes does not destroy the reticulate body.  During the course of growth, more elementary bodies are formed and remain within the vacuole.  Eventually either the phagocytic cell dies or the reticulate body filled phagosome is exocytosed leading to the release of the infectious reticulate bodies.   Chlamydia psittaci and Chlamydia pneumoniae both infect the respiratory tract and can cause pneumoniae.  In the case of C. psittaci transmission involves inhalation of contaminated bird droppings especially those of the parrot family (Psittacine family).  The resulting condition is referred to as ornithosis.  Transmission of C. pneumoniae is person to person.  C. pneumoniae infects the lungs and is another pathogen that can result in the condition referred to as atypical or walking pneumonia.

C. Mycobacterium tuberculosis causes the disease tuberculosis. Members of the genus Mycobacterium are long, thin rods whose cell walls have a high amount of wax in its cell wall so it does not stain well using the gram stain procedure. Using a special type of staining (acid fast staining) the bacteria can be visualized. This unusually cell wall helps these organisms avoid destruction in the phagolysosome. Once TB was thought to be near eradication in this country but recent increases in prevalence and decreased funding for control measures have shown that hope to be false. The bacillus is transmitted by inhalation of bacteria expelled from an infected person when they cough. The organism can survive for extended periods in the environment. The initial infection is of the lungs. Most persons infected do not develop the disease immediately and rapidly will eliminate the pathogen from their systems. Of those that do not eliminate the pathogen a long term infection develops that can last a lifetime.

1. Early in a tuberculosis infection (Primary tuberculosis) the bacteria are phagocytized but not destroyed by the phagocyte. They multiple in the phagocyte. Upon the death of the phagocyte the microorganisms are released. This results in the attraction of more mononuclear cells and the local site of infections is "walled off" by a fibrous capsule. This is referred to as a tubercle. Bacteria continue to survive in the center of the tubercle. This will limit the ability of the bacteria to leave this initial site of infection.

a. Miliary tuberculosis is the dissemination of M. tuberculosis to sites throughout the body. This results from the migration of macrophages that have ingested but not destroyed M. tuberculosis away from the initial site of infection into the lymphatic system. Death of the macrophage leads to release of large numbers of bacteria into the lymph and eventual spread of these organisms throughout the body. Tubercles develop in many sites other than the lungs.

b. The center of these tubercles can become necrotic leading to a lesion which is referred as a caseous lesion (caseous means cheese-like).

c. Within the tubercle the bacteria can survive for many years.

d. Usually the organism is all but eliminated, the lesion is calcified (referred to as a Ghon complex) and no further problems are encountered.

2. If the organisms are not all killed in the caseous lesions the progression of the lesion is towards an air filled tuberculous cavity. Within the cavity rapid proliferation of the microbe occurs. Rupture of the lesion sets loose large numbers of microbes. These pathogens overwhelm the body's ability to handle them. At this point the individual has secondary tuberculosis. The person becomes lethargic, looses weight and coughs vigorously. Without treatment the patient will die.

3. Diagnosis of the TB relies upon the identification of the bacteria in clinical samples or by growth of the organisms in pure culture. This bacteria is a very slow grower and requires several months before a negative is declared. Lung X-rays will readily show the Ghon complexes and caseous lesions and are used along after a skin test has demonstrated hypersensitivity to TB antigens.

4. Treatment requires administration of more than one antibiotic over a period of 12-24 months. The current first line drugs of choice are isoniazid (INH) used in conjunction with one of many other drugs. Strains of TB which are resist to several antibiotics are starting to emerge. These strains, referred to as multidrug-resistant tuberculosis (MDR-TB or MR-TB), are found in as many as 30% of newly diagnosed cases in certain areas (New York, San Francisco, etc.). For this reason the bacteria needs to isolated and check for antibiotic sensitivity. In those areas with high incidence of MDR-TB four drug regimes are now being recommended for all new cases of TB.

a. Drugs have allowed the infected person to remain in society. This is due to the lack of viable free bacteria in the lung during antibiotic therapy. The problem arises when a person does not comply with their therapy regiment and thus continues to shed pathogenic bacteria.

b. Poverty, overcrowding, poor sanitation and nutrition are several of the key factors involved in the spread of the disease. These conditions effect homeless persons to a much higher degree than any other population. Thus they are more susceptible. Due to lack of compliance by members within the homeless population, the introduction of the bacteria itself occurs at a high rate. This population has seen and continues to see an increasing rate of infection.

D.  Legionella pneumophilia is the most common human pathogen of the genus Legionella. These organisms are gram negative, aerobic, non-spore forming, and non-encapsulated. In tissue it appears coccobacillary.  The natural habitat of Legionella is aquatic bodies including rivers, lakes and man-made reservoirs. The organism is chlorine tolerant and survives usual water treatment processes.  The organism is unusual for its mode of transmission.  It is transmitted via aspiration of infected water or inhalation of aerosolized infected water.  Person to person transmission has never been demonstrated! 

1.  Two clinical conditions result from infection with Legionella pneumophila: the more serious legionellosis (legionnaire’s’ disease) and the more mild Pontiac fever.  It is estimated that about 25,000 people develop legionellosis in the United States each year. An additional unknown number are infected with the legionella bacterium and have mild symptoms or no illness at all.  Cases occur sporadically and in outbreaks. Outbreaks occur most often in the summer but cases occur all year round

a.  The bacteria multiply intracellularly in alveolar macrophages. Recruited neutrophils and monocytes, as well as bacterial enzymes, produce destructive alveolar inflammation.  The early symptoms of legionellosis may be flu-like with muscle aches, headache, tiredness and dry cough followed by high fever, chills and occasionally diarrhea.  Temperatures commonly reach 102-105°F and chest X-rays often show lobar pneumonia. The disease most often affects middle-aged or older men, particularly those who smoke or drink heavily. People with underlying illnesses such as cancer or those with lowered immune system resistance to disease are also at higher risk.

b.  The symptoms and signs of Legionellosis are similar to those caused by other organisms, including influenza virus and other types of bacterial pneumonia. Since diagnosis depends on culturing the organisms (often not done initially but only after other, more common causes, are ruled out) or comparison of blood tests taken during and several weeks after the illness, the diagnosis may not be confirmed until after the person is well or dead.

c.  The primary host defense is thought to be cell mediated immunity.  The activation of infected macrophages by the release of substances from helper T cells  (IL-2 and the like) helps limit the growth of the bacterium within these macrophages.   This appears to help the body control the progression of the disease.  Thus more severe cases occur within patients with decreased cell mediated immunity (particularly post-transplant).  Humoral immunity has only secondary role and does not significantly promote killing of bacteria. 

E. The influenza virus causes a respiratory tract infection which is severe and can be fatal. "Flu" is a term used to describe many clinical conditions which do not involve infection with influenza virus. It should be noted that colds (upper respiratory tract infection usually caused by rhinoviruses) and GI tract problems (not associated with a previous respiratory tract infection) are not caused by influenza. There are three types of influenza virus, Type A, B and C. Type A has caused most of the human pathology and thus will be focused upon here. Influenza Type A virus infection is transmitted via aerosolized respiratory secretions. The virus attaches to and enters the epithelial cells of the respiratory tract. Within 1 to 3 days of initial exposure the person begins to have a nasal discharge, sore throat, high fever, cough and muscle aches. Symptoms and signs are usually moderate to severe. In most cases the patient recovers with no intervention. When infection effects the lower respiratory tract, damage to the ciliary escalator and general edema can lead to a secondary bacterial pneumonia. At this point the patient condition is considered to be much more serious. For the most part, deaths related to influenza follow this pattern.

F. The paramyxoviruses are fairly similar to the influenza being roughly spherical, enveloped, RNA viruses.  The virion is composed of inner helical nucleocapsid containing capsomere proteins associated with the genomic RNA.  The envelope is studded with “spikes”.  In most, but not all paramyxoviruses, these spikes are a hemagglutinin protein and neuraminidase similar in function but antigenically distinct from H and N proteins of influenza virus.   For the most part these viruses cause respiratory tract infections and sometimes spread causing serious systemic disorders.    Many Paramyxoviruses are able  to induce cell fusion. Neighboring cells join up to form large multinucleate syncytia or giant cells.  Multinucleated giant cells can sometimes be seen in lung sections from children dying with Paramyxovirus infection in the lung.  With regard to humans, the most significant members of this group are the parainfluenza viruses types 1, 2  3 and 4, and respiratory syncytial virus Historically two other members,  mumps virus and measles virus, caused significant morbidity but their impact has been dissipated by the use of vaccines.

1. Parainfluenza viruses types 1, 2, 3 and 4 can all cause minor infections in children and adults. They may be associated with more severe lower respiratory tract disease in children.  In studies in this country, 30% of acute laryngo-tracheo-bronchitis (LTB) cases yielded parainfluenza viruses.  Often it is the inflammation from this type of infections that can lead to “croup”.   Type 1 is especially associated with LTB, sometimes also type 2.  Parainfluenza viruses have also been isolated from patients with pneumonia.  It is thought that parainfluenza viruses are responsible for 15-30% of acute childhood respiratory disease.

a.  Parainfluenza virus is inhaled in droplets or droplet nuclei from the aerosolized respiratory secretions of an infected individual.  The virus grows locally in the epithelial cells of the upper respiratory tract’s mucus membrane and it may subsequently  spread down into the lungs.  Production of IgA is induced.   These are present in the respiratory secretions and seem to be more important than the IgG  in the serum with regard to protection.  However, IgA  does not cross the placenta and babies thus have no maternal protection against this type of infection. Primary infections with para-influenza viruses usually occur in the first year or years of life. Reinfection usually causes only minor infection of the upper respiratory tract and is one of the causes of a common cold in children and adults.

b.  Currently no vaccine for this agent is available. 

2. Respiratory syncytial virus (RSV) type A and B are unlike most paramyxoviruses in that  RSV lacks the hemagglutinin and neuraminidase proteins.  In this country, RSV is responsible for the hospitalization of approximately 90,000 children and  4500 deaths per year.  British researchers have found that in children <1 year of age with respiratory tract problems: 78% of bronchiolitis, 38% of LTB, 36% of pneumonia, 35% of bronchitis and 12% of minor respiratory illness, were caused by RSV.  There is little reason to believe that the situation in this country is appreciably different.  It should be noted that most infections do not require medical intervention or hospitalization.

a.  RSV causes a fairly localized infection of the epithelial cells of the respiratory tract.  Once again IgA in the respiratory secretions is the most important  antibody in limiting this infection.  Infants may have antibodies in the serum from the mother but they have no maternal passive protection at the site where it is needed, the respiratory tract secretions.

b.  RSV is spread by hand-to-hand contact with any object harboring the pathogen. Infection is introduced by contact with the mucus membranes of the eyes and nose. It can also be spread by droplets from a cough or sneeze.  Infection with RSV  occurs throughout the year, but widespread outbreaks are usually limited to the winter months, with peak incidence in January and February.  After an initial infection, reinfections do occur but seem only to produce fairly minor URT illness.

c.  Because of its apparent importance, an attempt was made at vaccinating infants. However, when the RSV epidemic arrived, the vaccinated children suffered more severe reactions than unvaccinated children. Somehow the killed virus vaccine had unfortunately sensitized these children and exposure to the live virus then induced a type of allergic reaction. This drew attention to the possibility that RSV associated pathology may in fact be due to immune mechanisms. Because of the importance of RSV in childhood infections, intensive efforts to make a vaccine have continued, especially along the lines of sub-unit vaccines (parts of virions) avoiding those antigens which seem responsible for hypersensitization. However, no vaccine is as yet in general use.

G. A recently recognized viral disease that affects the respiratory tract is the Hantavirus pulmonary syndrome (HPS). It is caused by a previously unrecognized Hantavirus, was first isolated in May 1993.   The disease begins with non-specific symptoms that include fever, muscle aches, headache, abdominal pain, nausea, vomiting, and progresses to include coughing and shortness of breath.  The symptoms usually occur between one and six weeks after exposure to the excreta (urine and feces) of infected rodents.  The disease rapidly progresses to cardiac and respiratory failure, usually requiring intensive care management.

1.  This virus appears to establish a carrier state in rodents and is spread between rodents due to increased aggressive behavior that that virus appears to initiate.

2. To minimize the chances of becoming infected with the virus the following precautions should be taken when cleaning areas infested with rodents:

•  Wear rubber gloves

•  Don't stir up and breathe dust

•  Wet contaminated areas with disinfectant

•  Dispose of dead animals properly

•  Disinfect used gloves

Here at some links!!!!

RESPIRATORY SYSTEM

http://edcenter.med.cornell.edu/CUMC_PathNotes/Respiratory/Respiratory.html

Here is a very in-depth examination of the structure, function and pathology of the respiratory system. 

Infections of the Respiratory System     http://gsbs.utmb.edu/microbook/ch093.htm

Centers for Disease Control and Prevention - National Immunization Program http://www.cdc.gov/nip/diseases/child-vpd.htm

This site contains information on vaccines for childhood diseases. 

National Vaccine Program Office Pandemic Influenza

http://www.cdc.gov/od/nvpo/pandemics/fluprint.htm